Carlos M. Isada, MD, FCCP

In 2007, Falagas et al¹ provided a systematic review of studies focusing on infection-related morbidity and mortality in patients with connective tissue diseases. Many of the studies reviewed were published prior to the introduction of biologic agents for the treatment of rheumatologic disorders. In 39 studies focusing on infection incidence, patient outcomes, or both in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis, granulomatosis with polyangiitis (GPA, [Wegener’s granulomatosis]), and systemic sclerosis, serious infection developed in 29% of patients and 24% of these died due to the infection with a median attributable mortality of 5.2%. Most of the reported infections were common bacterial syndromes such as pneumonia or bacteremia, and opportunistic fungal (Pneumocystis) infections.

Similarly, in 2006 Alarcón² reported that 25% to 50% of patients with SLE had significant morbidity primarily from common bacterial infections, with viral, fungal, and parasitic infection less common. Staphylococcus aureus was a common cause of soft tissue infection, septic arthritis, and bacteremia. Streptococcus pneumoniae typically caused respiratory infections, although meningitis and sepsis were reported with SLE. Gram-negative bacteria such as Escherichia coli, Klebsiella species, and Pseudomonas species usually caused urinary tract infections and nosocomial pneumonia. Other bacterial infections included Nocardia species, Mycobacterium tuberculosis, and, rarely, Listeria monocytogenes. The most common viral infection was herpes zoster. Fungal infections included Pneumocystis jirovecii (formerly known as Pneumocystis carinii) and Candida species.

In scleroderma, another connective tissue disease evaluated in the literature by Alarcón,² reports of bacterial, viral, and fungal infections are limited to case reports. In scleroderma patients, viral infections with cytomegalovirus (CMV), parvovirus B19, and P jirovecii were similar to pathogens observed with SLE.

In polymyositis/dermatomyositis, gram-positive pneumonia affected 15% to 20% of patients and S aureus occurred frequently in the juvenile form of the disease. Herpes zoster was commonly observed, but CMV was relatively rare. Other viral infections included Coxsackie virus, parvovirus B19, and hepatitis C in polymyositis/dermatomyositis. Infection with P jirovecii is frequently fatal in these patients. Other fungal infections seen in polymyositis/dermatomyositis include candidiasis and histoplasmosis.²

Since the approval of antitumor necrosis factor (anti-TNF) agents for RA in the late 1990s, as well as other more recent biologic agents, there has been heightened awareness of infectious complications in rheumatologic patients. A major concern with the anti-TNF agents is the risk of granulomatous infection, particularly mycobacterial disease and dimorphic fungal infections such as histoplasmosis and coccidioidomycosis. Formation of granulomas is the major host defense against mycobacterial infection and is mediated in large part by TNF-alpha. The precise risk of infection associated with each of the various biologic agents is still under study, and rates from randomized trials have differed from postmarketing surveillance studies. Important pathogens associated with biologic agents include Nocardia, CMV, Listeria, Aspergillus, and JC virus (JCV).^3,4 Delays in the diagnosis of these infections in immunocompromised patients have led to poor outcomes.

KEY PATHOGENS IN INFECTIONS OF IMMUNOCOMPROMISED HOSTS

Pneumocystis jirovecii

For many decades, P jirovecii was classified as a protozoan but, based on gene sequencing, the organism has been reclassified as a fungus. P jirovecii is a low-virulence, unicellular organism that is the causative agent of Pneumocystis pneumonia (PCP). Epidemiologically, primary infection most likely occurs in infants and children. Colonization may be transient, entering the airways and then resolving over a period of weeks or months. Alternatively, the organism may enter a latent state similar to tuberculosis with reactivation occurring during times of intense immunosuppression. However, molecular epidemiology studies show that new cases of PCP are likely environmentally acquired through multiple exposures rather than reactivation of latent infection.^5,6 Transmission is thought to be airborne from person to person. Pathogenically, the trophic form of the organism attaches to type 1 alveolar cells and remains in the extracellular compartment of the alveoli. This colonization evokes an influx of inflammatory cells (CD8 cells, neutrophils, and macrophages). However, not all colonizations result in pneumonia—even in advanced human immunodeficiency virus (HIV) infection. While there is an innate immunity through alveolar macrophages and pulmonary surfactant, alveolar macrophage response is impaired in HIV when the CD4 count is low. Cell-mediated immunity is the main defense against progression to pneumonia with assistance from costimulatory molecules (such as CD28 and CD2) as well as B cells.

Pathogenesis and clinical presentation of PCP. In HIV-infected patients with CD4 counts less than 200 cells/mm³, foamy eosinophilic interstitial debris may develop.⁷ HIV patients often present with subacute PCP after having symptoms for days to weeks. In non-HIV patients, the presentation is often more acute, at times with severe fulminant infection. Infected patients often experience dyspnea as well as nonproductive cough and fever. Examination may reveal crackles. Chest x-ray shows diffuse bilateral interstitial infiltrates and, less commonly, nodules, cavities, unilateral infiltrates, effusions, and spontaneous pneumothoraces. Lung examination can be clear, however, confounding the diagnosis. If chest x-ray shows reticular or interstitial infiltrates, one approach would be to obtain a bronchoalveolar lavage (BAL) or sputum sample. If the chest x-ray is clear but the suspicion of PCP is still high, the next step would be high-resolution computed tomography (CT). The finding of ground glass opacities is highly suggestive of P jirovecii, particularly in HIV patients. Sputum or BAL fluid should still be obtained to confirm the diagnosis of P jirovecii (Figure 1). If the CT is clear, then P jirovecii is unlikely, particularly in HIV-positive patients where, in one study, the sensitivity of the CT approaches 100%.⁸

Laboratory diagnosis. P jirovecii cannot be grown in culture for clinical purposes, and it is extremely difficult to culture even in the research setting. Cytologic stains such as the Wright-Giemsa and methamine silver stains are the mainstay of laboratory diagnosis. The yield for P jirovecii from routine expectorated sputum is very low and some laboratories discourage this approach. The sensitivity of nebulized sputum using hypertonic saline ranges from 50% to 90%.⁹

In patients with acquired immune deficiency syndrome (AIDS), bronchoscopy provides 90% to 98% sensitivity by BAL. Transbronchial biopsy may provide some additional yield over BAL in a few situations, such as patients who have been receiving partial P jirovecii prophylaxis. Immunofluorescence techniques using monoclonal antibodies to P jirovecii are commercially available and are first-line diagnostic tools in some laboratories. Recently, polymerase chain reaction (PCR) assay has been introduced into clinical practice as a reproducible test with high sensitivity.

Primary therapy. Primary therapy for PCP consists of trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine. TMP-SMX is considered the drug of choice and is usually administered intravenously for 21 days in HIV patients and 14 days for non-HIV patients. The oral form may be used in patients with less severe PCP with a functioning gastrointestinal tract. Common adverse reactions to TMP-SMX include rash, Stevens-Johnson syndrome, neutropenia, changes in pulmonary function, and nausea/vomiting/diarrhea.¹⁰ Pentamidine is as effective as TMP-SMX, but is associated with renal toxicity, hypotension, severe hypoglycemia, cardiac arrhythmias, and diabetes.¹¹ It is generally reserved for severe cases of PCP in patients who are allergic to or otherwise intolerant of sulfa. Other treatments include atovaquone and trimethoprim-dapsone. Adjunctive corticosteroids have been shown to be beneficial in moderate to severe PCP in HIV patients to reduce the local host inflammatory response to dead or dying organisms. Recent guidelines have recommended corticosteroids for HIV patients with PCP who have an arterial oxygen pressure of 70 mm Hg or less on room air, or an alveolar-arterial (A-a) gradient of oxygen 35 mm Hg or greater.¹² Little is known about the role of adjunctive corticosteroids in non-HIV patients, given a lack of clinical studies.

