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(Chest. 2005;128:153-161.)
© 2005 American College of Chest Physicians

Risk Factors for Bronchiolitis Obliterans in Allogeneic Hematopoietic Stem-Cell Transplantation for Leukemia*

Linus H. Santo Tomas, MD, MS; Fausto R. Loberiza, Jr, MD, MS; John P. Klein, PhD; Peter M. Layde, MD, MS; Randolph J. Lipchik, MD; J. Douglas Rizzo, MD; Christopher N. Bredeson, MD, MS and Mary M. Horowitz, MD, MS

* From the Division of Pulmonary and Critical Care Medicine (Drs. Santo Tomas and Lipchik), Department of Medicine; Division of Epidemiology (Dr. Layde), Health Policy Institute; and International Bone Marrow Transplant Registry (Drs. Loberiza, Klein, Rizzo, Bredeson, and Horowitz), Medical College of Wisconsin, Milwaukee, WI.

Correspondence to: Linus H. Santo Tomas, MD, MS, Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 9200 West Wisconsin Ave, Milwaukee, WI 53226; e-mail: santo{at}mcw.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Reported risk factors for bronchiolitis obliterans (BO) in allogeneic hematopoietic stem-cell transplant recipients come from modest-sized studies and are limited to experiences of single institutions. We sought to identify risk factors for BO using data from the International Bone Marrow Transplant Registry.

Methods: Registry data on 6,275 adult patients with leukemia who received human leukocyte antigen-identical sibling transplants from 1989 to 1997 and survived at least 100 days after transplantation were evaluated for the study. Risk factors for BO were analyzed using proportional hazards regression.

Results: Seventy-six patients were found to have BO, with an incidence rate of 1.7% at 2 years after transplantation. The Kaplan-Meier estimate of median time to onset of BO was 431 days. Histologic evaluation was performed in 36 patients (47%). In 28 patients (37%), diagnosis was based on pulmonary function tests, CT scans of the chest, or a combination of both. On multivariate analysis, the factors that were associated with an increased risk for BO included the following: peripheral blood-derived stem cell, a busulfan-based conditioning regimen, interval from diagnosis to transplant ≥ 14 months, female donor to male recipient sex match, prior interstitial pneumonitis, and an episode of moderate-to-severe acute graft-vs-host disease (GVHD).

Conclusion: In addition to corroborating previously reported risk factors, such as acute GVHD and a busulfan-based conditioning regimen, we found that peripheral blood stem-cell transplantation, long duration to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis are associated with an increased risk for BO.

Key Words: bone marrow transplantation • chronic airflow obstruction • obstructive lung disease • peripheral blood stem cell transplantation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Leukemia is the leading indication for allogeneic transplantation, accounting for 75% of 33,741 allogeneic transplants reported to the International Bone Marrow Transplant Registry (IBMTR) between 1964 and 1995.1 Pulmonary complications are a major cause of morbidity and mortality in transplant recipients, occurring in 40 to 60% of patients.2345 Though relatively uncommon, bronchiolitis obliterans (BO) is an important respiratory complication leading to late morbidity and decreased survival after hematopoietic stem-cell transplantation (HSCT).6789

After the first case of "necrotizing obliterative bronchiolitis" in an allogeneic bone marrow transplant recipient was reported by Roca et al10 in 1982, the syndrome of progressive obstructive lung disease occurring after HSCT was increasingly recognized, with an incidence ranging from 2 to 26%.341112 While histologic diagnosis is available for only a minority of patients with posttransplant obstructive lung disease, BO is identified as the most common pathologic finding in patients undergoing biopsy or at autopsy.1314 Despite diagnostic uncertainties, there is a growing tendency to attribute most cases of posttransplant chronic airflow obstruction to BO even in the absence of histologic confirmation.

