> Table of Contents > Cryptogenic Organizing Pneumonia
Cryptogenic Organizing Pneumonia
Roselyn Jan Wuthrich Clemente-Fuentes, MD
Merima Bucaj, DO
image BASICS
DESCRIPTION
  • Cryptogenic organizing pneumonia or COP (previously known as bronchiolitis obliterans organizing pneumonia or BOOP) is a primary (cryptogenic) or secondary process of the lungs characterized by granulation-like tissue involving the distal airways and alveoli.
  • COP is a restrictive problem that is completely reversible.
  • A specific reaction of lung tissue to a variety of injuries, but exact pathogenesis is unknown
  • It may occur as patchy infiltrates, or it may be nodular or secondary to another lung disease.
  • May also appear to be a migrating process
  • May have a gradual or sudden onset.
  • Lungs show a pattern of multiple patchy pneumonia, which are seen on the chest x-ray (CXR) as patchy alveolar or ground glass opacifications, with or without interstitial infiltrates; there may be air bronchograms as well.
  • Most cases will respond to corticosteroids, which may have to be given for a year or more.
  • Synonym(s): bronchiolitis obliterans organizing pneumonia; intraluminal fibrosis of distal airways; idiopathic BOOP; obliterative bronchiolitis
Geriatric Considerations
More common than originally thought and may be sudden and very severe
Pediatric Considerations
Rare but has been reported after viral pneumonia
EPIDEMIOLOGY
  • Incidence/prevalence in the United States: estimated at 0.01% but may be underdiagnosed
  • Predominant age: reported cases range age 0 to 70 years; most commonly seen in age 40s to 60s
Prevalence
Unknown
ETIOLOGY AND PATHPHYSIOLOGY
Idiopathic: a complex response to a variety of injuries such as toxic inhalation, postmycoplasma, viral and bacterial infection, aspiration, immunologic factors, drugs
Genetics
No known genetic component
RISK FACTORS
  • Immunocompromised patients, including transplant recipients and AIDS patients
  • Other autoimmune conditions
  • Reported frequency of tobacco use in diagnosed cases 25-50%, making smoking unlikely to be a precipitating factor
GENERAL PREVENTION
Except for prevention of relapse, none known
ASSOCIATED CONDITIONS
  • Drug-induced pneumonitis
    • Paraquat poisoning
    • Amiodarone toxicity
    • Acebutolol toxicity
    • Amphotericin B
  • &bgr;-Blockers
    • Bleomycin
    • Carbamazepine
    • Cephalosporins
    • Gold
    • Minocycline
    • Nitrofurantoin
    • Phenytoin
    • Sulfamethoxypyridazine
    • Sulfasalazine
    • Ticlopidine
  • Antineoplastic agents
    • Freebase cocaine pulmonary toxicity
    • Overdose of L-tryptophan
  • Infections
    • Chronic infectious pneumonia
    • Malaria
    • Chlamydia
    • Legionella
    • Mycoplasma
    • Pneumocystis
    • Cryptococcus
  • Immunocompromised (AIDS or bone marrow, lung, renal transplantation)
  • Malignancy: colon, breast, lymphoma
  • Bronchial obstruction (lack of mucociliary clearance), which is lung cancer
  • Connective tissue diseases
    • COP itself is an autoimmune connective tissue disorder, so autoimmune connective tissue disorders confer a higher risk of acquiring the disease.
    • Rheumatoid arthritis
    • Sjögren syndrome
    • Polymyositis
    • Scleroderma
    • Essential mixed cryoglobulinemia
    • Wegener granulomatosis
  • Miscellaneous
    • Cystic fibrosis
    • Bronchopulmonary dysplasia
    • Renal failure
    • Congestive heart failure (CHF)
    • Adult respiratory distress syndrome (ARDS)
  • Idiopathic pulmonary fibrosis
    • Chronic eosinophilic pneumonia
    • Hypersensitivity pneumonitis
    • Histiocytosis X
    • Sarcoidosis
    • Pneumoconioses
  • Radiation pneumonitis
image DIAGNOSIS
Consider differential in patients presenting with
  • Flulike illness that lasts 4 to 10 weeks or longer. Most have been treated with empiric antibiotics without success.
  • Fatigue, fever, and weight loss >10 lbs
  • Persistent nonproductive cough
  • Dyspnea may be severe.