Prevention. Recent estimates of disease burden from a meta-analysis of 11,900 patients with connective tissue diseases found PCP in 12% of patients with GPA, in 6% of those with polydermatomyositis, in 5% of those with SLE, and in 1% of those with RA.¹ Mortality due to PCP is higher in patients with rheumatic diseases, ranging from 30% in RA to 63% in GPA, than in those with HIV (10% to 20%).¹³ One key risk factor predisposing patients with connective tissue diseases to infection with P jirovecii is recent corticosteroid use. Among patients with connective tissue disease, more than 90% of those infected with P jirovecii have recently received steroid therapy.¹⁴ Additionally, in almost all patients with P jirovecii, lymphopenia with absolute lymphocyte counts less than 1,000/mm³ is present.¹⁵

In patients with HIV, prophylaxis is initiated at a CD4 level of 200/mm³.¹³ However, the cutoff is less clear for non-HIV rheumatic patients. A cutoff of less than 300 cells/mm³ has been proposed for prophylaxis of PCP. However, at that range, approximately 50% of patients with connective tissue disease would remain above the threshold.¹³ One possible solution is to screen by PCR and treat colonization. Other algorithms have been proposed, but there is no general consensus on treatment of non-HIV rheumatic patients.^13,16 Generally, prophylaxis should be considered in patients at the highest risk for PCP. These include patients taking prednisone at doses greater than 20 mg/day for 1 month plus a cytotoxic agent, a TNF inhibitor plus glucocorticoids, and methotrexate plus glucocorticoids in GPA.¹³

 

Nocardia asteroides and Nocardia species

Nocardia species are ubiquitous bacteria found worldwide in soil, dust, and decaying material. On Gram stain the organism is weakly gram-positive with a filamentous “beaded” and branching appearance (Figure 2). Disease results from inhalation of contaminated material in the environment with subsequent lung colonization. Nocardiosis is an opportunistic infection generally seen in persons with defective T-cell (cell-mediated) immunity. Cases have been reported in patients with connective tissue diseases, including SLE, and RA treated with corticosteroids alone and corticosteroids plus methotrexate.^17–19 Nocardiosis has been increasingly recognized with anti-TNF therapy. Animal models have demonstrated that TNF plays an important role in clearance of Nocardia infections.²⁰ In one review, eight cases of nocardiosis were identified from some 300,000 patients receiving an anti-TNF agent.²¹

Classically, Nocardia infection results in abscess formation with infiltrates of polymorphonuclear cells, debris, and thin-walled abscesses. The most frequent site of primary infection is pulmonary. Characteristically, multiple pulmonary nodules or cavities are seen, and Nocardia should be considered in the differential diagnosis of an immunocompromised patient with nodular pneumonia. The nodules can also be masslike in appearance (greater than 2 cm). The presentation of new cavitary lung opacities with systemic symptoms may be mistaken for GPA.²²Nocardia may disseminate to the central nervous system (CNS), skin, joints, and spine, usually causing suppurative infection at these sites. Nocardia has a very strong tropism for neural tissue. In the CNS, Nocardia can cause single or multiple brain abscesses that may be asymptomatic; patients with pulmonary nocardiosis require imaging to rule out occult CNS involvement.

Nocardia species are resistant to several antibiotics. The treatment of choice for Nocardia species is TMPSMX, but imipenem, amikacin, third-generation cephalosporins, and other options such as minocycline and linezolid may be considered depending on the species and the antimicrobial susceptibility pattern.

Histoplasma capsulatum

Histoplasma capsulatum is a dimorphic fungus that causes disease in both healthy and immunocompromised hosts. The organism differs from other pathogenic fungi in that it is an intracellular organism, mainly involving the reticuloendothelial system, and is rarely in the extracellular space. In the United States, infections are clustered endemically in areas such as the Mississippi and Ohio River Valleys, but infections are common worldwide. The fungus is found in soil, mulch, bird excrement, and bat guano. Asymptomatic or mild infections are common in healthy persons residing in endemic areas and occur on a sporadic basis. Epidemics can occur when contaminated material is aerosolized. Histoplasmosis is also an opportunistic infection in patients with impaired T-cell immunity such as persons with AIDS, organ transplant recipients, hematologic malignancies, and corticosteroid use. Clinically significant cases of histoplasmosis have been described in patients with RA while receiving methotrexate alone, corticosteroids alone, and combinations of disease-modifying agents.²³ Histoplasmosis was recently identified in 240 patients in association with TNF inhibitors, translating to 17 per 100,000 patients treated with infliximab.^21,24

Pathogenesis. Infection initially occurs through inhalation of contaminated material from the environment, primarily causing pulmonary infection. The organism converts from a mold form in the environment to a pathogenic yeast form in the host. Once inhaled, the mediastinal lymph nodes provide the first line of defense. Following draining of the lymph nodes, the organism enters the bloodstream in both immunocompetent and immunosuppressed patients. It is spread hematogenously into the spleen, liver, and reticulo-endothelial system, where it is eventually cleared. In immunocompetent patients, cellular immunity limits infection within 7 to 14 days and humoral immunity is not protective.²⁵ Granuloma formation is the hallmark of host defense.

Spectrum of illness. Histoplasmosis is associated with a wide spectrum of illness, with presentation ranging from asymptomatic to mild pulmonary illness to overwhelming pneumonia. Symptomatic pulmonary histoplasmosis typically presents with fever, flulike symptoms, and cough, often with retrosternal chest pain. X-rays show patchy or nodular infiltrates, with hilar or mediastinal lymphadenopathy. In some cases the lung parenchyma is clear and the main feature is fever and bilateral hilar adenopathy. Pulmonary histoplasmosis may be difficult to distinguish from sarcoidosis and tuberculosis. Extrapulmonary disease can present as hepatitis, infective endocarditis, and chronic meningitis. In immunocompromised patients, histoplasmosis can present as a progressive disseminated disease which can be acute, subacute, or chronic. Chronic disseminated histoplasmosis is characterized by cough, persistent fever, wasting, hepatosplenomegaly, oral ulcerations, and progressive cytopenias. Acute disseminated histoplasmosis has a much more fulminant course characterized by respiratory insufficiency, hypotension, multisystem organ failure, coagulopathies, and encephalopathy. Histoplasmosis is primarily a pulmonary disease, but in disseminated disease more than 50% of patients have no pulmonary symptoms and 30% may have normal chest x-rays.²⁶ In one series of infliximab-related cases (n = 10), all came from an endemic area 1 week to 6 months after the first dose of infliximab. Patients presented with cough, fever, and shortness of breath.²⁷ The pathogenesis of histoplasmosis in patients receiving TNF inhibitors is not entirely clear; such patients may be suffering a new primary infection, a reinfection, or, least likely, reactivation of latent infection.

Definitive diagnosis requires culture confirmation from appropriate body fluids or identification of characteristic yeast forms from histopathologic sections of tissue biopsies. Serologic tests may also be used to confirm the diagnosis. Detection of H and M precipitins or bands by immunodiffusion is a routine test in many laboratories. M bands are present in 50% of acute cases but their presence does not distinguish acute from remote infection. H bands are present in only 10% of all acute cases, but their presence is very specific for acute histoplasmosis.²⁸

When looking at complement fixation antibodies to yeast (HY) and mycelial (HMy) forms in pulmonary histoplasmosis, a fourfold rise in titer establishes the diagnosis retrospectively, and a single titer greater than 1:32 is strongly suggestive of active infection. However, in progressive disseminated histoplasmosis, the complement fixation antibodies are frequently negative.²⁹ Detection of antigen in urine and serum by enzyme immunoassay has become a mainstay of diagnosis, with a sensitivity of approximately 90% in progressive disseminated disease.³⁰ Of note, most cases of histoplasmosis associated with biologic agents have detectable urinary antigen tests.

Treatment. Acute pulmonary histoplasmosis is usually self-limited, requiring no treatment. The 2007 Infective Diseases Society of America (IDSA) guidelines recommend observation alone in most cases of mild to moderate pulmonary histoplasmosis unless symptoms persist longer than 1 month. For moderately severe or severe acute pulmonary histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 to 5.0 mg/kg/day) or deosycholate amphotericin B (0.7 to 1.0 mg/kg/day) for 1 to 2 weeks followed by itraconazole 200 mg twice daily for a total of 12 weeks. Methylprednisolone at a dose of 0.5 to 1.0 mg/kg/day intravenously for 1 to 2 weeks is also recommended. For moderately severe to severe disseminated histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 mg/kg/day) for 1 to 2 weeks followed by oral itraconazole 200 mg three times daily for 3 days and then 200 mg twice daily for a total of at least 12 months.³¹ Commonly, the immunosuppressive agent is held during treatment.

 

 

Aspergillus species

Another emerging pathogen is Aspergillus species—a ubiquitous mold spread by aerosols of spores. There are many different species of Aspergillus, but the most common human pathogens include A fumigates, A niger, and A flavus. To date, 39 cases of Aspergillus infection associated with infliximab and etanercept have been reported in the Adverse Event Reporting System, translating to 9 to 12 cases per 100,000 patients.²¹

Manifestations of the various types of Aspergillus infection include invasive pulmonary aspergillosis, which is classically a cavitary disease with a halo effect; chronic necrotizing pneumonia, which has no specific identifying characteristics; and disseminated CNS aspergillosis, causing abscesses in immunosuppressed patients (Figure 3).

