Constrictive Bronchiolitis

Posted by Daniela Lamas • July 20th, 2011

A soldier returns from deployment in Iraq. A non-smoker without a history of asthma or other lung disease, he begins to notice that he’s no longer able to complete the army exercise regimen without becoming short of breath. The onset is insidious, but the impairment real: he isn’t even able to meet the fitness standard for the two-mile run.

He consults his post physician. A chest x-ray is unrevealing, as is a follow-up CT scan. Pulmonary function and cardiopulmonary exercise testing are within normal limits.  Troubled by the discrepancy between exercise tolerance and radiographic findings, the physician refers him to a tertiary center where a lung biopsy is done.

Our patient’s presentation is not unusual. Respiratory complaints among soldiers returning from service in the Middle East have been frequently described. Reports suggest a link to exposures overseas, but the specific pathological mechanism remains unknown.

To address this question, Matthew S. King and colleagues evaluated a population of soldiers who suffered new dyspnea on exertion following return from Iraq and Afghanistan. Their case series, published in this week’s NEJM, reports a provocative finding. In a majority of these previously well soldiers with unexplained dyspnea, biopsy data revealed constrictive bronchiolitis: a rare lung disease associated with toxic inhalation, but more often seen following organ transplantation or in rheumatologic disorders.

In this study, “Constrictive Bronchiolitis in Soldiers Returning from Iraq and Afghanistan,” King et al. report on 80 soldiers from Fort Campbell, Kentucky whom they saw from2004 to 2008.  All had served in Iraq or Afghanistan, and were referred to Vanderbilt University after they failed to meet the army’s fitness standard for the two-mile run –  (ranging from 16.5 to 19.5 minutes, depending on age) – a standard which all had met prior to service. Many, but not all, of these soldiers reported that they had been exposed to fire from a sulfur mine in Iraq.

Of the 80 soldiers followed, 49 underwent video-assisted thoracoscopic lung biopsy to characterize their respiratory impairment. The remaining soldiers did not undergo biopsy, either because they had other causes of dyspnea such as asthma or bronchitis, refused the diagnostic procedure or were lost to follow-up. Among those biopsied, 38 received the histologic diagnosis of constrictive bronchiolitis –- defined as a narrowing of the bronchioles by fibrosis and smooth muscle hypertrophy.  When the specimens were examined at high resolution, many samples showed “polarizable material” in the bronchioles. The authors noted that this finding is consistent with an inhalational exposure.

The authors spend much of this series detailing background characteristics and workup of the 38 soldiers with constrictive bronchiolitis on biopsy. Most were non-smokers. Their median age at enrollment was 33. They had served a variety of positions within the army, ranging from infantry members to pilots to police officers. Diagnostic studies were initially unrevealing, with normal cardiopulmonary exams, largely normal chest x-rays and CT scans.  Of note, pulmonary function tests were within normal limits but lower than those of healthy military controls. The soldiers did not have baseline pulmonary function tests prior to service for comparison.

This finding raises a key question: did these soldiers share an exposure? And if so, what was it? A majority of the soldiers had served in Iraq in 2003 where they were exposed to smoke from a sulfur-mine fire. Although sulfur exposure has a known link to pulmonary disease, not all soldiers with constrictive bronchiolitis witnessed this event. Indeed, although most recalled severe dust storms and some had been exposed to incinerated human waste, there was not one clear exposure they all shared.

This is, perhaps, the most provocative aspect of King et al.’s case series; if the development of constrictive bronchiolitis is not limited to those soldiers exposed to a sulfur-mine fire or similar unique event, how many soldiers could potentially suffer this disease?  While the authors describe a strong association, they did not establish cause and effect. The question is meaningful, however, as the soldiers remained impaired during the time of study follow-up. By 2010, six years after the first cases enrolled in the study, a majority reported continued dyspnea after climbing one flight of stairs, and half had left the service due to disability.

“These soldiers are serving their country and the nature of their symptoms is such that they might be overlooked,” says pulmonologist and NEJM editor-in-chief Dr. Jeffrey Drazen. “We published this to raise awareness among physicians caring for returning veterans regarding this unusual cause of shortness of breath.”

Question: What would you do if these soldiers were your responsibility? Would you advocate for pulmonary function tests prior to service? Are there other measures you would take?

Constrictive bronchiolitis, arteriopathy and peribronchial pigment deposition

The photomicrographs show some of the pathological features seen in the 38 soldiers in whom constrictive bronchiolitis was diagnosed. The disorder was associated with subepithelial fibrosis (Panel A, arrow; hematoxylin and eosin), smooth-muscle hypertrophy (Panel B, arrow; hematoxylin and eosin), fibrosis between the epithelium and the muscle layer (Panel C, arrow; stained red with Masson’s trichrome), smooth-muscle hypertrophy (Panel D, black arrow) with marked intimal fibrosis and medial hypertrophy of the adjacent pulmonary artery (white arrow) and peribronchiolar pigment deposition (arrowhead; hematoxylin and eosin), and smooth-muscle hypertrophy (Panel E, arrow) with adjacent pigment deposition (arrowhead; hematoxylin and eosin). Panel F shows the field shown in Panel E with the pigment refringent under polarized light.

One Response to “Constrictive Bronchiolitis”

  1. Sahar says:

    I think this study needs to be complemented by gene expression analyses for enzymes like the Lysine Oxidase because it would be interesting to know the underlying molecular events. This is feasible since you have lung biopsies obtained from those patients.

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