Excerpt from Bronchiolitis Obliterans Organizing Pneumonia

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Background

Organizing pneumonia features granulation tissue in the distal air spaces. When organizing pneumonia is associated with granulation tissue in the bronchiolar lumen, the qualifying term bronchiolitis obliterans (BO) is added.

Organizing pneumonia may be classified according to the following criteria¹:

• The cause has been determined.
• The cause remains undetermined but is occurring in a specific and relevant context.
• The disease is cryptogenic (idiopathic) organizing pneumonia (COP).

Cryptogenic organizing pneumonia (COP) is often confused with bronchiolitis obliterans organizing pneumonia (BOOP). COP is a clinicopathologic syndrome that is rapidly resolved with corticosteroids but that is also marked by frequent relapses when treatment is tapered off or stopped.

Radiologically identical peripheral airspace consolidation occurs in patients with chronic eosinophilic pneumonia (CEP) and BOOP. CEP primarily involves the upper lobe, while in BOOP, consolidation is predominantly in the lower zones, although some patients have pathologic characteristics of CEP and BOOP.

A tissue biopsy specimen is needed for a precise diagnosis, but clinicoradiologic characteristics determined through biopsy-based studies may provide enough diagnostic information. This article discusses BOOP in the general context of organizing pneumonia; it combines data from BOOP and COP patient research. Organizing pneumonias that are of known cause are indistinguishable from those that are of unknown cause.²

Pathophysiology

About 50% of BOOP cases are idiopathic.³ The following conditions are associated with BOOP:

• Conditions in which the cause is determined
• • Radiation therapy - In patients treated with radiation therapy for small-cell bronchogenic carcinoma or breast cancer, BOOP may affect the ipsilateral or contralateral lung.
  • Infections - BOOP can be caused by Coxiella burnetii and  Pseudomonas aeruginosa, as well as by Mycoplasma species. BOOP possibly may be associated with human herpesvirus 7 infection following lung transplantation and with Pneumocystis jiroveci (formerly, P. carinii) in patients receiving tacrolimus (after liver transplantation). Infection also can be caused by influenza A virus, measles virus, parvovirus B19, human immunodeficiency virus (HIV), Chlamydia species, Plasmodium vivax, and Plasmodium malariae.
  • Drugs and toxins - BOOP is associated with exposure to minocycline, gold, cephalosporin, acebutolol, sulfasalazine, mesalazine, bucillamine, interferon beta-1a, nitrofurantoin, amiodarone, ticlopidine, carbamazepine, phenytoin, sotalol, and rapid intravenous cyclophosphamide pulse therapy; a combination of cytosine arabinoside, anthracyclines, and massive L-tryptophan ingestion; Sauropus androgynus vegetable poisoning; exposure to paint aerosols in textile workers; nylon flock–related disease; silo-filler's disease; freebase cocaine use; and smoke inhalation.
• Associated pathologies
• • Connective tissue diseases - Rheumatoid arthritis, Sjögren syndrome, ankylosing spondylitis, polymyositis-dermatomyositis, cutaneous vasculitis, Behçet syndrome, Wegener granulomatosis, ulcerative colitis, regional enteritis, systemic sclerosis, systemic lupus erythematosus, systemic lupus erythematosus with antiphospholipid-antibody syndrome, primary biliary cirrhosis, and thyroiditis
  • Immunosuppressed states - Hematopoietic stem cell transplantation (HSCT), graft versus host disease of the liver after allogeneic bone marrow transplantation, renal transplantation, coronary artery bypass graft surgery, kidney transplantation with Fabry disease, T-cell leukemia, primary non-Hodgkin lymphoma, malignancies in children, myelodysplastic syndrome, recent surgery, severe pneumonia, adult respiratory distress syndrome, and acquired immunodeficiency syndrome (AIDS)
  • Miscellaneous conditions
  • • Sarcoidosis, lung cancer, lung atelectasis, asthma, cystic fibrosis, secondary amyloidosis, acute febrile neutrophilic dermatosis (Sweet disease), idiopathic thrombocytopenic purpura, Evans syndrome, essential mixed cryoglobulinemia, and chronic sinusitis
    • A seasonal variety
    • Menstrual- and pregnancy-related BOOP