Varicella zoster

Herpes zoster infection is caused by reactivation of latent infection. In the United States, 95% of adults are seropositive for herpes zoster with a 10% to 30% lifetime risk of zoster reactivation.³² It is the most common viral infection in multiple series of patients with connective tissue diseases. In a multivariate analysis by Wolfe et al³³ of patients with RA, cyclophosphamide (hazard ratio [HR] 4.2), azathioprine (HR 2.0), and prednisone (HR 1.5) were significant predictors of herpes zoster. TNF inhibitor risk (HR 1.82) is less clear, with studies demonstrating no definitively increased risk. Manifestations of herpes zoster include localized disease (thoracic zoster as the most common presentation), disseminated cutaneous zoster, and disseminated visceral zoster (with encephalitis, myelitis, and angiitis) (Figure 4).

JC virus

More than 80% of adults are seropositive for JCV, a DNA virus of the genus Polyomavirus that causes lytic infection of oligodendrocytes.³⁴ In immunocompromised hosts, JCV causes progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease. PML was first described in malignancy, leukemia, and various other immunocompromised states, prior to its strong association with AIDS in the 1980s. More recently, JCV has been associated with natalizumab for multiple sclerosis and Crohn disease, rituximab for oncology patients, efalizumab for psoriasis,³⁵ and mycophenolate mofetil for transplant recipients.³⁶

In 2006 the US Food and Drug Administration issued a safety alert regarding PML in two patients with SLE treated with rituximab and other immunosuppressives.³⁷ In a review of PML in rheumatic disease, 36 cases were identified in patients who had not previously received a biologic agent. Most of these patients (60%) had SLE.³⁸ Of these, many had little or no immunosuppression over the 6 months prior to the diagnosis of PML, suggesting that SLE itself may predispose to PML. Interestingly, PML is rarely associated with TNF inhibitors.

Classic presentation of PML includes motor weakness, aphasia, dysarthria, vision loss, and cognitive loss. Atypical presentation includes seizures, headaches, and brainstem involvement. PML usually spares the optic nerves, spinal cord, peripheral nerves, and muscles. In persons with underlying rheumatic diseases, PML can be difficult to distinguish from neuropsychiatric SLE or CNS vasculitis.

Diagnosis. On magnetic resonance imaging, typical presentation of PML shows T2 and fluid attenuated inversion recovery hyperintense regions in the white matter, asymmetric parietal and occipital radiations, and occasional cerebellum and basal ganglia involvement (Figure 5). If magnetic resonance imaging is normal, PML usually can be excluded. Cerebrospinal fluid examination shows a mean of 7 white blood cells/μL. PCR for JCV in cerebrospinal fluid has a specificity of close to 100% in persons with advanced HIV based on data prior to the use of highly active antiretroviral therapy.³⁹ Sensitivity using older assays is approximately 70% to 90% while the sensitivity of newer quantitative “ultrasensitive” PCR assays is greater than 90%.^40,41

Treatment. In clinical trials no antiviral agent has been effective in the treatment of PML. In HIV patients who develop PML, highly active antiretroviral therapy should be initiated (if antiretroviral-naïve) or existing antiviral regimens optimized. Antiretroviral therapy in this situation may stabilize disease and possibly increase survival.⁴² For HIV-negative patients who develop PML, the cornerstone of management is immediate decrease or discontinuation of immunosuppression.⁴³ Several adjunctive measures have been reported mainly in natalizumab-associated PML, including corticosteroids, mirtazapine, plasma exchange, and others.

VACCINES

Vaccination is important in the prevention of infectious disease in immunocompromised patients with connective tissue diseases. Because live vaccines are contraindicated in immunocompromised patients, inactivated or component vaccines should be used. It is recommended that patients who will start immunosuppressive therapy be vaccinated 2 to 4 weeks before beginning therapy. If this is not possible, vaccination should be administered during disease remission, 3 months after immunosuppression and 1 to 3 months after administration of high-dose corticosteroids.

Table 1 lists common live (attenuated) vaccines and inactivated vaccines. Live influenza vaccine is available as a nasal spray, but that route of administration is contraindicated in immunocompromised patients and those aged over 50 years. To further define the contraindications in immunocompromised patients, corticosteroids are not a contraindication to live-virus vaccines when corticosteroid administration is:

• Short-term (less than 14 days)
• At a dose of less than 20 mg/day of prednisone or equivalent
• Long-term on alternate days with short-acting preparations
• At a physiologic dose of prednisone
• Topical, inhaled, intra-articular, bursal, or via tendon.⁴⁴

No data are available to guide immunization while a patient is taking anti-TNF agents, but the Centers for Disease Control and Prevention (CDC) recommend “caution in the use of live vaccines” with these drugs with “avoidance” unless the benefit, by case, greatly outweighs the risk.⁴⁴ Similarly, there are no data on vaccine safety or specific recommendations with rituximab treatment. However, following the recommendations for “functional asplenia” in the CDC guidelines, pneumococcal, meningococcal, and Haemophilus influenzae type b (Hib) vaccine (if not given in infancy) would be indicated. Table 2 summarizes the CDC recommendations for vaccinating immunocompromised adults (excluding those with HIV).

Until definitive guidelines are developed, practitioners must evaluate and treat each patient individually to maximize the efficacy of disease treatments while preventing infection morbidity and mortality in their patients with connective tissue diseases.

In 2007, Falagas et al¹ provided a systematic review of studies focusing on infection-related morbidity and mortality in patients with connective tissue diseases. Many of the studies reviewed were published prior to the introduction of biologic agents for the treatment of rheumatologic disorders. In 39 studies focusing on infection incidence, patient outcomes, or both in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis, granulomatosis with polyangiitis (GPA, [Wegener’s granulomatosis]), and systemic sclerosis, serious infection developed in 29% of patients and 24% of these died due to the infection with a median attributable mortality of 5.2%. Most of the reported infections were common bacterial syndromes such as pneumonia or bacteremia, and opportunistic fungal (Pneumocystis) infections.

Similarly, in 2006 Alarcón² reported that 25% to 50% of patients with SLE had significant morbidity primarily from common bacterial infections, with viral, fungal, and parasitic infection less common. Staphylococcus aureus was a common cause of soft tissue infection, septic arthritis, and bacteremia. Streptococcus pneumoniae typically caused respiratory infections, although meningitis and sepsis were reported with SLE. Gram-negative bacteria such as Escherichia coli, Klebsiella species, and Pseudomonas species usually caused urinary tract infections and nosocomial pneumonia. Other bacterial infections included Nocardia species, Mycobacterium tuberculosis, and, rarely, Listeria monocytogenes. The most common viral infection was herpes zoster. Fungal infections included Pneumocystis jirovecii (formerly known as Pneumocystis carinii) and Candida species.

In scleroderma, another connective tissue disease evaluated in the literature by Alarcón,² reports of bacterial, viral, and fungal infections are limited to case reports. In scleroderma patients, viral infections with cytomegalovirus (CMV), parvovirus B19, and P jirovecii were similar to pathogens observed with SLE.

In polymyositis/dermatomyositis, gram-positive pneumonia affected 15% to 20% of patients and S aureus occurred frequently in the juvenile form of the disease. Herpes zoster was commonly observed, but CMV was relatively rare. Other viral infections included Coxsackie virus, parvovirus B19, and hepatitis C in polymyositis/dermatomyositis. Infection with P jirovecii is frequently fatal in these patients. Other fungal infections seen in polymyositis/dermatomyositis include candidiasis and histoplasmosis.²

Since the approval of antitumor necrosis factor (anti-TNF) agents for RA in the late 1990s, as well as other more recent biologic agents, there has been heightened awareness of infectious complications in rheumatologic patients. A major concern with the anti-TNF agents is the risk of granulomatous infection, particularly mycobacterial disease and dimorphic fungal infections such as histoplasmosis and coccidioidomycosis. Formation of granulomas is the major host defense against mycobacterial infection and is mediated in large part by TNF-alpha. The precise risk of infection associated with each of the various biologic agents is still under study, and rates from randomized trials have differed from postmarketing surveillance studies. Important pathogens associated with biologic agents include Nocardia, CMV, Listeria, Aspergillus, and JC virus (JCV).^3,4 Delays in the diagnosis of these infections in immunocompromised patients have led to poor outcomes.

