Board Exam Corner

Nontuberculous mycobacterial pulmonary disease is a broad term for a group of pulmonary disorders caused and characterized by exposure to environmental mycobacteria other than those belonging to the Mycobacterium tuberculosis complex and Mycobacterium leprae. Mycobacteria are aerobic, nonmotile organisms that appear positive with acid-fast alcohol stains. Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and have been recovered from domestic and natural water sources, soil, and food products, and from around livestock, cattle, and wildlife.^1-3 To date, no evidence exists of human-to-human or animal-to-human transmission of NTM in the general population. Infections in humans are usually acquired from environmental exposures, although the specific source of infection cannot always be identified. Similarly, the mode of infection with NTM has not been established with certainty, but it is highly likely that the organism is implanted, ingested, aspirated, or inhaled. Aerosolization of droplets associated with use of bathroom showerheads and municipal water sources and soil contamination are some of the factors associated with the transmission of infection. Proven routes of transmission include showerheads and potting soil dust.^2,3

NTM pulmonary disease occurs in individuals with or without comorbid conditions such as bronchiectasis, chronic obstructive pulmonary disease, pulmonary fibrosis, or structural lung diseases. Slender, middle-aged or elderly white females with marfanoid body habitus, with or without apparent immune or genetic disorders, showing impaired airway and mucus clearance present with this infection as a form of underlying bronchiectasis (Lady Windermere syndrome). It is unclear why NTM infections and escalation to clinical disease occur in certain individuals. Many risk factors, including inherited and acquired defects of host immune response (eg, cystic fibrosis trait and α1 antitrypsin deficiency), have been associated with increased susceptibility to NTM infections.⁴

NTM infection can lead to chronic symptoms, frequent exacerbations, progressive functional and structural lung destruction, and impaired quality of life, and is associated with an increased risk of hospitalization and higher 5-year all-cause mortality. As such, NTM disease is drawing increasing attention at the clinical, academic, and research levels.⁵ This case-based review outlines the clinical features of NTM infection, with a focus on the challenges in diagnosis, treatment, and management of NTM pulmonary disease. The cases use Mycobacterium avium complex (MAC), a slow-growing mycobacteria (SGM), and Mycobacterium abscessus, a rapidly growing mycobacteria (RGM), as prototypes in a non–cystic fibrosis, non-HIV clinical setting.

Epidemiology

Of the almost 200 isolated species of NTM, the most prevalent pathogens for respiratory disease in the United States are MAC, Mycobacterium kansasii, and M. abscessus. MAC accounts for more than 80% of cases of NTM respiratory disease in the United States.⁶ The prevalence of NTM disease is increasing at a rate of about 8% each year, with 75,000 to 105,000 patients diagnosed with NTM lung disease in the United States annually. NTM infections in the United States are increasing among patients aged 65 years and older, a population that is expected to nearly double by 2030.^7,8

Isolation and prevalence of many NTM species are higher in certain geographic areas of the United States, especially in the southeast. The US coastal regions have a higher prevalence of NTM pulmonary disease, and account for 70% of NTM cases in the United States each year. Half of patients diagnosed with NTM lung disease reside in 7 states: Florida, New York, Texas, California, Pennsylvania, New Jersey, and Ohio, with 1 in 7 residing in Florida. Three parishes in Louisiana are among the top 10 counties with the highest prevalence in United States. The prevalence of NTM infection–associated hospitalizations is increasing worldwide as well. Co-infection with tuberculosis and multiple NTMs in individual patients has been observed clinically and documented in patients with and without HIV.^9,10

It is not clear why the prevalence of NTM pulmonary disease is increasing, but there may be several contributing factors: (1) an increased awareness and identification of NTM infection sources in the environment; (2) an expanding cohort of immunocompromised individuals with exogenous or endogenous immune deficiencies; (3) availability of improved diagnostic techniques, such as use of high-performance liquid chromatography (HPLC), DNA probes, and gene sequencing; and (4) an increased awareness of the morbidity and mortality associated with NTM pulmonary disease. However, it is important to recognize that to best understand the clinical relevance of epidemiologic studies based on laboratory diagnosis and identification, the findings must be evaluated by correlating them with the microbiological and other clinical criteria established by the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines.¹¹

Continue to: Mycobacterium avium Complex

Mycobacterium avium Complex

Case Patient 1

A 48-year-old woman who has never smoked and has no past medical problems, except seasonal allergic rhinitis and “colds and flu-like illness” once or twice a year, is evaluated for a chronic lingering cough with occasional sputum production. The patient denies any other chronic symptoms and is otherwise active. Physical examination reveals no specific findings except mild pectus excavatum and mild scoliosis. Body mass index is 22 kg/m². Chest radiograph shows nonspecific increased markings in the lower zones. Computed tomography (CT) scan of the chest reveals minimal nodular and cylindrical bronchiectasis in both lungs (Figure 1). No previous radiographs are available for comparison. The patient is HIV-negative. Sputum tests reveal normal flora, and both fungus and acid-fast bacilli smear are negative. Culture for mycobacteria shows scanty growth of MAC in 1 specimen.

What is the clinical presentation of MAC pulmonary disease?

Among NTM, MAC is the most common cause of pulmonary disease worldwide.⁶ MAC primarily includes 2 species: M. avium and Mycobacterium intracellulare. M. avium is the more important pathogen in disseminated disease, whereas M. intracellulare is the more common respiratory pathogen.¹¹ These organisms are genetically similar and generally not differentiated in the clinical microbiology laboratory, although there are isolated reports in the literature suggesting differences in prevalence, presentation, and prognosis in M. avium infection versus M. intracellulare infection.¹²

Three major disease syndromes are produced by MAC in humans: pulmonary disease, usually in adults whose systemic immunity is intact; disseminated disease, usually in patients with advanced HIV infection; and cervical lymphadenitis.¹³ Pulmonary disease caused by MAC may take on 1 of several clinically different forms, including asymptomatic “colonization” or persistent minimal infection without obvious clinical significance; endobronchial involvement; progressive pulmonary disease with radiographic and clinical deterioration and nodular bronchiectasis or cavitary lung disease; hypersensitivity pneumonitis; or persistent, overwhelming mycobacterial growth with symptomatic manifestations, often in a lung with underlying damage due to either chronic obstructive lung disease or pulmonary fibrosis (Table 1).¹⁴

Cavitary Disease

The traditionally recognized presentation of MAC lung disease has been apical cavitary lung disease in men in their late 40s and early 50s who have a history of cigarette smoking, and frequently, excessive alcohol use. If left untreated, or in the case of erratic treatment or macrolide drug resistance, this form of disease is generally progressive within a relatively short time and can result in extensive cavitary lung destruction and progressive respiratory failure.¹⁵

Nodular Bronchiectasis

The more common presentation of MAC lung disease, which is outlined in the case described here, is interstitial nodular infiltrates, frequently involving the right middle lobe or lingula and predominantly occurring in postmenopausal, nonsmoking white women. This is sometimes labelled “Lady Windermere syndrome.” These patients with M. avium infection appear to have similar clinical characteristics and body types, including lean build, scoliosis, pectus excavatum, and mitral valve prolapse.^16,17 The mechanism by which this body morphotype predisposes to pulmonary mycobacterial infection is not defined, but ineffective mucociliary clearance is a possible explanation. Evidence suggests that some patients may be predisposed to NTM lung disease because of preexisting bronchiectasis. Some potential etiologies of bronchiectasis in this population include chronic sinusitis, gastroesophageal reflux with chronic aspiration, α1 antitrypsin deficiency, and cystic fibrosis genetic traits and mutations.¹⁸ Risk factors for increased morbidity and mortality include the development of cavitary disease, age, weight loss, lower body mass index, and other comorbid conditions.

This form of disease, termed nodular bronchiectasis, tends to have a much slower progression than cavitary disease, such that long-term follow-up (months to years) may be necessary to demonstrate clinical or radiographic changes.¹¹ The radiographic term “tree-in-bud” has been used to describe what may reflect inflammatory changes, including bronchiolitis. High-resolution CT scans of the chest are especially helpful for diagnosing this pattern of MAC lung disease, as bronchiectasis and small nodules may not be easily discernible on plain chest radiograph. The nodular/bronchiectasis radiographic pattern can also be seen with other NTM pathogens, including M. abscessus, Mycobacterium simiae, and M. kansasii. Solitary nodules and dense consolidation have also been described. Pleural effusions are uncommon, but reactive pleural thickening is frequently seen. Co-pathogens may be isolated from culture, including Pseudomonas aeruginosa, Staphylococcus aureus, and, occasionally, other NTM such as M. abscessus or Mycobacterium chelonae.^19-21

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis, initially described in patients who were exposed to hot tubs, mimics allergic hypersensitivity pneumonitis, with respiratory symptoms and culture/tissue identification of MAC or sometimes other NTM. It is unclear whether hypersensitivity pneumonitis is an inflammatory process, an infection, or both, and opinion regarding the need for specific antibiotic treatment is divided.^11,22 However, avoidance of exposure is prudent and recommended.

Disseminated Disease

Disseminated NTM disease is associated with very low CD4+ lymphocyte counts and is seen in approximately 5% of patients with HIV infection.^23-25 Although disseminated NTM disease is rarely seen in immunosuppressed patients without HIV infection, it has been reported in patients who have undergone renal or cardiac transplant, patients on long-term corticosteroid therapy, and those with leukemia or lymphoma. More than 90% of infections are caused by MAC; other potential pathogens include M. kansasii, M. chelonae, M. abscessus, and Mycobacterium haemophilum. Although seen less frequently since the advent of highly active antiretroviral therapy, disseminated infection can develop progressively from an apparently indolent or localized infection or a respiratory or gastrointestinal source. Signs and symptoms of disseminated infection (specifically MAC-associated disease) are nonspecific and include fever, night sweats, weight loss, and abdominal tenderness. Disseminated MAC disease occurs primarily in patients with more advanced HIV disease (CD4+ count typically < 50 cells/μL). Clinically, disseminated MAC manifests as intermittent or persistent fever, constitutional symptoms with organomegaly and organ-specific abnormalities (eg, anemia, neutropenia from bone marrow involvement, adenopathy, hepatosplenomegaly), and elevations of liver enzymes or lung infiltrates from pulmonary involvement.

Continue to: What are the criteria for diagnosing NTM pulmonary disease?

What are the criteria for diagnosing NTM pulmonary disease?

The diagnosis of NTM disease is based on clinical, radiologic, and mycobacterial correlation with good communication between the experts in this field. The ATS/IDSA criteria for diagnosing NTM lung disease are shown in Figure 2. These criteria best apply to MAC, M. kansasii, and M. abscessus, but are also clinically applied to other NTM respiratory pathogens. The diagnosis of MAC infection is most readily established by culture of blood, bone marrow, respiratory secretions/fluid, or tissue specimens from suspected sites of involvement. Due to erratic shedding of MAC into the respiratory secretions in patients with nodular bronchiectasis, as compared to those with the cavitary form of the disease, sputum may be intermittently positive, with variable colony counts and polyclonal infections.¹² Prior to the advent of high-resolution CT, isolation of MAC organisms from the sputum of such patients was frequently dismissed as colonization.

Mycobacterial Testing

Because of the nonspecific symptoms and lack of diagnostic specificity of chest imaging, the diagnosis of NTM lung disease requires microbiologic confirmation. Specimens sent to the laboratory for identification of NTM must be handled with care to prevent contamination and false-positive results. Transport media and preservatives should be avoided, and transportation of the specimens should be prompt. These measures will prevent bacterial overgrowth. Furthermore, the yield of NTM may be affected if the patient has used antibiotics, such as macrolides and fluoroquinolones, prior to obtaining the specimen.

NTM should be identified at the species and subspecies level, although this is not practical in community practice settings. The preferred staining procedure in the laboratory is the fluorochrome method. Some species require special growth conditions and/or lower incubation temperatures, and other identification methods may have to be employed, such as DNA probes, polymerase chain reaction genotyping, nucleic acid sequence determination, and high-performance liquid chromatography. As a gold standard, clinical specimens for mycobacterial cultures should be inoculated onto 1 or more solid media (eg, Middlebrook 7H11 media and/or Lowenstein-Jensen media, the former of which is the preferred medium for NTM) and into a liquid medium (eg, BACTEC 12B broth or Mycobacteria growth indicator tube broth). Growth of visible colonies on solid media typically requires 2 to 4 weeks, but liquid media (eg, the radiometric BACTEC system), used as a supplementary and not as an exclusive test, usually produce results within 10 to 14 days. Furthermore, even after initial growth, identification of specific isolates based on the growth characteristics on solid media requires additional time. Use of specific nucleic acid probes for MAC and M. kansasii and HPLC testing of mycolic acid patterns in acid-fast bacilli smear–positive specimens can reduce the turnaround time of specific identification of a primary culture–positive sample. However, HPLC is not sufficient for definitive identification of many NTM species, including the RGM. Other newer techniques, including 16S ribosomal DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis, also allow NTM to be identified and speciated more reliably and rapidly from clinical specimens.

Cost and other practical considerations limit widespread adoption of these techniques. However, the recognition that M. abscessus can be separated into more than 1 subspecies, and that there are important prognostic implications of that separation, lends urgency to the broader adoption of newer molecular techniques in the mycobacteriology laboratory. Susceptibility testing is based on the broth microdilution method; RGM usually grow within 7 days of subculture, and the laboratory time to culture is a helpful hint, although not necessarily specific. Recognizing the morphology of mycobacterial colony growth may also be helpful in identification.

Are skin tests helpful in diagnosing NTM infection?

Tuberculin skin testing remains a nonspecific marker of mycobacterial infection and does not help in further elucidating NTM infection. However, epidemiologic and laboratory studies with well-characterized antigens have shown that dual skin testing with tuberculosis- versus NTM-derived tuberculin can discriminate between prior NTM and prior tuberculosis disease. Species-specific skin test antigens are not commercially available and are not helpful in the diagnosis of NTM disease because of cross-reactivity of M. tuberculosis and some NTM. However, increased prevalence of NTM sensitization based on purified protein derivative testing has been noted in a recent survey, which is consistent with an observed increase in the rates of NTM infections, specifically MAC, in the United States.^26,27

Interferon-gamma release assays (IGRAs) are now being used as an alternative to tuberculin skin testing to diagnose M. tuberculosis infection. Certain NTM species also contain gene sequences that encode for ESAT-6 or CFP-10 antigens used in the IGRAs, and hence, yield a positive IGRA test. These include M. marinum, M. szulgai, and M. kansasii.^28,29 However, MAC organisms do not produce positive results on assays that use these antigens.

Continue to: What is the approach to management of NTM pulmonary disease?

What is the approach to management of NTM pulmonary disease?

The correlation of symptoms with radiographic and microbiologic evidence is essential to categorize the disease and determine the need for therapy. Making the diagnosis of NTM lung disease does not necessitate the institution of therapy. The decision to treat should be weighed against potential risks and benefits to the individual patient based on symptomatic, radiographic, and microbiologic criteria, as well as underlying systemic or pulmonary immune status. In the absence of evidence of clinical, radiologic, or mycobacterial progression of disease, pursuing airway clearance therapy and clinical surveillance without initiating specific anti-MAC therapy is a reasonable option.¹¹ Identifying the sustained presence of NTM infection, especially MAC, in a patient with underlying clinical and radiographic evidence of bronchiectasis is of value in determining comprehensive treatment and management strategies. Close observation is indicated if the decision not to treat is made. If treatment is initiated, comprehensive management includes long-term follow-up with periodic bacteriologic surveillance, watching for drug toxicity and drug-drug interactions, ensuring adherence and compliance to treatment, and managing comorbidity.

The Bronchiectasis Severity Index is a useful clinical predictive tool that identifies patients at risk of future mortality, hospitalization, and exacerbations and can be used to evaluate the need for specific treatment.30 The index is based on dyspnea score, lung function tests, colonization of pathogens, and extent of disease.

Case 1 Continued

After approximately 2 months of observation and symptomatic treatment, without specific antibiotic therapy, the patient’s symptoms continue. She now develops intermittent hemoptysis. Repeat sputum studies reveal moderate growth of M. avium. A follow-up CT scan shows progression of disease, with an increase in the tree-in-bud pattern (Figure 3).

What treatment protocols are recommended for MAC pulmonary disease?

As per the ATS/IDSA statement, macrolides are the mainstay of treatment for pulmonary MAC disease.¹¹ Macrolides achieve an increased concentration in the lung, and when used for treatment of pulmonary MAC disease, there is a strong correlation between in vitro susceptibility, in vivo (clinical) response, and the immunomodulating effects of macrolides.^31,32 Macrolide-containing regimens have demonstrated efficacy in patients with MAC pulmonary disease^33,34; however, macrolide monotherapy should be avoided to prevent the development of resistance.

At the outset, it is critical to establish the objective criteria for determining response and to ensure that the patient understands the goals of the treatment and expectations of the treatment plan. Moreover, experts suggest that due to the possibility of drug intolerance, side effects, and the need for prolonged therapy, a “step ladder” ramping up approach to treatment could be adopted, with gradual introduction of therapy within a short time period; this approach may improve compliance and adherence to treatment.¹¹ If this approach is used, the doses may have to be divided. Patients who are unable to tolerate daily medications, even with dosage adjustment, should be tried on an intermittent treatment regimen. Older female patients frequently require gradual introduction of medications (ie, 1 medication added to the regimen every 1 to 2 weeks) to evaluate tolerance to each medication and medication dose.¹¹ Commonly encountered adverse effects of NTM treatment include intolerance to clarithromycin due to gastrointestinal problems, low body mass index, or age older than 70 years.

After determining that the patient requires therapy, the standard recommended treatment for MAC pulmonary disease includes the following: for most patients with nodular/bronchiectasis disease, a thrice-weekly regimen of clarithromycin (1000 mg) or azithromycin (500 mg), rifampin (600 mg), and ethambutol (25 mg/kg) is recommended. For patients with cavitary MAC pulmonary disease or severe nodular/bronchiectasis disease, the guidelines recommend a daily regimen of clarithromycin (500-1000 mg) or azithromycin (250 mg), rifampin (600 mg) or rifabutin (150–300 mg), and ethambutol (15 mg/kg), with consideration of intravenous (IV) amikacin 3 times/week early in therapy (Table 2).¹¹

The treatment of MAC hypersensitivity-like disease speaks to the controversy of whether this is an inflammatory process, infectious process, or a combination of inflammation and infection. Avoidance of exposure is the mainstay of management. In some cases, steroids are used with or without a short course of anti-MAC therapy (ie, clarithromycin or azithromycin with rifampin and ethambutol).

Prophylaxis for disseminated MAC disease should be given to adults with HIV infection who have a CD4+ count less than 50 cells/μL. Azithromycin 1200 mg/week or clarithromycin 1000 mg/day has proven efficacy, and rifabutin 300 mg/day is also effective but less well tolerated. Rifabutin is more active in vitro against MAC than rifampin, and is used in HIV-positive patients because of drug-drug interaction between antiretroviral drugs and rifampin.

Continue to: Case 1 Continued

Case 1 Continued

The patient is treated with clarithromycin, rifampin, and ethambutol for 1 year, with sputum conversion after 9 months. In the latter part of her treatment, she experiences decreased visual acuity. Treatment is discontinued prematurely after 1 year due to drug toxicity and continued intolerance to drug therapy. The patient remains asymptomatic for 8 months, and then begins to experience mild to moderate hemoptysis, with increasing cough and sputum production associated with postural changes during exercise. Physical examination overall remains unchanged. Three sputum results reveal heavy growth of MAC, and a CT scan of the chest shows a cavitary lesion in the left upper lobe along with the nodular bronchiectasis (Figure 4).

What are the management options at this stage?

Based on this patient’s continued symptoms, progression of radiologic abnormalities, and current culture growth, she requires re-treatment. With the adverse effects associated with ethambutol during the first round of therapy, the drug regimen needs to be modified. Several considerations are relevant at this stage. Relapse rates range from 20% to 30% after treatment with a macrolide-based therapy.^11,34 Obtaining a culture-sensitivity profile is imperative in these cases. Of note, treatment should not be discontinued altogether, but instead the toxic agent should be removed from the treatment regimen. Continuing treatment with a 2-drug regimen of clarithromycin and rifampin may be considered in this patient. Re-infection with multiple genotypes may also occur after successful drug therapy, but this is primarily seen in MAC patients with nodular bronchiectasis.^34,35 Patients in whom previous therapy has failed, even those with macrolide-susceptible MAC isolates, are less likely to respond to subsequent therapy. Data suggest that intermittent medication dosing is not effective for patients with severe or cavitary disease or in those in whom previous therapy has failed.³⁶ In this case, treatment should include a daily 3-drug therapy, with an injectable thrice-weekly aminoglycoside. Other agents such as linezolid and clofazimine may have to be tried. Cycloserine, ethionamide, and other agents are sometimes used, but their efficacy is unproven and doubtful. Pyrazinamide and isoniazid have no activity against MAC.

Treatment Failure and Drug Resistance

Treatment failure is considered to have occurred if patients have not had a response (microbiologic, clinical, or radiographic) after 6 months of appropriate therapy or had not achieved conversion of sputum to culture-negative after 12 months of appropriate therapy.¹¹ This occurs in about 40% of patients. Multiple factors can interfere with the successful treatment of MAC pulmonary disease, including medication nonadherence, medication side effects or intolerance, lack of response to a medication regimen, or the emergence of a macrolide-resistant or multidrug-resistant strain. Inducible macrolide resistance remains a potential factor.^34-36 A number of characteristics of NTM contribute to the poor response to currently used antibiotics: the organisms have a lipid outer membrane and prefer to adhere to surfaces and form biofilms, which makes them relatively impermeable to antibiotics.³⁷ Also, NTM replicate in phagocytic cells, allowing them to subvert normal cellular defense mechanisms. Furthermore, NTM can display colony variants, whereby single colony isolates switch between antibiotic-susceptible and -resistant variants. These factors have also impeded in development of new antibiotics for NTM infection.³⁷

Recent limited approval of amikacin liposomal inhalation suspension (ALIS) for treatment failure and refractory MAC infection in combination with guideline-based antimicrobial therapy (GBT) is a promising addition to the available treatment armamentarium. In a multinational trial, the addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion rates by month 6 than GBT alone, with comparable rates of serious adverse events.³⁸

Is therapeutic drug monitoring recommended during treatment of MAC pulmonary disease?

Treatment failure may also be drug-related, including poor drug penetration into the damaged lung tissue or drug-drug interactions leading to suboptimal drug levels. Peak serum concentrations have been found to be below target ranges in approximately 50% of patients using a macrolide and ethambutol. Concurrent use of rifampin decreases the peak serum concentration of macrolides and quinolones, with acceptable target levels seen in only 18% to 57% of cases. Whether this alters patient outcomes is not clear.^39-42 Factors identified as contributing to the poor response to therapy include poor compliance, cavitary disease, previous treatment for MAC pulmonary disease, and a history of chronic obstructive lung disease. Studies by Koh and colleagues⁴⁰ and van Ingen and colleagues⁴¹ with pharmacokinetic and pharmacodynamics data showed that, in patients on MAC treatment with both clarithromycin and rifampicin, plasma levels of clarithromycin were lower than the recommended minimal inhibitory concentrations (MIC) against MAC for that drug. The studies also showed that rifampicin lowered clarithromycin concentrations more than did rifabutin, with the AUC/MIC ratio being suboptimal in nearly half the cases. However, low plasma clarithromycin concentrations did not have any correlation with treatment outcomes, as the peak plasma drug concentrations and the peak plasma drug concentration/MIC ratios did not differ between patients with unfavorable treatment outcomes and those with favorable outcomes. This is further compounded by the fact that macrolides achieve higher levels in lung tissue than in plasma, and hence the significance of low plasma levels is unclear; however, it is postulated that achieving higher drug levels could, in fact, lead to better clinical outcomes. Pending specific well-designed, prospective randomized controlled trials, routine therapeutic drug monitoring is not currently recommended, although some referral centers do this as their practice pattern.

Is surgery an option in this case?

The overall 5-year mortality for MAC pulmonary disease was approximately 28% in a retrospective analysis, with patients with cavitary disease at increased risk for death at 5 years.⁴² As such, surgery is an option in selected cases as part of adjunctive therapy along with anti-MAC therapy based on mycobacterial sensitivity. Surgery is used as either a curative approach or a “debulking” measure.¹¹ When present, clearly localized disease, especially in the upper lobe, lends itself best to surgical intervention. Surgical resection of a solitary pulmonary nodule due to MAC, in addition to concomitant medical treatment, is recommended. Surgical intervention should be considered early in the course of the disease because it may provide a cure without prolonged treatment and its associated problems, and this approach may lead to early sputum conversion. Surgery should also be considered in patients with macrolide-resistant or multidrug-resistant MAC infection or in those who cannot tolerate the side effects of therapy, provided that the disease is focal and limited. Patients with poor preoperative lung function have poorer outcomes than those with good lung function, and postoperative complications arising from treatment, especially with a right-sided pneumonectomy, tend to occur more frequently in these patients. Thoracic surgery for NTM pulmonary disease must be considered cautiously, as this is associated with significant morbidity and mortality and is best performed at specialized centers that have expertise and experience in this field.⁴³

Continue to: Mycobacterium abscessus Complex

Mycobacterium abscessus Complex

Case Patient 2

A 64-year-old man who is an ex-smoker presents with chronic cough, mild shortness of breath on exertion, low-grade fever, and unintentional weight loss of 10 lb. Physical exam is unremarkable. The patient was diagnosed with immunoglobulin deficiency (low IgM and low IgG4) in 2002, and has been on replacement therapy since then. He also has had multiple episodes of NTM infection, with MAC and M. kansasii infections diagnosed in 2012-2014, which required 18 months of multi-drug antibiotic treatment that resulted in sputum conversion. Pulmonary function testing done on this visit in 2017 shows mild obstructive impairment.

