Constrictive Bronchiolitis Obliterans: The Fibrotic Airway Disorder

Gary R. Epler


Expert Rev Resp Med. 2007;1(1):139-147. 

In This Article

Cause & Clinical Settings

There are several causes and clinical settings associated with the CB obliterans lesion ( Box 1 ).

Idiopathic obliterative bronchiolitis disorder is rare and has been described in only a few case reports.[7] The illness begins with shortness of breath and a nonproductive cough with no associated systemic symptoms. Lung examination shows early inspiratory crackles and sometimes 'squeaks'. The chest radiograph is often normal. The inspiratory chest CT scan is often associated with mosaic attenuation or diffuse decreased attenuation. The expiratory chest CT shows air trapping.

Pulmonary function shows varying degrees of airflow obstruction with the forced expiratory volume in 1 s (FEV1) often below 1 l. The clinical course is variable with periods of stability and exacerbations. Bronchodilators are utilized if helpful and a brief course of corticosteroid therapy can be utilized for exacerbations. The pathological findings show typical CB.

Fume-exposure bronchiolitis obliterans that results from typical acidic toxic fumes, as in silofillers disease, has a three-stage illness consisting of two latency periods; the first of a few hours and the second of several days. [7] Immediately after the toxic fume exposure, there may be burning of the eyes and throat but minimal if any respiratory symptoms. This asymptomatic latency period of a few hours is followed by acute respiratory distress syndrome. If recovery occurs, a second asymptomatic latency period of several days is observed, followed by the development of either intraluminal polyps with obliteration (e.g., after nitrogen dioxide exposure) or concentric bronchiolitis lesion with irreversible airflow obstruction (e.g., after sulfur dioxide exposure). This disorder usually occurs after accidental exposures to these toxic fumes. The toxic fume either consistently causes intraluminal polyps or concentric bronchiolitis, but not both.

There has been a report of concentric bronchiolitis obliterans from mustard gas occurring during a chemical warfare attack in a man aged 37 years who had cough, sputum production, shortness of breath and airflow obstruction for 14 years after the exposure.[8] In 2004, Ghanei and colleagues used high-resolution chest CT scan findings for the diagnosis of bronchiolitis obliterans in a group of individuals exposed to the same mustard gas attack.[9] After 2 years, these investigators wrote a report regarding the 18 individuals with bronchodilator treatment and 18 with IFN-γ-1b plus daily prednisolone 7.5 mg .[10] They found that the group treated with bronchodilator therapy had a baseline FEV1 of 49.3%, which increased to 57.3% after 6 months, while the group treated with IFN-γ had a significantly higher improvement from a baseline of 48.7% to 66.3% after treatment (p = 0.001). The vital capacity measurements showed similar improvement.

A 2002 report of workers at a microwave popcorn plant indicated some workers had occupational bronchiolitis obliterans caused by the inhalation of volatile butter-flavoring ingredients.[11] A report of nine popcorn factory workers indicated airflow obstruction and biopsy of some of these individuals showed CB.[12] The ketone butter flavoring diacetyl appeared to be the common exposure among these workers. The chest CT features of diacetyl-related bronchiolitis are similar to those of other forms of bronchiolitis. A 2005 case report indicated a 42-year-old police officer exposed to the dust and ill-defined toxins in the cloud from the New York City World Trade Center disaster of September 11, 2001, developed decreased vital capacity, FEV1 and FEV1:forced vital capacity (FVC) ratio in April 2002.[13] The lung biopsy showed regions of CB. He was treated with oral corticosteroid therapy and azithromycin. There were initially continued decreases in vital capacity and FEV1 with a normal FEV1:FVC ratio until April 2003 when functional studies returned to normal values, which is an unusual favorable outcome for CB.