KEY PATHOGENS IN INFECTIONS OF IMMUNOCOMPROMISED HOSTS

Pneumocystis jirovecii

For many decades, P jirovecii was classified as a protozoan but, based on gene sequencing, the organism has been reclassified as a fungus. P jirovecii is a low-virulence, unicellular organism that is the causative agent of Pneumocystis pneumonia (PCP). Epidemiologically, primary infection most likely occurs in infants and children. Colonization may be transient, entering the airways and then resolving over a period of weeks or months. Alternatively, the organism may enter a latent state similar to tuberculosis with reactivation occurring during times of intense immunosuppression. However, molecular epidemiology studies show that new cases of PCP are likely environmentally acquired through multiple exposures rather than reactivation of latent infection.^5,6 Transmission is thought to be airborne from person to person. Pathogenically, the trophic form of the organism attaches to type 1 alveolar cells and remains in the extracellular compartment of the alveoli. This colonization evokes an influx of inflammatory cells (CD8 cells, neutrophils, and macrophages). However, not all colonizations result in pneumonia—even in advanced human immunodeficiency virus (HIV) infection. While there is an innate immunity through alveolar macrophages and pulmonary surfactant, alveolar macrophage response is impaired in HIV when the CD4 count is low. Cell-mediated immunity is the main defense against progression to pneumonia with assistance from costimulatory molecules (such as CD28 and CD2) as well as B cells.

Pathogenesis and clinical presentation of PCP. In HIV-infected patients with CD4 counts less than 200 cells/mm³, foamy eosinophilic interstitial debris may develop.⁷ HIV patients often present with subacute PCP after having symptoms for days to weeks. In non-HIV patients, the presentation is often more acute, at times with severe fulminant infection. Infected patients often experience dyspnea as well as nonproductive cough and fever. Examination may reveal crackles. Chest x-ray shows diffuse bilateral interstitial infiltrates and, less commonly, nodules, cavities, unilateral infiltrates, effusions, and spontaneous pneumothoraces. Lung examination can be clear, however, confounding the diagnosis. If chest x-ray shows reticular or interstitial infiltrates, one approach would be to obtain a bronchoalveolar lavage (BAL) or sputum sample. If the chest x-ray is clear but the suspicion of PCP is still high, the next step would be high-resolution computed tomography (CT). The finding of ground glass opacities is highly suggestive of P jirovecii, particularly in HIV patients. Sputum or BAL fluid should still be obtained to confirm the diagnosis of P jirovecii (Figure 1). If the CT is clear, then P jirovecii is unlikely, particularly in HIV-positive patients where, in one study, the sensitivity of the CT approaches 100%.⁸

Laboratory diagnosis. P jirovecii cannot be grown in culture for clinical purposes, and it is extremely difficult to culture even in the research setting. Cytologic stains such as the Wright-Giemsa and methamine silver stains are the mainstay of laboratory diagnosis. The yield for P jirovecii from routine expectorated sputum is very low and some laboratories discourage this approach. The sensitivity of nebulized sputum using hypertonic saline ranges from 50% to 90%.⁹

In patients with acquired immune deficiency syndrome (AIDS), bronchoscopy provides 90% to 98% sensitivity by BAL. Transbronchial biopsy may provide some additional yield over BAL in a few situations, such as patients who have been receiving partial P jirovecii prophylaxis. Immunofluorescence techniques using monoclonal antibodies to P jirovecii are commercially available and are first-line diagnostic tools in some laboratories. Recently, polymerase chain reaction (PCR) assay has been introduced into clinical practice as a reproducible test with high sensitivity.

Primary therapy. Primary therapy for PCP consists of trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine. TMP-SMX is considered the drug of choice and is usually administered intravenously for 21 days in HIV patients and 14 days for non-HIV patients. The oral form may be used in patients with less severe PCP with a functioning gastrointestinal tract. Common adverse reactions to TMP-SMX include rash, Stevens-Johnson syndrome, neutropenia, changes in pulmonary function, and nausea/vomiting/diarrhea.¹⁰ Pentamidine is as effective as TMP-SMX, but is associated with renal toxicity, hypotension, severe hypoglycemia, cardiac arrhythmias, and diabetes.¹¹ It is generally reserved for severe cases of PCP in patients who are allergic to or otherwise intolerant of sulfa. Other treatments include atovaquone and trimethoprim-dapsone. Adjunctive corticosteroids have been shown to be beneficial in moderate to severe PCP in HIV patients to reduce the local host inflammatory response to dead or dying organisms. Recent guidelines have recommended corticosteroids for HIV patients with PCP who have an arterial oxygen pressure of 70 mm Hg or less on room air, or an alveolar-arterial (A-a) gradient of oxygen 35 mm Hg or greater.¹² Little is known about the role of adjunctive corticosteroids in non-HIV patients, given a lack of clinical studies.

Prevention. Recent estimates of disease burden from a meta-analysis of 11,900 patients with connective tissue diseases found PCP in 12% of patients with GPA, in 6% of those with polydermatomyositis, in 5% of those with SLE, and in 1% of those with RA.¹ Mortality due to PCP is higher in patients with rheumatic diseases, ranging from 30% in RA to 63% in GPA, than in those with HIV (10% to 20%).¹³ One key risk factor predisposing patients with connective tissue diseases to infection with P jirovecii is recent corticosteroid use. Among patients with connective tissue disease, more than 90% of those infected with P jirovecii have recently received steroid therapy.¹⁴ Additionally, in almost all patients with P jirovecii, lymphopenia with absolute lymphocyte counts less than 1,000/mm³ is present.¹⁵

In patients with HIV, prophylaxis is initiated at a CD4 level of 200/mm³.¹³ However, the cutoff is less clear for non-HIV rheumatic patients. A cutoff of less than 300 cells/mm³ has been proposed for prophylaxis of PCP. However, at that range, approximately 50% of patients with connective tissue disease would remain above the threshold.¹³ One possible solution is to screen by PCR and treat colonization. Other algorithms have been proposed, but there is no general consensus on treatment of non-HIV rheumatic patients.^13,16 Generally, prophylaxis should be considered in patients at the highest risk for PCP. These include patients taking prednisone at doses greater than 20 mg/day for 1 month plus a cytotoxic agent, a TNF inhibitor plus glucocorticoids, and methotrexate plus glucocorticoids in GPA.¹³

 

Nocardia asteroides and Nocardia species

Nocardia species are ubiquitous bacteria found worldwide in soil, dust, and decaying material. On Gram stain the organism is weakly gram-positive with a filamentous “beaded” and branching appearance (Figure 2). Disease results from inhalation of contaminated material in the environment with subsequent lung colonization. Nocardiosis is an opportunistic infection generally seen in persons with defective T-cell (cell-mediated) immunity. Cases have been reported in patients with connective tissue diseases, including SLE, and RA treated with corticosteroids alone and corticosteroids plus methotrexate.^17–19 Nocardiosis has been increasingly recognized with anti-TNF therapy. Animal models have demonstrated that TNF plays an important role in clearance of Nocardia infections.²⁰ In one review, eight cases of nocardiosis were identified from some 300,000 patients receiving an anti-TNF agent.²¹

Classically, Nocardia infection results in abscess formation with infiltrates of polymorphonuclear cells, debris, and thin-walled abscesses. The most frequent site of primary infection is pulmonary. Characteristically, multiple pulmonary nodules or cavities are seen, and Nocardia should be considered in the differential diagnosis of an immunocompromised patient with nodular pneumonia. The nodules can also be masslike in appearance (greater than 2 cm). The presentation of new cavitary lung opacities with systemic symptoms may be mistaken for GPA.²²Nocardia may disseminate to the central nervous system (CNS), skin, joints, and spine, usually causing suppurative infection at these sites. Nocardia has a very strong tropism for neural tissue. In the CNS, Nocardia can cause single or multiple brain abscesses that may be asymptomatic; patients with pulmonary nocardiosis require imaging to rule out occult CNS involvement.

Nocardia species are resistant to several antibiotics. The treatment of choice for Nocardia species is TMPSMX, but imipenem, amikacin, third-generation cephalosporins, and other options such as minocycline and linezolid may be considered depending on the species and the antimicrobial susceptibility pattern.