Chest radiograph and CT scan show bilateral bronchiectasis (Figure 5 and Figure 6).

The results of serial sputum microbiology testing performed over the course of 6 months are outlined below:

• 5/2017 (bronchoalveolar lavage): 2+; M. abscessus
• 9/2017 × 2: smear (–); group IV RGM
• 11/2017: smear (–); M. abscessus (> 50 CFU)
• 12/2017: smear (–); M. abscessus (> 50 CFU)

What are the clinical considerations in this patient with multiple NTM infections?

M. abscessus complex was originally described in soft tissue abscesses and skin infections possibly resulting from soil or water contamination. Subspeciation of M. abscessus complex during laboratory testing is critical to facilitate selection of a specific therapeutic approach; treatment decisions are impacted by the presence of an active erm gene and in vitro macrolide sensitivity, which differ between subspecies. The most acceptable classification outlines 3 species in the M. abscessus complex: Mycobacterium abscessus subsp abscessus, Mycobacterium abscessus subsp bolletii (both with an active erm gene responsible for macrolide resistance), and Mycobacterium abscessus subsp massiliense (with an inactive erm gene and therefore susceptible to macrolides).⁴⁴

RGM typically manifest in skin, soft tissue, and bone, and can cause soft tissue, surgical wound, and catheter-related infections. Although the role of RGM as pulmonary pathogens is unclear, underlying diseases associated with RGM include previously treated mycobacterial disease, coexistent pulmonary diseases with or without MAC, cystic fibrosis, malignancies, and gastroesophageal disorders. M. abscessus is the third most commonly identified respiratory NTM and accounts for the majority (80%) of RGM respiratory isolates. Other NTM reported to cause both lung disease and skin, bone, and joint infections include Mycobacterium simiae, Mycobacterium xenopi, and Mycobacterium malmoense. Ocular granulomatous diseases, such as chorioretinitis and keratitis, have been reported with both RGM and Runyon group III SGM, such as MAC or M. szulgai, following trauma or refractive surgery. These can mimic fungal, herpetic, or amebic keratitis. The pulmonary syndromes associated with multiple culture positivity are seen in elderly women with bronchiectasis or cavitary lung disease and/or associated with gastrointestinal symptoms of acid reflux, with or without achalasia and concomitant lipoid interstitial pneumonia.⁴⁵

Generally, pulmonary disease progresses slowly, but lung disease attributed to RGM can result in respiratory failure. Thus, RGM should be recognized as a possible cause of chronic mycobacterial lung disease, especially in immunocompromised patients, and respiratory isolates should be assessed carefully. Identification and drug susceptibility testing are essential before initiation of treatment for RGM.

What is the approach to management of M. abscessus pulmonary disease in a patient without cystic fibrosis?

The management of M. abscessus pulmonary infection as a subset of RGM requires a considered step-wise approach. The criteria for diagnosis and threshold for starting treatment are the same as those used in the management of MAC pulmonary disease,¹¹ but the treatment of M. abscessus pulmonary infection is more complex and has lower rates of success and cure. Also, antibiotic treatment presents challenges related to rapid identification of the causative organism, nomenclature, resistance patterns, and tolerance of treatment and side effects. If a source such as catheter, access port, or any surgical site is identified, prompt removal and clearance of the infected site are strongly advised

In the absence of any controlled clinical trials, treatment of RGM is based on in vitro susceptibility testing and expert opinion. As in MAC pulmonary disease, macrolides are the mainstay of treatment, with an induction phase of intravenous antibiotics. Treatment may include a combination of injectable aminoglycosides, imipenem, or cefoxitin and oral drugs such as a macrolide (eg, clarithromycin, azithromycin), doxycycline, fluoroquinolones, trimethoprim/sulfamethoxazole, or linezolid. While antibiotic treatment of M. abscessus pulmonary disease is based on in vitro sensitivity pattern to a greater degree than is treatment of MAC pulmonary disease, this approach has significant practical limitations and hence variable applicability. The final choice of antibiotics is best based on the extended susceptibility results, if available. The presence of an active erm gene on a prolonged growth specimen in M. abscessus subsp abscessus and M. abscessus subsp bolletii precludes the use of a macrolide. In such cases, amikacin, especially in an intravenous form, is the mainstay of treatment based on MIC. Recently, there has been a resurgence in interest in the use of clofazimine in combination with amikacin when treatment is not successful in patients with M. abscessus subsp abscessus or M. bolletii with an active erm gene.^45,46 When localized abscess formation is noted, surgery may be the best option, with emphasis on removal of implants and catheters if implicated in RGM infection.

Attention must also be given to confounding pulmonary and associated comorbidities. This includes management of bronchiectasis with appropriately aggressive airway clearance techniques; anti-reflux measures for prevention of micro-aspiration; and management of other comorbid pulmonary conditions, such as chronic obstructive pulmonary disease, pulmonary fibrosis, and sarcoidosis, if applicable. These interventions play a critical role in clearing the M. abscessus infection, preventing progression of disease, and reducing morbidity. The role of immunomodulatory therapy needs to be considered on a regular, ongoing basis. Identification of genetic factors and correction of immune deficiencies may help in managing the infection.

Case Patient 2 Conclusion

The treatment regimen adopted in this case includes a 3-month course of daily intravenous amikacin and imipenem with oral azithromycin, followed by a continuation phase of azithromycin with clofazimine and linezolid. Airway clearance techniques such as Vest/Acapella/CPT are intensified and monthly intravenous immunoglobulin therapy is continued. The patient responds to treatment, with resolution of his clinical symptoms and reduction in the colony count of M. abscessus in the sputum.

Summary

NTM are ubiquitous in the environment, and NTM infection has variable manifestations, especially in patients with no recognizable immune impairments. Underlying comorbid conditions with bronchiectasis complicate its management. Treatment strategies must be individualized based on degree of involvement, associated comorbidities, immune deficiencies, goals of therapy, outcome-based risk-benefit ratio assessment, and patient engagement and expectations. In diffuse pulmonary disease, drug treatment remains difficult due to poor match of in vitro and in vivo culture sensitivity, side effects of medications, and high failure rates. When a localized resectable foci of infection is identified, especially in RGM disease, surgical treatment may be the best approach in selected patients, but it must be performed in centers with expertise and experience in this field. 

Nontuberculous mycobacterial pulmonary disease is a broad term for a group of pulmonary disorders caused and characterized by exposure to environmental mycobacteria other than those belonging to the Mycobacterium tuberculosis complex and Mycobacterium leprae. Mycobacteria are aerobic, nonmotile organisms that appear positive with acid-fast alcohol stains. Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and have been recovered from domestic and natural water sources, soil, and food products, and from around livestock, cattle, and wildlife.^1-3 To date, no evidence exists of human-to-human or animal-to-human transmission of NTM in the general population. Infections in humans are usually acquired from environmental exposures, although the specific source of infection cannot always be identified. Similarly, the mode of infection with NTM has not been established with certainty, but it is highly likely that the organism is implanted, ingested, aspirated, or inhaled. Aerosolization of droplets associated with use of bathroom showerheads and municipal water sources and soil contamination are some of the factors associated with the transmission of infection. Proven routes of transmission include showerheads and potting soil dust.^2,3

NTM pulmonary disease occurs in individuals with or without comorbid conditions such as bronchiectasis, chronic obstructive pulmonary disease, pulmonary fibrosis, or structural lung diseases. Slender, middle-aged or elderly white females with marfanoid body habitus, with or without apparent immune or genetic disorders, showing impaired airway and mucus clearance present with this infection as a form of underlying bronchiectasis (Lady Windermere syndrome). It is unclear why NTM infections and escalation to clinical disease occur in certain individuals. Many risk factors, including inherited and acquired defects of host immune response (eg, cystic fibrosis trait and α1 antitrypsin deficiency), have been associated with increased susceptibility to NTM infections.⁴

NTM infection can lead to chronic symptoms, frequent exacerbations, progressive functional and structural lung destruction, and impaired quality of life, and is associated with an increased risk of hospitalization and higher 5-year all-cause mortality. As such, NTM disease is drawing increasing attention at the clinical, academic, and research levels.⁵ This case-based review outlines the clinical features of NTM infection, with a focus on the challenges in diagnosis, treatment, and management of NTM pulmonary disease. The cases use Mycobacterium avium complex (MAC), a slow-growing mycobacteria (SGM), and Mycobacterium abscessus, a rapidly growing mycobacteria (RGM), as prototypes in a non–cystic fibrosis, non-HIV clinical setting.

Epidemiology

Of the almost 200 isolated species of NTM, the most prevalent pathogens for respiratory disease in the United States are MAC, Mycobacterium kansasii, and M. abscessus. MAC accounts for more than 80% of cases of NTM respiratory disease in the United States.⁶ The prevalence of NTM disease is increasing at a rate of about 8% each year, with 75,000 to 105,000 patients diagnosed with NTM lung disease in the United States annually. NTM infections in the United States are increasing among patients aged 65 years and older, a population that is expected to nearly double by 2030.^7,8

Isolation and prevalence of many NTM species are higher in certain geographic areas of the United States, especially in the southeast. The US coastal regions have a higher prevalence of NTM pulmonary disease, and account for 70% of NTM cases in the United States each year. Half of patients diagnosed with NTM lung disease reside in 7 states: Florida, New York, Texas, California, Pennsylvania, New Jersey, and Ohio, with 1 in 7 residing in Florida. Three parishes in Louisiana are among the top 10 counties with the highest prevalence in United States. The prevalence of NTM infection–associated hospitalizations is increasing worldwide as well. Co-infection with tuberculosis and multiple NTMs in individual patients has been observed clinically and documented in patients with and without HIV.^9,10

It is not clear why the prevalence of NTM pulmonary disease is increasing, but there may be several contributing factors: (1) an increased awareness and identification of NTM infection sources in the environment; (2) an expanding cohort of immunocompromised individuals with exogenous or endogenous immune deficiencies; (3) availability of improved diagnostic techniques, such as use of high-performance liquid chromatography (HPLC), DNA probes, and gene sequencing; and (4) an increased awareness of the morbidity and mortality associated with NTM pulmonary disease. However, it is important to recognize that to best understand the clinical relevance of epidemiologic studies based on laboratory diagnosis and identification, the findings must be evaluated by correlating them with the microbiological and other clinical criteria established by the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines.¹¹

Continue to: Mycobacterium avium Complex

Mycobacterium avium Complex

Case Patient 1

A 48-year-old woman who has never smoked and has no past medical problems, except seasonal allergic rhinitis and “colds and flu-like illness” once or twice a year, is evaluated for a chronic lingering cough with occasional sputum production. The patient denies any other chronic symptoms and is otherwise active. Physical examination reveals no specific findings except mild pectus excavatum and mild scoliosis. Body mass index is 22 kg/m². Chest radiograph shows nonspecific increased markings in the lower zones. Computed tomography (CT) scan of the chest reveals minimal nodular and cylindrical bronchiectasis in both lungs (Figure 1). No previous radiographs are available for comparison. The patient is HIV-negative. Sputum tests reveal normal flora, and both fungus and acid-fast bacilli smear are negative. Culture for mycobacteria shows scanty growth of MAC in 1 specimen.

What is the clinical presentation of MAC pulmonary disease?

Among NTM, MAC is the most common cause of pulmonary disease worldwide.⁶ MAC primarily includes 2 species: M. avium and Mycobacterium intracellulare. M. avium is the more important pathogen in disseminated disease, whereas M. intracellulare is the more common respiratory pathogen.¹¹ These organisms are genetically similar and generally not differentiated in the clinical microbiology laboratory, although there are isolated reports in the literature suggesting differences in prevalence, presentation, and prognosis in M. avium infection versus M. intracellulare infection.¹²

Three major disease syndromes are produced by MAC in humans: pulmonary disease, usually in adults whose systemic immunity is intact; disseminated disease, usually in patients with advanced HIV infection; and cervical lymphadenitis.¹³ Pulmonary disease caused by MAC may take on 1 of several clinically different forms, including asymptomatic “colonization” or persistent minimal infection without obvious clinical significance; endobronchial involvement; progressive pulmonary disease with radiographic and clinical deterioration and nodular bronchiectasis or cavitary lung disease; hypersensitivity pneumonitis; or persistent, overwhelming mycobacterial growth with symptomatic manifestations, often in a lung with underlying damage due to either chronic obstructive lung disease or pulmonary fibrosis (Table 1).¹⁴

Cavitary Disease

The traditionally recognized presentation of MAC lung disease has been apical cavitary lung disease in men in their late 40s and early 50s who have a history of cigarette smoking, and frequently, excessive alcohol use. If left untreated, or in the case of erratic treatment or macrolide drug resistance, this form of disease is generally progressive within a relatively short time and can result in extensive cavitary lung destruction and progressive respiratory failure.¹⁵

Nodular Bronchiectasis

The more common presentation of MAC lung disease, which is outlined in the case described here, is interstitial nodular infiltrates, frequently involving the right middle lobe or lingula and predominantly occurring in postmenopausal, nonsmoking white women. This is sometimes labelled “Lady Windermere syndrome.” These patients with M. avium infection appear to have similar clinical characteristics and body types, including lean build, scoliosis, pectus excavatum, and mitral valve prolapse.^16,17 The mechanism by which this body morphotype predisposes to pulmonary mycobacterial infection is not defined, but ineffective mucociliary clearance is a possible explanation. Evidence suggests that some patients may be predisposed to NTM lung disease because of preexisting bronchiectasis. Some potential etiologies of bronchiectasis in this population include chronic sinusitis, gastroesophageal reflux with chronic aspiration, α1 antitrypsin deficiency, and cystic fibrosis genetic traits and mutations.¹⁸ Risk factors for increased morbidity and mortality include the development of cavitary disease, age, weight loss, lower body mass index, and other comorbid conditions.

This form of disease, termed nodular bronchiectasis, tends to have a much slower progression than cavitary disease, such that long-term follow-up (months to years) may be necessary to demonstrate clinical or radiographic changes.¹¹ The radiographic term “tree-in-bud” has been used to describe what may reflect inflammatory changes, including bronchiolitis. High-resolution CT scans of the chest are especially helpful for diagnosing this pattern of MAC lung disease, as bronchiectasis and small nodules may not be easily discernible on plain chest radiograph. The nodular/bronchiectasis radiographic pattern can also be seen with other NTM pathogens, including M. abscessus, Mycobacterium simiae, and M. kansasii. Solitary nodules and dense consolidation have also been described. Pleural effusions are uncommon, but reactive pleural thickening is frequently seen. Co-pathogens may be isolated from culture, including Pseudomonas aeruginosa, Staphylococcus aureus, and, occasionally, other NTM such as M. abscessus or Mycobacterium chelonae.^19-21

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis, initially described in patients who were exposed to hot tubs, mimics allergic hypersensitivity pneumonitis, with respiratory symptoms and culture/tissue identification of MAC or sometimes other NTM. It is unclear whether hypersensitivity pneumonitis is an inflammatory process, an infection, or both, and opinion regarding the need for specific antibiotic treatment is divided.^11,22 However, avoidance of exposure is prudent and recommended.

Disseminated Disease

Disseminated NTM disease is associated with very low CD4+ lymphocyte counts and is seen in approximately 5% of patients with HIV infection.^23-25 Although disseminated NTM disease is rarely seen in immunosuppressed patients without HIV infection, it has been reported in patients who have undergone renal or cardiac transplant, patients on long-term corticosteroid therapy, and those with leukemia or lymphoma. More than 90% of infections are caused by MAC; other potential pathogens include M. kansasii, M. chelonae, M. abscessus, and Mycobacterium haemophilum. Although seen less frequently since the advent of highly active antiretroviral therapy, disseminated infection can develop progressively from an apparently indolent or localized infection or a respiratory or gastrointestinal source. Signs and symptoms of disseminated infection (specifically MAC-associated disease) are nonspecific and include fever, night sweats, weight loss, and abdominal tenderness. Disseminated MAC disease occurs primarily in patients with more advanced HIV disease (CD4+ count typically < 50 cells/μL). Clinically, disseminated MAC manifests as intermittent or persistent fever, constitutional symptoms with organomegaly and organ-specific abnormalities (eg, anemia, neutropenia from bone marrow involvement, adenopathy, hepatosplenomegaly), and elevations of liver enzymes or lung infiltrates from pulmonary involvement.

Continue to: What are the criteria for diagnosing NTM pulmonary disease?

What are the criteria for diagnosing NTM pulmonary disease?

The diagnosis of NTM disease is based on clinical, radiologic, and mycobacterial correlation with good communication between the experts in this field. The ATS/IDSA criteria for diagnosing NTM lung disease are shown in Figure 2. These criteria best apply to MAC, M. kansasii, and M. abscessus, but are also clinically applied to other NTM respiratory pathogens. The diagnosis of MAC infection is most readily established by culture of blood, bone marrow, respiratory secretions/fluid, or tissue specimens from suspected sites of involvement. Due to erratic shedding of MAC into the respiratory secretions in patients with nodular bronchiectasis, as compared to those with the cavitary form of the disease, sputum may be intermittently positive, with variable colony counts and polyclonal infections.¹² Prior to the advent of high-resolution CT, isolation of MAC organisms from the sputum of such patients was frequently dismissed as colonization.

Mycobacterial Testing

Because of the nonspecific symptoms and lack of diagnostic specificity of chest imaging, the diagnosis of NTM lung disease requires microbiologic confirmation. Specimens sent to the laboratory for identification of NTM must be handled with care to prevent contamination and false-positive results. Transport media and preservatives should be avoided, and transportation of the specimens should be prompt. These measures will prevent bacterial overgrowth. Furthermore, the yield of NTM may be affected if the patient has used antibiotics, such as macrolides and fluoroquinolones, prior to obtaining the specimen.

NTM should be identified at the species and subspecies level, although this is not practical in community practice settings. The preferred staining procedure in the laboratory is the fluorochrome method. Some species require special growth conditions and/or lower incubation temperatures, and other identification methods may have to be employed, such as DNA probes, polymerase chain reaction genotyping, nucleic acid sequence determination, and high-performance liquid chromatography. As a gold standard, clinical specimens for mycobacterial cultures should be inoculated onto 1 or more solid media (eg, Middlebrook 7H11 media and/or Lowenstein-Jensen media, the former of which is the preferred medium for NTM) and into a liquid medium (eg, BACTEC 12B broth or Mycobacteria growth indicator tube broth). Growth of visible colonies on solid media typically requires 2 to 4 weeks, but liquid media (eg, the radiometric BACTEC system), used as a supplementary and not as an exclusive test, usually produce results within 10 to 14 days. Furthermore, even after initial growth, identification of specific isolates based on the growth characteristics on solid media requires additional time. Use of specific nucleic acid probes for MAC and M. kansasii and HPLC testing of mycolic acid patterns in acid-fast bacilli smear–positive specimens can reduce the turnaround time of specific identification of a primary culture–positive sample. However, HPLC is not sufficient for definitive identification of many NTM species, including the RGM. Other newer techniques, including 16S ribosomal DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis, also allow NTM to be identified and speciated more reliably and rapidly from clinical specimens.

Cost and other practical considerations limit widespread adoption of these techniques. However, the recognition that M. abscessus can be separated into more than 1 subspecies, and that there are important prognostic implications of that separation, lends urgency to the broader adoption of newer molecular techniques in the mycobacteriology laboratory. Susceptibility testing is based on the broth microdilution method; RGM usually grow within 7 days of subculture, and the laboratory time to culture is a helpful hint, although not necessarily specific. Recognizing the morphology of mycobacterial colony growth may also be helpful in identification.

Are skin tests helpful in diagnosing NTM infection?

Tuberculin skin testing remains a nonspecific marker of mycobacterial infection and does not help in further elucidating NTM infection. However, epidemiologic and laboratory studies with well-characterized antigens have shown that dual skin testing with tuberculosis- versus NTM-derived tuberculin can discriminate between prior NTM and prior tuberculosis disease. Species-specific skin test antigens are not commercially available and are not helpful in the diagnosis of NTM disease because of cross-reactivity of M. tuberculosis and some NTM. However, increased prevalence of NTM sensitization based on purified protein derivative testing has been noted in a recent survey, which is consistent with an observed increase in the rates of NTM infections, specifically MAC, in the United States.^26,27

Interferon-gamma release assays (IGRAs) are now being used as an alternative to tuberculin skin testing to diagnose M. tuberculosis infection. Certain NTM species also contain gene sequences that encode for ESAT-6 or CFP-10 antigens used in the IGRAs, and hence, yield a positive IGRA test. These include M. marinum, M. szulgai, and M. kansasii.^28,29 However, MAC organisms do not produce positive results on assays that use these antigens.

Continue to: What is the approach to management of NTM pulmonary disease?

What is the approach to management of NTM pulmonary disease?

The correlation of symptoms with radiographic and microbiologic evidence is essential to categorize the disease and determine the need for therapy. Making the diagnosis of NTM lung disease does not necessitate the institution of therapy. The decision to treat should be weighed against potential risks and benefits to the individual patient based on symptomatic, radiographic, and microbiologic criteria, as well as underlying systemic or pulmonary immune status. In the absence of evidence of clinical, radiologic, or mycobacterial progression of disease, pursuing airway clearance therapy and clinical surveillance without initiating specific anti-MAC therapy is a reasonable option.¹¹ Identifying the sustained presence of NTM infection, especially MAC, in a patient with underlying clinical and radiographic evidence of bronchiectasis is of value in determining comprehensive treatment and management strategies. Close observation is indicated if the decision not to treat is made. If treatment is initiated, comprehensive management includes long-term follow-up with periodic bacteriologic surveillance, watching for drug toxicity and drug-drug interactions, ensuring adherence and compliance to treatment, and managing comorbidity.

The Bronchiectasis Severity Index is a useful clinical predictive tool that identifies patients at risk of future mortality, hospitalization, and exacerbations and can be used to evaluate the need for specific treatment.30 The index is based on dyspnea score, lung function tests, colonization of pathogens, and extent of disease.

Case 1 Continued

After approximately 2 months of observation and symptomatic treatment, without specific antibiotic therapy, the patient’s symptoms continue. She now develops intermittent hemoptysis. Repeat sputum studies reveal moderate growth of M. avium. A follow-up CT scan shows progression of disease, with an increase in the tree-in-bud pattern (Figure 3).

What treatment protocols are recommended for MAC pulmonary disease?

As per the ATS/IDSA statement, macrolides are the mainstay of treatment for pulmonary MAC disease.¹¹ Macrolides achieve an increased concentration in the lung, and when used for treatment of pulmonary MAC disease, there is a strong correlation between in vitro susceptibility, in vivo (clinical) response, and the immunomodulating effects of macrolides.^31,32 Macrolide-containing regimens have demonstrated efficacy in patients with MAC pulmonary disease^33,34; however, macrolide monotherapy should be avoided to prevent the development of resistance.

At the outset, it is critical to establish the objective criteria for determining response and to ensure that the patient understands the goals of the treatment and expectations of the treatment plan. Moreover, experts suggest that due to the possibility of drug intolerance, side effects, and the need for prolonged therapy, a “step ladder” ramping up approach to treatment could be adopted, with gradual introduction of therapy within a short time period; this approach may improve compliance and adherence to treatment.¹¹ If this approach is used, the doses may have to be divided. Patients who are unable to tolerate daily medications, even with dosage adjustment, should be tried on an intermittent treatment regimen. Older female patients frequently require gradual introduction of medications (ie, 1 medication added to the regimen every 1 to 2 weeks) to evaluate tolerance to each medication and medication dose.¹¹ Commonly encountered adverse effects of NTM treatment include intolerance to clarithromycin due to gastrointestinal problems, low body mass index, or age older than 70 years.

After determining that the patient requires therapy, the standard recommended treatment for MAC pulmonary disease includes the following: for most patients with nodular/bronchiectasis disease, a thrice-weekly regimen of clarithromycin (1000 mg) or azithromycin (500 mg), rifampin (600 mg), and ethambutol (25 mg/kg) is recommended. For patients with cavitary MAC pulmonary disease or severe nodular/bronchiectasis disease, the guidelines recommend a daily regimen of clarithromycin (500-1000 mg) or azithromycin (250 mg), rifampin (600 mg) or rifabutin (150–300 mg), and ethambutol (15 mg/kg), with consideration of intravenous (IV) amikacin 3 times/week early in therapy (Table 2).¹¹

The treatment of MAC hypersensitivity-like disease speaks to the controversy of whether this is an inflammatory process, infectious process, or a combination of inflammation and infection. Avoidance of exposure is the mainstay of management. In some cases, steroids are used with or without a short course of anti-MAC therapy (ie, clarithromycin or azithromycin with rifampin and ethambutol).

Prophylaxis for disseminated MAC disease should be given to adults with HIV infection who have a CD4+ count less than 50 cells/μL. Azithromycin 1200 mg/week or clarithromycin 1000 mg/day has proven efficacy, and rifabutin 300 mg/day is also effective but less well tolerated. Rifabutin is more active in vitro against MAC than rifampin, and is used in HIV-positive patients because of drug-drug interaction between antiretroviral drugs and rifampin.

