PEDIATRICS Vol. 109 No. 5 May 2002, pp. 965-971
EXPERIENCE AND REASON |
Diffuse Alveolar Hemorrhage in Pediatric Hematopoietic Cell Transplant Patients
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective. Diffuse alveolar hemorrhage (DAH) is defined as a syndrome of hypoxia, dyspnea, infiltrates on chest radiograph, and bloody fluid on successive bronchoalveolar lavages without apparent infection. Minimal experience has been reported with DAH after hematopoietic cell transplant (HCT) in children. We reviewed the incidence, management and outcome of DAH in a pediatric HCT population.
Methods. Retrospective review of 138 patients undergoing allogeneic (n = 89) or autologous (n = 49) HCT at a referral children’s medical center between January 1996 and April 2000.
Results. Seven (5.1%) of 138 patients met criteria for DAH; all were allogeneic recipients. Mean age of DAH patients was 11 years (range: 1.4–15.2). Median onset of DAH following HCT was day 24 (range: 10–50), median day of engraftment day 20 and white blood cell count 0.54 x 109/L (range: < 0.1–7.03), with no difference between survivors and nonsurvivors. All patients developed clinical respiratory failure and 6 required intubation, with PaO2/fraction of inspired oxygen <200. Patients were intubated a median of 12 days (range: 1–75). All patients experienced >1 episode of bleeding and 3 patients required reintubation after successful extubation resulting from recurrent DAH. Bronchoalveolar lavage fluid cultures were negative for viruses, bacteria and fungi. All DAH patients received steroids. Three patients died with progressive pulmonary failure and other organ system involvement. Four of 7 DAH patients (57%) survived to discharge, but 3 died from disease relapse at days 116, 138, and 273 post-HCT.
Conclusion. DAH occurred more frequently in allogeneic HCT recipients compared with autologous recipients. Onset of DAH coincided closely with white blood cell engraftment. Although associated with significant respiratory failure and need for mechanical ventilation, HCT patients can survive DAH.
Key Words: bone marrow transplant • pulmonary hemorrhage • respiratory failure • pediatric • bronchoalveolar lavage
Abbreviations: DAH, diffuse alveolar hemorrhage • BAL, bronchoalveolar lavage • CXR, chest radiograph • HCT, hematopoietic cell transplant • BMT, bone marrow transplant • GVHD, graft-versus-host disease • WBC, white blood cell • FIO2, fraction of inspired oxygen • AML, acute myeloblastic leukemia
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Diffuse alveolar hemorrhage (DAH) is a form of noninfectious pneumonitis that has been reported in adult recipients of both autologous and allogeneic hematopoietic cell (bone marrow and/or peripheral blood progenitor cell) transplants.1–8 First described by Robbins et al in 1989, DAH is defined as a syndrome of hypoxia, progressive dyspnea, cough, infiltrates on chest radiograph (CXR), progressively more blood in successive aliquots of bronchoalveolar lavage (BAL) fluid, and absence of evidence for infectious etiologies in BAL fluid cultures or other diagnostic studies.1 In this seminal study, 29 (21%) of 141 adult hematopoietic cell transplant (HCT) recipients met criteria for DAH.1 Subsequent studies in adult HCT recipients have shown an incidence of DAH that ranges from 5% to 14%.2,3,7 However, a review of the literature has revealed only 1 case report of DAH in a child who received an allogeneic bone marrow transplant (BMT).9 To our knowledge, there has not been a comprehensive evaluation of DAH in pediatric HCT recipients. We reviewed the incidence, management and outcome of DAH in an exclusively pediatric HCT population at a large children’s medical center.
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METHODS AND PATIENTS |
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TOPABSTRACTINTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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We reviewed the medical records of consecutive pediatric patients undergoing allogeneic or autologous HCT from January 1996–April 2000 at Children’s Healthcare of Atlanta at Egleston, a 205-bed children’s hospital that cares for approximately 120 new pediatric oncology patients annually. The facility is a regional referral center for pediatric HCT. Patients were identified for this review from the institutional HCT database, which included patients receiving HCT for neoplastic and nonneoplastic diseases. The charts of HCT patients admitted to the pediatric intensive care unit during that time period were reviewed to identify patients with DAH using the criteria of Robbins et al1: hypoxia, dyspnea, infiltrates on CXR, bloody fluid on BAL, and no apparent infection.
