Context.-Bone marrow transplantation (BMT) is used to treat various malignant and nonmalignant disorders. Pulmonary complications are some of the most common causes of mortality in BMT recipients. Poor general health and bleeding tendency frequently preclude the use of definitive diagnostic tests, such as open lung biopsy, in these patients.
Objective.-To identify pulmonary complications after BMT and their role as the cause of death (COD).
Design.-The autopsy and bronchoalveolar lavage (BAL) slides and microbiology studies of BMT recipients from a 7-year period were reviewed.
Results.-Pulmonary complications were identified in 40 (80%) of the 50 cases. The most common complications were diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage (DAH). Pulmonary complications were the sole or 1 of multiple CODs in 37 cases (74%). All complications were more common in allogeneic BMT recipients. In 19 (51%) of the 37 cases in which pulmonary complications contributed to the death, cultures were negative. Both DAD and DAH, complications commonly reported in the early post-BMT period, were seen more than 100 days after BMT in 33% and 12% of cases, respectively. Five (83%) of 6 cases of invasive pulmonary aspergillosis diagnosed at autopsy were negative for fungi ante mortem (by BAL and cultures).
Conclusions.-Pulmonary complications are a significant COD in BMT recipients, many of which, especially the fungal infections, are difficult to diagnose ante mortem. The etiology of DAD and DAH is likely to be multifactorial, and these complications are not limited to the early posttransplantation period. Autopsy examination is important in determining the COD in BMT recipients.
(Arch Pathol Lab Med. 2005;129:366-371)
Bone marrow transplantation (BMT) has been used with increasing frequency to treat malignant and nonmalignant hematologie disorders and metabolic and genetic diseases. Infectious and noninfectious pulmonary complications are reported in 307% to 60% of all BMT recipients and result in a high morbidity and mortality.'"11 Multiple factors contribute to the development of pulmonary complications, including immunologie defects secondary to the underlying disease and its treatment, conditioning regimens, development of graft-vs-host disease (GVHD), and the type of transplantation. Many BMT recipients are affected by more than one condition that involves multiple organ systems, which may obscure the contribution of pulmonary complications as a cause of morbidity and mortality. In addition, a significant number of these patients have poor general health and have significant thrombocytopenia, precluding the use of some of the diagnostic tests, such as open lung biopsy and sometimes even bronchoalveolar lavage (BAL), to accurately identify the underlying pulmonary disease.4"7 The aim of this study was to identify the autopsy-documented pulmonary complications after BMT and their role as the cause of death (COD).
MATERIALS AND METHODS
The autopsy files of the University of Minnesota were searched for complete autopsies performed on BMT recipients between January 1, 1996, and December 31, 2002. The autopsy slides and the slides from BAL procedures performed within 2 weeks of death were reviewed. The autopsy protocol at the University of Minnesota Hospitals requires at least one section from each lobe of the lungs with additional sections taken from grossly abnormal areas. Papanicolaou-stained slides for cytomegalovirus (CMV) detection and Gomori methenamine silver-stained slides for fungal detection were available for review in all BAL specimens. The primary diagnosis, transplantation type, and followup information were obtained from electronic reports and medical record reviews. All microbiology results within 1 week of death and the microbiology studies performed on autopsy tissues and/or blood were also reviewed and correlated to the histologie and cytologie findings. The BAL, sputum, and antemortem and postmortem lung tissue cultures were considered lung cultures. All pathogens (bacteria, viral, and fungal) are included. Diffuse alveolar hemorrhage was defined as the presence of intra-alveolar hemorrhage in more than 30% of the pulmonary tissue/ Diffuse alveolar damage was defined as hyaline membrane formation (exudative phase) or extensive proliferation of fibroblasts and type 2 pneumocytes (proliferative or organizing phase).
