Pulmonary Medicine

Pulmonary Complications of Hematologic Diseases, Including Leukemia and Bone Marrow Transplantation

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What every physician needs to know:

Introduction

Pulmonary complications of hematologic diseases like leukemia or after bone marrow or hematopoietic stem cell transplantations (HSCT) are common. Making the correct diagnosis and implementing an appropriate treatment plan require an understanding of the underlying malignancy, the potential toxicities of current or prior chemotherapy and radiation, the immunosuppressive effects of the malignancy, subsequent treatment regimens, and in the case of HSCT, allo-immune mediated responses.

Both infectious and non-infectious complications may cause respiratory complications. As widespread implementation of prophylactic antimicrobial regimens has reduced the overall incidence of infectious complications after HSCT, the relative importance of non-infectious pulmonary complications as major causes of morbidity and mortality has increased.

Since a number of distinct pulmonary syndromes occur after HSCT, this topic is discussed separately.

Classification

Pulmonary infections

Leukemic involvement

  • Pulmonary leukostasis

  • Leukemic infiltration

  • Leukemic cell lysis pneumopathy

Other pulmonary complications

  • Pulmonary edema

  • Alveolar hemorrhage

  • Pulmonary alveolar proteinosis (PAP)

  • Drug toxicity

  • Transfusion-related acute lung injury

Pulmonary complications of human stem cell transplantation (HSCT)

Non-infectious complications after HSCT—Early (before day 100)

  • Idiopathic pneumonia syndrome

  • Diffuse alveolar hemorrhage

  • Peri-engraftment respiratory distress syndrome

Non-infectious complications after HSCT—Late (beyond day 100)

  • Bronchiolitis obliterans

  • Restrictive lung disease

Other complications

  • Pulmonary veno-occlusive disease

Pulmonary infections

Patients with hematologic malignancies are at high risk for infectious complications.

Leukemic involvement

Several distinct manifestations of leukemic involvement of the lung, including leukemic infiltration, pulmonary leukostasis and leukemic cell lysis pneumopathy, may be seen.

Leukemic infiltration

Leukemic infiltration (LI), perhaps the most common pulmonary manifestation, has been reported in up to two-thirds (in autopsy series) of patients whose deaths were directly attributable to leukemia.

Pulmonary leukostasis (PL)

Pulmonary leukostasis (PL) is a potentially life-threatening condition seen most often in patients with acute myeloid leukemias with severe leukocytosis, although it may also be seen in patients with acute lymphoblastic leukemias.

Leukemic cell lysis pneumopathy

Leukemic cell lysis pneumopathy is a rare condition in patients with markedly elevated leukocyte counts. The condition is characterized by the development of severe respiratory distress/respiratory failure, hypoxemia, and diffuse pulmonary infiltrates shortly (typically with days) after initiating chemotherapy.

Other pulmonary complications

Alveolar hemorrhage

Alveolar hemorrhage is commonly noted on autopsy in patients with leukemia. Hemoptysis is rare in patients with alveolar hemorrhage.

Pulmonary Alveolar Proteinosis (PAP)

Pulmonary alveolar proteinosis is a rare complication seen in patients with hematologic malignancies--usually acute and chronic myeloid leukemias and myelodysplastic syndrome.

Drug toxicity

Drug toxicity should always be considered in the differential diagnosis in patients with respiratory distress or radiographic evidence of diffuse or multifocal pulmonary infiltrates.

Transfusion-related Acute Lung Injury (TRALI)

TRALI is difficult to diagnose but should be included in the differential diagnosis of respiratory distress in patients with diffuse pulmonary infiltrates. Patients with hematologic malignancies often receive repeated transfusions with various blood products, thereby presenting an ongoing risk of TRALI.

Pulmonary complications of HSCT

HSCT is an important treatment option for select patients with hematologic malignancies or for solid tumors, where this procedure serves as a "rescue" therapy to restore immunologic and hematologic competence after myeloablative radiation and/or chemotherapy. HSCT is also considered for treatment of a variety of non-malignant disorders characterized by dysfunctional marrow function or autoimmunity, which are major causes of treatment-related death and morbidity.

Complications after standard or myeloablative HSCT procedures occur in any of three phases. The immediate post-transplant period before engraftment is the "pre-engraftment" or neutropenic phase, the period from engraftment until day 100 is defined somewhat arbitrarily as the "early phase," and complications that develop beyond day 100 occur in the "late phase."

Respiratory infections after HSCT

The patient is at particularly high risk for pneumonia during the neutropenic phase. Even when neutropenia has resolved in the early post-engraftment period, significant deficits in innate and cell-mediated immunity remain. Infectious complications during the late phase depend upon the presence of hypogammaglobulinemia (which is seen in most patients), the function of the adaptive immune system (which may take more than a year to fully recover), the intensity of exogenous immunosuppression, and the presence and severity of chronic GVHD. Chronic GVHD is itself an independent and, in severe cases, a profoundly immunosuppressive condition.

Non-infectious complications after HSCT—Early (before day 100)

Pulmonary edema is a common early post-transplant complication. Other complications include idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, and engraftment syndrome.

Idiopathic pneumonia syndrome (IPS)

Several distinct acute lung injury syndromes that have been described early after HSCT fall under the broadly defined term "idiopathic pneumonia syndrome," which is a devastating early complication after HSCT. It was initially adopted by the National Institute of Health in 1993 to describe the development of pneumonia symptoms, hypoxemia and widespread alveolar infiltrates in the absence of lower respiratory tract infection and cardiogenic pulmonary edema.

Published reports on the incidence of IPS has varied from 3 percent to 15 percent; however, in one of the largest studies of IPS (a retrospective review of 1,165 consecutive patients who underwent myeloablative HSCT from 1988-1991 at a single institution), the incidence of IPS was found to be 5.7 percent after autologous procedures and 7.6 percent after allogeneic procedures. More recent studies have reported similar incidence rates. Notably, recipients of reduced intensity condition regimens appear to have a lower rate of developing IPS. Median time to onset is 2-7 weeks after HSCT. IPS has been associated with high mortality rates, which approach 80 percent in some series.

Several distinct disorders with distinguishing clinical features that fall under the general category of IPS include diffuse alveolar hemorrhage and the engraftment syndrome.

Diffuse alveolar hemorrhage (DAH)

DAH is one of the most severe forms of acute lung injury after HSCT. It occurs in approximately 5 percent of HSCT recipients, but it may be seen in 40 percent of patients admitted to the ICU for respiratory failure. The timing of DAH is unpredictable; it may occur before, during, or after engraftment.

Engraftment syndrome (ES)

ES is another condition with pulmonary manifestations that fall under the category of IPS. ES, which has been reported after both allogeneic and autologous HSCT, may be difficult to distinguish from acute GVHD in the allogeneic setting. Variable incidence rates have been reported (5%-20%).

Non-infectious complications after HSCT—Late (beyond day 100)

Bothobstructive and restrictive lung diseases have been described afterHSCT and are important causes of late morbidity and death.