Histoplasma capsulatum

Histoplasma capsulatum is a dimorphic fungus that causes disease in both healthy and immunocompromised hosts. The organism differs from other pathogenic fungi in that it is an intracellular organism, mainly involving the reticuloendothelial system, and is rarely in the extracellular space. In the United States, infections are clustered endemically in areas such as the Mississippi and Ohio River Valleys, but infections are common worldwide. The fungus is found in soil, mulch, bird excrement, and bat guano. Asymptomatic or mild infections are common in healthy persons residing in endemic areas and occur on a sporadic basis. Epidemics can occur when contaminated material is aerosolized. Histoplasmosis is also an opportunistic infection in patients with impaired T-cell immunity such as persons with AIDS, organ transplant recipients, hematologic malignancies, and corticosteroid use. Clinically significant cases of histoplasmosis have been described in patients with RA while receiving methotrexate alone, corticosteroids alone, and combinations of disease-modifying agents.²³ Histoplasmosis was recently identified in 240 patients in association with TNF inhibitors, translating to 17 per 100,000 patients treated with infliximab.^21,24

Pathogenesis. Infection initially occurs through inhalation of contaminated material from the environment, primarily causing pulmonary infection. The organism converts from a mold form in the environment to a pathogenic yeast form in the host. Once inhaled, the mediastinal lymph nodes provide the first line of defense. Following draining of the lymph nodes, the organism enters the bloodstream in both immunocompetent and immunosuppressed patients. It is spread hematogenously into the spleen, liver, and reticulo-endothelial system, where it is eventually cleared. In immunocompetent patients, cellular immunity limits infection within 7 to 14 days and humoral immunity is not protective.²⁵ Granuloma formation is the hallmark of host defense.

Spectrum of illness. Histoplasmosis is associated with a wide spectrum of illness, with presentation ranging from asymptomatic to mild pulmonary illness to overwhelming pneumonia. Symptomatic pulmonary histoplasmosis typically presents with fever, flulike symptoms, and cough, often with retrosternal chest pain. X-rays show patchy or nodular infiltrates, with hilar or mediastinal lymphadenopathy. In some cases the lung parenchyma is clear and the main feature is fever and bilateral hilar adenopathy. Pulmonary histoplasmosis may be difficult to distinguish from sarcoidosis and tuberculosis. Extrapulmonary disease can present as hepatitis, infective endocarditis, and chronic meningitis. In immunocompromised patients, histoplasmosis can present as a progressive disseminated disease which can be acute, subacute, or chronic. Chronic disseminated histoplasmosis is characterized by cough, persistent fever, wasting, hepatosplenomegaly, oral ulcerations, and progressive cytopenias. Acute disseminated histoplasmosis has a much more fulminant course characterized by respiratory insufficiency, hypotension, multisystem organ failure, coagulopathies, and encephalopathy. Histoplasmosis is primarily a pulmonary disease, but in disseminated disease more than 50% of patients have no pulmonary symptoms and 30% may have normal chest x-rays.²⁶ In one series of infliximab-related cases (n = 10), all came from an endemic area 1 week to 6 months after the first dose of infliximab. Patients presented with cough, fever, and shortness of breath.²⁷ The pathogenesis of histoplasmosis in patients receiving TNF inhibitors is not entirely clear; such patients may be suffering a new primary infection, a reinfection, or, least likely, reactivation of latent infection.

Definitive diagnosis requires culture confirmation from appropriate body fluids or identification of characteristic yeast forms from histopathologic sections of tissue biopsies. Serologic tests may also be used to confirm the diagnosis. Detection of H and M precipitins or bands by immunodiffusion is a routine test in many laboratories. M bands are present in 50% of acute cases but their presence does not distinguish acute from remote infection. H bands are present in only 10% of all acute cases, but their presence is very specific for acute histoplasmosis.²⁸

When looking at complement fixation antibodies to yeast (HY) and mycelial (HMy) forms in pulmonary histoplasmosis, a fourfold rise in titer establishes the diagnosis retrospectively, and a single titer greater than 1:32 is strongly suggestive of active infection. However, in progressive disseminated histoplasmosis, the complement fixation antibodies are frequently negative.²⁹ Detection of antigen in urine and serum by enzyme immunoassay has become a mainstay of diagnosis, with a sensitivity of approximately 90% in progressive disseminated disease.³⁰ Of note, most cases of histoplasmosis associated with biologic agents have detectable urinary antigen tests.

Treatment. Acute pulmonary histoplasmosis is usually self-limited, requiring no treatment. The 2007 Infective Diseases Society of America (IDSA) guidelines recommend observation alone in most cases of mild to moderate pulmonary histoplasmosis unless symptoms persist longer than 1 month. For moderately severe or severe acute pulmonary histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 to 5.0 mg/kg/day) or deosycholate amphotericin B (0.7 to 1.0 mg/kg/day) for 1 to 2 weeks followed by itraconazole 200 mg twice daily for a total of 12 weeks. Methylprednisolone at a dose of 0.5 to 1.0 mg/kg/day intravenously for 1 to 2 weeks is also recommended. For moderately severe to severe disseminated histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 mg/kg/day) for 1 to 2 weeks followed by oral itraconazole 200 mg three times daily for 3 days and then 200 mg twice daily for a total of at least 12 months.³¹ Commonly, the immunosuppressive agent is held during treatment.

 

 

Aspergillus species

Another emerging pathogen is Aspergillus species—a ubiquitous mold spread by aerosols of spores. There are many different species of Aspergillus, but the most common human pathogens include A fumigates, A niger, and A flavus. To date, 39 cases of Aspergillus infection associated with infliximab and etanercept have been reported in the Adverse Event Reporting System, translating to 9 to 12 cases per 100,000 patients.²¹

Manifestations of the various types of Aspergillus infection include invasive pulmonary aspergillosis, which is classically a cavitary disease with a halo effect; chronic necrotizing pneumonia, which has no specific identifying characteristics; and disseminated CNS aspergillosis, causing abscesses in immunosuppressed patients (Figure 3).

Varicella zoster

Herpes zoster infection is caused by reactivation of latent infection. In the United States, 95% of adults are seropositive for herpes zoster with a 10% to 30% lifetime risk of zoster reactivation.³² It is the most common viral infection in multiple series of patients with connective tissue diseases. In a multivariate analysis by Wolfe et al³³ of patients with RA, cyclophosphamide (hazard ratio [HR] 4.2), azathioprine (HR 2.0), and prednisone (HR 1.5) were significant predictors of herpes zoster. TNF inhibitor risk (HR 1.82) is less clear, with studies demonstrating no definitively increased risk. Manifestations of herpes zoster include localized disease (thoracic zoster as the most common presentation), disseminated cutaneous zoster, and disseminated visceral zoster (with encephalitis, myelitis, and angiitis) (Figure 4).

JC virus

More than 80% of adults are seropositive for JCV, a DNA virus of the genus Polyomavirus that causes lytic infection of oligodendrocytes.³⁴ In immunocompromised hosts, JCV causes progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease. PML was first described in malignancy, leukemia, and various other immunocompromised states, prior to its strong association with AIDS in the 1980s. More recently, JCV has been associated with natalizumab for multiple sclerosis and Crohn disease, rituximab for oncology patients, efalizumab for psoriasis,³⁵ and mycophenolate mofetil for transplant recipients.³⁶

In 2006 the US Food and Drug Administration issued a safety alert regarding PML in two patients with SLE treated with rituximab and other immunosuppressives.³⁷ In a review of PML in rheumatic disease, 36 cases were identified in patients who had not previously received a biologic agent. Most of these patients (60%) had SLE.³⁸ Of these, many had little or no immunosuppression over the 6 months prior to the diagnosis of PML, suggesting that SLE itself may predispose to PML. Interestingly, PML is rarely associated with TNF inhibitors.

Classic presentation of PML includes motor weakness, aphasia, dysarthria, vision loss, and cognitive loss. Atypical presentation includes seizures, headaches, and brainstem involvement. PML usually spares the optic nerves, spinal cord, peripheral nerves, and muscles. In persons with underlying rheumatic diseases, PML can be difficult to distinguish from neuropsychiatric SLE or CNS vasculitis.

