Corticosteroid Therapy for Diffuse Alveolar Hemorrhage in Autologous Bone Marrow Transplant Recipients Nelson J. Chao, MD; Steven R. Duncan, MD; Gwynn D. Long, MD; Sandra J. Horning, MD; and Karl G. Blume, MD Annals of Internal Medicine. 1991;114:145-146.
Robbins and colleagues (1) recently reported a syndrome of diffuse alveolar hemorrhage seen in patients after autologous bone marrow transplantation. This entity was noted in 29 of 141 patients (21%) and was associated with an 80% mortality rate (23 of the 29 patients died). Risk factors associated with the development of this syndrome included age over 40 years, underlying solid tumors, high fevers, severe mucositis, leukocyte recovery, and renal insufficiency. The Memorial Sloan-Kettering group (2) also recently reported their experience with pulmonary complications after autologous bone marrow transplantation. Pulmonary hemorrhage was seen 11 of 31 patients (35%) receiving transplants for lymphoma, with a mortality rate of 100% (2). Case Reports Between December 1987 and March 1990, 77 patients received autologous bone marrow transplants for lymphoma at Stanford University Medical Center. Four patients (five percent) developed diffuse alveolar hemFrom the Stanford University Medical Center, Stanford, California. For current author addresses, see end of text.
orrhage, defined by the association of progressive dyspnea, hypoxia, cough, and diffuse consolidation on chest roentgenogram. Bronchoalveolar lavage fluid became progressively bloodier with each aliquot, as described by Robbins and colleagues (1). Stains and cultures revealed no bacterial, fungal, or viral pathogens. The clinical characteristics of these 4 patients are outlined in Table 1. All 4 patients were diagnosed within 24 hours of the onset of symptoms by bronchoscopy and were given high-dose methylprednisolone therapy consisting of 1 g/d intravenously for 3 days. The dose was then reduced to 500 mg/d for 3 days. The dose was then further reduced by 50%, to 250 mg/d for 3 days. In this manner, it was reduced to 60 mg/d. Therapy with prednisone, at an equivalent dose, was then started and tapered gradually over 2 months. All patients received prophylactic trimethoprim-sulfamethoxazole and ketoconazole. Two of the four patients developed respiratory failure and required ventilatory support for 3 and 7 days, respectively. All four patients were discharged from the hospital to home. No patient developed infectious complications secondary to the high-dose corticosteroid therapy. Three patients are alive and free of disease from 3 to 17 months after bone marrow transplantation. These three patients are asymptomatic and without residual pulmonary abnormalities on chest roentgenogram. The fourth patient developed autologous graft failure and received an allogeneic graft from his HLA-identical sibling 54 days after autologous bone marrow transplantation, but died from graft-versus-host disease. Discussion The incidence of diffuse alveolar hemorrhage among our patients (5%) was much lower than that reported by
Table 1. Clinical Information on Four Patients Who Developed Diffuse Alveolar Hemorrhage and Were Successfully Treated with High-Dose Steroid Therapy* SPN Age Diagnosis Stage
Previous Treatment
Status before BMT
BMT Regimen
CreaPlatelet ProDay Maximum Leukocyte tinine Count thrombin of TemperaCount Clearance Time Onset turet
y 9 57
112 167
28 Hodgkin disease
IV-A MOPP/ABVD; Resistant XRT; CCNU third relapse 34 Hodgkin II-B MOPP; vinblas- Resistant disease tine; MOPP/ third ABVD; XRT; relapse ABV/prednisone; CCNU/VP-16 42 Diffuse, IV-A CHOP/VP-16; Primary mixed XRT therapy lymphoma failure 50 Diffuse, IV-A XRT; CHOP; small, CEPP; DHAP Sensitive third cleavedrelapse cell lymphoma
°C
x ltflixL
mgldL x ltf/pL
s
FTBI/VP-16/CY
20
37.8
0.4
1.4
26
12.4
BCNU/VP-16/CY
15
38
1.2
1.1
37
12.5
FTBI/VP-16/CY
14
38.5
4.3
1.5
35
11.4
FTBI/VP-16/CY
17
37.8
1.8
1.5
55
12.0
* SPN = Stanford patient number; BMT = bone marrow transplantation; XRT = radiation therapy; FTBI/VP-16/CY = fractionated total body irradiation (1200 cGy), etoposide (60 mg/kg body weight), cyclophosphamide (100 mg/kg); BCNU/VP-16/CY = carmustine (15 mg/kg), etoposide (60 mg/kg), cyclophosphamide (100 mg/kg); MOPP = mechlorethamine, vincristine, procarbazine, prednisone; ABVD = doxorubicin, bleomycin, vinblastine, decarbazine; CCNU = lomustine; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CEPP* = cyclophosphamide, etoposide, procarbazine, prednisone; DHAP = dexamethasone, cytosine arabinoside, cisplatin. t Over the past 24 hours. 15 January 1991 • Annals of Internal Medicine
• Volume 114 • Number 2
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145
