Constrictive Bronchiolitis Obliterans: The Fibrotic Airway Disorder

Gary R. Epler

Expert Rev Resp Med.  2007;1(1):139-147.  ?2007 Future Drugs Ltd.
Posted 10/26/2007

Abstract and Introduction

Abstract

Constrictive bronchiolitis obliterans is an important respiratory illness because of its underlying irreversible fibrotic process, and is defined as concentric fibrosis in the bronchiolar submucosal layer with continual external circular scarring. The fibrotic and destructive nature of this lesion is the defining characteristic. Although patchy, the airway may become slit-like or obliterated from this fibrotic process, resulting in bronchiolitis obliterans. Constrictive bronchiolitis is limited to the bronchioles and does not extend into the alveoli. The clinical features of constrictive bronchiolitis consist of a chest radiograph that is often normal, early inspiratory crackles and irreversible airflow obstruction by pulmonary function testing. Chest CT scans show a mosaic pattern, air trapping by the expiratory film, bronchiolectasis and thickened small airway walls. Although idiopathic constrictive bronchiolitis is rare, the lesion is common among lung-transplant recipients. The lesion also occurs from certain types of toxic fumes, some of the connective tissue diseases, specific types of medications and post respiratory infection. Unusual exposures have also been described as a cause of constrictive bronchiolitis, such as consumption of the leafy vegetable Sauropus androgynus in far eastern Asia and from inhaling diacetyl, the ketone butter flavoring used in microwave popcorn production. Empirical treatment consists of corticosteroid and immunosuppressive agents. Antifibrotic agents may be successful in the future. This is generally a nonsteroid-responsive lesion and for disabling disease, lung transplantation can be a successful option.

Introduction

Constrictive bronchiolitis (CB) obliterans is an important respiratory illness of the small airways because of its fibrotic irreversible nature. For the clinician, the bronchiolar airway obliteration diseases can be divided into two major lesions, one predominantly fibrotic and the other inflammatory. The first lesion is CB, which is an irreversible lesion that develops by concentric fibrosis in the bronchiole submucosa layer with continual external circular scarring. The fibrotic and destructive nature of this lesion is the defining characteristic. Although patchy, the airway may become slit-like or obliterated from the fibrotic process, resulting in bronchiolitis obliterans. The second lesion is proliferative bronchiolitis with intraluminal polyps, which is a steroid-reversible lesion developing from the internal layer that fills the lumen causing bronchiolitis obliterans.

CB is limited to the bronchioles and does not extend into the alveoli. Proliferative bronchiolitis with intraluminal polyps may be limited to the bronchioles, but often extends into respiratory bronchioles and alveoli with intra-alveolar buds of granulation tissue resulting in bronchiolitis obliterans organizing pneumonia (BOOP). The lung architecture is maintained in BOOP without fibrotic destruction. With CB, there may be severe and extensive fibrotic airway remodeling.

CB obliterans and proliferative bronchiolitis with intraluminal polyps are two distinct pathological lesions, probably with different cellular and cytokine pathogenic pathways. Details of these pathways have not yet been fully established. They both appear to begin early with an inflammatory reaction, but the elements of this reaction are probably different as CB proceeds to a fibrotic process and the proliferative bronchiolitis with intraluminal polyps continues as an inflammatory process. Similar to CB, BOOP is also patchy in nature. The BOOP lesion is not a temporal spectrum of disease as first occurring in the bronchioles and later extending into the alveoli, but a simultaneous process occurring in the distal bronchioles, respiratory bronchioles and alveoli.

With regard to causes and coexisting medical conditions, in some situations there is an overlap between CB and proliferative bronchiolitis with intraluminal polyps while in other situations there is no overlap. Both lesions occur in the connective tissue diseases, although one may be more prominent than the other, such as CB occurring in scleroderma and BOOP occurring in lupus and mixed connective tissue disorders. There is no overlap drug-related reactions. Penicillamine may cause CB obliterans and amiodarone causes BOOP. Certain types of toxic fumes, such as sulfur dioxide and ammonia, may cause CB, while nitrogen dioxide causes intraluminal polyps with obliteration. Clinicians need to take a detailed occupational history when evaluating patients with nontransplant bronchiolitis obliterans as the best treatment is prevention from further exposure, and it is important to alert others of the possible risk. For lung transplantation, CB or BOOP may occur in transplant recipients, but for different reasons, CB is from chronic organ rejection, while BOOP is due to a viral infection or nonchronic rejection.