Previous studies of posttransplant obstructive lung disease and BO are either case reports or case series. The larger retrospective cohort studies121516 include patients treated in single institutions. Moreover, most previous studies on risk factors for BO lack adequate consideration of multiple potential predictors and adjustment for confounding variables (Table 1 ). Evaluating the occurrence of BO in HSCT recipients using a large observational database, like that maintained by the IBMTR, provides an opportunity to validate findings from previous smaller studies and offers increased statistical power. The objective of this study was to identify patient-, disease-, and transplant-related risk factors for BO in persons receiving allogeneic HSCT for leukemia. Some of the results presented in this article have been previously reported in the form of an abstract.31


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  		Table 1. Studies of Obstructive Lung Disease and BO After HSCT*

 

   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
IBMTR Database
The IBMTR is a voluntary working group of > 350 transplantation centers worldwide that contribute detailed data on consecutive allogeneic HSCTs to a statistical center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee. Based on data collected in the Centers for Disease Control Hospital Surveys and the US Government Accounting Office and worldwide surveys of transplant activity, approximately 40% of allogeneic transplants worldwide are registered with the IBMTR. Participating centers are required to report all transplantations consecutively; compliance is monitored by on-site audits. Patients are followed up longitudinally, with yearly follow-up.

The IBMTR collects data at two levels: registration and research. Registration data include disease type, age, sex, pretransplant disease stage and chemotherapy responsiveness, date of diagnosis, graft type (bone marrow- and/or blood-derived stem cells), high-dose conditioning regimen, posttransplant disease progression and survival, development of a new malignancy, and cause of death. Requests for data on progression or death for registered patients are at 6-month intervals. All IBMTR teams contribute registration data. Research data are collected on subsets of registered patients and includes comprehensive pretransplant and posttransplant clinical information. Computerized checks for errors, physician reviews of submitted data, and on-site audits of participating centers ensure the quality of data.32

Patient Selection
The study population included all patients ≥ 18 years of age receiving human leukocyte antigen (HLA)-identical sibling HSCT for leukemia from January 1989 to December 1997, who were reported to the IBMTR and who survived at least 100 days after transplantation. Only patients receiving their first transplant were considered. Patients with pretransplant diagnoses of asthma, COPD, emphysema, chronic bronchitis, and bronchiectasis were excluded from the analysis.

Outcomes
The main outcome of interest is the reported development of BO. The diagnosis of BO was made using any of the following methods: transbronchial biopsy, open-lung biopsy, or autopsy. Pulmonary function studies, CT scan of the chest, or a combination of both were also considered valid diagnostic tests. The time interval from the date of transplantation to the date of diagnosis of BO was noted.

Predictor Variables
Variables evaluated for association with BO are summarized in Table 2 . Acute graft-vs-host disease (GVHD) was classified as none to mild (grades 0 to I) vs moderate to severe (grades II to IV). Data on the development of chronic GVHD were also retrieved. However, since the questionnaire used for collecting the data listed BO as a possible manifestation of chronic GVHD, an unbiased assessment of the association between these two variables could not be undertaken. This confounding by definition was not a problem with acute GVHD and allowed us to analyze the association of BO with acute GVHD. The third quartile was used as the cutoff point to dichotomize the time interval from diagnosis to transplant based on previous findings that a longer interval is a risk factor for poorer HSCT outcome.733


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  		Table 2. Variables Tested in Multivariate Analysis for Association With Development of BO*

 
Statistical Analysis
Cox proportional hazards regression with a stepwise approach was used for multivariate analyses.34 The time interval from transplantation to the diagnosis of BO was defined as the event of interest. Cohort members who did not have BO but were still alive just before the end of the study period were censored. The estimate of risk of one category vs the reference category is reported as the hazard ratio (HR), with the reference group’s hazard rate as the denominator. A variable had to be significant at the 0.05 level to remain in the final model.

Since status may change on follow-up for any given individual, interstitial pneumonitis and acute GVHD were entered as time-dependent variables. Time to the first onset of these variables was measured from date of transplantation. Missing data were handled using the complete-subject analysis method.3536 This led to deletion of 371 subjects (1 with a diagnosis of BO) in the final model due to missing covariate values.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Cohort Characteristics
A total of 8,276 patients receiving HLA-identical sibling transplants for leukemia between 1989 and 1997 were identified based on the inclusion criteria. Excluding those who survived < 100 days after transplant, 6,341 patients remained. Another 66 patients were excluded because of preexisting obstructive lung disease prior to transplant. Eight patients with a diagnosis of BO were excluded: five patients who survived < 100 days, and three patients with preexisting obstructive lung disease. The characteristics of the remaining 6,275 transplants from 238 institutions are summarized in Table 3 . Chronic myelogenous leukemia (CML) was the most common indication for allogeneic HSCT, constituting 45% of the cohort. Four hundred ninety-eight patients (8%) underwent peripheral blood stem-cell transplantation (PBSCT) and the remainder underwent bone marrow transplantation (BMT). Pretransplant functional status was generally good, with 80% having Karnofsky scores ≥ 90. However, other coexisting disease or organ impairment was noted in 23%. A comparable number of recipients (62%) and donors (58%) were found to be seropositive for cytomegalovirus (CMV) prior to transplantation. Thirty-five percent of recipients had a positive smoking history, with a median of 10 pack-years of smoking.