Robbins and colleagues (21%) (1). Bone marrow transplantation for solid tumors was a significant risk factor for the development of diffuse alveolar hemorrhage in Robbins and coworkers' series (1); our study, however, included only patients receiving transplants for lymphoma. Most of our other patients are thrombocytopenic and febrile during the period when patients are at risk for the development of diffuse alveolar hemorrhage. In this small group of patients, there was no apparent association between the development of this entity and engraftment of leukocytes, platelet count, renal insufficiency, or coagulopathy (Table 1). A drop in hemoglobin level was not noted in conjunction with the development of diffuse alveolar hemorrhage in our patients and was not reported by Robbins and colleagues (1) as an associated clinical event. We cannot comment on the influence of radiation in the preparative regimen on the incidence of diffuse alveolar hemorrhage, because too few patients in our study were affected. Diffuse alveolar hemorrhage, a nonspecific syndrome, can result from various injuries or insults, such as lymphangiogram dye, penicillamine, toluene disocyanide, phenytoin, and many vasculitides, perhaps suggesting a common pathogenesis of endothelial injury (3). Severe pulmonary hemorrhage may also be associated with invasive fungal disease and bacterial pneumonitis in immunocompromised patients (4). Neutrophils can cause pulmonary injury, and neutrophil influx may play a role in diffuse alveolar hemorrhage in some patients (1). The use of dimethyl sulfoxide in the cryopreservation of bone marrow is a possible cause of diffuse alveolar hemorrhage that is unique to recipients of autologous bone marrow transplants. Dimethyl sulfoxide is known to cause acute shortness of breath when bone marrow is being re-infused (Chao NJ. Unpublished observation). The concomitant use of specific high-dose agents in the preparative regimen and dimethyl sulfoxide can possibly damage the alveolar endothelial lining and cause or
146
15 January 1991 • Annals of Internal Medicine
predispose patients to the development of diffuse alveolar hemorrhage. Unfortunately, under the clinical circumstances of diffuse alveolar hemorrhage, biopsy and histopathologic examination of the affected lung usually is not possible. Our experience suggests that recovery from diffuse alveolar hemorrhage after autologous bone marrow transplantation may been enhanced by prompt diagnosis and therapy with high doses of corticosteroids. Diffuse alveolar hemorrhage, however, can result from some infectious causes in immunocompromised patients (4); infection should be ruled out before instituting therapy with corticosteroids in this setting. Acknowledgments: The authors thank the Stanford medical housestafif and hematology and oncology fellows and the staff of the Compromised Host Unit for patient care. Grant Support: By grant CA 49605 from the National Institutes of Health. Requests for Reprints: Nelson J. Chao, MD, Bone Marrow Transplantation Program, H-1353, Stanford University Medical Center, Stanford, CA 94305. Current Author Addresses: Drs. Chao and Blume: Bone Marrow Transplantation Program, H-1353, Stanford University Medical Center, Stanford, CA 94305. Drs. Long and Horning: Division of Medical Oncology, M-211, Stanford University Medical Center, Stanford, CA 94305. Dr. Duncan: Pulmonary and Critical Care Medicine, University of Pittsburgh, 440 Scaife Hall, Pittsburgh, PA 15261. References 1. Robbins RA, Under J, Stahl MG, et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med. 1989; 87:511-8. 2. Jules-Elysee K, Gulati S, Stover DE, White DA. Pulmonary complications in autologous bone marrow transplantation [Abstract]. Am Rev Respir Dis. 1990;141:A604. 3. Leatherman JW, Davies SF, Hoidal JR. Alveolar hemorrhage syndromes: diffuse microvascular lung hemorrhage in immune and idiopathic disorders. Medicine. 1984;63:343-61. 4. Kahn FW, Jones JM, England DM. Diagnosis of pulmonary hemorrhage in the immunocompromised host. Am Rev Respir Dis. 1987; 136:155-60. © 1991 American College of Physicians
• Volume 114 • Number 2
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/19720/ by a Duke Medical Library User on 07/19/2017
Robbins and colleagues (1) recently reported a syndrome of diffuse alveolar hemorrhage seen in patients after autologous bone marrow transplantation. This entity was noted in 29 of 141 patients (21%) and was associated with an 80% mortality rate (23 of the 29 patients died). Risk factors associated with the development of this syndrome included age over 40 years, underlying solid tumors, high fevers, severe mucositis, leukocyte recovery, and renal insufficiency. The Memorial Sloan-Kettering group (2) also recently reported their experience with pulmonary complications after autologous bone marrow transplantation. Pulmonary hemorrhage was seen 11 of 31 patients (35%) receiving transplants for lymphoma, with a mortality rate of 100% (2). Case Reports Between December 1987 and March 1990, 77 patients received autologous bone marrow transplants for lymphoma at Stanford University Medical Center. Four patients (five percent) developed diffuse alveolar hemFrom the Stanford University Medical Center, Stanford, California. For current author addresses, see end of text.
