Pulmonology

Researchers used a machine learning algorithm to identify a molecular signature for usual interstitial pneumonia in patients with suspected idiopathic pulmonary fibrosis, according to recent research published in the Lancet Respiratory Medicine.

The results of the molecular test, called the Envisia Genomic Classifier (Veracyte; San Francisco), had a high positive predictive value of proven usual interstitial pneumonia, and could be used in place of surgical lung biopsy to confirm a diagnosis of idiopathic pulmonary fibrosis (IPF), wrote Ganesh Raghu, MD, director at the Center for Interstitial Lung Diseases and professor of medicine at the University of Washington, Seattle, and his colleagues.* The Envisia Genomic Classifier recently received final Medicare local coverage determination for IPF diagnosis, according to a recent press release by Veracyte.

“IPF is often challenging to distinguish from other [interstitial lung disease], but timely and accurate diagnosis is critical so that patients with IPF can access therapies that may slow progression of the disease, while avoiding potentially harmful treatments,” Dr. Raghu stated in a press release. “Our results with molecular classification through machine learning [the Envisia classifier] are promising and, along with clinical information and radiological features in high-resolution CT imaging, physicians through multidisciplinary discussions, may be able to utilize the molecular classification as a diagnostic tool to make a more informed and confident diagnoses.”

The researchers prospectively recruited 237 patients from 29 centers in the United States and Europe who were evaluated with the Bronchial Sample Collection for a Novel Genomic Test for suspected interstitial lung disease and who underwent surgical biopsy, transbronchial biopsy, or cryobiopsy for sample collection. They used histopathology and RNA sequence data from 90 patients to create a training data set of an unusual interstitial pneumonia pattern for the machine learning algorithm.

The classifier found usual interstitial pneumonia diagnoses in 49 patients; the test had a specificity of 88% (95% confidence interval, 70%-98%) and a sensitivity of 70% (95% CI, 47%-87%). Of 42 patients with inconsistent or possible usual interstitial pneumonia identified from high-resolution CT imaging, there was a positive predictive value of 81% (95% CI, 54%-96%). When multidisciplinary teams made diagnoses with the molecular classifier data, there was a clinical agreement of 86% (95% CI, 78%-92%) with diagnoses made using histopathology data. In 18 cases of IPF, there was an improvement in diagnostic confidence using the molecular classifier data, with 89% of diagnoses designated as high confidence, compared with 56% of cases based on histopathologic data (P = .0339). In 48 patients with nondiagnostic pathology or nonclassifiable fibrosis histopathology, 63% of diagnoses with the molecular classifier data were high confidence, compared with 42% using histopathologic data (P = .0412).

This study was funded by Veracyte, creator of the Envisia Genomic Classifier. Some authors reported relationships with Veracyte and other companies.

SOURCE: Raghu G et al. Lancet Respir Med. 2019 Apr 1. doi: 10.1016/S2213-8587(19)300.

Correction, 4/25/19: An earlier version of this article misstated how the Envisia Genomic Classifier could be used. The Envisia test is not intended to replace high-resolution chest CT (HRCT). It is used when HRCT is inconclusive to help prevent patients from having to undergo invasive diagnostic procedures.

Researchers used a machine learning algorithm to identify a molecular signature for usual interstitial pneumonia in patients with suspected idiopathic pulmonary fibrosis, according to recent research published in the Lancet Respiratory Medicine.

The results of the molecular test, called the Envisia Genomic Classifier (Veracyte; San Francisco), had a high positive predictive value of proven usual interstitial pneumonia, and could be used in place of surgical lung biopsy to confirm a diagnosis of idiopathic pulmonary fibrosis (IPF), wrote Ganesh Raghu, MD, director at the Center for Interstitial Lung Diseases and professor of medicine at the University of Washington, Seattle, and his colleagues.* The Envisia Genomic Classifier recently received final Medicare local coverage determination for IPF diagnosis, according to a recent press release by Veracyte.

“IPF is often challenging to distinguish from other [interstitial lung disease], but timely and accurate diagnosis is critical so that patients with IPF can access therapies that may slow progression of the disease, while avoiding potentially harmful treatments,” Dr. Raghu stated in a press release. “Our results with molecular classification through machine learning [the Envisia classifier] are promising and, along with clinical information and radiological features in high-resolution CT imaging, physicians through multidisciplinary discussions, may be able to utilize the molecular classification as a diagnostic tool to make a more informed and confident diagnoses.”

The researchers prospectively recruited 237 patients from 29 centers in the United States and Europe who were evaluated with the Bronchial Sample Collection for a Novel Genomic Test for suspected interstitial lung disease and who underwent surgical biopsy, transbronchial biopsy, or cryobiopsy for sample collection. They used histopathology and RNA sequence data from 90 patients to create a training data set of an unusual interstitial pneumonia pattern for the machine learning algorithm.

The classifier found usual interstitial pneumonia diagnoses in 49 patients; the test had a specificity of 88% (95% confidence interval, 70%-98%) and a sensitivity of 70% (95% CI, 47%-87%). Of 42 patients with inconsistent or possible usual interstitial pneumonia identified from high-resolution CT imaging, there was a positive predictive value of 81% (95% CI, 54%-96%). When multidisciplinary teams made diagnoses with the molecular classifier data, there was a clinical agreement of 86% (95% CI, 78%-92%) with diagnoses made using histopathology data. In 18 cases of IPF, there was an improvement in diagnostic confidence using the molecular classifier data, with 89% of diagnoses designated as high confidence, compared with 56% of cases based on histopathologic data (P = .0339). In 48 patients with nondiagnostic pathology or nonclassifiable fibrosis histopathology, 63% of diagnoses with the molecular classifier data were high confidence, compared with 42% using histopathologic data (P = .0412).

This study was funded by Veracyte, creator of the Envisia Genomic Classifier. Some authors reported relationships with Veracyte and other companies.

SOURCE: Raghu G et al. Lancet Respir Med. 2019 Apr 1. doi: 10.1016/S2213-8587(19)300.

Correction, 4/25/19: An earlier version of this article misstated how the Envisia Genomic Classifier could be used. The Envisia test is not intended to replace high-resolution chest CT (HRCT). It is used when HRCT is inconclusive to help prevent patients from having to undergo invasive diagnostic procedures.

Researchers used a machine learning algorithm to identify a molecular signature for usual interstitial pneumonia in patients with suspected idiopathic pulmonary fibrosis, according to recent research published in the Lancet Respiratory Medicine.

The results of the molecular test, called the Envisia Genomic Classifier (Veracyte; San Francisco), had a high positive predictive value of proven usual interstitial pneumonia, and could be used in place of surgical lung biopsy to confirm a diagnosis of idiopathic pulmonary fibrosis (IPF), wrote Ganesh Raghu, MD, director at the Center for Interstitial Lung Diseases and professor of medicine at the University of Washington, Seattle, and his colleagues.* The Envisia Genomic Classifier recently received final Medicare local coverage determination for IPF diagnosis, according to a recent press release by Veracyte.

“IPF is often challenging to distinguish from other [interstitial lung disease], but timely and accurate diagnosis is critical so that patients with IPF can access therapies that may slow progression of the disease, while avoiding potentially harmful treatments,” Dr. Raghu stated in a press release. “Our results with molecular classification through machine learning [the Envisia classifier] are promising and, along with clinical information and radiological features in high-resolution CT imaging, physicians through multidisciplinary discussions, may be able to utilize the molecular classification as a diagnostic tool to make a more informed and confident diagnoses.”

The researchers prospectively recruited 237 patients from 29 centers in the United States and Europe who were evaluated with the Bronchial Sample Collection for a Novel Genomic Test for suspected interstitial lung disease and who underwent surgical biopsy, transbronchial biopsy, or cryobiopsy for sample collection. They used histopathology and RNA sequence data from 90 patients to create a training data set of an unusual interstitial pneumonia pattern for the machine learning algorithm.

The classifier found usual interstitial pneumonia diagnoses in 49 patients; the test had a specificity of 88% (95% confidence interval, 70%-98%) and a sensitivity of 70% (95% CI, 47%-87%). Of 42 patients with inconsistent or possible usual interstitial pneumonia identified from high-resolution CT imaging, there was a positive predictive value of 81% (95% CI, 54%-96%). When multidisciplinary teams made diagnoses with the molecular classifier data, there was a clinical agreement of 86% (95% CI, 78%-92%) with diagnoses made using histopathology data. In 18 cases of IPF, there was an improvement in diagnostic confidence using the molecular classifier data, with 89% of diagnoses designated as high confidence, compared with 56% of cases based on histopathologic data (P = .0339). In 48 patients with nondiagnostic pathology or nonclassifiable fibrosis histopathology, 63% of diagnoses with the molecular classifier data were high confidence, compared with 42% using histopathologic data (P = .0412).

This study was funded by Veracyte, creator of the Envisia Genomic Classifier. Some authors reported relationships with Veracyte and other companies.

SOURCE: Raghu G et al. Lancet Respir Med. 2019 Apr 1. doi: 10.1016/S2213-8587(19)300.

Correction, 4/25/19: An earlier version of this article misstated how the Envisia Genomic Classifier could be used. The Envisia test is not intended to replace high-resolution chest CT (HRCT). It is used when HRCT is inconclusive to help prevent patients from having to undergo invasive diagnostic procedures.

The pace of reporting of new measles cases has increased over the last month, bringing the total number for the year to 555 in the United States, according to the Centers for Disease Control and Prevention.

The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.

New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.

Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.

The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.

rfranki@mdedge.com

The pace of reporting of new measles cases has increased over the last month, bringing the total number for the year to 555 in the United States, according to the Centers for Disease Control and Prevention.

The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.

New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.

Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.

The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.

rfranki@mdedge.com

The pace of reporting of new measles cases has increased over the last month, bringing the total number for the year to 555 in the United States, according to the Centers for Disease Control and Prevention.

The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.

New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.

Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.

The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.

rfranki@mdedge.com

Hematopoietic stem cell transplantation (HSCT) is widely used in the economically developed world to treat a variety of hematologic malignancies as well as nonmalignant diseases and solid tumors. An estimated 17,900 HSCTs were performed in 2011, and survival rates continue to increase.¹ Pulmonary complications post HSCT are common, with rates ranging from 40% to 60%, and are associated with increased morbidity and mortality.²

Clinical diagnosis of pulmonary complications in the HSCT population has been aided by a previously well-defined chronology of the most common diseases.³ Historically, early pulmonary complications were defined as pulmonary complications occurring within 100 days of HSCT (corresponding to the acute graft-versus-host disease [GVHD] period). Late pulmonary complications are those that occur thereafter. This timeline, however, is now more variable given the increasing indications for HSCT, the use of reduced-intensity conditioning strategies, and varied individual immune reconstitution. This article discusses the management of early post-HSCT pulmonary complications; late post-HSCT pulmonary complications will be discussed in a separate follow-up article.

Transplant Basics

The development of pulmonary complications is affected by many factors associated with the transplant. Autologous transplantation involves the collection of a patient’s own stem cells, appropriate storage and processing, and re-implantation after induction therapy. During induction therapy, the patient undergoes high-dose chemotherapy or radiation therapy that ablates the bone marrow. The stem cells are then transfused back into the patient to repopulate the bone marrow. Allogeneic transplants involve the collection of stem cells from a donor. Donors are matched as closely as possible to the recipient’s histocompatibility antigen (HLA) haplotypes to prevent graft failure and rejection. The donor can be related or unrelated to the recipient. If there is not a possibility of a related match (from a sibling), then a national search is undertaken to look for a match through the National Marrow Donor Program. There are fewer transplant reactions and occurrences of GVHD if the major HLAs of the donor and recipient match. Table 1 reviews basic definitions pertaining to HSCT.

How the cells for transplantation are obtained is also an important factor in the rate of complications. There are 3 main sources: peripheral blood, bone marrow, and umbilical cord. Peripheral stem cell harvesting involves exposing the donor to granulocyte-colony stimulating factor (gCSF), which increases peripheral circulation of stem cells. These cells are then collected and infused into the recipient after the recipient has completed an induction regimen involving chemotherapy and/or radiation, depending on the protocol. This procedure is called peripheral blood stem cell transplant (PBSCT). Stem cells can also be directly harvested from bone marrow cells, which are collected from repeated aspiration of bone marrow from the posterior iliac crest.⁴ This technique is most common in children, whereas in adults peripheral blood stem cells are the most common source. Overall mortality does not differ based on the source of the stem cells. It is postulated that GVHD may be more common in patients undergoing PBSCT, but the graft failure rate may be lower.⁵

The third option is umbilical cord blood (UCB) as the source of stem cells. This involves the collection of umbilical cord blood that is prepared and frozen after birth. It has a smaller volume of cells, and although fewer cells are needed when using UCB, 2 separate donors may be required for a single adult recipient. The engraftment of the stem cells is slower and infections in the post-transplant period are more common. Prior reports indicate GVHD rates may be lower.⁴ While the use of UCB is not common in adults, the incidence has doubled over the past decade, increasing from 3% to 6%.

The conditioning regimen can influence pulmonary complications. Traditionally, an ablative transplant involves high-dose chemotherapy or radiation to eradicate the recipient’s bone marrow. This regimen can lead to many complications, especially in the immediate post-transplant period. In the past 10 years, there has been increasing interest in non-myeloablative, or reduced-intensity, conditioning transplants.⁶ These “mini transplants” involve smaller doses of chemotherapy or radiation, which do not totally eradicate the bone marrow; after the transplant a degree of chimerism develops where the donor and recipient stem cells coexist. The medications in the preparative regimen also should be considered because they can affect pulmonary complications after transplant. Certain chemotherapeutic agents such as carmustine, bleomycin, and many others can lead to acute and chronic presentations of pulmonary diseases such as hypersensitivity pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome, and abnormal pulmonary function testing.

After the HSCT, GVHD can develop in more than 50% of allogeneic recipients.³ The incidence of GVHD has been reported to be increasing over the past 12 years.It is divided into acute GVHD (which traditionally happens in the first 100 days after transplant) and chronic GVHD (after day 100). This calendar-day–based system has been augmented based on a 2006 National Institutes of Health working group report emphasizing the importance of organ-specific features of chronic GVHD in the clinical presentation of GVHD.⁷ Histologic changes in chronic organ GVHD tend to include more fibrotic features, whereas in acute GVHD more inflammatory changes are seen. The NIH working group report also stressed the importance of obtaining a biopsy specimen for histopathologic review and interdisciplinary collaboration to arrive at a consensus diagnosis, and noted the limitations of using histologic changes as the sole determinant of a “gold standard” diagnosis.⁷ GVHD can directly predispose patients to pulmonary GVHD and indirectly predispose them to infectious complications because the mainstay of therapy for GVHD is increased immunosuppression.

Pretransplant Evaluation

Case Patient 1

A 56-year-old man is diagnosed with acute myeloid leukemia (AML) after presenting with signs and symptoms consistent with pancytopenia. He has a past medical history of chronic sinus congestion, arthritis, depression, chronic pain, and carpal tunnel surgery. He is employed as an oilfield worker and has a 40-pack-year smoking history, but he recently cut back to half a pack per day. He is being evaluated for allogeneic transplant with his brother as the donor and the planned conditioning regimen is total body irradiation (TBI), thiotepa, cyclophosphamide, and antithymocyte globulin with T-cell depletion. Routine pretransplant pulmonary function testing (PFT) reveals a restrictive pattern and he is sent for pretransplant pulmonary evaluation.

Physical exam reveals a chronically ill appearing man. He is afebrile, the respiratory rate is 16 breaths/min, blood pressure is 145/88 mm Hg, heart rate is 92 beats/min, and oxygen saturation is 95%. He is in no distress. Auscultation of the chest reveals slightly diminished breath sounds bilaterally but is clear and without wheezes, rhonchi, or rales. Heart exam shows regular rate and rhythm without murmurs, rubs, or gallops. Extremities reveal no edema or rashes. Otherwise, the remainder of the exam is normal. The patient’s PFT results are shown in Table 2.

• What aspects of this patient’s history put him at risk for pulmonary complications after transplantation?

Risk Factors for Pulmonary Complications

Predicting who is at risk for pulmonary complications is difficult. Complications are generally divided into infectious and noninfectious categories. Regardless of category, allogeneic HSCT recipients are at increased risk compared with autologous recipients, but even in autologous transplants, more than 25% of patients will develop pulmonary complications in the first year.⁸ Prior to transplant, patients undergo full PFT. Early on, many studies attempted to show relationships between various factors and post-transplant pulmonary complications. Factors that were implicated were forced expiratory volume in 1 second (FEV₁), diffusing capacity of the lung for carbon monoxide (Dlco), total lung capacity (TLC), GVHD prophylaxis, TBI, and FEV₁/forced vital capacity (FEV₁/FVC) ratio.^9-15 Generally, poor baseline pulmonary functional status has been shown to correlate with higher risk for pulmonary complications. The most widely accepted pre-transplant PFT values examined for determining risk for developing pulmonary complications are FEV₁ and Dlco.

Another sometimes overlooked risk before transplantation is restrictive lung disease. One study showed a twofold increase in respiratory failure and mortality if there was pretransplant restriction based on TLC < 80%.¹⁶

An interesting study by one group in pretransplant evaluation found decreased muscle strength by maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength, and 6-minute walk test (6MWT) distance prior to allogeneic transplant, but did not find a relationship between these variables and mortality.¹⁷ While this study had a small sample size, these findings likely deserve continued investigation.¹⁸

• What methods are used to calculate risk for complications?

Risk Scoring Systems

Several pretransplantation risk scores have been developed. In a study that looked at more than 2500 allogeneic transplants, Parimon et al showed that risk of mortality and respiratory failure could be estimated prior to transplant using a scoring system—the Lung Function Score (LFS)—that combines the FEV₁ and Dlco.¹⁹ They assigned a score to the FEV₁ and Dlco based on the percentage of predicted values on PFT. Values greater than 80% were assigned 1 point, values 70% to 80% 2 points, 60% to 70% 3 points, and less than 60% 4 points. Combining the values for the FEV₁ and Dlco provides the LFS. A normal score is 2 (1 point each for FEV₁ and Dlco values > 80%) and is category I. A score of 3–4 is mildly decreased, category II; a score of 5–6 is moderately decreased, category III; and 7–8 is severely decreased, category IV. The hazard ratios (HR) for acute respiratory failure after transplant were 1.4, 2.2, and 3.1 for categories II, III, and IV, respectively. The HRs for mortality were 1.2, 2.2, and 2.7 for the same categories.¹⁹ This LFS has been used post-transplantation as well to categorize pulmonary GVHD.²⁰

The Pretransplantation Assessment of Mortality score, initially developed in 2006, predicts mortality within the first 2 years after HSCT based on 8 clinical factors: disease risk, age at transplant, donor type, conditioning regimen, and markers of organ function (percentage of predicted FEV₁, percentage of predicted Dlco, serum creatinine level, serum alanine aminotransferase level). Given the increased use of reduced-intensity conditioning regimens, the authors reevaluated the PAM score and following this analysis, creatinine, percent predicted Dlco, and liver function tests were found to no longer be statistically significant and were removed from the PAM score in 2015.^21,22 Another widely used score is the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI),²³ which predicts mortality following allogeneic stem cell transplantation. The HCT-CI also uses the FEV₁ and the Dlco as the 2 objective measures of pulmonary function.²³ While these pulmonary tests help with risk stratification, they are not perfect and it is not advised to use an isolated low Dlco to exclude individuals from transplant.²⁴ Recently, Coffey et al looked at the practice of correcting Dlco for hemoglobin by the Cotes method as suggested by the American Thoracic Society (ATS) versus the Dinakara method that was used in the HCT-CI.²⁵ In this study, the use of the Cotes method resulted in an elevated HCT-CI in 45% of patients, and in 33% it resulted in higher mortality risk predictions. Since the HCT-CI is validated using the Dinakara method, that method should be used in the HCT-CI calculations.²⁵

• What other preoperative testing or interventions should be considered in this patient?

