Bronchiolitis Obliterans (BO; Obliterative Bronchiolitis)

History

1835: bronchiolitis obliterans was first described by Reynaud

Classification of Bronchiolar Disorders

Etiology

Infection

General Comments
- Epidemiology
  - Cases occur predominantly in children
  - Prevalence of post-infection BO is presumed to be low (considering the large number of these infections and small number of observed BO cases)
Adenovirus (see Adenovirus)
Influenza Virus (see Influenza Virus)
Legionellosis (see Legionellosis)
Measles Virus (see Measles Virus)
Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae)
Parainfluenza Virus (see Parainfluenza Virus)
Respiratory Syncytial Virus (RSV) (see Respiratory Syncytial Virus)

Connective Tissue Disease

Eosinophilic Fasciitis (see Eosinophilic Fasciitis)
Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis)
- Epidemiology: RA is the connective tissue disease most commonly associated with BO
  - RA-associated BO was originally thought to be associated with gold/penicillamine use -> however, the persistent incidence of RA-associated BO despite decreased use of these drugs suggests that RA itself is responsible
  - Peak Group: long-standing RA seropositive females in 40’s-50’s -> these cases may have rapid clinical progression
Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus)
- Epidemiology: only a few reported cases
Polydermatomyositis (see Polydermatomyositis)
- Epidemiology: only a few reported cases

Post-Hematopoietic Stem Cell Transplant (HSCT) (Bone Marrow Transplant, BMT) (see Hematopoietic Stem Cell Transplant)

Epidemiology: BO is the most common non-infectious pulmonary complication following allogeneic BMT/SCT
- Increasing Incidence: BO associated with BMT/SCT has increased in incidence over the last 30 yrs
- Incidence: 5.5% in allogeneic BMT/SCT (incidence is 14% in subpopulation of patients with extrathoracic chronic graft vs host disease)
Risk Factors
- Acute Graft vs Host Disease (GVHD) (see Graft vs Host Disease)
- Busulfan Conditioning Regimen (see Busulfan)
- Chronic Graft vs Host Disease (GVHD) (see Graft vs Host Disease): chronic GVHD occurs in 33% of long-term survivors of allo-BMT -> BO occurs in 10% of chronic GVHD cases
- Factors Related to Transplant Type: there is an increased risk of BO with the use of peripheral blood stem cells
- Gastroesophageal Reflux Disease (GERD) (see Gastroesophageal Reflux Disease)
- Greater Degree of HLA Mismatch
- Hypogammaglobulinemia (see Hypogammaglobulinemia)
- Methotrexate (see Methotrexate): causes BO only in combination with chronic GVHD, not alone (methotrexate induces MHC expression, which are targets for T-cell in GVHD)
- Older Age of Donor/Recipient
- Tobacco Abuse (see Tobacco)
- Underlying Hematologic Disease
- Use of Graft vs Host Disease Prophylaxis (see Graft vs Host Disease): immunosuppression for GVHD increases viral infection risk
- Viral Infection: viral infection occurs in 25-30% of post-SCT BO cases
  - Respiratory Syncytial Virus/Parainfluenza Virus (see Respiratory Syncytial Virus and Parainfluenza Virus): infection with these viruses within the first 100 days post-BMT/SCT increases risk for BO within the first year after transplantation [MEDLINE]
Physiology: BO likely represents chronic graft vs host disease in the lung

Post-Heart-Lung or Lung Transplant (see Cardiac Transplant) and Lung Transplant)

Epidemiology
- 10 Year Incidence: 70% of cases develop BO [MEDLINE]
- Risk Related to Type of Immunosuppression: incidence of BO is lower with taccolimus, as compared to cyclosporine A [MEDLINE]
Physiology: related to chronic allograft rejection (associated with HLA locus mismatch)
- Cofactors: PCP, CMV, altered mucociliary clearance, altered blood flow due to bronchial artery ligation, immunosuppression, and aspiration due to loss of cough)