  • Bilateral crackles
PHYSICAL EXAM
  • Hypoxia
  • Cyanosis
  • Respiratory distress
  • Bilateral crackles
  • Wheezing
  • Dry cough
  • Shortness of breath
  • Rarely: hemoptysis, respiratory distress
DIFFERENTIAL DIAGNOSIS
  • Usual interstitial pneumonitis
  • Noninfectious diseases
  • Tuberculosis
  • Sarcoidosis
  • Histoplasmosis
  • Berylliosis
  • Goodpasture syndrome
  • Neoplasm
  • Polyarteritis nodosa
  • Systemic lupus erythematosus
  • Wegener granulomatosis
  • Sjögren syndrome
  • Chronic eosinophilic pneumonia
  • Cryptogenic bronchiolitis
DIAGNOSTIC TESTS & INTERPRETATION
  • May have normal or nonspecific laboratory findings
  • Leukocytosis with a normal differential
  • Elevated ESR/CRP
  • Eosinophilia
  • If secondary to autoimmune process, it may have elevated levels of antinuclear antibodies (ANA), rheumatoid factor (RF), anti-SSA/Ro, anti-SSB/La, anti-Jo, etc.
  • Check HIV status.
  • Negative cultures
  • Negative serology for Mycoplasma, Coxiella, Legionella, psittacosis, and fungus
  • Negative viral studies
  • CXR: often appears more normal than the physical examination
    • CXR may show bilateral patchy alveolar opacities (typical pattern), often in the middle or upper lung area, a ground glass pattern that may have air bronchograms.
    • CXR can also reveal a solitary focal nodule or mass known as a focal pattern (1)[B].
  • Throughout the disease, new infiltrates may appear or may seem to migrate.
  • Effusions and cavitary lesions are rare on x-ray.
  • Patients with linear opacities at lung bases may have a poorer prognosis.
  • CT scans more accurately define the distribution and extent of the patchy alveolar opacities with areas of hyperlucency. Findings are commonly described as a “reversed halo sign” or “atoll sign,” a focal round area of ground glass attenuation; however, this is a nonspecific finding (2,3)[A].
  • Up to 90% of CT scans may show airspace consolidation with air bronchograms.
  • Pulmonary function shows a restrictive/obstructive pattern.
  • P.245

  • Flow-volume loop shows terminal airway obstruction.
  • The involved area may seem to migrate.
  • Ventilation-perfusion ratio scan: matched patchy defects
Diagnostic Procedures/Other
  • In one study, open lung biopsy established the correct diagnosis in 1/3 of patients (4)[B].
  • Transbronchial biopsy has yielded a correct diagnosis in 2/3 of cases (4,5)[B].
  • Consider steroids for a diagnostic trial. If a diagnostic trial is successful, be prepared to treat the patient for at least 1 year. Relapses are common after stopping treatment.
  • Bronchoalveolar lavage (BAL) fluid in patients with COP have shown larger amounts of natural killer cells, natural killer T-like cells, Fas and tumor necrosis factor receptor expression indicating cytotoxicity and local inflammation (5,6)[C]. In one specific study, the most frequent BAL profile was mixed alveolitis with lymphocytic predominance, a CD4/CD8 index of 0.4, and foamy macrophages, which was shown to be specific (88.8%) but not sensitive (4)[C].
Test Interpretation
  • Intraluminal fibrosis of distal airspaces is the major pathologic feature.
  • Fibroblasts and plugs of inflammatory cells and loose connective tissue fill these distal airways, known as Masson bodies.
    • Characteristic “butterfly” pattern of intraluminal granulation tissue plugs extending from alveoli to bronchioles
  • Inflammatory cells are mainly lymphocytes and plasma cells.
  • Interstitial fibrosis is present.
  • Plugs of edematous granulation tissue in the terminal and respiratory bronchioles and alveolar ducts do not cause permanent damage.
image TREATMENT
  • Observation for patients with minimal symptoms and absent/mild PFT abnormalities as may spontaneously resolve. Reassess at 8 to 12 week intervals (8)[C].
  • Inpatient care may be required for rapidly progressive disease or respiratory failure for high dose IV steroids and supportive care
GENERAL MEASURES
  • Monitor blood gases or pulse oximetry.
  • Oxygen, as necessary
MEDICATION
First Line
Prednisone
  • 1 mg/kg (up to 60 mg/day) for 1 to 3 months, then 40 mg/day for 3 months, then 10 to 20 mg/day for up to 1 year (1)[A]
  • May consider a 6-month-only taper or alternate day dosing for 1 year to limit steroid exposure
  • Increase length of taper for patients on long-term therapy to avoid precipitating Addisonian crisis.
  • Treatment may be needed for ≥1 year.
