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Miami, FL
Dr. Colin is Professor of Pediatrics, and Director, Division of Pediatric Pulmonology, and Dr. Ali-Dinar is Fellow, Pediatric Pulmonology, Miller School of Medicine, University of Miami.
Correspondence to: Andrew Colin, MD, University of Miami, Batchelor Children’s Institute, Department of Pediatrics, Division of Pediatric Pulmonology, 1580 NW Tenth Ave, First Floor (D-820), Miami, FL 33136; e-mail: colin{at}med.miami.edu
In this issue of CHEST (see page 1710), Regamey et al1 report on the quality of endobronchial biopsy (EBB) specimens obtained by flexible bronchoscopy in pediatric patients with cystic fibrosis (CF). As a stand-alone article on quality of material obtained from biopsies and the factors that determine quality, this is an informative, scientifically valid report, with appropriate analyses. It follows previous publications by the same group addressing the safety of EBB in patients with CF2 and similarly patients with asthma.34
The previous report2 on safety was followed by an editorial5 that questioned the ethics of the procedure in children, citing regulatory guidelines for research procedures developed by the US authorities. The authors have forcefully defended the ethics of their studies in a rebuttal.6 While they made some excellent points, the current study continues to leave the reader with the sense of unease voiced by Dr. Mallory,5 suggesting that EBB crosses a line of perceived invasiveness that exceeds that of the standard BAL.
The comments that follow express our thoughts on the state of EBB in pediatric bronchoscopy, in both research and clinical practice, as it emerges from this study in the wider context of recent literature and not limited to CF. In a 2000 article, Bush and Pohunek7 wrote on future directions in bronchoscopy-related research: "These studies must have a clearly defined hypothesis and plan of investigation that are clinically and scientifically valid, and should not merely degenerate into haphazard specimen collection." In keeping with these statements, the "Discussion" section in the current study outlines an elaborate and interesting hypothesis; yet importantly, neither the current study nor the previous study2 on safety contribute directly to elucidation of the hypothesis. As it stands now, the authors have shown that these studies are safe and yielding quality material; but the core question, namely, what were the results of these studies that provided the scientific justification for EBB? remains unanswered. The authors in the "Discussion" section appropriately address this point, stating that the readership should not assume that these are studies that should be done.
A study8 using EBB in asthma published in 2003 appears to satisfy the expectation of clearly posing and answering the scientific question driving the study. In contrast, a study9 on EBB in children with persistent respiratory problems published in the same year lacks the desired clarity. This large study9 of 170 children has become the benchmark reference on the safety of EBB, including a citation in the current article. It states clinical indications: bronchoscopy with EBB used after a thorough evaluation did not yield a diagnosis, or medical management failed to improve the clinical state of the patients. However, the stated institutional review board approval was to "collect data prospectively on children presenting for bronchoscopy." The ultimate clinical results from the study are summarized as follows: "While broad conclusions about the biopsy findings are not possible owing to the variability in the patients’ symptoms and drug treatment regimens, that was not the purpose of this report. Our aim was to document the safety of the procedure." The aim of the study remains equivocal, but more importantly the specific advantage of EBB over standard BAL for patient management in this unconventional interventional study has not been addressed by further publication in the 4 years since the report. Thus, the single publication emanating from the largest research study on EBB in the literature is a statement on the safety of the procedure. However, in their conclusions the authors state, "We hope this report will encourage other practitioners to consider endobronchial biopsy in evaluating children with respiratory conditions that are hard to diagnose." Otherwise stated, based on safety results, the study is viewed as a license and encouragement to perform EBB without elucidating what information the biopsies provided.
The series reported in the current study and previously tabulated published studies6 did not reveal significant adverse effects of EBB. It is probable, however, that complications of many procedures are underreported.10 Physicians are unlikely to publish accidents, failures, or negative results, particularly since reputable journals discourage anecdotal case reports. We are therefore biased toward a sense of safety that is occasionally disturbed by comprehensive analyses that include such "unlikely" complications as pneumothorax following EBB at one of the leading bronchoscopy centers in the world.11 While in this report no serious complication occurred, the risk in CF must not be understated. The authors write that the safety margin may be reduced by the increase in bronchial blood flow seen in advanced CF lung disease. Such blood flow anomalies occur in asthma, but life-threatening airway hemorrhage is a frequent occurrence, unique to CF. The source of the bleeding in CF is arterial and systemic. When visualized by arteriography, bronchial vessels are tortuous and grossly abnormal. Branches of these arteries presumably run close enough to the surface to bleed from inflammation-related erosion. Since such events occur spontaneously, it stands to reason that laceration, such as by EBB, can inadvertently reach the level of a vessel, a risk that is likely to increase with progressive inflammation.
The position of these reviewers is not that ethics dictate obtaining all possible information with every procedure as was previously suggested.12 We think that performing procedures which may carry risk, should not be exploratory but focused toward well-defined scientific or clinical questions. We also view the statement from the above-cited review7 on bronchoscopy to now encompass EBB: "There is nothing that we need to know about the techniques of bronchoscopy, the safety of the procedure, and the ethical constraints to the procedure. What we do need to know is how we can ethically use this technique to greater advantage, and what areas are likely to be most fruitful for study." Future publications on EBB in children should state a clear hypothesis up front, and transparently state the informed consent and institutional review board detail. They should elucidate the scientific or unique merits of such procedures rather than their byproducts, such as technique and safety.
Footnotes
The authors have no conflicts of interest to disclose.
References
Related Article
This article has been cited by other articles:
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  N. Regamey, T. N. Hilliard, S. Saglani, J. Zhu, I. M. Balfour-Lynn, M. Rosenthal, P. K. Jeffery, E. W. F. W. Alton, A. Bush, J. C. Davies, et al. Endobronchial Biopsy in Childhood Chest, January 1, 2008; 133(1): 312 - 313. [Full Text] [PDF]
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