The autopsy slides from 50 BMT recipients (25 male recipients and 25 female recipients) who had complete autopsies were available for review. The mean patient age was 31 years (range, 6 months to 68 years). Nineteen patients (38%) were younger than 18 years. Seven patients had undergone autologous and 43 patients had undergone allogeneic BMT. None of the patients had undergone nonmyeloablative BMT. The primary disorder was malignant in 32 patients (64%) (3 chronic myeloid leukemia, 3 chronic lymphocytic leukemia, 6 acute myeloid leukemia, 2 acute lymphoblastic leukemia, 6 myelodysplastic syndrome, 2 multiple myeloma, 9 non-Hodgkin lymphoma, and 1 metastatic breast carcinoma) and nonmalignant in 18 patients (36%) (7 Fanconi anemia, 5 Hurler syndrome, 1 aplastic anemia, 1 Wolman disease, 1 Gaucher disease, 1 Canavan disease, 1 hemophagocytic syndrome, and 1 Sjögren syndrome). The average time from transplantation to death was 158 days (range, 6-1217 days). Twenty-four (48%) of 50 deaths occurred more than 100 days after BMT.
Pulmonary complications were found in 40 (80%) of 50 cases, 19 of which had more than one pulmonary finding. Pulmonary complications that were observed were classified as follows: diffuse alveolar damage (DAD) in 18 cases (36%) (Figure 1, A through C), diffuse alveolar hemorrhage (DAH) in 12 cases (24%) (Figure 2), pulmonary edema in 6 cases (12%), invasive pulmonary aspergillosis in 6 cases (12%) (Figure 3, A through C), bronchopneumonia in 6 cases (12%), focal hemorrhage in 7 cases (14%), pulmonary hypertension in 5 cases (10%), thromboemboli in 2 cases (4%), posttransplantation lymphoproliferative disorder (PTLD) in 2 cases (4%), and bronchiolitis obliterans with organizing pneumonia (BOOP), pulmonary cytolytic thrombi (Figure 4), and emphysema each in 1 case (2%) (Table 1). Nineteen (100%) of 19 pediatrie patients and 24 (77%) of 31 adult patients had allogeneic BMT. All of the pulmonary complications showed a higher incidence in allogeneic BMT recipients. A higher incidence of DAH (8/19, 42'Xo) was revealed in the pediatrie age group compared with adults (4/31, 13%). All other complications were more common in adult patients. Six (33%) of 18 DAD cases and 5 (42%) of 12 DAH cases occurred in patients who survived more than 100 days after BMT. Pulmonary complications were the only cause of death in 32 cases (64%) and were 1 of multiple causes of death in 5 patients (10%). All cases of DAD, DAH, pulmonary edema, invasive pulmonary aspergillosis, and bronchopneumonia were the only COD or 1 of multiple contributing factors. Seven of 18 DAD cases also showed DAH. Four of 7 focal hemorrhage cases had nonpulmonary complications as the only cause of death (massive gastrointestinal bleeding, herpes simplex virus hepatitis, intracranial hemorrhage, and residual or recurrent leukemia). The remaining 3 cases of focal hemorrhage were associated with DAD (2 cases) and bronchopneumonia (1 case). In this latter group, the significance, if any, of focal hemorrhage as the COD could not be determined. Pulmonary hypertension was seen in 5 cases. The etiology of pulmonary hypertension could not be determined, although 1 of those cases also had thromboemboli. There was no cases with venoocclusive disease of the lungs. Two patients had pulmonary emboli, one of whom died of massive embolism and the other of nonpulmonary complications (severe gastrointestinal bleeding and GVHD). Two patients had PTLD that involved the lungs: one was treated and the tumor was necrotic; the other case was an incidental finding at autopsy. The former died of nonpulmonary complications, whereas the latter had DAH. One case with BOOP also had DAH as the COD. Pulmonary cytolytic thrombi (PCTs) were found in one case as an incidental finding because the patient died of congestive heart failure. A patient with emphysema died of hepatic veno-occlusive disease, and emphysema was not considered to be a contributor to the patient's demise. Pulmonary edema was present in 6 patients, 2 of whom also had DAH and DAD, respectively.
Other, nonpulmonary complications that led to death included the following (some patients had more than 1 complication): gastrointestinal bleeding (3 patients), multiorgan failure secondary to tumor involvement (3 patients), GVHD (2 patients), intracranial hemorrhage (2 patients), myocardial infarction (1 patient), sepsis (1 patient), thrombotic thrombocytopenic purpura (1 patient), capillary leak syndrome (1 patient), congestive heart failure secondary to coronary artery disease (1 patient), multiorgan hemorrhage secondary to thrombocytopenia (1 patient), veno-occlusive disease of the liver (2 patients), herpes simplex virus hepatitis (1 patient), and autoimmune hemolytic anemia (1 patient).