Clinical findings may be indistinguishable between CB and proliferative bronchiolitis occurring in the mid to distal bronchiolar airways. However, the clinical findings are distinctively different between CB and proliferative bronchiolitis, extending into the alveoli as BOOP. For CB obliterans, the chest radiograph is often normal, there are early inspiratory crackles and there is irreversible airflow obstruction by pulmonary function testing. For BOOP, the chest radiograph shows bilateral patchy infiltrates, there are end-inspiratory crackles, there is no airflow obstruction and there is a decreased diffusing capacity by pulmonary function testing.

The response to steroid therapy and prognosis differs widely between the CB and BOOP lesions. CB is not responsive to corticosteroid therapy and has a poor prognosis, while the BOOP lesion is highly responsive to steroid therapy with a cure rate of 65-80%. Therefore, it is important for the pathologist and clinician to distinguish between these two lesions. The treatment challenge for the clinician is to develop a program to successfully manage individuals with CB and to cure individuals with the BOOP lesion. This review will be a discussion of CB regarding the causes and coexisting diseases, as well as the clinical, radiologic and physiological findings.

Pathological Description

The term 'constrictive bronchiolitis' (or 'CB') is used for the concentric fibrotic lesion of the bronchiolar submucosa. This lesion is characterized by "a peribronchiolar fibrotic process that surrounds rather than fills the lumen", resulting in extrinsic compression and obliteration of the airway.[1] There is mural thickening by submucosal collagenous fibrosis with progressive concentric narrowing associated with luminal distortion, mucous stasis and chronic inflammation.[2] CB is a late, fibrotic, concentric bronchiolitis that occurs with or without complete obliteration.[3]. Popper wrote that CB was called 'fibrosing bronchiolitis' in the old German pathology literature.[4] The lesion preferentially involves membranous bronchioles and is characterized by fibrosis of the stroma and narrowing of the lumen in a concentric fashion. The muscle layer may be hypertrophic in early lesions, atrophic in late stages and replaced by fibrotic tissue at the end stage. Homma and colleagues noted that constrictive obliterative bronchiolitis is characterized by concentric narrowing or complete obliteration of the airway lumen due to a submucosal lesion occurring in the membranous bronchioles and sparing the distal respiratory bronchioles.[5] Visscher and Myers noted that CB is often patchy and focal, making the diagnosis difficulty from a transbronchial biopsy, and advanced cases may be especially inconspicuous because of lack of active inflammation and disappearance of bronchioles[6].

Cause & Clinical Settings

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

Idiopathic Obliterative Bronchiolitis

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

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

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.[14-16] 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

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

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 & Drug-related Bronchiolitis Obliterans

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

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]

Miscellaneous Constrictive Bronchiolitis

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]

Lung-transplant Bronchiolitis Obliterans

Improved survival after lung transplantation continues at an accelerated rate while post lung-transplantation fibrotic constrictive obliterative bronchiolitis continues to be a major lifethreatening complication.[37,38] The surgical group from the University of Virginia (VA, USA) reported a 1-year survival rate of 86%, a 3-year rate of 71% and a 5-year rate of 55%.[39] They found no difference in survival rate between those over or under 60 years of age for single lung transplantation.[38] There has been an explosion of research in the obliterative bronchiolitis lesion, with 853 publications from 1990 to 2005 [38], and more than 1000 publications by the end of 2006.

