© 2003 American Thoracic Society
Allogeneic Stem Cell Transplant, Lung Disease, and Airflow ObstructionDivision of Pulmonary, Allergy, and Critical Care Medicine Departments of Medicine and Cell Biology Duke University Medical Center Durham, North Carolina Pulmonary complications following both myeloablative and nonmyeloablative chemo/radiation therapy with hematopoietic stem cell transplant for the treatment of solid and hematologic-derived tumors have long been recognized to contribute to significant morbidity and mortality. One of the most severe forms of lung disease encountered has been termed idiopathic pneumonia syndrome (1), which may result from a common end-stage pathway of several distinct pathologic entities affecting the lung parenchyma (2). However, an increasingly more common, non-infectious, posttransplant pulmonary complication primarily affecting the airways manifests as chronic, progressive airflow obstruction and is termed bronchiolitis obliterans. Following stem cell transplant, bronchiolitis obliterans occurs almost exclusively in patients undergoing allogeneic transplant (3); it is only rarely reported following autologous stem cell transplant (4). Validation of an accurate, safe, reliable, and inexpensive test for the early diagnosis of bronchiolitis obliterans could greatly facilitate our understanding and management of this complication. In this issue of AJRCCM (pp. 208–214), Chien and coworkers (5) examine the epidemiology of chronic airflow obstruction and its associated mortality in 1,131 eligible patients receiving allogeneic stem cell transplant over a 12-year period (patients enrolled between the years 1990 to 2000). From this analysis, several important observations are worth emphasizing. First, Chien and colleagues present a new operational definition of chronic airflow obstruction (5). Using spirometry alone, patients are diagnosed with chronic airflow obstruction if the annualized rate of decline in percent predicted FEV1 is greater than 5% (over at least a 5-year period) and the lowest documented posttransplant FEV1/FVC ratio was less than 0.8 (5). Using this definition, the incidence of chronic airflow obstruction was found to be 26%, a marked increase from their previously published studies that suggested the incidence to be closer to 12% (6). In the earlier studies, however, they used a different criterion of airflow obstruction: a fall in FEV1/FVC to less than 0.7 after transplant. Therefore, the higher incidence in the current study is unlikely to represent an actual change in the incidence but rather a change in the definition. The previous criterion based on the FEV1/FVC ratio can be criticized in that it fails to capture patients who significantly drop their FEV1/FVC ratio, but it remains greater than 0.7. Because the magnitude of drop in FEV1 needed to satisfy the criterion of an annualized rate of decline in percent predicted FEV1 of greater than 5% is not intuitive, I have summarized both the annualized rate of decline in FEV1 (ml/year) and the 5-year cumulative loss in FEV1 secondary to normal aging and to a 5% annualized loss in percent predicted FEV1 over a 5-year period (see Table E1 in online supplement). Using this definition, a 30-year-old man would have to lose more than 1,254 ml in FEV1 over 5 years versus a loss of 122 ml secondary to normal aging (9). Similarly, a 70-year-old woman would have to lose more than 645 ml in FEV1 over 5 years versus the expected loss of 128 ml secondary to aging. These are impressive values and unlikely to arise from variability in the test procedure. These examples highlight one potentially important caveat to this definition: older patients and/or women require a smaller absolute loss in FEV1 to meet the criterion of chronic airflow obstruction, thus potentially skewing the groups. Criteria for the diagnosis of chronic airflow obstruction in lung transplant patients, where the incidence of bronchiolitis obliterans approaches 60% and the 5-year survival after diagnosis is only 30–40% (7), also utilize spirometry data; the specific criteria, however, employ a drop in FEV1 and/or midexpiratory flow from baseline (7). The rationale for using a drop in midexpiratory flow rates is that it appears to deteriorate before FEV1 at the onset of disease (7). Spirometry appears to have evolved as the method of choice for detecting chronic airflow obstruction associated with the development of bronchiolitis obliterans. Which spirometric variable, however, most closely parallels the degree of bronchiolitis obliterans has yet to be determined. Invasive approaches, such as open lung biopsy, while heralded for sensitivity and specificity, are fraught with serious complications, particularly in this patient population, and radiographic studies are not sensitive to early pathologic changes in small airways, although high-resolution chest tomography shows promise (8). A second finding of Chien and colleagues is the identification of risk factors for the development of airflow obstruction (5). Age greater than 60 years, pretransplant FEV1/FVC less than 0.8, respiratory virus infection, and quiescent or progressive onset of chronic graft-versus-host disease were all associated with its development. Knowledge of these factors might help in stratifying individuals for close follow-up or for alternative, potentially less toxic, regimens. Third, the authors demonstrated that the development of airflow obstruction independently contributes to a 2.3-fold increased risk of mortality following stem cell transplant. Thus, this new definition of airflow obstruction appears to impart useful prognostic information. Important questions remain. First, the annualized rate of decline in percent predicted FEV1 is based on limited spirometry data, and we do not know if the drop is acute or progressive throughout the follow-up period. This could have important implications for diagnosis and/or treatment. Second, requiring at least one posttransplant FEV1/FVC to be less than 0.8 will likely eliminate restrictive lung disease. This consideration, however, does not eliminate neuromuscular and/or effort-related effects, which could lead to an incorrect diagnosis of airflow obstruction. Third, the authors provide no clinical or lung pathology data to directly validate a relationship between a greater than 5% decline in percent predicted FEV1 and an airway pathology. This issue may be less relevant for patients with more severe airflow obstruction, but becomes more relevant for patients who experience decreases in percent predicted FEV1 unrelated to obstructive or restrictive lung disease. Thus, the sensitivity and specificity of this spirometric variable in diagnosing a pathologic airway process remains to be defined. Notwithstanding, future prospective studies could address some of these important limitations with the goal of improving our understanding of processes, such as bronchiolitis obliterans, that complicate stem cell transplant. FOOTNOTES This editorial has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org Conflict of Interest Statement: R.J.F. is currently being funded by Boehringer Ingelheim to study the long-term effect of tiotropium on lung function in COPD. RJF has recently been funded by Pfizer to study the safety and efficacy of C-J-13,610 in adults with persistent asthma. REFERENCES
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