Continue to: Case 1 Continued

Case 1 Continued

The patient is treated with clarithromycin, rifampin, and ethambutol for 1 year, with sputum conversion after 9 months. In the latter part of her treatment, she experiences decreased visual acuity. Treatment is discontinued prematurely after 1 year due to drug toxicity and continued intolerance to drug therapy. The patient remains asymptomatic for 8 months, and then begins to experience mild to moderate hemoptysis, with increasing cough and sputum production associated with postural changes during exercise. Physical examination overall remains unchanged. Three sputum results reveal heavy growth of MAC, and a CT scan of the chest shows a cavitary lesion in the left upper lobe along with the nodular bronchiectasis (Figure 4).

What are the management options at this stage?

Based on this patient’s continued symptoms, progression of radiologic abnormalities, and current culture growth, she requires re-treatment. With the adverse effects associated with ethambutol during the first round of therapy, the drug regimen needs to be modified. Several considerations are relevant at this stage. Relapse rates range from 20% to 30% after treatment with a macrolide-based therapy.^11,34 Obtaining a culture-sensitivity profile is imperative in these cases. Of note, treatment should not be discontinued altogether, but instead the toxic agent should be removed from the treatment regimen. Continuing treatment with a 2-drug regimen of clarithromycin and rifampin may be considered in this patient. Re-infection with multiple genotypes may also occur after successful drug therapy, but this is primarily seen in MAC patients with nodular bronchiectasis.^34,35 Patients in whom previous therapy has failed, even those with macrolide-susceptible MAC isolates, are less likely to respond to subsequent therapy. Data suggest that intermittent medication dosing is not effective for patients with severe or cavitary disease or in those in whom previous therapy has failed.³⁶ In this case, treatment should include a daily 3-drug therapy, with an injectable thrice-weekly aminoglycoside. Other agents such as linezolid and clofazimine may have to be tried. Cycloserine, ethionamide, and other agents are sometimes used, but their efficacy is unproven and doubtful. Pyrazinamide and isoniazid have no activity against MAC.

Treatment Failure and Drug Resistance

Treatment failure is considered to have occurred if patients have not had a response (microbiologic, clinical, or radiographic) after 6 months of appropriate therapy or had not achieved conversion of sputum to culture-negative after 12 months of appropriate therapy.¹¹ This occurs in about 40% of patients. Multiple factors can interfere with the successful treatment of MAC pulmonary disease, including medication nonadherence, medication side effects or intolerance, lack of response to a medication regimen, or the emergence of a macrolide-resistant or multidrug-resistant strain. Inducible macrolide resistance remains a potential factor.^34-36 A number of characteristics of NTM contribute to the poor response to currently used antibiotics: the organisms have a lipid outer membrane and prefer to adhere to surfaces and form biofilms, which makes them relatively impermeable to antibiotics.³⁷ Also, NTM replicate in phagocytic cells, allowing them to subvert normal cellular defense mechanisms. Furthermore, NTM can display colony variants, whereby single colony isolates switch between antibiotic-susceptible and -resistant variants. These factors have also impeded in development of new antibiotics for NTM infection.³⁷

Recent limited approval of amikacin liposomal inhalation suspension (ALIS) for treatment failure and refractory MAC infection in combination with guideline-based antimicrobial therapy (GBT) is a promising addition to the available treatment armamentarium. In a multinational trial, the addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion rates by month 6 than GBT alone, with comparable rates of serious adverse events.³⁸

Is therapeutic drug monitoring recommended during treatment of MAC pulmonary disease?

Treatment failure may also be drug-related, including poor drug penetration into the damaged lung tissue or drug-drug interactions leading to suboptimal drug levels. Peak serum concentrations have been found to be below target ranges in approximately 50% of patients using a macrolide and ethambutol. Concurrent use of rifampin decreases the peak serum concentration of macrolides and quinolones, with acceptable target levels seen in only 18% to 57% of cases. Whether this alters patient outcomes is not clear.^39-42 Factors identified as contributing to the poor response to therapy include poor compliance, cavitary disease, previous treatment for MAC pulmonary disease, and a history of chronic obstructive lung disease. Studies by Koh and colleagues⁴⁰ and van Ingen and colleagues⁴¹ with pharmacokinetic and pharmacodynamics data showed that, in patients on MAC treatment with both clarithromycin and rifampicin, plasma levels of clarithromycin were lower than the recommended minimal inhibitory concentrations (MIC) against MAC for that drug. The studies also showed that rifampicin lowered clarithromycin concentrations more than did rifabutin, with the AUC/MIC ratio being suboptimal in nearly half the cases. However, low plasma clarithromycin concentrations did not have any correlation with treatment outcomes, as the peak plasma drug concentrations and the peak plasma drug concentration/MIC ratios did not differ between patients with unfavorable treatment outcomes and those with favorable outcomes. This is further compounded by the fact that macrolides achieve higher levels in lung tissue than in plasma, and hence the significance of low plasma levels is unclear; however, it is postulated that achieving higher drug levels could, in fact, lead to better clinical outcomes. Pending specific well-designed, prospective randomized controlled trials, routine therapeutic drug monitoring is not currently recommended, although some referral centers do this as their practice pattern.

Is surgery an option in this case?

The overall 5-year mortality for MAC pulmonary disease was approximately 28% in a retrospective analysis, with patients with cavitary disease at increased risk for death at 5 years.⁴² As such, surgery is an option in selected cases as part of adjunctive therapy along with anti-MAC therapy based on mycobacterial sensitivity. Surgery is used as either a curative approach or a “debulking” measure.¹¹ When present, clearly localized disease, especially in the upper lobe, lends itself best to surgical intervention. Surgical resection of a solitary pulmonary nodule due to MAC, in addition to concomitant medical treatment, is recommended. Surgical intervention should be considered early in the course of the disease because it may provide a cure without prolonged treatment and its associated problems, and this approach may lead to early sputum conversion. Surgery should also be considered in patients with macrolide-resistant or multidrug-resistant MAC infection or in those who cannot tolerate the side effects of therapy, provided that the disease is focal and limited. Patients with poor preoperative lung function have poorer outcomes than those with good lung function, and postoperative complications arising from treatment, especially with a right-sided pneumonectomy, tend to occur more frequently in these patients. Thoracic surgery for NTM pulmonary disease must be considered cautiously, as this is associated with significant morbidity and mortality and is best performed at specialized centers that have expertise and experience in this field.⁴³

Continue to: Mycobacterium abscessus Complex

Mycobacterium abscessus Complex

Case Patient 2

A 64-year-old man who is an ex-smoker presents with chronic cough, mild shortness of breath on exertion, low-grade fever, and unintentional weight loss of 10 lb. Physical exam is unremarkable. The patient was diagnosed with immunoglobulin deficiency (low IgM and low IgG4) in 2002, and has been on replacement therapy since then. He also has had multiple episodes of NTM infection, with MAC and M. kansasii infections diagnosed in 2012-2014, which required 18 months of multi-drug antibiotic treatment that resulted in sputum conversion. Pulmonary function testing done on this visit in 2017 shows mild obstructive impairment.

Chest radiograph and CT scan show bilateral bronchiectasis (Figure 5 and Figure 6).

The results of serial sputum microbiology testing performed over the course of 6 months are outlined below:

• 5/2017 (bronchoalveolar lavage): 2+; M. abscessus
• 9/2017 × 2: smear (–); group IV RGM
• 11/2017: smear (–); M. abscessus (> 50 CFU)
• 12/2017: smear (–); M. abscessus (> 50 CFU)

What are the clinical considerations in this patient with multiple NTM infections?

M. abscessus complex was originally described in soft tissue abscesses and skin infections possibly resulting from soil or water contamination. Subspeciation of M. abscessus complex during laboratory testing is critical to facilitate selection of a specific therapeutic approach; treatment decisions are impacted by the presence of an active erm gene and in vitro macrolide sensitivity, which differ between subspecies. The most acceptable classification outlines 3 species in the M. abscessus complex: Mycobacterium abscessus subsp abscessus, Mycobacterium abscessus subsp bolletii (both with an active erm gene responsible for macrolide resistance), and Mycobacterium abscessus subsp massiliense (with an inactive erm gene and therefore susceptible to macrolides).⁴⁴

RGM typically manifest in skin, soft tissue, and bone, and can cause soft tissue, surgical wound, and catheter-related infections. Although the role of RGM as pulmonary pathogens is unclear, underlying diseases associated with RGM include previously treated mycobacterial disease, coexistent pulmonary diseases with or without MAC, cystic fibrosis, malignancies, and gastroesophageal disorders. M. abscessus is the third most commonly identified respiratory NTM and accounts for the majority (80%) of RGM respiratory isolates. Other NTM reported to cause both lung disease and skin, bone, and joint infections include Mycobacterium simiae, Mycobacterium xenopi, and Mycobacterium malmoense. Ocular granulomatous diseases, such as chorioretinitis and keratitis, have been reported with both RGM and Runyon group III SGM, such as MAC or M. szulgai, following trauma or refractive surgery. These can mimic fungal, herpetic, or amebic keratitis. The pulmonary syndromes associated with multiple culture positivity are seen in elderly women with bronchiectasis or cavitary lung disease and/or associated with gastrointestinal symptoms of acid reflux, with or without achalasia and concomitant lipoid interstitial pneumonia.⁴⁵

Generally, pulmonary disease progresses slowly, but lung disease attributed to RGM can result in respiratory failure. Thus, RGM should be recognized as a possible cause of chronic mycobacterial lung disease, especially in immunocompromised patients, and respiratory isolates should be assessed carefully. Identification and drug susceptibility testing are essential before initiation of treatment for RGM.

What is the approach to management of M. abscessus pulmonary disease in a patient without cystic fibrosis?

The management of M. abscessus pulmonary infection as a subset of RGM requires a considered step-wise approach. The criteria for diagnosis and threshold for starting treatment are the same as those used in the management of MAC pulmonary disease,¹¹ but the treatment of M. abscessus pulmonary infection is more complex and has lower rates of success and cure. Also, antibiotic treatment presents challenges related to rapid identification of the causative organism, nomenclature, resistance patterns, and tolerance of treatment and side effects. If a source such as catheter, access port, or any surgical site is identified, prompt removal and clearance of the infected site are strongly advised

In the absence of any controlled clinical trials, treatment of RGM is based on in vitro susceptibility testing and expert opinion. As in MAC pulmonary disease, macrolides are the mainstay of treatment, with an induction phase of intravenous antibiotics. Treatment may include a combination of injectable aminoglycosides, imipenem, or cefoxitin and oral drugs such as a macrolide (eg, clarithromycin, azithromycin), doxycycline, fluoroquinolones, trimethoprim/sulfamethoxazole, or linezolid. While antibiotic treatment of M. abscessus pulmonary disease is based on in vitro sensitivity pattern to a greater degree than is treatment of MAC pulmonary disease, this approach has significant practical limitations and hence variable applicability. The final choice of antibiotics is best based on the extended susceptibility results, if available. The presence of an active erm gene on a prolonged growth specimen in M. abscessus subsp abscessus and M. abscessus subsp bolletii precludes the use of a macrolide. In such cases, amikacin, especially in an intravenous form, is the mainstay of treatment based on MIC. Recently, there has been a resurgence in interest in the use of clofazimine in combination with amikacin when treatment is not successful in patients with M. abscessus subsp abscessus or M. bolletii with an active erm gene.^45,46 When localized abscess formation is noted, surgery may be the best option, with emphasis on removal of implants and catheters if implicated in RGM infection.

Attention must also be given to confounding pulmonary and associated comorbidities. This includes management of bronchiectasis with appropriately aggressive airway clearance techniques; anti-reflux measures for prevention of micro-aspiration; and management of other comorbid pulmonary conditions, such as chronic obstructive pulmonary disease, pulmonary fibrosis, and sarcoidosis, if applicable. These interventions play a critical role in clearing the M. abscessus infection, preventing progression of disease, and reducing morbidity. The role of immunomodulatory therapy needs to be considered on a regular, ongoing basis. Identification of genetic factors and correction of immune deficiencies may help in managing the infection.

Case Patient 2 Conclusion

The treatment regimen adopted in this case includes a 3-month course of daily intravenous amikacin and imipenem with oral azithromycin, followed by a continuation phase of azithromycin with clofazimine and linezolid. Airway clearance techniques such as Vest/Acapella/CPT are intensified and monthly intravenous immunoglobulin therapy is continued. The patient responds to treatment, with resolution of his clinical symptoms and reduction in the colony count of M. abscessus in the sputum.

Summary

NTM are ubiquitous in the environment, and NTM infection has variable manifestations, especially in patients with no recognizable immune impairments. Underlying comorbid conditions with bronchiectasis complicate its management. Treatment strategies must be individualized based on degree of involvement, associated comorbidities, immune deficiencies, goals of therapy, outcome-based risk-benefit ratio assessment, and patient engagement and expectations. In diffuse pulmonary disease, drug treatment remains difficult due to poor match of in vitro and in vivo culture sensitivity, side effects of medications, and high failure rates. When a localized resectable foci of infection is identified, especially in RGM disease, surgical treatment may be the best approach in selected patients, but it must be performed in centers with expertise and experience in this field. 

Nontuberculous mycobacterial pulmonary disease is a broad term for a group of pulmonary disorders caused and characterized by exposure to environmental mycobacteria other than those belonging to the Mycobacterium tuberculosis complex and Mycobacterium leprae. Mycobacteria are aerobic, nonmotile organisms that appear positive with acid-fast alcohol stains. Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and have been recovered from domestic and natural water sources, soil, and food products, and from around livestock, cattle, and wildlife.^1-3 To date, no evidence exists of human-to-human or animal-to-human transmission of NTM in the general population. Infections in humans are usually acquired from environmental exposures, although the specific source of infection cannot always be identified. Similarly, the mode of infection with NTM has not been established with certainty, but it is highly likely that the organism is implanted, ingested, aspirated, or inhaled. Aerosolization of droplets associated with use of bathroom showerheads and municipal water sources and soil contamination are some of the factors associated with the transmission of infection. Proven routes of transmission include showerheads and potting soil dust.^2,3

NTM pulmonary disease occurs in individuals with or without comorbid conditions such as bronchiectasis, chronic obstructive pulmonary disease, pulmonary fibrosis, or structural lung diseases. Slender, middle-aged or elderly white females with marfanoid body habitus, with or without apparent immune or genetic disorders, showing impaired airway and mucus clearance present with this infection as a form of underlying bronchiectasis (Lady Windermere syndrome). It is unclear why NTM infections and escalation to clinical disease occur in certain individuals. Many risk factors, including inherited and acquired defects of host immune response (eg, cystic fibrosis trait and α1 antitrypsin deficiency), have been associated with increased susceptibility to NTM infections.⁴

NTM infection can lead to chronic symptoms, frequent exacerbations, progressive functional and structural lung destruction, and impaired quality of life, and is associated with an increased risk of hospitalization and higher 5-year all-cause mortality. As such, NTM disease is drawing increasing attention at the clinical, academic, and research levels.⁵ This case-based review outlines the clinical features of NTM infection, with a focus on the challenges in diagnosis, treatment, and management of NTM pulmonary disease. The cases use Mycobacterium avium complex (MAC), a slow-growing mycobacteria (SGM), and Mycobacterium abscessus, a rapidly growing mycobacteria (RGM), as prototypes in a non–cystic fibrosis, non-HIV clinical setting.

Epidemiology

Of the almost 200 isolated species of NTM, the most prevalent pathogens for respiratory disease in the United States are MAC, Mycobacterium kansasii, and M. abscessus. MAC accounts for more than 80% of cases of NTM respiratory disease in the United States.⁶ The prevalence of NTM disease is increasing at a rate of about 8% each year, with 75,000 to 105,000 patients diagnosed with NTM lung disease in the United States annually. NTM infections in the United States are increasing among patients aged 65 years and older, a population that is expected to nearly double by 2030.^7,8

Isolation and prevalence of many NTM species are higher in certain geographic areas of the United States, especially in the southeast. The US coastal regions have a higher prevalence of NTM pulmonary disease, and account for 70% of NTM cases in the United States each year. Half of patients diagnosed with NTM lung disease reside in 7 states: Florida, New York, Texas, California, Pennsylvania, New Jersey, and Ohio, with 1 in 7 residing in Florida. Three parishes in Louisiana are among the top 10 counties with the highest prevalence in United States. The prevalence of NTM infection–associated hospitalizations is increasing worldwide as well. Co-infection with tuberculosis and multiple NTMs in individual patients has been observed clinically and documented in patients with and without HIV.^9,10

It is not clear why the prevalence of NTM pulmonary disease is increasing, but there may be several contributing factors: (1) an increased awareness and identification of NTM infection sources in the environment; (2) an expanding cohort of immunocompromised individuals with exogenous or endogenous immune deficiencies; (3) availability of improved diagnostic techniques, such as use of high-performance liquid chromatography (HPLC), DNA probes, and gene sequencing; and (4) an increased awareness of the morbidity and mortality associated with NTM pulmonary disease. However, it is important to recognize that to best understand the clinical relevance of epidemiologic studies based on laboratory diagnosis and identification, the findings must be evaluated by correlating them with the microbiological and other clinical criteria established by the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines.¹¹

Continue to: Mycobacterium avium Complex

Mycobacterium avium Complex

Case Patient 1

A 48-year-old woman who has never smoked and has no past medical problems, except seasonal allergic rhinitis and “colds and flu-like illness” once or twice a year, is evaluated for a chronic lingering cough with occasional sputum production. The patient denies any other chronic symptoms and is otherwise active. Physical examination reveals no specific findings except mild pectus excavatum and mild scoliosis. Body mass index is 22 kg/m². Chest radiograph shows nonspecific increased markings in the lower zones. Computed tomography (CT) scan of the chest reveals minimal nodular and cylindrical bronchiectasis in both lungs (Figure 1). No previous radiographs are available for comparison. The patient is HIV-negative. Sputum tests reveal normal flora, and both fungus and acid-fast bacilli smear are negative. Culture for mycobacteria shows scanty growth of MAC in 1 specimen.

What is the clinical presentation of MAC pulmonary disease?

Among NTM, MAC is the most common cause of pulmonary disease worldwide.⁶ MAC primarily includes 2 species: M. avium and Mycobacterium intracellulare. M. avium is the more important pathogen in disseminated disease, whereas M. intracellulare is the more common respiratory pathogen.¹¹ These organisms are genetically similar and generally not differentiated in the clinical microbiology laboratory, although there are isolated reports in the literature suggesting differences in prevalence, presentation, and prognosis in M. avium infection versus M. intracellulare infection.¹²

Three major disease syndromes are produced by MAC in humans: pulmonary disease, usually in adults whose systemic immunity is intact; disseminated disease, usually in patients with advanced HIV infection; and cervical lymphadenitis.¹³ Pulmonary disease caused by MAC may take on 1 of several clinically different forms, including asymptomatic “colonization” or persistent minimal infection without obvious clinical significance; endobronchial involvement; progressive pulmonary disease with radiographic and clinical deterioration and nodular bronchiectasis or cavitary lung disease; hypersensitivity pneumonitis; or persistent, overwhelming mycobacterial growth with symptomatic manifestations, often in a lung with underlying damage due to either chronic obstructive lung disease or pulmonary fibrosis (Table 1).¹⁴

Cavitary Disease

The traditionally recognized presentation of MAC lung disease has been apical cavitary lung disease in men in their late 40s and early 50s who have a history of cigarette smoking, and frequently, excessive alcohol use. If left untreated, or in the case of erratic treatment or macrolide drug resistance, this form of disease is generally progressive within a relatively short time and can result in extensive cavitary lung destruction and progressive respiratory failure.¹⁵

Nodular Bronchiectasis

The more common presentation of MAC lung disease, which is outlined in the case described here, is interstitial nodular infiltrates, frequently involving the right middle lobe or lingula and predominantly occurring in postmenopausal, nonsmoking white women. This is sometimes labelled “Lady Windermere syndrome.” These patients with M. avium infection appear to have similar clinical characteristics and body types, including lean build, scoliosis, pectus excavatum, and mitral valve prolapse.^16,17 The mechanism by which this body morphotype predisposes to pulmonary mycobacterial infection is not defined, but ineffective mucociliary clearance is a possible explanation. Evidence suggests that some patients may be predisposed to NTM lung disease because of preexisting bronchiectasis. Some potential etiologies of bronchiectasis in this population include chronic sinusitis, gastroesophageal reflux with chronic aspiration, α1 antitrypsin deficiency, and cystic fibrosis genetic traits and mutations.¹⁸ Risk factors for increased morbidity and mortality include the development of cavitary disease, age, weight loss, lower body mass index, and other comorbid conditions.

This form of disease, termed nodular bronchiectasis, tends to have a much slower progression than cavitary disease, such that long-term follow-up (months to years) may be necessary to demonstrate clinical or radiographic changes.¹¹ The radiographic term “tree-in-bud” has been used to describe what may reflect inflammatory changes, including bronchiolitis. High-resolution CT scans of the chest are especially helpful for diagnosing this pattern of MAC lung disease, as bronchiectasis and small nodules may not be easily discernible on plain chest radiograph. The nodular/bronchiectasis radiographic pattern can also be seen with other NTM pathogens, including M. abscessus, Mycobacterium simiae, and M. kansasii. Solitary nodules and dense consolidation have also been described. Pleural effusions are uncommon, but reactive pleural thickening is frequently seen. Co-pathogens may be isolated from culture, including Pseudomonas aeruginosa, Staphylococcus aureus, and, occasionally, other NTM such as M. abscessus or Mycobacterium chelonae.^19-21

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis, initially described in patients who were exposed to hot tubs, mimics allergic hypersensitivity pneumonitis, with respiratory symptoms and culture/tissue identification of MAC or sometimes other NTM. It is unclear whether hypersensitivity pneumonitis is an inflammatory process, an infection, or both, and opinion regarding the need for specific antibiotic treatment is divided.^11,22 However, avoidance of exposure is prudent and recommended.

Disseminated Disease

Disseminated NTM disease is associated with very low CD4+ lymphocyte counts and is seen in approximately 5% of patients with HIV infection.^23-25 Although disseminated NTM disease is rarely seen in immunosuppressed patients without HIV infection, it has been reported in patients who have undergone renal or cardiac transplant, patients on long-term corticosteroid therapy, and those with leukemia or lymphoma. More than 90% of infections are caused by MAC; other potential pathogens include M. kansasii, M. chelonae, M. abscessus, and Mycobacterium haemophilum. Although seen less frequently since the advent of highly active antiretroviral therapy, disseminated infection can develop progressively from an apparently indolent or localized infection or a respiratory or gastrointestinal source. Signs and symptoms of disseminated infection (specifically MAC-associated disease) are nonspecific and include fever, night sweats, weight loss, and abdominal tenderness. Disseminated MAC disease occurs primarily in patients with more advanced HIV disease (CD4+ count typically < 50 cells/μL). Clinically, disseminated MAC manifests as intermittent or persistent fever, constitutional symptoms with organomegaly and organ-specific abnormalities (eg, anemia, neutropenia from bone marrow involvement, adenopathy, hepatosplenomegaly), and elevations of liver enzymes or lung infiltrates from pulmonary involvement.

Continue to: What are the criteria for diagnosing NTM pulmonary disease?

What are the criteria for diagnosing NTM pulmonary disease?

The diagnosis of NTM disease is based on clinical, radiologic, and mycobacterial correlation with good communication between the experts in this field. The ATS/IDSA criteria for diagnosing NTM lung disease are shown in Figure 2. These criteria best apply to MAC, M. kansasii, and M. abscessus, but are also clinically applied to other NTM respiratory pathogens. The diagnosis of MAC infection is most readily established by culture of blood, bone marrow, respiratory secretions/fluid, or tissue specimens from suspected sites of involvement. Due to erratic shedding of MAC into the respiratory secretions in patients with nodular bronchiectasis, as compared to those with the cavitary form of the disease, sputum may be intermittently positive, with variable colony counts and polyclonal infections.¹² Prior to the advent of high-resolution CT, isolation of MAC organisms from the sputum of such patients was frequently dismissed as colonization.

Mycobacterial Testing

Because of the nonspecific symptoms and lack of diagnostic specificity of chest imaging, the diagnosis of NTM lung disease requires microbiologic confirmation. Specimens sent to the laboratory for identification of NTM must be handled with care to prevent contamination and false-positive results. Transport media and preservatives should be avoided, and transportation of the specimens should be prompt. These measures will prevent bacterial overgrowth. Furthermore, the yield of NTM may be affected if the patient has used antibiotics, such as macrolides and fluoroquinolones, prior to obtaining the specimen.

NTM should be identified at the species and subspecies level, although this is not practical in community practice settings. The preferred staining procedure in the laboratory is the fluorochrome method. Some species require special growth conditions and/or lower incubation temperatures, and other identification methods may have to be employed, such as DNA probes, polymerase chain reaction genotyping, nucleic acid sequence determination, and high-performance liquid chromatography. As a gold standard, clinical specimens for mycobacterial cultures should be inoculated onto 1 or more solid media (eg, Middlebrook 7H11 media and/or Lowenstein-Jensen media, the former of which is the preferred medium for NTM) and into a liquid medium (eg, BACTEC 12B broth or Mycobacteria growth indicator tube broth). Growth of visible colonies on solid media typically requires 2 to 4 weeks, but liquid media (eg, the radiometric BACTEC system), used as a supplementary and not as an exclusive test, usually produce results within 10 to 14 days. Furthermore, even after initial growth, identification of specific isolates based on the growth characteristics on solid media requires additional time. Use of specific nucleic acid probes for MAC and M. kansasii and HPLC testing of mycolic acid patterns in acid-fast bacilli smear–positive specimens can reduce the turnaround time of specific identification of a primary culture–positive sample. However, HPLC is not sufficient for definitive identification of many NTM species, including the RGM. Other newer techniques, including 16S ribosomal DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis, also allow NTM to be identified and speciated more reliably and rapidly from clinical specimens.