Drugs

Amiodarone (Cordarone) (see Amiodarone)
Carmustine (see Carmustine)
Gold (see Gold)
- Epidemiology: unclear etiologic association (as cases occurred in RA patients that were treated with this drug)
Penicillamine (see Penicillamine)
- Epidemiology: unclear etiologic association (as cases occurred in RA patients that were treated with this drug)
Topotecan (Hycamtin) (see Topotecan)

Toxic Fume Exposure

2,3-Pentanedione (see 2,3-Pentanedione)
- Epidemiology: used in manufacture of food flavorings
Ammonia Gas (see Ammonia)
Chlorine Inhalation (see Chlorine)
Chromic Acid Inhalation (see Chromic Acid)
Cocaine (see Cocaine)
Diacetyl (see Diacetyl)
- Epidemiology
  - Diacetyl-Associated BO Cases Have Been Reported in Workers mManufacturing Butter Flavoring Used in Popcorn Processing Plants
  - Diacetyl is Also a Component (or is Used in the Manufacturing Process) of Buttered Popcorn/Chips, Candy, Butter, Ice Cream, Baked Goods, and Coffee Flavorings
Hydrogen Fluoride Inhalation (see Hydrogen Fluoride Gas)
Hydrogen Sulfide Inhalation (see Hydrogen Sulfide Gas)
- Epidemiology: reports of hydrogen sulfide-associated BO date back to World War I (1914-1918) and the Iran-Iraq War (1980-1988), during which this agent was used
- Clinical: acute chemical pneumonitis (chest tightness, dyspnea, massive hemoptysis) -> fibrous exudates and granulation tissue in bronchi/distal bronchioles -> eventual development of bronchiolitis obliterans
Nitrogen Oxides: used in fertilizer production (probably involved in silo-filler’s disease)
- Nitrogen Dioxide Inhalation (see Nitrogen Dioxide)
  - Epidemiology: BO occurs in only 5% of cases
Ozone Inhalation (see Ozone)
Phosgene Gas Inhalation (see Phosgene Gas)
Smoke Inhalation (see Smoke Inhalation)
Sulfur Dioxide (see Sulfur Dioxide)
- Epidemiology
  - Reports of US Soldiers from Iraq/Afghanistan with BO Who Were in Proximity to a Fire in a Sulfur Mine in 2003 (fire produced high ambient air levels of sulfur dioxide, a known cause of BO), exposure to dust storms, exposure to incinerated solid/human waste, and/or exposure to combat smoke (NEJM, 2011) [MEDLINE]
Sulfur Mustard Gas Inhalation (see Sulfur Mustard Gas)
- Epidemiology
  - Reports of Sulfur Mustard-Associated BO Date Back to World War I (1914-1918) and the Iran-Iraq War (1980-1988), During Which this Agent was Used
- Clinical: acute chemical pneumonitis (chest tightness, dyspnea, massive hemoptysis) -> fibrous exudates and granulation tissue in bronchi/distal bronchioles -> eventual development of bronchiolitis obliterans

Other Toxic Exposures

Fiberglass
Papaverine (see Papaverine)
- Epidemiology: Sauropus Androgynus (Katuk) juice is used for weight loss
- Physiology: papaverine is found in juice extracted from Sauropus Androgynus (Katuk)
- Clinical: respiratory symptoms develop several weeks after ingestion

Other

Hypersensitivity Pneumonitis (HP) (see Hypersensitivity Pneumonitis)
Cystic Fibrosis (CF) (see Cystic Fibrosis)
IgA Nephropathy (see IgA Nephropathy)
- Epidemiology: case report [MEDLINE]
Neuroendocrine Cell Hyperplasia/Multiple Carcinoid Tumorlets (see Carcinoid)

Idiopathic Bronchiolitis Obliterans

May Occur

Physiology

Injury to and Inflammation of Small Airway Epithelial Cells and Subepithelial Structures, Leading to Excessive Fibroproliferation (and Ineffective Epithelial Regeneration)
- Decreased Number of Club Cells (formerly called Clara Cells): these cells are known to promote regeneration of bronchiolar epitheliam
- Polymorphisms in Innate Immune System Genes: associated with transplant-associated BO

Diagnosis

Arterial Blood Gas (ABG) (see Arterial Blood Gas)

Hypoxemia (see Hypoxemia): variable (depending on extent of disease)
Hypocapnia (see Hypocapnia)