Bronchiolitis obliterans (BO) or obliterative bronchiolitis (OB)

BO is the most common late-onset complication of allogeneic transplantation. Since it occurs almost exclusively in allogeneic recipients and usually in the presence of extrapulmonary chronic GVHD, this complication is thought to represent a pulmonary manifestation of chronic GVHD. The reported incidence after allogeneic HSCT varies (1.7%-26%) and depends on whether pulmonary function testing (PFT) criteria or pathologic criteria is used to define the condition. Using the NIH's consensus definition for chronic pulmonary GVHD, a recent review of almost 1000 patients transplanted at a single center showed a 5-year incidence rate of 5.8 percent.

Restrictive Lung Diseases

Restrictive lung diseases are uncommon after HSCT. In one series of 179 consecutive allogeneic HSCT recipients who survived at least 3 months, bronchiolitis obliterans organizing pneumonia (BOOP) and non-classifiable interstitial pneumonitis (NCIP) was seen in 1.7 percent and 4.4 percent respectively. More recently, in a study of patients who received T-cell depleted grafts, BOOP was seen in only 0.5 percent.

BOOP should be distinguished from BO. Despite similarities in the name, they are very different processes. BOOP is a restrictive lung disorder that primarily affects the alveolar spaces and is radiographically indistinguishable from pneumonia, while BO is a small airway centric process.

NCIP is an important late complication associated with the toxicity of chemotherapy and radiation administered prior to HSCT or as part of the conditioning regimen.

Other restrictive disorders reported after HSCT include chronic eosinophilic pneumonia and pulmonary alveolar proteinosis.

Other complications: Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) is a rare, life-threatening complication of HSCT. It may present within weeks to months after HSCT, although both earlier and later presentations have been reported.

Are you sure your patient has a pulmonary complication of a hematologic disease? What should you expect to find?

Pulmonary complications of hematologic disease are common, and they carry a high risk for morbidity and mortality. Consequently, any new respiratory symptoms or radiographic evidence of pulmonary abnormalities should trigger consideration of a pulmonary complication. The nature, time of onset, level of immunosuppression, and tempo of respiratory complaints vary depending on the underlying nature of the pulmonary complication, so clinicians must evaluate patients with the onset of any new respiratory symptoms after diagnosis of leukemia, especially if HSCT was performed. Vague symptoms of fatigue and weakness may also be the presenting manifestations of pulmonary complications. Presentations of some specific conditions are listed below.

Leukemic infiltration:

Leukemic infiltration of the lung is commonly found at autopsy, but symptomatic infiltration is uncommon, with only a minority of cases diagnosed before death. When they are present, symptoms are usually non-specific—fatigue, dyspnea, and a dry cough. Fever may also be present. Suspicion for leukemic infiltration may be raised in asymptomatic patients with incidental findings noted on CXR or high resolution chest CT scan (HRCT). However, severe symptoms with progression to ARDS have also been reported.

Pulmonary leukostasis:

Presenting symptoms usually range from mild dyspnea with exertion to severe respiratory distress. Fever may also be present. Concurrent neurologic symptoms like confusion, somnolence, blurry vision, and gait instability should raise suspicion for hyperviscosity syndrome with PL.

Pulmonary alveolar proteinosis (PAP):

The diagnosis should be suspected in patients with dyspnea and pulmonary infiltrates. PAP may be mistaken for pneumonia; persistence of symptoms and radiologic infiltrates—despite antibiotic therapy—should raise suspicion for non-infectious process such as PAP.

Transfusion-related acute lung injury:

Symptoms that develop within 6 hours of transfusion should raise suspicion for TRALI.

Idiopathic pneumonia syndrome:

Symptoms of IPS include fever, dyspnea, and nonproductive cough that, in many cases, rapidly evolve into respiratory failure.

Diffuse alveolar hemorrhage:

Patients typically present with fever, dyspnea, and non-productive cough and may rapidly progress to respiratory failure. Since this is an alveolar process, rather than a bronchiolar process, hemoptysis is uncommon.

Engraftment syndrome:

As the name implies, ES describes a constellation of clinical findings that occur around the time of neutrophil recovery. In its most severe form, fever, rash, diarrhea, and diffuse capillary leak with noncardiogenic pulmonary edema may be seen, with progression to multi-organ system failure and hemodynamic collapse. The pulmonary manifestation of ES is termed the peri-engraftment respiratory distress syndrome, or PERDS.

Bronchiolitis obliterans after HSCT:

Most cases of BO present within the first 2 years after HSCT although later development has been described. BO usually develops insidiously, often after a respiratory viral infection. Presenting symptoms include nonproductive cough, dyspnea, and wheezing, and patients may be asymptomatic at early stages of the disease. However, fever and other signs of active infection are usually absent in advanced stages. Bronchiolar obstruction can lead to bronchiectasis, colonization with bacterial and fungal pathogens, and recurrent pneumonia.

Pulmonary veno-occlusive disease after HSCT:

Clinically, patients usually present with symptoms of increasing dyspnea on exertion, orthopnea and fatigue. With more advanced stages, symptoms of decompensated congestive heart failure may develop. The triad of pulmonary arterial hypertension, normal PAOP and radiographic signs of congestive heart failure should raise suspicion for PVOD.

Beware: There are other diseases that can mimic a pulmonary complication of a hematologic disease

Numerous and diverse respiratory complications occur that are specific to leukemia and bone marrow transplantation, but these patients may also develop more common conditions that simulate one of the pulmonary complications of hematologic disease reviewed in this chapter. For instance, underlying chronic cardiopulmonary disease may present as an exacerbation of COPD or decompensation of heart failure. Patients may also develop venous thromboembolic disease or a pneumothorax.

How and/or why did the patient develop a pulmonary complication of a hematologic disease?

Pulmonary infections

Immune system deficits occur with these conditions. For example, patients with chronic lymphocytic leukemia (CLL) are often hypogammaglobulinemic, while patients with multiple myeloma may be functionally hypogammaglobulinemic. This condition increases the risk of pneumonia, especially with encapsulated bacteria (e.g., Streptococcus pneumoniaand Haemophilus influenza).

In addition to humoral immunity, other deficits in immune system function may also exist. Patients with CLL often have pronounced dysfunction of cell-mediated and innate immune responses (e.g., neutropenia, monocytopenia), which increases the risk of respiratory infections with viral, fungal, mycobacterial, and atypical or opportunistic pathogens. Treatment with chemotherapy further impairs immunologic function (especially neutropenia). Prolonged hospitalization and malnutrition further increases the risk for serious infections, such as Klebsiella pneumonia, Pseudomonas aeruginosa, and Staphylococcus aureus.

Leukemic infiltration

Neoplastic leukemic cells can infiltrate the lung along lymphatic routes (i.e., interlobular septal and peribronchovascular areas). Rarely, pleural involvement may result in effusion or pleural thickening.

