Transbronchial Cryobiopsy Can Diagnose Constrictive Bronchiolitis in ...

CORRESPONDENCE Transbronchial Cryobiopsy Can Diagnose Constrictive Bronchiolitis in Veterans of Recent Conflicts in the Middle East To the Editor: Transbronchial lung biopsy with a cryoprobe, or cryobiopsy, provides larger tissue samples than traditional forceps biopsy (1, 2). Investigations of this technique in diffuse parenchymal lung diseases have reported favorable results, with diagnostic yield similar to surgical lung biopsy, while maintaining the safety profile of traditional bronchoscopic biopsy (1–8). We hypothesized that cryobiopsy would be able to diagnose other conditions poorly evaluated by traditional transbronchial biopsy, including the bronchiolitides (9). Since describing the phenomenon in 2011 (10), our institution has maintained an interest in postdeployment constrictive bronchiolitis affecting veterans returning from recent conflicts in the Middle East. This series represents our initial investigation into the use of cryobiopsy as a possible alternative to surgical lung biopsy for establishing this diagnosis. An abbreviated version of this work was presented as a poster discussion at the ATS Conference in 2015 (11). Methods

This retrospective series was approved by the Vanderbilt University Institutional Review Board (IRB# 151099). Patient identification and data collection. The four patients referred to our interventional pulmonary practice to date with specific concern about postdeployment constrictive bronchiolitis requiring lung biopsy for further characterization were included. All developed dyspnea on exertion, causing significant exercise limitation, since their last deployments, with normal or nonspecifically abnormal noninvasive evaluations. Clinical data were retrospectively extracted from the medical record. Cryobiopsy procedure. Bronchoscopies with cryobiopsy were performed as previously described for diagnosing diffuse parenchymal lung disease at our institution (3). If no abnormalities were present on high-resolution computed tomography scan of the chest to guide cryobiopsy location, they were performed in the right lower lobe. One to three cryobiopsies were obtained according to operator preference.

Support was provided by Vanderbilt Clinical and Translational Science Award UL1 RR024975, USA Med Research grant W81XW-11-1-0216, and National Institutes of Health grant K08 HL121174. Data collection used the Research Electronic Data Capture (REDCap) tool developed and maintained with Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from National Center for Advancing Translational Sciences/National Institutes of Health). The funding institutions had no role in conception, design, or conduct of the study; collection, management, analysis, interpretation, or presentation of the data; or preparation, review, or approval of the manuscript. Author Contributions: Study concept and design: R.J.L., J.P.F., and O.B.R.; acquisition of data: R.J.L. and J.E.J.; analysis and interpretation of data: R.J.L., J.P.F., J.E.J., F.M., R.F.M., and O.B.R.; drafting of the manuscript: R.J.L.; critical revision of the manuscript for important intellectual content: R.J.L., J.P.F., J.E.J., F.M., R.F.M., and O.B.R.; and study supervision: R.J.L. and O.B.R. R.J.L. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Pathological evaluation. Biopsies were processed as previously described (3). An expert lung pathologist provided pathological interpretations. Constrictive bronchiolitis was diagnosed if either of the following were present with otherwise normal lung parenchyma: narrowing of the bronchiole lumen as a result of subepithelial fibrosis or narrowing of membranous bronchioles as a result of smooth muscle hypertrophy. Pathologic narrowing was considered present if bronchiole lumen was equal to or smaller than the diameter of the companion artery. Results

The four previously healthy male patients in this series reported extensive burn pit exposure during their recent deployments to Iraq and/or Afghanistan. Demographic data and noninvasive evaluation results are detailed in Table 1. A total of nine cryobiopsies were obtained with mean diameter 7.1 mm (SD, 3.5 mm; range, 4–15 mm). Three of four patients were diagnosed with constrictive bronchiolitis based on cryobiopsy pathology (see Figure 1 for a representative example). Peribronchial pigment deposition was present in all cases of constrictive bronchiolitis. Cryobiopsy revealed mild focal peribronchial smooth muscle hyperplasia not meeting the pathological definition of constrictive bronchiolitis in one case. There were no procedural complications, and all patients were discharged after 2 hours of observation. Discussion