The histological findings of post lung-transplant lesions indicate the fibrotic CB obliterans lesion. A clinical system based on FEV1 for the clinical diagnosis of bronchiolitis obliterans has been established for two major reasons [40]: the disease is common among post-transplant recipients (affecting up to 50-60% of patients who survive 5 years after transplantation)[37]; and an invasive procedure is needed to established a definitive diagnosis because the lesion is so patchy that transbronchial biopsies are of limited value. The current accepted criteria include a five-stage classification ( Table 1 ).[41]

As bronchiolitis obliterans syndrome (BOS) is a clinical diagnosis and probably has a mix of the fibrotic and inflammatory bronchiolar lesions, studies are needed to determine its usefulness. A 2005 study of the potential BOS stage 0 (BOS 0-p) concluded that the FEV1 criterion of 81-90% of baseline provides useful predictive information for the risk of developing BOS or death in single-lung-transplant recipients.[42] Among patients who met the BOS 0-p criterion, 81% developed BOS or died within 3 years. Martinu reviewed the histological findings of the explanted lung in 12 patients who had undergone pulmonary retransplantation for BOS and found a good correlation between fibrotic CB obliterans and BOS. Even though the explanted lungs showed some degree of epithelial fibrosis and inflammation, not all had severe fibrotic changes and four had other findings that resulted in the classification.[40] These findings included two with interstitial fibrosis, one with focal invasive aspergillosis and one with chronic vascular rejection.

Risk factors for lung-transplant obliterative bronchiolitis continue to evolve with the expansion of extensive research. The group at Stanford University (CA, USA) initially described the disorder in 1984. In 2006, among 77 heart-lung-transplant recipients and 51 double-lung-transplant recipients, these researchers demonstrated the same rates of BOS for both groups, confirming heart-lung-transplant recipients are not protected from developing BOS.[43] Acute rejection is the "single most important risk factor" for bronchiolitis obliterans.[38] The Stanford group found that risk factors among their heart-lung and double-lung recipients also included non-use of cardiopulmonary bypass (p = 0.001) and use of muromonab (OKT3)-induction therapy (p = 0.0001)[43].

Primary graft dysfunction has now been established as a well-defined syndrome occurring during the initial post-transplant phase and is an important risk factor for the development of bronchiolitis obliterans.[44-46] The syndrome is characterized by diffuse infiltrates considered to be reperfusion edema and in severe situations represents acute respiratory distress syndrome. Reperfusion edema has been associated with high perioperative mortality, but also with poor long-term survival and more rapid progression to BOS.[44] The International Society for Heart and Lung Transplantation has proposed a standard definition of primary graft dysfunction based on chest x-ray appearance and the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FiO2) ratio ( Table 2 ).

Daud and colleagues found that among 334 lung-transplant recipients, 130 (39%) had grade 1 primary graft dysfunction, 69 (20%) had grade 2, and 70 (21%) had grade 3.[45] All grades of primary graft dysfunction were associated with increased risk of BOS stage 1 with increasing risk with increase grades of primary graft dysfunction from a risk ratio of 1.73 for grade 1 to 2.53 for grade 3. This risk was independent of acute rejection and there was no association between primary graft dysfunction and acute rejection.

The pathogenesis and mechanism of lung-transplant-related bronchiolitis obliterans begins with injury and inflammation of bronchiolar airway epithelial cells causing excessive fibroproliferation because of ineffective epithelial regeneration and aberrant tissue repair[47]. Acute rejection is one of the major factors causing the injury by inducing immunologic injuries directed toward epithelial and endothelial cells, especially if the acute rejection is severe and recurrent. Others factors causing injury include HLA mismatch, Cytomegalovirus infections, other lung infections and gastroesophageal reflux. Acute vascular injury from acute rejection is also linked to chronic bronchiolar airway disease. A 2006 study demonstrated that a decrease in microvascular supply to the small airways precedes bronchiolitis obliterans, and onset of the fibrotic airway disease was associated with an increased number of smaller vessels, suggesting neovascularization[49]. Exhaled nitric oxide has been proposed as a noninvasive marker of small airway reaction, yet the ability of expired nitric oxide to predict BOS in an individual patient has not been established.[37] An exhaled breath condensate pH study of patients with allograft rejection after lung transplantation showed the condensate pH was significantly decreased in patients with BOS.[48]