Pulmonary leukostasis

Pathogenesis has traditionally been thought to be related to blood hyperviscosity and subsequent obstruction of small vessels in the lung by leukemic cells. However, it's likely that other factors are also important. Local production of pro-inflammatory cytokines and chemokines and interactions between pulmonary endothelial and epithelial structures with leukemic cells have been proposed as contributing to the clinical manifestations of PL.

Leukemic cell pneumopathy

Although its pathogenesis is not well understood, leukemic cell pneumopathy is thought to be related to lung injury caused by chemotherapy and the release of harmful products (e.g., elastase, lysozyme) from damaged leukemic cells.

Alveolar hemorrhage

Alveolar hemorrhage is related to infections, toxicity of chemotherapy, and inflammation triggered by leukemic involvement of the lung. Severe thrombocytopenia may exacerbate both alveolar and bronchiolar bleeding.

Pulmonary alveolar proteinosis

Unlike the idiopathic variant of PAP, secondary PAP is not associated with autoantibodies to GM-CSF. Pathogenesis is not well understood. Recently, mutations in GATA2, a transcription factor essential for hematopoietic differentiation and lymphatic formation, has been associated with the development of acute myeloid leukemia and myelodysplastic syndrome. Interestingly, a third of these patients also develop PAP. This association is being actively investigated to better understand why patients with leukemia sometimes develop PAP.

Pulmonary complications after HSCT

Pulmonary complications after HSCT may be infectious or non-infectious and have been reported to occur in 30 to 60 percent of patients.

Engraftment syndrome after HSCT

The pathophysiology of ES is not well understood, but its timing implicates a role for injury that develops in the setting of rapid immune system reconstitution.

Bronchiolitis obliterans after HSCT

This complication is thought to be a pulmonary manifestation of chronic GVHD.

Pulmonary veno-occlusive disease after HSCT

The pathogenesis of PVOD is not well understood; vascular injury and resultant endothelial dysfunction from treatment with chemotherapy and radiation is similar to what has been hypothesized to trigger the development of hepatic veno-occlusive disease. Occult respiratory infections and aberrant immunologic/inflammatory responses may also contribute to pathogenesis.

Which individuals are at greatest risk of developing a pulmonary complication of a hematologic disease?

All patients with hematologic disease have some risk for pulmonary complications, with the highest risk in patients who undergo bone marrow transplantation.

Pulmonary infections

Patients with severe and/or prolonged immune defects or decreased effective granulocyte counts are at special risk for infectious complications.

Pulmonary leukostasis

Leukocyte counts higher than 100,000/microliter increase the risk for pulmonary leukostasis.

Diffuse alveolar hemorrhage

Bleeding diatheses and thrombocytopenia increase the risk for alveolar hemorrhage, although this complication can also occur in the absence of these factors.

Pulmonary alveolar proteinosis

Acute and chronic myeloid leukemias and myelodysplastic syndrome have the greatest risk.

Drug toxicities

Many commonly used agents have well-known early and late pulmonary toxicities, including bleomycin, busulfan, mitomycin, fludarabine, cyclophosphamide, and cytosine arabinoside. Toxicities have also been reported with newer agents like rituximab and imatinib. The clinician should be aware of these toxicities, and as new therapies are added to treatment armamentariums, consider consulting with a pharmacist and performing a literature review to keep abreast of the latest reports of adverse respiratory events.

HSCT-related pulmonary complications

Risk factors for pulmonary complications of HSCT include the type of transplant procedure (e.g., autologous vs. allogeneic); intensity of the conditioning regimen; rapidity and pattern of immune system reconstitution; type, duration, and compliance with prophylactic antimicrobial therapies; and the development of extrapulmonary alloimmune complications like graft versus host disease (GVHD).

Respiratory infections after HSCT

The risk of infectious complications after HSCT depends largely upon the duration and severity of pre-transplant immune deficits, pre-transplant colonization with pathogens (e.g., aspergillus), the type of transplant procedure (autologous vs. allogeneic; T-cell depletion of graft), the intensity of the conditioning regimen (myeloablative vs. reduced intensity), the status and duration of immune system reconstitution, the level of exogenous post-transplant immunosuppression administration, and the presence and severity of GVHD.

The patient is at particularly high risk for pneumonia during the neutropenic phase. Severe bacterial infections predominate, including gram-positive and gram-negative infections. Nosocomial pathogens in particular should be considered. Patients are also at high risk for fungal pneumonias, especially invasive aspergillosis, during this period. Respiratory virus infections, including RSV, adenovirus, influenza, parainfluenza, human metapneumovirus, rhinovirus, cytomegalovirus (CMV), and herpes simplex virus (HSV) have all been reported to cause pneumonitis during this phase and are all associated with high mortality rates. The neuropenic period is considerably shorter after autologous transplantation—usually less than 14 days—so infectious complications are reduced. Neutropenia is usually absent or persistent for only a short period after reduced-intensity conditioning regimens.

In the early post-engraftment period, significant deficits in innate and cell-mediated immunity remain. During this period, viral infections, especially CMV and community-acquired respiratory viruses, are a particular concern. CMV-mismatched patients (e.g., CMV-IgG donor-negative/CMV-IgG-positive recipient) are at particularly high risk for infection in the absence of CMV prophylactic medications. Fungal and mycobacterial infections may also be seen during this period.

Infectious complications during the late phase depend upon the presence of hypogammaglobulinemia, which is seen in the majority of patients; the function of the adaptive immune system, which may take more than a year to recover fully; the intensity of exogenous immunosuppression; and the presence and severity of chronic GVHD. Chronic GVHD is itself an independent and, in severe cases, a profoundly immunosuppressive condition.

Approximately half of HLA-identical allogeneic sibling transplant recipients and up to 80 percent of unrelated donor transplant recipients develop some degree of chronic GVHD. Affected patients, especially if they are treated with potent immunosuppressive agents, are at high risk for all types of infections, including bacterial (especially with encapsulated bacteria if functional asplenia is present), viral, Pneumocystis jirovecii, and invasive fungal pneumonias.

Idiopathic Pneumonia Syndrome

Risk factors for IPS include older age, conditioning-regimen-related toxicity, and high-grade GVHD in allogeneic recipients. The finding of relatively similar rates of IPS in both autologous and allogeneic recipients highlights the central role of conditioning-regimen-related toxicity in pathogenesis. Further support for this hypothesis comes from a recent study that demonstrates significantly lower rates of IPS in recipients of reduced-intensity non-myeloablative conditioning regimens compared to recipients of traditional myeloablative conditioning (2.2% vs. 8.4%). In recipients of allogeneic transplants, the presence of higher grade acute GVHD increases risk of IPS, highlighting the importance of alloimmune-mediated injury in these patients.

Engraftment syndrome

Risk factors for engraftment syndrome include older age and female sex. It has been hypothesized that more rapid neutrophil recovery seen after use of mobilized peripheral stem cells, rather than bone-derived stem cells, may partly explain the increased incidence of this condition. In addition, routine use of granulocyte-colony or granulocyte-macrophage-colony-stimulating factors may further increase risk.

