Karen L. Wood, MD

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

 

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

When there is another manifestation of chronic GVHD, only the first 3 criteria are necessary.¹⁰

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

 

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

  Cryptogenic organizing pneumonia (COP) occurs less frequently than BOS but may also represent pulmonary GVHD, although this is less certain.¹⁶ Organizing pneumonia is a nonspecific pathologic finding associated with various lung diseases.⁴⁸ Clinically, COP resembles pneumonia with fevers, cough, migratory infiltrates, and restrictive lung disease, but there are no infectious organisms identified. It occurs in nontransplant patients as well; in these patients COP has been associated with many different inciting causes, although the etiology often is unknown.⁴⁹ COP responds to prolonged steroid treatment. It is usually treated with high-dose systemic steroids started at 1 mg/kg per day, with rapid weaning over a few weeks but prolonged to 6 months to 1 year.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

 

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

When there is another manifestation of chronic GVHD, only the first 3 criteria are necessary.¹⁰

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

 

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

  Cryptogenic organizing pneumonia (COP) occurs less frequently than BOS but may also represent pulmonary GVHD, although this is less certain.¹⁶ Organizing pneumonia is a nonspecific pathologic finding associated with various lung diseases.⁴⁸ Clinically, COP resembles pneumonia with fevers, cough, migratory infiltrates, and restrictive lung disease, but there are no infectious organisms identified. It occurs in nontransplant patients as well; in these patients COP has been associated with many different inciting causes, although the etiology often is unknown.⁴⁹ COP responds to prolonged steroid treatment. It is usually treated with high-dose systemic steroids started at 1 mg/kg per day, with rapid weaning over a few weeks but prolonged to 6 months to 1 year.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

 

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

When there is another manifestation of chronic GVHD, only the first 3 criteria are necessary.¹⁰

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

 

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

  Cryptogenic organizing pneumonia (COP) occurs less frequently than BOS but may also represent pulmonary GVHD, although this is less certain.¹⁶ Organizing pneumonia is a nonspecific pathologic finding associated with various lung diseases.⁴⁸ Clinically, COP resembles pneumonia with fevers, cough, migratory infiltrates, and restrictive lung disease, but there are no infectious organisms identified. It occurs in nontransplant patients as well; in these patients COP has been associated with many different inciting causes, although the etiology often is unknown.⁴⁹ COP responds to prolonged steroid treatment. It is usually treated with high-dose systemic steroids started at 1 mg/kg per day, with rapid weaning over a few weeks but prolonged to 6 months to 1 year.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

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.

Treatment of IPS centers around moderate to high doses of corticosteroids. Based on IPS experimental modes, tumor necrosis factor (TNF)-α has been implicated as an important mediator. Unfortunately, several studies evaluating etanercept have produced conflicting results, and this agent’s clinical effects on morbidity and mortality remain in question.⁷⁶

• 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.

Treatment of IPS centers around moderate to high doses of corticosteroids. Based on IPS experimental modes, tumor necrosis factor (TNF)-α has been implicated as an important mediator. Unfortunately, several studies evaluating etanercept have produced conflicting results, and this agent’s clinical effects on morbidity and mortality remain in question.⁷⁶

• 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.

Treatment of IPS centers around moderate to high doses of corticosteroids. Based on IPS experimental modes, tumor necrosis factor (TNF)-α has been implicated as an important mediator. Unfortunately, several studies evaluating etanercept have produced conflicting results, and this agent’s clinical effects on morbidity and mortality remain in question.⁷⁶

• 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.