Although constrictive bronchiolitis has been diagnosed by cryobiopsy once previously in a series of patients with diffuse parenchymal lung disease (3), this series is the first to evaluate cryobiopsy specifically for small airway disease, and it clearly provides proof of concept that this technique is capable of diagnosing bronchiolar lesions. We were able to diagnose three of four patients with constrictive bronchiolitis, obviating the need for surgical lung biopsy in these individuals. Constrictive bronchiolitis is a primary disorder of the bronchioles in which inflammation, smooth muscle hypertrophy, and/or fibrosis leads to narrowing of the lumen (9). It is associated with chronic lung transplant rejection, graft-versushost disease in allogeneic hematopoietic cell transplantation, healed infections, collagen-vascular and inflammatory bowel disease, microcarcinoid tumorlets, gastroesophageal reflux, drugs, and inhalation of mineral dust or toxic fumes (9). Constrictive bronchiolitis in otherwise healthy individuals is rare and often difficult to diagnose. This is well demonstrated by the 2011 series in which King and colleagues reported the unexpected diagnosis of constrictive bronchiolitis in 38 previously healthy soldiers recently returned from service in Iraq and/or Afghanistan, all of whom ultimately required surgical lung biopsy to establish the diagnosis after extensive nondiagnostic noninvasive evaluation (10). Surgical lung biopsy is, however, a major invasive procedure requiring general anesthesia, postoperative chest drains, and several days of hospitalization. When performed for diffuse lung disease, associated mortality rates of 1–5% are commonly reported, and they may be as high as 10% (8). In contrast, only one peri-procedural death associated with cryobiopsy performed for the same

American Journal of Respiratory and Critical Care Medicine Volume 193 Number 7 | April 1 2016

CORRESPONDENCE Table 1. Demographic Data, Noninvasive Evaluations, and Cryobiopsy Results Patient 1 Age, yr Sex Race Smoking Service theater Exposures during service

48 Male White Never Iraq Burn pits

History of respiratory disease HRCT chest

No Normal

PFT pattern FEV1, % predicted FVC, % predicted TLC, % predicted DLCO, % predicted CPET pattern Cryobiopsy diagnostic of CB

Restriction 71 76 76 95 Not performed No

Patient 2

Patient 3

33 Male White Never Iraq Burn pits, combat smoke No 3-mm nodule Normal 94 89 100 108 No cardiac limitation Yes

Patient 4

42 Male White Never Afghanistan Burn pits

26 Male White Never Iraq and Afghanistan Burn pits

No Right middle lobe bronchial thickening Normal 81 78 80 92 Not performed Yes

No Air trapping, mild Mixed obstruction/restriction 66 78 64 97 Not performed Yes

Definition of abbreviations: CB = constrictive bronchiolitis; CPET = cardiopulmonary exercise test; DLCO = diffusing capacity of the lung for carbon monoxide; HRCT = high-resolution computed tomography; PFT = pulmonary function test; TLC = total lung capacity.

indication has been reported, of more than 300 published procedures (1–7). Studies to date have reported rates of 0–7% pneumothorax requiring chest tube thoracostomy and rare serious hemorrhage (1–5), excluding two studies with pneumothorax rate of 19–20%, in which biopsies were targeted very close to the chest wall (6, 7). In conclusion, by using cryobiopsy to establish the diagnosis of postdeployment constrictive bronchiolitis in three of four patients in this small series, we have demonstrated this bronchoscopic technique is able to diagnose bronchiolar disorders. Future study is required to evaluate the sensitivity and specificity of cryobiopsy for constrictive bronchiolitis and

related diseases. If efficacious, cryobiopsy may be a safer alternative to surgical lung biopsy for the diagnosis of postdeployment constrictive bronchiolitis and other bronchiolar diseases. n Author disclosures are available with the text of this letter at www.atsjournals.org. Robert J. Lentz, M.D. Vanderbilt University School of Medicine Nashville, Tennessee Joshua P. Fessel, M.D., Ph.D. Joyce E. Johnson, M.D. Vanderbilt University School of Medicine Nashville, Tennessee and Department of Veterans Affairs Medical Center Nashville, Tennessee Fabien Maldonado, M.D. Robert F. Miller, M.D. Otis B. Rickman, D.O. Vanderbilt University School of Medicine Nashville, Tennessee