Chest X-Ray (see Chest X-Ray)

Usually Normal
Hyperinflation/Increased Linear or Reticular Markings Due to Airway Wall Thickening: suggestive, but non-specific, findings

Chest CT (see Chest Computed Tomography)

Expiratory Air Trapping (Mosaic or Diffuse Perfusion/Attenuation): due to hyperinflation of distal lung
Bronchial Wall Thickening (v or y-Shaped Opacities)
Centrilobular Nodules

High-Resolution-Chest CT (see High-Resolution Chest Computed Tomography)

General Comments: imaging procedure of choice
- Performed at Both TLC (Inspiratory) and RV (Expiratory)
- Expiratory HRCT is More Sensitive than PFT’s to Detect Gas Trapping, Resulting in Earlier Detection of Disease (Radiology, 2001) [MEDLINE]
Expiratory Air Trapping (Mosaic or Diffuse Perfusion/Attenuation): areas of decreased attenuation represent bronchial/bronchiolar gas trapping
Bronchial Wall Thickening (v or y-Shaped Opacities)
Centrilobular Nodules
Dilation and Thickening of Large Airways (Resembling Bronchiectasis): may be seen in advanced cases

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests)

Spirometry: obstruction without bronchodilator reversibility (although less commonly, cases have been described with either mixed obstruction-restriction or rarely, restriction)
- FEV1: decreased
- FVC: normal-slightly decreased
- FEV1/FVC: decreased
Lung Volumes: air trapping
- TLC: normal
- RV: increased
- RV/TLC: increased (consistent with gas trapping)
DLCO: initially normal, decreases with disease progression

Bronchoscopy (see Bronchoscopy)

Bronchoalveolar Lavage
- Increased Class 2 MHC Antigens
- Activated T-Cells: in heart-lung and lung transplant cases (primed lymphocyte, cell-mediated lympholysis tests correlate with risk of BO in these patients)
Bronchoalveolar Lavage in Lung Transplants
- CD4-Predominance Against Class 2 MHC: correlates with rejection
- CD8-Predominance Against Class 1 MHC: correlates with BO
Trans-Bronchial Biopsy (TBB)

Video-Assisted Thoracoscopic Surgery (VATS) with Lung Biopsy (see Video-Assisted Thoracoscopic Surgery)

“Constrictive Bronchiolitis” Pattern: fibroproliferative thickening of bronchiolar walls causing narrowing of bronchiolar lumen (may completely obliterate bronchioles)

Clinical Presentations

General Comments

Bronchiolitis Obliterans Syndrome (BOS): term used to describe the clinical entity of bone marrow/stem cell transplant or lung transplant-associated bronchiolitis obliterans (small airways obstruction with airflow limitation, etc) in the absence of histologic confirmation

Toxic Fume Exposure-Associated Bronchiolitis Obliterans

Onset: insidious onset of symptoms about 2-8 wks after toxic fume exposure
Clinical
- Dry Cough (see Cough)
- Dyspnea (see Dyspnea)
- Expiratory Wheezing (see Obstructive Lung Disease): may be heard (although exam is usually normal)

Infection-Associated Bronchiolitis Obliterans

Onset: insidious onset of symptoms about 2-8 wks after infection
- Disease may evolve for months-years after the initial pneumonia/respiratory illness
Clinical
- Dry Cough (see Cough)
- Dyspnea (see Dyspnea)
- Expiratory Wheezing (see Obstructive Lung Disease): may be heard (although exam is usually normal)

Connective Tissue Disease-Associated Bronchiolitis Obliterans

Rheumatoid Arthritis-Associated Cases: rapid progression (although some cases have more insidious course)
- Dry Cough (see Cough)
- Dyspnea (see Dyspnea)