  • In one study, the best response to corticosteroid therapy was seen in individuals <35 years of age, nonsmokers, and with morphologic features (large bronchial plugs, mild inflammatory reaction) and immunohistochemical markers (presence of collagen IV, absence of collagen III, CD-68-positive cells and positive VEGF) (7)[B].
  • Precautions: Be aware of the patient's TB status and history of peptic ulcer disease. Long-term steroid treatment is associated with significant adverse effects, including adrenal suppression, infection, Cushing syndrome, fluid retention, osteoporosis, hyperkalemia, and poor wound healing.
Pediatric Considerations
Prednisone: 1 mg/kg q24h for 1 month, followed by weaning over several months
Second Line
  • Steroids other than prednisone may be used.
  • Prescribe antimicrobials if the original infection is persistent. The proper choice depends on the pathogen.
  • Anecdotal use of inhaled triamcinolone and cyclophosphamide has been reported.
  • Macrolide antibiotics have also been used for their anti-inflammatory properties; however, not employed in most cases (4)[C].
  • If unresponsive to systemic glucocorticoids, can consider second immunosuppressive such as azathioprine or cyclophosphamide (9,10)[C]
ISSUES FOR REFERRAL
Patients should be followed by a pulmonologist.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Frequent visits, weekly at first
  • Prednisone must be continued because of the chance of relapse.
  • Monitor the lung disease and the side effects of prednisone therapy.
    • Annual TB screening
    • Monthly CBC
    • Funduscopic examination every 3 to 6 months
    • Serial dual energy x-ray absorptiometry (DEXA) scans for osteoporosis
DIET
No special diet
PATIENT EDUCATION
  • Compliance: Emphasize the need to continue prednisone because of the chance of a relapse.
  • Recurrence in up to 1/3 who do not complete full steroid treatment (1)
PROGNOSIS
Typically complete recovery, but individual case management is mandatory.
REFERENCES
1. Cottin V, Cordier JF. Cryptogenic organizing pneumonia. Semin Respir Crit Care Med. 2012;33(5):462-475.
2. Marchiori E, Zanetti G, Hochhegger B, et al. Reversed halo sign on computed tomography: state-of-the-art review. Lung. 2012;190(4):389-394.
3. Marchiori E, Irion KL, Zanetti G, et al. Atoll sign or reversed halo sign? Which term should be used? Thorax. 2011;66(11):1009-1010.
4. Drakopanagiotakis F, Paschalaki K, Abu-Hijleh M, et al. Cryptogenic and secondary organizing pneumonia: clinical presentation, radiographic findings, treatment response, and prognosis. Chest. 2011;139(4):893-900.
5. Jara-Palomares L, Gomez-Izquierdo L, Gonzalez-Vergara D, et al. Utility of high-resolution computed tomography and BAL in cryptogenic organizing pneumonia. Respir Med. 2010;104(11):1706-1711.
6. Papakosta D, Manika K, Gounari E, et al. Bronchoalveolar lavage fluid and blood natural killer and natural killer T-like cells in cryptogenic organizing pneumonia. Respirology. 2014;19(5):748-754.
7. Ye Q, Dai H, Sarria R, et al. Increased expression of tumor necrosis factor receptors in cryptogenic organizing pneumonia. Respir Med. 2011;105(2):292-297.
8. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008;63(Suppl 5):v1-v58.
9. Purcell IF, Bourke SJ, Marshall SM. Cyclophosphamide in severe steroid-resistant bronchiolitis obliterans organizing pneumonia. Respir Med. 1997;91(3):175-177.
10. Vaz AP, Morais A, Melo N, et al. Azithromycin as an adjuvant therapy in cryptogenic organizing pneumonia [in Portuguese]. Rev Port Pneumol. 2011;17(4):186-189.
See-Also
&NA;
Sjögren syndrome
Codes
&NA;
ICD10
J84.116 Cryptogenic organizing pneumonia
Clinical Pearls
&NA;
  • COP is a restrictive problem that is completely reversible.
  • Major risk factors for COP include immunosuppression. No known association with smoking.
  • Consider COP in prolonged respiratory illness with fatigue, nonproductive cough, and weight loss unresponsive to multiple antibiotics.
  • When diagnosing COP, one should perform an autoimmune workup.
  • The classic CT finding of COP is the “reversed halo sign” also known as “atoll sign.”
  • The histopathology characteristic of excessive proliferation of granulation tissue that may extend into the “butterfly” pattern
  • COP treatment is a prolonged course of corticosteroids.