References

Figure 1. Representative hematoxylin and eosin–stained cryobiopsy diagnostic of constrictive bronchiolitis. The bronchiolar wall is abnormally thickened by a combination of smooth muscle hyperplasia and collagen deposition. There is an adventitial chronic inflammatory infiltrate and deposition of black pigment in the bronchovascular notch (arrows). The lumen (b) contains prominent infoldings and is smaller in diameter than the accompanying artery (a). There is prominent goblet cell metaplasia (3100).

Correspondence

1. Babiak A, Hetzel J, Krishna G, Fritz P, Moeller P, Balli T, Hetzel M. Transbronchial cryobiopsy: a new tool for lung biopsies. Respiration 2009;78:203–208. 2. Pajares V, Puzo C, Castillo D, Lerma E, Montero MA, Ramos-Barbon ´ D, Amor-Carro O, Gil de Bernabe´ A, Franquet T, Plaza V, et al. Diagnostic yield of transbronchial cryobiopsy in interstitial lung disease: a randomized trial. Respirology 2014;19:900–906. 3. Kropski JA, Pritchett JM, Mason WR, Sivarajan L, Gleaves LA, Johnson JE, Lancaster LH, Lawson WE, Blackwell TS, Steele MP, et al. Bronchoscopic cryobiopsy for the diagnosis of diffuse parenchymal lung disease. PLoS One 2013;8:e78674. 4. Griff S, Schonfeld ¨ N, Ammenwerth W, Blum T-G, Grah C, Bauer TT, Gruning ¨ W, Mairinger T, Wurps H. Diagnostic yield of transbronchial

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CORRESPONDENCE cryobiopsy in non-neoplastic lung disease: a retrospective case series. BMC Pulm Med 2014;14:171. 5. Hernandez-Gonz ´ alez ´ F, Lucena CM, Ram´ırez J, Sanchez ´ M, Jimenez MJ, Xaubet A, Sellares J, Agust´ı C. Cryobiopsy in the diagnosis of diffuse interstitial lung disease: yield and cost-effectiveness analysis. Arch Bronconeumol 2015;51:261–267. 6. Casoni GL, Tomassetti S, Cavazza A, Colby TV, Dubini A, Ryu JH, Carretta E, Tantalocco P, Piciucchi S, Ravaglia C, et al. Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases. PLoS One 2014;9:e86716. 7. Hagmeyer L, Theegarten D, Wohlschlager ¨ J, Treml M, Matthes S, Priegnitz C, Randerath WJ. The role of transbronchial cryobiopsy and surgical lung biopsy in the diagnostic algorithm of interstitial lung disease. Clin Respir J [online ahead of print] 26 Jan 2015; DOI: 10.1111/crj.12261. 8. Fibla JJ, Brunelli A, Cassivi SD, Deschamps C. Aggregate risk score for predicting mortality after surgical biopsy for interstitial lung disease. Interact Cardiovasc Thorac Surg 2012;15:276–279. 9. Ryu JH. Classification and approach to bronchiolar diseases. Curr Opin Pulm Med 2006;12:145–151. 10. King MS, Eisenberg R, Newman JH, Tolle JJ, Harrell FE Jr, Nian H, Ninan M, Lambright ES, Sheller JR, Johnson JE, et al. Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan. N Engl J Med 2011;365:222–230. 11. Lentz RJ, Fessel JP, Johnson JE, Miller R, Rickman OB. Transbronchial cryobiopsy for the diagnosis of constrictive bronchiolitis in veterans returning from service in Iraq and Afghanistan: a proof-of-concept case series [abstract]. Am J Respir Crit Care Med 2015;191:A3730.