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  		Table 3. Cohort Characteristics*

 
Slightly more than half the cohort (56%) received irradiation prior to transplantation. Of the 3,477 patients who received irradiation, all but 22 received total body irradiation (TBI). Most of the other 2,977 patients who did not undergo TBI received a busulfan-based conditioning regimen prior to transplantation (95%). Cyclosporine (95%) and methotrexate (71%) alone or in combination were the most widely used prophylaxis for GVHD. More than half of the cohort (58%) acquired grade II, III or IV acute GVHD. Forty-four percent acquired chronic GVHD, 69% of whom had a prior episode of acute GVHD. Of the 2,767 patients with a diagnosis of chronic GVHD, only 2.6% had BO. The Kaplan-Meier estimate of median follow-up time for the cohort was 26 months. The longest follow-up time was 111 months.

Diagnosis of BO
Of the 6,275 cohort members, BO was diagnosed in 76 patients, yielding a probability of 1.7% at 2 years. The Kaplan-Meier estimate of median time interval from transplant to the diagnosis of BO was 431days. All but one case were diagnosed by 1,600 days (52 months). The earliest case was diagnosed at 65 days and the latest at 2,444 days after transplantation (Fig 1 ). Five of the patients with a BO diagnosis did not have manifestations of chronic GVHD in other organs. As shown in Table 4 , a diagnostic procedure for the evaluation of BO was reported in 64 of the 76 cases (84%). Only 36 patients underwent an invasive procedure to attempt histologic confirmation. The remainder underwent pulmonary function studies, CT scans of the chest, or a combination of both to support the diagnosis of BO. The original reports and results of these diagnostic tests were not available for review.



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  		Figure 1. Frequency of diagnosis of BO plotted against the time interval from transplant.

 

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  		Table 4. Diagnostic Tests Done To Evaluate the 76 Cohort Members With BO

 
Multivariate Analysis
The results of the stepwise regression analysis using a proportional hazards model are summarized in Table 5 . Only 8% of the cohort had PBSCT, but this conferred a threefold increase in risk for BO compared to BMT on multivariate analysis (HR, 3.35; 95% confidence interval [CI], 1.79 to 6.27; p = 0.0002). Pretransplant factors associated with an increased risk for BO included the following: busulfan-based conditioning regimen (HR, 2.24; 95% CI, 1.39 to 3.60; p = 0.0009); interval from diagnosis to transplant ≥ 14 months (HR, 1.93; 95% CI, 1.22 to 3.07; p = 0.0053); and female donor to male recipient sex match (HR, 1.78; 95% CI, 1.12 to 2.85; p = 0.0152). Posttransplant factors associated with an increased risk for BO after multivariate analysis included: moderate-to-severe acute GVHD (HR, 2.12; 95% CI, 1.34 to 3.37; p = 0.0014), and a previous episode of interstitial pneumonitis (HR, 2.28; 95% CI, 1.33 to 3.92; p = 0.0029). The median interval from diagnosis of interstitial pneumonitis to diagnosis of BO was 114 days (interquartile, 38 to 320 days).


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  		Table 5. Factors Associated With the Risk of BO in Recipients of Allogeneic HSCT for Leukemia After Multivariable Analysis Using a Proportional Hazards Regression Model*

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study of 6,275 adult recipients of HLA-identical sibling matched HSCT for leukemia we found several factors associated with an increased risk for the development of BO. Aside from validating previously described risk factors such as GVHD and type of conditioning regimen, our analysis indicates that, PBSCT, a long interval from diagnosis to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis are risk factors. The large number of patients reported to this database provided greater power to detect risk factors, while the uniform reporting requirements for several variables allowed us to consider the effects of various pretransplant and posttransplant factors in the analysis. Analysis of data from several institutions is another unique feature of this study.