Since there is a high risk of infectious complications after transplant, the question of whether pretransplantation patients should undergo screening imaging may arise. There is no evidence that routine chest computed tomography (CT) reduces the risk of infectious complications after transplantation.²⁶ An area that may be insufficiently addressed in the pretransplantation evaluation is smoking cessation counseling.²⁷ Studies have shown an elevated risk of mortality in smokers.^28-30 Others have found a higher incidence of respiratory failure but not an increased mortality.³¹ Overall, with the good rates of smoking cessation that can be accomplished, smokers should be counseled to quit before transplantation.

In summary, patients should undergo full PFTs prior to transplantation to help stratify risk for pulmonary complications and mortality and to establish a clinical baseline. The LFS (using FEV₁ and Dlco) can help categorize risk of respiratory failure and mortality after transplant. Absolute cut-off values for FEV₁ and Dlco are debated, but < 40% predicted and < 30% to 40% predicted, respectively, are considered contraindications to transplant. Smoking cessation should be advised if applicable during the pretransplant visit and optimization of reversible lung conditions should be stressed. There are no formal recommendations about reducing risk of early complications, but early mobilization, incentive spirometry, and use of inhalers if there is any history of obstructive lung disease should be considered.

Case Patient 1 Conclusion

The patient undergoes transplantation due to his lack of other treatment options. Evaluation prior to transplant, however, shows that he is at high risk for pulmonary complications. He has a LFS of 7 prior to transplant (using the Dlco corrected for hemoglobin), which puts him in class IV, with a HR of 3.1 for early respiratory failure and a HR of 2.7 for mortality. Additionally, he is still smoking at the time of transplantation. He does well immediately after transplantation, but has a complicated course with worsening mixed restrictive and obstructive pulmonary function abnormality. He becomes oxygen dependent and eventually undergoes video-assisted thoracoscopic surgery (VATS), which shows both usual interstitial pneumonia and restrictive bronchiolitis with changes consistent with mild to moderate pulmonary hypertension. He dies 2 years to the month after transplantation.

Early Infectious Pulmonary Complications

Case Patient 2

A 27-year-old man with a medical history significant for AML and allogeneic HSCT presents with cough productive of a small amount of clear to white sputum, dyspnea on exertion, and fevers for 1 week. He also has mild nausea and a decrease in appetite. He underwent HSCT 2.5 months prior to admission, which was a matched unrelated bone marrow transplant with TBI and cyclophosphamide conditioning. His past medical history is significant only for exercise-induced asthma for which he takes a rescue inhaler infrequently prior to transplantation. His pretransplant PFTs showed normal spirometry with an FEV₁ of 106% of predicted and Dlco of 54% of predicted. He does not smoke. His post-transplant medical course was complicated by severe acute skin GVHD as well as diarrhea, with sigmoidoscopy showing GVHD.

Physical exam is notable for fever of 101.0°F, heart rate 80 beats/min, respiratory rate 16 breaths/ min, and blood pressure 142/78 mm Hg; an admission oxygen saturation is 93% on room air. Lungs show bibasilar crackles and the remainder of the exam is normal. Laboratory testing shows a white blood cell count of 2400 cells/μL, hemoglobin 7.6 g/dL, and platelet count 66 × 10³/μL. Creatinine is 1.0 mg/dL. Chest radiograph shows ill-defined bilateral lower-lobe infiltrates. CT scans are shown in the Figure.

• For which infectious complications is this patient most at risk?

Pneumonia

A prospective trial in the HSCT population reported a pneumonia incidence rate of 68%, and pneumonia is more common in allogeneic HSCT with prolonged immunosuppressive therapy.³² Development of pneumonia within 100 days of transplant directly correlates with nonrelapsed mortality.³³ Early detection is key, and bronchoscopy within the first 5 days of symptoms has been shown to change therapy in approximately 40% of cases but has not been shown to affect mortality.³⁴ The clinical presentation of pneumonia in the HSCT population can be variable because of the presence of neutropenia and profound immunosuppression. Traditionally accepted diagnostic criteria of fevers, sputum production, and new infiltrates should be used with caution, and an appropriately high index of suspicion should be maintained. Progression to respiratory failure, regardless of causative organism of infection, portends a poor prognosis, with mortality rates estimated at 70% to 90%.^35,36 Several transplant-specific factors may affect early infections. For instance, UCB transplants have been found to have a higher incidence of invasive aspergillosis and cytomegalovirus (CMV) infections but without higher mortality attributed to the infections.³⁷

Bacterial Pneumonia

Bacterial pneumonia accounts for 20% to 50% of pneumonia cases in HSCT recipients.³⁸ Gram-negative organisms, specifically Pseudomonas aeruginosa and Escherichia coli, were reported to be the most common pathologic bacteria in recent prospective trials, whereas previous retrospective trials showed that common community-acquired organisms were the most common cause of pneumonia in HSCT recipients.^32,39 This underscores the importance of being aware of the clinical prevalence of microorganisms and local antibiograms, along with associated institutional susceptibility profiles. Initiation of immediate empiric broad-spectrum antibiotics is essential when bacterial pneumonia is suspected.

Viral Pneumonia

The prevalence of viral pneumonia in stem cell transplant recipients is estimated at 28%,³² with most cases being caused by community viral pathogens such as rhinovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza.³⁹ The prevention, prophylaxis, and early treatment of viral pneumonias, specifically CMV infection, have decreased the mortality associated with early pneumonia after HSCT. Co-infection with bacterial organisms must be considered and has been associated with increased mortality in the intensive care unit setting.⁴⁰

Supportive treatment with rhinovirus infection is sufficient as the disease is usually self-limited in immunocompromised patients. In contrast, infection with RSV in the lower respiratory tract is associated with increased mortality in prior reports, and recent studies suggest that further exploration of prophylaxis strategies is warranted.⁴¹ Treatment with ribavirin remains the backbone of therapy, but drug toxicity continues to limit its use. The addition of immunomodulators such as RSV immune globulin or palivizumab to ribavirin remains controversial, but a retrospective review suggests that early treatment may prevent progression to lower respiratory tract infection and lead to improved mortality.⁴² Infection with influenza A/B must be considered during influenza season. Treatment with oseltamivir may shorten the duration of disease when influenza A/B or parainfluenza are detected. Reactivation of latent herpes simplex virus during the pre-engraftment phase should also be considered. Treatment is similar to that in nonimmunocompromised hosts. When CMV pneumonia is suspected, careful history regarding compliance with prophylactic antivirals and CMV status of both the recipient and donor are key. A presumptive diagnosis can be made with the presence of appropriate clinical scenario, supportive radiographic images showing areas of ground-glass opacification or consolidation, and positive CMV polymerase chain reaction (PCR) assay. Visualization of inclusion bodies on lung biopsy tissue remains the gold standard for diagnosis. Treatment consists of CMV immunoglobulin and ganciclovir.

Fungal Pneumonia

Early fungal pneumonias have been associated with increased mortality in the HSCT population.⁴³ Clinical suspicion should remain high and compliance with antifungal prophylaxis should be questioned thoroughly. Invasive aspergillosis (IA) remains the most common fungal infection. A bimodal distribution of onset of infection peaking on day 16 and again on day 96 has been described in the literature.⁴⁴ Patients often present with classic pneumonia symptoms, but these may be accompanied by hemoptysis. Proven IA diagnosis requires visualization of fungal forms from biopsy or needle aspiration or a positive culture obtained in a sterile fashion.⁴⁵ Most clinical data comes from experience with probable and possible diagnosis of IA. Bronchoalveolar lavage with testing with Aspergillus galactomannan assay has been shown to be clinically useful in establishing the clinical diagnosis in the HSCT population.⁴⁶ Classic air-crescent findings on chest CT are helpful in establishing a possible diagnosis, but retrospective analysis reveals CT findings such as focal infiltrates and pulmonary nodular patterns are more common.⁴⁷ First-line treatment with voriconazole has been shown to decrease short-term mortality attributable to IA but has not had an effect on long-term, all-cause mortality.⁴⁸ Surgical resection is reserved for patients with refractory disease or patients presenting with massive hemoptysis.

Mucormycosis is an emerging disease with ever increasing prevalence in the HSCT population, reflecting the improved prophylaxis and treatment of IA. Initial clinical presentation is similar to IA, most commonly affecting the lung, although craniofacial involvement is classic for mucormycosis, especially in HSCT patients with diabetes.⁴⁹Mucor infections can present with massive hemoptysis due to tissue invasion and disregard for tissue and fascial planes. Diagnosis of mucormycosis is associated with as much as a six-fold increase in risk for death. Diagnosis requires identification of the organism by examination or culture and biopsy is often necessary.^50,51 Amphotericin B remains first-line therapy as mucormycosis is resistant to azole antifungals, with higher doses recommended for cerebral involvement.⁵²

Candida pulmonary infections during the early HSCT period are becoming increasingly rare due to widespread use of fluconazole prophylaxis and early treatment of mucosal involvement during neutropenia. Endemic fungal infections such as blastomycosis, coccidioidomycosis, and histoplasmosis should be considered in patients inhabiting specific geographic areas or with recent travel to these areas.

• What test should be performed to evaluate for infectious causes of pneumonia?

Role of Flexible Fiberoptic Bronchoscopy

The utility of flexible fiberoptic bronchoscopy (FOB) in immune-compromised patients for the evaluation of pulmonary infiltrates is a frequently debated topic. Current studies suggest a diagnosis can be made in approximately 80% of cases in the immune-compromised population.^32,53 Noninvasive testing such as urine and serum antigens, sputum cultures, Aspergillus galactomannan assays, viral nasal swabs, and PCR studies often lead to a diagnosis in appropriate clinical scenarios. Conservative management would dictate the use of noninvasive testing whenever possible, and randomized controlled trials have shown noninvasive testing to be noninferior to FOB in preventing need for mechanical ventilation, with no difference in overall mortality.⁵⁴ FOB has been shown to be most useful in establishing a diagnosis when an infectious etiology is suspected.⁵⁵ In multivariate analysis, a delay in the identification of the etiology of pulmonary infiltrate was associated with increased mortality.⁵⁶ Additionally, early FOB was found to be superior to late FOB in revealing a diagnosis. ^32,57 Despite its ability to detect the cause of pulmonary disease, direct antibiotic therapy, and possibly change therapy, FOB with diagnostic maneuvers has not been shown to affect mortality.⁵⁸ In a large case series, FOB with bronchoalveolar lavage (BAL) revealed a diagnosis in approximately 30% to 50% of cases. The addition of transbronchial biopsy did not improve diagnostic utility.⁵⁸ More recent studies have confirmed that the addition of transbronchial biopsy does not add to diagnostic yield and is associated with increased adverse events.⁵⁹ The appropriate use of advanced techniques such as endobronchial ultrasound–guided transbronchial needle aspirations, endobronchial biopsy, and CT-guided navigational bronchoscopy has not been established and should be considered on a case-by-case basis. In summary, routine early BAL is the diagnostic test of choice, especially when infectious pulmonary complications are suspected.

Contraindications for FOB in this population mirror those in the general population. These include acute severe hypoxemic respiratory failure, myocardial ischemia or acute coronary syndrome within 2 weeks of procedure, severe thrombocytopenia, and inability to provide or obtain informed consent from patient or health care power of attorney. Coagulopathy and thrombocytopenia are common comorbid conditions in the HSCT population. A platelet count of < 20 × 10³/µL has generally been used as a cut-off for routine FOB with BAL.⁶⁰ Risks of the procedures should be discussed clearly with the patient, but simple FOB for airway evaluation and BAL is generally well tolerated even under these conditions.

Early Nonifectious Pulmonary Complications

Case Patient 2 Continued

Bronchoscopy with BAL performed the day after admission is unremarkable and stains and cultures are negative for viral, bacterial, and fungal organisms. The patient is initially started on broad-spectrum antibiotics, but his oxygenation continues to worsen to the point that he is placed on noninvasive positive pressure ventilation. He is started empirically on amphotericin B and eventually is intubated. VATS lung biopsy is ultimately performed and pathology is consistent with diffuse alveolar damage.

• Based on these biopsy findings, what is the diagnosis?

Based on the pathology consistent with diffuse alveolar damage, a diagnosis of idiopathic pneumonia syndrome (IPS) is made.

• What noninfectious pulmonary complications occur in the early post-transplant period?

The overall incidence of noninfectious pulmonary complications after HSCT is generally estimated at 20% to 30%.³² Acute pulmonary edema is a common very early noninfectious pulmonary complication and clinically the most straightforward to treat. Three distinct clinical syndromes—peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage (DAH), and IPS—comprise the remainder of the pertinent early noninfectious complications. Clinical presentation differs based upon the disease entity. Recent studies have evaluated the role of angiotensin-converting enzyme polymorphisms as a predictive marker for risk of developing early noninfectious pulmonary complications.⁶¹

Peri-Engraftment Respiratory Distress Syndrome

PERDS is a clinical syndrome comprising the cardinal features of erythematous rash and fever along with noncardiogenic pulmonary infiltrates and hypoxemia that occur in the peri-engraftment period, defined as recovery of absolute neutrophil count to > 500/μL on 2 consecutive days.⁶² PERDS occurs in the autologous HSCT population and may be a clinical correlate to early GVHD in the allogeneic HSCT population. It is hypothesized that the pathophysiology underlying PERDS is an autoimmune-related capillary leak caused by pro-inflammatory cytokine release.⁶³ Treatment remains anecdotal and currently consists of supportive care and high-dose corticosteroids. Some have favored limiting the use of gCSF given its role in stimulating rapid white blood cell recovery.³³ Prognosis is favorable, but progression to fulminant respiratory failure requiring mechanical ventilation portends a poor prognosis.

Diffuse Alveolar Hemorrhage

DAH is clinical syndrome consisting of diffuse alveolar infiltrates on pulmonary imaging combined with progressively bloodier return per aliquot during BAL in 3 different subsegments or more than 20% hemosiderin-laden macrophages on BAL fluid evaluation. Classically, DAH is defined in the absence of pulmonary infection or cardiac dysfunction. The pathophysiology is thought to be related to inflammation of pulmonary vasculature within the alveolar walls leading to alveolitis. Although no prospective trials exist, early use of high-dose corticosteroid therapy is thought to improve outcomes;^64,65 a recent study, however, showed low-dose steroids may be associated with the lowest mortality.⁶⁶ Mortality is directly linked to the presence of superimposed infection, need for mechanical ventilation, late onset, and development of multiorgan failure.⁶⁷

Idiopathic Pneumonia Syndrome

IPS is a complex clinical syndrome whose pathology is felt to stem from a variety of possible lung insults such as direct myeloablative drug toxicity, occult pulmonary infection, or cytokine-driven inflammation. The ATS published an article further subcategorizing IPS as different clinical entities based upon whether the primary insult involves the vascular endothelium, interstitial tissue, and airway tissue, truly idiopathic, or unclassified.⁶⁸ In clinical practice, IPS is defined as widespread alveolar injury in the absence of evidence of renal failure, heart failure, and excessive fluid resuscitation. In addition, negative testing for a variety of bacterial, viral, and fungal causes is also necessary.⁶⁹ Clinical syndromes included within the IPS definition are ARDS, acute interstitial pneumonia, DAH, cryptogenic organizing pneumonia, and BOS.⁷⁰ Risk factors for developing IPS include TBI, older age of recipient, acute GVHD, and underlying diagnosis of AML or myelodysplastic syndrome.¹² In addition, it has been shown that risk for developing IPS is lower in patients undergoing allogeneic HSCT who receive non-myeloablative conditioning regimens.⁷¹ The pathologic finding in IPS is diffuse alveolar damage. A 2006 study in which investigators reviewed BAL samples from patients with IPS found that 3% of the patients had PCR evidence of human metapneumovirus infection, and a study in 2015 found PCR evidence of infection in 53% of BAL samples from patients diagnosed with IPS.^72,73 This fuels the debate on whether IPS is truly an infection-driven process where the source of infection, pulmonary or otherwise, simply escapes detection. Various surfactant proteins, which play a role in decreasing surface tension within the alveolar interface and function as mediators within the innate immunity of the lung, have been studied in regard to development of IPS. Small retrospective studies have shown a trend toward lower pre-transplant serum protein surfactant D and the development of IPS.⁷⁴

The diagnosis of IPS does not require pathologic diagnosis in most circumstances. The correct clinical findings in association with a negative infectious workup lead to a presumptive diagnosis of IPS. The extent of the infectious workup that must be completed to adequately rule out infection is often a difficult clinical question. Recent recommendations include BAL fluid evaluation for routine bacterial cultures, appropriate viral culture, and consideration of PCR testing to evaluate for Mycoplasma, Chlamydia, and Aspergillus antigens.⁷⁵ Transbronchial biopsy continues to appear in recommendations, but is not routinely performed and should be completed as the patient’s clinical status permits.^8,68 Table 3 reviews basic features of early noninfectious pulmonary complications.

• What treatment should be offered to the patient with diffuse alveolar damage on biopsy?

Treatment consists of supportive care and empiric broad-spectrum antibiotics with consideration of high-dose corticosteroids. Based upon early studies in murine models implicating TNF, pilot studies were performed evaluating etanercept as a possible safe and effective addition to high-dose systemic corticosteroids.⁷⁷ Although these results were promising, data from a truncated randomized control clinical trial failed to show improvement in patient response in the adult population.⁷⁶ More recent data from the same author suggests that pediatric populations with IPS are, however, responsive to etanercept and high-dose corticosteroid therapy.⁷⁸ When IPS develops as a late complication, treatment with high-dose corticosteroids (2 mg/kg/day) and etanercept (0.4 mg/kg twice weekly) has been shown to improve 2-year survival.⁷⁹

Case Patient 2 Conclusion

The patient is started on steroids and makes a speedy recovery. He is successfully extubated 5 days later.

Conclusion

Careful pretransplant evaluation, including a full set of pulmonary function tests, can help predict a patient’s risk for pulmonary complications after transplant, allowing risk factor modification strategies to be implemented prior to transplant, including smoking cessation. It also helps identify patients at high risk for complications who will require closer monitoring after transplantation. Early posttransplant complications include infectious and noninfectious entities. Bacterial, viral, and fungal pneumonias are in the differential of infectious pneumonia, and bronchoscopy can be helpful in establishing a diagnosis. A common, important noninfectious cause of early pulmonary complications is IPS, which is treated with steroids and sometimes anti-TNF therapy.

