CORRESPONDENCE staining. Similarly to Perros and colleagues, we have also detected CXCL13 staining in acellular areas of B cell–rich lymphoid follicles, but we could not detect intracellular staining in any of the cell populations present (Figure 1). This is presumably due to the low intensity of the signal and the relatively low amplification achieved by immunofluorescence staining compared with immunohistochemistry. We have therefore used a much more sensitive method based on fluorescence-activated cell sorting and real-time PCR, and found that in lung samples of patients with COPD, highly purified fluorescence-activated cell sorting–sorted CD191 B cells but not CD452 stromal cells are the dominant populations that express high levels of CXCL13 mRNA in vivo (1). In addition, in culture, purified lung B cells from these patients produce CXCL13 protein that is up-regulated by stimuli relevant to COPD pathogenesis (1). These data combined provide solid evidence for the role of B cells in CXCL13 production. n Author disclosures are available with the text of this letter at www.atsjournals.org. Eleni Litsiou, Ph.D. Evaggelismos General Hospital Athens, Greece Maria Semitekolou, Ph.D. Ioanna Galani, Ph.D. Ioannis Morianos, Ph.D. Biomedical Research Foundation of the Academy of Athens Athens, Greece Aikaterini Tsoutsa, Ph.D. Panagiota Kara, M.D. Dimitra Rontogianni, M.D. Ion Bellenis, M.D. Evaggelismos General Hospital Athens, Greece Maria Konstantinou, B.Sc. Konstantinos Potaris, M.D., Ph.D. Sotiria Chest Hospital Athens, Greece Evangelos Andreakos, Ph.D. Paschalis Sideras, Ph.D. Biomedical Research Foundation of the Academy of Athens Athens, Greece Spyros Zakynthinos, M.D., Ph.D. Maria Tsoumakidou, M.D., Ph.D. Evaggelismos General Hospital Athens, Greece
References 1. Litsiou E, Semitekolou M, Galani IE, Morianos I, Tsoutsa A, Kara P, Rontogianni D, Bellenis I, Konstantinou M, Potaris K, et al. CXCL13 production in B cells via Toll-like receptor/lymphotoxin receptor signaling is involved in lymphoid neogenesis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187: 1194–1202. 2. Perros F, Dorfm uller ¨ P, Montani D, Hammad H, Waelput W, Girerd B, Raymond N, Mercier O, Mussot S, Cohen-Kaminsky S, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;185: 311–321.
Copyright © 2014 by the American Thoracic Society
Correspondence
Surgical Lung Biopsy over Bronchoalveolar Lavage in Chronic Hypersensitivity Pneumonitis To the Editor: We read with great interest the article by Hodnett and Naidich (1), which presents a diagnostic algorithm for delineating among fibrotic interstitial lung diseases (FILDs)—specifically idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP)—according to high-resolution computed tomography (HRCT) radiographic pattern(s). HRCT imaging is an integral diagnostic tool in accurate FILD classification, which is essential for prognostication and therapeutic assessment in clinical trials. We agree with the emphasis on lobular air-trapping, centrilobular nodules, and relative basilar sparing as radiographic features inconsistent with a usual interstitial pneumonia pattern that should prompt further diagnostic investigation and consideration of HP. However, the authors de-emphasize the role of surgical lung biopsy in patients with suggested HP in favor of performing bronchoalveolar lavage (BAL). Given the inconsistent and contradictory data on BAL findings in fibrotic HP, the proposed dependence on BAL analysis over surgical lung biopsy is unjustified. Vourlekis and colleagues demonstrated significantly lower mean BAL total lymphocyte count in subjects with HP with fibrosis (15 6 31 3 106 cells/ml) compared with those without fibrosis (46 6 31 3 106 cells/ml) (2). American Thoracic Society guidelines acknowledge that a BAL lymphocyte differential count greater than 50% suggests HP or cellular NSIP (3). However, in unpublished analysis of a previously described HP cohort, we found a lymphocyte differential count greater than 50% in only 25% of patients (2 of 8) (4). Furthermore, Ohshimo and colleagues evaluated BAL utility in patients with suspected idiopathic pulmonary fibrosis, and demonstrated BAL lymphocytosis greater than 30% in 8% (6 of 74) of patients, in which further pathologic analysis ultimately classified three patients as NSIP and three as HP (5). Based upon literature to date, BAL lymphocytosis has an unproven role in differentiating HP from other FILDs due to both poor sensitivity, likely due to variances in HP phenotype, antigen exposure, smoking use, and/or exacerbations, and specificity, due to elevated levels in NSIP. Further studies are needed to evaluate novel BAL biomarkers that could have better diagnostic utility in differentiating HP from other FILDs. For now, we advocate that surgical lung biopsy remain the standard for improving the diagnostic certainty of FILD, specifically HP. n
