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San Francisco, CA
Dr. Collard is Assistant Professor of Medicine, San Francisco General Hospital, University of California San Francisco.
Correspondence to: Harold R. Collard, MD, FCCP, San Francisco General Hospital, 1001 Potrero Ave, 5K1, San Francisco, CA, 94110; e-mail: hcollard{at}medsfgh.ucsf.edu
Defining the clinical behavior of rare diseases presents huge challenges, as few practicing physicians see more than a case or two in their professional lifetime. Historically, case reports and series from quaternary care centers have made up the bulk of the medical literature on such diseases, and physicians have relied on review articles to summarize these data and provide clinical insight. Such has been the case with respiratory bronchiolitis-interstitial lung disease (RBILD).
Over the 20 years since RBILD was described by Myers and colleagues,1 a handful of case series have been reported,1234 and most reviews56 have concluded that it is a relatively benign disease with, in most cases, improvement or stabilization in symptoms and lung function over time. A case series published in this issue of CHEST (see page 664) by Portnoy and colleagues7 challenges this conventional wisdom, reporting a substantially less benign course.
Discordance among clinical studies addressing the same hypothesis is either due to differences in study design (so-called clinical heterogeneity) or to error. Error in clinical research can be categorized into two types.8 The first is random error, or error due to chance. Perhaps chance led to the inclusion of unusually healthy or unusually sick patients in some of the published studies of RBILD. The larger the study population, the less likely it is that random error will influence the results. By this measure, the cohort of Portnoy et al7 seems the least likely to be affected by random error, as its sample size is twice that of the next largest study. The second type of error in clinical research is systematic error, or error due to bias. To some degree, bias is present in all clinical investigation, although a rigorous study design can minimize its impact. A common source of bias in case series from highly specialized referral centers is called referral bias. Patients seen at these centers often differ substantially from the general population of patients with a given disorder. These differences may be obvious (eg, the patients are sicker, younger, have more aggressive disease, or are more likely to have tried and not responded to treatment) or more subtle (eg, the patients are better educated, more motivated, or better insured). It is likely that referral bias is present in many, if not all, published case series of RBILD, and this may further explain some of the variability in results.
Systematic reviews can be useful tools in identifying and accounting for sources of error in clinical research. Systematic reviews identify all completed studies addressing a research question through a rigorous literature search, evaluate the methodology used in each study, and, when appropriate attempt to combine the results into a summary estimate through metaanalysis. They are highly sensitive, however, to clinical heterogeneity among included studies and are of minimal value when dealing with substantial variations in study design.9
Can systematic review help us to understand the natural history of RBILD? A search of MEDLINE using the search terms "respiratory bronchiolitis" and "interstitial lung disease" identified 748 articles. Limiting these to human studies published in the English language revealed 542 articles. Using two criteria for final inclusion (surgical biopsy-proven RBILD and the presence of longitudinal data), seven articles123471011 were identified reporting on a total of 81 patients with RBILD. Individual and summary data are presented in Table 1 . Unfortunately, substantial clinical heterogeneity is present in these studies, including differences in the rate of smoking cessation, the rate of treatment with prednisone, the follow-up time, and outcome definitions. Combining the existing literature on RBILD through systematic review is minimally informative as there is too much clinical heterogeneity for meaningful summary estimates.
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In the mean time, where are we with regard to our understanding of the natural history of RBILD? Importantly, Portnoy and colleagues7 remind us that RBILD may be a more progressive disease than is generally appreciated. Physicians should recognize the diagnosis of RBILD as a serious condition, aggressively encourage and assist their patients to quit smoking, and consider therapy with corticosteroids early in the treatment of patients with cases that are progressive or severe in nature.
Footnotes
The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
References
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