Approval for patient medical record review was obtained from the institutional human investigations committee. Data were analyzed by standard statistical software, using parametric (
2, Fisher exact test) and nonparametric (Mann-Whitney) tests.
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ILLUSTRATIVE CASE REPORTS |
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TOPABSTRACTINTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Patient 1
A 13-year-old male with high risk B-cell acute lymphocytic leukemia underwent a 5/6 human leukocyte antigen-matched BMT from a volunteer unrelated donor after conditioning with high-dose cyclophosphamide and total body irradiation. Fourteen days after BMT, he developed a skin rash consistent with acute graft-versus-host disease (GVHD) and was started on intravenous methylprednisolone (2 mg/kg daily). Seventeen days after BMT, the patient acutely developed dyspnea, hypoxia and hemoptysis. CXR showed bilateral alveolar infiltrates, and BAL revealed bloody lavage fluid from both upper lobes. Gram stain of fluid showed many red blood cells, few white blood cells (WBCs), and no organisms. Cultures of BAL fluid were negative for bacteria, fungi, viruses, and Legionella. Other studies of BAL fluid, including silver stain for Pneumocystis carinii and direct fluorescent antibody analyses for respiratory syncytial virus, cytomegalovirus, influenza A and B, parainfluenza 1, 2, and 3, herpes simplex virus, and adenovirus, were all negative. The patient remained intubated after BAL and required a peak end-expiratory pressure of 10 mm Hg and fraction of inspired oxygen (FIO2) of 0.5. He remained on broad-spectrum antibiotics for fever of undetermined origin. The dosage of methylprednisolone was increased to 500 mg/d for 5 days and then tapered slowly. The patient showed gradual improvement in pulmonary function and was extubated to continuous positive airway pressure 11 days later. However, he continued to require supplemental oxygen. Thirty-eight days after BMT he developed worsening respiratory distress that required emergent endotracheal intubation. Bright red blood was suctioned from the airway after intubation. He required pressure control ventilation with peak inspiratory pressure 35 mm Hg, peak expiratory pressure 12 mm Hg and FIO2 of 0.5 to 1.0. Methylprednisolone was increased to 250 mg daily. The patient developed a recurrence of grade IV GVHD and hepatic veno-occlusive disease and died 45 days after BMT with multiple organ failure. Postmortem examination showed extensive severe acute GVHD, massive pulmonary hemorrhage and hepatic veno-occlusive disease (Fig 1and 2).
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Patient 2
A 14-year-old male with previously treated osteogenic sarcoma developed myelodysplastic syndrome that was unresponsive to conventional therapy. After undergoing a conditioning regimen of busulfan and cyclophosphamide he received a 6/6 human leukocyte angiten-matched BMT from a male sibling. Sixteen days later he developed chest pain and a right lower lobe infiltrate by CXR, and was placed on broad antiinfective coverage. He experienced gradually worsening respiratory distress but did not require supplemental oxygen. Bronchoscopy 24 days after BMT showed bloody secretions in both main stem bronchi but no blood distally or with saline lavage. Airway mucosa appeared pink and healthy, without ulcers or erosions. Over 24 hours he acutely worsened with tachypnea, increased work of breathing, poor air entry and oxygen requirement requiring endotracheal intubation. CXR showed diffuse alveolar infiltrates (Fig 3). Repeat bronchoscopy revealed blood throughout the airways and on BAL of distal airways. Gram stain of BAL specimen showed many red blood cells, few WBCs, and no organisms. BAL cultures and other diagnostic studies (as previously described) were negative for all infectious etiologies. The patient remained on parenteral broad-spectrum antimicrobial therapy and was started on methylprednisolone 1000 mg/d, followed by a dose reduction of 50% every 3 days to a dose of 60 mg/d and then by a slow tapering. Initial ventilation management included high peak end-expiratory pressure (maximum 10 mm Hg) and FIO2 of 0.4. He subsequently improved and was extubated after 10 days of mechanical ventilation, weaned to room air, and discharged from the hospital 48 days after his transplant. Eighty days after BMT he developed acute myeloblastic leukemia (AML) that had evolved from antecedent myelodysplastic syndrome and was unresponsive to therapy. He died with refractory AML 116 days after BMT. Postmortem examination showed evidence of old and recent pulmonary hemorrhage, acute bronchopneumonia, and disseminated AML.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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During the time period of this study, 138 consecutive patients (89 allogeneic and 49 autologous) underwent HCT. Ninety-six patients (70%) were male, and 42 (30%) were female. The mean age was 6.2 years, with a range of 3 months to 18 years.