Of the 37 cases in which pulmonary complications were the only or 1 of multiple CODs, 18 had positive cultures within the last week of life or from lung and/or blood obtained at the time of autopsy (lung and blood cultures positive in 3 cases, lung cultures positive in 11 cases, and blood cultures positive in 4 cases). The remaining 19 (51%) of the 37 cases had no documented pathogens from lungs or blood. Microbiology culture results obtained within 1 week of death and, in some patients, culture results from the tissue or blood obtained at autopsy and common pulmonary complications diagnosed at autopsy are given in Tables 2 through 4. Only 2 of 6 bronchopneumonia cases had pathogens cultured within 1 week of death (both bacterial and both from the lungs).
Twenty-three patients had a BAL performed within 2 weeks of death, all of which produced negative results for viral inclusions. One BAL result was positive for Aspergillus identified on Gomori methenamine silver-stained slides. This patient was treated and did not have any evidence of fungal infection at autopsy. Five of the 6 patients who had Aspergillus infections of the lungs diagnosed at autopsy had no evidence of fungal organisms in the BAL performed within 2 weeks of death. Only 3 of 6 patients with Aspergillus infections documented at autopsy had prior positive cultures from the lung, all of which were positive for bacteria and none for fungal organisms. The 3 patients whose BAL cytologie specimens showed atypical cells had diffuse alveolar damage diagnosed at autopsy. Information on the color of the BAL specimen was available in 14 cases. All 6 BAL specimens from DAH cases were grossly red; however, only 6 of the 14 BAL specimens that were grossly red were from DAH cases.
Pulmonary complications were the most common cause of mortality in BMT recipients in this study, representing the only proximate COD in 64% or 1 of multiple CODs in an additional 10% of cases. The BMT recipients have significant immunosuppression due to the underlying disorder and the conditioning therapy (chemotherapy and total body irradiation) that they are subjected to before the transplantation, resulting in impaired cell-mediated and humoral immune function abnormalities for 6 to 12 months.1* Nearly all of the immunologie system is impaired during the first 4 to 5 months after a BMT, with polymorphonuclear leukocytes recovering in 2 to 4 weeks and the lymphocyte count not returning to normal values for months, resulting in serious life-threatening infections of the lungs and other organ systems.9,10
In 51% of the cases in which pulmonary complications were the only or 1 of multiple CODs, blood and lung cultures were negative during the last week of life, suggesting noninfectious pulmonary complications as a significant contributor to the demise of these patients. Immediate noninfectious pulmonary complications occur within the first few weeks after BMT and are thought to be secondary to the cytoreductive therapy (chemotherapy and radiation). Fourteen (74%) of the 19 patients who died of pulmonary complications and had negative blood and lung cultures died more than 3 weeks after the BMT. The relatively large proportion of patients who died more than 3 weeks after the BMT without positive cultures may indicate either nondocumented pathogens or noncytoreductive therapy-related complications such as GVHD. Thirty-three percent of the DAD and 42% of the DAH cases, which are more commonly reported in the early post-BMT period, died more than 100 days after the BMT.
The most common pulmonary complication that we identified in this autopsy series was DAD, which was present in 36% of cases. Other studies have also found DAD to be the most common fatal lung complication in BMT recipients.11,12 The DAD is a final common pathway for various types of acute lung injury, such as infections, drugs, or radiation therapy. The DAD commonly does not have an identifiable infectious etiology in BMT recipients.11,13 In the present series, half (9/18) of the DAD cases had negative antemortem and postmortem cultures, suggesting some form of noninfectious injury as the underlying etiology.