Diagnosis. On magnetic resonance imaging, typical presentation of PML shows T2 and fluid attenuated inversion recovery hyperintense regions in the white matter, asymmetric parietal and occipital radiations, and occasional cerebellum and basal ganglia involvement (Figure 5). If magnetic resonance imaging is normal, PML usually can be excluded. Cerebrospinal fluid examination shows a mean of 7 white blood cells/μL. PCR for JCV in cerebrospinal fluid has a specificity of close to 100% in persons with advanced HIV based on data prior to the use of highly active antiretroviral therapy.³⁹ Sensitivity using older assays is approximately 70% to 90% while the sensitivity of newer quantitative “ultrasensitive” PCR assays is greater than 90%.^40,41

Treatment. In clinical trials no antiviral agent has been effective in the treatment of PML. In HIV patients who develop PML, highly active antiretroviral therapy should be initiated (if antiretroviral-naïve) or existing antiviral regimens optimized. Antiretroviral therapy in this situation may stabilize disease and possibly increase survival.⁴² For HIV-negative patients who develop PML, the cornerstone of management is immediate decrease or discontinuation of immunosuppression.⁴³ Several adjunctive measures have been reported mainly in natalizumab-associated PML, including corticosteroids, mirtazapine, plasma exchange, and others.

VACCINES

Vaccination is important in the prevention of infectious disease in immunocompromised patients with connective tissue diseases. Because live vaccines are contraindicated in immunocompromised patients, inactivated or component vaccines should be used. It is recommended that patients who will start immunosuppressive therapy be vaccinated 2 to 4 weeks before beginning therapy. If this is not possible, vaccination should be administered during disease remission, 3 months after immunosuppression and 1 to 3 months after administration of high-dose corticosteroids.

Table 1 lists common live (attenuated) vaccines and inactivated vaccines. Live influenza vaccine is available as a nasal spray, but that route of administration is contraindicated in immunocompromised patients and those aged over 50 years. To further define the contraindications in immunocompromised patients, corticosteroids are not a contraindication to live-virus vaccines when corticosteroid administration is:

• Short-term (less than 14 days)
• At a dose of less than 20 mg/day of prednisone or equivalent
• Long-term on alternate days with short-acting preparations
• At a physiologic dose of prednisone
• Topical, inhaled, intra-articular, bursal, or via tendon.⁴⁴

No data are available to guide immunization while a patient is taking anti-TNF agents, but the Centers for Disease Control and Prevention (CDC) recommend “caution in the use of live vaccines” with these drugs with “avoidance” unless the benefit, by case, greatly outweighs the risk.⁴⁴ Similarly, there are no data on vaccine safety or specific recommendations with rituximab treatment. However, following the recommendations for “functional asplenia” in the CDC guidelines, pneumococcal, meningococcal, and Haemophilus influenzae type b (Hib) vaccine (if not given in infancy) would be indicated. Table 2 summarizes the CDC recommendations for vaccinating immunocompromised adults (excluding those with HIV).

Until definitive guidelines are developed, practitioners must evaluate and treat each patient individually to maximize the efficacy of disease treatments while preventing infection morbidity and mortality in their patients with connective tissue diseases.

In 2007, Falagas et al¹ provided a systematic review of studies focusing on infection-related morbidity and mortality in patients with connective tissue diseases. Many of the studies reviewed were published prior to the introduction of biologic agents for the treatment of rheumatologic disorders. In 39 studies focusing on infection incidence, patient outcomes, or both in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis, granulomatosis with polyangiitis (GPA, [Wegener’s granulomatosis]), and systemic sclerosis, serious infection developed in 29% of patients and 24% of these died due to the infection with a median attributable mortality of 5.2%. Most of the reported infections were common bacterial syndromes such as pneumonia or bacteremia, and opportunistic fungal (Pneumocystis) infections.

Similarly, in 2006 Alarcón² reported that 25% to 50% of patients with SLE had significant morbidity primarily from common bacterial infections, with viral, fungal, and parasitic infection less common. Staphylococcus aureus was a common cause of soft tissue infection, septic arthritis, and bacteremia. Streptococcus pneumoniae typically caused respiratory infections, although meningitis and sepsis were reported with SLE. Gram-negative bacteria such as Escherichia coli, Klebsiella species, and Pseudomonas species usually caused urinary tract infections and nosocomial pneumonia. Other bacterial infections included Nocardia species, Mycobacterium tuberculosis, and, rarely, Listeria monocytogenes. The most common viral infection was herpes zoster. Fungal infections included Pneumocystis jirovecii (formerly known as Pneumocystis carinii) and Candida species.

In scleroderma, another connective tissue disease evaluated in the literature by Alarcón,² reports of bacterial, viral, and fungal infections are limited to case reports. In scleroderma patients, viral infections with cytomegalovirus (CMV), parvovirus B19, and P jirovecii were similar to pathogens observed with SLE.

In polymyositis/dermatomyositis, gram-positive pneumonia affected 15% to 20% of patients and S aureus occurred frequently in the juvenile form of the disease. Herpes zoster was commonly observed, but CMV was relatively rare. Other viral infections included Coxsackie virus, parvovirus B19, and hepatitis C in polymyositis/dermatomyositis. Infection with P jirovecii is frequently fatal in these patients. Other fungal infections seen in polymyositis/dermatomyositis include candidiasis and histoplasmosis.²

Since the approval of antitumor necrosis factor (anti-TNF) agents for RA in the late 1990s, as well as other more recent biologic agents, there has been heightened awareness of infectious complications in rheumatologic patients. A major concern with the anti-TNF agents is the risk of granulomatous infection, particularly mycobacterial disease and dimorphic fungal infections such as histoplasmosis and coccidioidomycosis. Formation of granulomas is the major host defense against mycobacterial infection and is mediated in large part by TNF-alpha. The precise risk of infection associated with each of the various biologic agents is still under study, and rates from randomized trials have differed from postmarketing surveillance studies. Important pathogens associated with biologic agents include Nocardia, CMV, Listeria, Aspergillus, and JC virus (JCV).^3,4 Delays in the diagnosis of these infections in immunocompromised patients have led to poor outcomes.

KEY PATHOGENS IN INFECTIONS OF IMMUNOCOMPROMISED HOSTS

Pneumocystis jirovecii

For many decades, P jirovecii was classified as a protozoan but, based on gene sequencing, the organism has been reclassified as a fungus. P jirovecii is a low-virulence, unicellular organism that is the causative agent of Pneumocystis pneumonia (PCP). Epidemiologically, primary infection most likely occurs in infants and children. Colonization may be transient, entering the airways and then resolving over a period of weeks or months. Alternatively, the organism may enter a latent state similar to tuberculosis with reactivation occurring during times of intense immunosuppression. However, molecular epidemiology studies show that new cases of PCP are likely environmentally acquired through multiple exposures rather than reactivation of latent infection.^5,6 Transmission is thought to be airborne from person to person. Pathogenically, the trophic form of the organism attaches to type 1 alveolar cells and remains in the extracellular compartment of the alveoli. This colonization evokes an influx of inflammatory cells (CD8 cells, neutrophils, and macrophages). However, not all colonizations result in pneumonia—even in advanced human immunodeficiency virus (HIV) infection. While there is an innate immunity through alveolar macrophages and pulmonary surfactant, alveolar macrophage response is impaired in HIV when the CD4 count is low. Cell-mediated immunity is the main defense against progression to pneumonia with assistance from costimulatory molecules (such as CD28 and CD2) as well as B cells.

Pathogenesis and clinical presentation of PCP. In HIV-infected patients with CD4 counts less than 200 cells/mm³, foamy eosinophilic interstitial debris may develop.⁷ HIV patients often present with subacute PCP after having symptoms for days to weeks. In non-HIV patients, the presentation is often more acute, at times with severe fulminant infection. Infected patients often experience dyspnea as well as nonproductive cough and fever. Examination may reveal crackles. Chest x-ray shows diffuse bilateral interstitial infiltrates and, less commonly, nodules, cavities, unilateral infiltrates, effusions, and spontaneous pneumothoraces. Lung examination can be clear, however, confounding the diagnosis. If chest x-ray shows reticular or interstitial infiltrates, one approach would be to obtain a bronchoalveolar lavage (BAL) or sputum sample. If the chest x-ray is clear but the suspicion of PCP is still high, the next step would be high-resolution computed tomography (CT). The finding of ground glass opacities is highly suggestive of P jirovecii, particularly in HIV patients. Sputum or BAL fluid should still be obtained to confirm the diagnosis of P jirovecii (Figure 1). If the CT is clear, then P jirovecii is unlikely, particularly in HIV-positive patients where, in one study, the sensitivity of the CT approaches 100%.⁸

Laboratory diagnosis. P jirovecii cannot be grown in culture for clinical purposes, and it is extremely difficult to culture even in the research setting. Cytologic stains such as the Wright-Giemsa and methamine silver stains are the mainstay of laboratory diagnosis. The yield for P jirovecii from routine expectorated sputum is very low and some laboratories discourage this approach. The sensitivity of nebulized sputum using hypertonic saline ranges from 50% to 90%.⁹

In patients with acquired immune deficiency syndrome (AIDS), bronchoscopy provides 90% to 98% sensitivity by BAL. Transbronchial biopsy may provide some additional yield over BAL in a few situations, such as patients who have been receiving partial P jirovecii prophylaxis. Immunofluorescence techniques using monoclonal antibodies to P jirovecii are commercially available and are first-line diagnostic tools in some laboratories. Recently, polymerase chain reaction (PCR) assay has been introduced into clinical practice as a reproducible test with high sensitivity.

