© 2002 American Thoracic Society
Diffuse Alveolar Hemorrhage in Hematopoietic Stem Cell Transplant RecipientsDepartment of Medicine, Divisions of Pulmonary and Critical Care Medicine and Hematology, Mayo Clinic and Foundation, Rochester, Minnesota Correspondence and requests for reprints should be addressed to Bekele Afessa, M.D., 200 First Street SW, Mayo Clinic, Rochester, MN 55905. E-mail: afessa.bekele{at}mayo.edu Hematopoietic stem cell transplantation (HSCT) is used for the treatment of hematologic and solid tumors as well as for various benign diseases worldwide. The International Bone Marrow Transplant and the Autologous Blood and Marrow Transplant Registries estimate that approximately 50,000 hematopoietic stem cell transplants were performed in 1998. Approximately 17,000 of these were allogeneic, and over 30,000 were autologous. Pulmonary complications develop in 30 to 60% of HSCT recipients (1, 2). Because of graft-versus-host disease and immunosuppressant medications, both infectious and noninfectious pulmonary complications are more common in allogeneic than in autologous HSCT recipients. Compared with bone marrow, the use of peripheral blood as the source of stem cells may lead to fewer infectious pulmonary complications and bleeding during the early post-HSCT period because of its association with a shorter neutrophil and platelet recovery time (3). The late-onset noninfectious pulmonary complications have been addressed in a recent publication (4). Although alveolar hemorrhage can be caused by infections, diffuse alveolar hemorrhage (DAH) is considered to be a noninfectious pulmonary complication that usually occurs in the early posttransplant period. This commentary focuses on the frequency, risk factors, pathogenesis, clinical manifestation, treatment, and prognosis of DAH. DIAGNOSTIC CRITERIA DAH is a syndrome with nonspecific clinical and radiologic features. Although pulmonary infections can cause alveolar hemorrhage, the term DAH in the HSCT recipient is reserved for alveolar hemorrhage of noninfectious etiology. The diagnostic criteria of DAH in the HSCT recipient are as follows: (1) evidence of widespread alveolar injury manifested by multilobar pulmonary infiltrate, symptoms and signs of pneumonia, and abnormal pulmonary physiology with increased alveolar to arterial oxygen gradient and restrictive ventilatory defect; (2) absence of infection compatible with the diagnosis; and (3) bronchoalveolar lavage (BAL) showing progressively bloodier return from three separate subsegmental bronchi or the presence of 20% or more hemosiderin-laden macrophages or the presence of blood in at least 30% of the alveolar surfaces of lung tissue (5–7). INCIDENCE The frequency of DAH has varied among reported series because of differences in patient mix, diagnostic approaches, and diagnostic criteria. The factors that influence the incidence of DAH have changed over time and varied among HSCT centers. Although bronchoscopy and surgical lung biopsy have been used for decades, their application in HSCT recipients with pulmonary infiltrates has not been well standardized. Because underlying conditions may prohibit invasive procedures, some clinicians prefer to initiate empiric antibiotics for suspected infection leading to underdiagnosis of DAH. Moreover, although BAL is widely used for the diagnosis of DAH, the diagnostic criteria have elements of subjectivity and are not uniformly applied. In seven studies that included 3,806 HSCT recipients, 204 cases of DAH were reported, for a frequency of 5%, with a range between 2% and 14% (8–14). The reported frequency of DAH varies from 1 to 21% in autologous and from 2 to 17% in allogeneic HSCT recipients (1, 2, 5, 9–12, 15–22). DAH has been reported in 123 of 2,616 (5%) autologous and 91 of 1,748 (5%) allogeneic HSCT recipients (1, 2, 5, 9–12, 15–22). The recent increase in the incidence of DAH has not been associated with uses of granulocyte colony-stimulating factor and peripheral blood stem cell source (10). Among 469 HSCT recipients who underwent bronchoscopy, DAH was reported in 44 (9%), with a range between 1% and 19% (23–28). In patients admitted to the intensive care unit for respiratory failure, the prevalence of DAH may exceed 40% (29, 30). DAH has been reported in approximately 10% of autopsies (7, 31). RISK FACTORS Pretransplant intensive chemotherapy, including conditioning regimen, total body irradiation, thoracic irradiation, and old age, is associated with DAH (2, 5, 8, 20, 21, 31). Despite few studies showing that solid tumors and breast cancer may be associated with the development of DAH (5, 32), we have not found such an association. Combining the results reported in different studies, 15 of 329 HSCT recipients (5%) treated for solid tumor had DAH compared with 89 of 1,730 HSCT recipients (5%) treated for hematologic malignancies (1, 2, 5, 8, 10, 13, 15, 16, 18–22). Although DAH occurs in both autologous and allogeneic HSCT recipients, the initial studies included predominantly autologous HSCT recipients (5). In data that we compiled from reported studies, we did not find significant difference in the incidence of DAH between autologous and allogeneic HSCT recipients: 123 