Author disclosures are available with the text of this letter at www.atsjournals.org. Joshua J. Mooney, M.D. Stanford University Stanford, California Laura L. Koth, M.D. University of California San Francisco San Francisco, California
371
CORRESPONDENCE References 1. Hodnett PA, Naidich DP. Fibrosing interstitial lung disease: a practical high-resolution computed tomography-based approach to diagnosis and management and a review of the literature. Am J Respir Crit Care Med 2013;188:141–149. 2. Vourlekis JS, Schwarz MI, Cherniack RM, Curran-Everett D, Cool CD, Tuder RM, King TE Jr, Brown KK. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med 2004; 116:662–668. 3. Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, Drent M, Haslam PL, Kim DS, Nagai S, et al.; American Thoracic Society Committee on BAL in Interstitial Lung Disease. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med 2012;185:1004–1014. 4. Mooney JJ, Elicker BM, Urbania TH, Agarwal MR, Ryerson CJ, Nguyen ML, Woodruff PG, Jones KD, Collard HR, King TE Jr, et al. Radiographic fibrosis score predicts survival in hypersensitivity pneumonitis. Chest 2013;144:586–592. 5. Ohshimo S, Bonella F, Cui A, Beume M, Kohno N, Guzman J, Costabel U. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179: 1043–1047.
Copyright © 2014 by the American Thoracic Society
Reply From the Authors: It is with considerable interest that we read the commentary of Mooney and Koth regarding our article recommending the use of bronchoalveolar lavage (BAL) for investigating patients with suspected hypersensitivity pneumonitis (HP) (1). As they correctly point out and as we clearly acknowledge, the use of BAL for evaluating patients with suspected HP is controversial (1). However, we remain convinced that there is an important supportive role for the use of BAL as an initial diagnostic test, especially in patients in whom there is a pattern suspicious for HP on HRCT in the setting of a questionable or inconclusive exposure history. As previously oft recommended (2, 3) and most recently reiterated in the 2012 American Thoracic Society Clinical Practice Guidelines regarding the clinical utility of BAL for interstitial lung disease (4), HP may be associated with a CD81 lymphocytosis, especially when greater than 50%. We are aware that BAL findings likely vary with the timing of antigenic exposure. It is also well established that a lymphocytosis greater than 50% essentially rules out idiopathic pulmonary fibrosis—findings most recently supported by Ohshimo and coworkers, who reported in a number of patients (albeit a small number) with a lymphocystosis greater than 30%, half proved to have nonspecific interstitial pneumonitis, while the other half had HP (5). Equally important, there are no data currently available that purport to show that in the specific setting of HRCT findings suggestive of HP—including air-trapping and relative basilar sparing—that a lymphocytosis greater than 50% is either inconsistent or contradictory. In this regard, evidence suggesting that BAL is of limited value for the diagnosis of HP solely on the HRCT findings of “fibrosis” in itself is unsatisfactory, without including air-trapping and basilar sparing as a precondition for establishing a role for BAL. Further, it is worth emphasizing that this does not take into account 372
the potential of HRCT to direct the precise region for performing BAL (4) or correlating HRCT with serologic findings to further improve the sensitivity of BAL. Finally, even if it is acknowledged that BAL is only diagnostic in 25% of cases—likely a serious underestimation—there is ample reason to consider BAL as the first step in investigating patients with a high index of suspicion based on HRCT findings, as this would obviate surgical intervention in a sufficient number of cases to strongly warrant recommendation. We repeatedly acknowledge that surgical intervention in the appropriate clinical setting is justified for definitive diagnosis in cases of otherwise undiagnosed interstitial lung disease. n Author disclosures are available with the text of this letter at www.atsjournals.org. Philip Hodnett, M.D. David Naidich, M.D. New York University New York, New York
References 1. Hodnett PA, Naidich DP. Fibrosting interstitial lung disease: a practical high-resolution computed tomography-based approach to diagnosis and management and review of the literature. Am J Respir Crit Care Med 2013;188:141–149. 2. Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol 2001;108: 661–670. 3. Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest 1997;111:534–536. 4. Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, Drent M, Haslam PL, Kim DS, Nagai S, et al.; American Thoracic Society Committee on BAL in Interstitial Lung Disease. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med 2012;185:1004–1014. 5. Ohshimo S, Bonella F, Cui A, Beume M, Kohno N, Guzman J, Costabel U. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179: 1043–1047.