Hematopoietic stem cell transplantation (HSCT) is widely used in the economically developed world to treat a variety of hematologic malignancies as well as nonmalignant diseases and solid tumors. An estimated 17,900 HSCTs were performed in 2011, and survival rates continue to increase.¹ Pulmonary complications post HSCT are common, with rates ranging from 40% to 60%, and are associated with increased morbidity and mortality.²

Clinical diagnosis of pulmonary complications in the HSCT population has been aided by a previously well-defined chronology of the most common diseases.³ Historically, early pulmonary complications were defined as pulmonary complications occurring within 100 days of HSCT (corresponding to the acute graft-versus-host disease [GVHD] period). Late pulmonary complications are those that occur thereafter. This timeline, however, is now more variable given the increasing indications for HSCT, the use of reduced-intensity conditioning strategies, and varied individual immune reconstitution. This article discusses the management of early post-HSCT pulmonary complications; late post-HSCT pulmonary complications will be discussed in a separate follow-up article.

Transplant Basics

The development of pulmonary complications is affected by many factors associated with the transplant. Autologous transplantation involves the collection of a patient’s own stem cells, appropriate storage and processing, and re-implantation after induction therapy. During induction therapy, the patient undergoes high-dose chemotherapy or radiation therapy that ablates the bone marrow. The stem cells are then transfused back into the patient to repopulate the bone marrow. Allogeneic transplants involve the collection of stem cells from a donor. Donors are matched as closely as possible to the recipient’s histocompatibility antigen (HLA) haplotypes to prevent graft failure and rejection. The donor can be related or unrelated to the recipient. If there is not a possibility of a related match (from a sibling), then a national search is undertaken to look for a match through the National Marrow Donor Program. There are fewer transplant reactions and occurrences of GVHD if the major HLAs of the donor and recipient match. Table 1 reviews basic definitions pertaining to HSCT.

How the cells for transplantation are obtained is also an important factor in the rate of complications. There are 3 main sources: peripheral blood, bone marrow, and umbilical cord. Peripheral stem cell harvesting involves exposing the donor to granulocyte-colony stimulating factor (gCSF), which increases peripheral circulation of stem cells. These cells are then collected and infused into the recipient after the recipient has completed an induction regimen involving chemotherapy and/or radiation, depending on the protocol. This procedure is called peripheral blood stem cell transplant (PBSCT). Stem cells can also be directly harvested from bone marrow cells, which are collected from repeated aspiration of bone marrow from the posterior iliac crest.⁴ This technique is most common in children, whereas in adults peripheral blood stem cells are the most common source. Overall mortality does not differ based on the source of the stem cells. It is postulated that GVHD may be more common in patients undergoing PBSCT, but the graft failure rate may be lower.⁵

The third option is umbilical cord blood (UCB) as the source of stem cells. This involves the collection of umbilical cord blood that is prepared and frozen after birth. It has a smaller volume of cells, and although fewer cells are needed when using UCB, 2 separate donors may be required for a single adult recipient. The engraftment of the stem cells is slower and infections in the post-transplant period are more common. Prior reports indicate GVHD rates may be lower.⁴ While the use of UCB is not common in adults, the incidence has doubled over the past decade, increasing from 3% to 6%.

The conditioning regimen can influence pulmonary complications. Traditionally, an ablative transplant involves high-dose chemotherapy or radiation to eradicate the recipient’s bone marrow. This regimen can lead to many complications, especially in the immediate post-transplant period. In the past 10 years, there has been increasing interest in non-myeloablative, or reduced-intensity, conditioning transplants.⁶ These “mini transplants” involve smaller doses of chemotherapy or radiation, which do not totally eradicate the bone marrow; after the transplant a degree of chimerism develops where the donor and recipient stem cells coexist. The medications in the preparative regimen also should be considered because they can affect pulmonary complications after transplant. Certain chemotherapeutic agents such as carmustine, bleomycin, and many others can lead to acute and chronic presentations of pulmonary diseases such as hypersensitivity pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome, and abnormal pulmonary function testing.

After the HSCT, GVHD can develop in more than 50% of allogeneic recipients.³ The incidence of GVHD has been reported to be increasing over the past 12 years.It is divided into acute GVHD (which traditionally happens in the first 100 days after transplant) and chronic GVHD (after day 100). This calendar-day–based system has been augmented based on a 2006 National Institutes of Health working group report emphasizing the importance of organ-specific features of chronic GVHD in the clinical presentation of GVHD.⁷ Histologic changes in chronic organ GVHD tend to include more fibrotic features, whereas in acute GVHD more inflammatory changes are seen. The NIH working group report also stressed the importance of obtaining a biopsy specimen for histopathologic review and interdisciplinary collaboration to arrive at a consensus diagnosis, and noted the limitations of using histologic changes as the sole determinant of a “gold standard” diagnosis.⁷ GVHD can directly predispose patients to pulmonary GVHD and indirectly predispose them to infectious complications because the mainstay of therapy for GVHD is increased immunosuppression.

Pretransplant Evaluation

Case Patient 1

A 56-year-old man is diagnosed with acute myeloid leukemia (AML) after presenting with signs and symptoms consistent with pancytopenia. He has a past medical history of chronic sinus congestion, arthritis, depression, chronic pain, and carpal tunnel surgery. He is employed as an oilfield worker and has a 40-pack-year smoking history, but he recently cut back to half a pack per day. He is being evaluated for allogeneic transplant with his brother as the donor and the planned conditioning regimen is total body irradiation (TBI), thiotepa, cyclophosphamide, and antithymocyte globulin with T-cell depletion. Routine pretransplant pulmonary function testing (PFT) reveals a restrictive pattern and he is sent for pretransplant pulmonary evaluation.

Physical exam reveals a chronically ill appearing man. He is afebrile, the respiratory rate is 16 breaths/min, blood pressure is 145/88 mm Hg, heart rate is 92 beats/min, and oxygen saturation is 95%. He is in no distress. Auscultation of the chest reveals slightly diminished breath sounds bilaterally but is clear and without wheezes, rhonchi, or rales. Heart exam shows regular rate and rhythm without murmurs, rubs, or gallops. Extremities reveal no edema or rashes. Otherwise, the remainder of the exam is normal. The patient’s PFT results are shown in Table 2.

• What aspects of this patient’s history put him at risk for pulmonary complications after transplantation?

Risk Factors for Pulmonary Complications

Predicting who is at risk for pulmonary complications is difficult. Complications are generally divided into infectious and noninfectious categories. Regardless of category, allogeneic HSCT recipients are at increased risk compared with autologous recipients, but even in autologous transplants, more than 25% of patients will develop pulmonary complications in the first year.⁸ Prior to transplant, patients undergo full PFT. Early on, many studies attempted to show relationships between various factors and post-transplant pulmonary complications. Factors that were implicated were forced expiratory volume in 1 second (FEV₁), diffusing capacity of the lung for carbon monoxide (Dlco), total lung capacity (TLC), GVHD prophylaxis, TBI, and FEV₁/forced vital capacity (FEV₁/FVC) ratio.^9-15 Generally, poor baseline pulmonary functional status has been shown to correlate with higher risk for pulmonary complications. The most widely accepted pre-transplant PFT values examined for determining risk for developing pulmonary complications are FEV₁ and Dlco.

Another sometimes overlooked risk before transplantation is restrictive lung disease. One study showed a twofold increase in respiratory failure and mortality if there was pretransplant restriction based on TLC < 80%.¹⁶

An interesting study by one group in pretransplant evaluation found decreased muscle strength by maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength, and 6-minute walk test (6MWT) distance prior to allogeneic transplant, but did not find a relationship between these variables and mortality.¹⁷ While this study had a small sample size, these findings likely deserve continued investigation.¹⁸

• What methods are used to calculate risk for complications?

Risk Scoring Systems

Several pretransplantation risk scores have been developed. In a study that looked at more than 2500 allogeneic transplants, Parimon et al showed that risk of mortality and respiratory failure could be estimated prior to transplant using a scoring system—the Lung Function Score (LFS)—that combines the FEV₁ and Dlco.¹⁹ They assigned a score to the FEV₁ and Dlco based on the percentage of predicted values on PFT. Values greater than 80% were assigned 1 point, values 70% to 80% 2 points, 60% to 70% 3 points, and less than 60% 4 points. Combining the values for the FEV₁ and Dlco provides the LFS. A normal score is 2 (1 point each for FEV₁ and Dlco values > 80%) and is category I. A score of 3–4 is mildly decreased, category II; a score of 5–6 is moderately decreased, category III; and 7–8 is severely decreased, category IV. The hazard ratios (HR) for acute respiratory failure after transplant were 1.4, 2.2, and 3.1 for categories II, III, and IV, respectively. The HRs for mortality were 1.2, 2.2, and 2.7 for the same categories.¹⁹ This LFS has been used post-transplantation as well to categorize pulmonary GVHD.²⁰

The Pretransplantation Assessment of Mortality score, initially developed in 2006, predicts mortality within the first 2 years after HSCT based on 8 clinical factors: disease risk, age at transplant, donor type, conditioning regimen, and markers of organ function (percentage of predicted FEV₁, percentage of predicted Dlco, serum creatinine level, serum alanine aminotransferase level). Given the increased use of reduced-intensity conditioning regimens, the authors reevaluated the PAM score and following this analysis, creatinine, percent predicted Dlco, and liver function tests were found to no longer be statistically significant and were removed from the PAM score in 2015.^21,22 Another widely used score is the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI),²³ which predicts mortality following allogeneic stem cell transplantation. The HCT-CI also uses the FEV₁ and the Dlco as the 2 objective measures of pulmonary function.²³ While these pulmonary tests help with risk stratification, they are not perfect and it is not advised to use an isolated low Dlco to exclude individuals from transplant.²⁴ Recently, Coffey et al looked at the practice of correcting Dlco for hemoglobin by the Cotes method as suggested by the American Thoracic Society (ATS) versus the Dinakara method that was used in the HCT-CI.²⁵ In this study, the use of the Cotes method resulted in an elevated HCT-CI in 45% of patients, and in 33% it resulted in higher mortality risk predictions. Since the HCT-CI is validated using the Dinakara method, that method should be used in the HCT-CI calculations.²⁵

• What other preoperative testing or interventions should be considered in this patient?

Since there is a high risk of infectious complications after transplant, the question of whether pretransplantation patients should undergo screening imaging may arise. There is no evidence that routine chest computed tomography (CT) reduces the risk of infectious complications after transplantation.²⁶ An area that may be insufficiently addressed in the pretransplantation evaluation is smoking cessation counseling.²⁷ Studies have shown an elevated risk of mortality in smokers.^28-30 Others have found a higher incidence of respiratory failure but not an increased mortality.³¹ Overall, with the good rates of smoking cessation that can be accomplished, smokers should be counseled to quit before transplantation.

In summary, patients should undergo full PFTs prior to transplantation to help stratify risk for pulmonary complications and mortality and to establish a clinical baseline. The LFS (using FEV₁ and Dlco) can help categorize risk of respiratory failure and mortality after transplant. Absolute cut-off values for FEV₁ and Dlco are debated, but < 40% predicted and < 30% to 40% predicted, respectively, are considered contraindications to transplant. Smoking cessation should be advised if applicable during the pretransplant visit and optimization of reversible lung conditions should be stressed. There are no formal recommendations about reducing risk of early complications, but early mobilization, incentive spirometry, and use of inhalers if there is any history of obstructive lung disease should be considered.

Case Patient 1 Conclusion

The patient undergoes transplantation due to his lack of other treatment options. Evaluation prior to transplant, however, shows that he is at high risk for pulmonary complications. He has a LFS of 7 prior to transplant (using the Dlco corrected for hemoglobin), which puts him in class IV, with a HR of 3.1 for early respiratory failure and a HR of 2.7 for mortality. Additionally, he is still smoking at the time of transplantation. He does well immediately after transplantation, but has a complicated course with worsening mixed restrictive and obstructive pulmonary function abnormality. He becomes oxygen dependent and eventually undergoes video-assisted thoracoscopic surgery (VATS), which shows both usual interstitial pneumonia and restrictive bronchiolitis with changes consistent with mild to moderate pulmonary hypertension. He dies 2 years to the month after transplantation.

Early Infectious Pulmonary Complications

Case Patient 2

A 27-year-old man with a medical history significant for AML and allogeneic HSCT presents with cough productive of a small amount of clear to white sputum, dyspnea on exertion, and fevers for 1 week. He also has mild nausea and a decrease in appetite. He underwent HSCT 2.5 months prior to admission, which was a matched unrelated bone marrow transplant with TBI and cyclophosphamide conditioning. His past medical history is significant only for exercise-induced asthma for which he takes a rescue inhaler infrequently prior to transplantation. His pretransplant PFTs showed normal spirometry with an FEV₁ of 106% of predicted and Dlco of 54% of predicted. He does not smoke. His post-transplant medical course was complicated by severe acute skin GVHD as well as diarrhea, with sigmoidoscopy showing GVHD.

Physical exam is notable for fever of 101.0°F, heart rate 80 beats/min, respiratory rate 16 breaths/ min, and blood pressure 142/78 mm Hg; an admission oxygen saturation is 93% on room air. Lungs show bibasilar crackles and the remainder of the exam is normal. Laboratory testing shows a white blood cell count of 2400 cells/μL, hemoglobin 7.6 g/dL, and platelet count 66 × 10³/μL. Creatinine is 1.0 mg/dL. Chest radiograph shows ill-defined bilateral lower-lobe infiltrates. CT scans are shown in the Figure.

• For which infectious complications is this patient most at risk?

Pneumonia

A prospective trial in the HSCT population reported a pneumonia incidence rate of 68%, and pneumonia is more common in allogeneic HSCT with prolonged immunosuppressive therapy.³² Development of pneumonia within 100 days of transplant directly correlates with nonrelapsed mortality.³³ Early detection is key, and bronchoscopy within the first 5 days of symptoms has been shown to change therapy in approximately 40% of cases but has not been shown to affect mortality.³⁴ The clinical presentation of pneumonia in the HSCT population can be variable because of the presence of neutropenia and profound immunosuppression. Traditionally accepted diagnostic criteria of fevers, sputum production, and new infiltrates should be used with caution, and an appropriately high index of suspicion should be maintained. Progression to respiratory failure, regardless of causative organism of infection, portends a poor prognosis, with mortality rates estimated at 70% to 90%.^35,36 Several transplant-specific factors may affect early infections. For instance, UCB transplants have been found to have a higher incidence of invasive aspergillosis and cytomegalovirus (CMV) infections but without higher mortality attributed to the infections.³⁷

Bacterial Pneumonia

Bacterial pneumonia accounts for 20% to 50% of pneumonia cases in HSCT recipients.³⁸ Gram-negative organisms, specifically Pseudomonas aeruginosa and Escherichia coli, were reported to be the most common pathologic bacteria in recent prospective trials, whereas previous retrospective trials showed that common community-acquired organisms were the most common cause of pneumonia in HSCT recipients.^32,39 This underscores the importance of being aware of the clinical prevalence of microorganisms and local antibiograms, along with associated institutional susceptibility profiles. Initiation of immediate empiric broad-spectrum antibiotics is essential when bacterial pneumonia is suspected.

Viral Pneumonia

The prevalence of viral pneumonia in stem cell transplant recipients is estimated at 28%,³² with most cases being caused by community viral pathogens such as rhinovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza.³⁹ The prevention, prophylaxis, and early treatment of viral pneumonias, specifically CMV infection, have decreased the mortality associated with early pneumonia after HSCT. Co-infection with bacterial organisms must be considered and has been associated with increased mortality in the intensive care unit setting.⁴⁰

Supportive treatment with rhinovirus infection is sufficient as the disease is usually self-limited in immunocompromised patients. In contrast, infection with RSV in the lower respiratory tract is associated with increased mortality in prior reports, and recent studies suggest that further exploration of prophylaxis strategies is warranted.⁴¹ Treatment with ribavirin remains the backbone of therapy, but drug toxicity continues to limit its use. The addition of immunomodulators such as RSV immune globulin or palivizumab to ribavirin remains controversial, but a retrospective review suggests that early treatment may prevent progression to lower respiratory tract infection and lead to improved mortality.⁴² Infection with influenza A/B must be considered during influenza season. Treatment with oseltamivir may shorten the duration of disease when influenza A/B or parainfluenza are detected. Reactivation of latent herpes simplex virus during the pre-engraftment phase should also be considered. Treatment is similar to that in nonimmunocompromised hosts. When CMV pneumonia is suspected, careful history regarding compliance with prophylactic antivirals and CMV status of both the recipient and donor are key. A presumptive diagnosis can be made with the presence of appropriate clinical scenario, supportive radiographic images showing areas of ground-glass opacification or consolidation, and positive CMV polymerase chain reaction (PCR) assay. Visualization of inclusion bodies on lung biopsy tissue remains the gold standard for diagnosis. Treatment consists of CMV immunoglobulin and ganciclovir.

Fungal Pneumonia

Early fungal pneumonias have been associated with increased mortality in the HSCT population.⁴³ Clinical suspicion should remain high and compliance with antifungal prophylaxis should be questioned thoroughly. Invasive aspergillosis (IA) remains the most common fungal infection. A bimodal distribution of onset of infection peaking on day 16 and again on day 96 has been described in the literature.⁴⁴ Patients often present with classic pneumonia symptoms, but these may be accompanied by hemoptysis. Proven IA diagnosis requires visualization of fungal forms from biopsy or needle aspiration or a positive culture obtained in a sterile fashion.⁴⁵ Most clinical data comes from experience with probable and possible diagnosis of IA. Bronchoalveolar lavage with testing with Aspergillus galactomannan assay has been shown to be clinically useful in establishing the clinical diagnosis in the HSCT population.⁴⁶ Classic air-crescent findings on chest CT are helpful in establishing a possible diagnosis, but retrospective analysis reveals CT findings such as focal infiltrates and pulmonary nodular patterns are more common.⁴⁷ First-line treatment with voriconazole has been shown to decrease short-term mortality attributable to IA but has not had an effect on long-term, all-cause mortality.⁴⁸ Surgical resection is reserved for patients with refractory disease or patients presenting with massive hemoptysis.

Mucormycosis is an emerging disease with ever increasing prevalence in the HSCT population, reflecting the improved prophylaxis and treatment of IA. Initial clinical presentation is similar to IA, most commonly affecting the lung, although craniofacial involvement is classic for mucormycosis, especially in HSCT patients with diabetes.⁴⁹Mucor infections can present with massive hemoptysis due to tissue invasion and disregard for tissue and fascial planes. Diagnosis of mucormycosis is associated with as much as a six-fold increase in risk for death. Diagnosis requires identification of the organism by examination or culture and biopsy is often necessary.^50,51 Amphotericin B remains first-line therapy as mucormycosis is resistant to azole antifungals, with higher doses recommended for cerebral involvement.⁵²

Candida pulmonary infections during the early HSCT period are becoming increasingly rare due to widespread use of fluconazole prophylaxis and early treatment of mucosal involvement during neutropenia. Endemic fungal infections such as blastomycosis, coccidioidomycosis, and histoplasmosis should be considered in patients inhabiting specific geographic areas or with recent travel to these areas.