of the 2,616 autologous HSCT recipients (5%) had DAH compared with 91 of the 1,748 allogeneic HSCT recipients (5%) (1, 2, 5, 9–12, 15–22). Pulmonary function tests have shown that there is no association between the development of DAH and pretransplant FVC FEV1, total lung capacity, or diffusing capacity for carbon monoxide (5). Pretransplant bronchoscopy has shown a higher number of bronchial neutrophils and eosinophils in patients who develop DAH after HSCT compared with those who do not develop DAH (13). In the study by Sisson and colleagues, the pretransplant presence of bronchial neutrophils of more than 20% and of eosinophils of more than 0% was associated with the development of DAH (13). White blood cell recovery and renal insufficiency, but not prolonged prothrombin or partial thromboplastin time or low platelets, are associated with the development of DAH (2, 5). Although most patients with DAH have thrombocytopenia, the DAH is not corrected with platelet transfusion (5). PATHOGENESIS Various conditions, including mitral valve disease, systemic vasculitides, collagen vascular diseases, drugs, anticoagulation, cocaine inhalation, and infections, have been implicated as causing alveolar hemorrhage in non-HSCT recipients. These conditions are associated with injury to the pulmonary arterioles, venules, and capillaries disrupting the alveolar–capillary basement membrane. Penicillamine, abciximab, propylthiouracil, amiodarone, nitrofurantoin, and cytotoxic medications are among drugs associated with alveolar hemorrhage. Drug-induced alveolar hemorrhage usually results from direct toxic effects and indirect inflammatory or immunologic processes. Despite the recognition of the risk factors, the etiology and pathogenesis of DAH in the HSCT recipient have not been clearly established. Lung tissue injury, inflammation, and cytokine release are implicated in the pathogenesis of both idiopathic pneumonia syndrome (IPS) and DAH. In a murine model of HSCT, the critical early proinflammatory events associated with IPS have been found to be due to donor T cells (33).
Lung Injury Vasculopathy of small muscular arteries and thrombotic microangiopathy have been reported in HSCT recipients with DAH (37). The vasculopathy of small muscular arteries manifests as concentric intimal or medial hyperplasia with luminal narrowing, prominent myxoid change, extravasated red blood cells, and the presence of some foamy histiocytes with no evidence of thrombotic microangiopathy. Thrombotic microangiopathy has also been associated with DAH in the HSCT recipient (37). It is characterized by the presence of fragmented erythrocytes on peripheral smears, decreased hemoglobin and platelet counts, refractoriness to platelet transfusions, and the absence of disseminated intravascular coagulation (37). The use of dimethyl sulfoxide for cryopreservation of blood stem cells has been implicated in causing damage to the alveolar endothelial lining and thus leading to the development of DAH (16, 38).
Inflammation
Cytokine Release CLINICAL FINDINGS AND COURSE In the nontransplant patient population, the classic presentation of DAH consists of hemoptysis and dyspnea in the setting of iron deficiency anemia and a chest radiograph showing bilateral air-space consolidation with apical sparing. However, these features are variable and may be absent. In the HSCT recipient, DAH is characterized by progressive dyspnea, hypoxia, cough, diffuse consolidation on chest radiograph, and characteristic BAL fluid findings developing within 1 to 7 days (5). DAH should be distinguished from localized pulmonary hemorrhage with diffuse aspiration of blood caused by chronic bronchitis, bronchiectasis, tumors, or infections. The onset of DAH is usually within the first 30 (median between 11 and 19) days after HSCT (2, 5, 10, 16, 21). However, cases of DAH with onset after the first month of transplant are not uncommon (31). HSCT recipients with DAH often have dyspnea and dry cough (5). Although coexistent sepsis and mucositis may obscure the clinical picture, fever is a common finding (2, 5, 16, 21, 38). Hemoptysis is rare and is limited to a few case reports (2, 38). None of the 29 patients had hemoptysis in the study by Robbins and colleagues (5). Compared with patients without DAH, those with DAH tend to have more severe mucositis (5). LABORATORY AND RADIOGRAPHIC FINDINGS HSCT recipients with DAH are typically too ill to perform pulmonary function testing. Arterial blood gas studies show hypoxemia. BAL fluid shows a median leukocyte count of 130 per µL and a median red blood cell count of 48,375 per µL (10). Chest radiograph shows diffuse interstitial and alveolar infiltrates, primarily central, and involving predominantly lower and middle lung zones (14). The earliest radiographic manifestation is the presence of bilateral fine reticular opacities (14). Radiographic abnormalities present at a mean of 11 days after transplant (range, 0–24) and 3 days before clinical diagnosis of DAH (14). The radiographic findings deteriorate in the first 6 days (14). In one study of 39 HSCT recipients with DAH, an initial chest X-ray showed bilateral abnormality in 27, unilateral in 10, and normal in 2; it