Cost and other practical considerations limit widespread adoption of these techniques. However, the recognition that M. abscessus can be separated into more than 1 subspecies, and that there are important prognostic implications of that separation, lends urgency to the broader adoption of newer molecular techniques in the mycobacteriology laboratory. Susceptibility testing is based on the broth microdilution method; RGM usually grow within 7 days of subculture, and the laboratory time to culture is a helpful hint, although not necessarily specific. Recognizing the morphology of mycobacterial colony growth may also be helpful in identification.

Are skin tests helpful in diagnosing NTM infection?

Tuberculin skin testing remains a nonspecific marker of mycobacterial infection and does not help in further elucidating NTM infection. However, epidemiologic and laboratory studies with well-characterized antigens have shown that dual skin testing with tuberculosis- versus NTM-derived tuberculin can discriminate between prior NTM and prior tuberculosis disease. Species-specific skin test antigens are not commercially available and are not helpful in the diagnosis of NTM disease because of cross-reactivity of M. tuberculosis and some NTM. However, increased prevalence of NTM sensitization based on purified protein derivative testing has been noted in a recent survey, which is consistent with an observed increase in the rates of NTM infections, specifically MAC, in the United States.^26,27

Interferon-gamma release assays (IGRAs) are now being used as an alternative to tuberculin skin testing to diagnose M. tuberculosis infection. Certain NTM species also contain gene sequences that encode for ESAT-6 or CFP-10 antigens used in the IGRAs, and hence, yield a positive IGRA test. These include M. marinum, M. szulgai, and M. kansasii.^28,29 However, MAC organisms do not produce positive results on assays that use these antigens.

Continue to: What is the approach to management of NTM pulmonary disease?

What is the approach to management of NTM pulmonary disease?

The correlation of symptoms with radiographic and microbiologic evidence is essential to categorize the disease and determine the need for therapy. Making the diagnosis of NTM lung disease does not necessitate the institution of therapy. The decision to treat should be weighed against potential risks and benefits to the individual patient based on symptomatic, radiographic, and microbiologic criteria, as well as underlying systemic or pulmonary immune status. In the absence of evidence of clinical, radiologic, or mycobacterial progression of disease, pursuing airway clearance therapy and clinical surveillance without initiating specific anti-MAC therapy is a reasonable option.¹¹ Identifying the sustained presence of NTM infection, especially MAC, in a patient with underlying clinical and radiographic evidence of bronchiectasis is of value in determining comprehensive treatment and management strategies. Close observation is indicated if the decision not to treat is made. If treatment is initiated, comprehensive management includes long-term follow-up with periodic bacteriologic surveillance, watching for drug toxicity and drug-drug interactions, ensuring adherence and compliance to treatment, and managing comorbidity.

The Bronchiectasis Severity Index is a useful clinical predictive tool that identifies patients at risk of future mortality, hospitalization, and exacerbations and can be used to evaluate the need for specific treatment.30 The index is based on dyspnea score, lung function tests, colonization of pathogens, and extent of disease.

Case 1 Continued

After approximately 2 months of observation and symptomatic treatment, without specific antibiotic therapy, the patient’s symptoms continue. She now develops intermittent hemoptysis. Repeat sputum studies reveal moderate growth of M. avium. A follow-up CT scan shows progression of disease, with an increase in the tree-in-bud pattern (Figure 3).

What treatment protocols are recommended for MAC pulmonary disease?

As per the ATS/IDSA statement, macrolides are the mainstay of treatment for pulmonary MAC disease.¹¹ Macrolides achieve an increased concentration in the lung, and when used for treatment of pulmonary MAC disease, there is a strong correlation between in vitro susceptibility, in vivo (clinical) response, and the immunomodulating effects of macrolides.^31,32 Macrolide-containing regimens have demonstrated efficacy in patients with MAC pulmonary disease^33,34; however, macrolide monotherapy should be avoided to prevent the development of resistance.

At the outset, it is critical to establish the objective criteria for determining response and to ensure that the patient understands the goals of the treatment and expectations of the treatment plan. Moreover, experts suggest that due to the possibility of drug intolerance, side effects, and the need for prolonged therapy, a “step ladder” ramping up approach to treatment could be adopted, with gradual introduction of therapy within a short time period; this approach may improve compliance and adherence to treatment.¹¹ If this approach is used, the doses may have to be divided. Patients who are unable to tolerate daily medications, even with dosage adjustment, should be tried on an intermittent treatment regimen. Older female patients frequently require gradual introduction of medications (ie, 1 medication added to the regimen every 1 to 2 weeks) to evaluate tolerance to each medication and medication dose.¹¹ Commonly encountered adverse effects of NTM treatment include intolerance to clarithromycin due to gastrointestinal problems, low body mass index, or age older than 70 years.

After determining that the patient requires therapy, the standard recommended treatment for MAC pulmonary disease includes the following: for most patients with nodular/bronchiectasis disease, a thrice-weekly regimen of clarithromycin (1000 mg) or azithromycin (500 mg), rifampin (600 mg), and ethambutol (25 mg/kg) is recommended. For patients with cavitary MAC pulmonary disease or severe nodular/bronchiectasis disease, the guidelines recommend a daily regimen of clarithromycin (500-1000 mg) or azithromycin (250 mg), rifampin (600 mg) or rifabutin (150–300 mg), and ethambutol (15 mg/kg), with consideration of intravenous (IV) amikacin 3 times/week early in therapy (Table 2).¹¹

The treatment of MAC hypersensitivity-like disease speaks to the controversy of whether this is an inflammatory process, infectious process, or a combination of inflammation and infection. Avoidance of exposure is the mainstay of management. In some cases, steroids are used with or without a short course of anti-MAC therapy (ie, clarithromycin or azithromycin with rifampin and ethambutol).

Prophylaxis for disseminated MAC disease should be given to adults with HIV infection who have a CD4+ count less than 50 cells/μL. Azithromycin 1200 mg/week or clarithromycin 1000 mg/day has proven efficacy, and rifabutin 300 mg/day is also effective but less well tolerated. Rifabutin is more active in vitro against MAC than rifampin, and is used in HIV-positive patients because of drug-drug interaction between antiretroviral drugs and rifampin.

Continue to: Case 1 Continued

Case 1 Continued

The patient is treated with clarithromycin, rifampin, and ethambutol for 1 year, with sputum conversion after 9 months. In the latter part of her treatment, she experiences decreased visual acuity. Treatment is discontinued prematurely after 1 year due to drug toxicity and continued intolerance to drug therapy. The patient remains asymptomatic for 8 months, and then begins to experience mild to moderate hemoptysis, with increasing cough and sputum production associated with postural changes during exercise. Physical examination overall remains unchanged. Three sputum results reveal heavy growth of MAC, and a CT scan of the chest shows a cavitary lesion in the left upper lobe along with the nodular bronchiectasis (Figure 4).

What are the management options at this stage?

Based on this patient’s continued symptoms, progression of radiologic abnormalities, and current culture growth, she requires re-treatment. With the adverse effects associated with ethambutol during the first round of therapy, the drug regimen needs to be modified. Several considerations are relevant at this stage. Relapse rates range from 20% to 30% after treatment with a macrolide-based therapy.^11,34 Obtaining a culture-sensitivity profile is imperative in these cases. Of note, treatment should not be discontinued altogether, but instead the toxic agent should be removed from the treatment regimen. Continuing treatment with a 2-drug regimen of clarithromycin and rifampin may be considered in this patient. Re-infection with multiple genotypes may also occur after successful drug therapy, but this is primarily seen in MAC patients with nodular bronchiectasis.^34,35 Patients in whom previous therapy has failed, even those with macrolide-susceptible MAC isolates, are less likely to respond to subsequent therapy. Data suggest that intermittent medication dosing is not effective for patients with severe or cavitary disease or in those in whom previous therapy has failed.³⁶ In this case, treatment should include a daily 3-drug therapy, with an injectable thrice-weekly aminoglycoside. Other agents such as linezolid and clofazimine may have to be tried. Cycloserine, ethionamide, and other agents are sometimes used, but their efficacy is unproven and doubtful. Pyrazinamide and isoniazid have no activity against MAC.

Treatment Failure and Drug Resistance

Treatment failure is considered to have occurred if patients have not had a response (microbiologic, clinical, or radiographic) after 6 months of appropriate therapy or had not achieved conversion of sputum to culture-negative after 12 months of appropriate therapy.¹¹ This occurs in about 40% of patients. Multiple factors can interfere with the successful treatment of MAC pulmonary disease, including medication nonadherence, medication side effects or intolerance, lack of response to a medication regimen, or the emergence of a macrolide-resistant or multidrug-resistant strain. Inducible macrolide resistance remains a potential factor.^34-36 A number of characteristics of NTM contribute to the poor response to currently used antibiotics: the organisms have a lipid outer membrane and prefer to adhere to surfaces and form biofilms, which makes them relatively impermeable to antibiotics.³⁷ Also, NTM replicate in phagocytic cells, allowing them to subvert normal cellular defense mechanisms. Furthermore, NTM can display colony variants, whereby single colony isolates switch between antibiotic-susceptible and -resistant variants. These factors have also impeded in development of new antibiotics for NTM infection.³⁷

Recent limited approval of amikacin liposomal inhalation suspension (ALIS) for treatment failure and refractory MAC infection in combination with guideline-based antimicrobial therapy (GBT) is a promising addition to the available treatment armamentarium. In a multinational trial, the addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion rates by month 6 than GBT alone, with comparable rates of serious adverse events.³⁸

Is therapeutic drug monitoring recommended during treatment of MAC pulmonary disease?

Treatment failure may also be drug-related, including poor drug penetration into the damaged lung tissue or drug-drug interactions leading to suboptimal drug levels. Peak serum concentrations have been found to be below target ranges in approximately 50% of patients using a macrolide and ethambutol. Concurrent use of rifampin decreases the peak serum concentration of macrolides and quinolones, with acceptable target levels seen in only 18% to 57% of cases. Whether this alters patient outcomes is not clear.^39-42 Factors identified as contributing to the poor response to therapy include poor compliance, cavitary disease, previous treatment for MAC pulmonary disease, and a history of chronic obstructive lung disease. Studies by Koh and colleagues⁴⁰ and van Ingen and colleagues⁴¹ with pharmacokinetic and pharmacodynamics data showed that, in patients on MAC treatment with both clarithromycin and rifampicin, plasma levels of clarithromycin were lower than the recommended minimal inhibitory concentrations (MIC) against MAC for that drug. The studies also showed that rifampicin lowered clarithromycin concentrations more than did rifabutin, with the AUC/MIC ratio being suboptimal in nearly half the cases. However, low plasma clarithromycin concentrations did not have any correlation with treatment outcomes, as the peak plasma drug concentrations and the peak plasma drug concentration/MIC ratios did not differ between patients with unfavorable treatment outcomes and those with favorable outcomes. This is further compounded by the fact that macrolides achieve higher levels in lung tissue than in plasma, and hence the significance of low plasma levels is unclear; however, it is postulated that achieving higher drug levels could, in fact, lead to better clinical outcomes. Pending specific well-designed, prospective randomized controlled trials, routine therapeutic drug monitoring is not currently recommended, although some referral centers do this as their practice pattern.

Is surgery an option in this case?

The overall 5-year mortality for MAC pulmonary disease was approximately 28% in a retrospective analysis, with patients with cavitary disease at increased risk for death at 5 years.⁴² As such, surgery is an option in selected cases as part of adjunctive therapy along with anti-MAC therapy based on mycobacterial sensitivity. Surgery is used as either a curative approach or a “debulking” measure.¹¹ When present, clearly localized disease, especially in the upper lobe, lends itself best to surgical intervention. Surgical resection of a solitary pulmonary nodule due to MAC, in addition to concomitant medical treatment, is recommended. Surgical intervention should be considered early in the course of the disease because it may provide a cure without prolonged treatment and its associated problems, and this approach may lead to early sputum conversion. Surgery should also be considered in patients with macrolide-resistant or multidrug-resistant MAC infection or in those who cannot tolerate the side effects of therapy, provided that the disease is focal and limited. Patients with poor preoperative lung function have poorer outcomes than those with good lung function, and postoperative complications arising from treatment, especially with a right-sided pneumonectomy, tend to occur more frequently in these patients. Thoracic surgery for NTM pulmonary disease must be considered cautiously, as this is associated with significant morbidity and mortality and is best performed at specialized centers that have expertise and experience in this field.⁴³

Continue to: Mycobacterium abscessus Complex

Mycobacterium abscessus Complex

Case Patient 2

A 64-year-old man who is an ex-smoker presents with chronic cough, mild shortness of breath on exertion, low-grade fever, and unintentional weight loss of 10 lb. Physical exam is unremarkable. The patient was diagnosed with immunoglobulin deficiency (low IgM and low IgG4) in 2002, and has been on replacement therapy since then. He also has had multiple episodes of NTM infection, with MAC and M. kansasii infections diagnosed in 2012-2014, which required 18 months of multi-drug antibiotic treatment that resulted in sputum conversion. Pulmonary function testing done on this visit in 2017 shows mild obstructive impairment.

Chest radiograph and CT scan show bilateral bronchiectasis (Figure 5 and Figure 6).

The results of serial sputum microbiology testing performed over the course of 6 months are outlined below:

• 5/2017 (bronchoalveolar lavage): 2+; M. abscessus
• 9/2017 × 2: smear (–); group IV RGM
• 11/2017: smear (–); M. abscessus (> 50 CFU)
• 12/2017: smear (–); M. abscessus (> 50 CFU)

What are the clinical considerations in this patient with multiple NTM infections?

M. abscessus complex was originally described in soft tissue abscesses and skin infections possibly resulting from soil or water contamination. Subspeciation of M. abscessus complex during laboratory testing is critical to facilitate selection of a specific therapeutic approach; treatment decisions are impacted by the presence of an active erm gene and in vitro macrolide sensitivity, which differ between subspecies. The most acceptable classification outlines 3 species in the M. abscessus complex: Mycobacterium abscessus subsp abscessus, Mycobacterium abscessus subsp bolletii (both with an active erm gene responsible for macrolide resistance), and Mycobacterium abscessus subsp massiliense (with an inactive erm gene and therefore susceptible to macrolides).⁴⁴

RGM typically manifest in skin, soft tissue, and bone, and can cause soft tissue, surgical wound, and catheter-related infections. Although the role of RGM as pulmonary pathogens is unclear, underlying diseases associated with RGM include previously treated mycobacterial disease, coexistent pulmonary diseases with or without MAC, cystic fibrosis, malignancies, and gastroesophageal disorders. M. abscessus is the third most commonly identified respiratory NTM and accounts for the majority (80%) of RGM respiratory isolates. Other NTM reported to cause both lung disease and skin, bone, and joint infections include Mycobacterium simiae, Mycobacterium xenopi, and Mycobacterium malmoense. Ocular granulomatous diseases, such as chorioretinitis and keratitis, have been reported with both RGM and Runyon group III SGM, such as MAC or M. szulgai, following trauma or refractive surgery. These can mimic fungal, herpetic, or amebic keratitis. The pulmonary syndromes associated with multiple culture positivity are seen in elderly women with bronchiectasis or cavitary lung disease and/or associated with gastrointestinal symptoms of acid reflux, with or without achalasia and concomitant lipoid interstitial pneumonia.⁴⁵

Generally, pulmonary disease progresses slowly, but lung disease attributed to RGM can result in respiratory failure. Thus, RGM should be recognized as a possible cause of chronic mycobacterial lung disease, especially in immunocompromised patients, and respiratory isolates should be assessed carefully. Identification and drug susceptibility testing are essential before initiation of treatment for RGM.

What is the approach to management of M. abscessus pulmonary disease in a patient without cystic fibrosis?

The management of M. abscessus pulmonary infection as a subset of RGM requires a considered step-wise approach. The criteria for diagnosis and threshold for starting treatment are the same as those used in the management of MAC pulmonary disease,¹¹ but the treatment of M. abscessus pulmonary infection is more complex and has lower rates of success and cure. Also, antibiotic treatment presents challenges related to rapid identification of the causative organism, nomenclature, resistance patterns, and tolerance of treatment and side effects. If a source such as catheter, access port, or any surgical site is identified, prompt removal and clearance of the infected site are strongly advised

In the absence of any controlled clinical trials, treatment of RGM is based on in vitro susceptibility testing and expert opinion. As in MAC pulmonary disease, macrolides are the mainstay of treatment, with an induction phase of intravenous antibiotics. Treatment may include a combination of injectable aminoglycosides, imipenem, or cefoxitin and oral drugs such as a macrolide (eg, clarithromycin, azithromycin), doxycycline, fluoroquinolones, trimethoprim/sulfamethoxazole, or linezolid. While antibiotic treatment of M. abscessus pulmonary disease is based on in vitro sensitivity pattern to a greater degree than is treatment of MAC pulmonary disease, this approach has significant practical limitations and hence variable applicability. The final choice of antibiotics is best based on the extended susceptibility results, if available. The presence of an active erm gene on a prolonged growth specimen in M. abscessus subsp abscessus and M. abscessus subsp bolletii precludes the use of a macrolide. In such cases, amikacin, especially in an intravenous form, is the mainstay of treatment based on MIC. Recently, there has been a resurgence in interest in the use of clofazimine in combination with amikacin when treatment is not successful in patients with M. abscessus subsp abscessus or M. bolletii with an active erm gene.^45,46 When localized abscess formation is noted, surgery may be the best option, with emphasis on removal of implants and catheters if implicated in RGM infection.

Attention must also be given to confounding pulmonary and associated comorbidities. This includes management of bronchiectasis with appropriately aggressive airway clearance techniques; anti-reflux measures for prevention of micro-aspiration; and management of other comorbid pulmonary conditions, such as chronic obstructive pulmonary disease, pulmonary fibrosis, and sarcoidosis, if applicable. These interventions play a critical role in clearing the M. abscessus infection, preventing progression of disease, and reducing morbidity. The role of immunomodulatory therapy needs to be considered on a regular, ongoing basis. Identification of genetic factors and correction of immune deficiencies may help in managing the infection.

Case Patient 2 Conclusion

The treatment regimen adopted in this case includes a 3-month course of daily intravenous amikacin and imipenem with oral azithromycin, followed by a continuation phase of azithromycin with clofazimine and linezolid. Airway clearance techniques such as Vest/Acapella/CPT are intensified and monthly intravenous immunoglobulin therapy is continued. The patient responds to treatment, with resolution of his clinical symptoms and reduction in the colony count of M. abscessus in the sputum.

Summary

NTM are ubiquitous in the environment, and NTM infection has variable manifestations, especially in patients with no recognizable immune impairments. Underlying comorbid conditions with bronchiectasis complicate its management. Treatment strategies must be individualized based on degree of involvement, associated comorbidities, immune deficiencies, goals of therapy, outcome-based risk-benefit ratio assessment, and patient engagement and expectations. In diffuse pulmonary disease, drug treatment remains difficult due to poor match of in vitro and in vivo culture sensitivity, side effects of medications, and high failure rates. When a localized resectable foci of infection is identified, especially in RGM disease, surgical treatment may be the best approach in selected patients, but it must be performed in centers with expertise and experience in this field. 

Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.

Medical Therapy

Prostanoids

Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.¹

Epoprostenol

Epoprostenol is also known as synthetic prostaglandin I₂ or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.^2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.^4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.⁶ The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.⁷ Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.⁸ No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.⁹ Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.

Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).¹⁰ Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.¹¹ MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.

Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.

Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.

Treprostinil

Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.¹² Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.¹³ Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.

Iloprost

Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,¹⁴ survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.¹⁵ Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.

Selexipag

Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.¹⁶ In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.¹⁷ This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.

Endothelin Receptor Antagonists

Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.¹⁸

Bosentan

Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.¹⁹ One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.²⁰ All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.²¹ Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.

In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.¹⁴ One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.²² The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.

Ambrisentan

Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.²³ Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.²⁴ Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.²⁵ Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.

Macitentan

Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.²⁶ Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.

Phosphodiesterase-5 Inhibitors

Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.

Sildenafil

Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.²⁷ Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.

Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.²⁸ Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.²⁹ All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm^–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.

Tadalafil

Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).^30,31

Guanylate Cyclase Stimulator

Riociguat

Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.^32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.³⁴ Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.

Medications to Avoid

Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.³⁵ The authors concluded that the use of beta-blockers should be avoided in this patient population.

Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.

Transplantation

Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.³⁶ The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.

To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.³⁷ In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),³⁸ and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm^–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.³⁷ However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.³⁸ Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.

Review of Outcomes

A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.³⁹ Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.

Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.

The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.¹¹ POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.

Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.⁴⁰ Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.

We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.⁴¹ Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.

Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.⁴² The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.¹¹ Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.⁴³

Patient Selection

In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.⁴⁴ UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm^–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.⁴⁵ Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.⁴⁶ One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.

Conclusion

Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.

Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.

Medical Therapy

Prostanoids

Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.¹

Epoprostenol

Epoprostenol is also known as synthetic prostaglandin I₂ or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.^2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.^4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.⁶ The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.⁷ Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.⁸ No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.⁹ Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.

Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).¹⁰ Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.¹¹ MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.

Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.

Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.

Treprostinil

Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.¹² Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.¹³ Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.

Iloprost

Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,¹⁴ survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.¹⁵ Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.

Selexipag

Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.¹⁶ In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.¹⁷ This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.

Endothelin Receptor Antagonists

Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.¹⁸

Bosentan

Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.¹⁹ One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.²⁰ All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.²¹ Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.

In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.¹⁴ One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.²² The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.

Ambrisentan

Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.²³ Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.²⁴ Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.²⁵ Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.

Macitentan

Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.²⁶ Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.

Phosphodiesterase-5 Inhibitors

Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.

Sildenafil

Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.²⁷ Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.

Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.²⁸ Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.²⁹ All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm^–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.

Tadalafil

Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).^30,31

Guanylate Cyclase Stimulator

Riociguat

Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.^32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.³⁴ Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.

Medications to Avoid

Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.³⁵ The authors concluded that the use of beta-blockers should be avoided in this patient population.

Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.

Transplantation

Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.³⁶ The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.

To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.³⁷ In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),³⁸ and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm^–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.³⁷ However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.³⁸ Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.

Review of Outcomes

A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.³⁹ Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.

Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.

The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.¹¹ POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.

Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.⁴⁰ Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.

We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.⁴¹ Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.

Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.⁴² The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.¹¹ Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.⁴³

Patient Selection

In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.⁴⁴ UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm^–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.⁴⁵ Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.⁴⁶ One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.

Conclusion

Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.

Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.

Medical Therapy

Prostanoids

Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.¹

Epoprostenol

Epoprostenol is also known as synthetic prostaglandin I₂ or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.^2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.^4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.⁶ The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.⁷ Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.⁸ No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.⁹ Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.

Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).¹⁰ Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.¹¹ MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.

Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.

Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.

Treprostinil

Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.¹² Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.¹³ Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.

Iloprost

Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,¹⁴ survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.¹⁵ Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.

Selexipag

Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.¹⁶ In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.¹⁷ This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.

Endothelin Receptor Antagonists

Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.¹⁸

Bosentan

Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.¹⁹ One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.²⁰ All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.²¹ Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.

In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.¹⁴ One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.²² The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.

Ambrisentan

Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.²³ Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.²⁴ Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.²⁵ Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.

Macitentan

Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.²⁶ Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.

Phosphodiesterase-5 Inhibitors

Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.

Sildenafil

Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.²⁷ Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.

Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.²⁸ Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.²⁹ All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm^–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.

Tadalafil

Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).^30,31

Guanylate Cyclase Stimulator

Riociguat

Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.^32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.³⁴ Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.

Medications to Avoid

Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.³⁵ The authors concluded that the use of beta-blockers should be avoided in this patient population.

Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.

Transplantation

Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.³⁶ The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.

To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.³⁷ In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),³⁸ and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm^–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.³⁷ However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.³⁸ Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.

Review of Outcomes

A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.³⁹ Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.

Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.

The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.¹¹ POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.

Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.⁴⁰ Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.

We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.⁴¹ Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.

Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.⁴² The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.¹¹ Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.⁴³

Patient Selection

In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.⁴⁴ UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm^–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.⁴⁵ Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.⁴⁶ One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.

Conclusion

Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Initial management decisions for patients with community-acquired pneumonia (CAP) will depend on severity of infection, with need for hospitalization being one of the first decisions. Because empiric antibiotics are the mainstay of treatment and the causative organisms are seldom identified, underlying medical conditions and epidemiologic risk factors are considered when selecting an empiric regimen. As with other infections, duration of therapy is not standardized, but rather is guided by clinical improvement. Prevention of pneumonia centers around vaccination and smoking cessation. This article, the second in a 2-part review of CAP in adults, focuses on site of care decision, empiric and directed therapies, length of treatment, and prevention strategies. Evaluation and diagnosis of CAP are discussed in a separate article.

Site of Care Decision

For patients diagnosed with CAP, the clinician must decide whether treatment will be done in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or in the intensive care unit (ICU). Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guide site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters, and radiographic findings, to stratify patients into 5 mortality risk classes.¹ On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients.¹

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure, and age ≥ 65 years (Table 1).^2,3 A modification to the CURB-65 algorithm tool was CRB-65, which excludes urea nitrogen, making it optimal for making determinations in a clinic-based setting. It should be emphasized that these tools do not take into account other factors that should be used in determining location of treatment, such as stable home, mental illness, or concerns about compliance with medications. In many instances, it is these factors that preclude low-risk patients from being treated as outpatients.^4,5 Similarly, these scoring systems have not been validated for immunocompromised patients or those who would qualify as having health care–associated pneumonia.

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia, and admission to the ICU should be considered for these patients. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU.⁶ American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths/minute, PaO₂ fraction ≤ 250 mm Hg, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia, and hypotension.⁶ These factors are associated with increased mortality due to CAP, and ICU admission is indicated if 3 of the minor criteria for severe CAP are present.