orrhage, defined by the association of progressive dyspnea, hypoxia, cough, and diffuse consolidation on chest roentgenogram. Bronchoalveolar lavage fluid became progressively bloodier with each aliquot, as described by Robbins and colleagues (1). Stains and cultures revealed no bacterial, fungal, or viral pathogens. The clinical characteristics of these 4 patients are outlined in Table 1. All 4 patients were diagnosed within 24 hours of the onset of symptoms by bronchoscopy and were given high-dose methylprednisolone therapy consisting of 1 g/d intravenously for 3 days. The dose was then reduced to 500 mg/d for 3 days. The dose was then further reduced by 50%, to 250 mg/d for 3 days. In this manner, it was reduced to 60 mg/d. Therapy with prednisone, at an equivalent dose, was then started and tapered gradually over 2 months. All patients received prophylactic trimethoprim-sulfamethoxazole and ketoconazole. Two of the four patients developed respiratory failure and required ventilatory support for 3 and 7 days, respectively. All four patients were discharged from the hospital to home. No patient developed infectious complications secondary to the high-dose corticosteroid therapy. Three patients are alive and free of disease from 3 to 17 months after bone marrow transplantation. These three patients are asymptomatic and without residual pulmonary abnormalities on chest roentgenogram. The fourth patient developed autologous graft failure and received an allogeneic graft from his HLA-identical sibling 54 days after autologous bone marrow transplantation, but died from graft-versus-host disease. Discussion The incidence of diffuse alveolar hemorrhage among our patients (5%) was much lower than that reported by
Table 1. Clinical Information on Four Patients Who Developed Diffuse Alveolar Hemorrhage and Were Successfully Treated with High-Dose Steroid Therapy* SPN Age Diagnosis Stage
Previous Treatment
Status before BMT
BMT Regimen
CreaPlatelet ProDay Maximum Leukocyte tinine Count thrombin of TemperaCount Clearance Time Onset turet
y 9 57
112 167
28 Hodgkin disease
IV-A MOPP/ABVD; Resistant XRT; CCNU third relapse 34 Hodgkin II-B MOPP; vinblas- Resistant disease tine; MOPP/ third ABVD; XRT; relapse ABV/prednisone; CCNU/VP-16 42 Diffuse, IV-A CHOP/VP-16; Primary mixed XRT therapy lymphoma failure 50 Diffuse, IV-A XRT; CHOP; small, CEPP; DHAP Sensitive third cleavedrelapse cell lymphoma
°C
x ltflixL
mgldL x ltf/pL
s
FTBI/VP-16/CY
20
37.8
0.4
1.4
26
12.4
BCNU/VP-16/CY
15
38
1.2
1.1
37
12.5
FTBI/VP-16/CY
14
38.5
4.3
1.5
35
11.4
FTBI/VP-16/CY
17
37.8
1.8
1.5
55
12.0
* SPN = Stanford patient number; BMT = bone marrow transplantation; XRT = radiation therapy; FTBI/VP-16/CY = fractionated total body irradiation (1200 cGy), etoposide (60 mg/kg body weight), cyclophosphamide (100 mg/kg); BCNU/VP-16/CY = carmustine (15 mg/kg), etoposide (60 mg/kg), cyclophosphamide (100 mg/kg); MOPP = mechlorethamine, vincristine, procarbazine, prednisone; ABVD = doxorubicin, bleomycin, vinblastine, decarbazine; CCNU = lomustine; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CEPP* = cyclophosphamide, etoposide, procarbazine, prednisone; DHAP = dexamethasone, cytosine arabinoside, cisplatin. t Over the past 24 hours. 15 January 1991 • Annals of Internal Medicine
• Volume 114 • Number 2
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145