Copyright © 2016 by the American Thoracic Society

Aerosolized Antibiotics for Patients with Bronchiectasis To the Editor: Bronchiectasis is the anatomic distortion of conducting airways that results in chronic infection with cough, sputum production, and recurrent exacerbations of infection (1). The causes of bronchiectasis are many, but patients are commonly classified into those with cystic fibrosis (CF) and those with another diagnosis (i.e., non-CF bronchiectasis [NCFB]) (2). There are several medications approved for use in the treatment of CF bronchiectasis, and it is intuitive that we could translate those therapies to our patients with NCFB (2); however, studies have not demonstrated the same clinical benefit. For example, inhaled antibiotics are the standard of care to suppress chronic Pseudomonas infections of the CF airways (3, 4), but clinical trials of aerosolized antibiotics in NCFB have not demonstrated clinical benefit (5–7). Nonetheless, our clinical experience has been that select patients with NCFB have responded well to aerosolized antibiotics. We reviewed clinical data derived from patients with NCFB seen between 2006 and 2014 to characterize the clinical phenotype of patients successfully treated with aerosolized antibiotics and to define the clinical outcomes that demonstrate benefit. Some of the results of these studies have been previously reported in the form of an abstract (8). This retrospective case series was approved by the Medical University of South Carolina institutional review board. Our inclusion criteria included all patients older than 18 years who had a prior diagnosis of bronchiectasis (excluding CF documented by a normal sweat chloride 6 genotyping) confirmed by computed 808

tomography of the chest. We routinely attempt to diagnose the etiology of bronchiectasis. We compared those patients treated with chronic aerosolized antibiotic therapy (study cohort) with those not treated (control cohort). The study cohort was matched with the control cohort by age and sex in a 1:2 fashion. Clinical, radiological, and treatment history was obtained from the electronic health records. If the cause of bronchiectasis was not reported in the reviewed medical record, then it was assumed to be idiopathic in nature. An exacerbation was defined as worsening of respiratory symptoms treated with oral or intravenous antibiotics. The analysis of the data was done using SPSS, version 22 (IBM Corp, Armonk, NY). Comparison between the study and control cohorts were performed using independent t test or Pearson’s chi-square test. A P value less than 0.05 was considered statistically significant. Data were collated from 91 patients, of whom 31 (34%) were treated with inhaled antibiotics (Table 1), using dosage regimens similar to those prescribed for patients with CF. Six of the 31 patients discontinued therapy because of adverse effects (n = 3), inability to afford therapy (n = 2), or perceived lack of benefit (n = 1). Baseline characteristics (Table 1) were generally well balanced between the two groups. Most patients had Pseudomonas present in sputum cultures (more in the study cohort); other pathogens were present (e.g., Haemophilus, Staphylococcus), but in less than l0% of patients. Key differences between the groups included (Table 1) a greater number of exacerbations in the year before inhaled antibiotics in the study cohort (P , 0.0001), a significantly lower lung function in the study cohort (P = 0.001), and a greater presence of nodules (P = 0.027) and cysts (P = 0.05) on chest computed tomography in the study cohort. Last, the bronchiectasis severity index, a predictive tool that identifies patients at risk of future mortality, hospitalization, and exacerbations (9), was significantly higher (i.e., worse) in the study cohort compared with the control cohort (P , 0.0001). In the year after initiation of inhaled antibiotics, there was significant reduction in the number of exacerbations in the study group (P = 0.003; Figure 1). Discussion

We suggest that for patients with NCFB, an important risk factor predicting benefit from inhaled antibiotics is a history of frequent pulmonary exacerbations, and a key clinical endpoint is a reduction in the occurrence of pulmonary exacerbations. We acknowledge that we attribute the reduction in exacerbation frequency in our patients to the addition of the inhaled antibiotics, but there could be other hypotheses that should be tested. Nonetheless, our results are in contrast to clinical trials of aerosolized antibiotics for patients with NCFB, in which no clinical benefit has been demonstrated, including exacerbations (5, 6), yet are consistent with a small study of inhaled gentamicin compared with saline in patients who had more than two prior exacerbations in which there was a significant reduction in pulmonary exacerbations as a secondary endpoint (10). So why did we not see a clinical benefit in these studies of aerosolized antibiotics for NCFB? It is likely that the subjects recruited into the trials would not all be expected to benefit

American Journal of Respiratory and Critical Care Medicine Volume 193 Number 7 | April 1 2016