Another clinical calculator that can be used for assessing severity of CAP is SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation and arterial pH).⁷ This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and a specificity of 64% in predicting ICU admission, whereas CURB-65 has a pooled sensitivity of 57.2% and specificity of 77.2%.⁸

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. A CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and Streptococcus pneumoniae for only 5%.⁹ This study highlighted the fact that despite advances in molecular techniques, no pathogen is identified for most patients with pneumonia.⁹ Given the lack of discernable pathogens in the majority of cases, patients should continue to be treated with antibiotics unless a nonbacterial etiology is found.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 2)¹⁰ can be treated with monotherapy. Hospitalized patients are usually treated with combination intravenous therapy, although non-ICU patients who receive a respiratory fluoroquinolone can be treated orally.

As previously mentioned, antibiotic therapy is typically empiric, since neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, antimicrobial coverage should be expanded to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center.⁶

Staphylococcus aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents.¹¹ Daptomycin, another agent used against MRSA, is not indicated in the setting of pneumonia because daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia.¹² Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication.^13,14 Similarly, other agents known to have antibacterial properties against MRSA, such as trimethoprim/sulfamethoxazole and doxycycline, have not been studied for this indication. Clindamycin has been used to treat MRSA in children, and IDSA guidelines on the treatment of MRSA list clindamycin as an alternative¹⁵ if MRSA is known to be sensitive.

A summary of recommended empiric antibiotic therapy is presented in Table 3.¹⁶

Three antibiotics were approved by the US Food and Drug Administration (FDA) for the treatment of CAP after the release of the IDSA/ATS guidelines in 2007. Ceftaroline fosamil is a fifth-generation cephalosporin that has coverage for MRSA and was approved in November 2010.¹⁷ It can only be administered intravenously and needs dose adjustment for renal function. Omadacycline is a new tetracycline that was approved by the FDA in October 2018.¹⁸ It is available in both intravenous injectable and oral forms. No dose adjustment is needed for renal function. Lefamulin is a first-in-class novel pleuromutilin antibiotic which was FDA-approved in August 2019. It can be administered intravenously or orally, with no dosage adjustment necessary in patients with renal impairment.¹⁹

Antibiotic Therapy for Selected Pathogens

Streptococcus pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin, but at a higher dose (4 million units intravenously [IV] every 4 hours), or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy.²⁰

Staphylococcus aureus

Staphylococcus aureus is more commonly associated with hospital-acquired pneumonia, but it may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect.²¹

Legionella

Legionellosis can be treated with tetra¬cyclines, macrolides, or fluoroquinolones. For non-immunocompromised patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days.²²

Chlamydophila pneumoniae

As with other atypical organisms, Chlamydophila pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; treating with doxycycline 100 mg twice daily generally requires 14 to 21 days, whereas moxifloxacin 400 mg daily requires 10 days.²³

Mycoplasma pneumoniae

As with C. pneumoniae, length of therapy of Mycoplasma pneumoniae varies by which antimicrobial regimen is used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone.²⁴ It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States.²⁵

Duration of Treatment

Most patients with CAP respond to appropriate therapy within 72 hours. IDSA/ATS guidelines recommend that patients with routine cases of CAP be treated for a minimum of 5 days. Despite this, many patients are treated for an excessive amount of time, with over 70% of patients reported to have received antibiotics for more than 10 days for uncomplicated CAP.²⁶ There are instances that require longer courses of antibiotics, including cases caused by Pseudomonas aeruginosa, S. aureus, and Legionella species and patients with lung abscesses or necrotizing infections, among others.²⁷

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 4), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met.⁶ C-reactive protein (CRP) level has been postulated as an additional measure of stability, specifically monitoring for a greater than 50% reduction in CRP; however, this was validated only for those with complicated pneumonia.²⁸ Patients discharged from the hospital with instability have higher risk of readmission or death.²⁹

Transition to Oral Therapy

IDSA/ATS guidelines⁶ recommend that patients should be transitioned from intravenous to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients.¹⁵ Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics or delay in achieving clinical stability, as defined in Table 4, after 72 hours of treatment.³⁰ Risk factors associated with nonresponding pneumonia³¹ are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status require prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, a question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic work-up and/or changing antibiotics. History should be reviewed, with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viruses account for up to 20% of pneumonias and that there are also noninfectious causes that can mimic pyogenic infections.³² If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics, as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with computed tomography (CT) scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions, or a pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and, when combined with biopsy, can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should try to determine the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment and recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics.²⁰

Other Treatment

Several agents have been evaluated as adjunctive treatment of pneumonia to decrease the inflammatory response associated with pneumonia; namely, steroids, macrolide antibiotics, and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) has been shown to decrease treatment failure, decrease risk of acute respiratory distress syndrome, and possibly reduce length of stay and duration of intravenous antibiotics, without effect on mortality or adverse side effects.^33,34 However, a recent double-blind randomized study conducted in Australia in which patients admitted with CAP were prescribed prednisolone acetate (50 mg/day for 7 days) and de-escalated from parenteral to oral antibiotics according to standardized criteria revealed no difference in mortality, length of stay, or readmission rates between the corticosteroids group and the control group at 90-day follow-up.³⁵ At this point, corticosteroid as an adjunctive treatment for CAP is still controversial and the new 2019 ATS/IDSA guidelines recommend not routinely using corticosteroids in all patients with CAP.³⁶ Other adjunctive methods have not been found to have significant impact.⁶

Prevention of Pneumonia

Prevention of pneumococcal pneumonia involves vaccinations to prevent infection caused by S. pneumoniae and influenza viruses. As influenza is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can help prevent bacterial pneumonia.³⁷ In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons older than age 6 months, unless otherwise contraindicated.³⁸

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes.³⁹ PPSV23 is reported to be protective against invasive pneumococcal infection, although there is no consensus regarding whether PPSV23 leads to decreased rates of pneumonia.⁴⁰ On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and CAP in adults aged 65 years or older.⁴¹ The CDC recommends that all children aged 2 years or younger receive PCV13, and those aged 65 or older receive PCV13 followed by a dose of PPSV23.^42,43 The dose of PPSV23 should be given at least 1 year after the dose of PCV13 is administered.⁴⁴ Persons younger than 65 years with immunocompromising and certain other conditions should also receive vaccination (Table 5).⁴⁴ Full recommendations, many scenarios, and details on timing of vaccinations can be found at the CDC’s website.

Cigarette smoking increases the risk of respiratory infections, as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease.¹¹ As this is a modifiable risk factor, smoking cessation should be part of a comprehensive approach toward prevention of pneumonia.

Summary

Most patients with CAP are treated empirically with antibiotics, with therapy selection based on the site of care, likely pathogen, and antimicrobial resistance issues. Those treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment usually receive empiric antibiotic on admission, and antimicrobial therapy is adjusted accordingly once the etiology has been determined by microbiologic or serologic means. At this time, the use of corticosteroid as an adjunctive treatment for CAP is still controversial, so not all patients with CAP should routinely receive corticosteroids. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians should strive for 100% vaccination rates in persons without contraindications.

Initial management decisions for patients with community-acquired pneumonia (CAP) will depend on severity of infection, with need for hospitalization being one of the first decisions. Because empiric antibiotics are the mainstay of treatment and the causative organisms are seldom identified, underlying medical conditions and epidemiologic risk factors are considered when selecting an empiric regimen. As with other infections, duration of therapy is not standardized, but rather is guided by clinical improvement. Prevention of pneumonia centers around vaccination and smoking cessation. This article, the second in a 2-part review of CAP in adults, focuses on site of care decision, empiric and directed therapies, length of treatment, and prevention strategies. Evaluation and diagnosis of CAP are discussed in a separate article.

Site of Care Decision

For patients diagnosed with CAP, the clinician must decide whether treatment will be done in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or in the intensive care unit (ICU). Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guide site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters, and radiographic findings, to stratify patients into 5 mortality risk classes.¹ On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients.¹

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure, and age ≥ 65 years (Table 1).^2,3 A modification to the CURB-65 algorithm tool was CRB-65, which excludes urea nitrogen, making it optimal for making determinations in a clinic-based setting. It should be emphasized that these tools do not take into account other factors that should be used in determining location of treatment, such as stable home, mental illness, or concerns about compliance with medications. In many instances, it is these factors that preclude low-risk patients from being treated as outpatients.^4,5 Similarly, these scoring systems have not been validated for immunocompromised patients or those who would qualify as having health care–associated pneumonia.

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia, and admission to the ICU should be considered for these patients. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU.⁶ American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths/minute, PaO₂ fraction ≤ 250 mm Hg, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia, and hypotension.⁶ These factors are associated with increased mortality due to CAP, and ICU admission is indicated if 3 of the minor criteria for severe CAP are present.

Another clinical calculator that can be used for assessing severity of CAP is SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation and arterial pH).⁷ This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and a specificity of 64% in predicting ICU admission, whereas CURB-65 has a pooled sensitivity of 57.2% and specificity of 77.2%.⁸

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. A CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and Streptococcus pneumoniae for only 5%.⁹ This study highlighted the fact that despite advances in molecular techniques, no pathogen is identified for most patients with pneumonia.⁹ Given the lack of discernable pathogens in the majority of cases, patients should continue to be treated with antibiotics unless a nonbacterial etiology is found.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 2)¹⁰ can be treated with monotherapy. Hospitalized patients are usually treated with combination intravenous therapy, although non-ICU patients who receive a respiratory fluoroquinolone can be treated orally.

As previously mentioned, antibiotic therapy is typically empiric, since neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, antimicrobial coverage should be expanded to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center.⁶

Staphylococcus aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents.¹¹ Daptomycin, another agent used against MRSA, is not indicated in the setting of pneumonia because daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia.¹² Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication.^13,14 Similarly, other agents known to have antibacterial properties against MRSA, such as trimethoprim/sulfamethoxazole and doxycycline, have not been studied for this indication. Clindamycin has been used to treat MRSA in children, and IDSA guidelines on the treatment of MRSA list clindamycin as an alternative¹⁵ if MRSA is known to be sensitive.

A summary of recommended empiric antibiotic therapy is presented in Table 3.¹⁶

Three antibiotics were approved by the US Food and Drug Administration (FDA) for the treatment of CAP after the release of the IDSA/ATS guidelines in 2007. Ceftaroline fosamil is a fifth-generation cephalosporin that has coverage for MRSA and was approved in November 2010.¹⁷ It can only be administered intravenously and needs dose adjustment for renal function. Omadacycline is a new tetracycline that was approved by the FDA in October 2018.¹⁸ It is available in both intravenous injectable and oral forms. No dose adjustment is needed for renal function. Lefamulin is a first-in-class novel pleuromutilin antibiotic which was FDA-approved in August 2019. It can be administered intravenously or orally, with no dosage adjustment necessary in patients with renal impairment.¹⁹

Antibiotic Therapy for Selected Pathogens

Streptococcus pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin, but at a higher dose (4 million units intravenously [IV] every 4 hours), or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy.²⁰

Staphylococcus aureus

Staphylococcus aureus is more commonly associated with hospital-acquired pneumonia, but it may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect.²¹

Legionella

Legionellosis can be treated with tetra¬cyclines, macrolides, or fluoroquinolones. For non-immunocompromised patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days.²²

Chlamydophila pneumoniae

As with other atypical organisms, Chlamydophila pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; treating with doxycycline 100 mg twice daily generally requires 14 to 21 days, whereas moxifloxacin 400 mg daily requires 10 days.²³

Mycoplasma pneumoniae

As with C. pneumoniae, length of therapy of Mycoplasma pneumoniae varies by which antimicrobial regimen is used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone.²⁴ It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States.²⁵

Duration of Treatment

Most patients with CAP respond to appropriate therapy within 72 hours. IDSA/ATS guidelines recommend that patients with routine cases of CAP be treated for a minimum of 5 days. Despite this, many patients are treated for an excessive amount of time, with over 70% of patients reported to have received antibiotics for more than 10 days for uncomplicated CAP.²⁶ There are instances that require longer courses of antibiotics, including cases caused by Pseudomonas aeruginosa, S. aureus, and Legionella species and patients with lung abscesses or necrotizing infections, among others.²⁷

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 4), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met.⁶ C-reactive protein (CRP) level has been postulated as an additional measure of stability, specifically monitoring for a greater than 50% reduction in CRP; however, this was validated only for those with complicated pneumonia.²⁸ Patients discharged from the hospital with instability have higher risk of readmission or death.²⁹

Transition to Oral Therapy

IDSA/ATS guidelines⁶ recommend that patients should be transitioned from intravenous to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients.¹⁵ Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics or delay in achieving clinical stability, as defined in Table 4, after 72 hours of treatment.³⁰ Risk factors associated with nonresponding pneumonia³¹ are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status require prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, a question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic work-up and/or changing antibiotics. History should be reviewed, with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viruses account for up to 20% of pneumonias and that there are also noninfectious causes that can mimic pyogenic infections.³² If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics, as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with computed tomography (CT) scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions, or a pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and, when combined with biopsy, can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should try to determine the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment and recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics.²⁰

Other Treatment

Several agents have been evaluated as adjunctive treatment of pneumonia to decrease the inflammatory response associated with pneumonia; namely, steroids, macrolide antibiotics, and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) has been shown to decrease treatment failure, decrease risk of acute respiratory distress syndrome, and possibly reduce length of stay and duration of intravenous antibiotics, without effect on mortality or adverse side effects.^33,34 However, a recent double-blind randomized study conducted in Australia in which patients admitted with CAP were prescribed prednisolone acetate (50 mg/day for 7 days) and de-escalated from parenteral to oral antibiotics according to standardized criteria revealed no difference in mortality, length of stay, or readmission rates between the corticosteroids group and the control group at 90-day follow-up.³⁵ At this point, corticosteroid as an adjunctive treatment for CAP is still controversial and the new 2019 ATS/IDSA guidelines recommend not routinely using corticosteroids in all patients with CAP.³⁶ Other adjunctive methods have not been found to have significant impact.⁶

Prevention of Pneumonia

Prevention of pneumococcal pneumonia involves vaccinations to prevent infection caused by S. pneumoniae and influenza viruses. As influenza is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can help prevent bacterial pneumonia.³⁷ In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons older than age 6 months, unless otherwise contraindicated.³⁸

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes.³⁹ PPSV23 is reported to be protective against invasive pneumococcal infection, although there is no consensus regarding whether PPSV23 leads to decreased rates of pneumonia.⁴⁰ On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and CAP in adults aged 65 years or older.⁴¹ The CDC recommends that all children aged 2 years or younger receive PCV13, and those aged 65 or older receive PCV13 followed by a dose of PPSV23.^42,43 The dose of PPSV23 should be given at least 1 year after the dose of PCV13 is administered.⁴⁴ Persons younger than 65 years with immunocompromising and certain other conditions should also receive vaccination (Table 5).⁴⁴ Full recommendations, many scenarios, and details on timing of vaccinations can be found at the CDC’s website.

Cigarette smoking increases the risk of respiratory infections, as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease.¹¹ As this is a modifiable risk factor, smoking cessation should be part of a comprehensive approach toward prevention of pneumonia.

Summary

Most patients with CAP are treated empirically with antibiotics, with therapy selection based on the site of care, likely pathogen, and antimicrobial resistance issues. Those treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment usually receive empiric antibiotic on admission, and antimicrobial therapy is adjusted accordingly once the etiology has been determined by microbiologic or serologic means. At this time, the use of corticosteroid as an adjunctive treatment for CAP is still controversial, so not all patients with CAP should routinely receive corticosteroids. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians should strive for 100% vaccination rates in persons without contraindications.

Initial management decisions for patients with community-acquired pneumonia (CAP) will depend on severity of infection, with need for hospitalization being one of the first decisions. Because empiric antibiotics are the mainstay of treatment and the causative organisms are seldom identified, underlying medical conditions and epidemiologic risk factors are considered when selecting an empiric regimen. As with other infections, duration of therapy is not standardized, but rather is guided by clinical improvement. Prevention of pneumonia centers around vaccination and smoking cessation. This article, the second in a 2-part review of CAP in adults, focuses on site of care decision, empiric and directed therapies, length of treatment, and prevention strategies. Evaluation and diagnosis of CAP are discussed in a separate article.

Site of Care Decision

For patients diagnosed with CAP, the clinician must decide whether treatment will be done in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or in the intensive care unit (ICU). Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guide site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters, and radiographic findings, to stratify patients into 5 mortality risk classes.¹ On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients.¹

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure, and age ≥ 65 years (Table 1).^2,3 A modification to the CURB-65 algorithm tool was CRB-65, which excludes urea nitrogen, making it optimal for making determinations in a clinic-based setting. It should be emphasized that these tools do not take into account other factors that should be used in determining location of treatment, such as stable home, mental illness, or concerns about compliance with medications. In many instances, it is these factors that preclude low-risk patients from being treated as outpatients.^4,5 Similarly, these scoring systems have not been validated for immunocompromised patients or those who would qualify as having health care–associated pneumonia.

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia, and admission to the ICU should be considered for these patients. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU.⁶ American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths/minute, PaO₂ fraction ≤ 250 mm Hg, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia, and hypotension.⁶ These factors are associated with increased mortality due to CAP, and ICU admission is indicated if 3 of the minor criteria for severe CAP are present.

Another clinical calculator that can be used for assessing severity of CAP is SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation and arterial pH).⁷ This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and a specificity of 64% in predicting ICU admission, whereas CURB-65 has a pooled sensitivity of 57.2% and specificity of 77.2%.⁸

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. A CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and Streptococcus pneumoniae for only 5%.⁹ This study highlighted the fact that despite advances in molecular techniques, no pathogen is identified for most patients with pneumonia.⁹ Given the lack of discernable pathogens in the majority of cases, patients should continue to be treated with antibiotics unless a nonbacterial etiology is found.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 2)¹⁰ can be treated with monotherapy. Hospitalized patients are usually treated with combination intravenous therapy, although non-ICU patients who receive a respiratory fluoroquinolone can be treated orally.

As previously mentioned, antibiotic therapy is typically empiric, since neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, antimicrobial coverage should be expanded to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center.⁶

Staphylococcus aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents.¹¹ Daptomycin, another agent used against MRSA, is not indicated in the setting of pneumonia because daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia.¹² Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication.^13,14 Similarly, other agents known to have antibacterial properties against MRSA, such as trimethoprim/sulfamethoxazole and doxycycline, have not been studied for this indication. Clindamycin has been used to treat MRSA in children, and IDSA guidelines on the treatment of MRSA list clindamycin as an alternative¹⁵ if MRSA is known to be sensitive.

A summary of recommended empiric antibiotic therapy is presented in Table 3.¹⁶

Three antibiotics were approved by the US Food and Drug Administration (FDA) for the treatment of CAP after the release of the IDSA/ATS guidelines in 2007. Ceftaroline fosamil is a fifth-generation cephalosporin that has coverage for MRSA and was approved in November 2010.¹⁷ It can only be administered intravenously and needs dose adjustment for renal function. Omadacycline is a new tetracycline that was approved by the FDA in October 2018.¹⁸ It is available in both intravenous injectable and oral forms. No dose adjustment is needed for renal function. Lefamulin is a first-in-class novel pleuromutilin antibiotic which was FDA-approved in August 2019. It can be administered intravenously or orally, with no dosage adjustment necessary in patients with renal impairment.¹⁹

Antibiotic Therapy for Selected Pathogens

Streptococcus pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin, but at a higher dose (4 million units intravenously [IV] every 4 hours), or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy.²⁰

Staphylococcus aureus

Staphylococcus aureus is more commonly associated with hospital-acquired pneumonia, but it may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect.²¹

Legionella

Legionellosis can be treated with tetra¬cyclines, macrolides, or fluoroquinolones. For non-immunocompromised patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days.²²

Chlamydophila pneumoniae

As with other atypical organisms, Chlamydophila pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; treating with doxycycline 100 mg twice daily generally requires 14 to 21 days, whereas moxifloxacin 400 mg daily requires 10 days.²³

Mycoplasma pneumoniae

As with C. pneumoniae, length of therapy of Mycoplasma pneumoniae varies by which antimicrobial regimen is used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone.²⁴ It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States.²⁵

Duration of Treatment

Most patients with CAP respond to appropriate therapy within 72 hours. IDSA/ATS guidelines recommend that patients with routine cases of CAP be treated for a minimum of 5 days. Despite this, many patients are treated for an excessive amount of time, with over 70% of patients reported to have received antibiotics for more than 10 days for uncomplicated CAP.²⁶ There are instances that require longer courses of antibiotics, including cases caused by Pseudomonas aeruginosa, S. aureus, and Legionella species and patients with lung abscesses or necrotizing infections, among others.²⁷

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 4), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met.⁶ C-reactive protein (CRP) level has been postulated as an additional measure of stability, specifically monitoring for a greater than 50% reduction in CRP; however, this was validated only for those with complicated pneumonia.²⁸ Patients discharged from the hospital with instability have higher risk of readmission or death.²⁹

Transition to Oral Therapy

IDSA/ATS guidelines⁶ recommend that patients should be transitioned from intravenous to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients.¹⁵ Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics or delay in achieving clinical stability, as defined in Table 4, after 72 hours of treatment.³⁰ Risk factors associated with nonresponding pneumonia³¹ are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status require prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, a question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic work-up and/or changing antibiotics. History should be reviewed, with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viruses account for up to 20% of pneumonias and that there are also noninfectious causes that can mimic pyogenic infections.³² If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics, as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with computed tomography (CT) scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions, or a pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and, when combined with biopsy, can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should try to determine the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment and recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics.²⁰

Other Treatment

Several agents have been evaluated as adjunctive treatment of pneumonia to decrease the inflammatory response associated with pneumonia; namely, steroids, macrolide antibiotics, and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) has been shown to decrease treatment failure, decrease risk of acute respiratory distress syndrome, and possibly reduce length of stay and duration of intravenous antibiotics, without effect on mortality or adverse side effects.^33,34 However, a recent double-blind randomized study conducted in Australia in which patients admitted with CAP were prescribed prednisolone acetate (50 mg/day for 7 days) and de-escalated from parenteral to oral antibiotics according to standardized criteria revealed no difference in mortality, length of stay, or readmission rates between the corticosteroids group and the control group at 90-day follow-up.³⁵ At this point, corticosteroid as an adjunctive treatment for CAP is still controversial and the new 2019 ATS/IDSA guidelines recommend not routinely using corticosteroids in all patients with CAP.³⁶ Other adjunctive methods have not been found to have significant impact.⁶

Prevention of Pneumonia

Prevention of pneumococcal pneumonia involves vaccinations to prevent infection caused by S. pneumoniae and influenza viruses. As influenza is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can help prevent bacterial pneumonia.³⁷ In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons older than age 6 months, unless otherwise contraindicated.³⁸

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes.³⁹ PPSV23 is reported to be protective against invasive pneumococcal infection, although there is no consensus regarding whether PPSV23 leads to decreased rates of pneumonia.⁴⁰ On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and CAP in adults aged 65 years or older.⁴¹ The CDC recommends that all children aged 2 years or younger receive PCV13, and those aged 65 or older receive PCV13 followed by a dose of PPSV23.^42,43 The dose of PPSV23 should be given at least 1 year after the dose of PCV13 is administered.⁴⁴ Persons younger than 65 years with immunocompromising and certain other conditions should also receive vaccination (Table 5).⁴⁴ Full recommendations, many scenarios, and details on timing of vaccinations can be found at the CDC’s website.

Cigarette smoking increases the risk of respiratory infections, as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease.¹¹ As this is a modifiable risk factor, smoking cessation should be part of a comprehensive approach toward prevention of pneumonia.

Summary

Most patients with CAP are treated empirically with antibiotics, with therapy selection based on the site of care, likely pathogen, and antimicrobial resistance issues. Those treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment usually receive empiric antibiotic on admission, and antimicrobial therapy is adjusted accordingly once the etiology has been determined by microbiologic or serologic means. At this time, the use of corticosteroid as an adjunctive treatment for CAP is still controversial, so not all patients with CAP should routinely receive corticosteroids. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians should strive for 100% vaccination rates in persons without contraindications.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2017, 49,157 patients in the United States died from the disease.¹ Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens.² This review is the first of 2 articles focusing on the management of community-acquired pneumonia (CAP). Here, we review CAP epidemiology, microbiology, predisposing factors, and diagnosis; current treatment and prevention of CAP are reviewed in a separate article.

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system.³ A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually.⁴ About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU).⁵ In-hospital mortality is considerable (~10% in population-based studies),⁶ and 30-day mortality was found to be as high as 23% in a review by File and Marrie.⁷ CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age.⁸

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. Until recently, many studies had demonstrated that pneumococcus was the most common cause of CAP. However, in the CDC Etiology of Pneumonia in the Community (EPIC) study team’s 2015 prospective, multicenter, population-based study, no pathogen was detected in the majority of patients diagnosed with CAP requiring hospitalization. The most common pathogens they detected were rhinovirus (9%), followed by influenza virus (6%) and pneumococcus (5%).⁹ Factors considered to be contributing to the decrease in the percentage of pneumococcus in patients diagnosed with CAP are the widespread use of pneumococcal vaccine and reduced rates of smoking.^10,11

Predisposing Factors

Most people diagnosed with CAP have 1 or more predisposing factors (Table 2).^12,13 Patients who develop CAP typically have a combination of these predisposing factors rather than a single factor. Aging, in combination with other risk factors, increases the susceptibility of a person to pneumonia.