Bone Marrow/Stem Cell Transplant-Associated Bronchiolitis Obliterans

Onset
- Latency of Chronic GVHD: chronic GVHD presents with mucositis, esophagitis, rash about 2-3 months post-BMT
- Latency of BO: BO typically occurs 4-6 mo later
  - Range: BO has been reported to occur from 30 days-2 yrs post-BMT/SCT (>90% of affected cases develop within 18 mo post-BMT/SCT)
Diagnosis
- CXR: normal-hyperinflated
Clinical
- Bibasilar Rales
- Dry Cough (see Cough)
- Dyspnea (see Dyspnea): may be severe and progressive
- Expiratory Wheezing (see Obstructive Lung Disease)
- Hypoxemia (see Hypoxemia)

Heart-Lung/Lung Transplant-Associated Bronchiolitis Obliterans

Latency: BO may occur months-years after transplant
- Mean Latency: 16-20 mo after transplant (but may occur as early as 3 mo post-lung transplant)
Diagnosis
- CXR: usually normal
- HRCT: peripheral bronchiectasis, patchy consolidation, decreased peripheral vascular markings, mosaic attentuation (due to air trapping), and bronchial dilation
- FOB with TBB: used to exclude infection, anastomotic complications, and acute rejection and to diagnose BO (TBB has 15-80% sensitivity for diagnosis of BO)
- PFT’s: FEV1 and FEF25-75are used to clinically stage BO
Clinical: may be asymptomatic
- Productive Cough (see Cough)
- Dyspnea (see Dyspnea): which may be progressive
- Hypoxemia (see Hypoxemia)
- Hypocapnia
- Irreversible Airflow Obstruction with Moderately Decreased DLCO
Prevention
- Azithromycin (Zithromax) (see Azithromycin): my be effective in decreasing the incidence of BO [MEDLINE]
- Azathioprine (Imuran) (see Azathioprine): decreases risk of BO
- Surveillance for Rejection: decreases risk of chronic rejection and therefore, BO

Treatment

Specific Treatment of Toxic Fume-Associated Bronchiolitis Obliterans

General Comments: there is no curative treatment
Bronchodilators
- Shown to Be Useful in Sulfur Mustard Gas-Associated Cases (Inhal Toxicol, 2007) [MEDLINE]
Inhaled Corticosteroids (see Corticosteroids)
- Shown to Be Useful in Sulfur Mustard Gas-Associated Cases (Inhal Toxicol, 2007) [MEDLINE]
Systemic Corticosteroids with/without Cyclophosphamide (Cytoxan) (see Corticosteroids and Cyclophosphamide)
- Shown to be Ineffective in Diacetyl-Associated Cases (Eur Respir J, 2004) [MEDLINE]
N-Acetylcysteine (Mucomyst) (see N-Acetylcysteine)
- Shown to Be Useful in Sulfur Mustard Gas-Associated Cases (Respir Med, 2008) [MEDLINE]
Interferon Gamma-1b (Actimmune) (see Interferon Gamma-1b):
- Shown to Be Useful in Sulfur Mustard Gas-Associated Cases (J Immunotoxicol, 2014) [MEDLINE]

Specific Treatment of Bone Marrow Transplant/Stem Cell Transplant-Associated Bronchiolitis Obliterans

General Comments: general approach is to increase immunosuppression
- High-Dose Systemic Corticosteroids (see Corticosteroids)
- Imatinib (Gleevec) (see Imatinib)
- Inhaled Corticosteroids (see Corticosteroids)
- Montelukast (xxx) (see Montelukast)
- Rituximab (Rituxan) (see Anti-CD20 Therapy)
- Thalidomide (see Thalidomide)

Specific Treatment of Heart-Lung/Lung Transplant-Associated Bronchiolitis Obliterans

General Comments: general approach is to increase immunosuppression
- Alemtuzumab (see Alemtuzumab)
- Azathioprine (Imuran) (see Azathioprine)
- Azithromycin (see Azithromycin): may be useful (Clin Transplant, 2011) [MEDLINE]
  - Azithromycin Decreases the Mortality Rate in Lung Transplant-Associated BO (J Heart Lung Transplant, 2010) [MEDLINE]
- Cyclosporine A (see Cyclosporine A)
- Methotrexate (see Methotrexate)
- Montelukast (Singulair) (see Montelukast)
- Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil)
- Sirolimus (see Sirolimus)
- Tacrolimus (see Tacrolimus)

Lung Transplantation (see Lung Transplant)