Management of BOS begins with prevention and early detection, which includes not limiting the use of cardiopulmonary bypass, and using the least toxic induction and post-transplant therapies. Current immune-suppressive regimens generally include a calcineurin inhibitor, a purine synthesis inhibitor and a corticosteroid.[37] The calcineurin inhibitor tacrolimus has emerged as an alternative to cyclosporine for patients with recurrent acute rejection; although there have been no convincing studies indicating that this agent is more effective in preventing BOS.[38] Calcineurin induces IL-2 and, therefore, cyclosporine and tacrolimus decrease cytokine IL-2 levels, leading to a decreased inflammatory response. In some centers, mycophenolate mofetil is replacing azathioprine as the purine synthesis inhibitor of choice.[38]

Treatment of established BOS consists of augmenting immunosuppression by changing medications within therapeutic classes, by adding medications or by applying immune-modulating therapies.[37] As BOS represents a heterogeneous syndrome with alloimmune and nonalloimmune mechanisms, vigorous efforts to identify and treat infections are needed during exacerbations.

Macrolides, such as clarythromycin and azithromycin, are being evaluated for the treatment of BOS. The macrolide's anti-inflammatory action has been used successfully for the treatment of suppurative and inflammatory lung disorders. The macrolides were shown to be very effective for the treatment of inflammatory disorder diffuse pan-bronchiolitis many years ago, improving the 10-year survival in patients with Pseudomonas aeruginosa infection from less than 15% to more than 90% among these patients.[50] As the BOOP lesion is an inflammatory process, macrolides appear to be effective in patients with this disorder.[51] Whether macrolides will be effective for the fibrotic lesion of lung-transplantation CB obliterans is not known. It would be anticipated that results will be variable because BOS is a clinically based diagnosis that probably includes patients with the nonresponsive fibrotic CB obliterans lesion and the responsive inflammatory proliferative polypoid bronchiolitis obliterans lesion. For example, Shitrit and colleagues in Israel found short-term improvement in lung function in five out of six lung-transplant recipients with BOS. For example, Shitrit and colleagues in Israel found 10 months of azithromycin treatment had no effect in 11 patients whose mean FEV1 was 40% at initiation of treatment and 38% after 10 months.[52] Yet, in a successful study, Yates and colleagues in England found low-dose macrolides reversed declining lung function in patients with BOS.[53] The San Antonio and Johns Hopkins lung-transplant groups urge a prospective, mulitcenter, randomized trial of azithromycin to make the determination.[54] In 2007, Vanaudenaerde and colleagues found that macrolides inhibit airway cellular IL-8 production, while corticosteroids, tacrolimus, cyclosporine and rapamycin do not.[55]

Rapamycin (sirolimus) may be useful for stabilizing or improving pulmonary function in patients with BOS, yet the adverse effects, such as infections and myelosuppression, must be considered.[56] Pirfenidone may be an effective antifibrotic agent for the treatment of the fibrotic CB obliterans lesions, although no clinical trials have been undertaken.[57]

Radiologic Features

The routine chest radiograph is generally of minimal value in CB obliterans as the films are usually normal or may show slight hyperinflation. High-resolution chest CT scans are helpful for establishing a diagnosis of CB by showing a mosaic pattern of pulmonary lobules of increased and decreased lung density, and air trapping.[58] Bronchiectasis and bronchiolectasis are also seen. The expiratory image showing air trapping is useful for establishing a diagnosis of post lung-transplant BOS, but this single finding is not useful for early detection.[59] However, a composite CT score, which includes bronchiectasis, mucus plugging, airway wall thickening, consolidation, mosaic pattern during inspiration and air trapping during expiration, correlates with FEV1 and indicates a potential means of early detection.

Pulmonary Function Testing

Pulmonary function tests traditionally show major airway irreversible obstruction with decreased FEV1 and FEV1:FVC ratio with no response to bronchodilator inhalation. However, as the large airways are not involved, a restrictive pattern may occur with decreased vital capacity and corresponding FEV1, resulting in no decrease in the FEV1:FVC ratio. In this setting, the small airways are often completely obliterated on a focal basis, resulting in a normal diffusing capacity because remaining lung is normally ventilated and perfused. Markopoulou and others found that among 19 patients with bronchiolar obliteration from both fibrotic and inflammatory lesions, 11 had airflow obstruction, one had restrictive pattern, one had mixed obstructive and restriction, two had air trapping, and four had normal spirometric values.[61]

Clinical Course

There are generally two clinical tracks that a patient's course may follow in individuals with the fibrotic obliterative bronchiolitis lesion. The first is a relentless progressive course occurring during several months or slowly over many years. The second is a course of exacerbations over years, sometimes returning to baseline and sometimes progressively worsening after each exacerbation. In unusual situations, the course may be static and stable after the initial presenting episode and, if mild or moderate, the individual will do well. However, if the initial lesion is severe, the naturally occurring yearly decreasing lung function will eventually result in respiratory failure.