Seven (5.1%) of the 138 HCT patients met the criteria for DAH (Table 1). All of these patients had received allogeneic transplants (P = .0507 by Fisher exact test compared with autologous recipients). One patient was female, and 6 were male. The mean age of the DAH group was 11 years (median: 13.4 years; range: 1.4–15.2). Five patients underwent HCT for hematologic malignancies and 2 for nonmalignant disease (aplastic anemia and mucopolysaccharidosis I-H [Hurler syndrome], respectively). All 7 patients received high-dose cyclophosphamide as a component of the pre-HCT conditioning regimen. In addition, 4 received total body irradiation, 2 busulfan, and 1 both busulfan and antithymocyte globulin. These preparative regimens were similar to those used for the majority of patients undergoing HCT. There was no discernible difference in the preparative regimen used for patients with DAH when comparing survivors versus nonsurvivors, although the small numbers made comparisons difficult. Median onset of DAH was 24 days (range: 10–50) after HCT. Median day of WBC engraftment was 20 days (range: 15–40) after HCT. The onset of DAH occurred at a median of 3 days before WBC engraftment (range: 14 days before to 35 days after engraftment). At the time of onset of DAH, the median WBC was 540/mm3 (range: 100-7030/mm3; 0.54 x 109/L range: <0.1 to 7.03 x 109/L), with no significant difference in survivors versus nonsurvivors. All patients had normal coagulation studies at the time of DAH.
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All DAH patients experienced acute onset of hypoxia and dyspnea. Two patients had gross hemoptysis. All DAH patients developed clinical respiratory failure, and 6 required intubation (Table 2). Measured PaO2/FIO2 was <200 in 6 of 7 patients. Patients were intubated a median of 12 days (range: 1–75). Two patients required high-frequency oscillatory ventilation for severe hypoxia on maximal settings with conventional ventilation. One of these 2 died within 24 hours of onset of DAH, while the other is a long-term survivor. One patient was managed with noninvasive nasal mask bilevel positive pressure ventilation alone. All patients experienced recurrent bleeding while on assisted ventilation, and 3 had recurrent DAH requiring reintubation after resolution of initial DAH episodes and successful extubation.
Cultures and other diagnostic studies of BAL fluid showed no evidence of infectious agents in DAH patients. These studies included routine bacterial, fungal, and viral cultures, Legionella culture, silver stain for Pneumocystis carinii, and direct fluorescent antibody for respiratory syncytial virus, cytomegalovirus, influenza A and B, parainfluenza 1, 2, and 3, herpes simplex virus, and adenovirus.
All DAH patients received therapeutic doses of corticosteroids. Four received 1000 mg of methylprednisolone daily for 3 days, and 3 received <500 mg daily, followed by a gradual taper over 2 months. Three of the 4 patients who received high-dose steroids and 1 of the 3 patients who received lower doses survived DAH (not significant; P = .4857 by Fisher exact test).