First described in autologous BMT recipients, DAH is a clinical syndrome characterized by an acute onset of alveolar infiltrates, bloody BAL, and hypoxemia in the absence of infection.8 The clinical and radiologie features of DAH are nonspecific. Although pulmonary infections may also cause hemorrhage, the term DAH is reserved for BMT recipients without documented infectious etiology. Commonly, DAH occurs within 2 or 3 weeks of BMT (range, 1-8 weeks) when most patients are still neutropenic.14,15 Diffuse alveolar hemorrhage is associated with a mortality that exceeds 70%, although higher survival rates have been reported in some series.8,14 Initially described in autologous BMT recipients, DAH was later found to be more common in allogeneic BMT recipients with a higher mortality rate, especially in the pediatric age group.16,17 In our study, all DAH cases occurred in allogeneic BMT recipients. The incidence of DAH was higher in pediatric compared with adult cases (42% vs 13%). This may be, in part, explained by the fact that all pediatrie patients were allogeneic BMT recipients in this series. Although DAH is a clinical entity, the diagnosis of which is based on clinical, bronchoscopy, and radiologie findings, we used this term to describe the pathology of cases in which blood was present in at least 30% of the alveolar surfaces of the lung tissue.16,18,19 We identified DAH in 24% of all BMT recipients who had an autopsy in our institution during the study period. A total of 58% of DAH cases had positive cultures before death, raising the possibility that infection may be the underlying cause or contribute to the etiology of DAH, whereas the remaining cases (42%) had negative lung cultures within 1 week of death. The exact cause of DAH in not clear and is likely multifactorial. Some authors believe DAH is secondary to cytoreductive therapy, whereas others claim that the influx of neutrophils into the lung is the underlying pathogenesis, since the onset of DAH frequently coincides with the onset of bone marrow engraftment (1-3 weeks).9,20 However, 3 (60%) of 5 culture-negative DAH cases were seen after 3 weeks of the BMT. The latter finding is consistent with the high proportion (42%) of late-onset DAH found in other series.8 One possible underlying cause of noninfectious and late-onset DAH is acute GHVD.16,21 However, causes other than GVHD are likely, since DAH is commonly associated with autologous BMT, whereas GVHD is rare in these patients.8,15 Similar to DAH, DAD shows intra-alveolar hemorrhage. Coexistence of DAH and DAD in 7 cases raises the possibility that a subset of DAH actually represents DAD with extensive intra-alveolar hemorrhage. On the other hand, this may indicate that the same etiologic agent may cause 2 histologie patterns of injury. As defined in this study, DAH (blood in more than 30% of the alveolar surface) may not be completely superimposable to the clinically diagnosed DAH. The presence of bloody (grossly red colored) BAL specimens received in all of DAH patients who had BAL performed, however, suggests a significant overlap between "clinical" and "pathologic" DAH. Further studies are needed to correlate the pathologically diagnosed DAH to the clinically diagnosed DAH.
Focal hemorrhage, defined as involving less than 30% of the lungs, was seen in 7 cases, most of which involved less than 10% of the tissue. Four of these patients died of nonpulmonary complications. In these patients, focal hemorrhage might be a terminal event related to cardiopulmonary resuscitation efforts. It is unlikely that focal hemorrhage cases are early phases of DAH, although this possibility cannot be entirely ruled out. In 2 cases, focal hemorrhage was associated and may be a part of DAD.
Two patients had secondary malignancy, both of which were PTLD. The cumulative incidence of PTLD after BMT at 10 years is between 0% and 1%, and most post-BMT PTLD develops within 6 months of transplantation.22-24 In our series, one case was diagnosed ante mortem, and this patient was being treated at the time of death. This case had multiple, small nonviable tumor nodules in the lungs. The other case was diagnosed at autopsy and involved the lungs focally.
A recently described complication of BMT, PCTs were seen in one patient who died of congestive heart failure. The PCTs are exclusively seen in pediatric allogeneic BMT recipients at the time of GVHD in other organ systems, suggesting an acute GVHD of the lungs in which the endothelial cells are the target.25,26 Usually, PCTs present as pulmonary nodules and spontaneously resolve, although rare fatal cases have been reported.27 One case of PCT in this series was diagnosed post mortem in a 1-year-old patient with Hurler disease that had allogeneic BMT.