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, patients presenting with the constellation of symptoms of fever ≥ 100°F (37.8°C), productive cough, and tachycardia is more suggestive of pneumonia.¹⁴ Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon to avoid delayed diagnosis and treatment.¹⁵

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected.¹⁶ However, there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes.¹⁷

There are case reports and case series demonstrating false-negative plain chest radiographs in dehydrated patients¹⁸ or in patients in a neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status.¹⁹ There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs.²⁰

A chest computed tomography (CT) scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected.²¹ A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease, and empyema. It also has the advantage of better defining anatomical changes than plain films.²²

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Clearing of pulmonary infiltrate or consolidation sometimes can take 6 weeks or longer.²³

Laboratory Evaluation

Generally, the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, determining the etiologic agent of the pneumonia allows the clinician to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus).²⁴

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, Streptococcus pneumoniae and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain more than 25 neutrophils and less than 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture. The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively.²⁴ In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time.²⁵

For patients who cannot provide sputum samples or are intubated, deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure may be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain, if deemed clinically necessary.

The 2019 ATS/IDSA guidelines for diagnosis and treatment of adults with CAP recommend sputum culture in patients with severe disease and in all inpatients empirically treated for MRSA or Pseudomonas aeruginosa.²⁶

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is low (5%–14%), blood cultures are not recommended for all patients with CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases.²⁷ However, the 2019 ATS/IDSA guidelines recommend blood culture in patients with severe disease and in all inpatients treated empirically for MRSA or P. aeruginosa.²⁶

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP.²⁸ Analysis of the data demonstrated no association between pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality, or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 US Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires’ disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%).^29,30

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory. A multicenter, prospective surveillance study of hospitalized patients with CAP showed that the 2007 IDSA/ATS guidelines’ recommended indications for S. pneumoniae and L. pneumophila urinary antigen tests do not have sufficient sensitivity and specificity to identify patients with positive tests.³¹

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR testing of nasopharyngeal swabs for diagnosis of influenza has become standard in many US medical facilities. The great advantages of using PCR to diagnose influenza are its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia, and mycobacterial species.²⁴

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora.³²

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests, and imaging studies to assist in the diagnosis and treatment of CAP.²⁴ Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream, resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable procalcitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany) is the preferred test to use because of its high sensitivity.³³ A meta-analysis of 12 studies involving more than 2400 patients with CAP demonstrated that serum procalcitonin does not have sufficient sensitivity or specificity to distinguish between bacterial and nonbacterial pneumonia. The authors concluded that procalcitonin level cannot be used to decide whether an antibiotic should be administered.³⁴

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization.³⁵ An update of the 2012 Cochrane review that examined the safety and efficacy of using procalcitonin for starting or stopping antibiotics again demonstrated procalcitonin use was associated with a reduction of antibiotic use (2.4 days).³⁶ A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP, whereas decreasing procalcitonin levels is associated with a favorable outcome.³⁷

Because of conflicting data, the 2019 ATS/IDSA guidelines do not recommend using procalcitonin to determine need for initial antibacterial therapy.²⁶

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients who presented with cough showed that a CRP level > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively.³⁸

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that S. pneumoniae was detected in only 5% of patients diagnosed with CAP. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, because no single test is sensitive and specific enough to be a stand-alone test, they should be used in conjunction with history, physical examination, and imaging studies.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2017, 49,157 patients in the United States died from the disease.¹ Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens.² This review is the first of 2 articles focusing on the management of community-acquired pneumonia (CAP). Here, we review CAP epidemiology, microbiology, predisposing factors, and diagnosis; current treatment and prevention of CAP are reviewed in a separate article.

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system.³ A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually.⁴ About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU).⁵ In-hospital mortality is considerable (~10% in population-based studies),⁶ and 30-day mortality was found to be as high as 23% in a review by File and Marrie.⁷ CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age.⁸

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. Until recently, many studies had demonstrated that pneumococcus was the most common cause of CAP. However, in the CDC Etiology of Pneumonia in the Community (EPIC) study team’s 2015 prospective, multicenter, population-based study, no pathogen was detected in the majority of patients diagnosed with CAP requiring hospitalization. The most common pathogens they detected were rhinovirus (9%), followed by influenza virus (6%) and pneumococcus (5%).⁹ Factors considered to be contributing to the decrease in the percentage of pneumococcus in patients diagnosed with CAP are the widespread use of pneumococcal vaccine and reduced rates of smoking.^10,11

Predisposing Factors

Most people diagnosed with CAP have 1 or more predisposing factors (Table 2).^12,13 Patients who develop CAP typically have a combination of these predisposing factors rather than a single factor. Aging, in combination with other risk factors, increases the susceptibility of a person to pneumonia.

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, patients presenting with the constellation of symptoms of fever ≥ 100°F (37.8°C), productive cough, and tachycardia is more suggestive of pneumonia.¹⁴ Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon to avoid delayed diagnosis and treatment.¹⁵

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected.¹⁶ However, there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes.¹⁷

There are case reports and case series demonstrating false-negative plain chest radiographs in dehydrated patients¹⁸ or in patients in a neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status.¹⁹ There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs.²⁰

A chest computed tomography (CT) scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected.²¹ A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease, and empyema. It also has the advantage of better defining anatomical changes than plain films.²²

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Clearing of pulmonary infiltrate or consolidation sometimes can take 6 weeks or longer.²³

Laboratory Evaluation

Generally, the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, determining the etiologic agent of the pneumonia allows the clinician to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus).²⁴

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, Streptococcus pneumoniae and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain more than 25 neutrophils and less than 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture. The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively.²⁴ In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time.²⁵

For patients who cannot provide sputum samples or are intubated, deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure may be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain, if deemed clinically necessary.

The 2019 ATS/IDSA guidelines for diagnosis and treatment of adults with CAP recommend sputum culture in patients with severe disease and in all inpatients empirically treated for MRSA or Pseudomonas aeruginosa.²⁶

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is low (5%–14%), blood cultures are not recommended for all patients with CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases.²⁷ However, the 2019 ATS/IDSA guidelines recommend blood culture in patients with severe disease and in all inpatients treated empirically for MRSA or P. aeruginosa.²⁶

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP.²⁸ Analysis of the data demonstrated no association between pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality, or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 US Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires’ disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%).^29,30

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory. A multicenter, prospective surveillance study of hospitalized patients with CAP showed that the 2007 IDSA/ATS guidelines’ recommended indications for S. pneumoniae and L. pneumophila urinary antigen tests do not have sufficient sensitivity and specificity to identify patients with positive tests.³¹

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR testing of nasopharyngeal swabs for diagnosis of influenza has become standard in many US medical facilities. The great advantages of using PCR to diagnose influenza are its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia, and mycobacterial species.²⁴

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora.³²

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests, and imaging studies to assist in the diagnosis and treatment of CAP.²⁴ Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream, resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable procalcitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany) is the preferred test to use because of its high sensitivity.³³ A meta-analysis of 12 studies involving more than 2400 patients with CAP demonstrated that serum procalcitonin does not have sufficient sensitivity or specificity to distinguish between bacterial and nonbacterial pneumonia. The authors concluded that procalcitonin level cannot be used to decide whether an antibiotic should be administered.³⁴

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization.³⁵ An update of the 2012 Cochrane review that examined the safety and efficacy of using procalcitonin for starting or stopping antibiotics again demonstrated procalcitonin use was associated with a reduction of antibiotic use (2.4 days).³⁶ A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP, whereas decreasing procalcitonin levels is associated with a favorable outcome.³⁷

Because of conflicting data, the 2019 ATS/IDSA guidelines do not recommend using procalcitonin to determine need for initial antibacterial therapy.²⁶

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients who presented with cough showed that a CRP level > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively.³⁸

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that S. pneumoniae was detected in only 5% of patients diagnosed with CAP. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, because no single test is sensitive and specific enough to be a stand-alone test, they should be used in conjunction with history, physical examination, and imaging studies.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2017, 49,157 patients in the United States died from the disease.¹ Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens.² This review is the first of 2 articles focusing on the management of community-acquired pneumonia (CAP). Here, we review CAP epidemiology, microbiology, predisposing factors, and diagnosis; current treatment and prevention of CAP are reviewed in a separate article.

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system.³ A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually.⁴ About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU).⁵ In-hospital mortality is considerable (~10% in population-based studies),⁶ and 30-day mortality was found to be as high as 23% in a review by File and Marrie.⁷ CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age.⁸

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. Until recently, many studies had demonstrated that pneumococcus was the most common cause of CAP. However, in the CDC Etiology of Pneumonia in the Community (EPIC) study team’s 2015 prospective, multicenter, population-based study, no pathogen was detected in the majority of patients diagnosed with CAP requiring hospitalization. The most common pathogens they detected were rhinovirus (9%), followed by influenza virus (6%) and pneumococcus (5%).⁹ Factors considered to be contributing to the decrease in the percentage of pneumococcus in patients diagnosed with CAP are the widespread use of pneumococcal vaccine and reduced rates of smoking.^10,11

Predisposing Factors

Most people diagnosed with CAP have 1 or more predisposing factors (Table 2).^12,13 Patients who develop CAP typically have a combination of these predisposing factors rather than a single factor. Aging, in combination with other risk factors, increases the susceptibility of a person to pneumonia.

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, patients presenting with the constellation of symptoms of fever ≥ 100°F (37.8°C), productive cough, and tachycardia is more suggestive of pneumonia.¹⁴ Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon to avoid delayed diagnosis and treatment.¹⁵

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected.¹⁶ However, there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes.¹⁷

There are case reports and case series demonstrating false-negative plain chest radiographs in dehydrated patients¹⁸ or in patients in a neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status.¹⁹ There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs.²⁰

A chest computed tomography (CT) scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected.²¹ A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease, and empyema. It also has the advantage of better defining anatomical changes than plain films.²²

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Clearing of pulmonary infiltrate or consolidation sometimes can take 6 weeks or longer.²³

Laboratory Evaluation

Generally, the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, determining the etiologic agent of the pneumonia allows the clinician to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus).²⁴

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, Streptococcus pneumoniae and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain more than 25 neutrophils and less than 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture. The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively.²⁴ In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time.²⁵

For patients who cannot provide sputum samples or are intubated, deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure may be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain, if deemed clinically necessary.

The 2019 ATS/IDSA guidelines for diagnosis and treatment of adults with CAP recommend sputum culture in patients with severe disease and in all inpatients empirically treated for MRSA or Pseudomonas aeruginosa.²⁶

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is low (5%–14%), blood cultures are not recommended for all patients with CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases.²⁷ However, the 2019 ATS/IDSA guidelines recommend blood culture in patients with severe disease and in all inpatients treated empirically for MRSA or P. aeruginosa.²⁶

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP.²⁸ Analysis of the data demonstrated no association between pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality, or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 US Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires’ disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%).^29,30

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory. A multicenter, prospective surveillance study of hospitalized patients with CAP showed that the 2007 IDSA/ATS guidelines’ recommended indications for S. pneumoniae and L. pneumophila urinary antigen tests do not have sufficient sensitivity and specificity to identify patients with positive tests.³¹

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR testing of nasopharyngeal swabs for diagnosis of influenza has become standard in many US medical facilities. The great advantages of using PCR to diagnose influenza are its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia, and mycobacterial species.²⁴

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora.³²

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests, and imaging studies to assist in the diagnosis and treatment of CAP.²⁴ Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream, resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable procalcitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany) is the preferred test to use because of its high sensitivity.³³ A meta-analysis of 12 studies involving more than 2400 patients with CAP demonstrated that serum procalcitonin does not have sufficient sensitivity or specificity to distinguish between bacterial and nonbacterial pneumonia. The authors concluded that procalcitonin level cannot be used to decide whether an antibiotic should be administered.³⁴

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization.³⁵ An update of the 2012 Cochrane review that examined the safety and efficacy of using procalcitonin for starting or stopping antibiotics again demonstrated procalcitonin use was associated with a reduction of antibiotic use (2.4 days).³⁶ A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP, whereas decreasing procalcitonin levels is associated with a favorable outcome.³⁷

Because of conflicting data, the 2019 ATS/IDSA guidelines do not recommend using procalcitonin to determine need for initial antibacterial therapy.²⁶

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients who presented with cough showed that a CRP level > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively.³⁸

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that S. pneumoniae was detected in only 5% of patients diagnosed with CAP. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, because no single test is sensitive and specific enough to be a stand-alone test, they should be used in conjunction with history, physical examination, and imaging studies.

Malignant pleural effusion (MPE) is a common clinical problem in patients with advanced stage cancer. Each year in the United States, more than 150,000 individuals are diagnosed with MPE, and there are approximately 126,000 admissions for MPE.^1-3 Providing effective therapeutic management remains a challenge, and currently available therapeutic interventions are palliative rather than curative. This article, the second in a 2-part review of MPE, focuses on the available management options.

Therapeutic Thoracentesis

Evaluation of pleural fluid cytology is a crucial step in the diagnosis and staging of disease. As a result, large-volume fluid removal is often the first therapeutic intervention for patients who present with symptomatic effusions. A patient’s clinical response to therapeutic thoracentesis dictates which additional therapeutic options are appropriate for palliation. Lack of symptom relief suggests that other comorbid conditions or trapped lung physiology may be the primary cause of the patient’s symptoms and discourages more invasive interventions. Radiographic evidence of lung re-expansion after fluid removal is also an important predictor of success for potential pleurodesis.^4,5

There are no absolute contraindications to thoracentesis. However, caution should be used for patients with risk factors that may predispose to complications of pneumothorax and bleeding, such as coagulopathy, treatment with anticoagulation medications, thrombocytopenia, platelet dysfunction (eg, antiplatelet medications, uremia), positive pressure ventilation, and small effusion size. These factors are only relative contraindications, however, as thoracentesis can still be safely performed by experienced operators using guidance technology such as ultrasonography.

A retrospective review of 1009 ultrasound-guided thoracenteses with risk factors of an international normalized ratio (INR) greater than 1.6, platelet values less than 50,000/μL, or both, reported an overall rate of hemorrhagic complication of 0.4%, with no difference between procedures performed with (n = 303) or without (n = 706) transfusion correction of coagulopathy or thrombocytopenia.⁶ A similar retrospective evaluation of 1076 ultrasound-guided thoracenteses, including 267 patients with an INR greater than 1.5 and 58 patients with a platelet count less than 50,000/μL, reported a 0% complication rate.⁷ Small case series have also demonstrated low hemorrhagic complication rates for thoracentesis in patients treated with clopidogrel^8,9 and with increased bleeding risk from elevated INR (liver disease or warfarin therapy) and renal disease.¹⁰

Complications from pneumothorax can similarly be affected by patient- and operator-dependent risk factors. Meta-analysis of 24 studies including 6605 thoracenteses demonstrated an overall pneumothorax rate of 6.0%, with 34.1% requiring chest tube insertion.¹¹ Lower pneumothorax rates were associated with the use of ultrasound guidance (odds ratio, 0.3; 95% confidence interval, 0.2-0.7). Experienced operators also had fewer pneumothorax complications, though this factor was not significant in the studies directly comparing this variable. Therapeutic thoracentesis and use of a larger-bore needle were also significantly correlated with pneumothorax, while mechanical ventilation had a nonsignificant trend towards increased risk.

Although there is no consensus on the volume of pleural fluid that may be safely removed, it is recommended not to remove more than 1.5 L during a procedure in order to avoid precipitating re-expansion pulmonary edema.^2,12 However, re-expansion pulmonary edema rates remain low even when larger volumes are removed if the patient remains symptom-free during the procedure and pleural manometry pressure does not exceed –20 cm H₂O.¹³ Patient symptoms alone, however, are neither a sensitive nor specific indicator that pleural pressures exceed –20 cm H₂O.¹⁴ Use of excessive negative pressure during drainage, such as from a vacuum bottle, should also be avoided. Comparison of suction generated manually with a syringe versus a vacuum bottle suggests decreased complications with manual drainage, though the sample size in the supporting study was small relative to the infrequency of the complications being evaluated.¹⁵

Given the low morbidity and noninvasive nature of the procedure, serial large-volume thoracentesis remains a viable therapeutic intervention for patients who are unable or unwilling to undergo more invasive interventions, especially for patients with a slow fluid re-accumulation rate or who are anticipated to have limited survival. Unfortunately, many symptomatic effusions will recur within a short interval time span, which necessitates repeat procedures.^16,17 Therefore, factors such as poor symptom control, patient inconvenience, recurrent procedural risk, and utilization of medical resources need to be considered as well.

Tunneled pleural catheters (TPCs) are a potentially permanent and minimally invasive therapy which allow intermittent drainage of pleural fluid (Figure 1). The catheter is tunneled under the skin to prevent infection. A polyester cuff attached to the catheter is positioned within the tunnel and induces fibrosis around the catheter, thereby securing the catheter in place. Placement can be performed under local anesthesia at the patient’s bedside or in an outpatient procedure space. Fluid can then be drained via specialized drainage bottles or bags by the patient, a family member, or visiting home nurse. The catheter can also be removed in the event of a complication or the development of spontaneous pleurodesis.

TPCs are an effective palliative management strategy for patients with recurrent effusions and are an efficacious alternative to pleurodesis.^18-20 TPCs may be used in patients with poor prognosis or trapped lung or in those in whom prior pleurodesis has failed.^21-23 Meta-analysis of 19 studies showed symptomatic improvement in 95.6% of patients, with development of spontaneous pleurodesis in 45.6% of patients (range, 11.8% to 76.4%) after an average of 52 days.²⁴ However, most of the studies included in this analysis were retrospective case series. Development of spontaneous pleurodesis from TPC drainage in prospective, controlled trials has been considerably more modest, supporting a range of approximately 20% to 30% with routine drainage strategies.^20,25-27 Spontaneous pleurodesis develops greater rapidity and frequency in patients undergoing daily drainage compared to every-other-day or symptom-directed drainage strategies.^25,26 However, there is no appreciable improvement in quality of life scores with a specific drainage strategy. Small case series also demonstrate that TPC drainage may induce spontaneous pleurodesis in some patients initially presenting with trapped lung physiology.²²

Catheter placement can be performed successfully in the vast majority of patients.²⁸ Increased bleeding risk, significant malignancy-related involvement of the skin and chest wall, and pleural loculations can complicate TPC placement. TPC-related complications are relatively uncommon, but include pneumothorax, catheter malfunction and obstruction, and infections including soft tissue and pleural space infections.²⁴ In a multicenter retrospective series of 1021 patients, only 4.9% developed a TPC-related pleural infection.²⁹ Over 94% were successfully managed with antibiotic therapy, and the TPC was able to be preserved in 54%. Staphylococcus aureus was the most common causative organism and was identified in 48% of cases. Of note, spontaneous pleurodesis occurred in 62% of cases following a pleural space infection, which likely occurred as sequelae of the inflammatory nature of the infection. Retrospective analysis suggests that the risk of TPC-related infections is not substantially higher for patients with higher risks of immunosuppression from chemotherapy or hematologic malignancies.^30,31 Tumor metastasis along the catheter tract is a rare occurrence (< 1%), but is most notable with mesothelioma, which has an incidence as high as 10%.^24,32 In addition, development of pleural loculations can impede fluid drainage and relief of dyspnea. Intrapleural instillation of fibrinolytics can be used to improve drainage and improve symptom palliation.³³

Pleurodesis

Pleurodesis obliterates the potential pleural space by inducing inflammation and fibrosis, resulting in adherence of the visceral and parietal pleura together. This process can be induced through mechanical abrasion of the pleural surface, introduction of chemical sclerosants, or from prolonged use of a chest tube. Chemical sclerosants are the most commonly used method for MPEs and are introduced through a chest tube or under visual guidance such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS). The pleurodesis process is thought to occur by induction of a systemic inflammatory response with localized deposition of fibrin.³⁴ Activation of fibroblasts and successful pleurodesis have been correlated with higher basic fibroblast growth factor (bFGF) levels in pleural fluid.³⁵ Increased tumor burden is associated with lower bFGF levels, suggesting a possible mechanism for reduced pleurodesis success in these cases. Corticosteroids may reduce the likelihood of pleurodesis due to a reduction of inflammation, as demonstrated in a rabbit model using talc and doxycycline.^36,37 Animal data also suggests that use of nonsteroidal anti-inflammatory drugs may hinder the likelihood of successful pleurodesis, but this has not been observed in humans.^38,39

Patients selected for pleurodesis should have significant symptom relief from large-volume removal of pleural fluid, good functional status, and evidence of full lung re-expansion after thoracentesis. Lack of visceral and parietal pleural apposition will prevent pleural adhesion from developing. As a result, trapped lung is associated with chemical pleurodesis failure and is an absolute contraindication to the procedure.^4,5,12 The pleurodesis process typically requires 5 to 7 days, during which time the patient is hospitalized for chest tube drainage and pain control. When pleural fluid output diminishes, the chest tube is removed and the patient can be discharged. Modified protocols are now emerging which may shorten the required hospitalization associated with pleurodesis procedures.

A variety of chemical sclerosants have been used for pleurodesis, including talc, bleomycin, tetracycline, doxycycline, iodopovidone, and mepacrine. Published data regarding these agents are heterogenous, with significant variability in reported outcomes. However, systematic review and meta-analysis suggests that talc is likely to have higher success rates compared to other agents or chest tube drainage alone for treatment of MPE.^40,41

Additional factors have been shown to be associated with pleurodesis outcomes. Pleurodesis success is negatively associated with low pleural pH, with receiver operating curve thresholds of 7.28 to 7.34.^42,43 Trapped lung, large bulky tumor lining the pleural surfaces, and elevated adenosine deaminase levels are also associated with poor pleurodesis outcomes.^4,5,12,35,43 In contrast, pleural fluid output less than 200 mL per day and the presence of EGFR (epidermal growth factor receptor) mutation treated with targeted tyrosine kinase inhibitors are associated with successful pleurodesis.^44,45

The most common complications associated with chemical pleurodesis are fever and pain. Other potential complications include soft tissue infections at the chest tube site and of the pleural space, arrhythmias, cardiac arrest, myocardial infarction, and hypotension. Doxycycline is commonly associated with greater pleuritic pain than talc. Acute respiratory distress syndrome (ARDS), acute pneumonitis, and respiratory failure have been described with talc pleurodesis. ARDS secondary to talc pleurodesis occurs in 1% to 9% of cases, though this may be related to the use of ungraded talc. A prospective description of 558 patients treated with large particle talc (> 5 μm) reported no occurrences of ARDS, suggesting the safety of graded large particle talc.⁴⁶

Pleurodesis Methods

Chest tube thoracostomy is an inpatient procedure performed under local anesthesia or conscious sedation. It can be used for measured, intermittent drainage of large effusions for immediate symptom relief, as well as to demonstrate complete lung re-expansion prior to instillation of a chemical sclerosant. Pleurodesis using a chest tube is performed by instillation of a slurry created by mixing the sclerosing agent of choice with 50 to 100 mL of sterile saline. This slurry is instilled into the pleural cavity through the chest tube. The chest tube is clamped for 1 to 2 hours before being reconnected to suction. Intermittent rotation of the patient has not been shown to improve distribution of the sclerosant or result in better procedural outcomes.^47,48 Typically, a 24F to 32F chest tube is used because of the concern about obstruction of smaller bore tubes by fibrin plugs. A noninferiority study comparing 12F to 24F chest tubes for talc pleurodesis demonstrated a higher procedure failure rate with the 12F tube (30% versus 24%) and failed to meet noninferiority criteria.³⁹ However, larger caliber tubes are also associated with greater patient discomfort compared to smaller bore tubes.

Medical thoracoscopy and VATS are minimally invasive means to visualize the pleural space, obtain visually guided biopsy of the parietal pleura, perform lysis of adhesions, and introduce chemical sclerosants for pleurodesis (Figure 2). Medical thoracoscopy can be performed under local anesthesia with procedural sedation in an endoscopy suite or procedure room.

VATS has several distinct and clinically important differences. The equipment is slightly larger but otherwise similar in concept to rigid medical thoracoscopes. A greater number of diagnostic and therapeutic options, such as diagnostic biopsy of lung parenchyma and select hilar lymph nodes, are also possible. However, VATS requires surgical training and is performed in an operating room setting, which necessitates additional ancillary and logistical support. VATS also uses at least 2 trocar insertion sites, requires general anesthesia, and utilizes single-lung ventilation through a double-lumen endotracheal tube. Procedure-related complications for medical thoracoscopy and VATS include pneumothorax, subcutaneous emphysema, fever, and pain.⁴⁹

Data comparing talc slurry versus talc poudrage are heterogenous, without clear advantage for either method. Reported rates of successful pleurodesis are generally in the range of 70% to 80% for both methods.^19,20,40,50 There is a possible suggestion of benefit with talc poudrage compared to slurry, but data is lacking to support either as a definitive choice in current guidelines.^12,51 An advantage of medical thoracoscopy or VATS is that pleural biopsy can be performed simultaneously, if necessary, thereby allowing both diagnostic and therapeutic interventions.⁵² Visualizing the thoracic cavity may also permit creation of optimal conditions for pleurodesis in select individuals by allowing access to loculated spaces and providing visual confirmation of complete drainage of pleural fluid and uniform distribution of the chemical sclerosant.