To our knowledge, a higher risk for developing BO with PBSCT, as compared to BMT, has not been reported previously. Selection of stem-cell source may be influenced by patient-donor characteristics. We used multivariate analyses to adjust for the potential confounding effects of the variables listed in Table 2. Some studies37383940 have reported a higher incidence of chronic GVHD or more severe chronic GVHD with PBSCT compared to BMT, but the incidence of BO was not different. However, these studies were not designed nor powered to detect this difference.

In consonance with previous studies,101213141617192124284142 we found that GVHD is a risk factor for BO. Acute GVHD is described as a risk factor not only for BO but also for subsequent chronic GVHD. Though we are able to satisfactorily estimate the association of acute GVHD with BO, we are unable to obtain an unbiased estimate of the effect of chronic GVHD because the registry questionnaire incorporates BO as a manifestation of chronic GVHD. This introduces a differential misclassification leading to a greater estimate of association between chronic GVHD and BO than might be otherwise observed. Nevertheless, 5 of the 76 patients (7%) with BO did not have manifestations of chronic GVHD in other organs. A study by Dudek et al9 found a higher proportion of patients (13%) who acquired BO without chronic GVHD.

It is unclear how many patients were classified as having chronic GVHD based solely on the diagnosis of BO. It is noteworthy that six patients received a diagnosis of BO prior to a diagnosis of chronic GVHD. Although BO preceding development of chronic GVHD has been reported, most other authors have observed the contrary.1316234344 It is possible that there are more patients who have chronic GVHD who also have undiagnosed BO. This could happen with subclinical airflow obstruction or mild disease. A more standardized criteria and strategy for screening may identify these patients better in future studies. Both BO and chronic GVHD can present insidiously, and the fact that they ultimately occur within a specified period of time may be more relevant clinically than their exact temporal relationship. It remains to be determined whether BO in HSCT recipients with chronic GVHD results from autoimmune injury to the bronchial tree or other complications that accompany chronic GVHD.

Though both busulfan and irradiation have been described to cause pulmonary toxicity, we found that a busulfan-based conditioning regimen increased the risk for BO at least twofold when compared to a TBI-based regimen. The possible detrimental effect of a busulfan-based regimen on development of late pulmonary impairment following allogeneic HSCT was previously described by Beinert et al.6 CML patients were more likely to receive a busulfan-based regimen, which may explain previously reported higher risk for BO in this subgroup.22

The adverse influence of a long interval from diagnosis to transplantation on overall posttransplant survival, as well as on interstitial pneumonitis, has been described in other investigations.733 An association with BO has not been previously reported. Some authors suggest that this reflects the cumulative toxic sequelae of chemotherapy administered prior to transplantation.3341

Interstitial pneumonitis usually occurs much earlier than BO, with a median onset at 50 to 80 days.3345 Up to 40% of transplantation-related deaths in the early posttransplant period (< 100 days) are attributed to interstitial pneumonitis.2433 It is likely that those who survive an episode of interstitial pneumonitis have residual scarring of both the interstitium and peribronchiolar structures. In a study of six patients with biopsy-proven BO reported by Holland et al,23 three patients had concomitant histologic evidence for interstitial pneumonitis. It is also possible that survivors of interstitial pneumonitis may have decreased respiratory function reserve, which can lead to more respiratory complaints and subsequent surveillance bias.

The association between BO and donor-recipient sex match has been reported previously by Chien et al,12 although the association did not persist in multivariate analysis. Several authors have determined the importance of sex-match status in other transplant outcomes such as GVHD and survival.46474849 It has been suggested that alloreactivity to Y-chromosome antigens and other minor sex-related antigens may play a role in the pathogenesis GVHD. In addition, previously parous women may have experienced maternal alloimmunization to unshared fetal antigens.505152 Thus, it is possible that sex-match status may influence the development of BO, at least in part, via mechanisms related to GVHD. Identifying sex-match status as an independent risk factor for BO may be considered as supportive evidence that an immune-mediated injury to the bronchiolar structures is involved in the pathogenesis of BO.