Robbins and colleagues (21%) (1). Bone marrow transplantation for solid tumors was a significant risk factor for the development of diffuse alveolar hemorrhage in Robbins and coworkers' series (1); our study, however, included only patients receiving transplants for lymphoma. Most of our other patients are thrombocytopenic and febrile during the period when patients are at risk for the development of diffuse alveolar hemorrhage. In this small group of patients, there was no apparent association between the development of this entity and engraftment of leukocytes, platelet count, renal insufficiency, or coagulopathy (Table 1). A drop in hemoglobin level was not noted in conjunction with the development of diffuse alveolar hemorrhage in our patients and was not reported by Robbins and colleagues (1) as an associated clinical event. We cannot comment on the influence of radiation in the preparative regimen on the incidence of diffuse alveolar hemorrhage, because too few patients in our study were affected. Diffuse alveolar hemorrhage, a nonspecific syndrome, can result from various injuries or insults, such as lymphangiogram dye, penicillamine, toluene disocyanide, phenytoin, and many vasculitides, perhaps suggesting a common pathogenesis of endothelial injury (3). Severe pulmonary hemorrhage may also be associated with invasive fungal disease and bacterial pneumonitis in immunocompromised patients (4). Neutrophils can cause pulmonary injury, and neutrophil influx may play a role in diffuse alveolar hemorrhage in some patients (1). The use of dimethyl sulfoxide in the cryopreservation of bone marrow is a possible cause of diffuse alveolar hemorrhage that is unique to recipients of autologous bone marrow transplants. Dimethyl sulfoxide is known to cause acute shortness of breath when bone marrow is being re-infused (Chao NJ. Unpublished observation). The concomitant use of specific high-dose agents in the preparative regimen and dimethyl sulfoxide can possibly damage the alveolar endothelial lining and cause or
146
15 January 1991 • Annals of Internal Medicine
predispose patients to the development of diffuse alveolar hemorrhage. Unfortunately, under the clinical circumstances of diffuse alveolar hemorrhage, biopsy and histopathologic examination of the affected lung usually is not possible. Our experience suggests that recovery from diffuse alveolar hemorrhage after autologous bone marrow transplantation may been enhanced by prompt diagnosis and therapy with high doses of corticosteroids. Diffuse alveolar hemorrhage, however, can result from some infectious causes in immunocompromised patients (4); infection should be ruled out before instituting therapy with corticosteroids in this setting. Acknowledgments: The authors thank the Stanford medical housestafif and hematology and oncology fellows and the staff of the Compromised Host Unit for patient care. Grant Support: By grant CA 49605 from the National Institutes of Health. Requests for Reprints: Nelson J. Chao, MD, Bone Marrow Transplantation Program, H-1353, Stanford University Medical Center, Stanford, CA 94305. Current Author Addresses: Drs. Chao and Blume: Bone Marrow Transplantation Program, H-1353, Stanford University Medical Center, Stanford, CA 94305. Drs. Long and Horning: Division of Medical Oncology, M-211, Stanford University Medical Center, Stanford, CA 94305. Dr. Duncan: Pulmonary and Critical Care Medicine, University of Pittsburgh, 440 Scaife Hall, Pittsburgh, PA 15261. References 1. Robbins RA, Under J, Stahl MG, et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med. 1989; 87:511-8. 2. Jules-Elysee K, Gulati S, Stover DE, White DA. Pulmonary complications in autologous bone marrow transplantation [Abstract]. Am Rev Respir Dis. 1990;141:A604. 3. Leatherman JW, Davies SF, Hoidal JR. Alveolar hemorrhage syndromes: diffuse microvascular lung hemorrhage in immune and idiopathic disorders. Medicine. 1984;63:343-61. 4. Kahn FW, Jones JM, England DM. Diagnosis of pulmonary hemorrhage in the immunocompromised host. Am Rev Respir Dis. 1987; 136:155-60. © 1991 American College of Physicians
• Volume 114 • Number 2
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/19720/ by a Duke Medical Library User on 07/19/2017