Copyright © 2014 by the American Thoracic Society
Arousal Threshold in Obstructive Sleep Apnea To the Editor: I read with interest the article by Eckert and colleagues regarding phenotypic causes of obstructive sleep apnea (OSA) (1). One of their findings was an elevated respiratory arousal threshold in adults with OSA, and it was noted that direct comparisons of the respiratory arousal threshold between patients with OSA and control subjects have not been previously performed. In fact, studies have shown that
Supported by National Institutes of Health grants R01 HL58585 and UL1TR000003.
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 3 | February 1 2014
References 1. Litsiou E, Semitekolou M, Galani IE, Morianos I, Tsoutsa A, Kara P, Rontogianni D, Bellenis I, Konstantinou M, Potaris K, et al. CXCL13 production in B cells via Toll-like receptor/lymphotoxin receptor signaling is involved in lymphoid neogenesis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187: 1194–1202. 2. Perros F, Dorfm uller ¨ P, Montani D, Hammad H, Waelput W, Girerd B, Raymond N, Mercier O, Mussot S, Cohen-Kaminsky S, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;185: 311–321.
Copyright © 2014 by the American Thoracic Society
Correspondence
Surgical Lung Biopsy over Bronchoalveolar Lavage in Chronic Hypersensitivity Pneumonitis To the Editor: We read with great interest the article by Hodnett and Naidich (1), which presents a diagnostic algorithm for delineating among fibrotic interstitial lung diseases (FILDs)—specifically idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP)—according to high-resolution computed tomography (HRCT) radiographic pattern(s). HRCT imaging is an integral diagnostic tool in accurate FILD classification, which is essential for prognostication and therapeutic assessment in clinical trials. We agree with the emphasis on lobular air-trapping, centrilobular nodules, and relative basilar sparing as radiographic features inconsistent with a usual interstitial pneumonia pattern that should prompt further diagnostic investigation and consideration of HP. However, the authors de-emphasize the role of surgical lung biopsy in patients with suggested HP in favor of performing bronchoalveolar lavage (BAL). Given the inconsistent and contradictory data on BAL findings in fibrotic HP, the proposed dependence on BAL analysis over surgical lung biopsy is unjustified. Vourlekis and colleagues demonstrated significantly lower mean BAL total lymphocyte count in subjects with HP with fibrosis (15 6 31 3 106 cells/ml) compared with those without fibrosis (46 6 31 3 106 cells/ml) (2). American Thoracic Society guidelines acknowledge that a BAL lymphocyte differential count greater than 50% suggests HP or cellular NSIP (3). However, in unpublished analysis of a previously described HP cohort, we found a lymphocyte differential count greater than 50% in only 25% of patients (2 of 8) (4). Furthermore, Ohshimo and colleagues evaluated BAL utility in patients with suspected idiopathic pulmonary fibrosis, and demonstrated BAL lymphocytosis greater than 30% in 8% (6 of 74) of patients, in which further pathologic analysis ultimately classified three patients as NSIP and three as HP (5). Based upon literature to date, BAL lymphocytosis has an unproven role in differentiating HP from other FILDs due to both poor sensitivity, likely due to variances in HP phenotype, antigen exposure, smoking use, and/or exacerbations, and specificity, due to elevated levels in NSIP. Further studies are needed to evaluate novel BAL biomarkers that could have better diagnostic utility in differentiating HP from other FILDs. For now, we advocate that surgical lung biopsy remain the standard for improving the diagnostic certainty of FILD, specifically HP. n
Author disclosures are available with the text of this letter at www.atsjournals.org. Joshua J. Mooney, M.D. Stanford University Stanford, California Laura L. Koth, M.D. University of California San Francisco San Francisco, California
371
CORRESPONDENCE References 1. Hodnett PA, Naidich DP. Fibrosing interstitial lung disease: a practical high-resolution computed tomography-based approach to diagnosis and management and a review of the literature. Am J Respir Crit Care Med 2013;188:141–149. 2. Vourlekis JS, Schwarz MI, Cherniack RM, Curran-Everett D, Cool CD, Tuder RM, King TE Jr, Brown KK. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med 2004; 116:662–668. 3. Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, Drent M, Haslam PL, Kim DS, Nagai S, et al.; American Thoracic Society Committee on BAL in Interstitial Lung Disease. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med 2012;185:1004–1014. 4. Mooney JJ, Elicker BM, Urbania TH, Agarwal MR, Ryerson CJ, Nguyen ML, Woodruff PG, Jones KD, Collard HR, King TE Jr, et al. Radiographic fibrosis score predicts survival in hypersensitivity pneumonitis. Chest 2013;144:586–592. 5. Ohshimo S, Bonella F, Cui A, Beume M, Kohno N, Guzman J, Costabel U. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179: 1043–1047.