• What test should be performed to evaluate for infectious causes of pneumonia?

Role of Flexible Fiberoptic Bronchoscopy

The utility of flexible fiberoptic bronchoscopy (FOB) in immune-compromised patients for the evaluation of pulmonary infiltrates is a frequently debated topic. Current studies suggest a diagnosis can be made in approximately 80% of cases in the immune-compromised population.^32,53 Noninvasive testing such as urine and serum antigens, sputum cultures, Aspergillus galactomannan assays, viral nasal swabs, and PCR studies often lead to a diagnosis in appropriate clinical scenarios. Conservative management would dictate the use of noninvasive testing whenever possible, and randomized controlled trials have shown noninvasive testing to be noninferior to FOB in preventing need for mechanical ventilation, with no difference in overall mortality.⁵⁴ FOB has been shown to be most useful in establishing a diagnosis when an infectious etiology is suspected.⁵⁵ In multivariate analysis, a delay in the identification of the etiology of pulmonary infiltrate was associated with increased mortality.⁵⁶ Additionally, early FOB was found to be superior to late FOB in revealing a diagnosis. ^32,57 Despite its ability to detect the cause of pulmonary disease, direct antibiotic therapy, and possibly change therapy, FOB with diagnostic maneuvers has not been shown to affect mortality.⁵⁸ In a large case series, FOB with bronchoalveolar lavage (BAL) revealed a diagnosis in approximately 30% to 50% of cases. The addition of transbronchial biopsy did not improve diagnostic utility.⁵⁸ More recent studies have confirmed that the addition of transbronchial biopsy does not add to diagnostic yield and is associated with increased adverse events.⁵⁹ The appropriate use of advanced techniques such as endobronchial ultrasound–guided transbronchial needle aspirations, endobronchial biopsy, and CT-guided navigational bronchoscopy has not been established and should be considered on a case-by-case basis. In summary, routine early BAL is the diagnostic test of choice, especially when infectious pulmonary complications are suspected.

Contraindications for FOB in this population mirror those in the general population. These include acute severe hypoxemic respiratory failure, myocardial ischemia or acute coronary syndrome within 2 weeks of procedure, severe thrombocytopenia, and inability to provide or obtain informed consent from patient or health care power of attorney. Coagulopathy and thrombocytopenia are common comorbid conditions in the HSCT population. A platelet count of < 20 × 10³/µL has generally been used as a cut-off for routine FOB with BAL.⁶⁰ Risks of the procedures should be discussed clearly with the patient, but simple FOB for airway evaluation and BAL is generally well tolerated even under these conditions.

Early Nonifectious Pulmonary Complications

Case Patient 2 Continued

Bronchoscopy with BAL performed the day after admission is unremarkable and stains and cultures are negative for viral, bacterial, and fungal organisms. The patient is initially started on broad-spectrum antibiotics, but his oxygenation continues to worsen to the point that he is placed on noninvasive positive pressure ventilation. He is started empirically on amphotericin B and eventually is intubated. VATS lung biopsy is ultimately performed and pathology is consistent with diffuse alveolar damage.

• Based on these biopsy findings, what is the diagnosis?

Based on the pathology consistent with diffuse alveolar damage, a diagnosis of idiopathic pneumonia syndrome (IPS) is made.

• What noninfectious pulmonary complications occur in the early post-transplant period?

The overall incidence of noninfectious pulmonary complications after HSCT is generally estimated at 20% to 30%.³² Acute pulmonary edema is a common very early noninfectious pulmonary complication and clinically the most straightforward to treat. Three distinct clinical syndromes—peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage (DAH), and IPS—comprise the remainder of the pertinent early noninfectious complications. Clinical presentation differs based upon the disease entity. Recent studies have evaluated the role of angiotensin-converting enzyme polymorphisms as a predictive marker for risk of developing early noninfectious pulmonary complications.⁶¹

Peri-Engraftment Respiratory Distress Syndrome

PERDS is a clinical syndrome comprising the cardinal features of erythematous rash and fever along with noncardiogenic pulmonary infiltrates and hypoxemia that occur in the peri-engraftment period, defined as recovery of absolute neutrophil count to > 500/μL on 2 consecutive days.⁶² PERDS occurs in the autologous HSCT population and may be a clinical correlate to early GVHD in the allogeneic HSCT population. It is hypothesized that the pathophysiology underlying PERDS is an autoimmune-related capillary leak caused by pro-inflammatory cytokine release.⁶³ Treatment remains anecdotal and currently consists of supportive care and high-dose corticosteroids. Some have favored limiting the use of gCSF given its role in stimulating rapid white blood cell recovery.³³ Prognosis is favorable, but progression to fulminant respiratory failure requiring mechanical ventilation portends a poor prognosis.

Diffuse Alveolar Hemorrhage

DAH is clinical syndrome consisting of diffuse alveolar infiltrates on pulmonary imaging combined with progressively bloodier return per aliquot during BAL in 3 different subsegments or more than 20% hemosiderin-laden macrophages on BAL fluid evaluation. Classically, DAH is defined in the absence of pulmonary infection or cardiac dysfunction. The pathophysiology is thought to be related to inflammation of pulmonary vasculature within the alveolar walls leading to alveolitis. Although no prospective trials exist, early use of high-dose corticosteroid therapy is thought to improve outcomes;^64,65 a recent study, however, showed low-dose steroids may be associated with the lowest mortality.⁶⁶ Mortality is directly linked to the presence of superimposed infection, need for mechanical ventilation, late onset, and development of multiorgan failure.⁶⁷

Idiopathic Pneumonia Syndrome

IPS is a complex clinical syndrome whose pathology is felt to stem from a variety of possible lung insults such as direct myeloablative drug toxicity, occult pulmonary infection, or cytokine-driven inflammation. The ATS published an article further subcategorizing IPS as different clinical entities based upon whether the primary insult involves the vascular endothelium, interstitial tissue, and airway tissue, truly idiopathic, or unclassified.⁶⁸ In clinical practice, IPS is defined as widespread alveolar injury in the absence of evidence of renal failure, heart failure, and excessive fluid resuscitation. In addition, negative testing for a variety of bacterial, viral, and fungal causes is also necessary.⁶⁹ Clinical syndromes included within the IPS definition are ARDS, acute interstitial pneumonia, DAH, cryptogenic organizing pneumonia, and BOS.⁷⁰ Risk factors for developing IPS include TBI, older age of recipient, acute GVHD, and underlying diagnosis of AML or myelodysplastic syndrome.¹² In addition, it has been shown that risk for developing IPS is lower in patients undergoing allogeneic HSCT who receive non-myeloablative conditioning regimens.⁷¹ The pathologic finding in IPS is diffuse alveolar damage. A 2006 study in which investigators reviewed BAL samples from patients with IPS found that 3% of the patients had PCR evidence of human metapneumovirus infection, and a study in 2015 found PCR evidence of infection in 53% of BAL samples from patients diagnosed with IPS.^72,73 This fuels the debate on whether IPS is truly an infection-driven process where the source of infection, pulmonary or otherwise, simply escapes detection. Various surfactant proteins, which play a role in decreasing surface tension within the alveolar interface and function as mediators within the innate immunity of the lung, have been studied in regard to development of IPS. Small retrospective studies have shown a trend toward lower pre-transplant serum protein surfactant D and the development of IPS.⁷⁴

The diagnosis of IPS does not require pathologic diagnosis in most circumstances. The correct clinical findings in association with a negative infectious workup lead to a presumptive diagnosis of IPS. The extent of the infectious workup that must be completed to adequately rule out infection is often a difficult clinical question. Recent recommendations include BAL fluid evaluation for routine bacterial cultures, appropriate viral culture, and consideration of PCR testing to evaluate for Mycoplasma, Chlamydia, and Aspergillus antigens.⁷⁵ Transbronchial biopsy continues to appear in recommendations, but is not routinely performed and should be completed as the patient’s clinical status permits.^8,68 Table 3 reviews basic features of early noninfectious pulmonary complications.

• What treatment should be offered to the patient with diffuse alveolar damage on biopsy?

Treatment consists of supportive care and empiric broad-spectrum antibiotics with consideration of high-dose corticosteroids. Based upon early studies in murine models implicating TNF, pilot studies were performed evaluating etanercept as a possible safe and effective addition to high-dose systemic corticosteroids.⁷⁷ Although these results were promising, data from a truncated randomized control clinical trial failed to show improvement in patient response in the adult population.⁷⁶ More recent data from the same author suggests that pediatric populations with IPS are, however, responsive to etanercept and high-dose corticosteroid therapy.⁷⁸ When IPS develops as a late complication, treatment with high-dose corticosteroids (2 mg/kg/day) and etanercept (0.4 mg/kg twice weekly) has been shown to improve 2-year survival.⁷⁹

Case Patient 2 Conclusion

The patient is started on steroids and makes a speedy recovery. He is successfully extubated 5 days later.

Conclusion

Careful pretransplant evaluation, including a full set of pulmonary function tests, can help predict a patient’s risk for pulmonary complications after transplant, allowing risk factor modification strategies to be implemented prior to transplant, including smoking cessation. It also helps identify patients at high risk for complications who will require closer monitoring after transplantation. Early posttransplant complications include infectious and noninfectious entities. Bacterial, viral, and fungal pneumonias are in the differential of infectious pneumonia, and bronchoscopy can be helpful in establishing a diagnosis. A common, important noninfectious cause of early pulmonary complications is IPS, which is treated with steroids and sometimes anti-TNF therapy.

Hematopoietic stem cell transplantation (HSCT) is widely used in the economically developed world to treat a variety of hematologic malignancies as well as nonmalignant diseases and solid tumors. An estimated 17,900 HSCTs were performed in 2011, and survival rates continue to increase.¹ Pulmonary complications post HSCT are common, with rates ranging from 40% to 60%, and are associated with increased morbidity and mortality.²

Clinical diagnosis of pulmonary complications in the HSCT population has been aided by a previously well-defined chronology of the most common diseases.³ Historically, early pulmonary complications were defined as pulmonary complications occurring within 100 days of HSCT (corresponding to the acute graft-versus-host disease [GVHD] period). Late pulmonary complications are those that occur thereafter. This timeline, however, is now more variable given the increasing indications for HSCT, the use of reduced-intensity conditioning strategies, and varied individual immune reconstitution. This article discusses the management of early post-HSCT pulmonary complications; late post-HSCT pulmonary complications will be discussed in a separate follow-up article.

Transplant Basics

The development of pulmonary complications is affected by many factors associated with the transplant. Autologous transplantation involves the collection of a patient’s own stem cells, appropriate storage and processing, and re-implantation after induction therapy. During induction therapy, the patient undergoes high-dose chemotherapy or radiation therapy that ablates the bone marrow. The stem cells are then transfused back into the patient to repopulate the bone marrow. Allogeneic transplants involve the collection of stem cells from a donor. Donors are matched as closely as possible to the recipient’s histocompatibility antigen (HLA) haplotypes to prevent graft failure and rejection. The donor can be related or unrelated to the recipient. If there is not a possibility of a related match (from a sibling), then a national search is undertaken to look for a match through the National Marrow Donor Program. There are fewer transplant reactions and occurrences of GVHD if the major HLAs of the donor and recipient match. Table 1 reviews basic definitions pertaining to HSCT.

How the cells for transplantation are obtained is also an important factor in the rate of complications. There are 3 main sources: peripheral blood, bone marrow, and umbilical cord. Peripheral stem cell harvesting involves exposing the donor to granulocyte-colony stimulating factor (gCSF), which increases peripheral circulation of stem cells. These cells are then collected and infused into the recipient after the recipient has completed an induction regimen involving chemotherapy and/or radiation, depending on the protocol. This procedure is called peripheral blood stem cell transplant (PBSCT). Stem cells can also be directly harvested from bone marrow cells, which are collected from repeated aspiration of bone marrow from the posterior iliac crest.⁴ This technique is most common in children, whereas in adults peripheral blood stem cells are the most common source. Overall mortality does not differ based on the source of the stem cells. It is postulated that GVHD may be more common in patients undergoing PBSCT, but the graft failure rate may be lower.⁵

The third option is umbilical cord blood (UCB) as the source of stem cells. This involves the collection of umbilical cord blood that is prepared and frozen after birth. It has a smaller volume of cells, and although fewer cells are needed when using UCB, 2 separate donors may be required for a single adult recipient. The engraftment of the stem cells is slower and infections in the post-transplant period are more common. Prior reports indicate GVHD rates may be lower.⁴ While the use of UCB is not common in adults, the incidence has doubled over the past decade, increasing from 3% to 6%.

The conditioning regimen can influence pulmonary complications. Traditionally, an ablative transplant involves high-dose chemotherapy or radiation to eradicate the recipient’s bone marrow. This regimen can lead to many complications, especially in the immediate post-transplant period. In the past 10 years, there has been increasing interest in non-myeloablative, or reduced-intensity, conditioning transplants.⁶ These “mini transplants” involve smaller doses of chemotherapy or radiation, which do not totally eradicate the bone marrow; after the transplant a degree of chimerism develops where the donor and recipient stem cells coexist. The medications in the preparative regimen also should be considered because they can affect pulmonary complications after transplant. Certain chemotherapeutic agents such as carmustine, bleomycin, and many others can lead to acute and chronic presentations of pulmonary diseases such as hypersensitivity pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome, and abnormal pulmonary function testing.

After the HSCT, GVHD can develop in more than 50% of allogeneic recipients.³ The incidence of GVHD has been reported to be increasing over the past 12 years.It is divided into acute GVHD (which traditionally happens in the first 100 days after transplant) and chronic GVHD (after day 100). This calendar-day–based system has been augmented based on a 2006 National Institutes of Health working group report emphasizing the importance of organ-specific features of chronic GVHD in the clinical presentation of GVHD.⁷ Histologic changes in chronic organ GVHD tend to include more fibrotic features, whereas in acute GVHD more inflammatory changes are seen. The NIH working group report also stressed the importance of obtaining a biopsy specimen for histopathologic review and interdisciplinary collaboration to arrive at a consensus diagnosis, and noted the limitations of using histologic changes as the sole determinant of a “gold standard” diagnosis.⁷ GVHD can directly predispose patients to pulmonary GVHD and indirectly predispose them to infectious complications because the mainstay of therapy for GVHD is increased immunosuppression.

Pretransplant Evaluation

Case Patient 1

A 56-year-old man is diagnosed with acute myeloid leukemia (AML) after presenting with signs and symptoms consistent with pancytopenia. He has a past medical history of chronic sinus congestion, arthritis, depression, chronic pain, and carpal tunnel surgery. He is employed as an oilfield worker and has a 40-pack-year smoking history, but he recently cut back to half a pack per day. He is being evaluated for allogeneic transplant with his brother as the donor and the planned conditioning regimen is total body irradiation (TBI), thiotepa, cyclophosphamide, and antithymocyte globulin with T-cell depletion. Routine pretransplant pulmonary function testing (PFT) reveals a restrictive pattern and he is sent for pretransplant pulmonary evaluation.

Physical exam reveals a chronically ill appearing man. He is afebrile, the respiratory rate is 16 breaths/min, blood pressure is 145/88 mm Hg, heart rate is 92 beats/min, and oxygen saturation is 95%. He is in no distress. Auscultation of the chest reveals slightly diminished breath sounds bilaterally but is clear and without wheezes, rhonchi, or rales. Heart exam shows regular rate and rhythm without murmurs, rubs, or gallops. Extremities reveal no edema or rashes. Otherwise, the remainder of the exam is normal. The patient’s PFT results are shown in Table 2.

• What aspects of this patient’s history put him at risk for pulmonary complications after transplantation?

Risk Factors for Pulmonary Complications

Predicting who is at risk for pulmonary complications is difficult. Complications are generally divided into infectious and noninfectious categories. Regardless of category, allogeneic HSCT recipients are at increased risk compared with autologous recipients, but even in autologous transplants, more than 25% of patients will develop pulmonary complications in the first year.⁸ Prior to transplant, patients undergo full PFT. Early on, many studies attempted to show relationships between various factors and post-transplant pulmonary complications. Factors that were implicated were forced expiratory volume in 1 second (FEV₁), diffusing capacity of the lung for carbon monoxide (Dlco), total lung capacity (TLC), GVHD prophylaxis, TBI, and FEV₁/forced vital capacity (FEV₁/FVC) ratio.^9-15 Generally, poor baseline pulmonary functional status has been shown to correlate with higher risk for pulmonary complications. The most widely accepted pre-transplant PFT values examined for determining risk for developing pulmonary complications are FEV₁ and Dlco.

Another sometimes overlooked risk before transplantation is restrictive lung disease. One study showed a twofold increase in respiratory failure and mortality if there was pretransplant restriction based on TLC < 80%.¹⁶

An interesting study by one group in pretransplant evaluation found decreased muscle strength by maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength, and 6-minute walk test (6MWT) distance prior to allogeneic transplant, but did not find a relationship between these variables and mortality.¹⁷ While this study had a small sample size, these findings likely deserve continued investigation.¹⁸

• What methods are used to calculate risk for complications?

Risk Scoring Systems

Several pretransplantation risk scores have been developed. In a study that looked at more than 2500 allogeneic transplants, Parimon et al showed that risk of mortality and respiratory failure could be estimated prior to transplant using a scoring system—the Lung Function Score (LFS)—that combines the FEV₁ and Dlco.¹⁹ They assigned a score to the FEV₁ and Dlco based on the percentage of predicted values on PFT. Values greater than 80% were assigned 1 point, values 70% to 80% 2 points, 60% to 70% 3 points, and less than 60% 4 points. Combining the values for the FEV₁ and Dlco provides the LFS. A normal score is 2 (1 point each for FEV₁ and Dlco values > 80%) and is category I. A score of 3–4 is mildly decreased, category II; a score of 5–6 is moderately decreased, category III; and 7–8 is severely decreased, category IV. The hazard ratios (HR) for acute respiratory failure after transplant were 1.4, 2.2, and 3.1 for categories II, III, and IV, respectively. The HRs for mortality were 1.2, 2.2, and 2.7 for the same categories.¹⁹ This LFS has been used post-transplantation as well to categorize pulmonary GVHD.²⁰

The Pretransplantation Assessment of Mortality score, initially developed in 2006, predicts mortality within the first 2 years after HSCT based on 8 clinical factors: disease risk, age at transplant, donor type, conditioning regimen, and markers of organ function (percentage of predicted FEV₁, percentage of predicted Dlco, serum creatinine level, serum alanine aminotransferase level). Given the increased use of reduced-intensity conditioning regimens, the authors reevaluated the PAM score and following this analysis, creatinine, percent predicted Dlco, and liver function tests were found to no longer be statistically significant and were removed from the PAM score in 2015.^21,22 Another widely used score is the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI),²³ which predicts mortality following allogeneic stem cell transplantation. The HCT-CI also uses the FEV₁ and the Dlco as the 2 objective measures of pulmonary function.²³ While these pulmonary tests help with risk stratification, they are not perfect and it is not advised to use an isolated low Dlco to exclude individuals from transplant.²⁴ Recently, Coffey et al looked at the practice of correcting Dlco for hemoglobin by the Cotes method as suggested by the American Thoracic Society (ATS) versus the Dinakara method that was used in the HCT-CI.²⁵ In this study, the use of the Cotes method resulted in an elevated HCT-CI in 45% of patients, and in 33% it resulted in higher mortality risk predictions. Since the HCT-CI is validated using the Dinakara method, that method should be used in the HCT-CI calculations.²⁵

• What other preoperative testing or interventions should be considered in this patient?