Bronchiolitis obliterans

Other than chronic GVHD, reported risk factors for BO include recipient age, pre-transplant obstructive physiology on PFT, hematopoietic cells from peripheral blood source, ABO incompatibility between donor and recipient, busulfan conditioning or methotrexate use, and early post-HSCT respiratory viral infections. A recent report indicating a significantly lower rate of BO after reduced-intensity conditioning regimens compared to standard myeloablative regimens suggests that conditioning-regimen-related injury to the small airways may also be important.

Restrictive lung disease

BOOP is seen primarily in allogeneic recipients, which supports the hypothesis that this condition may be another pulmonary manifestation of GVHD. However, BOOP has also been described after autologous transplantation and in non-transplant patients who are undergoing treatment for malignancies. Therefore, it is likely that toxicity from chemotherapy, radiation, and pulmonary infections are also important factors. NCIP is an important late complication that is associated with the toxicity of chemotherapy and radiation administered prior to HSCT or as part of the conditioning regimen.

Respiratory complications after HSCT

Key to recognizing potential complications is understanding the type of transplant procedure (e.g., autologous vs. allogeneic); the intensity of the conditioning regimen; the rapidity and pattern of immune-system reconstitution; the type, duration, and compliance with prophylactic antimicrobial therapies; and the development of extrapulmonary alloimmune complications like graft versus host disease (GVHD).

Pulmonary edema after HSCT

Administration of large volumes of intravenous fluid and chemoradiation-induced cardiac dysfunction increase the risk of developing hydrostatic pulmonary edema. Risks for non-cardiogenic pulmonary edema include aspiration, sepsis, TRALI, and conditioning-regimen-related toxicity (direct damage and indirect damage from release of pro-inflammatory cytokines).

Diffuse alveolar hemorrhage after HSCT

For DAH to occur, there must be extensive damage to the alveolar-capillary basement membranes so red blood cells can escape the vascular compartment and traverse through the interstitium and into the alveolar space. DAH was first described in autologous transplant recipients but then it was reported after both allogeneic and autologous HSCT. DAH appears to occur less frequently after reduced-intensity conditioning regimens, implicating the toxicity of the conditioning regimen in pathogenesis.

Risk factors for DAH include age over forty, infection with occult pathogens, and the presence of pre-transplant pulmonary inflammation, defined as BAL fluid neutrophilia (<20%) and/or eosinophilia. Thrombocytopenia and coagulopathy are not specific risk factors for DAH; they are seen with similar frequency in patients that do not develop DAH.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Pulmonary infections

CBC with differential sputum gram and special stains; specific studies for respiratory pathogens, such as serum aspergillus PCR or galactomannan enzyme, an assay that detects fungal wall constituent of aspergillus and if positive suggests strongly suggests the diagnosis of invasive aspergillosis in recipients of HSCT; CMV-PCR assay; and nasal swab for PCR analysis for community acquired respiratory viruses (CARV) can help make the diagnosis. For serum immunoglobulin assays, infectious complications during the late phase of HSCT depend upon the presence of hypogammaglobulinemia, which is seen in the majority of patients.

Leukemic infiltration

This condition is not typically associated with elevations in the white blood cell count.

Pulmonary leukostasis

The diagnosis is strongly supported by the finding of markedly elevated leukocyte counts and blasts. White blood cell counts in excess of 100,000/mcL are typical findings, but PL has been reported with lower counts. Although arterial blood gas measurements often demonstrate severe hypoxemia, this value should be interpreted with caution since the hypermetabolic activity of leukemic cells may lead to excess oxygen consumption in the sample and result in pseudohypoxemia. Pulse oximetry is a more reliable measure of oxygenation in this setting.

Diffuse alveolar hemorrhage

Thrombocytopenia and coagulopathy are not specific risk factors for DAH; these findings are seen with similar frequency in patients who do not develop DAH.

What imaging studies will be helpful in making or excluding the diagnosis of a pulmonary complication of a hematologic disease?

Standard radiographs and CT scans are the primary imaging approaches for patients with hematologic disease and new respiratory complaints. Special considerations for specific conditions are listed below.

Leukemic infiltration

Radiographic findings suggestive of LI are non-specific and include focal or diffuse abnormalities. On high-resolution CT (HRCT), thickened bronchovascular bundles and interlobular septae, as well as sub-centimeter pulmonary nodules and ground-glass opacities have been reported. Rarely, pleural involvement may result in effusion or pleural thickening.

Pulmonary leukostasis

Although radiographic findings can sometimes be normal, diffuse interstitial and alveolar infiltrates are usually seen.

Pulmonary alveolar proteinosis

The most common radiographic finding on HRCT is diffuse GGO. However, the classic description of "crazy-paving" or prominent interlobular septal markings with superimposed GGO was seen in only 12 percent of patients in one report.

Diffuse alveolar hemorrhage

Radiographic findings are non-specific, but they usually show dense bilateral alveolar infiltrates.

Bronchiolitis obliterans after HSCT

Characteristic radiographic abnormalities, which are best seen on HRCT of the chest, include air trapping, especially on expiratory images (mosaic pattern of hypoattenuation of lung parenchyma), and bronchial thickening with or without bronchiectasis.

Pulmonary veno-occlusive disease

CXR findings include pulmonary vascular congestion, Kerley B lines, bilateral pulmonary infiltrates, and pleural effusions.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a pulmonary complication of a hematologic disease?

Pulmonary function testing plays an essential role in assessing the risk of post-transplant complications and identifying patients who have BO.

Risk assessment

Identifying patients before HSCT who are at greatest risk for severe post-transplant respiratory complications and death has been challenging. Although studies have reported a number of risk factors, such as age, type of transplant, intensity of the conditioning regimen, and severity of GVHD, these factors alone have not been sufficient for precise determination of the risk to the individual patient. PFTs are routinely performed at many centers prior to HSCT to identify pre-existing respiratory abnormalities.

No individual PFT measurement (including DLCO) has consistently been shown to predict the likelihood of post-HSCT respiratory complications or death, so individual measurements should not be used alone to determine candidacy for HSCT. However, a combination of parameters may be helpful. For example, investigators at the Fred Hutchinson Cancer center reviewed the cases of 2,852 consecutive recipients of allogeneic transplants with pre-transplant PFT data and found that 396 patients (14%) developed respiratory failure. The investigators were able to identify the group of patients with the highest risk by calculating a lung function score that incorporated two distinct PFT parameters: the diffusing capacity (DLCO) and the FEV1.