Three patients died with progressive pulmonary failure and multiple organ system involvement at 1, 45, and 48 days, respectively, after HCT. Autopsies demonstrated extensive pulmonary hemorrhage in 2 patients (no autopsy on 1 patient). One of these patients also had postmortem lung cultures positive for yeast and Klebsiella pneumoniae, although BAL cultures at time of DAH isolated no organism. Four (57%) of the 7 DAH patients survived and were discharged from the hospital. Three subsequently died from relapse of hematologic malignancies at 116, 138, and 273 days, respectively, after HCT. In 2 of those patients, autopsies were performed; both had evidence of resolving pulmonary hemorrhage, and 1 had a recent pulmonary hemorrhage as well.
In addition to the 7 DAH patients described, 18 other HCT patients experienced respiratory failure requiring intubation. Nine patients underwent bronchoscopy. Four were found to have pulmonary hemorrhage but were excluded from this analysis because of associated BAL studies indicating infection at the time of initial hemorrhage. Two patients had viral infections (influenza A, cytomegalovirus and subsequently adenovirus), 1 had infection with Escherichia coli and 1 had Candida albicans. All 4 patients with infection-associated pulmonary hemorrhage remained on mechanical ventilation and died with progressive respiratory failure and multisystem organ dysfunction. Of the remaining 5 who underwent bronchoscopy without associated hemorrhage, 3 had infectious etiologies; these included Aspergillus, parainfluenza 3, and respiratory syncytial virus. Only 2 of the 18 non-DAH patients with respiratory failure (11%) survived to hospital discharge, compared with 4 of 7 DAH patients.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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DAH and associated mortality have been extensively reported in adults after HCT. Robbins et al1 found 23 of 29 adult DAH patients (73%) died. Subsequent studies have noted DAH mortality of 0% to 77%.2,3,7 However recent studies in adults have shown improved outcomes in DAH patients treated with high-dose corticosteroids. Chao et al described 4 patients who developed DAH (after autologous BMT) diagnosed by BAL within 24 hours of onset of symptoms. These patients received methylprednisolone (1000 mg daily) for 3 days, followed by a 50% taper every 3 days to 60 mg/d, followed by a gradual taper and discontinuation over 2 months. Two of these patients developed respiratory failure and required mechanical ventilation, but all 4 survived to hospital discharge.2 In a retrospective review by Metcalf et al,3 63 patients with DAH after autologous or allogeneic HCT received supportive therapy alone (12 patients), low-dose corticosteroids (
30 mg methylprednisolone or its equivalent daily; 10 patients), or high-dose corticosteroids (> 30 mg daily; 43 patients). Survival to discharge was significantly increased in the high-dose steroid group compared with the other two groups combined (33% vs 9.1%; P = .038). Treatment with low-dose steroids did not increase survival over supportive therapy alone. Recent studies assessing the outcome of children requiring intubation and mechanical ventilation after HCT have revealed survival rates of 9% to 36%.10–14 Although respiratory failure-related mortality has been described in this pediatric population, the specific incidence and outcome of DAH has not been previously reported. Bojko et al10 identified DAH as a cause of respiratory failure in 2 autologous HCT recipients in their series of 43 pediatric HCT patients who developed acute hypoxemic respiratory failure. Thirty-eight of the 43 patients (88%) died in the pediatric intensive care unit. In a study by Todd et al,11 3 of 42 pediatric HCT patients with a parenchymal pulmonary process were identified as having pulmonary hemorrhage as the cause for their respiratory failure, and none survived to extubation. It is unclear whether these patients met the defined criteria for DAH. In our experience, the presence of DAH was not invariably fatal, and we would not recommend using the presence of DAH as an indication for discontinuing aggressive ventilatory support.
The exact cause of DAH remains uncertain. In agreement with previous reports,1,3,5,8,10 we noted a close association between the onset of DAH and WBC engraftment (Fig 4). Although we do not perform quantitative BAL cell counts, 2 studies have reported the presence of large numbers of neutrophils on cytocentrifuged preparations of BAL fluid in patients with DAH,1,3 even in the presence of low peripheral WBC counts. The improved survival in patients treated with high-dose steroids in our series and in that of Metcalf et al3 may in part reflect steroid-induced suppression of neutrophil-mediated lung injury, reduction in production of proinflammatory cytokines, or similar processes.