Since there is a high risk of infectious complications after transplant, the question of whether pretransplantation patients should undergo screening imaging may arise. There is no evidence that routine chest computed tomography (CT) reduces the risk of infectious complications after transplantation.²⁶ An area that may be insufficiently addressed in the pretransplantation evaluation is smoking cessation counseling.²⁷ Studies have shown an elevated risk of mortality in smokers.^28-30 Others have found a higher incidence of respiratory failure but not an increased mortality.³¹ Overall, with the good rates of smoking cessation that can be accomplished, smokers should be counseled to quit before transplantation.

In summary, patients should undergo full PFTs prior to transplantation to help stratify risk for pulmonary complications and mortality and to establish a clinical baseline. The LFS (using FEV₁ and Dlco) can help categorize risk of respiratory failure and mortality after transplant. Absolute cut-off values for FEV₁ and Dlco are debated, but < 40% predicted and < 30% to 40% predicted, respectively, are considered contraindications to transplant. Smoking cessation should be advised if applicable during the pretransplant visit and optimization of reversible lung conditions should be stressed. There are no formal recommendations about reducing risk of early complications, but early mobilization, incentive spirometry, and use of inhalers if there is any history of obstructive lung disease should be considered.

Case Patient 1 Conclusion

The patient undergoes transplantation due to his lack of other treatment options. Evaluation prior to transplant, however, shows that he is at high risk for pulmonary complications. He has a LFS of 7 prior to transplant (using the Dlco corrected for hemoglobin), which puts him in class IV, with a HR of 3.1 for early respiratory failure and a HR of 2.7 for mortality. Additionally, he is still smoking at the time of transplantation. He does well immediately after transplantation, but has a complicated course with worsening mixed restrictive and obstructive pulmonary function abnormality. He becomes oxygen dependent and eventually undergoes video-assisted thoracoscopic surgery (VATS), which shows both usual interstitial pneumonia and restrictive bronchiolitis with changes consistent with mild to moderate pulmonary hypertension. He dies 2 years to the month after transplantation.

Early Infectious Pulmonary Complications

Case Patient 2

A 27-year-old man with a medical history significant for AML and allogeneic HSCT presents with cough productive of a small amount of clear to white sputum, dyspnea on exertion, and fevers for 1 week. He also has mild nausea and a decrease in appetite. He underwent HSCT 2.5 months prior to admission, which was a matched unrelated bone marrow transplant with TBI and cyclophosphamide conditioning. His past medical history is significant only for exercise-induced asthma for which he takes a rescue inhaler infrequently prior to transplantation. His pretransplant PFTs showed normal spirometry with an FEV₁ of 106% of predicted and Dlco of 54% of predicted. He does not smoke. His post-transplant medical course was complicated by severe acute skin GVHD as well as diarrhea, with sigmoidoscopy showing GVHD.

Physical exam is notable for fever of 101.0°F, heart rate 80 beats/min, respiratory rate 16 breaths/ min, and blood pressure 142/78 mm Hg; an admission oxygen saturation is 93% on room air. Lungs show bibasilar crackles and the remainder of the exam is normal. Laboratory testing shows a white blood cell count of 2400 cells/μL, hemoglobin 7.6 g/dL, and platelet count 66 × 10³/μL. Creatinine is 1.0 mg/dL. Chest radiograph shows ill-defined bilateral lower-lobe infiltrates. CT scans are shown in the Figure.

• For which infectious complications is this patient most at risk?

Pneumonia

A prospective trial in the HSCT population reported a pneumonia incidence rate of 68%, and pneumonia is more common in allogeneic HSCT with prolonged immunosuppressive therapy.³² Development of pneumonia within 100 days of transplant directly correlates with nonrelapsed mortality.³³ Early detection is key, and bronchoscopy within the first 5 days of symptoms has been shown to change therapy in approximately 40% of cases but has not been shown to affect mortality.³⁴ The clinical presentation of pneumonia in the HSCT population can be variable because of the presence of neutropenia and profound immunosuppression. Traditionally accepted diagnostic criteria of fevers, sputum production, and new infiltrates should be used with caution, and an appropriately high index of suspicion should be maintained. Progression to respiratory failure, regardless of causative organism of infection, portends a poor prognosis, with mortality rates estimated at 70% to 90%.^35,36 Several transplant-specific factors may affect early infections. For instance, UCB transplants have been found to have a higher incidence of invasive aspergillosis and cytomegalovirus (CMV) infections but without higher mortality attributed to the infections.³⁷

Bacterial Pneumonia

Bacterial pneumonia accounts for 20% to 50% of pneumonia cases in HSCT recipients.³⁸ Gram-negative organisms, specifically Pseudomonas aeruginosa and Escherichia coli, were reported to be the most common pathologic bacteria in recent prospective trials, whereas previous retrospective trials showed that common community-acquired organisms were the most common cause of pneumonia in HSCT recipients.^32,39 This underscores the importance of being aware of the clinical prevalence of microorganisms and local antibiograms, along with associated institutional susceptibility profiles. Initiation of immediate empiric broad-spectrum antibiotics is essential when bacterial pneumonia is suspected.

Viral Pneumonia

The prevalence of viral pneumonia in stem cell transplant recipients is estimated at 28%,³² with most cases being caused by community viral pathogens such as rhinovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza.³⁹ The prevention, prophylaxis, and early treatment of viral pneumonias, specifically CMV infection, have decreased the mortality associated with early pneumonia after HSCT. Co-infection with bacterial organisms must be considered and has been associated with increased mortality in the intensive care unit setting.⁴⁰

Supportive treatment with rhinovirus infection is sufficient as the disease is usually self-limited in immunocompromised patients. In contrast, infection with RSV in the lower respiratory tract is associated with increased mortality in prior reports, and recent studies suggest that further exploration of prophylaxis strategies is warranted.⁴¹ Treatment with ribavirin remains the backbone of therapy, but drug toxicity continues to limit its use. The addition of immunomodulators such as RSV immune globulin or palivizumab to ribavirin remains controversial, but a retrospective review suggests that early treatment may prevent progression to lower respiratory tract infection and lead to improved mortality.⁴² Infection with influenza A/B must be considered during influenza season. Treatment with oseltamivir may shorten the duration of disease when influenza A/B or parainfluenza are detected. Reactivation of latent herpes simplex virus during the pre-engraftment phase should also be considered. Treatment is similar to that in nonimmunocompromised hosts. When CMV pneumonia is suspected, careful history regarding compliance with prophylactic antivirals and CMV status of both the recipient and donor are key. A presumptive diagnosis can be made with the presence of appropriate clinical scenario, supportive radiographic images showing areas of ground-glass opacification or consolidation, and positive CMV polymerase chain reaction (PCR) assay. Visualization of inclusion bodies on lung biopsy tissue remains the gold standard for diagnosis. Treatment consists of CMV immunoglobulin and ganciclovir.

Fungal Pneumonia

Early fungal pneumonias have been associated with increased mortality in the HSCT population.⁴³ Clinical suspicion should remain high and compliance with antifungal prophylaxis should be questioned thoroughly. Invasive aspergillosis (IA) remains the most common fungal infection. A bimodal distribution of onset of infection peaking on day 16 and again on day 96 has been described in the literature.⁴⁴ Patients often present with classic pneumonia symptoms, but these may be accompanied by hemoptysis. Proven IA diagnosis requires visualization of fungal forms from biopsy or needle aspiration or a positive culture obtained in a sterile fashion.⁴⁵ Most clinical data comes from experience with probable and possible diagnosis of IA. Bronchoalveolar lavage with testing with Aspergillus galactomannan assay has been shown to be clinically useful in establishing the clinical diagnosis in the HSCT population.⁴⁶ Classic air-crescent findings on chest CT are helpful in establishing a possible diagnosis, but retrospective analysis reveals CT findings such as focal infiltrates and pulmonary nodular patterns are more common.⁴⁷ First-line treatment with voriconazole has been shown to decrease short-term mortality attributable to IA but has not had an effect on long-term, all-cause mortality.⁴⁸ Surgical resection is reserved for patients with refractory disease or patients presenting with massive hemoptysis.

Mucormycosis is an emerging disease with ever increasing prevalence in the HSCT population, reflecting the improved prophylaxis and treatment of IA. Initial clinical presentation is similar to IA, most commonly affecting the lung, although craniofacial involvement is classic for mucormycosis, especially in HSCT patients with diabetes.⁴⁹Mucor infections can present with massive hemoptysis due to tissue invasion and disregard for tissue and fascial planes. Diagnosis of mucormycosis is associated with as much as a six-fold increase in risk for death. Diagnosis requires identification of the organism by examination or culture and biopsy is often necessary.^50,51 Amphotericin B remains first-line therapy as mucormycosis is resistant to azole antifungals, with higher doses recommended for cerebral involvement.⁵²

Candida pulmonary infections during the early HSCT period are becoming increasingly rare due to widespread use of fluconazole prophylaxis and early treatment of mucosal involvement during neutropenia. Endemic fungal infections such as blastomycosis, coccidioidomycosis, and histoplasmosis should be considered in patients inhabiting specific geographic areas or with recent travel to these areas.

• What test should be performed to evaluate for infectious causes of pneumonia?

Role of Flexible Fiberoptic Bronchoscopy

The utility of flexible fiberoptic bronchoscopy (FOB) in immune-compromised patients for the evaluation of pulmonary infiltrates is a frequently debated topic. Current studies suggest a diagnosis can be made in approximately 80% of cases in the immune-compromised population.^32,53 Noninvasive testing such as urine and serum antigens, sputum cultures, Aspergillus galactomannan assays, viral nasal swabs, and PCR studies often lead to a diagnosis in appropriate clinical scenarios. Conservative management would dictate the use of noninvasive testing whenever possible, and randomized controlled trials have shown noninvasive testing to be noninferior to FOB in preventing need for mechanical ventilation, with no difference in overall mortality.⁵⁴ FOB has been shown to be most useful in establishing a diagnosis when an infectious etiology is suspected.⁵⁵ In multivariate analysis, a delay in the identification of the etiology of pulmonary infiltrate was associated with increased mortality.⁵⁶ Additionally, early FOB was found to be superior to late FOB in revealing a diagnosis. ^32,57 Despite its ability to detect the cause of pulmonary disease, direct antibiotic therapy, and possibly change therapy, FOB with diagnostic maneuvers has not been shown to affect mortality.⁵⁸ In a large case series, FOB with bronchoalveolar lavage (BAL) revealed a diagnosis in approximately 30% to 50% of cases. The addition of transbronchial biopsy did not improve diagnostic utility.⁵⁸ More recent studies have confirmed that the addition of transbronchial biopsy does not add to diagnostic yield and is associated with increased adverse events.⁵⁹ The appropriate use of advanced techniques such as endobronchial ultrasound–guided transbronchial needle aspirations, endobronchial biopsy, and CT-guided navigational bronchoscopy has not been established and should be considered on a case-by-case basis. In summary, routine early BAL is the diagnostic test of choice, especially when infectious pulmonary complications are suspected.

Contraindications for FOB in this population mirror those in the general population. These include acute severe hypoxemic respiratory failure, myocardial ischemia or acute coronary syndrome within 2 weeks of procedure, severe thrombocytopenia, and inability to provide or obtain informed consent from patient or health care power of attorney. Coagulopathy and thrombocytopenia are common comorbid conditions in the HSCT population. A platelet count of < 20 × 10³/µL has generally been used as a cut-off for routine FOB with BAL.⁶⁰ Risks of the procedures should be discussed clearly with the patient, but simple FOB for airway evaluation and BAL is generally well tolerated even under these conditions.

Early Nonifectious Pulmonary Complications

Case Patient 2 Continued

Bronchoscopy with BAL performed the day after admission is unremarkable and stains and cultures are negative for viral, bacterial, and fungal organisms. The patient is initially started on broad-spectrum antibiotics, but his oxygenation continues to worsen to the point that he is placed on noninvasive positive pressure ventilation. He is started empirically on amphotericin B and eventually is intubated. VATS lung biopsy is ultimately performed and pathology is consistent with diffuse alveolar damage.

• Based on these biopsy findings, what is the diagnosis?

Based on the pathology consistent with diffuse alveolar damage, a diagnosis of idiopathic pneumonia syndrome (IPS) is made.

• What noninfectious pulmonary complications occur in the early post-transplant period?

The overall incidence of noninfectious pulmonary complications after HSCT is generally estimated at 20% to 30%.³² Acute pulmonary edema is a common very early noninfectious pulmonary complication and clinically the most straightforward to treat. Three distinct clinical syndromes—peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage (DAH), and IPS—comprise the remainder of the pertinent early noninfectious complications. Clinical presentation differs based upon the disease entity. Recent studies have evaluated the role of angiotensin-converting enzyme polymorphisms as a predictive marker for risk of developing early noninfectious pulmonary complications.⁶¹

Peri-Engraftment Respiratory Distress Syndrome

PERDS is a clinical syndrome comprising the cardinal features of erythematous rash and fever along with noncardiogenic pulmonary infiltrates and hypoxemia that occur in the peri-engraftment period, defined as recovery of absolute neutrophil count to > 500/μL on 2 consecutive days.⁶² PERDS occurs in the autologous HSCT population and may be a clinical correlate to early GVHD in the allogeneic HSCT population. It is hypothesized that the pathophysiology underlying PERDS is an autoimmune-related capillary leak caused by pro-inflammatory cytokine release.⁶³ Treatment remains anecdotal and currently consists of supportive care and high-dose corticosteroids. Some have favored limiting the use of gCSF given its role in stimulating rapid white blood cell recovery.³³ Prognosis is favorable, but progression to fulminant respiratory failure requiring mechanical ventilation portends a poor prognosis.

Diffuse Alveolar Hemorrhage

DAH is clinical syndrome consisting of diffuse alveolar infiltrates on pulmonary imaging combined with progressively bloodier return per aliquot during BAL in 3 different subsegments or more than 20% hemosiderin-laden macrophages on BAL fluid evaluation. Classically, DAH is defined in the absence of pulmonary infection or cardiac dysfunction. The pathophysiology is thought to be related to inflammation of pulmonary vasculature within the alveolar walls leading to alveolitis. Although no prospective trials exist, early use of high-dose corticosteroid therapy is thought to improve outcomes;^64,65 a recent study, however, showed low-dose steroids may be associated with the lowest mortality.⁶⁶ Mortality is directly linked to the presence of superimposed infection, need for mechanical ventilation, late onset, and development of multiorgan failure.⁶⁷

Idiopathic Pneumonia Syndrome

IPS is a complex clinical syndrome whose pathology is felt to stem from a variety of possible lung insults such as direct myeloablative drug toxicity, occult pulmonary infection, or cytokine-driven inflammation. The ATS published an article further subcategorizing IPS as different clinical entities based upon whether the primary insult involves the vascular endothelium, interstitial tissue, and airway tissue, truly idiopathic, or unclassified.⁶⁸ In clinical practice, IPS is defined as widespread alveolar injury in the absence of evidence of renal failure, heart failure, and excessive fluid resuscitation. In addition, negative testing for a variety of bacterial, viral, and fungal causes is also necessary.⁶⁹ Clinical syndromes included within the IPS definition are ARDS, acute interstitial pneumonia, DAH, cryptogenic organizing pneumonia, and BOS.⁷⁰ Risk factors for developing IPS include TBI, older age of recipient, acute GVHD, and underlying diagnosis of AML or myelodysplastic syndrome.¹² In addition, it has been shown that risk for developing IPS is lower in patients undergoing allogeneic HSCT who receive non-myeloablative conditioning regimens.⁷¹ The pathologic finding in IPS is diffuse alveolar damage. A 2006 study in which investigators reviewed BAL samples from patients with IPS found that 3% of the patients had PCR evidence of human metapneumovirus infection, and a study in 2015 found PCR evidence of infection in 53% of BAL samples from patients diagnosed with IPS.^72,73 This fuels the debate on whether IPS is truly an infection-driven process where the source of infection, pulmonary or otherwise, simply escapes detection. Various surfactant proteins, which play a role in decreasing surface tension within the alveolar interface and function as mediators within the innate immunity of the lung, have been studied in regard to development of IPS. Small retrospective studies have shown a trend toward lower pre-transplant serum protein surfactant D and the development of IPS.⁷⁴

The diagnosis of IPS does not require pathologic diagnosis in most circumstances. The correct clinical findings in association with a negative infectious workup lead to a presumptive diagnosis of IPS. The extent of the infectious workup that must be completed to adequately rule out infection is often a difficult clinical question. Recent recommendations include BAL fluid evaluation for routine bacterial cultures, appropriate viral culture, and consideration of PCR testing to evaluate for Mycoplasma, Chlamydia, and Aspergillus antigens.⁷⁵ Transbronchial biopsy continues to appear in recommendations, but is not routinely performed and should be completed as the patient’s clinical status permits.^8,68 Table 3 reviews basic features of early noninfectious pulmonary complications.

• What treatment should be offered to the patient with diffuse alveolar damage on biopsy?

Treatment consists of supportive care and empiric broad-spectrum antibiotics with consideration of high-dose corticosteroids. Based upon early studies in murine models implicating TNF, pilot studies were performed evaluating etanercept as a possible safe and effective addition to high-dose systemic corticosteroids.⁷⁷ Although these results were promising, data from a truncated randomized control clinical trial failed to show improvement in patient response in the adult population.⁷⁶ More recent data from the same author suggests that pediatric populations with IPS are, however, responsive to etanercept and high-dose corticosteroid therapy.⁷⁸ When IPS develops as a late complication, treatment with high-dose corticosteroids (2 mg/kg/day) and etanercept (0.4 mg/kg twice weekly) has been shown to improve 2-year survival.⁷⁹

Case Patient 2 Conclusion

The patient is started on steroids and makes a speedy recovery. He is successfully extubated 5 days later.

Conclusion

Careful pretransplant evaluation, including a full set of pulmonary function tests, can help predict a patient’s risk for pulmonary complications after transplant, allowing risk factor modification strategies to be implemented prior to transplant, including smoking cessation. It also helps identify patients at high risk for complications who will require closer monitoring after transplantation. Early posttransplant complications include infectious and noninfectious entities. Bacterial, viral, and fungal pneumonias are in the differential of infectious pneumonia, and bronchoscopy can be helpful in establishing a diagnosis. A common, important noninfectious cause of early pulmonary complications is IPS, which is treated with steroids and sometimes anti-TNF therapy.