Management & Treatment

The management of CB usually begins with an empirical course of high-dose corticosteroid therapy in the order of 1 mg/kg for.[50] This approach will treat the inflammatory component and in some situations may be curative if the process is the inflammatory intraluminal polypoid process. For the purely fibrotic lesion, the corticosteroid should be stopped shortly after stabilization as adverse reactions and possible interference with the natural healing process outweigh the benefit. However, additional empirical use of corticosteroid therapy can be beneficial for future intermittent exacerbations.

Bronchodilator inhalers and inhaled corticosteroids are beneficial for a small percentage of patients with CB and can be administered during the early stages of the disease to determine efficacy. Rapid and aggressive treatment of respiratory infections is fundamental to the management of this disorder. After stabilization, a pulmonary rehabilitation program with an ongoing home exercise program is very beneficial for this group of patients, who are able to improve their muscular conditioning as well as their sense of well being.

For development of the BOS among lung-transplant recipients, treatment consists of increasing the dose of immune suppression agents, adding new immune-suppressive or immune-modulating therapies. The regimen generally includes increasing dosage of a corticosteroid, a calcineurin inhibitor, such as cyclosporine or tacrolimus, and a purine synthesis inhibitor, such as azathioprine or mycophenolate mofetil.[35,36] For individuals with the purely fibrotic bronchiolar lesion who have not responded to corticosteroid therapy, antifibrotic agents could be utilized; however, this would be on an anecdotal basis, because controlled clinical studies have not yet established an effective agent.

A 3-month empirical course of a macrolide, such as azithromycin 250 mg three-times weekly, can be considered in certain situations, especially if there is an inflammatory component to the lesion as this agent is well tolerated by patients, has few adverse reactions at this dosage and has been shown to be beneficial in individuals with an inflammatory airway lesion.[51] This agent will probably not be effective for a purely fibrotic CB lesion and therefore can be stopped after 3 months if there has been no improvement. Finally, although this option should be avoided until it is clear the patient has no other choice, for severe and lifethreatening progressive illness, lung transplantation is an effective and successful lifesaving treatment.

Summary & Conclusions

CB is concentric submucosal fibrosis of the bronchiolar airway leading to narrowing and obliteration. Shortness of breath is the most common presenting symptom and early inspiratory crackles are heard by lung auscultation. Pulmonary function demonstrates irreversible airflow obstruction with decreased FEV1:FVC ratio, although a restrictive pattern may be seen. The chest radiograph shows normal lungs or hyperinflation, while the chest CT shows air trapping by the expiratory view, a mosaic pattern, bronchiolectasis and small airway wall thickening. Corticosteroid therapy is effective for the inflammatory component of the illness and for exacerbations. Immunosuppressive agents may be effective in some individuals. Antifibrotic agents may be effective in the future. Lung transplantation is an option for life-threatening, disabling disease.

Expert Commentary

CB obliterans is an important respiratory illness because of its irreversibility. Although idiopathic CB is rare, the lesion is common among lung-transplant recipients. The lesion also occurs from certain types of toxic fumes, some connective tissue diseases, specific types of medications and post respiratory infection. Unusual exposures have recently been described as a cause of the fibrotic constrictive bronchiolar lesion, such as consumption of the leafy vegetable S. androgynus in far eastern Asia and from inhaling diacetyl, the ketone butter flavoring used in microwave popcorn production. Shortness of breath is the major symptom and the typical physiological finding is airflow obstruction that is nonresponsive to an inhaled bronchodilator agent. The chest radiograph is usually normal or may show hyperinflation. The high-resolution chest CT scan shows a mosaic pattern, air trapping by the expiratory film, bronchiolectasis and thickened small airway walls. Empirical treatment consists of a corticosteroid agent and immunosuppressive agents. Antifibrotic agents may be successful in the future. This is generally a nonsteroid-responsive lesion and, for disabling disease, lung transplantation can be a successful option.