The group of patients with a DLCO and FEV1 under 60 percent had the poorest rate of survival. Within this subset, the use of myeloablative-conditioning regimens that included total body irradiation was universally fatal. Therefore, a combination of PFT measurements may provide useful information to counsel patients about risk, and guide decisions regarding the intensity and type of conditioning regimen administered. This same group later showed that the FEV1 and DLCO, incorporated into a similar lung function scoring system proposed by the NIH Consensus Development Project on Grading Clinical Trials in Chronic GVHD, could also be determined post-transplantation (day 60-120) in survivors and that the score was predictive of long-term (5-year) non-relapse mortality.

Finally, a low DLCO in combination with a high value on the more comprehensive Pretransplant Assessment of Mortality (PAM) scoring system that includes the FEV1, measures of renal and hepatic function, type of transplant, and conditioning regimen utilized, is associated with significant risk for nonrelapse mortality.

Diagnosis of BO

The diagnosis of BO is based on spirometry measurements that show evidence of progressive airflow obstruction in the absence of other causes of airflow obstruction (e.g., acute viral bronchiolitis). There is no consensus diagnostic spirometric criteria to aid in establishing the diagnosis at an early stage; published diagnostic criteria are variable: forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio less than 0.7 with an acute drop in FEV1; a reduced FEV1/FVC ratio with a greater than 20 percent decline in FEV1 compared to pre-transplant baseline measurement and a greater than 5 percent drop in the annualized decline in FEV1; and FEV1/FVC ratio less than 0.8.

In 2005, the NIH attempted to standardize the definition of BO by publishing the following criteria: FEV1 less than 75 percent of predicted and FEV1/FVC less than 0.7; signs of air trapping by PFT (e.g., residual volume greater than 120% of predicted) or on HRCT of chest; absence of active respiratory infection; and, in the absence of histological evidence of BO, at least one other extrapulmonary manifestation of chronic GVHD. However, a definitive diagnosis requires pathologic assessment.

Bronchoscopy with transbronchial biopsy is suboptimal. Because of the patchy nature of the bronchiolar process and the small size of the samples obtained, the diagnostic yield of transbronchial biopsy is low. Therefore, the role of bronchoscopy should be limited to excluding infectious causes of airflow obstruction. If the diagnosis of BO is uncertain after review of the patient's history, physical exam, imaging studies and PFTs, surgical lung biopsy could be considered if an alternative, potentially reversible diagnosis remains a consideration.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a pulmonary complication of a hematologic disease?

Bronchoscopy

Bronchoscopy is usually requested after initial detection of a respiratory complication in order to confirm a suspected clinical diagnosis or to identify alternative etiologies, especially if the patient is not responding to empiric therapy. Ruling out a potentially treatable infectious process is one of the most important indications for performing bronchoscopy. However, with the widespread use of potent broad-spectrum antimicrobial agents, even the development of sensitive imaging techniques (HRCT of chest) and other non-invasive tools to screen for respiratory infections (e.g., serum galactomannan enzyme immunoassay for invasive aspergillosis, CMV-PCR assay, nasal swab for PCR analysis for CARV), the likelihood of identifying an unsuspected infectious pathogen with bronchoscopy is lower than it has been in the past. Recent studies suggest that the diagnostic yield is greatest and most likely to result in a change in therapy if performed early—preferably within 24 hours of infiltrate detection.

With the exception of DAH, bronchoscopy is not helpful for diagnosing non-infectious complications. Although bronchoscopy with BAL is generally a low-risk procedure, even in thrombocytopenic patients who require mechanical ventilation, it is not without risk, and in patients whose condition is tenuous, the procedure may further compromise respiratory status. Thus, the potential risks of the procedure must be weighted against the possibility of identifying a process that will lead to a change in clinical management. Transbronchial biopsies increase the risk of bleeding, pneumothorax, and respiratory failure while adding little to the diagnostic yield.

If bronchoscopy is performed to assess for an infectious process, performing the procedure early in the disease course is more likely to yield a specific diagnosis and improve outcomes than is doing so later, after prolonged empiric therapy. Bronchoscopy may also be helpful in identifying a superimposed infectious process prior to initiating potent immunosuppressive therapy like etanercept or high-dose corticosteroids for treatment of non-infectious pulmonary complications. Finally, bronchoscopy with BAL should be performed to confirm the diagnosis of suspected DAH, especially if potentially high-risk therapies like recombinant factor VIIa are considered.

Findings in some specific conditions are listed below.

Leukemic infiltration

A definitive diagnosis of pulmonary LI requires tissue for pathologic review, although it may be difficult to obtain in the setting of severe thrombocytopenia or other comorbidities. However, the diagnosis of pulmonary LI may be supported by less invasive diagnostic procedures. For example, the absence of infection and the finding of leukemic cells on cytologic evaluation of bronchoalveolar lavage (BAL) or pleural fluid would strongly support the diagnosis.

Pulmonary alveolar proteinosis

The diagnosis of PAP is based on examination of BAL fluid or tissue obtained from lung biopsy that demonstrates that characteristic periodic acid Schiff (PAS) positive materials fill the alveoli. Superimposed infections are also frequently seen, and any change in clinical condition, especially fever, should prompt bronchoscopy for further evaluation.

Diffuse alveolar hemorrhage

Diagnosis requires performance of bronchoscopy and BAL from multiple segments. The finding of progressively bloodier BAL fluid from at least three subsegmental bronchi and/or the presence of 20 percent or more hemosiderin-laden macrophages on cytological assessment of BAL fluid strongly suggests the diagnosis of DAH.

Right heart catheterization

Pulmonary veno-occlusive disease

Right heart catheterization classically shows elevated pulmonary arterial pressures with a normal or low pulmonary arterial occlusion pressure (PAOP). A definitive diagnosis of PVOD requires surgical lung biopsy, but the risks of this procedure may be prohibitive in many clinical situations.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a pulmonary complication of a hematologic disease?

Leukemic infiltration

Classic histologic findings include leukemic infiltration along lymphatic routes (i.e., interlobular septal and peribronchovascular areas).

Leukemic cell pneumopathy

Histologic findings are non-specific and generally show evidence of diffuse alveolar damage and hemorrhage.

Idiopathic pneumonia syndrome

The most common pathologic findings observed on lung biopsy or autopsy specimens are interstitial pneumonitis and diffuse alveolar damage, similar to that observed in patients with ARDS.

Pulmonary veno-occlusive disease

Histopathologic findings are similar to what is seen in idiopathic PVOD and are characterized by intimal proliferation and fibrosis of post-capillary pulmonary venules and veins, resulting in progressive vascular obstruction.

If you decide the patient has a pulmonary complication of a hematologic disease, how should the patient be managed?

The history, physical examination, and radiographic studies often suggest a differential diagnosis that allows the initiation of empiric treatment. Treatment considerations for some specific conditions are listed below.

Pulmonary leukostasis

Urgent treatment with leukopheresis to reduce the number of circulating blasts is required if severe PL or neurologic symptoms are present.

Leukemic cell pneumopathy

Treatment is supportive.