The Food and Drug Administration has announced a potential temporary shortage of a type of Bivona tracheostomy tube manufactured by Smiths Medical caused by the closure of a large ethylene oxide sterilization facilities in Willowbrook, Ill., and the future planned closure of a similar facility.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The shortage may affect pediatric use because, although tubes are used for both adults and children, there are fewer alternative products on the market for pediatric patients. Parents and caregivers of children who use the Bivona tube are encouraged to check with Smiths Medical about available inventory and with their health care providers about alternative products.

Jeff Shuren, MD, director of the Center for Devices and Radiological Health, wrote in a press release, “I want to assure you that the FDA is working closely with the company to quickly resolve their sterilization challenges and bring these critical devices to the patients who need them as quickly as possible, which we anticipate will be made available again beginning the week of April 22.”

For patients currently using the Bivona tubes, Dr. Shuren noted, “The closure of the Willowbrook facility does not impact tubes already in use by patients at home or in health care settings. The company is communicating with patients about the tubes and how patients and caregivers can mitigate any potential impact, including reusing and cleaning tubes in accordance with the manufacturer’s instructions for use.”

Read the entire announcement at the FDA website.

tborden@mdedge.com

The Food and Drug Administration has announced a potential temporary shortage of a type of Bivona tracheostomy tube manufactured by Smiths Medical caused by the closure of a large ethylene oxide sterilization facilities in Willowbrook, Ill., and the future planned closure of a similar facility.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The shortage may affect pediatric use because, although tubes are used for both adults and children, there are fewer alternative products on the market for pediatric patients. Parents and caregivers of children who use the Bivona tube are encouraged to check with Smiths Medical about available inventory and with their health care providers about alternative products.

Jeff Shuren, MD, director of the Center for Devices and Radiological Health, wrote in a press release, “I want to assure you that the FDA is working closely with the company to quickly resolve their sterilization challenges and bring these critical devices to the patients who need them as quickly as possible, which we anticipate will be made available again beginning the week of April 22.”

For patients currently using the Bivona tubes, Dr. Shuren noted, “The closure of the Willowbrook facility does not impact tubes already in use by patients at home or in health care settings. The company is communicating with patients about the tubes and how patients and caregivers can mitigate any potential impact, including reusing and cleaning tubes in accordance with the manufacturer’s instructions for use.”

Read the entire announcement at the FDA website.

tborden@mdedge.com

The Food and Drug Administration has announced a potential temporary shortage of a type of Bivona tracheostomy tube manufactured by Smiths Medical caused by the closure of a large ethylene oxide sterilization facilities in Willowbrook, Ill., and the future planned closure of a similar facility.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The shortage may affect pediatric use because, although tubes are used for both adults and children, there are fewer alternative products on the market for pediatric patients. Parents and caregivers of children who use the Bivona tube are encouraged to check with Smiths Medical about available inventory and with their health care providers about alternative products.

Jeff Shuren, MD, director of the Center for Devices and Radiological Health, wrote in a press release, “I want to assure you that the FDA is working closely with the company to quickly resolve their sterilization challenges and bring these critical devices to the patients who need them as quickly as possible, which we anticipate will be made available again beginning the week of April 22.”

For patients currently using the Bivona tubes, Dr. Shuren noted, “The closure of the Willowbrook facility does not impact tubes already in use by patients at home or in health care settings. The company is communicating with patients about the tubes and how patients and caregivers can mitigate any potential impact, including reusing and cleaning tubes in accordance with the manufacturer’s instructions for use.”

Read the entire announcement at the FDA website.

tborden@mdedge.com

Preterm infants with bronchopulmonary dysplasia (BPD) discharged with supplemental oxygen showed slightly better weight and significantly improved weight-for-length scores, but were more likely to use medical resources and had rates of neurodevelopmental impairment similar to those of infants not discharged with oxygen, according to research published in Pediatrics.

Herjua/Thinkstock

“With this study, we provide important and novel information that may aid the decision of whether to discharge an infant with supplemental oxygen, particularly for those infants who might be weaned off by some clinicians and not by others,” wrote Sara B. DeMauro, MD, MSCE, of University of Pennsylvania, Philadelphia, and Children’s Hospital of Philadelphia, and her colleagues. “This study helps to clarify, both for clinicians and parents, the potential benefits and harms that might be expected from home oxygen therapy among the subset of infants for whom the best course of action is unclear.”

Dr. DeMauro and her colleagues examined 1,039 preterm infants with BPD given supplemental oxygen by nasal cannula between January 2006 and December 2014, who were propensity matched to infants in a control group with a similar severity of BPD who were not discharged with oxygen. The infants were born at less than 27 weeks’ gestation and began receiving oxygen therapy or respiratory support at 36 weeks’ postmenstrual age. These infants were then measured for growth, neurodevelopment, and resource use from discharge to follow-up at 22-26 months corrected age.

At follow-up, infants discharged with oxygen showed marginal weight improvement scores (adjusted mean difference, 0.11) and significantly improved weight-for-length scores (adjusted mean difference, 0.13), but they had rates of neurodevelopmental impairment similar to those of infants with BPD discharged without supplemental oxygen. In addition, infants discharged with oxygen had a greater likelihood of rehospitalization due to respiratory illness (adjusted relative risk, 1.33), use of asthma or BPD medication (adjusted RR, 1.30), and use of medical equipment such as a pulse oximeter (adjusted RR, 2.94).

The researchers noted that their study’s design prevented them from examining all infants with BPD discharged with supplemental oxygen and what factors influenced discharge of infants with supplemental oxygen, as well as the effects of various durations of supplemental oxygen exposure.

“Definitive evaluation of the risk/benefit ratio of this therapy will require prospective controlled trials,” Dr. DeMauro and her colleagues wrote. “Such research will facilitate a more evidence-based approach to clinical decisions about postdischarge care of infants with BPD.”

This study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and the National Institutes of Health. The authors reported no relevant financial disclosures.

SOURCE: DeMauro SB et al. Pediatrics. 2019 Apr 11. doi: 10.1542/peds.2018-2956.

Preterm infants with bronchopulmonary dysplasia (BPD) discharged with supplemental oxygen showed slightly better weight and significantly improved weight-for-length scores, but were more likely to use medical resources and had rates of neurodevelopmental impairment similar to those of infants not discharged with oxygen, according to research published in Pediatrics.

Herjua/Thinkstock

“With this study, we provide important and novel information that may aid the decision of whether to discharge an infant with supplemental oxygen, particularly for those infants who might be weaned off by some clinicians and not by others,” wrote Sara B. DeMauro, MD, MSCE, of University of Pennsylvania, Philadelphia, and Children’s Hospital of Philadelphia, and her colleagues. “This study helps to clarify, both for clinicians and parents, the potential benefits and harms that might be expected from home oxygen therapy among the subset of infants for whom the best course of action is unclear.”

Dr. DeMauro and her colleagues examined 1,039 preterm infants with BPD given supplemental oxygen by nasal cannula between January 2006 and December 2014, who were propensity matched to infants in a control group with a similar severity of BPD who were not discharged with oxygen. The infants were born at less than 27 weeks’ gestation and began receiving oxygen therapy or respiratory support at 36 weeks’ postmenstrual age. These infants were then measured for growth, neurodevelopment, and resource use from discharge to follow-up at 22-26 months corrected age.

At follow-up, infants discharged with oxygen showed marginal weight improvement scores (adjusted mean difference, 0.11) and significantly improved weight-for-length scores (adjusted mean difference, 0.13), but they had rates of neurodevelopmental impairment similar to those of infants with BPD discharged without supplemental oxygen. In addition, infants discharged with oxygen had a greater likelihood of rehospitalization due to respiratory illness (adjusted relative risk, 1.33), use of asthma or BPD medication (adjusted RR, 1.30), and use of medical equipment such as a pulse oximeter (adjusted RR, 2.94).

The researchers noted that their study’s design prevented them from examining all infants with BPD discharged with supplemental oxygen and what factors influenced discharge of infants with supplemental oxygen, as well as the effects of various durations of supplemental oxygen exposure.

“Definitive evaluation of the risk/benefit ratio of this therapy will require prospective controlled trials,” Dr. DeMauro and her colleagues wrote. “Such research will facilitate a more evidence-based approach to clinical decisions about postdischarge care of infants with BPD.”

This study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and the National Institutes of Health. The authors reported no relevant financial disclosures.

SOURCE: DeMauro SB et al. Pediatrics. 2019 Apr 11. doi: 10.1542/peds.2018-2956.

Preterm infants with bronchopulmonary dysplasia (BPD) discharged with supplemental oxygen showed slightly better weight and significantly improved weight-for-length scores, but were more likely to use medical resources and had rates of neurodevelopmental impairment similar to those of infants not discharged with oxygen, according to research published in Pediatrics.

Herjua/Thinkstock

“With this study, we provide important and novel information that may aid the decision of whether to discharge an infant with supplemental oxygen, particularly for those infants who might be weaned off by some clinicians and not by others,” wrote Sara B. DeMauro, MD, MSCE, of University of Pennsylvania, Philadelphia, and Children’s Hospital of Philadelphia, and her colleagues. “This study helps to clarify, both for clinicians and parents, the potential benefits and harms that might be expected from home oxygen therapy among the subset of infants for whom the best course of action is unclear.”

Dr. DeMauro and her colleagues examined 1,039 preterm infants with BPD given supplemental oxygen by nasal cannula between January 2006 and December 2014, who were propensity matched to infants in a control group with a similar severity of BPD who were not discharged with oxygen. The infants were born at less than 27 weeks’ gestation and began receiving oxygen therapy or respiratory support at 36 weeks’ postmenstrual age. These infants were then measured for growth, neurodevelopment, and resource use from discharge to follow-up at 22-26 months corrected age.

At follow-up, infants discharged with oxygen showed marginal weight improvement scores (adjusted mean difference, 0.11) and significantly improved weight-for-length scores (adjusted mean difference, 0.13), but they had rates of neurodevelopmental impairment similar to those of infants with BPD discharged without supplemental oxygen. In addition, infants discharged with oxygen had a greater likelihood of rehospitalization due to respiratory illness (adjusted relative risk, 1.33), use of asthma or BPD medication (adjusted RR, 1.30), and use of medical equipment such as a pulse oximeter (adjusted RR, 2.94).

The researchers noted that their study’s design prevented them from examining all infants with BPD discharged with supplemental oxygen and what factors influenced discharge of infants with supplemental oxygen, as well as the effects of various durations of supplemental oxygen exposure.

“Definitive evaluation of the risk/benefit ratio of this therapy will require prospective controlled trials,” Dr. DeMauro and her colleagues wrote. “Such research will facilitate a more evidence-based approach to clinical decisions about postdischarge care of infants with BPD.”

This study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and the National Institutes of Health. The authors reported no relevant financial disclosures.

SOURCE: DeMauro SB et al. Pediatrics. 2019 Apr 11. doi: 10.1542/peds.2018-2956.

The buildup of mucus in the lungs was found to precede airway changes and infection in young children with cystic fibrosis (CF), according to a cross-sectional cohort study.

Zerbor/Thinkstock

It has been difficult for researchers to pinpoint the mechanisms that initiate lung disease in people with CF, because it is challenging to study young people with the disease and “CF animal models often fail to recapitulate aspects of human CF disease and yield disparate findings,” wrote Charles R. Esther Jr., MD, of the division of pediatric pulmonology at the University of North Carolina at Chapel Hill and his colleagues in Science Translational Medicine.

The researchers studied 46 clinically stable young children (aged 3.3 years, plus or minus 1.7 years) with CF and 16 age-matched controls who did not have CF, but had respiratory symptoms (aged 3.2 years, plus or minus 2.0 years) using chest CT imaging and bronchoalveolar lavage fluid. BALF samples in CF patients were collected over 62 study visits and subsequently cultured for detection and quantification of pathogens. The children with CF were enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program.

“We analyzed the relationships between airway mucus, inflammation, and bacterial culture/microbiome,” the researchers wrote.

BALF total mucin levels were higher in CF samples versus non-CF controls. In addition, Dr. Esther and his colleagues found that these results were the same regardless of infection status and that increased densities of mucus flakes were also seen in samples from the CF patients. “Elevated total mucin concentrations and inflammatory markers were observed in children with CF despite a low incidence of pathogens identified by culture or molecular microbiology. This muco-inflammatory state also characterized our CF population with the earliest lung disease [without substantial CT-defined structural changes] in the setting of little or no pathogen infection,” they wrote.

Based on the findings, the investigators postulated that the airways of children with CF may show distinct defects in the clearance of recently created mucins, which could contribute to early CF lung disease.

A key limitation of the study was the prophylactic use of intermittent antibiotics. As a result, bacterial infection could have contributed to the development of early CF lung disease.

“Agents designed to remove permanent mucus covering airway surfaces of young children with CF appear to be rational strategies to prevent bacterial infection and disease progression,” they concluded.

The study was supported by the National Heart, Lung, and Blood Institute; the North Carolina Translational and Clinical Sciences Institute; the National Health and Medical Research Council; and the Cystic Fibrosis Foundation. Two coauthors reported financial affiliations with Parion Sciences.

SOURCE: Esther CR et al. Sci Transl Med. 2019 Apr 3. doi: 10.1126/scitranslmed.aav3488.

The buildup of mucus in the lungs was found to precede airway changes and infection in young children with cystic fibrosis (CF), according to a cross-sectional cohort study.

Zerbor/Thinkstock

It has been difficult for researchers to pinpoint the mechanisms that initiate lung disease in people with CF, because it is challenging to study young people with the disease and “CF animal models often fail to recapitulate aspects of human CF disease and yield disparate findings,” wrote Charles R. Esther Jr., MD, of the division of pediatric pulmonology at the University of North Carolina at Chapel Hill and his colleagues in Science Translational Medicine.

The researchers studied 46 clinically stable young children (aged 3.3 years, plus or minus 1.7 years) with CF and 16 age-matched controls who did not have CF, but had respiratory symptoms (aged 3.2 years, plus or minus 2.0 years) using chest CT imaging and bronchoalveolar lavage fluid. BALF samples in CF patients were collected over 62 study visits and subsequently cultured for detection and quantification of pathogens. The children with CF were enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program.

“We analyzed the relationships between airway mucus, inflammation, and bacterial culture/microbiome,” the researchers wrote.

BALF total mucin levels were higher in CF samples versus non-CF controls. In addition, Dr. Esther and his colleagues found that these results were the same regardless of infection status and that increased densities of mucus flakes were also seen in samples from the CF patients. “Elevated total mucin concentrations and inflammatory markers were observed in children with CF despite a low incidence of pathogens identified by culture or molecular microbiology. This muco-inflammatory state also characterized our CF population with the earliest lung disease [without substantial CT-defined structural changes] in the setting of little or no pathogen infection,” they wrote.

Based on the findings, the investigators postulated that the airways of children with CF may show distinct defects in the clearance of recently created mucins, which could contribute to early CF lung disease.

A key limitation of the study was the prophylactic use of intermittent antibiotics. As a result, bacterial infection could have contributed to the development of early CF lung disease.

“Agents designed to remove permanent mucus covering airway surfaces of young children with CF appear to be rational strategies to prevent bacterial infection and disease progression,” they concluded.

The study was supported by the National Heart, Lung, and Blood Institute; the North Carolina Translational and Clinical Sciences Institute; the National Health and Medical Research Council; and the Cystic Fibrosis Foundation. Two coauthors reported financial affiliations with Parion Sciences.

SOURCE: Esther CR et al. Sci Transl Med. 2019 Apr 3. doi: 10.1126/scitranslmed.aav3488.

The buildup of mucus in the lungs was found to precede airway changes and infection in young children with cystic fibrosis (CF), according to a cross-sectional cohort study.

Zerbor/Thinkstock

It has been difficult for researchers to pinpoint the mechanisms that initiate lung disease in people with CF, because it is challenging to study young people with the disease and “CF animal models often fail to recapitulate aspects of human CF disease and yield disparate findings,” wrote Charles R. Esther Jr., MD, of the division of pediatric pulmonology at the University of North Carolina at Chapel Hill and his colleagues in Science Translational Medicine.

The researchers studied 46 clinically stable young children (aged 3.3 years, plus or minus 1.7 years) with CF and 16 age-matched controls who did not have CF, but had respiratory symptoms (aged 3.2 years, plus or minus 2.0 years) using chest CT imaging and bronchoalveolar lavage fluid. BALF samples in CF patients were collected over 62 study visits and subsequently cultured for detection and quantification of pathogens. The children with CF were enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program.

“We analyzed the relationships between airway mucus, inflammation, and bacterial culture/microbiome,” the researchers wrote.

BALF total mucin levels were higher in CF samples versus non-CF controls. In addition, Dr. Esther and his colleagues found that these results were the same regardless of infection status and that increased densities of mucus flakes were also seen in samples from the CF patients. “Elevated total mucin concentrations and inflammatory markers were observed in children with CF despite a low incidence of pathogens identified by culture or molecular microbiology. This muco-inflammatory state also characterized our CF population with the earliest lung disease [without substantial CT-defined structural changes] in the setting of little or no pathogen infection,” they wrote.

Based on the findings, the investigators postulated that the airways of children with CF may show distinct defects in the clearance of recently created mucins, which could contribute to early CF lung disease.

A key limitation of the study was the prophylactic use of intermittent antibiotics. As a result, bacterial infection could have contributed to the development of early CF lung disease.

“Agents designed to remove permanent mucus covering airway surfaces of young children with CF appear to be rational strategies to prevent bacterial infection and disease progression,” they concluded.

The study was supported by the National Heart, Lung, and Blood Institute; the North Carolina Translational and Clinical Sciences Institute; the National Health and Medical Research Council; and the Cystic Fibrosis Foundation. Two coauthors reported financial affiliations with Parion Sciences.

SOURCE: Esther CR et al. Sci Transl Med. 2019 Apr 3. doi: 10.1126/scitranslmed.aav3488.

For most of us, social media is a daunting new reality that we are pressured to be part of but that we struggle to fit into our increasingly demanding schedules. My first social media foray as a physician was a Facebook fan page as a hobby rather than a professional presence. Years later, I have learned the incredible benefit that being on social media in other platforms brought to my profession.
 

What’s social media going to bring to my medical practice?
The days where physicians retreat to the safety of our offices to deliver our care, or to issue carefully structured opinions, or interactions with patients have made way for more direct interaction. Social media has, indeed, allowed us to share more personal glimpses of our daily struggle to save lives, behind-the-scenes snapshot of ethical struggles in decision making, our difficulties qualifying patients for therapies due to insurance complications, or real-time addressing medical news and combating misinformation. Moreover, when patients self-refer, or are referred to my practice, they look me up online before coming to my office. Online profiles are the new “first impression” of the bedside manner of a physician.

Other personal examples of social media benefits include being informed of new publications, since many journals now have an online presence; being able to interact in real-time with authors; learning from physicians in other countries how they handled issues, such as shortage of critical medications; or earning CME, such as the Twitter chats hosted by CHEST (eg, new biologic agents in difficult to treat asthma, or patient selection in triple therapy for COPD).