Five-year View

Unusual environmental or occupational causes of CB obliterans will continue to be discovered and described. A successful antifibrotic agent may emerge during the next 5 years.


Table 1. Classification of Bronchiolitis Obliterans Syndrome


Stage Classification details
BOS 0 1 > 90% of baseline and FEF2575 > 75% baseline
BOS 0-p* FEV1 81-90% of baseline and/or FEF25≤ 75% baseline
BOS 1 FEV1 66-80% of baseline
BOS 2 FEV1 51-65% of baseline
BOS 3 FEV1 50% or less of baseline

*This category has been created because studies suggest that FEF2575deteriorates before FEV1 in most recipientsp.[31,38]
BOS: Bronchiolitis obliterans syndrome; BOS 0-p: Potential BOS stage ;0; FEF2575:Forced mid-expiratory flow; FEV1: Forced expiratory volume in 1 s.

 

Table 2. Classification of Primary Graft Dysfunction


Grade Classification details
0 PaO2:FiO2 ratio >300 mmHg; normal x-ray
1 PaO2:FiO2 ratio >300 mmHg; pulmonary edema x-ray
2 PaO2:FiO2 ratio 200-300 mmHg; pulmonary edema x-ray
3 PaO2:FiO2 ratio <200 mmHg; pulmonary edema x-ray

PaO2:FiO2: Ratio of artial pressure of arterial oxygen to the fraction of inspired oxygen.; Data from [46].

 

Box 1. Causes and Clinical Associations of Constrictive Bronchiolits


  • Idiopathic

  • Fume or oral toxin exposure

    • Toxic fumes: sulfur dioxide, ammonia, methylisocyanate (industrial accident, Bhopal, India) or fire smoke
    • Mustard gas from chemical warfare

    • Diacetyl exposure from butter flavoring

    • Ingested liquid mixture of Sauropus androgynus

  • Bone marrow transplantation

  • Stem cell transplantation

  • Lung transplantation

  • Post infection

    • Mycoplasma pneumoniae

    • Adenovirus

    • Influenza virus

  • Drug reaction

    • Gold therapy

    • Penicillamine

  • Connective tissue disorders

    • Rheumatoid arthritis

    • Scleroderma

  • Miscellaneous disorders

    • Ulcerative colitis

    • Stevens-Johnson syndrome

    • Neuroendocrine cell hyperplasia

    • Neuroendocrine cell hyperplasia with carcinoid tumorlets

    • Aspiration of foreign bodies or esophageal gastric contents

 



References

Papers of special note have been highlighted as:
* of interest
** of considerable interest

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Sidebar: Key Issues

  • The pathologic defintion of constrictive bronchiolitis obliterans is concentric fibrosis in the bronchiolar submucosal layer with external circular scarring.

  • The causes of constricitve bronchiolitis include toxic fumes, oral toxins, respiratory infections, drugs and organ transplantation, while associated disorders include connective tissue diseases, ulcerative colitis and Stevens-Johnson syndrome.

  • Lung-transplantation bronchiolitis obliterans continues to occur commonly, especially after graft-versus-host reaction, and is a form of chronic organ rejection.

  • Radiologic features utilizing high-resolution CT scans include mosaic pattern, air trapping and bronchiectasis in late-stage disease.

  • Pulmonary function is variable and usually demonstrates a decreased FEV1:FVC ratio, although a mixed obstruction and restriction pattern is sometimes seen.

  • The expected clinical course is either a relentless progressive course or an intermittent course of exacerbations.

  • Treatment consists of an empiric course of high-dose corticosteroid therapy, a trial of bronchodilators and inhaled corticosteroids, immune-suppressive or immune-modulating therapy, and lung transplanation for disabling disease.



Gary R. Epler, Clinical Associate Professor, Harvard Medical School, Pulmonary & Critical Care Medicine Brigham & Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. gepler@partners.org