Other Surgical Interventions

Thoracotomy with decortication is rarely used as treatment of malignant effusions complicated by loculations or trapped lung due to the significantly increased procedural morbidity and mortality. Therefore, it is reserved for the limited population of patients in whom other therapeutic interventions have failed but who otherwise have significant symptoms with a long life expectancy. Mesothelioma is a specific situation in which variations of pleurectomy, such as radical pleurectomy with decortication, lung-sparing total pleurectomy, and extrapleural pneumonectomy (EPP), have been used as front-line therapy. The Mesothelioma and Radical Surgery (MARS) trial, the only randomized, controlled evaluation of EPP, demonstrated decreased median survival in patients treated by EPP compared to controls (14.4 months versus 19.5 months).⁵³ EPP is also associated with high procedure-related morbidity and mortality rates of approximately 50% and 4% to 15%, respectively.⁵⁴ While successful at achieving pleurodesis, use of EPP as a treatment for mesothelioma is now discouraged.^53,55 Less invasive surgical approaches, such as pleurectomy with decortication, are able to palliate symptoms with significantly less operative risk.⁵⁶

Management Considerations

Selection of Therapeutic Interventions

The ideal management strategy provides both immediate and long-term symptom palliation, has minimal associated morbidity and side effects, minimizes hospitalization time and clinic visits, avoids the risks and inconvenience of recurring procedures, is inexpensive, and minimizes utilization of medical resources. Unfortunately, no single palliation methodology fits these needs for all patients. When evaluating therapeutic options for patients with MPE, it is important to consider factors such as the severity of symptoms, fluid quantity, fluid re-accumulation rate, pleural physiology, functional status, overall prognosis, and anticipated response of the malignancy to therapy. One example management algorithm (Figure 4) demonstrates the impact of these variables on the appropriate treatment options. However, this is a simplified algorithm and the selected palliation strategy should be decided upon after shared decision-making between the patient and physician and should fit within the context of the patient’s desired goals of care. It is also crucial for patients to understand that these therapeutic interventions are palliative rather than curative.

When compared directly with pleurodesis, TPC provides similar control of symptoms but with a reduction in hospital length of stay by a median of 3.5 to 5.5 days.^19,57 In a nonrandomized trial where patients chose palliation by TPC or talc pleurodesis, more TPC patients had a significant immediate improvement in quality of life and dyspnea after the first 7 days of therapy.⁵⁸ This is reasonably attributed to the differences between the immediate relief from fluid drainage after TPC placement compared to the time required for pleural symphysis to occur with pleurodesis. However, control of dyspnea symptoms is similar between the 2 strategies after 6 weeks.¹⁹ Therefore, both TPC and pleurodesis strategies are viewed as first-line options for patients with expandable lung and no prior palliative interventions for MPE.⁵⁹

Pleural adhesions and trapped lung also pose specific dilemmas. Pleural adhesions can create loculated fluid pockets, thereby complicating drainage by thoracentesis or TPC and hindering dispersal of pleurodesis agents. Adhesiolysis by medical thoracoscopy or VATS may be useful in these patients to free up the pleural space and improve efficacy of long-term drainage options or facilitate pleurodesis. Intrapleural administration of fibrinolytics, such as streptokinase and urokinase, has also been used for treatment of loculated effusions and may improve drainage of pleural fluid and lung re-expansion.^60-63 However routine use of intrapleural fibrinolytics with pleurodesis has not been shown to be beneficial. In a randomized comparison using intrapleural urokinase prior to pleurodesis for patients with septated malignant pleural effusions, no difference in pleurodesis outcomes were identified.⁶³ As a result, TPC is the preferred palliation approach for patients with trapped lung physiology.^51,59

Combination Strategies

Combinations of different therapeutic interventions are being evaluated as a means for patients to achieve long-term benefits from pleurodesis while minimizing hospitalization time. One strategy using simultaneous treatment with thoracoscopic talc poudrage and insertion of a large-bore chest tube and TPC has been shown to permit early removal of the chest tube and discharge home using the TPC for continued daily pleural drainage. This “rapid pleurodesis” strategy has an 80% to 90% successful pleurodesis rate, permitting removal of the TPC at a median of 7 to 10 days.^64,65 With this approach, median hospitalization length of stay was approximately 2 days. While there was no control arm in these early reports with limited sample sizes, the pleurodesis success rate and length of hospitalization compare favorably to other published studies. A prospective, randomized trial of TPC versus an outpatient regimen of talc slurry via TPC has also shown promise, with successful pleurodesis after 35 days in 43% of those treated with the combination of talc slurry and TPC compared to only 23% in those treated by TPC alone.²⁷

Another novel approach to obtain the benefits of both TPC and pleurodesis strategies is the use of drug-eluting TPC to induce inflammation and promote adhesion of the visceral and parietal pleura. An early report of slow-release silver nitrate (AgNO₃) –coated TPC demonstrated an encouraging 89% spontaneous pleurodesis rate after a median of 4 days in the small subgroup of patients with fully expandable lung.⁶⁶ Device-related adverse events were relatively high at 24.6%, though only one was deemed a serious adverse event. Additional studies of these novel and combination strategies are ongoing at this time.

Costs

While cost of care is not a consideration in the decision-making for individual patients, it is important from a systems-based perspective. Upfront costs for pleurodesis are generally higher due to the facility and hospitalization costs, whereas TPC have ongoing costs for drainage bottles and supplies. In a prospective, randomized trial of TPC versus talc pleurodesis, there was no appreciable difference in overall costs between the 2 approaches.⁶⁷ The cost of TPC was significantly less, however, for patients with a shorter survival of less than 14 weeks.

Readmissions

Subsequent hospitalization requirements beyond just the initial treatment for a MPE remains another significant consideration for this patient population. A prospective, randomized trial comparing TPC to talc pleurodesis demonstrated a reduction in total all-cause hospital stay for TPC, with a median all-cause hospitalization time of 10 days for patients treated with TPC compared to 12 days for the talc pleurodesis group.²⁰ The primary difference in the number of hospitalization days was due to a difference in effusion-related hospital days (median 1 versus 4 days, respectively), which was primarily comprised of the initial hospitalization. In addition, fewer patients treated with TPC required subsequent ipsilateral invasive procedures (4.1% versus 22.5%, respectively). However, it is important to note that the majority of all-cause hospital days were not effusion-related, demonstrating that this population has a high utilization of acute inpatient services for other reasons related to their advanced malignancy. In a study of regional hospitals in the United States, 38.3% of patients admitted for a primary diagnosis of MPE were readmitted within 30 days.⁶⁸ There was remarkably little variability in readmission rates among hospitals, despite differences in factors such as institution size, location, patient distribution, and potential practice differences. This suggests that utilization of palliation strategies for MPE are only one component related to hospitalization in this population. Even at the best performing hospitals, there are significant common drivers for readmission that are not addressed. Therefore, additional effort should be focused on addressing aspects of care beyond just the palliation of MPE that predispose this population to requiring frequent treatment in an acute care setting.

MPEs represent advanced stage disease and frequently adversely affect a patient’s quality of life. The treating clinician has access to a variety of therapeutic options, though no single intervention strategy is universally superior in all circumstances. Initial thoracentesis is important in evaluating whether removal of a large volume of fluid provides significant symptom relief and restores functional status. Both talc pleurodesis and TPC provide similar control of symptoms and are first-line approaches for symptomatic patients with MPE and fully expandable lungs. Pleurodesis is associated with greater procedure-related risk and length of hospitalization and is contraindicated in patients with trapped lung, but does not require long-term catheter care or disposable resources. Determination of the appropriate therapeutic management strategy requires careful evaluation of the patient’s clinical situation and informed discussion with the patient to make sure that the treatment plan fits within the context of their goals of medical care.

Malignant pleural effusion (MPE) is a common clinical problem in patients with advanced stage cancer. Each year in the United States, more than 150,000 individuals are diagnosed with MPE, and there are approximately 126,000 admissions for MPE.^1-3 Providing effective therapeutic management remains a challenge, and currently available therapeutic interventions are palliative rather than curative. This article, the second in a 2-part review of MPE, focuses on the available management options.

Therapeutic Thoracentesis

Evaluation of pleural fluid cytology is a crucial step in the diagnosis and staging of disease. As a result, large-volume fluid removal is often the first therapeutic intervention for patients who present with symptomatic effusions. A patient’s clinical response to therapeutic thoracentesis dictates which additional therapeutic options are appropriate for palliation. Lack of symptom relief suggests that other comorbid conditions or trapped lung physiology may be the primary cause of the patient’s symptoms and discourages more invasive interventions. Radiographic evidence of lung re-expansion after fluid removal is also an important predictor of success for potential pleurodesis.^4,5

There are no absolute contraindications to thoracentesis. However, caution should be used for patients with risk factors that may predispose to complications of pneumothorax and bleeding, such as coagulopathy, treatment with anticoagulation medications, thrombocytopenia, platelet dysfunction (eg, antiplatelet medications, uremia), positive pressure ventilation, and small effusion size. These factors are only relative contraindications, however, as thoracentesis can still be safely performed by experienced operators using guidance technology such as ultrasonography.

A retrospective review of 1009 ultrasound-guided thoracenteses with risk factors of an international normalized ratio (INR) greater than 1.6, platelet values less than 50,000/μL, or both, reported an overall rate of hemorrhagic complication of 0.4%, with no difference between procedures performed with (n = 303) or without (n = 706) transfusion correction of coagulopathy or thrombocytopenia.⁶ A similar retrospective evaluation of 1076 ultrasound-guided thoracenteses, including 267 patients with an INR greater than 1.5 and 58 patients with a platelet count less than 50,000/μL, reported a 0% complication rate.⁷ Small case series have also demonstrated low hemorrhagic complication rates for thoracentesis in patients treated with clopidogrel^8,9 and with increased bleeding risk from elevated INR (liver disease or warfarin therapy) and renal disease.¹⁰

Complications from pneumothorax can similarly be affected by patient- and operator-dependent risk factors. Meta-analysis of 24 studies including 6605 thoracenteses demonstrated an overall pneumothorax rate of 6.0%, with 34.1% requiring chest tube insertion.¹¹ Lower pneumothorax rates were associated with the use of ultrasound guidance (odds ratio, 0.3; 95% confidence interval, 0.2-0.7). Experienced operators also had fewer pneumothorax complications, though this factor was not significant in the studies directly comparing this variable. Therapeutic thoracentesis and use of a larger-bore needle were also significantly correlated with pneumothorax, while mechanical ventilation had a nonsignificant trend towards increased risk.

Although there is no consensus on the volume of pleural fluid that may be safely removed, it is recommended not to remove more than 1.5 L during a procedure in order to avoid precipitating re-expansion pulmonary edema.^2,12 However, re-expansion pulmonary edema rates remain low even when larger volumes are removed if the patient remains symptom-free during the procedure and pleural manometry pressure does not exceed –20 cm H₂O.¹³ Patient symptoms alone, however, are neither a sensitive nor specific indicator that pleural pressures exceed –20 cm H₂O.¹⁴ Use of excessive negative pressure during drainage, such as from a vacuum bottle, should also be avoided. Comparison of suction generated manually with a syringe versus a vacuum bottle suggests decreased complications with manual drainage, though the sample size in the supporting study was small relative to the infrequency of the complications being evaluated.¹⁵

Given the low morbidity and noninvasive nature of the procedure, serial large-volume thoracentesis remains a viable therapeutic intervention for patients who are unable or unwilling to undergo more invasive interventions, especially for patients with a slow fluid re-accumulation rate or who are anticipated to have limited survival. Unfortunately, many symptomatic effusions will recur within a short interval time span, which necessitates repeat procedures.^16,17 Therefore, factors such as poor symptom control, patient inconvenience, recurrent procedural risk, and utilization of medical resources need to be considered as well.

Tunneled pleural catheters (TPCs) are a potentially permanent and minimally invasive therapy which allow intermittent drainage of pleural fluid (Figure 1). The catheter is tunneled under the skin to prevent infection. A polyester cuff attached to the catheter is positioned within the tunnel and induces fibrosis around the catheter, thereby securing the catheter in place. Placement can be performed under local anesthesia at the patient’s bedside or in an outpatient procedure space. Fluid can then be drained via specialized drainage bottles or bags by the patient, a family member, or visiting home nurse. The catheter can also be removed in the event of a complication or the development of spontaneous pleurodesis.

TPCs are an effective palliative management strategy for patients with recurrent effusions and are an efficacious alternative to pleurodesis.^18-20 TPCs may be used in patients with poor prognosis or trapped lung or in those in whom prior pleurodesis has failed.^21-23 Meta-analysis of 19 studies showed symptomatic improvement in 95.6% of patients, with development of spontaneous pleurodesis in 45.6% of patients (range, 11.8% to 76.4%) after an average of 52 days.²⁴ However, most of the studies included in this analysis were retrospective case series. Development of spontaneous pleurodesis from TPC drainage in prospective, controlled trials has been considerably more modest, supporting a range of approximately 20% to 30% with routine drainage strategies.^20,25-27 Spontaneous pleurodesis develops greater rapidity and frequency in patients undergoing daily drainage compared to every-other-day or symptom-directed drainage strategies.^25,26 However, there is no appreciable improvement in quality of life scores with a specific drainage strategy. Small case series also demonstrate that TPC drainage may induce spontaneous pleurodesis in some patients initially presenting with trapped lung physiology.²²

Catheter placement can be performed successfully in the vast majority of patients.²⁸ Increased bleeding risk, significant malignancy-related involvement of the skin and chest wall, and pleural loculations can complicate TPC placement. TPC-related complications are relatively uncommon, but include pneumothorax, catheter malfunction and obstruction, and infections including soft tissue and pleural space infections.²⁴ In a multicenter retrospective series of 1021 patients, only 4.9% developed a TPC-related pleural infection.²⁹ Over 94% were successfully managed with antibiotic therapy, and the TPC was able to be preserved in 54%. Staphylococcus aureus was the most common causative organism and was identified in 48% of cases. Of note, spontaneous pleurodesis occurred in 62% of cases following a pleural space infection, which likely occurred as sequelae of the inflammatory nature of the infection. Retrospective analysis suggests that the risk of TPC-related infections is not substantially higher for patients with higher risks of immunosuppression from chemotherapy or hematologic malignancies.^30,31 Tumor metastasis along the catheter tract is a rare occurrence (< 1%), but is most notable with mesothelioma, which has an incidence as high as 10%.^24,32 In addition, development of pleural loculations can impede fluid drainage and relief of dyspnea. Intrapleural instillation of fibrinolytics can be used to improve drainage and improve symptom palliation.³³

Pleurodesis

Pleurodesis obliterates the potential pleural space by inducing inflammation and fibrosis, resulting in adherence of the visceral and parietal pleura together. This process can be induced through mechanical abrasion of the pleural surface, introduction of chemical sclerosants, or from prolonged use of a chest tube. Chemical sclerosants are the most commonly used method for MPEs and are introduced through a chest tube or under visual guidance such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS). The pleurodesis process is thought to occur by induction of a systemic inflammatory response with localized deposition of fibrin.³⁴ Activation of fibroblasts and successful pleurodesis have been correlated with higher basic fibroblast growth factor (bFGF) levels in pleural fluid.³⁵ Increased tumor burden is associated with lower bFGF levels, suggesting a possible mechanism for reduced pleurodesis success in these cases. Corticosteroids may reduce the likelihood of pleurodesis due to a reduction of inflammation, as demonstrated in a rabbit model using talc and doxycycline.^36,37 Animal data also suggests that use of nonsteroidal anti-inflammatory drugs may hinder the likelihood of successful pleurodesis, but this has not been observed in humans.^38,39

Patients selected for pleurodesis should have significant symptom relief from large-volume removal of pleural fluid, good functional status, and evidence of full lung re-expansion after thoracentesis. Lack of visceral and parietal pleural apposition will prevent pleural adhesion from developing. As a result, trapped lung is associated with chemical pleurodesis failure and is an absolute contraindication to the procedure.^4,5,12 The pleurodesis process typically requires 5 to 7 days, during which time the patient is hospitalized for chest tube drainage and pain control. When pleural fluid output diminishes, the chest tube is removed and the patient can be discharged. Modified protocols are now emerging which may shorten the required hospitalization associated with pleurodesis procedures.

A variety of chemical sclerosants have been used for pleurodesis, including talc, bleomycin, tetracycline, doxycycline, iodopovidone, and mepacrine. Published data regarding these agents are heterogenous, with significant variability in reported outcomes. However, systematic review and meta-analysis suggests that talc is likely to have higher success rates compared to other agents or chest tube drainage alone for treatment of MPE.^40,41

Additional factors have been shown to be associated with pleurodesis outcomes. Pleurodesis success is negatively associated with low pleural pH, with receiver operating curve thresholds of 7.28 to 7.34.^42,43 Trapped lung, large bulky tumor lining the pleural surfaces, and elevated adenosine deaminase levels are also associated with poor pleurodesis outcomes.^4,5,12,35,43 In contrast, pleural fluid output less than 200 mL per day and the presence of EGFR (epidermal growth factor receptor) mutation treated with targeted tyrosine kinase inhibitors are associated with successful pleurodesis.^44,45

The most common complications associated with chemical pleurodesis are fever and pain. Other potential complications include soft tissue infections at the chest tube site and of the pleural space, arrhythmias, cardiac arrest, myocardial infarction, and hypotension. Doxycycline is commonly associated with greater pleuritic pain than talc. Acute respiratory distress syndrome (ARDS), acute pneumonitis, and respiratory failure have been described with talc pleurodesis. ARDS secondary to talc pleurodesis occurs in 1% to 9% of cases, though this may be related to the use of ungraded talc. A prospective description of 558 patients treated with large particle talc (> 5 μm) reported no occurrences of ARDS, suggesting the safety of graded large particle talc.⁴⁶

Pleurodesis Methods

Chest tube thoracostomy is an inpatient procedure performed under local anesthesia or conscious sedation. It can be used for measured, intermittent drainage of large effusions for immediate symptom relief, as well as to demonstrate complete lung re-expansion prior to instillation of a chemical sclerosant. Pleurodesis using a chest tube is performed by instillation of a slurry created by mixing the sclerosing agent of choice with 50 to 100 mL of sterile saline. This slurry is instilled into the pleural cavity through the chest tube. The chest tube is clamped for 1 to 2 hours before being reconnected to suction. Intermittent rotation of the patient has not been shown to improve distribution of the sclerosant or result in better procedural outcomes.^47,48 Typically, a 24F to 32F chest tube is used because of the concern about obstruction of smaller bore tubes by fibrin plugs. A noninferiority study comparing 12F to 24F chest tubes for talc pleurodesis demonstrated a higher procedure failure rate with the 12F tube (30% versus 24%) and failed to meet noninferiority criteria.³⁹ However, larger caliber tubes are also associated with greater patient discomfort compared to smaller bore tubes.

Medical thoracoscopy and VATS are minimally invasive means to visualize the pleural space, obtain visually guided biopsy of the parietal pleura, perform lysis of adhesions, and introduce chemical sclerosants for pleurodesis (Figure 2). Medical thoracoscopy can be performed under local anesthesia with procedural sedation in an endoscopy suite or procedure room.

VATS has several distinct and clinically important differences. The equipment is slightly larger but otherwise similar in concept to rigid medical thoracoscopes. A greater number of diagnostic and therapeutic options, such as diagnostic biopsy of lung parenchyma and select hilar lymph nodes, are also possible. However, VATS requires surgical training and is performed in an operating room setting, which necessitates additional ancillary and logistical support. VATS also uses at least 2 trocar insertion sites, requires general anesthesia, and utilizes single-lung ventilation through a double-lumen endotracheal tube. Procedure-related complications for medical thoracoscopy and VATS include pneumothorax, subcutaneous emphysema, fever, and pain.⁴⁹

Data comparing talc slurry versus talc poudrage are heterogenous, without clear advantage for either method. Reported rates of successful pleurodesis are generally in the range of 70% to 80% for both methods.^19,20,40,50 There is a possible suggestion of benefit with talc poudrage compared to slurry, but data is lacking to support either as a definitive choice in current guidelines.^12,51 An advantage of medical thoracoscopy or VATS is that pleural biopsy can be performed simultaneously, if necessary, thereby allowing both diagnostic and therapeutic interventions.⁵² Visualizing the thoracic cavity may also permit creation of optimal conditions for pleurodesis in select individuals by allowing access to loculated spaces and providing visual confirmation of complete drainage of pleural fluid and uniform distribution of the chemical sclerosant.

Other Surgical Interventions

Thoracotomy with decortication is rarely used as treatment of malignant effusions complicated by loculations or trapped lung due to the significantly increased procedural morbidity and mortality. Therefore, it is reserved for the limited population of patients in whom other therapeutic interventions have failed but who otherwise have significant symptoms with a long life expectancy. Mesothelioma is a specific situation in which variations of pleurectomy, such as radical pleurectomy with decortication, lung-sparing total pleurectomy, and extrapleural pneumonectomy (EPP), have been used as front-line therapy. The Mesothelioma and Radical Surgery (MARS) trial, the only randomized, controlled evaluation of EPP, demonstrated decreased median survival in patients treated by EPP compared to controls (14.4 months versus 19.5 months).⁵³ EPP is also associated with high procedure-related morbidity and mortality rates of approximately 50% and 4% to 15%, respectively.⁵⁴ While successful at achieving pleurodesis, use of EPP as a treatment for mesothelioma is now discouraged.^53,55 Less invasive surgical approaches, such as pleurectomy with decortication, are able to palliate symptoms with significantly less operative risk.⁵⁶

Management Considerations

Selection of Therapeutic Interventions

The ideal management strategy provides both immediate and long-term symptom palliation, has minimal associated morbidity and side effects, minimizes hospitalization time and clinic visits, avoids the risks and inconvenience of recurring procedures, is inexpensive, and minimizes utilization of medical resources. Unfortunately, no single palliation methodology fits these needs for all patients. When evaluating therapeutic options for patients with MPE, it is important to consider factors such as the severity of symptoms, fluid quantity, fluid re-accumulation rate, pleural physiology, functional status, overall prognosis, and anticipated response of the malignancy to therapy. One example management algorithm (Figure 4) demonstrates the impact of these variables on the appropriate treatment options. However, this is a simplified algorithm and the selected palliation strategy should be decided upon after shared decision-making between the patient and physician and should fit within the context of the patient’s desired goals of care. It is also crucial for patients to understand that these therapeutic interventions are palliative rather than curative.

When compared directly with pleurodesis, TPC provides similar control of symptoms but with a reduction in hospital length of stay by a median of 3.5 to 5.5 days.^19,57 In a nonrandomized trial where patients chose palliation by TPC or talc pleurodesis, more TPC patients had a significant immediate improvement in quality of life and dyspnea after the first 7 days of therapy.⁵⁸ This is reasonably attributed to the differences between the immediate relief from fluid drainage after TPC placement compared to the time required for pleural symphysis to occur with pleurodesis. However, control of dyspnea symptoms is similar between the 2 strategies after 6 weeks.¹⁹ Therefore, both TPC and pleurodesis strategies are viewed as first-line options for patients with expandable lung and no prior palliative interventions for MPE.⁵⁹

Pleural adhesions and trapped lung also pose specific dilemmas. Pleural adhesions can create loculated fluid pockets, thereby complicating drainage by thoracentesis or TPC and hindering dispersal of pleurodesis agents. Adhesiolysis by medical thoracoscopy or VATS may be useful in these patients to free up the pleural space and improve efficacy of long-term drainage options or facilitate pleurodesis. Intrapleural administration of fibrinolytics, such as streptokinase and urokinase, has also been used for treatment of loculated effusions and may improve drainage of pleural fluid and lung re-expansion.^60-63 However routine use of intrapleural fibrinolytics with pleurodesis has not been shown to be beneficial. In a randomized comparison using intrapleural urokinase prior to pleurodesis for patients with septated malignant pleural effusions, no difference in pleurodesis outcomes were identified.⁶³ As a result, TPC is the preferred palliation approach for patients with trapped lung physiology.^51,59

Combination Strategies

Combinations of different therapeutic interventions are being evaluated as a means for patients to achieve long-term benefits from pleurodesis while minimizing hospitalization time. One strategy using simultaneous treatment with thoracoscopic talc poudrage and insertion of a large-bore chest tube and TPC has been shown to permit early removal of the chest tube and discharge home using the TPC for continued daily pleural drainage. This “rapid pleurodesis” strategy has an 80% to 90% successful pleurodesis rate, permitting removal of the TPC at a median of 7 to 10 days.^64,65 With this approach, median hospitalization length of stay was approximately 2 days. While there was no control arm in these early reports with limited sample sizes, the pleurodesis success rate and length of hospitalization compare favorably to other published studies. A prospective, randomized trial of TPC versus an outpatient regimen of talc slurry via TPC has also shown promise, with successful pleurodesis after 35 days in 43% of those treated with the combination of talc slurry and TPC compared to only 23% in those treated by TPC alone.²⁷

Another novel approach to obtain the benefits of both TPC and pleurodesis strategies is the use of drug-eluting TPC to induce inflammation and promote adhesion of the visceral and parietal pleura. An early report of slow-release silver nitrate (AgNO₃) –coated TPC demonstrated an encouraging 89% spontaneous pleurodesis rate after a median of 4 days in the small subgroup of patients with fully expandable lung.⁶⁶ Device-related adverse events were relatively high at 24.6%, though only one was deemed a serious adverse event. Additional studies of these novel and combination strategies are ongoing at this time.

Costs

While cost of care is not a consideration in the decision-making for individual patients, it is important from a systems-based perspective. Upfront costs for pleurodesis are generally higher due to the facility and hospitalization costs, whereas TPC have ongoing costs for drainage bottles and supplies. In a prospective, randomized trial of TPC versus talc pleurodesis, there was no appreciable difference in overall costs between the 2 approaches.⁶⁷ The cost of TPC was significantly less, however, for patients with a shorter survival of less than 14 weeks.