May Be Considered for Select Cases

Prognosis

Epler-Colby Prognostic Classification (1983)

Toxic Fume Exposure-Associated BO: poor-good prognosis with steroid therapy
- Early steroid use may alter progression
Post-Infection-Associated BO: fair-good prognosis with steroids therapy
Connective Tissue Disease-Associated BO: poor-good prognosis with steroids
- RA cases rapidly progress with no consistent steroid response
Localized BO: good prognosis with surgical resection of area
Post-Transplant-Associated BO may respond to increased steroids/azathioprine/ATG/OKT3
- Early therapy may reverse disease
Post-BMT/SCT-Associated BO: usually poor response to steroids (especially with severe obstruction)
- Use immunosuppressives to treat GVHD
Idiopathic BO: fair-good prognosis with steroid therapy

References

General

Bronchiolitis obliterans and IgA nephropathy. A new cause of pulmonary-renal syndrome. Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):665-8 [MEDLINE]
Bronchiolar Disorders. A Clinical-Radiological Diagnostic Algorithm. Chest 2010; 137(4):938–951 [MEDLINE]
Occupational causes of constrictive bronchiolitis. Curr Opin Allergy Clin Immunol. 2013 Apr; 13(2): 167–172 [MEDLINE]
Obliterative bronchiolitis. N Engl J Med. 2014 May 8;370(19):1820-8. doi: 10.1056/NEJMra1204664 [MEDLINE]

Toxin-Associated Bronchiolitis Obliterans

Bronchiolitis obliterans from exposure to incinerator fly ash. J Occup Environ Med. 1995 Jul;37(7):850-5 [MEDLINE]
Bronchiolitis obliterans syndrome in popcorn production plant workers. Eur Respir J 2004;24:298-302 [MEDLINE]
Bronchiolitis obliterans following exposure to sulfur mustard: chest high resolution computed tomography. Eur J Radiol 2004;52:164-9 [MEDLINE]
Inhaled corticosteroids and long-acting beta 2-agonists in treatment of patients with chronic bronchiolitis following exposure to sulfur mustard. Inhal Toxicol 2007;19:889-94 [MEDLINE]
Therapeutics effect of N-acetyl cysteine on mustard gas exposed patients: evaluating clinical aspect in patients with impaired pulmonary function test. Respir Med 2008;102:443-8 [MEDLINE]
Sulfur mustard-induced pulmonary injury: therapeutic approaches to mitigating toxicity. Pulm Pharmacol Ther 2011;24:92-9 [MEDLINE]
Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan. N Engl J Med. 2011 Jul 21;365(3):222-30. doi: 10.1056/NEJMoa1101388 [MEDLINE]
Effect of recombinant human IFNγ in the treatment of chronic pulmonary complications due to sulfur mustard intoxication. J Immunotoxicol 2014;11:72-7 [MEDLINE]
The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review. Inhal Toxicol. 2014 Aug;26(9):507-23. doi: 10.3109/08958378.2014.920439 [MEDLINE]

Transplant-Associated Bronchiolitis Obliterans

Early bronchiolitis obliterans following lung transplantation: accuracy of expiratory thin-section CT for diagnosis. Radiology. 2000;216(2):472-477 [MEDLINE]
Bronchiolitis obliterans syndrome in heart-lung transplant recipients: diagnosis with expiratory CT. Radiology 2001;218:533-9 [MEDLINE]
Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003; 168:121-5 [MEDLINE]
Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses. J Infect Dis 2006;193:1619-25 [MEDLINE]
Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant 2010;29:531-7 [MEDLINE]
Clinical and immunological evaluation of 12-month azithromycin therapy in chronic lung allograft rejection. Clin Transplant 2011;25:E381-9 [MEDLINE]
A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J 2011;37:164-72 [MEDLINE]
The Registry of the International Society for Heart and Lung Transplantation: fifteenth pediatric lung and heart-lung transplantation report-2012. J Heart Lung Transplant 2012;31:1087-95 [MEDLINE]
The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung translant report-2012. J Heart Lung Transplant 2012;31:1073-86 [MEDLINE]
Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation. J Heart Lung Transplant 2012;31:797-804 [MEDLINE]