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.

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.

Table 1.

Demographic Data, Noninvasive Evaluations, and Cryobiopsy Results

	Patient 1	Patient 2	Patient 3	Patient 4
Age, yr	48	33	42	26
Sex	Male	Male	Male	Male
Race	White	White	White	White
Smoking	Never	Never	Never	Never
Service theater	Iraq	Iraq	Afghanistan	Iraq and Afghanistan
Exposures during service	Burn pits	Burn pits, combat smoke	Burn pits	Burn pits
History of respiratory disease	No	No	No	No
HRCT chest	Normal	3-mm nodule	Right middle lobe bronchial thickening	Air trapping, mild
PFT pattern	Restriction	Normal	Normal	Mixed obstruction/restriction
FEV1, % predicted	71	94	81	66
FVC, % predicted	76	89	78	78
TLC, % predicted	76	100	80	64
DlCO, % predicted	95	108	92	97
CPET pattern	Not performed	No cardiac limitation	Not performed	Not performed
Cryobiopsy diagnostic of CB	No	Yes	Yes	Yes

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

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.

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 (×100).

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-versus-host 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 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.