Bronchoalveolar lavage reveals the following cytologic and immunocytologic characteristics in patients with BOOP⁴:

• Cytologic examination demonstrates a mixed cell pattern, with an increase in lymphocytes (20-40%), neutrophils (10%), eosinophils (5%), mast cells, foamy macrophages, and occasional plasma cells.
• An increase in the percentages of neutrophils and lymphocytes in patients with BOOP differentiates the condition from idiopathic pulmonary fibrosis.
• Eosinophils are increased significantly in patients with CEP, with a small overlap with BOOP.
• The CD4⁺/CD8⁺ ratio is decreased.
• The percentage of CD57⁺ cells is within the reference range.
• Activation of T cells is increased in terms of human leukocyte antigen-DR (HLA-DR) expression and, occasionally, interleukin-2 receptor (CD25⁺) expression.
• All of the above findings are similar in extrinsic allergic alveolitis, except that CD25⁺ expression is always within the reference range in patients with BOOP and that levels of CD57⁺ cells are always increased in extrinsic allergic alveolitis.
• In patients with BOOP, the ratio of lymphocytes to CD8⁺ cells is significantly increased, and the CD4⁺/CD8⁺ ratio is significantly lower than the ratios in patients with usual interstitial pneumonia.

Frequency

United States

It is believed that BOOP is the source of 20-30% of all cases of chronic infiltrative lung disease.⁵

International

No significant difference has been reported between US and international rates.

Mortality/Morbidity

The overall mortality rate in patients with BOOP is 10%. Pulmonary complications—including BOOP, BO, and idiopathic pneumonia syndrome (IPS)—develop in 30-60% of patients with HSCT. BO and BOOP, which have a 61% and 21% mortality rate, respectively, occur exclusively in patients who have undergone allogenic HSCT. Patients with BOOP respond favorably to treatment with steroids, whereas patients with IPS have a 1-year survival rate of less than 15%.²

Race

No racial predilection is reported.

Sex

No sex predilection is described.

Age

Most patients present at age 40-70 years, but BOOP has been reported in children, particularly in those with underlying malignancy.^{6, 5}

Clinical Details

Approximately half of all patients give a history of an influenzalike illness followed by a second illness that lasts about 3 months (1-4 mo) and features a persistent, nonproductive cough; effort dyspnea; low-grade pyrexia; malaise; and weight loss. Less common symptoms include pleuritic chest pain and hemoptysis.⁵ 

Symptoms do not respond to broad-spectrum antibiotics. A significant number of patients have associated collagen disease (16%) and inhalation exposure to toxins (17%). BOOP may be the first manifestation of non-Hodgkin lymphoma and collagen disease.⁷ In most patients, clinical examination of the thorax demonstrates fine, dry lung crepitations. Clubbing is unusual. The erythrocyte sedimentation rate not only is invariably higher but may be greatly increased. Pulmonary function tests characteristically show a restrictive pattern. The diffusing capacity is reduced, the resting alveolar arterial oxygen gradient is widened, and exercise-related hypoxemia is present. By contrast, CEP involves an obstructive pattern of lung physiology.

Preferred Examination

As in most cases of suspected pulmonary pathology, plain radiography most often is used for the initial examination. However, computed tomography (CT) scans provide a better assessment of the disease pattern and distribution; therefore, CT scanning is superior to chest radiography in determining the optimal biopsy site.

Limitations of Techniques

Plain radiographic and CT-scan findings are nonspecific in patients with BOOP and may mimic findings from a variety of pulmonary fibrotic, inflammatory, and neoplastic processes.

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