Oral toxin-related bronchiolitis obliterans is a very unusual and unexpected lesion described in East-Asian countries. Consumption of the leafy vegetable Sauropus androgynus has been reported to cause bronchiolitis obliterans.[14,15,16] This vegetable is a Malaysian food, and women in Taiwan began using the vegetable for weight control. The leaves contain the alkaloid papaverine. Among 194 patients in Taiwan, the obstructive ventilatory defect was irreversible and deteriorated progressively in some patients, requiring lung transplantation. [15] Among a report of five patients in Japan, where the illness occurred 6 months after ingestion, four were mothers and daughters, and none improved with corticosteroid treatment.[16]

Bone marrow transplantation bronchiolitis obliterans may occur in 9% of patients.[17] In general, pulmonary complications occur during three time phases after bone marrow transplantation.[18] Pulmonary edema, diffuse alveolar hemorrhage and infections occur up to 30 days in Phase 1. Cytomegalovirus pneumonia and idiopathic pneumonia syndrome develop during days 31-100 in Phase 2. Complications of chronic graft-versus-host reaction develop after 100 days, in Phase 3. Bronchiolitis obliterans is usually seen 6-12 months after transplantation.

Bronchiolitis obliterans occurs only after graft-versus-host reaction, and thus is rarely seen among autologous transplant recipients.[17] Donor type 2 T-helper lymphocytes are the primary mediators. Histology shows typical concentric bronchiolar fibrosis. There is generally a poor response to corticosteroid therapy, with mortality of 40-100%[17] Azithromycin at 250 mg three-times weekly appeared to be effective in seven out of eight patients.[19] There has been a case report of successfully utilized living-donor lobar lung transplantation for bone marrow transplant-related obliterative bronchiolitis.[20]

Stem cell transplantation bronchiolitis obliterans occurs less commonly than bone marrow transplantation. Among 6275 adult recipients of human leukocyte antigen (HLA)-identical sibling-matched hematopoietic stem cell transplantation for leukemia, 76 were found to have bronchiolitis obliterans, with an incidence rate of 1.7% at 2 years after transplantation.[21] Known risk factors included an episode of acute graft-versus-host disease and busulfan-based conditioning regimen, and this study added four additional risk factors, including: peripheral blood-derived stem cells, long duration of 14 months or more from diagnosis of leukemia to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis.[21] Among a group of 369 patients who received allogeneic stem cell transplantation, 61 (16.5%) developed pulmonary complications and 13 (3.5%) developed obliterative bronchiolitis occurring at a late stage, at a median of 203 days [22]. The histological characteristic of stem cell transplantation-related obliterative bronchiolitis is the concentric bronchiolitis lesion.[23] Soubani and Uberti reported, "bronchiolitis obliterans is one of the most challenging pulmonary complciations facing clinicains who are taking care of hematopoietic stem cell transplanation recipients," and reviewed 22 reports of bronchiolitis obliterans after stem cell transplantation.[24]

Postinfection and drug-related bronchiolitis obliterans continue to occur in rare situations.[7] Infections that may result in the fibrotic constrictive bronchiolar lesion include Mycoplasma, adenovirus, influenza and parainfluenza. Drugs that cause the fibrotic bronchiolar lesion include penicillamine and gold therapy.[7]

Connective tissue bronchiolitis obliterans may be a serious and fatal complication of rheumatoid arthritis. The fibrotic constrictive bronchiolar lesion is rare in connective tissue disorders, and has been described in rheumatoid arthritis, scleroderma and lupus erythematosus; while there have been no published reports of the fibrotic obliterative lesion in polymyositis dermatomyositis, mixed connective tissue disease or Sjögren's syndrome.[25]

The constrictive fibrotic bronchiolitis lesion has been reported in individuals with miscellaneous disorders, including ulcerative colitis[26], Stevens-Johnson syndrome[27]neuroendocrine cell hyperplasia[28,29] with carcinoid tumorlets,[30,31] and paraneoplastic pemphigus.[32,33] The CB lesion has been reported after aspiration of foreign bodies and esophageal gastric contents.[34,35] In a 2005 study of lung-transplant recipients, three patients were found to have constrictive fibrotic bronchiolitis lesions due to aspiration and not from the rejection process.[36]


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