We limited our investigation to adult allogeneic transplant recipients since previous studies155354 have suggested that this population may be at greater risk for BO. However, the estimated risk for BO in this study, 1.7% at 2 years, is lower than noted in most previous investigations. This discrepancy may be due to differing diagnostic criteria and definition of the population at risk.55 Variability in the diagnostic surveillance practices of the institutions contributing data to the IBMTR may also play a role in this discrepancy.

The Kaplan-Meier estimate of median interval from transplant to diagnosis of BO (431 days) falls within the range of previous observations, as reflected in Table 1. It should be noted that there was one patient in our study in whom BO was diagnosed after 52 months. Using the proportional hazards model, this outlier may potentially bias the estimated risk effect toward the direction of the subject’s covariate values. However, for diseases with small or more typical risk rates, as in BO, this effect is negligible.

The advantage of a strategy aimed toward early detection and treatment of BO after HSCT remains controversial.13162842 In a study of 29 patients with chronic respiratory impairment after allogeneic transplantation, Schwarer et al56 noted partial or complete improvement in 83% after a course of immunosuppressive agents. However, only 62% of the patients in that series had a predominantly obstructive ventilatory impairment; which raises the question of heterogeneity of disease. In another study, Sanchez et al30 followed the course of 20 patients with obstructive airway disease who were treated with immunosuppression; 60% had complete or partial improvement in symptoms or pulmonary function tests. The experiences of other investigators have been less encouraging.15182023

Our findings support the argument that BO after HSCT is a multifactorial disease. A survey of the risk factors identified in this study suggests that a variety of mechanisms–immune-mediated, and treatment-related toxicity–alone or in combination, may be responsible for the pathogenesis of BO. It is likely that the responsiveness to treatment of BO depends not only on the histologic stage (early lymphocytic bronchiolitis vs complete cicatricial obliteration of the bronchiolar lumen), but also on the pathophysiology involved. The findings in this study can be used to prospectively stratify patients into risk categories to facilitate investigating the merits of an aggressive diagnostic and treatment strategy in particular risk groups.

In accordance with previous descriptions of BO as a new-onset obstructive lung disease in HSCT recipients, patients with obstructive lung disease prior to transplant were excluded from the analysis. This was also done to avoid surveillance and misclassification bias. The latter is especially a concern since we relied on the reported diagnosis of BO, with the criteria defined by individual centers. In the absence of prespecified criteria to distinguish BO from progression or exacerbation of prior obstructive lung disease, it would not be possible to remove the apparent effects of such a bias.

The analysis of this registry data, while providing a large number of patients from different institutions, also presents limitations. One concern is the underestimation of the incidence of BO since the registry questionnaire was not specifically designed to address this. This study used the reported diagnosis of BO as the main outcome of interest. Fewer than half of the patients diagnosed with BO had a diagnostic procedure to obtain histologic confirmation. This is comparable with the experience of other investigators (Table 1). As illustrated by these previous investigations, histologic verification of diagnosis is not always practical. In part, the difficulty of histologic diagnosis relates to its invasiveness in the context of patients that may be severely ill. Moreover, even if histologic specimens are obtained, BO may not be found due to the patchy distribution of the disease and tissue sampling limitations.57 Thus, even in lung transplant recipients, in whom BO eventually develops in 50%, clinical and physiologic criteria are used in management and research.58596061

Unlike studies on BO in lung transplant recipients, there is less uniformity in clinical criteria used for the diagnosis of BO in HSCT at present. A liberal spirometric criteria identifying airflow obstruction as an annualized FEV1 decline of ≥ 5% and FEV1/FVC ratio < 0.8 as proposed by Chien et al12 may overestimate the incidence of patients who have histologic BO. However, using these spirometric criteria to define probable BO may have the benefit of identifying progressive disease at an earlier stage, and will allow conduct of prospective studies to determine if early intervention can limit deterioration of obstruction and alter other outcomes. Chien et al62 have recommended closer monitoring of spirometry during the first year based on their findings that suggest patients who have the highest rate of decline in lung function during the first year have the highest mortality. Considering the importance of BO in influencing the course of HSCT outcomes, a consensus on a diagnostic strategy, and clinical criteria that includes spirometric and radiologic findings needs to be established.