Readmissions

Subsequent hospitalization requirements beyond just the initial treatment for a MPE remains another significant consideration for this patient population. A prospective, randomized trial comparing TPC to talc pleurodesis demonstrated a reduction in total all-cause hospital stay for TPC, with a median all-cause hospitalization time of 10 days for patients treated with TPC compared to 12 days for the talc pleurodesis group.²⁰ The primary difference in the number of hospitalization days was due to a difference in effusion-related hospital days (median 1 versus 4 days, respectively), which was primarily comprised of the initial hospitalization. In addition, fewer patients treated with TPC required subsequent ipsilateral invasive procedures (4.1% versus 22.5%, respectively). However, it is important to note that the majority of all-cause hospital days were not effusion-related, demonstrating that this population has a high utilization of acute inpatient services for other reasons related to their advanced malignancy. In a study of regional hospitals in the United States, 38.3% of patients admitted for a primary diagnosis of MPE were readmitted within 30 days.⁶⁸ There was remarkably little variability in readmission rates among hospitals, despite differences in factors such as institution size, location, patient distribution, and potential practice differences. This suggests that utilization of palliation strategies for MPE are only one component related to hospitalization in this population. Even at the best performing hospitals, there are significant common drivers for readmission that are not addressed. Therefore, additional effort should be focused on addressing aspects of care beyond just the palliation of MPE that predispose this population to requiring frequent treatment in an acute care setting.

MPEs represent advanced stage disease and frequently adversely affect a patient’s quality of life. The treating clinician has access to a variety of therapeutic options, though no single intervention strategy is universally superior in all circumstances. Initial thoracentesis is important in evaluating whether removal of a large volume of fluid provides significant symptom relief and restores functional status. Both talc pleurodesis and TPC provide similar control of symptoms and are first-line approaches for symptomatic patients with MPE and fully expandable lungs. Pleurodesis is associated with greater procedure-related risk and length of hospitalization and is contraindicated in patients with trapped lung, but does not require long-term catheter care or disposable resources. Determination of the appropriate therapeutic management strategy requires careful evaluation of the patient’s clinical situation and informed discussion with the patient to make sure that the treatment plan fits within the context of their goals of medical care.

Malignant pleural effusion (MPE) is a common clinical problem in patients with advanced stage cancer. Each year in the United States, more than 150,000 individuals are diagnosed with MPE, and there are approximately 126,000 admissions for MPE.^1-3 Providing effective therapeutic management remains a challenge, and currently available therapeutic interventions are palliative rather than curative. This article, the second in a 2-part review of MPE, focuses on the available management options.

Therapeutic Thoracentesis

Evaluation of pleural fluid cytology is a crucial step in the diagnosis and staging of disease. As a result, large-volume fluid removal is often the first therapeutic intervention for patients who present with symptomatic effusions. A patient’s clinical response to therapeutic thoracentesis dictates which additional therapeutic options are appropriate for palliation. Lack of symptom relief suggests that other comorbid conditions or trapped lung physiology may be the primary cause of the patient’s symptoms and discourages more invasive interventions. Radiographic evidence of lung re-expansion after fluid removal is also an important predictor of success for potential pleurodesis.^4,5

There are no absolute contraindications to thoracentesis. However, caution should be used for patients with risk factors that may predispose to complications of pneumothorax and bleeding, such as coagulopathy, treatment with anticoagulation medications, thrombocytopenia, platelet dysfunction (eg, antiplatelet medications, uremia), positive pressure ventilation, and small effusion size. These factors are only relative contraindications, however, as thoracentesis can still be safely performed by experienced operators using guidance technology such as ultrasonography.

A retrospective review of 1009 ultrasound-guided thoracenteses with risk factors of an international normalized ratio (INR) greater than 1.6, platelet values less than 50,000/μL, or both, reported an overall rate of hemorrhagic complication of 0.4%, with no difference between procedures performed with (n = 303) or without (n = 706) transfusion correction of coagulopathy or thrombocytopenia.⁶ A similar retrospective evaluation of 1076 ultrasound-guided thoracenteses, including 267 patients with an INR greater than 1.5 and 58 patients with a platelet count less than 50,000/μL, reported a 0% complication rate.⁷ Small case series have also demonstrated low hemorrhagic complication rates for thoracentesis in patients treated with clopidogrel^8,9 and with increased bleeding risk from elevated INR (liver disease or warfarin therapy) and renal disease.¹⁰

Complications from pneumothorax can similarly be affected by patient- and operator-dependent risk factors. Meta-analysis of 24 studies including 6605 thoracenteses demonstrated an overall pneumothorax rate of 6.0%, with 34.1% requiring chest tube insertion.¹¹ Lower pneumothorax rates were associated with the use of ultrasound guidance (odds ratio, 0.3; 95% confidence interval, 0.2-0.7). Experienced operators also had fewer pneumothorax complications, though this factor was not significant in the studies directly comparing this variable. Therapeutic thoracentesis and use of a larger-bore needle were also significantly correlated with pneumothorax, while mechanical ventilation had a nonsignificant trend towards increased risk.

Although there is no consensus on the volume of pleural fluid that may be safely removed, it is recommended not to remove more than 1.5 L during a procedure in order to avoid precipitating re-expansion pulmonary edema.^2,12 However, re-expansion pulmonary edema rates remain low even when larger volumes are removed if the patient remains symptom-free during the procedure and pleural manometry pressure does not exceed –20 cm H₂O.¹³ Patient symptoms alone, however, are neither a sensitive nor specific indicator that pleural pressures exceed –20 cm H₂O.¹⁴ Use of excessive negative pressure during drainage, such as from a vacuum bottle, should also be avoided. Comparison of suction generated manually with a syringe versus a vacuum bottle suggests decreased complications with manual drainage, though the sample size in the supporting study was small relative to the infrequency of the complications being evaluated.¹⁵

Given the low morbidity and noninvasive nature of the procedure, serial large-volume thoracentesis remains a viable therapeutic intervention for patients who are unable or unwilling to undergo more invasive interventions, especially for patients with a slow fluid re-accumulation rate or who are anticipated to have limited survival. Unfortunately, many symptomatic effusions will recur within a short interval time span, which necessitates repeat procedures.^16,17 Therefore, factors such as poor symptom control, patient inconvenience, recurrent procedural risk, and utilization of medical resources need to be considered as well.

Tunneled pleural catheters (TPCs) are a potentially permanent and minimally invasive therapy which allow intermittent drainage of pleural fluid (Figure 1). The catheter is tunneled under the skin to prevent infection. A polyester cuff attached to the catheter is positioned within the tunnel and induces fibrosis around the catheter, thereby securing the catheter in place. Placement can be performed under local anesthesia at the patient’s bedside or in an outpatient procedure space. Fluid can then be drained via specialized drainage bottles or bags by the patient, a family member, or visiting home nurse. The catheter can also be removed in the event of a complication or the development of spontaneous pleurodesis.

TPCs are an effective palliative management strategy for patients with recurrent effusions and are an efficacious alternative to pleurodesis.^18-20 TPCs may be used in patients with poor prognosis or trapped lung or in those in whom prior pleurodesis has failed.^21-23 Meta-analysis of 19 studies showed symptomatic improvement in 95.6% of patients, with development of spontaneous pleurodesis in 45.6% of patients (range, 11.8% to 76.4%) after an average of 52 days.²⁴ However, most of the studies included in this analysis were retrospective case series. Development of spontaneous pleurodesis from TPC drainage in prospective, controlled trials has been considerably more modest, supporting a range of approximately 20% to 30% with routine drainage strategies.^20,25-27 Spontaneous pleurodesis develops greater rapidity and frequency in patients undergoing daily drainage compared to every-other-day or symptom-directed drainage strategies.^25,26 However, there is no appreciable improvement in quality of life scores with a specific drainage strategy. Small case series also demonstrate that TPC drainage may induce spontaneous pleurodesis in some patients initially presenting with trapped lung physiology.²²

Catheter placement can be performed successfully in the vast majority of patients.²⁸ Increased bleeding risk, significant malignancy-related involvement of the skin and chest wall, and pleural loculations can complicate TPC placement. TPC-related complications are relatively uncommon, but include pneumothorax, catheter malfunction and obstruction, and infections including soft tissue and pleural space infections.²⁴ In a multicenter retrospective series of 1021 patients, only 4.9% developed a TPC-related pleural infection.²⁹ Over 94% were successfully managed with antibiotic therapy, and the TPC was able to be preserved in 54%. Staphylococcus aureus was the most common causative organism and was identified in 48% of cases. Of note, spontaneous pleurodesis occurred in 62% of cases following a pleural space infection, which likely occurred as sequelae of the inflammatory nature of the infection. Retrospective analysis suggests that the risk of TPC-related infections is not substantially higher for patients with higher risks of immunosuppression from chemotherapy or hematologic malignancies.^30,31 Tumor metastasis along the catheter tract is a rare occurrence (< 1%), but is most notable with mesothelioma, which has an incidence as high as 10%.^24,32 In addition, development of pleural loculations can impede fluid drainage and relief of dyspnea. Intrapleural instillation of fibrinolytics can be used to improve drainage and improve symptom palliation.³³

Pleurodesis

Pleurodesis obliterates the potential pleural space by inducing inflammation and fibrosis, resulting in adherence of the visceral and parietal pleura together. This process can be induced through mechanical abrasion of the pleural surface, introduction of chemical sclerosants, or from prolonged use of a chest tube. Chemical sclerosants are the most commonly used method for MPEs and are introduced through a chest tube or under visual guidance such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS). The pleurodesis process is thought to occur by induction of a systemic inflammatory response with localized deposition of fibrin.³⁴ Activation of fibroblasts and successful pleurodesis have been correlated with higher basic fibroblast growth factor (bFGF) levels in pleural fluid.³⁵ Increased tumor burden is associated with lower bFGF levels, suggesting a possible mechanism for reduced pleurodesis success in these cases. Corticosteroids may reduce the likelihood of pleurodesis due to a reduction of inflammation, as demonstrated in a rabbit model using talc and doxycycline.^36,37 Animal data also suggests that use of nonsteroidal anti-inflammatory drugs may hinder the likelihood of successful pleurodesis, but this has not been observed in humans.^38,39

Patients selected for pleurodesis should have significant symptom relief from large-volume removal of pleural fluid, good functional status, and evidence of full lung re-expansion after thoracentesis. Lack of visceral and parietal pleural apposition will prevent pleural adhesion from developing. As a result, trapped lung is associated with chemical pleurodesis failure and is an absolute contraindication to the procedure.^4,5,12 The pleurodesis process typically requires 5 to 7 days, during which time the patient is hospitalized for chest tube drainage and pain control. When pleural fluid output diminishes, the chest tube is removed and the patient can be discharged. Modified protocols are now emerging which may shorten the required hospitalization associated with pleurodesis procedures.

A variety of chemical sclerosants have been used for pleurodesis, including talc, bleomycin, tetracycline, doxycycline, iodopovidone, and mepacrine. Published data regarding these agents are heterogenous, with significant variability in reported outcomes. However, systematic review and meta-analysis suggests that talc is likely to have higher success rates compared to other agents or chest tube drainage alone for treatment of MPE.^40,41

Additional factors have been shown to be associated with pleurodesis outcomes. Pleurodesis success is negatively associated with low pleural pH, with receiver operating curve thresholds of 7.28 to 7.34.^42,43 Trapped lung, large bulky tumor lining the pleural surfaces, and elevated adenosine deaminase levels are also associated with poor pleurodesis outcomes.^4,5,12,35,43 In contrast, pleural fluid output less than 200 mL per day and the presence of EGFR (epidermal growth factor receptor) mutation treated with targeted tyrosine kinase inhibitors are associated with successful pleurodesis.^44,45

The most common complications associated with chemical pleurodesis are fever and pain. Other potential complications include soft tissue infections at the chest tube site and of the pleural space, arrhythmias, cardiac arrest, myocardial infarction, and hypotension. Doxycycline is commonly associated with greater pleuritic pain than talc. Acute respiratory distress syndrome (ARDS), acute pneumonitis, and respiratory failure have been described with talc pleurodesis. ARDS secondary to talc pleurodesis occurs in 1% to 9% of cases, though this may be related to the use of ungraded talc. A prospective description of 558 patients treated with large particle talc (> 5 μm) reported no occurrences of ARDS, suggesting the safety of graded large particle talc.⁴⁶

Pleurodesis Methods

Chest tube thoracostomy is an inpatient procedure performed under local anesthesia or conscious sedation. It can be used for measured, intermittent drainage of large effusions for immediate symptom relief, as well as to demonstrate complete lung re-expansion prior to instillation of a chemical sclerosant. Pleurodesis using a chest tube is performed by instillation of a slurry created by mixing the sclerosing agent of choice with 50 to 100 mL of sterile saline. This slurry is instilled into the pleural cavity through the chest tube. The chest tube is clamped for 1 to 2 hours before being reconnected to suction. Intermittent rotation of the patient has not been shown to improve distribution of the sclerosant or result in better procedural outcomes.^47,48 Typically, a 24F to 32F chest tube is used because of the concern about obstruction of smaller bore tubes by fibrin plugs. A noninferiority study comparing 12F to 24F chest tubes for talc pleurodesis demonstrated a higher procedure failure rate with the 12F tube (30% versus 24%) and failed to meet noninferiority criteria.³⁹ However, larger caliber tubes are also associated with greater patient discomfort compared to smaller bore tubes.

Medical thoracoscopy and VATS are minimally invasive means to visualize the pleural space, obtain visually guided biopsy of the parietal pleura, perform lysis of adhesions, and introduce chemical sclerosants for pleurodesis (Figure 2). Medical thoracoscopy can be performed under local anesthesia with procedural sedation in an endoscopy suite or procedure room.

VATS has several distinct and clinically important differences. The equipment is slightly larger but otherwise similar in concept to rigid medical thoracoscopes. A greater number of diagnostic and therapeutic options, such as diagnostic biopsy of lung parenchyma and select hilar lymph nodes, are also possible. However, VATS requires surgical training and is performed in an operating room setting, which necessitates additional ancillary and logistical support. VATS also uses at least 2 trocar insertion sites, requires general anesthesia, and utilizes single-lung ventilation through a double-lumen endotracheal tube. Procedure-related complications for medical thoracoscopy and VATS include pneumothorax, subcutaneous emphysema, fever, and pain.⁴⁹

Data comparing talc slurry versus talc poudrage are heterogenous, without clear advantage for either method. Reported rates of successful pleurodesis are generally in the range of 70% to 80% for both methods.^19,20,40,50 There is a possible suggestion of benefit with talc poudrage compared to slurry, but data is lacking to support either as a definitive choice in current guidelines.^12,51 An advantage of medical thoracoscopy or VATS is that pleural biopsy can be performed simultaneously, if necessary, thereby allowing both diagnostic and therapeutic interventions.⁵² Visualizing the thoracic cavity may also permit creation of optimal conditions for pleurodesis in select individuals by allowing access to loculated spaces and providing visual confirmation of complete drainage of pleural fluid and uniform distribution of the chemical sclerosant.

Other Surgical Interventions

Thoracotomy with decortication is rarely used as treatment of malignant effusions complicated by loculations or trapped lung due to the significantly increased procedural morbidity and mortality. Therefore, it is reserved for the limited population of patients in whom other therapeutic interventions have failed but who otherwise have significant symptoms with a long life expectancy. Mesothelioma is a specific situation in which variations of pleurectomy, such as radical pleurectomy with decortication, lung-sparing total pleurectomy, and extrapleural pneumonectomy (EPP), have been used as front-line therapy. The Mesothelioma and Radical Surgery (MARS) trial, the only randomized, controlled evaluation of EPP, demonstrated decreased median survival in patients treated by EPP compared to controls (14.4 months versus 19.5 months).⁵³ EPP is also associated with high procedure-related morbidity and mortality rates of approximately 50% and 4% to 15%, respectively.⁵⁴ While successful at achieving pleurodesis, use of EPP as a treatment for mesothelioma is now discouraged.^53,55 Less invasive surgical approaches, such as pleurectomy with decortication, are able to palliate symptoms with significantly less operative risk.⁵⁶

Management Considerations

Selection of Therapeutic Interventions

The ideal management strategy provides both immediate and long-term symptom palliation, has minimal associated morbidity and side effects, minimizes hospitalization time and clinic visits, avoids the risks and inconvenience of recurring procedures, is inexpensive, and minimizes utilization of medical resources. Unfortunately, no single palliation methodology fits these needs for all patients. When evaluating therapeutic options for patients with MPE, it is important to consider factors such as the severity of symptoms, fluid quantity, fluid re-accumulation rate, pleural physiology, functional status, overall prognosis, and anticipated response of the malignancy to therapy. One example management algorithm (Figure 4) demonstrates the impact of these variables on the appropriate treatment options. However, this is a simplified algorithm and the selected palliation strategy should be decided upon after shared decision-making between the patient and physician and should fit within the context of the patient’s desired goals of care. It is also crucial for patients to understand that these therapeutic interventions are palliative rather than curative.

When compared directly with pleurodesis, TPC provides similar control of symptoms but with a reduction in hospital length of stay by a median of 3.5 to 5.5 days.^19,57 In a nonrandomized trial where patients chose palliation by TPC or talc pleurodesis, more TPC patients had a significant immediate improvement in quality of life and dyspnea after the first 7 days of therapy.⁵⁸ This is reasonably attributed to the differences between the immediate relief from fluid drainage after TPC placement compared to the time required for pleural symphysis to occur with pleurodesis. However, control of dyspnea symptoms is similar between the 2 strategies after 6 weeks.¹⁹ Therefore, both TPC and pleurodesis strategies are viewed as first-line options for patients with expandable lung and no prior palliative interventions for MPE.⁵⁹

Pleural adhesions and trapped lung also pose specific dilemmas. Pleural adhesions can create loculated fluid pockets, thereby complicating drainage by thoracentesis or TPC and hindering dispersal of pleurodesis agents. Adhesiolysis by medical thoracoscopy or VATS may be useful in these patients to free up the pleural space and improve efficacy of long-term drainage options or facilitate pleurodesis. Intrapleural administration of fibrinolytics, such as streptokinase and urokinase, has also been used for treatment of loculated effusions and may improve drainage of pleural fluid and lung re-expansion.^60-63 However routine use of intrapleural fibrinolytics with pleurodesis has not been shown to be beneficial. In a randomized comparison using intrapleural urokinase prior to pleurodesis for patients with septated malignant pleural effusions, no difference in pleurodesis outcomes were identified.⁶³ As a result, TPC is the preferred palliation approach for patients with trapped lung physiology.^51,59

Combination Strategies

Combinations of different therapeutic interventions are being evaluated as a means for patients to achieve long-term benefits from pleurodesis while minimizing hospitalization time. One strategy using simultaneous treatment with thoracoscopic talc poudrage and insertion of a large-bore chest tube and TPC has been shown to permit early removal of the chest tube and discharge home using the TPC for continued daily pleural drainage. This “rapid pleurodesis” strategy has an 80% to 90% successful pleurodesis rate, permitting removal of the TPC at a median of 7 to 10 days.^64,65 With this approach, median hospitalization length of stay was approximately 2 days. While there was no control arm in these early reports with limited sample sizes, the pleurodesis success rate and length of hospitalization compare favorably to other published studies. A prospective, randomized trial of TPC versus an outpatient regimen of talc slurry via TPC has also shown promise, with successful pleurodesis after 35 days in 43% of those treated with the combination of talc slurry and TPC compared to only 23% in those treated by TPC alone.²⁷

Another novel approach to obtain the benefits of both TPC and pleurodesis strategies is the use of drug-eluting TPC to induce inflammation and promote adhesion of the visceral and parietal pleura. An early report of slow-release silver nitrate (AgNO₃) –coated TPC demonstrated an encouraging 89% spontaneous pleurodesis rate after a median of 4 days in the small subgroup of patients with fully expandable lung.⁶⁶ Device-related adverse events were relatively high at 24.6%, though only one was deemed a serious adverse event. Additional studies of these novel and combination strategies are ongoing at this time.

Costs

While cost of care is not a consideration in the decision-making for individual patients, it is important from a systems-based perspective. Upfront costs for pleurodesis are generally higher due to the facility and hospitalization costs, whereas TPC have ongoing costs for drainage bottles and supplies. In a prospective, randomized trial of TPC versus talc pleurodesis, there was no appreciable difference in overall costs between the 2 approaches.⁶⁷ The cost of TPC was significantly less, however, for patients with a shorter survival of less than 14 weeks.

Readmissions

Subsequent hospitalization requirements beyond just the initial treatment for a MPE remains another significant consideration for this patient population. A prospective, randomized trial comparing TPC to talc pleurodesis demonstrated a reduction in total all-cause hospital stay for TPC, with a median all-cause hospitalization time of 10 days for patients treated with TPC compared to 12 days for the talc pleurodesis group.²⁰ The primary difference in the number of hospitalization days was due to a difference in effusion-related hospital days (median 1 versus 4 days, respectively), which was primarily comprised of the initial hospitalization. In addition, fewer patients treated with TPC required subsequent ipsilateral invasive procedures (4.1% versus 22.5%, respectively). However, it is important to note that the majority of all-cause hospital days were not effusion-related, demonstrating that this population has a high utilization of acute inpatient services for other reasons related to their advanced malignancy. In a study of regional hospitals in the United States, 38.3% of patients admitted for a primary diagnosis of MPE were readmitted within 30 days.⁶⁸ There was remarkably little variability in readmission rates among hospitals, despite differences in factors such as institution size, location, patient distribution, and potential practice differences. This suggests that utilization of palliation strategies for MPE are only one component related to hospitalization in this population. Even at the best performing hospitals, there are significant common drivers for readmission that are not addressed. Therefore, additional effort should be focused on addressing aspects of care beyond just the palliation of MPE that predispose this population to requiring frequent treatment in an acute care setting.

MPEs represent advanced stage disease and frequently adversely affect a patient’s quality of life. The treating clinician has access to a variety of therapeutic options, though no single intervention strategy is universally superior in all circumstances. Initial thoracentesis is important in evaluating whether removal of a large volume of fluid provides significant symptom relief and restores functional status. Both talc pleurodesis and TPC provide similar control of symptoms and are first-line approaches for symptomatic patients with MPE and fully expandable lungs. Pleurodesis is associated with greater procedure-related risk and length of hospitalization and is contraindicated in patients with trapped lung, but does not require long-term catheter care or disposable resources. Determination of the appropriate therapeutic management strategy requires careful evaluation of the patient’s clinical situation and informed discussion with the patient to make sure that the treatment plan fits within the context of their goals of medical care.

Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.^1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.³ In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.⁴ Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.⁵ In addition, palliative measures for patients with MPE are probably underutilized.⁶

This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.

Pathogenesis and Etiology

Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.⁷ This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.⁸

Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).^9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.^11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.^13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.^13,15,16

Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.¹⁵

Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).^4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.¹⁷ The primary tumor origin remains unknown in approximately 10% of cases.⁴

Clinical Presentation and Response to Therapeutic Drainage

More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.¹⁵ The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.^18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.

A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (P_el) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.²¹Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H₂O being suggestive of trapped lung physiology.²² However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.²³

Pleural Fluid Analysis and Pleural Biopsy

While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.^24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.²⁶ The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.²⁷ Fluid may have a low glucose concentration and pH as well.

Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.¹ If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.²⁸ At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.^29,30

In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.³¹ Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.³²

In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.^33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.³³ Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.^33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.^36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.

Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.^38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.⁴⁰ However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.⁴¹ Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.

Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).³ In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.⁴²

Conclusion

MPEs represent advanced stage disease and frequently adversely affect a pa­tient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.

Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.^1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.³ In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.⁴ Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.⁵ In addition, palliative measures for patients with MPE are probably underutilized.⁶

This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.

Pathogenesis and Etiology

Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.⁷ This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.⁸

Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).^9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.^11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.^13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.^13,15,16

Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.¹⁵

Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).^4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.¹⁷ The primary tumor origin remains unknown in approximately 10% of cases.⁴

Clinical Presentation and Response to Therapeutic Drainage

More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.¹⁵ The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.^18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.

A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (P_el) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.²¹Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H₂O being suggestive of trapped lung physiology.²² However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.²³

Pleural Fluid Analysis and Pleural Biopsy

While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.^24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.²⁶ The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.²⁷ Fluid may have a low glucose concentration and pH as well.

Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.¹ If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.²⁸ At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.^29,30

In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.³¹ Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.³²

In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.^33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.³³ Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.^33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.^36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.

Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.^38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.⁴⁰ However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.⁴¹ Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.

Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).³ In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.⁴²

Conclusion

MPEs represent advanced stage disease and frequently adversely affect a pa­tient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.

Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.^1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.³ In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.⁴ Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.⁵ In addition, palliative measures for patients with MPE are probably underutilized.⁶

This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.

Pathogenesis and Etiology

Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.⁷ This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.⁸

Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).^9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.^11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.^13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.^13,15,16

Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.¹⁵

Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).^4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.¹⁷ The primary tumor origin remains unknown in approximately 10% of cases.⁴

Clinical Presentation and Response to Therapeutic Drainage

More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.¹⁵ The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.^18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.

A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (P_el) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.²¹Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H₂O being suggestive of trapped lung physiology.²² However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.²³

Pleural Fluid Analysis and Pleural Biopsy

While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.^24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.²⁶ The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.²⁷ Fluid may have a low glucose concentration and pH as well.

Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.¹ If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.²⁸ At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.^29,30

In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.³¹ Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.³²

In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.^33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.³³ Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.^33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.^36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.

Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.^38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.⁴⁰ However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.⁴¹ Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.

Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).³ In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.⁴²

Conclusion

MPEs represent advanced stage disease and frequently adversely affect a pa­tient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.