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The association between DAH and pulmonary infection remains controversial. Most studies describing DAH exclude patients with documented pulmonary infections, but it is possible that occult infection may be overlooked or underdiagnosed in some patients with DAH. The definition of DAH itself may require additional clarification. For example, in a study by Agusti et al4 11 adult HCT patients were diagnosed with DAH at autopsy. Six of these also had culture-positive lung infections but were still diagnosed with DAH because areas of infection were separate from regions of hemorrhage on microscopic examination. Of interest, 8 of these patients underwent bronchoscopy and BAL within 7 days before death; none had positive BAL cultures, and only 4 of the 8 had bloody BAL fluid, calling into question the accuracy of using BAL criteria for definition of DAH. Metcalf et al3 found a 40% incidence of subsequent infection in patients with DAH, but did not delineate the presence of pulmonary infection. In our review, 2 DAH patients had later evidence of pulmonary infection. One patient (described above) demonstrated fungal and bacterial pulmonary infection on autopsy. A second patient yielded a culture positive for Candida albicans on repeat BAL 19 days after the initial diagnosis of DAH.
Our review is limited by its retrospective nature and by the small numbers of affected patients. Although previous adult studies noted an increased incidence in DAH in autologous recipients,1–3,10 our study suggests a trend toward DAH in allogeneic HCT recipients. We were also unable to show any differences in outcome based on HCT preparative regimen or diagnosis leading to transplant. Preparative regimens, particularly radiation therapy, have been implicated in the etiology of DAH in previous studies.1,3,6
Four patients in our study received high-dose steroids as described by Chao et al,2 while 3 received lower dose steroids as previously described. The limited number of patients made comparisons between these groups difficult, and no conclusions regarding the appropriate use and dose of steroids can be made based on this data.
Although interpretation of the study results is limited in regard to risk factors and evaluation of therapy, strength of the study lies in the adherence to strict criteria for defining DAH and by the observation that patients can recover from this syndrome. Infectious etiologies were ruled out to the best of our ability in all patients included in data analyses. However, we believe that the relationship between pulmonary infection and DAH remains unclear. Many of our patients were already receiving antibiotics at the time of DAH, and, as indicated in previous studies,4,8 BAL may not accurately or adequately identify pulmonary infections.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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DAH appears to be more common after allogeneic HCT. Although associated with significant respiratory failure and need for mechanical ventilation, DAH is not uniformly fatal. The relationship between pulmonary infection and DAH remains uncertain, and infectious etiologies should be thoroughly investigated in all patients with pulmonary hemorrhage. High-dose corticosteroids may be useful in the treatment of DAH, but this therapeutic intervention in pediatric HCT patients needs to be evaluated in a prospective, randomized clinical trial.
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* Department of Pediatrics
Division of Critical Care,
Emory University School of Medicine
Atlanta, GA 30322
Department of Pediatrics
Division ofHematology/Oncology,
Emory University School of Medicine
Atlanta, GA 30322
Department of Pediatrics
Division of Pulmonary
Emory University School of Medicine
Atlanta, GA 30322
Division of Critical Care
Children’s Healthcare of Atlanta at Egleston
Atlanta, GA 30322
University of Pittsburgh Cancer Institute
Pittsburgh, PA 15213
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ACKNOWLEDGMENTS |
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We thank Carlos R. Abramowsky, MD, for provision of histologic specimens, and Mitchel Klein, PhD, for assistance with statistical analysis.
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FOOTNOTES |
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Received for publication Jul 19, 2001; Accepted Nov 21, 2001.
Reprint requests to (J.H.) Critical Care Division, Children’s Healthcare of Atlanta at Egleston, 1405 Clifton Rd NE, Atlanta, GA 30322. E-mail: judy_heggen{at}oz.ped.emory.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODS AND PATIENTSILLUSTRATIVE CASE REPORTSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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