Copyright © 2014 by the American Thoracic Society
Reply From the Authors: It is with considerable interest that we read the commentary of Mooney and Koth regarding our article recommending the use of bronchoalveolar lavage (BAL) for investigating patients with suspected hypersensitivity pneumonitis (HP) (1). As they correctly point out and as we clearly acknowledge, the use of BAL for evaluating patients with suspected HP is controversial (1). However, we remain convinced that there is an important supportive role for the use of BAL as an initial diagnostic test, especially in patients in whom there is a pattern suspicious for HP on HRCT in the setting of a questionable or inconclusive exposure history. As previously oft recommended (2, 3) and most recently reiterated in the 2012 American Thoracic Society Clinical Practice Guidelines regarding the clinical utility of BAL for interstitial lung disease (4), HP may be associated with a CD81 lymphocytosis, especially when greater than 50%. We are aware that BAL findings likely vary with the timing of antigenic exposure. It is also well established that a lymphocytosis greater than 50% essentially rules out idiopathic pulmonary fibrosis—findings most recently supported by Ohshimo and coworkers, who reported in a number of patients (albeit a small number) with a lymphocystosis greater than 30%, half proved to have nonspecific interstitial pneumonitis, while the other half had HP (5). Equally important, there are no data currently available that purport to show that in the specific setting of HRCT findings suggestive of HP—including air-trapping and relative basilar sparing—that a lymphocytosis greater than 50% is either inconsistent or contradictory. In this regard, evidence suggesting that BAL is of limited value for the diagnosis of HP solely on the HRCT findings of “fibrosis” in itself is unsatisfactory, without including air-trapping and basilar sparing as a precondition for establishing a role for BAL. Further, it is worth emphasizing that this does not take into account 372
the potential of HRCT to direct the precise region for performing BAL (4) or correlating HRCT with serologic findings to further improve the sensitivity of BAL. Finally, even if it is acknowledged that BAL is only diagnostic in 25% of cases—likely a serious underestimation—there is ample reason to consider BAL as the first step in investigating patients with a high index of suspicion based on HRCT findings, as this would obviate surgical intervention in a sufficient number of cases to strongly warrant recommendation. We repeatedly acknowledge that surgical intervention in the appropriate clinical setting is justified for definitive diagnosis in cases of otherwise undiagnosed interstitial lung disease. n Author disclosures are available with the text of this letter at www.atsjournals.org. Philip Hodnett, M.D. David Naidich, M.D. New York University New York, New York
References 1. Hodnett PA, Naidich DP. Fibrosting interstitial lung disease: a practical high-resolution computed tomography-based approach to diagnosis and management and review of the literature. Am J Respir Crit Care Med 2013;188:141–149. 2. Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol 2001;108: 661–670. 3. Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest 1997;111:534–536. 4. Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, Drent M, Haslam PL, Kim DS, Nagai S, et al.; American Thoracic Society Committee on BAL in Interstitial Lung Disease. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med 2012;185:1004–1014. 5. Ohshimo S, Bonella F, Cui A, Beume M, Kohno N, Guzman J, Costabel U. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179: 1043–1047.
Copyright © 2014 by the American Thoracic Society
Arousal Threshold in Obstructive Sleep Apnea To the Editor: I read with interest the article by Eckert and colleagues regarding phenotypic causes of obstructive sleep apnea (OSA) (1). One of their findings was an elevated respiratory arousal threshold in adults with OSA, and it was noted that direct comparisons of the respiratory arousal threshold between patients with OSA and control subjects have not been previously performed. In fact, studies have shown that
Supported by National Institutes of Health grants R01 HL58585 and UL1TR000003.
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 3 | February 1 2014