Why should I pay attention to social media presence?
The pace by which social media changed the landscape took the medical community by surprise. Patients, third-party websites, and online review agencies (official or not) adopted it well before physicians became comfortable with it. As such, when I decided to google myself online, I was shocked at the level of misinformation about me (as a pulmonologist, I didn’t know I had performed sigmoidoscopies, yet that’s what my patients learned before they met me). That was an important lesson: If I don’t control the narrative, someone else will. Consequently, I dedicated a few hours to establish an online presence in order to introduce myself accurately and to be accessible to my patients and colleagues online.

Who decides what’s ethical and what’s not?
As the lines blurred, our community struggled to define what was appropriate and what was not. Finally, we welcomed with relief the issuance of a Code of Ethics, regarding social media use by physicians, from several societies, including the American Medical Association (https://www.ama-assn.org/delivering-care/ethics/professionalism-use-social-media). The principles guiding physicians use of social media include respect for human dignity and rights, honesty and upholding the standards of professionalism, and the duty to safeguard patient confidences and privacy.

Which platform should I use? There are so many. 
While any content can be shared on any platform, social media sites have organically differentiated into being more amenable to one content vs the other. Some accounts tend to be more for professional use (ie, Twitter and LinkedIn), and other accounts for personal use (ie, Facebook, Instagram, Snapchat, and Pinterest). CHEST has selected Twitter to host its CME chats regarding preselected topics, post information about an upcoming lecture during the CHEST meeting, etc. New social media sites are now “physician only,” such as Sermo, Doximity, QuantiMD, and Doc2Doc. Many of these sites require doctors to submit their credentials to a site gatekeeper, recreating the intimacy of a “physicians’ lounge” in an online environment (J Med Internet Res. 2014:Feb 11;16[2]:e13). Lastly, Figure1 is a media sharing app between physicians allowing discussions of de-identified images or cases, recreating the “curbside” consult concept online.

I heard about hashtags. What are they?
Hashtags are simply clickable topic titles (#COPD #Sepsis # Education, etc.) that can be added to a post, in order to widen its reach. For instance, if I am interested in sepsis, I can click on the hashtag #Sepsis, and it would bring up all the posts on any Twitter account that added that hashtag. It’s a filter that takes me to that topic of interest. I can then click on the button “Like” on the message or the account itself where the post was found. The “Like” is similar to a bookmark for that account on my own Twitter. In the future, all the posts from that account would be available to me.

What are influencers or thought leaders?
Anyone who “liked” my account is now “following” me. The number of followers has become a measure of the popularity of anyone on social media. If it reaches a high level, then the person with the account is dubbed an “influencer.” Social media “influencers” are individuals whose opinion is followed by hundreds of thousands. Influencers may even be rewarded for harnessing their reach to make money off advertising. One can easily see how it is powerful for a physician to become an influencer or a “thought leader,” not to make money but to expand their reach on social media to spread the correct information about diets, drugs, e-cigarettes, and vaccinations, to name a few.

Can social media get me in trouble?
In 2012, a survey of the state medical boards published by JAMA (2012;307[11]:1141) revealed that approximately 30% of state medical boards reported complaints of “online violations of patient confidentiality.” More than 10% stated they had encountered a case of an “online depiction of intoxication.”

Another study a year earlier revealed that 13% of physicians reported they have discussed individual, though anonymized, cases with other physicians in public online forums (http://www.quantiamd.com/qqcp/DoctorsPatientSocialMedia.pdf).

Even if posted anonymously, or on a “personal” rather than professional social media site, various investigative methods may potentially be used to directly link information to a specific person or incident. The most current case law dictates that such information is “discoverable.” In fact, Facebook’s policy for the use of data informs users that, “we may access, preserve, and share your information in response to a legal request” both within and outside of U.S. jurisdiction”.

What kind of trouble could I be exposed to?
Poor quality of information, damage to our professional image, breaches of patient’s privacy, violation of patient-physician boundary, license revoking by state boards, and erroneous medical advice given in the absence of examining a patient, are all potential pitfalls for physicians in the careless use of social media.

• supplies offline contact information so that an appointment can be made, if desired; and

• identifies a source for emergency services if the inquirer cannot wait for an appointment.

In circumstances where a patient–physician relationship already exists, informed consent should be obtained, which should include a careful explanation regarding the risks of online communication, expected response times, and the handling of emergencies, then documented in the patient’s chart (PT. 2014 Jul;39[7]:491,520).

In Summary

Social media, much like any area of medicine one is interested in, can be daunting and exciting but fraught with potential difficulties. I liken its adoption in our daily practice to any other decision or interest, including being in a private or academic setting, adopting procedural medicine or sticking to diagnostic consultations, or participating in research. In the end, it’s an individual expression of our desire to practice medicine. However, verifying information already existing online about us is of paramount importance. If I don’t tell my story, someone else will, and they may not be as truthful.
 

Dr. Bencheqroun is Assistant Professor, University of California Riverside School of Medicine, Pulmonary/Critical Care Faculty Program Coordinator & Research Mentor - Internal Medicine Residency Program Desert Regional Medical Center, Palm Springs CA; and Immediate Past Chair of the CHEST Council of Networks.

For most of us, social media is a daunting new reality that we are pressured to be part of but that we struggle to fit into our increasingly demanding schedules. My first social media foray as a physician was a Facebook fan page as a hobby rather than a professional presence. Years later, I have learned the incredible benefit that being on social media in other platforms brought to my profession.
 

What’s social media going to bring to my medical practice?
The days where physicians retreat to the safety of our offices to deliver our care, or to issue carefully structured opinions, or interactions with patients have made way for more direct interaction. Social media has, indeed, allowed us to share more personal glimpses of our daily struggle to save lives, behind-the-scenes snapshot of ethical struggles in decision making, our difficulties qualifying patients for therapies due to insurance complications, or real-time addressing medical news and combating misinformation. Moreover, when patients self-refer, or are referred to my practice, they look me up online before coming to my office. Online profiles are the new “first impression” of the bedside manner of a physician.

Other personal examples of social media benefits include being informed of new publications, since many journals now have an online presence; being able to interact in real-time with authors; learning from physicians in other countries how they handled issues, such as shortage of critical medications; or earning CME, such as the Twitter chats hosted by CHEST (eg, new biologic agents in difficult to treat asthma, or patient selection in triple therapy for COPD).

Why should I pay attention to social media presence?
The pace by which social media changed the landscape took the medical community by surprise. Patients, third-party websites, and online review agencies (official or not) adopted it well before physicians became comfortable with it. As such, when I decided to google myself online, I was shocked at the level of misinformation about me (as a pulmonologist, I didn’t know I had performed sigmoidoscopies, yet that’s what my patients learned before they met me). That was an important lesson: If I don’t control the narrative, someone else will. Consequently, I dedicated a few hours to establish an online presence in order to introduce myself accurately and to be accessible to my patients and colleagues online.

Who decides what’s ethical and what’s not?
As the lines blurred, our community struggled to define what was appropriate and what was not. Finally, we welcomed with relief the issuance of a Code of Ethics, regarding social media use by physicians, from several societies, including the American Medical Association (https://www.ama-assn.org/delivering-care/ethics/professionalism-use-social-media). The principles guiding physicians use of social media include respect for human dignity and rights, honesty and upholding the standards of professionalism, and the duty to safeguard patient confidences and privacy.

Which platform should I use? There are so many. 
While any content can be shared on any platform, social media sites have organically differentiated into being more amenable to one content vs the other. Some accounts tend to be more for professional use (ie, Twitter and LinkedIn), and other accounts for personal use (ie, Facebook, Instagram, Snapchat, and Pinterest). CHEST has selected Twitter to host its CME chats regarding preselected topics, post information about an upcoming lecture during the CHEST meeting, etc. New social media sites are now “physician only,” such as Sermo, Doximity, QuantiMD, and Doc2Doc. Many of these sites require doctors to submit their credentials to a site gatekeeper, recreating the intimacy of a “physicians’ lounge” in an online environment (J Med Internet Res. 2014:Feb 11;16[2]:e13). Lastly, Figure1 is a media sharing app between physicians allowing discussions of de-identified images or cases, recreating the “curbside” consult concept online.

I heard about hashtags. What are they?
Hashtags are simply clickable topic titles (#COPD #Sepsis # Education, etc.) that can be added to a post, in order to widen its reach. For instance, if I am interested in sepsis, I can click on the hashtag #Sepsis, and it would bring up all the posts on any Twitter account that added that hashtag. It’s a filter that takes me to that topic of interest. I can then click on the button “Like” on the message or the account itself where the post was found. The “Like” is similar to a bookmark for that account on my own Twitter. In the future, all the posts from that account would be available to me.

What are influencers or thought leaders?
Anyone who “liked” my account is now “following” me. The number of followers has become a measure of the popularity of anyone on social media. If it reaches a high level, then the person with the account is dubbed an “influencer.” Social media “influencers” are individuals whose opinion is followed by hundreds of thousands. Influencers may even be rewarded for harnessing their reach to make money off advertising. One can easily see how it is powerful for a physician to become an influencer or a “thought leader,” not to make money but to expand their reach on social media to spread the correct information about diets, drugs, e-cigarettes, and vaccinations, to name a few.

Can social media get me in trouble?
In 2012, a survey of the state medical boards published by JAMA (2012;307[11]:1141) revealed that approximately 30% of state medical boards reported complaints of “online violations of patient confidentiality.” More than 10% stated they had encountered a case of an “online depiction of intoxication.”

Another study a year earlier revealed that 13% of physicians reported they have discussed individual, though anonymized, cases with other physicians in public online forums (http://www.quantiamd.com/qqcp/DoctorsPatientSocialMedia.pdf).

Even if posted anonymously, or on a “personal” rather than professional social media site, various investigative methods may potentially be used to directly link information to a specific person or incident. The most current case law dictates that such information is “discoverable.” In fact, Facebook’s policy for the use of data informs users that, “we may access, preserve, and share your information in response to a legal request” both within and outside of U.S. jurisdiction”.

What kind of trouble could I be exposed to?
Poor quality of information, damage to our professional image, breaches of patient’s privacy, violation of patient-physician boundary, license revoking by state boards, and erroneous medical advice given in the absence of examining a patient, are all potential pitfalls for physicians in the careless use of social media.

• supplies offline contact information so that an appointment can be made, if desired; and

• identifies a source for emergency services if the inquirer cannot wait for an appointment.

In circumstances where a patient–physician relationship already exists, informed consent should be obtained, which should include a careful explanation regarding the risks of online communication, expected response times, and the handling of emergencies, then documented in the patient’s chart (PT. 2014 Jul;39[7]:491,520).

In Summary

Social media, much like any area of medicine one is interested in, can be daunting and exciting but fraught with potential difficulties. I liken its adoption in our daily practice to any other decision or interest, including being in a private or academic setting, adopting procedural medicine or sticking to diagnostic consultations, or participating in research. In the end, it’s an individual expression of our desire to practice medicine. However, verifying information already existing online about us is of paramount importance. If I don’t tell my story, someone else will, and they may not be as truthful.
 

Dr. Bencheqroun is Assistant Professor, University of California Riverside School of Medicine, Pulmonary/Critical Care Faculty Program Coordinator & Research Mentor - Internal Medicine Residency Program Desert Regional Medical Center, Palm Springs CA; and Immediate Past Chair of the CHEST Council of Networks.

For most of us, social media is a daunting new reality that we are pressured to be part of but that we struggle to fit into our increasingly demanding schedules. My first social media foray as a physician was a Facebook fan page as a hobby rather than a professional presence. Years later, I have learned the incredible benefit that being on social media in other platforms brought to my profession.
 

What’s social media going to bring to my medical practice?
The days where physicians retreat to the safety of our offices to deliver our care, or to issue carefully structured opinions, or interactions with patients have made way for more direct interaction. Social media has, indeed, allowed us to share more personal glimpses of our daily struggle to save lives, behind-the-scenes snapshot of ethical struggles in decision making, our difficulties qualifying patients for therapies due to insurance complications, or real-time addressing medical news and combating misinformation. Moreover, when patients self-refer, or are referred to my practice, they look me up online before coming to my office. Online profiles are the new “first impression” of the bedside manner of a physician.

Other personal examples of social media benefits include being informed of new publications, since many journals now have an online presence; being able to interact in real-time with authors; learning from physicians in other countries how they handled issues, such as shortage of critical medications; or earning CME, such as the Twitter chats hosted by CHEST (eg, new biologic agents in difficult to treat asthma, or patient selection in triple therapy for COPD).

Why should I pay attention to social media presence?
The pace by which social media changed the landscape took the medical community by surprise. Patients, third-party websites, and online review agencies (official or not) adopted it well before physicians became comfortable with it. As such, when I decided to google myself online, I was shocked at the level of misinformation about me (as a pulmonologist, I didn’t know I had performed sigmoidoscopies, yet that’s what my patients learned before they met me). That was an important lesson: If I don’t control the narrative, someone else will. Consequently, I dedicated a few hours to establish an online presence in order to introduce myself accurately and to be accessible to my patients and colleagues online.

Who decides what’s ethical and what’s not?
As the lines blurred, our community struggled to define what was appropriate and what was not. Finally, we welcomed with relief the issuance of a Code of Ethics, regarding social media use by physicians, from several societies, including the American Medical Association (https://www.ama-assn.org/delivering-care/ethics/professionalism-use-social-media). The principles guiding physicians use of social media include respect for human dignity and rights, honesty and upholding the standards of professionalism, and the duty to safeguard patient confidences and privacy.

Which platform should I use? There are so many. 
While any content can be shared on any platform, social media sites have organically differentiated into being more amenable to one content vs the other. Some accounts tend to be more for professional use (ie, Twitter and LinkedIn), and other accounts for personal use (ie, Facebook, Instagram, Snapchat, and Pinterest). CHEST has selected Twitter to host its CME chats regarding preselected topics, post information about an upcoming lecture during the CHEST meeting, etc. New social media sites are now “physician only,” such as Sermo, Doximity, QuantiMD, and Doc2Doc. Many of these sites require doctors to submit their credentials to a site gatekeeper, recreating the intimacy of a “physicians’ lounge” in an online environment (J Med Internet Res. 2014:Feb 11;16[2]:e13). Lastly, Figure1 is a media sharing app between physicians allowing discussions of de-identified images or cases, recreating the “curbside” consult concept online.

I heard about hashtags. What are they?
Hashtags are simply clickable topic titles (#COPD #Sepsis # Education, etc.) that can be added to a post, in order to widen its reach. For instance, if I am interested in sepsis, I can click on the hashtag #Sepsis, and it would bring up all the posts on any Twitter account that added that hashtag. It’s a filter that takes me to that topic of interest. I can then click on the button “Like” on the message or the account itself where the post was found. The “Like” is similar to a bookmark for that account on my own Twitter. In the future, all the posts from that account would be available to me.

What are influencers or thought leaders?
Anyone who “liked” my account is now “following” me. The number of followers has become a measure of the popularity of anyone on social media. If it reaches a high level, then the person with the account is dubbed an “influencer.” Social media “influencers” are individuals whose opinion is followed by hundreds of thousands. Influencers may even be rewarded for harnessing their reach to make money off advertising. One can easily see how it is powerful for a physician to become an influencer or a “thought leader,” not to make money but to expand their reach on social media to spread the correct information about diets, drugs, e-cigarettes, and vaccinations, to name a few.

Can social media get me in trouble?
In 2012, a survey of the state medical boards published by JAMA (2012;307[11]:1141) revealed that approximately 30% of state medical boards reported complaints of “online violations of patient confidentiality.” More than 10% stated they had encountered a case of an “online depiction of intoxication.”

Another study a year earlier revealed that 13% of physicians reported they have discussed individual, though anonymized, cases with other physicians in public online forums (http://www.quantiamd.com/qqcp/DoctorsPatientSocialMedia.pdf).

Even if posted anonymously, or on a “personal” rather than professional social media site, various investigative methods may potentially be used to directly link information to a specific person or incident. The most current case law dictates that such information is “discoverable.” In fact, Facebook’s policy for the use of data informs users that, “we may access, preserve, and share your information in response to a legal request” both within and outside of U.S. jurisdiction”.

What kind of trouble could I be exposed to?
Poor quality of information, damage to our professional image, breaches of patient’s privacy, violation of patient-physician boundary, license revoking by state boards, and erroneous medical advice given in the absence of examining a patient, are all potential pitfalls for physicians in the careless use of social media.

• supplies offline contact information so that an appointment can be made, if desired; and

• identifies a source for emergency services if the inquirer cannot wait for an appointment.

In circumstances where a patient–physician relationship already exists, informed consent should be obtained, which should include a careful explanation regarding the risks of online communication, expected response times, and the handling of emergencies, then documented in the patient’s chart (PT. 2014 Jul;39[7]:491,520).

In Summary

Social media, much like any area of medicine one is interested in, can be daunting and exciting but fraught with potential difficulties. I liken its adoption in our daily practice to any other decision or interest, including being in a private or academic setting, adopting procedural medicine or sticking to diagnostic consultations, or participating in research. In the end, it’s an individual expression of our desire to practice medicine. However, verifying information already existing online about us is of paramount importance. If I don’t tell my story, someone else will, and they may not be as truthful.
 

Dr. Bencheqroun is Assistant Professor, University of California Riverside School of Medicine, Pulmonary/Critical Care Faculty Program Coordinator & Research Mentor - Internal Medicine Residency Program Desert Regional Medical Center, Palm Springs CA; and Immediate Past Chair of the CHEST Council of Networks.

In patients with hypersensitivity pneumonitis, presence of radiologic honeycombing suggests a poor prognosis in line with what might be expected with idiopathic pulmonary fibrosis, results of a recent study suggest.

When radiologic honeycombing was present, event-free survival was uniformly poor, regardless of whether the patient had hypersensitivity pneumonitis (HP) or idiopathic pulmonary fibrosis (IPF). By contrast, HP patients with nonhoneycomb fibrosis had longer event-free survival than IPF patients with honeycomb features on CT, wrote researchers led by Margaret L. Salisbury, MD, of the division of pulmonary and critical care medicine at the University of Michigan, Ann Arbor.

“Given the uniformly poor outcome among subjects with radiologic honeycombing, pursuit of invasive diagnostic tests directed at differentiating IPF from HP may be of limited value,” Dr. Salisbury and her coinvestigators wrote in Chest.

In the study, 117 patients with HP and 161 with IPF underwent high-resolution CT, results of which were evaluated by three thoracic radiologists. Patients with HP who had no fibrosis on CT had the best event-free median survival, or time to transplant or death, at greater than 14.73 years. For HP patients with nonhoneycomb fibrosis, that median survival was greater than 7.95 years, compared with just 5.20 years in IPF patients without honeycomb features.

Looking specifically at patients with honeycomb features, median event-free survival was poor for both HP and IPF patients, at 2.76 and 2.81 years, respectively.

The HP patients with no fibrosis had a significant improvement in percent predicted forced vital capacity over time, while fibrotic patients experienced significant declines, the investigators wrote. Thus, HP patients with nonhoneycomb fibrosis had forced vital capacity declines despite longer transplant-free survival.

“These results highlight the importance of making a correct diagnosis of HP versus IPF in patients with nonhoneycomb fibrosis, as well as the limited utility in differentiating HP from IPF among patients with radiologic honeycombing,” Dr. Salisbury and her coinvestigators concluded.