Primary therapy. Primary therapy for PCP consists of trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine. TMP-SMX is considered the drug of choice and is usually administered intravenously for 21 days in HIV patients and 14 days for non-HIV patients. The oral form may be used in patients with less severe PCP with a functioning gastrointestinal tract. Common adverse reactions to TMP-SMX include rash, Stevens-Johnson syndrome, neutropenia, changes in pulmonary function, and nausea/vomiting/diarrhea.¹⁰ Pentamidine is as effective as TMP-SMX, but is associated with renal toxicity, hypotension, severe hypoglycemia, cardiac arrhythmias, and diabetes.¹¹ It is generally reserved for severe cases of PCP in patients who are allergic to or otherwise intolerant of sulfa. Other treatments include atovaquone and trimethoprim-dapsone. Adjunctive corticosteroids have been shown to be beneficial in moderate to severe PCP in HIV patients to reduce the local host inflammatory response to dead or dying organisms. Recent guidelines have recommended corticosteroids for HIV patients with PCP who have an arterial oxygen pressure of 70 mm Hg or less on room air, or an alveolar-arterial (A-a) gradient of oxygen 35 mm Hg or greater.¹² Little is known about the role of adjunctive corticosteroids in non-HIV patients, given a lack of clinical studies.

Prevention. Recent estimates of disease burden from a meta-analysis of 11,900 patients with connective tissue diseases found PCP in 12% of patients with GPA, in 6% of those with polydermatomyositis, in 5% of those with SLE, and in 1% of those with RA.¹ Mortality due to PCP is higher in patients with rheumatic diseases, ranging from 30% in RA to 63% in GPA, than in those with HIV (10% to 20%).¹³ One key risk factor predisposing patients with connective tissue diseases to infection with P jirovecii is recent corticosteroid use. Among patients with connective tissue disease, more than 90% of those infected with P jirovecii have recently received steroid therapy.¹⁴ Additionally, in almost all patients with P jirovecii, lymphopenia with absolute lymphocyte counts less than 1,000/mm³ is present.¹⁵

In patients with HIV, prophylaxis is initiated at a CD4 level of 200/mm³.¹³ However, the cutoff is less clear for non-HIV rheumatic patients. A cutoff of less than 300 cells/mm³ has been proposed for prophylaxis of PCP. However, at that range, approximately 50% of patients with connective tissue disease would remain above the threshold.¹³ One possible solution is to screen by PCR and treat colonization. Other algorithms have been proposed, but there is no general consensus on treatment of non-HIV rheumatic patients.^13,16 Generally, prophylaxis should be considered in patients at the highest risk for PCP. These include patients taking prednisone at doses greater than 20 mg/day for 1 month plus a cytotoxic agent, a TNF inhibitor plus glucocorticoids, and methotrexate plus glucocorticoids in GPA.¹³

 

Nocardia asteroides and Nocardia species

Nocardia species are ubiquitous bacteria found worldwide in soil, dust, and decaying material. On Gram stain the organism is weakly gram-positive with a filamentous “beaded” and branching appearance (Figure 2). Disease results from inhalation of contaminated material in the environment with subsequent lung colonization. Nocardiosis is an opportunistic infection generally seen in persons with defective T-cell (cell-mediated) immunity. Cases have been reported in patients with connective tissue diseases, including SLE, and RA treated with corticosteroids alone and corticosteroids plus methotrexate.^17–19 Nocardiosis has been increasingly recognized with anti-TNF therapy. Animal models have demonstrated that TNF plays an important role in clearance of Nocardia infections.²⁰ In one review, eight cases of nocardiosis were identified from some 300,000 patients receiving an anti-TNF agent.²¹

Classically, Nocardia infection results in abscess formation with infiltrates of polymorphonuclear cells, debris, and thin-walled abscesses. The most frequent site of primary infection is pulmonary. Characteristically, multiple pulmonary nodules or cavities are seen, and Nocardia should be considered in the differential diagnosis of an immunocompromised patient with nodular pneumonia. The nodules can also be masslike in appearance (greater than 2 cm). The presentation of new cavitary lung opacities with systemic symptoms may be mistaken for GPA.²²Nocardia may disseminate to the central nervous system (CNS), skin, joints, and spine, usually causing suppurative infection at these sites. Nocardia has a very strong tropism for neural tissue. In the CNS, Nocardia can cause single or multiple brain abscesses that may be asymptomatic; patients with pulmonary nocardiosis require imaging to rule out occult CNS involvement.

Nocardia species are resistant to several antibiotics. The treatment of choice for Nocardia species is TMPSMX, but imipenem, amikacin, third-generation cephalosporins, and other options such as minocycline and linezolid may be considered depending on the species and the antimicrobial susceptibility pattern.

Histoplasma capsulatum

Histoplasma capsulatum is a dimorphic fungus that causes disease in both healthy and immunocompromised hosts. The organism differs from other pathogenic fungi in that it is an intracellular organism, mainly involving the reticuloendothelial system, and is rarely in the extracellular space. In the United States, infections are clustered endemically in areas such as the Mississippi and Ohio River Valleys, but infections are common worldwide. The fungus is found in soil, mulch, bird excrement, and bat guano. Asymptomatic or mild infections are common in healthy persons residing in endemic areas and occur on a sporadic basis. Epidemics can occur when contaminated material is aerosolized. Histoplasmosis is also an opportunistic infection in patients with impaired T-cell immunity such as persons with AIDS, organ transplant recipients, hematologic malignancies, and corticosteroid use. Clinically significant cases of histoplasmosis have been described in patients with RA while receiving methotrexate alone, corticosteroids alone, and combinations of disease-modifying agents.²³ Histoplasmosis was recently identified in 240 patients in association with TNF inhibitors, translating to 17 per 100,000 patients treated with infliximab.^21,24

Pathogenesis. Infection initially occurs through inhalation of contaminated material from the environment, primarily causing pulmonary infection. The organism converts from a mold form in the environment to a pathogenic yeast form in the host. Once inhaled, the mediastinal lymph nodes provide the first line of defense. Following draining of the lymph nodes, the organism enters the bloodstream in both immunocompetent and immunosuppressed patients. It is spread hematogenously into the spleen, liver, and reticulo-endothelial system, where it is eventually cleared. In immunocompetent patients, cellular immunity limits infection within 7 to 14 days and humoral immunity is not protective.²⁵ Granuloma formation is the hallmark of host defense.

Spectrum of illness. Histoplasmosis is associated with a wide spectrum of illness, with presentation ranging from asymptomatic to mild pulmonary illness to overwhelming pneumonia. Symptomatic pulmonary histoplasmosis typically presents with fever, flulike symptoms, and cough, often with retrosternal chest pain. X-rays show patchy or nodular infiltrates, with hilar or mediastinal lymphadenopathy. In some cases the lung parenchyma is clear and the main feature is fever and bilateral hilar adenopathy. Pulmonary histoplasmosis may be difficult to distinguish from sarcoidosis and tuberculosis. Extrapulmonary disease can present as hepatitis, infective endocarditis, and chronic meningitis. In immunocompromised patients, histoplasmosis can present as a progressive disseminated disease which can be acute, subacute, or chronic. Chronic disseminated histoplasmosis is characterized by cough, persistent fever, wasting, hepatosplenomegaly, oral ulcerations, and progressive cytopenias. Acute disseminated histoplasmosis has a much more fulminant course characterized by respiratory insufficiency, hypotension, multisystem organ failure, coagulopathies, and encephalopathy. Histoplasmosis is primarily a pulmonary disease, but in disseminated disease more than 50% of patients have no pulmonary symptoms and 30% may have normal chest x-rays.²⁶ In one series of infliximab-related cases (n = 10), all came from an endemic area 1 week to 6 months after the first dose of infliximab. Patients presented with cough, fever, and shortness of breath.²⁷ The pathogenesis of histoplasmosis in patients receiving TNF inhibitors is not entirely clear; such patients may be suffering a new primary infection, a reinfection, or, least likely, reactivation of latent infection.

