Prognostic Significance of Bronchoalveolar Lavage Cellular Analysis in Scleroderma Lung Disease/From the Authors

By Kinder, Brent W King, Talmadge E Jr; Strange, Charlie; Bolster, Marcy; Roth, Michael

To the Editor: Dr. Strange and colleagues concluded in their subgroup analysis of data from the Scleroderma Lung Study that abnormal bronchoalveolar lavage (BAL) cellularity was associated with more advanced interstitial lung disease (ILD), but was of no benefit in predicting disease progression or treatment response (1). We believe that there still might be a role for evaluation of BAL in these patients.

As acknowledged by the authors, several methodological issues raise the need for caution in interpretation of the data. The study appears underpowered, and the authors did not provide either their power calculation (including the estimated effect size) or the 95% confidence intervals for their outcomes. The control group (BAL-) may not be representative of the full spectrum of scleroderma ILD patients, especially since all (n = 36) had evidence of ground- glass opacity and were at high risk for disease progression. We disagree with the assertion that if no independent association between BAL cellularity and change in lung function are demonstrated, then BAL cellular examination is not clinically useful. Lung function and high-resolution computed tomography (HRCT) are not accurate markers of the histopathologic findings in ILD (except the presence of honeycomb change and emphysema). BAL cellu- larity could be a marker of the ”switch” from cellular nonspecific interstitial pneumonitis (NSIP) to fibrotic NSIP. It is possible that serial assessment of BAL (and the finding of persistent or ”new” neutrophilia or eosinophilia) might identify the subgroup that needs continued therapy (2).

Longitudinal trends in lung function have been used as surrogate outcomes for the most clinically meaningful outcome- mortality (primarily to maximize power and limit trial costs). However, these are not perfect surrogates and account for only a portion of mortality risk. Recent studies with larger numbers of patients and mortality outcome data in scleroderma ILD (2) and idiopathic pulmonary fibrosis (3) have demonstrated that BAL neutrophil percentage is a strong independent predictor of 1-year mortality (after adjustment for pulmonary function parameters and a composite physiologic index, which has a strong correlation with disease extent by HRCT [4]). It may be that the causal pathway between BAL neutrophil percentage and mortality does not progress through intermediary changes in FVC (e.g., by means of acute exacerbations). Alternatively, functional changes may occur prior to death, and studies have not been sufficiently able to capture these data. It is possible that with continued follow-up of this cohort, we will learn that abnormal BAL cellularity is an independent predictor of mortality.

Conflict of Interest Statement: B.W.K. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.E.K. has served on advisory boards for Actelion, Intermune, and GlaxoSmithKline; he has served as a consultant for Nektar, Alexza, AstraZeneca, Biogen, Centocor, Fibrogen, Genzyme, Human Genome Sciences, Merck, and CoTherix.

BRENT W. KINDER

University of Cincinnati College of Medicine

Cincinnati, Ohio

TALMADGE E. KING, JR.

University of California San Francisco School of Medicine

San Francisco, California

References

1. Strange C, Bolster MB, Roth MD, Silver RM, Theodore A, Goldin J, Clements P, Chung J, Elashoff RM, Suh R, et al. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med 2007;177:91-98.

2. Goh NS, Veeraraghavan S, Desai SR, Cramer D, Hansell DM, Denton CP, Black CM, du Bois RM, Wells AU. Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis-associated interstitial lung disease are not predictive of disease progression. Arthritis Rheum 2007;56:2005-2012.

3. Kinder BW, Brown KK, Schwarz MI, Ix JH, Kervitsky A, King TE Jr. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest 2008;133:226-232.

4. Wells AU, Hansell DM, Rubens MB, King AD, Cramer D, Black CM, du Bois RM. Fibrosing alveolitis in systemic sclerosis: indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum 1997;40:1229-1236.

From the Authors:

We thank Drs. Kinder and King for their thoughtful remarks on our article, which considered bronchoalveolar lavage (BAL) neutrophilia as a prognostic indicator in interstitial lung disease (1). They comment on three recent BAL reports that address this issue, in addition to our study (1), including retrospective analyses performed in 156 patients with idiopathic pulmonary fibrosis (IPF) (2) and 141 patients with scleroderma-related interstitial lung disease (SSc-ILD) (3), as well as our prospective randomized control trial in 158 patients with SSc-ILD. In each case, patients with BAL neutrophils in excess of 3% exhibited significantly worse pulmonary function and/or chest high-resolution computed tomography (HRCT) findings at baseline, suggesting thatBALcellularitymight define a unique subgroup or a subset withmore advanced disease.However, in the two SSc-ILDstudies, there were no differences in either progression of pulmonary function changes or in overallmortalitywhen results were adjusted for these baseline differences. Furthermore, in the Scleroderma Lung Study (4), neutrophilia was not found to be an independent predictor of clinical responses to cyclophosphamide.As such, both of the SSc-ILD studies concluded that addition of a bronchoscopy withBAL is not likely to add important clinical information to the treatment of these patients.

Exactly how these findings in SSc-ILD relate to IPF remains to be resolved. While all of the patients reported by Kinder and coworkers had biopsy-proven usual interstitial pneumonia (UIP), the majority of SSc-ILD patients exhibit findings consistent with nonspecific interstitial pneumonia (NSIP). This may account for the significant difference in mortality, which averaged 43% at 24 months in the IPF subjects followed by Kinder and coworkers, but only 4 to 17% over the same interval in the two SSc-ILD studies. It is possible that BAL neutrophilia adds to the prediction of mortality in IPF subjects in a manner that is not directly relevant to patients with SSc-ILD. Additional studies in IPF patients that allow correction for baseline HRCT findings (as performed in the two SSc-ILD studies), better control for other variables and treatment effects (i.e., a prospective design), or directly compare results in subjects with UIP with those with NSIP (to examine differences between these diseases) might be useful in addressing this question.

Furthermore, there might be other features of the BAL, such as profiles of cytokines, chemokines, and/or growth factors, that provide important new insights. While BAL might not fulfill the criteria for a first-line clinical tool in the management of patients with SSc-ILD, we agree with the general conclusion by Drs. Kinder and King that continued research employing BAL to address these and other questions should be promoted.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

CHARLIE STRANGE

MARCY BOLSTER

Medical University of South Carolina

Charleston, South Carolina

MICHAEL ROTH

David Geffen School of Medicine at UCLA

Los Angeles, California

References

1. Strange C, Bolster MB, Roth MD, Silver RM, Theodore A, Goldin J, Clements P, Chung J, Elashoff RM, Suh R, et al. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med 2007;177:91-98.

2. Kinder BW, Brown KK, Schwarz MI, Ix JH, Kervitsky A, King, TE, Jr. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest 2008;133:226-232.

3. Goh NS, Veeraraghavan S, Desai SR, Cramer D, Hansell DM, Denton CP, Black CM, du Bois RM, Wells AU. Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis-associated interstitial lung disease are not predictive of disease progression. Arthritis Rheum 2007;56:2005-2012.

4. Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM, Goldin J, Arriola E, Strange C, Bolster MB, et al. Effects of 1- year treatment with cyclophosphamide on outcomes at 2 years in sclero-derma lung disease. Am J Respir Crit Care Med 2007;176:1026- 1034.

Copyright American Thoracic Society Jun 1, 2008

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