Dr. Salisbury reported grants from the National Institutes of Health during the study. Her coauthors reported disclosures related to the NIH, Bayer, Centocor, Gilead, Promedior, Ikaria, Genentech, Nycomed/Takeda, Pfizer, and others.

SOURCE: Salisbury ML et al. Chest. 2019 Apr;155(4):699-711.

In patients with hypersensitivity pneumonitis, presence of radiologic honeycombing suggests a poor prognosis in line with what might be expected with idiopathic pulmonary fibrosis, results of a recent study suggest.

When radiologic honeycombing was present, event-free survival was uniformly poor, regardless of whether the patient had hypersensitivity pneumonitis (HP) or idiopathic pulmonary fibrosis (IPF). By contrast, HP patients with nonhoneycomb fibrosis had longer event-free survival than IPF patients with honeycomb features on CT, wrote researchers led by Margaret L. Salisbury, MD, of the division of pulmonary and critical care medicine at the University of Michigan, Ann Arbor.

“Given the uniformly poor outcome among subjects with radiologic honeycombing, pursuit of invasive diagnostic tests directed at differentiating IPF from HP may be of limited value,” Dr. Salisbury and her coinvestigators wrote in Chest.

In the study, 117 patients with HP and 161 with IPF underwent high-resolution CT, results of which were evaluated by three thoracic radiologists. Patients with HP who had no fibrosis on CT had the best event-free median survival, or time to transplant or death, at greater than 14.73 years. For HP patients with nonhoneycomb fibrosis, that median survival was greater than 7.95 years, compared with just 5.20 years in IPF patients without honeycomb features.

Looking specifically at patients with honeycomb features, median event-free survival was poor for both HP and IPF patients, at 2.76 and 2.81 years, respectively.

The HP patients with no fibrosis had a significant improvement in percent predicted forced vital capacity over time, while fibrotic patients experienced significant declines, the investigators wrote. Thus, HP patients with nonhoneycomb fibrosis had forced vital capacity declines despite longer transplant-free survival.

“These results highlight the importance of making a correct diagnosis of HP versus IPF in patients with nonhoneycomb fibrosis, as well as the limited utility in differentiating HP from IPF among patients with radiologic honeycombing,” Dr. Salisbury and her coinvestigators concluded.

Dr. Salisbury reported grants from the National Institutes of Health during the study. Her coauthors reported disclosures related to the NIH, Bayer, Centocor, Gilead, Promedior, Ikaria, Genentech, Nycomed/Takeda, Pfizer, and others.

SOURCE: Salisbury ML et al. Chest. 2019 Apr;155(4):699-711.

In patients with hypersensitivity pneumonitis, presence of radiologic honeycombing suggests a poor prognosis in line with what might be expected with idiopathic pulmonary fibrosis, results of a recent study suggest.

When radiologic honeycombing was present, event-free survival was uniformly poor, regardless of whether the patient had hypersensitivity pneumonitis (HP) or idiopathic pulmonary fibrosis (IPF). By contrast, HP patients with nonhoneycomb fibrosis had longer event-free survival than IPF patients with honeycomb features on CT, wrote researchers led by Margaret L. Salisbury, MD, of the division of pulmonary and critical care medicine at the University of Michigan, Ann Arbor.

“Given the uniformly poor outcome among subjects with radiologic honeycombing, pursuit of invasive diagnostic tests directed at differentiating IPF from HP may be of limited value,” Dr. Salisbury and her coinvestigators wrote in Chest.

In the study, 117 patients with HP and 161 with IPF underwent high-resolution CT, results of which were evaluated by three thoracic radiologists. Patients with HP who had no fibrosis on CT had the best event-free median survival, or time to transplant or death, at greater than 14.73 years. For HP patients with nonhoneycomb fibrosis, that median survival was greater than 7.95 years, compared with just 5.20 years in IPF patients without honeycomb features.

Looking specifically at patients with honeycomb features, median event-free survival was poor for both HP and IPF patients, at 2.76 and 2.81 years, respectively.

The HP patients with no fibrosis had a significant improvement in percent predicted forced vital capacity over time, while fibrotic patients experienced significant declines, the investigators wrote. Thus, HP patients with nonhoneycomb fibrosis had forced vital capacity declines despite longer transplant-free survival.

“These results highlight the importance of making a correct diagnosis of HP versus IPF in patients with nonhoneycomb fibrosis, as well as the limited utility in differentiating HP from IPF among patients with radiologic honeycombing,” Dr. Salisbury and her coinvestigators concluded.

Dr. Salisbury reported grants from the National Institutes of Health during the study. Her coauthors reported disclosures related to the NIH, Bayer, Centocor, Gilead, Promedior, Ikaria, Genentech, Nycomed/Takeda, Pfizer, and others.

SOURCE: Salisbury ML et al. Chest. 2019 Apr;155(4):699-711.

Rapid deterioration of life quality of patients with idiopathic pulmonary fibrosis (IPF) begins years before death and indicates that early, integrated palliative care should be a priority, according to the finding of a survey study.

IPFeditor/Wikimedia Commons

“Patients with IPF suffer from exceptionally low [health-related quality of life] together with severe breathlessness and fatigue already two years before death. In addition, physical and emotional well-being further deteriorates near death concurrently with escalating overall symptom burden,” wrote Kaisa Rajala, MD, and her colleagues at Helsinki University Hospital.

They conducted a substudy of patients in the larger FinnishIPF study to assess health-related quality of life (HRQOL) and symptom burden in the period before death. Among 300 patients invited to participate, 247 agreed. Patient disease and sociodemographic data were collected from the FinnishIPF records and the study group completed questionnaires five times at 6 month intervals. The study began in April 2015 and continued until August 2017, by which time 92 (37%) of the patients had died (BMC Pulmonary Medicine 2018;18:172; doi: 0.1186/s12890-018-0738-x).

The investigators used self-reporting tools to look at HRQOL and symptom burden: RAND 36-item Health Survey (RAND-36), the Modified Medical Research and Council Dyspnea Scale (MMRC), the Modified Edmonton Symptom Assessment Scale (ESAS), and the Numeric Rating Scale (NRS).

tborden@mdedge.com

SOURCE: Rajala K et al. BMC Pulm Med. 2018;18:172. doi: 0.1186/s12890-018-0738-x.

Rapid deterioration of life quality of patients with idiopathic pulmonary fibrosis (IPF) begins years before death and indicates that early, integrated palliative care should be a priority, according to the finding of a survey study.

IPFeditor/Wikimedia Commons

“Patients with IPF suffer from exceptionally low [health-related quality of life] together with severe breathlessness and fatigue already two years before death. In addition, physical and emotional well-being further deteriorates near death concurrently with escalating overall symptom burden,” wrote Kaisa Rajala, MD, and her colleagues at Helsinki University Hospital.

They conducted a substudy of patients in the larger FinnishIPF study to assess health-related quality of life (HRQOL) and symptom burden in the period before death. Among 300 patients invited to participate, 247 agreed. Patient disease and sociodemographic data were collected from the FinnishIPF records and the study group completed questionnaires five times at 6 month intervals. The study began in April 2015 and continued until August 2017, by which time 92 (37%) of the patients had died (BMC Pulmonary Medicine 2018;18:172; doi: 0.1186/s12890-018-0738-x).

The investigators used self-reporting tools to look at HRQOL and symptom burden: RAND 36-item Health Survey (RAND-36), the Modified Medical Research and Council Dyspnea Scale (MMRC), the Modified Edmonton Symptom Assessment Scale (ESAS), and the Numeric Rating Scale (NRS).

tborden@mdedge.com

SOURCE: Rajala K et al. BMC Pulm Med. 2018;18:172. doi: 0.1186/s12890-018-0738-x.

Rapid deterioration of life quality of patients with idiopathic pulmonary fibrosis (IPF) begins years before death and indicates that early, integrated palliative care should be a priority, according to the finding of a survey study.

IPFeditor/Wikimedia Commons

“Patients with IPF suffer from exceptionally low [health-related quality of life] together with severe breathlessness and fatigue already two years before death. In addition, physical and emotional well-being further deteriorates near death concurrently with escalating overall symptom burden,” wrote Kaisa Rajala, MD, and her colleagues at Helsinki University Hospital.

They conducted a substudy of patients in the larger FinnishIPF study to assess health-related quality of life (HRQOL) and symptom burden in the period before death. Among 300 patients invited to participate, 247 agreed. Patient disease and sociodemographic data were collected from the FinnishIPF records and the study group completed questionnaires five times at 6 month intervals. The study began in April 2015 and continued until August 2017, by which time 92 (37%) of the patients had died (BMC Pulmonary Medicine 2018;18:172; doi: 0.1186/s12890-018-0738-x).

The investigators used self-reporting tools to look at HRQOL and symptom burden: RAND 36-item Health Survey (RAND-36), the Modified Medical Research and Council Dyspnea Scale (MMRC), the Modified Edmonton Symptom Assessment Scale (ESAS), and the Numeric Rating Scale (NRS).

tborden@mdedge.com

SOURCE: Rajala K et al. BMC Pulm Med. 2018;18:172. doi: 0.1186/s12890-018-0738-x.

MAUI, HAWAII – Vigilance for the possibility of bronchiolitis is warranted in patients with rheumatoid arthritis, Sjögren’s syndrome, or systemic lupus erythematosus who develop shortness of breath and cough or a precipitous drop in their forced expiratory volume on pulmonary function testing, Aryeh Fischer, MD, said at the 2019 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“This is an underappreciated – and I think among the most potentially devastating – of the lung diseases we as rheumatologists will encounter in our patients,” said Dr. Fischer, a rheumatologist at the University of Colorado at Denver, Aurora, with a special interest in autoimmune lung disease.

“If you’re seeing patients with rheumatoid arthritis, SLE, or Sjögren’s and they’ve got bad asthma they can’t get under control, you’ve got to think about bronchiolitis because I can tell you your lung doc quite often is not thinking about this,” he added.

Bronchiolitis involves inflammation, narrowing, or obliteration of the small airways. The diagnosis is often missed because of the false sense of reassurance provided by the normal chest x-ray and regular CT findings, which are a feature of the disease.

“This is really important: You have to get a high-resolution CT that includes expiratory images, because that’s the only way you’re going to be able to tell if your patient has small airways disease,” he explained. “You must, must, must do an expiratory CT.”

A normal expiratory CT image should be gray, since the lungs are empty. Air is black on CT, so large areas of black intermixed with gray on an expiratory CT – a finding known as mosaicism – indicate air trapping due to small airways disease, Dr. Fischer noted.

Surgical lung biopsy will yield a pathologic report documenting isolated constrictive, follicular, and/or lymphocytic bronchiolitis. However, the terminology can be confusing: What pathologists describe as constrictive bronchiolitis is called obliterative by pulmonologists and radiologists.

Pulmonary function testing shows an obstructive defect. The diffusing capacity of the lungs for carbon monoxide (DLCO) is fairly normal, the forced expiratory volume in 1 second (FEV₁) is sharply reduced, and the forced vital capacity (FVC) is near normal, with a resultant abnormally low FEV₁/FVC ratio. A patient with bronchiolitis may or may not have a response to bronchodilators.

“I tell you, I’ve seen a bunch of these patients. They typically have a precipitous drop in their FEV1 and then stay stable at a very low level of lung function without much opportunity for improvement,” Dr. Fischer said. “Stability equals success in these patients. It’s really unusual to see much improvement.”

In theory, patients with follicular or lymphocytic bronchiolitis have an ongoing inflammatory process that should be amenable to rheumatologic ministrations. But there is no convincing evidence of treatment efficacy to date. And in obliterative bronchiolitis, marked by airway scarring, there is no reason to think anti-inflammatory therapies should be helpful. Anecdotally, Dr. Fischer said, he has seen immunosuppression help patients with obliterative bronchiolitis.

“Actually, the only proven therapy is lung transplantation,” he said.

He recommended that his fellow rheumatologists periodically use office spirometry to check the FEV₁ in their patients with rheumatoid arthritis, Sjögren’s, or SLE, the forms of connective tissue disease most often associated with bronchiolitis. Compared with all the other testing rheumatologists routinely order in their patients, having them blow into a tube is a simple enough matter.

“We really don’t have anything to impact the natural history, but I like the notion of not being surprised. What are you going to do with that [abnormal] FEV₁ data? I have no idea. But maybe it’s better to know earlier,” he said.

Dr. Fischer reported having no financial conflicts of interest regarding his presentation.

bjancin@mdedge.com

MAUI, HAWAII – Vigilance for the possibility of bronchiolitis is warranted in patients with rheumatoid arthritis, Sjögren’s syndrome, or systemic lupus erythematosus who develop shortness of breath and cough or a precipitous drop in their forced expiratory volume on pulmonary function testing, Aryeh Fischer, MD, said at the 2019 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“This is an underappreciated – and I think among the most potentially devastating – of the lung diseases we as rheumatologists will encounter in our patients,” said Dr. Fischer, a rheumatologist at the University of Colorado at Denver, Aurora, with a special interest in autoimmune lung disease.

“If you’re seeing patients with rheumatoid arthritis, SLE, or Sjögren’s and they’ve got bad asthma they can’t get under control, you’ve got to think about bronchiolitis because I can tell you your lung doc quite often is not thinking about this,” he added.

Bronchiolitis involves inflammation, narrowing, or obliteration of the small airways. The diagnosis is often missed because of the false sense of reassurance provided by the normal chest x-ray and regular CT findings, which are a feature of the disease.

“This is really important: You have to get a high-resolution CT that includes expiratory images, because that’s the only way you’re going to be able to tell if your patient has small airways disease,” he explained. “You must, must, must do an expiratory CT.”

A normal expiratory CT image should be gray, since the lungs are empty. Air is black on CT, so large areas of black intermixed with gray on an expiratory CT – a finding known as mosaicism – indicate air trapping due to small airways disease, Dr. Fischer noted.

Surgical lung biopsy will yield a pathologic report documenting isolated constrictive, follicular, and/or lymphocytic bronchiolitis. However, the terminology can be confusing: What pathologists describe as constrictive bronchiolitis is called obliterative by pulmonologists and radiologists.

Pulmonary function testing shows an obstructive defect. The diffusing capacity of the lungs for carbon monoxide (DLCO) is fairly normal, the forced expiratory volume in 1 second (FEV₁) is sharply reduced, and the forced vital capacity (FVC) is near normal, with a resultant abnormally low FEV₁/FVC ratio. A patient with bronchiolitis may or may not have a response to bronchodilators.

“I tell you, I’ve seen a bunch of these patients. They typically have a precipitous drop in their FEV1 and then stay stable at a very low level of lung function without much opportunity for improvement,” Dr. Fischer said. “Stability equals success in these patients. It’s really unusual to see much improvement.”

In theory, patients with follicular or lymphocytic bronchiolitis have an ongoing inflammatory process that should be amenable to rheumatologic ministrations. But there is no convincing evidence of treatment efficacy to date. And in obliterative bronchiolitis, marked by airway scarring, there is no reason to think anti-inflammatory therapies should be helpful. Anecdotally, Dr. Fischer said, he has seen immunosuppression help patients with obliterative bronchiolitis.

“Actually, the only proven therapy is lung transplantation,” he said.

He recommended that his fellow rheumatologists periodically use office spirometry to check the FEV₁ in their patients with rheumatoid arthritis, Sjögren’s, or SLE, the forms of connective tissue disease most often associated with bronchiolitis. Compared with all the other testing rheumatologists routinely order in their patients, having them blow into a tube is a simple enough matter.

“We really don’t have anything to impact the natural history, but I like the notion of not being surprised. What are you going to do with that [abnormal] FEV₁ data? I have no idea. But maybe it’s better to know earlier,” he said.

Dr. Fischer reported having no financial conflicts of interest regarding his presentation.

bjancin@mdedge.com

MAUI, HAWAII – Vigilance for the possibility of bronchiolitis is warranted in patients with rheumatoid arthritis, Sjögren’s syndrome, or systemic lupus erythematosus who develop shortness of breath and cough or a precipitous drop in their forced expiratory volume on pulmonary function testing, Aryeh Fischer, MD, said at the 2019 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“This is an underappreciated – and I think among the most potentially devastating – of the lung diseases we as rheumatologists will encounter in our patients,” said Dr. Fischer, a rheumatologist at the University of Colorado at Denver, Aurora, with a special interest in autoimmune lung disease.

“If you’re seeing patients with rheumatoid arthritis, SLE, or Sjögren’s and they’ve got bad asthma they can’t get under control, you’ve got to think about bronchiolitis because I can tell you your lung doc quite often is not thinking about this,” he added.

Bronchiolitis involves inflammation, narrowing, or obliteration of the small airways. The diagnosis is often missed because of the false sense of reassurance provided by the normal chest x-ray and regular CT findings, which are a feature of the disease.

“This is really important: You have to get a high-resolution CT that includes expiratory images, because that’s the only way you’re going to be able to tell if your patient has small airways disease,” he explained. “You must, must, must do an expiratory CT.”

A normal expiratory CT image should be gray, since the lungs are empty. Air is black on CT, so large areas of black intermixed with gray on an expiratory CT – a finding known as mosaicism – indicate air trapping due to small airways disease, Dr. Fischer noted.

Surgical lung biopsy will yield a pathologic report documenting isolated constrictive, follicular, and/or lymphocytic bronchiolitis. However, the terminology can be confusing: What pathologists describe as constrictive bronchiolitis is called obliterative by pulmonologists and radiologists.

Pulmonary function testing shows an obstructive defect. The diffusing capacity of the lungs for carbon monoxide (DLCO) is fairly normal, the forced expiratory volume in 1 second (FEV₁) is sharply reduced, and the forced vital capacity (FVC) is near normal, with a resultant abnormally low FEV₁/FVC ratio. A patient with bronchiolitis may or may not have a response to bronchodilators.

“I tell you, I’ve seen a bunch of these patients. They typically have a precipitous drop in their FEV1 and then stay stable at a very low level of lung function without much opportunity for improvement,” Dr. Fischer said. “Stability equals success in these patients. It’s really unusual to see much improvement.”

In theory, patients with follicular or lymphocytic bronchiolitis have an ongoing inflammatory process that should be amenable to rheumatologic ministrations. But there is no convincing evidence of treatment efficacy to date. And in obliterative bronchiolitis, marked by airway scarring, there is no reason to think anti-inflammatory therapies should be helpful. Anecdotally, Dr. Fischer said, he has seen immunosuppression help patients with obliterative bronchiolitis.

“Actually, the only proven therapy is lung transplantation,” he said.

He recommended that his fellow rheumatologists periodically use office spirometry to check the FEV₁ in their patients with rheumatoid arthritis, Sjögren’s, or SLE, the forms of connective tissue disease most often associated with bronchiolitis. Compared with all the other testing rheumatologists routinely order in their patients, having them blow into a tube is a simple enough matter.

“We really don’t have anything to impact the natural history, but I like the notion of not being surprised. What are you going to do with that [abnormal] FEV₁ data? I have no idea. But maybe it’s better to know earlier,” he said.

Dr. Fischer reported having no financial conflicts of interest regarding his presentation.

bjancin@mdedge.com