para>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 PATHOPHYSIOLOGY
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
- β-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
- Sj ĥgren 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
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
HISTORY
- Fatigue/malaise
- Fever/chills
- Weight loss
- Dry cough
- Dyspnea
- No improvement after multiple courses of antibiotics
- Other symptoms suggestive of connective tissue disease such as joint pain, dry eyes/mucus membranes, etc.
- A history of exposure to new medication, radiation, and other environmental exposures that may predispose
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
- Sj ĥgren 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.
- 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.
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.
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.
COMPLICATIONS
- Bronchiectasis
- Most people recover completely without permanent sequelae if full course of steroids completed.
- Death occurs in up to 7% but usually in individuals who are elderly or have preexisting comorbid conditions.
REFERENCES
11 Cottin V, Cordier JF. Cryptogenic organizing pneumonia. Semin Respir Crit Care Med. 2012;33(5):462-475.22 Marchiori E, Zanetti G, Hochhegger B, et al. Reversed halo sign on computed tomography: state-of-the-art review. Lung. 2012;190(4):389-394.33 Marchiori E, Irion KL, Zanetti G, et al. Atoll sign or reversed halo sign? Which term should be used? Thorax. 2011;66(11):1009-1010.44 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):893-900.55 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):1706-1711.66 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):748-754.77 Ye Q, Dai H, Sarria R, et al. Increased expression of tumor necrosis factor receptors in cryptogenic organizing pneumonia. Respir Med. 2011;105(2):292-297.88 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-v58.99 Purcell IF, Bourke SJ, Marshall SM. Cyclophosphamide in severe steroid-resistant bronchiolitis obliterans organizing pneumonia. Respir Med. 1997;91(3):175-177.1010 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
Sj ĥgren syndrome
CODES
ICD10
J84.116 Cryptogenic organizing pneumonia
ICD9
516.36 Cryptogenic organizing pneumonia
SNOMED
129458007 Bronchiolitis obliterans organizing pneumonia (disorder)
CLINICAL PEARLS
- 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.