Idiopathic pneumonia syndrome

Beyond supportive care, there is no proven therapy for IPS. Although high doses of corticosteroids are frequently administered, convincing evidence of benefit is absent. Because of the generally poor prognosis and absence of effective therapy, new strategies to treat IPS have been explored. For example, after pre-clinical investigations in murine models suggested that conditioning-regimen-related lung injury may be partially mediated by release of pro-inflammatory cytokines like TNF-alpha that blockade this cytokine-attenuated lung injury, human clinical trials were undertaken.

Recently, the results of a randomized, double-blind, placebo controlled clinical trial of 34 patients with IPS who were treated with corticosteroids (2 mg/kg for 7 days followed by taper) and the TNF-alpha-binding protein etanercept (0.4 mg/kg - max 25 mg twice weekly for a maximum of eight doses) were published. No statistically significant differences in 28-day or 1-year survival were noted. Although both groups had higher 28-day survival rates (~70%) than what has been reported in the past, 1-year survival remained poor. Notably, this study had numerous methodologic issues. Another contemporary study, this time a single center retrospective series of 39 patients, showed significantly improved short-term outcomes with etanercept, although long-term survival after IPS remained poor. Thus, the clinical benefit of etanercept remains uncertain; however, at many centers it has become established as standard therapy for the treatment of IPS.

Diffuse alveolar hemorrhage after HSCT

DAH treatment is supportive. Standard of care involves administration of high doses of corticosteroids (500-1000 mg/day in single or divided doses for 3-4 days followed by tapering). However, evidence supporting this therapy is based largely on case reports and small retrospective series, while prospective, randomized trials are notably absent. Several recent reports have indicated that treatment with hemostatic agents like recombinant factor VIIa (intravenous or aerosolized) or aminocaproic acid may lead to clinical improvement in patients with severe and refractory DAH. Larger and better-designed studies are needed to clarify the benefit, dose, route, duration, and risks of these therapies.

Engraftment syndrome after HSCT

Many cases of ES are mild and don't require treatment. Use of growth factors should be discontinued. More severe cases can be treated with corticosteroids.

Bronchiolitis obliterans

Treatment options for BO are limited. Conventional approaches, which are based on the strong association of BO with extrapulmonary chronic GVHD, typically involve augmenting immunosuppressive therapy (e.g., corticosteroids, calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and other antiproliferative agents and/or use of lymphocyte depleting antibodies). While a clinical response to this approach is seen in only a minority of patients, patients who do have a beneficial response to increased immunosuppression have a significantly better outcome, with one study reporting a 79 percent 5-year survival in responders compared to only 13 percent in nonresponders.

Because of the lack of benefit of conventional approaches for most patients, other types of treatments have been explored. For example, a small case series reported significant benefit in three of eight patients with mild to moderate post-HSCT BO after treatment with the immunomodulatory macrolide antibiotic azithromycin. The rationale for treatment with azithromycin was based on data from the lung transplant population that showed that approximately a third of lung recipients with BO, the histopathological manifestation of chronic rejection, had improvement in pulmonary function after chronic treatment with azithromycin (500 mg/day for 3 days followed by 250 mg 3x/week for 12 weeks).

Although this treatment is safe, especially when compared to conventional immunosuppressive agents, enthusiasm for its use has been somewhat tempered by a more recent randomized, placebo controlled study of 24 patients who did not show benefit. Reports from studies in lung transplantation suggest that patients with milder, potentially reversible BO and those with BAL neutrophilia are more likely to respond to azithromycin therapy. Further studies are required to determine whether azithromycin is useful for post-HSCT BO and to identify which subset of patients are most likely to derive benefit.

A recent prospective, double-blind, placebo-controlled study of 32 patients with mild to moderate BO after HSCT who were randomly assigned to receive budesonide/formoterol inhalation or placebo twice daily showed significant improvement in lung function in the treatment group. A combination treatment regimen for BO including fluticasone, montelukast, and prednisone is currently under investigation

Extracorporeal hotopheresis (ECP) is an immunomodulatory intervention that has been useful in the treatment of refractory cutaneous chronic GVHD, although a beneficial response for BO is inconsistently seen. A recent report indicated that six of nine patients with treatment refractory BO after HSCT had improvement or stabilization of pulmonary function after ECP.

Another immunomodulatory agent that may be considered for the treatment of BO is the tyrosine kinase inhibitor imatinib mesylate. This drug is thought to exhibit its anti-fibrotic effects by inhibiting signaling through transforming growth factor-beta (TGF-β) and platelet derived growth factor (PDGF) pathways. In a small study of 19 patients with chronic GVHD, 11 had pulmonary manifestations and 6 were reported to demonstrate improvement with imatinib mesylate. Further study is required before this treatment can be recommended.

Other drugs that have been reported for treatment include the anti-TNF agents etanercept and infliximab, thalidomide, rituximab, and the leukotriene antagonist montelukast. The quality of data for any medical therapy for BO is poor and no approach can be strongly recommended. For select patients with severe BO who are deemed to be cured of their underlying malignancy and are free from other comorbid conditions, lung transplantation could be considered as a life-saving therapeutic option.

Bronchiolitis obliterans with organizing pneumonia

The majority of patients with BOOP respond favorably to corticosteroid treatment, and the prognosis is generally better than that for patients with BO.

Pulmonary veno-occlusive disease

No therapy has been shown to be consistently effective, and prognosis is generally poor. Corticosteroids are typically administered, with published cases reporting benefit. There are also reports of benefit with pulmonary vasodilator therapy (e.g., epoprostenol, iloprost, sildenafil); however, these drugs must be used with caution. Arterial vasodilatation in the setting of fixed pulmonary venous resistance may precipitously increase transcapillary hydrostatic pressure and result in severe pulmonary edema and respiratory failure.

Standard therapies for pulmonary arterial hypertension, such as anticoagulation, have not been well studied in this population. Although there is increased interest in the novel agent defibrotide for the treatment of hepatic veno-occlusive disease, there are no published reports regarding its use in PVOD.

What is the prognosis for patients managed in the recommended ways?

Most of the respiratory complications associated with hematologic malignancies and HSCT have high rates of morbidity and mortality.

Respiratory failure after HSCT is an ominous complication. One of the largest studies to assess the impact of respiratory failure after HSCT, published in 1992, reported on the outcomes of almost 1500 consecutive HSCT recipients at the Fred Hutchinson Cancer Center. Of the 348 patients (23%) who required mechanical ventilation, only 4 percent survived to hospital discharge and none who required more than 9 days of ventilatory support survived. This dismal finding led some experts in the critical-care community to advocate withholding or limiting mechanical ventilation on the basis of medical futility.

More recent studies have indicated that outcomes of respiratory failure are better after autologous transplantation. Survival rates are also somewhat improved after allogeneic HSCT. For example, in a study of 122 consecutive allogeneic transplant recipients who required mechanical ventilation, almost 16 percent survived to hospital discharge. Another investigation reported a 22 percent survival rate. Even these recent studies have indicated that the concurrent development of extrapulmonary dysfunction (e.g., renal or hepatic failure, sepsis) with respiratory failure has an extremely poor prognosis. In this situation, the poor prognosis should be reviewed with patients and their families, and strong consideration should be given to limiting life-supporting modalities.