Definitive diagnosis requires culture confirmation from appropriate body fluids or identification of characteristic yeast forms from histopathologic sections of tissue biopsies. Serologic tests may also be used to confirm the diagnosis. Detection of H and M precipitins or bands by immunodiffusion is a routine test in many laboratories. M bands are present in 50% of acute cases but their presence does not distinguish acute from remote infection. H bands are present in only 10% of all acute cases, but their presence is very specific for acute histoplasmosis.²⁸

When looking at complement fixation antibodies to yeast (HY) and mycelial (HMy) forms in pulmonary histoplasmosis, a fourfold rise in titer establishes the diagnosis retrospectively, and a single titer greater than 1:32 is strongly suggestive of active infection. However, in progressive disseminated histoplasmosis, the complement fixation antibodies are frequently negative.²⁹ Detection of antigen in urine and serum by enzyme immunoassay has become a mainstay of diagnosis, with a sensitivity of approximately 90% in progressive disseminated disease.³⁰ Of note, most cases of histoplasmosis associated with biologic agents have detectable urinary antigen tests.

Treatment. Acute pulmonary histoplasmosis is usually self-limited, requiring no treatment. The 2007 Infective Diseases Society of America (IDSA) guidelines recommend observation alone in most cases of mild to moderate pulmonary histoplasmosis unless symptoms persist longer than 1 month. For moderately severe or severe acute pulmonary histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 to 5.0 mg/kg/day) or deosycholate amphotericin B (0.7 to 1.0 mg/kg/day) for 1 to 2 weeks followed by itraconazole 200 mg twice daily for a total of 12 weeks. Methylprednisolone at a dose of 0.5 to 1.0 mg/kg/day intravenously for 1 to 2 weeks is also recommended. For moderately severe to severe disseminated histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 mg/kg/day) for 1 to 2 weeks followed by oral itraconazole 200 mg three times daily for 3 days and then 200 mg twice daily for a total of at least 12 months.³¹ Commonly, the immunosuppressive agent is held during treatment.

 

 

Aspergillus species

Another emerging pathogen is Aspergillus species—a ubiquitous mold spread by aerosols of spores. There are many different species of Aspergillus, but the most common human pathogens include A fumigates, A niger, and A flavus. To date, 39 cases of Aspergillus infection associated with infliximab and etanercept have been reported in the Adverse Event Reporting System, translating to 9 to 12 cases per 100,000 patients.²¹

Manifestations of the various types of Aspergillus infection include invasive pulmonary aspergillosis, which is classically a cavitary disease with a halo effect; chronic necrotizing pneumonia, which has no specific identifying characteristics; and disseminated CNS aspergillosis, causing abscesses in immunosuppressed patients (Figure 3).

Varicella zoster

Herpes zoster infection is caused by reactivation of latent infection. In the United States, 95% of adults are seropositive for herpes zoster with a 10% to 30% lifetime risk of zoster reactivation.³² It is the most common viral infection in multiple series of patients with connective tissue diseases. In a multivariate analysis by Wolfe et al³³ of patients with RA, cyclophosphamide (hazard ratio [HR] 4.2), azathioprine (HR 2.0), and prednisone (HR 1.5) were significant predictors of herpes zoster. TNF inhibitor risk (HR 1.82) is less clear, with studies demonstrating no definitively increased risk. Manifestations of herpes zoster include localized disease (thoracic zoster as the most common presentation), disseminated cutaneous zoster, and disseminated visceral zoster (with encephalitis, myelitis, and angiitis) (Figure 4).

JC virus

More than 80% of adults are seropositive for JCV, a DNA virus of the genus Polyomavirus that causes lytic infection of oligodendrocytes.³⁴ In immunocompromised hosts, JCV causes progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease. PML was first described in malignancy, leukemia, and various other immunocompromised states, prior to its strong association with AIDS in the 1980s. More recently, JCV has been associated with natalizumab for multiple sclerosis and Crohn disease, rituximab for oncology patients, efalizumab for psoriasis,³⁵ and mycophenolate mofetil for transplant recipients.³⁶

In 2006 the US Food and Drug Administration issued a safety alert regarding PML in two patients with SLE treated with rituximab and other immunosuppressives.³⁷ In a review of PML in rheumatic disease, 36 cases were identified in patients who had not previously received a biologic agent. Most of these patients (60%) had SLE.³⁸ Of these, many had little or no immunosuppression over the 6 months prior to the diagnosis of PML, suggesting that SLE itself may predispose to PML. Interestingly, PML is rarely associated with TNF inhibitors.

Classic presentation of PML includes motor weakness, aphasia, dysarthria, vision loss, and cognitive loss. Atypical presentation includes seizures, headaches, and brainstem involvement. PML usually spares the optic nerves, spinal cord, peripheral nerves, and muscles. In persons with underlying rheumatic diseases, PML can be difficult to distinguish from neuropsychiatric SLE or CNS vasculitis.

Diagnosis. On magnetic resonance imaging, typical presentation of PML shows T2 and fluid attenuated inversion recovery hyperintense regions in the white matter, asymmetric parietal and occipital radiations, and occasional cerebellum and basal ganglia involvement (Figure 5). If magnetic resonance imaging is normal, PML usually can be excluded. Cerebrospinal fluid examination shows a mean of 7 white blood cells/μL. PCR for JCV in cerebrospinal fluid has a specificity of close to 100% in persons with advanced HIV based on data prior to the use of highly active antiretroviral therapy.³⁹ Sensitivity using older assays is approximately 70% to 90% while the sensitivity of newer quantitative “ultrasensitive” PCR assays is greater than 90%.^40,41

Treatment. In clinical trials no antiviral agent has been effective in the treatment of PML. In HIV patients who develop PML, highly active antiretroviral therapy should be initiated (if antiretroviral-naïve) or existing antiviral regimens optimized. Antiretroviral therapy in this situation may stabilize disease and possibly increase survival.⁴² For HIV-negative patients who develop PML, the cornerstone of management is immediate decrease or discontinuation of immunosuppression.⁴³ Several adjunctive measures have been reported mainly in natalizumab-associated PML, including corticosteroids, mirtazapine, plasma exchange, and others.

VACCINES

Vaccination is important in the prevention of infectious disease in immunocompromised patients with connective tissue diseases. Because live vaccines are contraindicated in immunocompromised patients, inactivated or component vaccines should be used. It is recommended that patients who will start immunosuppressive therapy be vaccinated 2 to 4 weeks before beginning therapy. If this is not possible, vaccination should be administered during disease remission, 3 months after immunosuppression and 1 to 3 months after administration of high-dose corticosteroids.

Table 1 lists common live (attenuated) vaccines and inactivated vaccines. Live influenza vaccine is available as a nasal spray, but that route of administration is contraindicated in immunocompromised patients and those aged over 50 years. To further define the contraindications in immunocompromised patients, corticosteroids are not a contraindication to live-virus vaccines when corticosteroid administration is:

• Short-term (less than 14 days)
• At a dose of less than 20 mg/day of prednisone or equivalent
• Long-term on alternate days with short-acting preparations
• At a physiologic dose of prednisone
• Topical, inhaled, intra-articular, bursal, or via tendon.⁴⁴

No data are available to guide immunization while a patient is taking anti-TNF agents, but the Centers for Disease Control and Prevention (CDC) recommend “caution in the use of live vaccines” with these drugs with “avoidance” unless the benefit, by case, greatly outweighs the risk.⁴⁴ Similarly, there are no data on vaccine safety or specific recommendations with rituximab treatment. However, following the recommendations for “functional asplenia” in the CDC guidelines, pneumococcal, meningococcal, and Haemophilus influenzae type b (Hib) vaccine (if not given in infancy) would be indicated. Table 2 summarizes the CDC recommendations for vaccinating immunocompromised adults (excluding those with HIV).

Until definitive guidelines are developed, practitioners must evaluate and treat each patient individually to maximize the efficacy of disease treatments while preventing infection morbidity and mortality in their patients with connective tissue diseases.