We conclude that several pretransplant and posttransplant factors were associated with an increased risk for BO. Our results corroborate previously reported risk factors, such as acute GVHD and a busulfan-based conditioning regimen. In addition, we found that PBSCT, long duration to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis are associated with an increased risk for BO.


   Footnotes
 
Abbreviations: BMT = bone marrow transplantation; BO = bronchiolitis obliterans; CI = confidence interval; CML = chronic myelogenous leukemia; CMV = cytomegalovirus; GVHD = graft-vs-host disease; HLA = human leukocyte antigen; HR = hazard ratio; HSCT = hematopoietic stem-cell transplantation; IBMTR = International Bone Marrow Transplant Registry; PBSCT = peripheral blood stem cell transplantation; TBI = total body irradiation

Received for publication September 24, 2004. Accepted for publication December 14, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Passweg, JR, Rowlings, PA, Armitage, JO, et al (1995) Report from the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry–North America. Clin Transplant ,117-127
  2. Quabeck, K The lung as a critical organ in marrow transplantation. Bone Marrow Transplant 1994;14,S19-S28
  3. Breuer, R, Lossos, IS, Berkman, N, et al Pulmonary complications of bone marrow transplantation. Respir Med 1993;87,571-579[CrossRef][ISI][Medline]
  4. Soubani, AO, Miller, KB, Hassoun, PM Pulmonary complications of bone marrow transplantation. Chest 1996;109,1066-1077[Free Full Text]
  5. Krowka, MJ, Staats, BA, Hoagland, HC A prospective study of airway reactivity before bone marrow transplantation. Mayo Clin Proc 1990;65,5-12[ISI][Medline]
  6. Beinert, T, Dull, T, Wolf, K, et al Late pulmonary impairment following allogeneic bone marrow transplantation. Eur J Med Res 1996;1,343-348[Medline]
  7. Socie, G, Stone, JV, Wingard, JR, et al Long-term survival and late deaths after allogeneic bone marrow transplantation: Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med 1999;341,14-21[Abstract/Free Full Text]
  8. Palmas, A, Tefferi, A, Myers, JL, et al Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998;100,680-687[CrossRef][ISI][Medline]
  9. Dudek, AZ, Mahaseth, H, DeFor, TE, et al Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant 2003;9,657-666[CrossRef][ISI][Medline]
  10. Roca, J, Granena, A, Rodriguez-Roisin, R, et al Fatal airway disease in an adult with chronic graft-versus-host disease. Thorax 1982;37,77-78[ISI][Medline]
  11. Crawford, SW, Clark, JG Bronchiolitis associated with bone marrow transplantation. Clin Chest Med 1993;14,741-749[ISI][Medline]
  12. Chien, JW, Martin, PJ, Gooley, TA, et al Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003;168,208-214[Abstract/Free Full Text]
  13. Chan, CK, Hyland, RH, Hutcheon, MA, et al Small-airways disease in recipients of allogeneic bone marrow transplants: an analysis of 11 cases and a review of the literature. Medicine 1987;66,327-340[Medline]
  14. Urbanski, SJ, Kossakowska, AE, Curtis, J, et al Idiopathic small airways pathology in patients with graft-versus-host disease following allogeneic bone marrow transplantation. Am J Surg Pathol 1987;11,965-971[CrossRef][ISI][Medline]
  15. Clark, JG, Crawford, SW, Madtes, DK, et al Obstructive lung disease after allogeneic marrow transplantation: clinical presentation and course. Ann Intern Med 1989;111,368-376[ISI][Medline]
  16. Clark, JG, Schwartz, DA, Flournoy, N, et al Risk factors for airflow obstruction in recipients of bone marrow transplants. Ann Intern Med 1987;107,648-656[ISI][Medline]
  17. Link, H, Reinhard, U, Niethammer, D, et al Obstructive ventilation disorder as a severe complication of chronic graft versus host disease after bone marrow transplantation. Exp Hematol 1982;10,92-93
  18. Ralph, DD, Springmeyer, SC, Sullivan, KM, et al Rapidly progressive air-flow obstruction in marrow transplant recipients: possible association between obliterative bronchiolitis and chronic graft-versus-host disease. Am Rev Respir Dis 1984;129,641-644[ISI][Medline]
