Bronchiolitis Obliterans (BO; Obliterative Bronchiolitis)

History

  • 1835: bronchiolitis obliterans was first described by Reynaud

Classification of Bronchiolar Disorders

BRONCHIOLAR DISORDERS

Etiology

Infection

  • General Comments
    • 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, [[Adenovirus]])
  • Influenza Virus (see Influenza Virus, [[Influenza Virus]])
  • Legionellosis (see Legionellosis, [[Legionellosis]])
  • Measles Virus (see Measles Virus, [[Measles Virus]])
  • Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae, [[Mycoplasma Pneumoniae]])
  • Parainfluenza Virus (see Parainfluenza Virus, [[Parainfluenza Virus]])
  • Respiratory Syncytial Virus (RSV) (see Respiratory Syncytial Virus, [[Respiratory Syncytial Virus]])

Connective Tissue Disease

  • Eosinophilic Fasciitis (see Eosinophilic Fasciitis, [[Eosinophilic Fasciitis]])
  • Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis, [[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, [[Systemic Lupus Erythematosus]])
    • Epidemiology: only a few reported cases
  • Polydermatomyositis (see Polydermatomyositis, [[Polydermatomyositis]])
    • Epidemiology: only a few reported cases

Post-Bone Marrow Transplant/Stem Cell Transplant (BMT/SCT) (see Bone Marrow Transplant, [[Bone Marrow 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 (see Graft vs Host Disease, [[Graft vs Host Disease]])
    • Busulfan Conditioning Regimen (see Busulfan, [[Busulfan]])
    • Chronic Graft vs Host Disease (GVHD) (see Graft vs Host Disease, [[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, [[Gastroesophageal Reflux Disease]])
    • Greater Degree of HLA Mismatch
    • Hypogammaglobulinemia (see Hypogammaglobulinemia, [[Hypogammaglobulinemia]])
    • Methotrexate (see Methotrexate, [[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, [[Tobacco]])
    • Underlying Hematologic Disease
    • Use of Graft vs Host Disease Prophylaxis (see Graft vs Host Disease, [[Graft vs Host Disease]]): immunosuppression for GVHD increases viral infection risk
    • Viral Infection: viral infection occurs in 25-30% of post-BMT/SCT BO cases
      • Respiratory Syncytial Virus/Parainfluenza Virus (see Respiratory Syncytial Virus, [[Respiratory Syncytial Virus]] and Parainfluenza Virus, [[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, [[Cardiac Transplant]]) and Lung Transplant, [[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, [[Amiodarone]])
  • Carmustine (see Carmustine, [[Carmustine]])
  • Gold (see Gold, [[Gold]]): unclear etiologic association (as cases occurred in RA patients that were treated with this drug)
  • Penicillamine (see Penicillamine, [[Penicillamine]]): unclear etiologic association (as cases occurred in RA patients that were treated with this drug)
  • Topotecan (Hycamtin) (see Topotecan, [[Topotecan]])

Toxic Fume Exposure

  • 2,3-Pentanedione (see 2,3-Pentanedione, [[2,3-Pentanedione]])
    • Epidemiology: used in manufacture of food flavorings
  • Ammonia Gas (see Ammonia, [[Ammonia]])
  • Chlorine Inhalation (see Chlorine, [[Chlorine]])
  • Chromic Acid Inhalation (see Chromic Acid, [[Chromic Acid]])
  • Cocaine (see Cocaine, [[Cocaine]])
  • Diacetyl (see Diacetyl, [[Diacetyl]])
    • Epidemiology
      • Diacetyl-associated BO cases have been reported in workers manufacturing butter flavoring used in popcorn processing plants
      • Diacetyl is also a component (or is used in the manufacture process) of buttered popcorn/chips, candy, butter, ice cream, baked goods, and coffee flavorings
  • Hydrogen Fluoride Inhalation (see Hydrogen Fluoride Gas, [[Hydrogen Fluoride Gas]])
  • Hydrogen Sulfide Inhalation (see Hydrogen Sulfide Gas, [[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, [[Nitrogen Dioxide]])
      • Epidemiology: BO occurs in only 5% of cases
  • Ozone Inhalation (see Ozone, [[Ozone]])
  • Phosgene Gas Inhalation (see Phosgene Gas, [[Phosgene Gas]])
  • Smoke Inhalation (see Smoke Inhalation, [[Smoke Inhalation]])
  • Sulfur Dioxide (see Sulfur Dioxide, [[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 (that 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 [MEDLINE]
  • Sulfur Mustard Gas Inhalation (see Sulfur Mustard Gas, [[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, [[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

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, [[Arterial Blood Gas]])

  • Hypoxemia (see Hypoxemia, [[Hypoxemia]]): variable (depending on extent of disease)
  • Hypocapnia (see Hypocapnia, [[Hypocapnia]])

Chest X-Ray (see Chest X-Ray, [[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, [[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, [[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 [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, [[Pulmonary Function Tests]])

  • Spirometry: obstruction without bronchodilator reversibility (although less commonly, cases have been described with either restriction or mixed obstruction-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, [[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

Lung Biopsy

  • “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, [[Cough]])
    • Dyspnea (see Dyspnea, [[Dyspnea]])
    • Expiratory Wheezing (see Obstructive Lung Disease, [[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, [[Cough]])
    • Dyspnea (see Dyspnea, [[Dyspnea]])
    • Expiratory Wheezing (see Obstructive Lung Disease, [[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, [[Cough]])
    • Dyspnea (see Dyspnea, [[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, [[Cough]])
    • Dyspnea (see Dyspnea, [[Dyspnea]]): may be severe and progressive
    • Expiratory Wheezing (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
    • Hypoxemia (see Hypoxemia, [[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, [[Cough]])
    • Dyspnea (see Dyspnea, [[Dyspnea]]): which may be progressive
    • Hypoxemia (see Hypoxemia, [[Hypoxemia]])
    • Hypocapnia
    • Irreversible Airflow Obstruction with Moderately Decreased DLCO
  • Prevention
    • Azithromycin (see Azithromycin, [[Azithromycin]]): my be effective in decreasing the incidence of BO [MEDLINE]
    • Azathioprine (Imuran) (see Azathioprine, [[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 [MEDLINE]
  • Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])
    • Shown to be useful in sulfur mustard gas-associated cases [MEDLINE]
  • Systemic Corticosteroids with/without Cyclophosphamide (Cytoxan) (see Corticosteroids, [[Corticosteroids]] and Cyclophosphamide, [[Cyclophosphamide]])
    • Shown to be ineffective in diacetyl-associated cases [MEDLINE]
  • N-Acetylcysteine (see N-Acetylcysteine, [[N-Acetylcysteine]])
    • Shown to be useful in sulfur mustard gas-associated cases [MEDLINE]
  • Interferon Gamma-1b (Actimmune) (see Interferon Gamma-1b, [[Interferon Gamma-1b]]):
    • Shown to be useful in sulfur mustard gas-associated cases [MEDLINE]

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

  • General Comments: general approach is to increase immunosuppression

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

  • General Comments: general approach is to increase immunosuppression

Lung Transplantation (see Lung Transplant, [[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]