Pulmonary alveolar proteinosis

PAP secondary to hematologic disorders appears to have a worse prognosis, and treatment with whole lung lavage is less effective than in patients with idiopathic pulmonary alveolar proteinosis.

Idiopathic pneumonia syndrome after HSCT

IPS has a grave prognosis, and the requirement for mechanical ventilation confers a particularly poor prognosis. Overall, IPS has a mortality rate that approaches 80 percent in some series, although more contemporary series indicate better short-term survival.

Diffuse alveolar hemorrhage after HSCT

Although early studies reported high mortality rates in patients with DAH, it appears that outcomes depend on the timing of DAH and the type of transplant procedure. For example, in a large retrospective series from the Mayo Clinic (1,215 patients transplanted between 1994 and 2002), 48 cases of DAH were identified. Mortality was approximately 30 percent for autologous HSCT recipients and for patients who developed DAH within the first 30 days. However, mortality rates were 70 percent for allogeneic recipients and later onset DAH.

Engraftment syndrome

The majority of patients with ES improve rapidly with corticosteroid treatment. Patients who present with shock or concurrent severe acute GVHD have a poorer prognosis.

Bronchiolitis obliterans with organizing pneumonia

In a review of 27 cases of post-HSCT BOOP, the mortality rate was 19 percent.

What other considerations exist for patients with a pulmonary complication of a hematologic disease?

Both the patient and the physician must have a high suspicion for a respiratory complication in this clinical setting because prompt initiation of therapy may improve outcome. Detection of a complication is challenging because early symptoms may be subtle.

What's the evidence?

Morrison, VA. "Management of infectious complications in patients with chronic lymphocytic leukemia". Hematology Am Soc Hematol Educ Program. 2007. pp. 332-8.

Rapoport, BL. "Management of the cancer patients with infection and neutropenia". Semin Oncol. vol. 38. 2011. pp. 424-30.

Wade, JC. "Viral infections in patients with hematological malignancies". Hematology Am Soc Hematol Educ Program. 2006. pp. 368-74.

Hildebrand, FL, Rosenow, EC, Habermann, TM, Tazelaar, HD. "Pulmonary complications of leukemia". Chest. vol. 98. 1990. pp. 1233-9.

Koh, TT, Colby, TV, Muller, NL. "Myeloid leukemias and lung involvement". Semin Respir Crit Care Med. vol. 26. 2005. pp. 514-9.

(This article provides an overview of the clinical, radiographic, and pathology manifestations of leukemic involvement in the lung. Leukemic infiltration of the lung, pulmonary leukostasis, and leukemic cell lysis pneumopathy are reviewed.)

Chung, JH, Pipavath, SJ, Myerson, DH, Godwin, D. "Secondary pulmonary alveolar proteinosis: a confusing and potentially serious complication of hematologic malignancy". J Thorac Imaging. vol. 24. 2009. pp. 115-8.

Meadors, M, Floyd, J, Perry, MC. "Pulmonary toxicity of chemotherapy". Semin Oncol. vol. 33. 2006. pp. 98-105.

(Overview of the pulmonary toxicities associated with commonly used chemotherapeutic agents.)

Chi, AK, Soubani, AO, White, AC, Miller, KB. "An update on pulmonary complications of hematopoietic stem cell transplantation [review]". Chest. vol. 144. 2013. pp. 1913-22.

(A general overview.)

Wingard, JR, Hsu, J, Hiemenz, JW. "Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology". Hematol Oncol Clin North Am. vol. 25. 2011. pp. 101-16.

(General review of HSCT, immunologic deficits associated with different types of HSCT, and infection risks [including pneumonia]. There is an excellent discussion on the rate and level of immune system reconstitution.)

Martin-Pena, A, Aguilar-Guisado, M, Espigado, I, Parody, R, Miguel Cisneros, J. "Prospective study of infectious complications in allogeneic hematopoietic stem cell transplant recipients". Clin Transplant. vol. 25. 2011. pp. 468-74.

Shah, DP, Ghantoji, SS, Mulanovich, VE. "Management of respiratory viral infections in hematopoietic cell transplant recipients". Am J Blood Res. vol. 2. 2012. pp. 203-18.

Nichols, WG, Gooley, T, Boeckh, M. "Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience". Biol Blood Marrow Transplant. vol. 7. 2001. pp. 11S-5S.

Kontoyiannis, DP, Marr, KA, Park, BJ. "Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. [Research Support, U.S. Gov't, P.H.S.]". Clin Infect Dis. vol. 50. 2010. pp. 1091-100.

Afessa, B, Peters, SG. "Noninfectious pneumonitis after blood and marrow transplant". Curr Opin Oncol. vol. 20. 2008. pp. 227-33.

(A detailed review of the various non-infectious pulmonary complications seen after HSCT.)

Panoskaltsis-Mortari, A, Griese, M, Madtes, DK, Belperio, JA, Haddad, IY, Folz, RJ. "An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome". Am J Respir Crit Care Med. vol. 183. 2011. pp. 1262-79.

(A comprehensive review of the clinical, radiographic, and pathologic findings of IPS. In addition, there is a comprehensive review of data from animal models of IPS that have led to significant advancement in our understanding of disease pathogenesis and development of novel treatment approaches.)

Spira, D, Faul, C, Schaup, V, Wirths, S, Schulze, M, Sauter, A. "HRCT findings in idiopathic pneumonia syndrome with documentation of the disease course". Eur J Radiol. vol. 81. 2012. pp. e147-52.

Yanik, GA, Horowitz, MM, Weisdorf, DJ. "Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol. Multicenter study". Biol Blood Marrow Transplant. vol. 20. 2014. pp. 858-64.

Tizon, R, Frey, N, Heitjan, DF. "High-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allo-SCT". Bone Marrow Transplant. vol. 47. 2012. pp. 1332-7.

(This article reviews the outcomes of the largest clinical trial to explore the role of Etanerept for the treatment of IPS.)

Afessa, B, Tefferi, A, Litzow, MR, Krowka, MJ, Wylam, ME, Peters, SG. "Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients". Am J Respir Crit Care Med. vol. 166. 2002. pp. 641-5.

(An excellent overview of DAH after HSCT.)

Majhail, NS, Parks, K, Defor, TE, Weisdorf, DJ. "Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes". Biol Blood Marrow Transplant. vol. 12. 2006. pp. 1038-46.

Gupta, S, Jain, A, Warneke, CL, Gupta, A, Shannon, VR, Morice, RC. "Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients". Bone Marrow Transplant. vol. 40. 2007. pp. 71-8.

Pastores, SM, Papadopoulos, E, Voigt, L, Halpern, NA. "Diffuse alveolar hemorrhage after allogeneic hematopoietic stem-cell transplantation: treatment with recombinant factor VIIa". Chest. vol. 124. 2003. pp. 2400-3.