  19. Wyatt, SE, Nunn, P, Hows, JM, et al Airways obstruction associated with graft versus host disease after bone marrow transplantation. Thorax 1984;39,887-894[Abstract]
  20. Kurzrock, R, Zander, A, Kanojia, M, et al Obstructive lung disease after allogeneic bone marrow transplantation. Transplantation 1984;37,156-160[ISI][Medline]
  21. Johnson, FL, Stokes, DC, Ruggiero, M, et al Chronic obstructive airways disease after bone marrow transplantation. J Pediatr 1984;105,370-376[CrossRef][ISI][Medline]
  22. Chan, CK, Hyland, RH, Hutcheon, MA, et al Risk factors for obstructive airways disease after allogeneic bone marrow transplantation [abstract]. Am Rev Respir Dis 1988;137,111
  23. Holland, HK, Wingard, JR, Beschorner, WE, et al Bronchiolitis obliterans in bone marrow transplantation and its relationship to chronic graft-v-host disease and low serum IgG. Blood 1988;72,621-627[Abstract/Free Full Text]
  24. Paz, HL, Crilley, P, Topolsky, DL, et al Bronchiolitis obliterans after bone marrow transplantation: the effect of preconditioning. Respiration 1993;60,109-114[ISI][Medline]
  25. Payne, L, Chan, CK, Fyles, G, et al Cyclosporine as possible prophylaxis for obstructive airways disease after allogeneic bone marrow transplantation. Chest 1993;104,114-118[Abstract/Free Full Text]
  26. Schultz, KR, Green, GJ, Wensley, D, et al Obstructive lung disease in children after allogeneic bone marrow transplantation. Blood 1994;84,3212-3220[Abstract/Free Full Text]
  27. Philit, F, Wiesendanger, T, Archimbaud, E, et al Post-transplant obstructive lung disease ("bronchiolitis obliterans"): a clinical comparative study of bone marrow and lung transplant patients. Eur Respir J 1995;8,551-558[Abstract]
  28. Curtis, DJ, Smale, A, Thien, F, et al Chronic airflow obstruction in long-term survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant 1995;16,169-173[ISI][Medline]
  29. Yokoi, T, Hirabayashi, N, Ito, M, et al Broncho-bronchiolitis obliterans as a complication of bone marrow transplantation: a clinicopathological study of eight autopsy cases; Nagoya BMT Group. Virchows Arch 1997;431,275-282[CrossRef][ISI][Medline]
  30. Sanchez, J, Torres, A, Serrano, J, et al Long-term follow-up of immunosuppressive treatment for obstructive airways disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1997;20,403-408[CrossRef][ISI][Medline]
  31. Santo Tomas, LH, Loberiza, FR, Klein, JP, et al Risk factors for bronchiolitis obliterans in allogeneic bone marrow transplant recipients for leukemia [abstract]. Chest 2003;124,109S
  32. Sobocinski, K The International Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries databases. Datum 1996;2,1-2
  33. Weiner, RS, Bortin, MM, Gale, RP, et al Interstitial pneumonitis after bone marrow transplantation: assessment of risk factors. Ann Intern Med 1986;104,168-175[ISI][Medline]
  34. Parmar, MKB, Machin, D Survival analysis: a practical approach. 1995 John Wiley and Sons. West Sussex, UK:
  35. Rothman, KJ, Greenland, S Modern epidemiology 2nd ed. 1998 Lippincott-Raven Publishers. Philadelphia, PA:
  36. Greenland, S, Finkle, WD A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995;142,1255-1264[Abstract/Free Full Text]
  37. Champlin, RE, Schmitz, N, Horowitz, MM, et al Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood 2000;95,3702-3709[Abstract/Free Full Text]
  38. Flowers, MED, Parker, PM, Johnston, LJ, et al Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood 2002;100,415-419[Abstract/Free Full Text]
  39. Storek, J, Gooley, T, Siadak, M, et al Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease. Blood 1997;90,4705-4709[Abstract/Free Full Text]
  40. Tanimoto, TE, Yamaguchi, T, Tanaka, Y, et al Comparative analysis of clinical outcomes after allogeneic bone marrow transplantation versus peripheral blood stem cell transplantation from a related donor in Japanese patients. Br J Haematol 2004;125,480-493[CrossRef][ISI][Medline]