also showed interstitial abnormality in 27 and alveolar abnormality in 10 (14). In the later phase of DAH, 70% of the patients develop alveolar pattern, and the interstitial pattern persists in 30% (14). Pleural effusion is seen in 14%, and cardiomegaly is seen in 19% (14). Although computed tomography may be helpful in patients in whom a focal abnormality is suspected, computed tomography and magnetic resonance imaging have a limited role in DAH. The most common computed tomography finding is bilateral areas of ground-glass attenuation or consolidation (44). BAL is the most commonly used diagnostic tool for confirming DAH. The diagnosis of alveolar hemorrhage is made by progressively bloodier BAL returns when hemorrhage is recent or by an increased number of hemosiderin-laden macrophages using Prussian blue staining (6). The BAL appearance and the iron stain complement each other. BAL may be progressively bloodier in early DAH, when hemosiderin-laden macrophages are absent. Iron staining adds an element of objectivity to the criteria used in the diagnosis of DAH. However, both false-positive and false-negative BAL have been reported (7, 25). Because blood in the distal airways may give progressively bloodier BAL return regardless of the source, the appearance of BAL return is not reliable for the diagnosis of DAH. The mere presence of hemosiderin-laden macrophages is insufficient to diagnose DAH, as normal individuals, particularly those who smoke cigarettes, may have hemosiderin-laden macrophages (45). After acute pulmonary hemorrhage, it may take 48 to 72 hours for hemosiderin-laden macrophages to appear in respiratory secretions and 2 to 4 weeks for the hemosiderin-laden macrophages to clear from the lungs and airways (46). Because of delay in the appearance of hemosiderin-laden macrophages in BAL fluid and hemosiderin clearance after a few days, the absence of hemosiderin in alveolar macrophages does not exclude the possibility of recent (less than 48 hours) or remote (greater than 12 days) alveolar bleeding (47). To avoid BAL false-positive results, Golde and associates introduced a ranking score, based on the hemosiderin content of macrophages (48). The Golde score measures the hemosiderin content of pulmonary macrophages: 200–300 macrophages of BAL fluid are counted. Each cell is graded for hemosiderin on a scale of 0 to 4, and a mean score for 100 cells is calculated (48). We use BAL hemosiderin-laden macrophages of 20% or more, which correlates well with and is easier than the Golde score, for the diagnosis of alveolar hemorrhage (6). Early BAL is essential to exclude other pulmonary complications. Because hemosiderin-laden macrophages may not be present in BAL fluid early after acute alveolar hemorrhage, repeat bronchoscopy may be needed within 2 to 5 days of the first bronchoscopy (10). Transbronchial lung biopsy is often contraindicated because of the bleeding risk. Lung tissues in DAH show histologic features consistent with diffuse alveolar damage (5, 7, 13). DAH at autopsy is defined by the presence of blood in at least 30% of the evaluated alveolar surfaces (7). DIFFERENTIATING DAH FROM PERIENGRAFTMENT RESPIRATORY SYNDROME AND IPS There are overlaps in the diagnostic criteria used to define DAH, IPS, and periengraftment respiratory distress syndrome (23, 49). We believe that DAH is a distinct subset of IPS. IPS is a heterogeneous entity that is characterized by evidence of widespread alveolar injury and the absence of lower respiratory tract infection (49). Despite similarities in the pathogenesis of DAH and IPS, DAH has its own peculiar characteristics. IPS is characterized by diffuse interstitial pneumonitis and alveolitis leading to interstitial fibrosis. The early period after HSCT is characterized by the presence of inflammatory cytokines whose net effect is to promote lymphocyte influx into lungs with minimal fibrosis (50). During the later period, gradual changes in leukocyte influx and activation lead to dysregulated wound repair resulting from the shift in the balance of cytokines that promote fibrosis. We think that DAH is characterized by the prevalence of an antifibrotic cytokine milieu compared with a profibrotic environment in IPS. The onset of DAH mostly coincides with the stem cell engraftment period. The onset of IPS is during the later posttransplant period and is not influenced by stem cell engraftment. Lung pathology in DAH is consistent with the proliferative phase of diffuse alveolar damage without fibrosis. IPS is more common in allogeneic than autologous HSCT recipients, whereas the incidence of DAH is similar between the two groups. The respiratory failure of most patients with DAH, unlike IPS, improves in response to corticosteroid therapy. More than 80% of the deaths in IPS are attributable to progressive respiratory failure compared with 15% in DAH. Based on these findings, we believe DAH is a distinct subset of IPS. Periengraftment respiratory distress syndrome is defined by the presence of fever, evidence of lung injury, absence of cardiac dysfunction, exclusion of infectious etiologies, and onset within 5 days of neutrophil engraftment (23). It has been reported in both autologous and allogeneic