Nonbacterial pathogens such as Aspergillus and CMV are difficult to identify ante mortem and are frequently only diagnosed at postmortem examination. In one study, 67% of Aspergillus and 65% of CMV infections were not diagnosed ante mortem.13 In another study, Aspergillus infection was missed with BAL and open lung biopsy in 40% of the patients with this complication.28-30 The diagnostic sensitivity of BAL is reported to be 30% to 50% in BMT recipients.31 Similarly in our study, none of the BAL specimens from patients with pulmonary Aspergillus infection documented at autopsy had morphologic evidence of fungal infection or positive antemortem cultures. This is a significant finding, especially since fungal infections are a common cause of morbidity and mortality in BMT recipients.12 An unexpected finding was the presence of bacterial pathogens in only 2 of 6 bronchopneumonia cases. However, these patients are frequently under broadspectrum antibiotic coverage, especially when they present with possible signs of infection.
Acute GVHD after BMT is common, seen in 40% to 70% of the BMT recipients and mostly involving the skin, liver, and gastrointestinal tract.33-35 Lymphocytic bronchitis and obliterative bronchiolitis, histopathologic correlates for acute and chronic GVHD of the lungs, respectively, are reported in 2% to 15% of allogeneic BMT recipients, with a mortality rate of 50%.36 We did not find GVHD that involved the lungs in any of our cases. This may be in part due to the relatively short interval between BMT and death in our cases and the relatively low number of long-term survivors in whom obliterative bronchiolitis could develop.
With the increasing number of long-term survivors after BMT, long-term complications, including secondary malignancies, are becoming a concern.3,37 Twenty-four (46%) of the 50 patients in the current series survived longer than 3 months after the BMT putting them at risk for late-onset noninfectious complications. The spectrum of late-onset, noninfectious pulmonary complications is rather poorly defined and includes, according to some authors, bronchiolitis obliterans, BOOP, DAD, lymphocytic interstitial pneumonia, and nonclassifiable interstitial pneumonia, whereas others include only bronchiolitis obliterans, BOOP, and idiopathic pneumonia syndrome.2,36,38 Recently, these complications have been collectively referred to as late-onset pulmonary syndrome.3 The rates of significant late-onset noninfectious pulmonary complications that involve the lungs are reported to be 10% to 40% in patients with BMT.36,39,40 However, most of these studies included adult patients, and results are conflicting because of range selection and evaluation criteria. Only one case in our series had a late-onset noninfectious pulmonary complication, namely BOOP. This low rate may be due to inclusion of pediatrie patients in this study or to selection bias in the autopsy requests where patients with acute or infectious complications not diagnosed before death are overrepresented.
There is an inherent bias in autopsy and retrospective studies. However, in BMT recipients, the use of transbronchial and open lung biopsy is limited, and many times the diagnosis and confirmation of pulmonary disease are only done at the time of autopsy, making the few autopsy studies reported in the literature a valuable resource. Future prospective studies may overcome some of these drawbacks.
In conclusion, pulmonary complications are a significant COD in BMT recipients. Currently, many of these complications, especially the fungal infections, are difficult to diagnose ante mortem, and autopsy examination is helpful in accurately establishing the COD in these patients. The etiology of both DAD and DAH is multifactorial, and in many of our cases there was no evidence of an infectious etiology. These complications are not limited to certain periods after the BMT and should be included in the differential diagnosis of late-onset pulmonary complications.
We thank Kathy Olson, BA, Laboratory Information Systems Specialist, for providing the microbiology results for the patients.
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Monika Roychowdhury, MD; Stefan E. Pambuccian, MD; Deniz L. Asian, MD; Jose jessurun, MD; Alan C. Rose, MD; J. Carlos Manivel, MD; H. Evin Gulbahce, MD
Accepted for publication November 2, 2004.
From the University of Minnesota Medical School, Fairview-University Medical Center, Minneapolis.
Presented in part at the annual meeting of the United States and Canadian Academy of Pathology, Vancouver, British Columbia, March 6-12,2004.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: H. Evin Gulbahce, MD, Division of Surgical Pathology, Mayo Building C422, MMC 76, 420 Delaware St SE, Minneapolis, MN 55455 (e-mail: firstname.lastname@example.org).
Copyright College of American Pathologists Mar 2005
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