Cryptogenic Organizing Pneumonitis

The North American Experience

¹ The Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, and Division of Pulmonary Sciences, University of Colorado Health Sciences Center, Denver.

Cryptogenic organizing pneumonitis is a clinical and pathologic syndrome characterized by a "pneumonia-like" illness with excessive proliferation of granulation tissue within small airways and alveolar ducts associated with chronic inflammation in the surrounding alveoli. The duration of illness prior to lung biopsy is short, usually less than 2 months, and it is markedly different from that of IPF. Interestingly, unlike in IPF where the patient has difficulty remembering the exact onset of symptoms, patients with COP are frequently very specific about the timing of their disease onset. This is because the disease onset is recent and is often dramatic with the development of a severe flulike illness, ie, cough, fever, malaise, fatigue, and weight loss. Inspiratory crackles are frequently present on chest examination. Pulmonary function is usually impaired with a restrictive defect being most common. Gas exchange abnormalities are extremely common with a reduction in Dco and resting hypoxemia being almost universal findings. The roentgenographic manifestations are quite distinctive with a pattern of bilateral, diffuse but inhomogeneous, groundglass or alveolar opacities being present in the majority of the cases. Bronchoalveolar lavage findings are nonspecific but usually reveal a lymphocytosis.

The response to corticosteroid treatment is quite favorable and death from progressive disease is uncommon in COP, especially if treatment is instituted early in the course of the disease. In our experience, the cases with the worse prognosis are those associated with another disease process, in particular, connective tissue disorders like rheumatoid arthritis. In fact, these patients are prone to develop a rapidly progressive form of BOOP with a clinical course similar to the "Hamman-Rich syndrome." Recurrences are relatively frequent, consequently, withdrawal of treatment should be done with extreme caution.

Corticosteroids have been the conventional initial treatment of COP, although to our knowledge, there are no controlled clinical trials to support it use. Antibiotics are not effective in treating this syndrome. Thus, based solely on our experience and that of others, we believe that highdose corticosteroid therapy should be used to treat COP, usually initiated with 1 to 1.5 mg/kg/day (using ideal body weight) not to exceed 100 mg/day. Prednisone is given as a single oral dose in the morning. We recommended maintaining this dose for 4 to 8 weeks. if the patient's condition is stable or improved, the prednisone dosage is gradually tapered to 0.5 to 1 mg/kg/day (using ideal body weight) for the ensuing 4 to 6 weeks. If the patient's condition has deteriorated despite the corticosteroid therapy, a cytotoxic agent is considered while generally maintaining corticosteroid therapy if tolerated. After 3 to 6 months of corticosteroid therapy, if the patient's condition remains stable or improved, the prednisone therapy is gradually tapered to zero. The patient should be followed up routinely, probably every 6 to 8 weeks during the first year and therapy should be reinstituted aggressively at the sign of any recurrence.

High-dose parenteral corticosteroid therapy has been recommended as the initial treatment in patients with rapidly progressive severe courses of COP Methylprednisolone, 250 mg every 6 h intravenously, has been used in an attempt to suppress the activity of disease as soon as possible. We recommend that this treatment be given for 3 to 5 days to see if it initiates a response, primarily a reduction in symptoms, clearing of the alveolar opacities, and improvement in gas exchange. Although therapy with corticosteroids is usually well-tolerated by patients, side effects are common. Some patients develop side effects of corticosteroids more readily than others at equivalent doses. Therefore, prevention and careful management of the many potential side effects of this therapy are necessary.

We have used cyclophosphamide (Cytoxan) to treat patients with COP who have progressive disease despite adequate corticosteroid therapy. Cyclophosphamide is usually administered in a daily oral dose. The recommended dose is approximately 2 mg/kg/day, although the optimal dose in COP is unknown. We usually start at 50 mg daily and slowly increase the dose over 2 to 4 weeks. We do not recommend exceeding 200 mg/day. A trial of at least 3 to 6 months is needed to ensure an adequate opportunity for clinical response. Hematologic alterations are common side effects of cyclophosphamide therapy and frequently require dose adjustment—the total white blood cell count should be maintained above 4,000. Leukopenia is the most commonly reported hematologic toxic reaction, with anemia and thrombocytopenia noted less often. In some cases, the hematologic effects of cyclophosphamide may persist for several months despite discontinuance of the drug therapy. Urologic complications of hemorrhagic cystitis and carcinoma of the bladder are known, although these are thought to be less common in the dose range used in COP as compared with the higher dosages recommended in chemotherapeutic regimens. Other complications are possible and should be addressed appropriately if they occur.

That COP is a specific disease appears certain to us. However, without better understanding of the etiology and pathogenesis, we cannot be certain where and how COP fits into the spectrum of diffuse lung diseases. Familiarity with the clinical and histopathologic features outlined above should increase the physician's ability to recognize, diagnose, and manage COP.