Wanko, SO, Broadwater, G, Folz, RJ, Chao, NJ. "Diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid". Biol Blood Marrow Transplant. vol. 12. 2006. pp. 949-53.

Carreras, E, Fernandez-Aviles, F, Silva, L, Guerrero, M, Fernandez de Larrea, C, Martinez, C. "Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center". Bone Marrow Transplant. vol. 45. pp. 1417-22.

Spitzer, TR. "Engraftment syndrome following hematopoietic stem cell transplantation". Bone Marrow Transplant. vol. 27. 2001. pp. 893-8.

Maiolino, A, Biasoli, I, Lima, J, Portugal, AC, Pulcheri, W, Nucci, M. "Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria". Bone Marrow Transplant. vol. 31. 2003. pp. 393-7.

Chang, L, Frame, D, Braun, T. "Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes". Biol Blood Marrow Transplant. vol. 20. 2014. pp. 1407-17.

Pandya, CM, Soubani, AO. "Bronchiolitis obliterans following hematopoietic stem cell transplantation: a clinical update". Clin Transplant. vol. 24. 2011. pp. 291-306.

(A comprehensive review of clinical, radiographic, and pathologic findings associated with post-HSCT BO. The similarities to BO after lung transplantation are also explored.)

Hildebrandt, GC, Fazekas, T, Lawitschka, A, Bertz, H, Greinix, H, Halter, J. "Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD". Bone Marrow Transplant. vol. 46. 2011. pp. 1283-95.

(A thorough review of diagnosis, clinical findings, imaging studies, and treatment of chronic pulmonary GVHD [bronchiolitis obliterans].)

Filipovich, AH, Weisdorf, D, Pavletic, S, Socie, G, Wingard, JR, Lee, SJ. "National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report". Biol Blood Marrow Transplant. vol. 11. 2005. pp. 945-56.

(The NIH establishes a consensus definition of chronic GVGD, including BO.)

Dudek, AZ, Mahaseth, H, DeFor, TE, Weisdorf, DJ. "Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes". Biol Blood Marrow Transplant. vol. 9. 2003. pp. 657-66.

Khalid, M, Al Saghir, A, Saleemi, S, Dammas, SA, Zeitouni, M, Mobeireek, AA. "Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study". Eur Respir J. vol. 25. 2005. pp. 490-3.

(The initial report describing the beneficial effects of the immunomodulatory macrolide azithromycin for treatment of BO after HSCT.)

Lam, DC, Lam, B, Wong, MK, Lu, C, Au, WY, Tse, EW. "Effects of Azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT: a randomized double-blinded placebo-controlled study". Bone Marrow Transplant. vol. 46. 2011. pp. 1551-6.

Sengsayadeth, SM, Srivastava, S, Jagasia, M, Savani, BN. "Time to explore preventive and novel therapies for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation [review]". Biol Blood Marrow Transplant. vol. 18. 2012. pp. 1479-87.

Bergeron, A, Chevret, S, Chagnon, K. "Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation". Am J Respir Crit Care Med. vol. 191. 2015. pp. 1242-49.

Olivieri, A, Locatelli, F, Zecca, M. "Imatinib for refractory chronic graft-versus-host disease with fibrotic features". Blood. vol. 114. 2009. pp. 709-18.

Afessa, B, Peters, SG. "Chronic lung disease after hematopoietic stem cell transplantation". Clin Chest Med. vol. 26. 2005. pp. 571-86.

Huisman, C, van der Straaten, HM, Canninga-van Dijk, MR, Fijnheer, R, Verdonck, LF. "Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease". Bone Marrow Transplant. vol. 38. 2006. pp. 561-6.

Limper, AH. "Chemotherapy-induced lung disease". Clin Chest Med. vol. 25. 2004. pp. 53-64.

Bunte, MC, Patnaik, MM, Pritzker, MR, Burns, LJ. "Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction". Bone Marrow Transplant. vol. 41. 2008. pp. 677-86.

(An excellent review of PVOD after HSCT.)

Cheng, GS, Edelman, JD, Madtes, DK, Martin, PJ, Flowers, ME. "Outcomes of lung transplantation after allogeneic hematopoietic stem cell transplantation". Biol Blood Marrow Transplant. vol. 20. 2014. pp. 1169-75.

White, P, Bonacum, JT, Miller, CB. "Utility of fiberoptic bronchoscopy in bone marrow transplant patients". Bone Marrow Transplant. vol. 20. 1997. pp. 681-7.

(Initial report questioning the utility of bronchoscopy in evaluating pulmonary infiltrates after HSCT.)

Hofmeister, CC, Czerlanis, C, Forsythe, S, Stiff, PJ. "Retrospective utility of bronchoscopy after hematopoietic stem cell transplant". Bone Marrow Transplant. vol. 38. 2006. pp. 693-8.

Shannon, VR, Andersson, BS, Lei, X, Champlin, RE, Kontoyiannis, DP. "Utility of early versus late fiberoptic bronchoscopy in the evaluation of new pulmonary infiltrates following hematopoietic stem cell transplantation". Bone Marrow Transplant. vol. 45. 2010. pp. 647-55.

Parimon, T, Madtes, DK, Au, DH, Clark, JG, Chien, JW. "Pretransplant lung function, respiratory failure, and mortality after stem cell transplantation". Am J Respir Crit Care Med. vol. 172. 2005. pp. 384-90.

(This study highlights the association of pre-transplant PFT abnormalities (FEV1 and DLCO) with respiratory complications and death.)

Walter, EC, Orozco-Levi, M, Ramirez-Sarmiento, A, Vigorito, A, Campregher, PV, Martin, PJ. "Lung function and long-term complications after allogeneic hematopoietic cell transplant". Biol Blood Marrow Transplant. vol. 16. pp. 53-61.

Chien, JW, Sullivan, KM. "Carbon monoxide diffusion capacity: how low can you go for hematopoietic cell transplantation eligibility?". Biol Blood Marrow Transplant. vol. 15. 2009. pp. 447-53.

Crawford, SW, Petersen, FB. "Long-term survival from respiratory failure after marrow transplantation for malignancy". Am Rev Respir Dis. vol. 145. 1992. pp. 510-4.

(Initial report on poor outcomes of patients who develop respiratory failure after HSCT.)

Schuster, DP. "Everything that should be done—not everything that can be done". Am Rev Respir Dis. vol. 145. 1992. pp. 508-9.

(Editorial questioning the rationale for critical care support for patients with prolonged ventilator-dependent respiratory failure.)

Pene, F, Aubron, C, Azoulay, E, Blot, F, Thiery, G, Raynard, B. "Outcome of critically ill allogeneic hematopoietic stem-cell transplantation recipients: a reappraisal of indications for organ failure supports". J Clin Oncol. vol. 24. 2006. pp. 643-9.

(A recent study highlighting somewhat improved outcomes associated with post-HSCT respiratory failure.)
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