  41. Sullivan, KM, Shulman, HM Chronic graft-versus-host disease, obliterative bronchiolitis, and graft-versus-leukemia effect: case histories. Transplant Proc 1989;21,51-62[ISI][Medline]
  42. Forsyth, CJ, Cremer, PD, Torzillo, P, et al Thalidomide responsive chronic pulmonary GVHD. Bone Marrow Transplant 1996;17,291-293[ISI][Medline]
  43. Epler, GR Bronchiolitis obliterans and airways obstruction associated with graft-versus-host disease. Clin Chest Med 1988;9,551-556[ISI][Medline]
  44. Chan, C, Spaner, D, Hyland, R Bronchiolitis obliterans after bone marrow transplantation. Blood 1989;73,355-356[Free Full Text]
  45. Weiner, RS, Horowitz, MM, Gale, RP, et al Risk factors for interstitial pneumonia following bone marrow transplantation for severe aplastic anaemia. Br J Haematol 1989;71,535-543[ISI][Medline]
  46. Gale, RP, Bortin, MM, van Bekkum, DW, et al Risk factors for acute graft-versus-host disease. Br J Haematol 1987;67,397-406[ISI][Medline]
  47. Bortin, MM Acute graft-versus-host disease following bone marrow transplantation in humans: prognostic factors: Advisory Committee of the International Bone Marrow Transplant Registry. Transplant Proc 1987;19,2655-2657[ISI][Medline]
  48. Storb, R, Prentice, RL, Thomas, ED Treatment of aplastic anemia by marrow transplantation from HLA identical siblings: prognostic factors associated with graft versus host disease and survival. J Clin Invest 1977;59,625-632[ISI][Medline]
  49. Randolph, SS, Gooley, TA, Warren, EH, et al Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 2004;103,347-352[Abstract/Free Full Text]
  50. Adams, KM, Holmberg, LA, Leisenring, W, et al Risk factors for syngeneic graft-versus-host disease after adult hematopoietic cell transplantation. Blood 2004;104,1894-1897[Abstract/Free Full Text]
  51. Flowers, ME, Pepe, MS, Longton, G, et al Previous donor pregnancy as a risk factor for acute graft-versus-host disease in patients with aplastic anaemia treated by allogeneic marrow transplantation. Br J Haematol 1990;74,492-496[ISI][Medline]
  52. Adams, KM, Lambert, NC, Heimfeld, S, et al Male DNA in female donor apheresis and CD34-enriched products. Blood 2003;102,3845-3847[Abstract/Free Full Text]
  53. Kaplan, EB, Wodell, RA, Wilmott, RW, et al Chronic graft-versus-host disease and pulmonary function. Pediatr Pulmonol 1992;14,141-148[ISI][Medline]
  54. Paz, HL, Crilley, P, Patchefsky, A, et al Bronchiolitis obliterans after autologous bone marrow transplantation. Chest 1992;101,775-778[Abstract/Free Full Text]
  55. Afessa, B, Litzow, MR, Tefferi, A Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;28,425-434[CrossRef][ISI][Medline]
  56. Schwarer, AP, Hughes, JM, Trotman-Dickenson, B, et al A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation. Transplantation 1992;54,1002-1008[ISI][Medline]
  57. Ward, S, Muller, NL Pulmonary complications following lung transplantation. Clin Radiol 2000;55,332-339[CrossRef][ISI][Medline]
  58. Cooper, JD, Billingham, M, Egan, T, et al A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts: International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993;12,713-716[ISI][Medline]
  59. Sharples, LD, McNeil, K, Stewart, S, et al Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant 2002;21,271-281[CrossRef][ISI][Medline]
  60. Scott, JP, Peters, SG, McDougall, JC, et al Posttransplantation physiologic features of the lung and obliterative bronchiolitis. Mayo Clin Proc 1997;72,170-174[ISI][Medline]
  61. Estenne, M, Maurer, JR, Boehler, A, et al Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21,297-310[CrossRef][ISI][Medline]
  62. Chien, JW, Martin, PJ, Flowers, ME, et al Implications of early airflow decline after myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 2004;33,759-764[CrossRef][ISI][Medline]




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