HSCT recipients. Despite the paucity of data, neutrophils are considered to play a major role in its development. The absence of DAH in two-thirds of the patients with periengraftment respiratory distress syndrome and the occurrence of DAH beyond the periengraftment period suggest differences between these two syndromes despite their overlap. TREATMENT Because the pathogenesis of DAH is considered to be an inflammatory response to various insults and based on anecdotal experiences and retrospective studies, HSCT recipients with DAH are treated with systemic corticosteroids (11, 16, 21, 40). However, there are no prospective, randomized trials addressing the treatment of DAH in HSCT recipients. In a retrospective study, Metcalf and colleagues compared three groups: no corticosteroids, daily methylprednisolone of 30 mg or less, and daily methylprednisolone of more than 30 mg (11). The pretreatment arterial oxygen tension was lower in patients in the high-dose methylprednisolone group. However, the mortality rate was lower and fewer patients required invasive mechanical ventilation in the high-dose methylprednisolone group (11). The methylprednisolone dose for the high-dose group was 125 to 250 mg every 6 hours for the first 4 to 5 days and then tapered over 2 to 4 weeks (11). Low-dose methylprednisolone therapy was not better than no steroid therapy (11). In a more recent study of 15 HSCT recipients with DAH treated with 250 mg to 2 g/day of methylprednisolone, transient clinical improvement was seen in 10 patients (10). However, the overall mortality of 74% was not significantly different from previous reports (5, 10). The infection rate is not increased by short-course corticosteroid treatment of DAH (11). Although many HSCT recipients may subsequently die from other complications, the respiratory status of most patients with DAH improves in response to corticosteroid therapy (10, 11, 16, 21, 40). We commonly use methylprednisolone of approximately 1 g daily in four divided doses for 5 days, followed by 1 mg/kg for 3 days, and tapering off over 2 to 4 weeks. Although immunosuppressive therapy, plasma exchange, and plasmapheresis have been tried to treat DAH in other patient populations, there is no evidence to justify their use in HSCT recipients. Fresh frozen plasma transfusion and plasmapheresis have been tried in one study with inconclusive results (37). PROGNOSIS DAH is a major complication of HSCT, contributing significantly to morbidity and mortality (5, 31). The majority of HSCT recipients with DAH require mechanical ventilator support for respiratory failure (9, 10, 13, 21, 30). HSCT recipients with DAH are at high risk for subsequent infectious complications (11). The reported mortality rate of DAH in HSCT recipients is approximately 80%, with a range between 64% and 100% (2, 5, 8, 10, 11, 13, 14, 30). Although the initial presentation of DAH in HSCT recipients may be respiratory failure, the two most common causes of death are multiple organ failure and sepsis (10, 11). Respiratory failure with active pulmonary hemorrhage is responsible for less than 15% of the deaths (11). Despite the high mortality rate, long-term survivors of HSCT recipients with DAH can have normal respiratory function (10, 21). CONCLUSION Although some of the risk factors have been recognized, the etiology and pathogenesis of DAH have not been identified, and diagnostic criteria have not been clearly defined. Criteria for defining clinically relevant subsets of IPS are needed. We need future studies to determine whether there are differences in pathogenesis, clinical presentation, clinical course, and response to corticosteroid therapy between early-onset (the first 30 days after HSCT) and late-onset DAH. Despite the wide application of corticosteroid therapy, little scientific evidence is available, and the optimal dose and duration of treatment are unknown. Based on the high mortality rate of untreated DAH in the HSCT recipient and retrospective experiences showing beneficial effects of systemic corticosteroids, it may be difficult to justify a prospective, randomized, placebo-controlled clinical trial. However, prospective clinical trials would be needed to identify the optimal dose, duration, and tapering schedule of corticosteroids. Studies focusing on the prevention of DAH are almost nonexistent. Preliminary data showing that corticosteroids may reduce the incidence of early posttransplant complications, including DAH, merit further investigation (17). The high mortality rate despite corticosteroid therapy suggests the need for a better understanding of the pathogenesis of DAH. Trials of innovative treatment modalities aimed at modifying injurious inflammatory processes and their cytokine mediators may result in improved outcomes. Because the high mortality rate of DAH is associated with the development of sepsis and multiple organ failure, future studies should also address the prevention and treatment of these complications. Received in original form December 18, 2001; accepted in final form May 30, 2002 REFERENCES
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, and lipopolysaccharides have been associated with DAH in HSCT recipients (
