Introduction
Cryptogenic organizing pneumonia (COP) is characterized by subacute illness of cough, flulike illness, and dyspnea and classified as one of acute or subacute idiopathic interstitial pneumonias (IIP). COP is discriminated with secondary organizing pneumonia which appears with collagen vascular disease, infection, and drug reaction. Diagnosis of COP can be made in the absence of associated such diseases. The histopathologic pattern is characterized primarily by organizing pneumonia involving alveolar ducts and alveoli with or without bronchial intraluminal polyps. High resolution computerized tomogram (HRCT) findings are nonspecific and usually includes patchy and often migratory consolidation in a subpleural, peribronchial, or band-like pattern
1.
Majority of patients recover completely with oral steroids, but some patient dose not respond to long-term use of steroid. Furthermore, relapses after discontinuing of steroid, residual and progressive interstitial fibrosis were observed in small number of patients
2. For patients who do not respond to steroid, macrolides (clarithromycin or erythromycin) and cyclosporine A has been used for alternate treatment
3,4,5. Few reports described treatment failure with clarithromycin in patients with COP who did not respond to steroid.
Herein, we report two cases of COP who showed difference responses to clarithromycin. One recovered completely, but the other gradually showed lung fibrosis with clarithromycin.
Discussion
In the present study, we showed clarithromycin-responsive and -resistant patients with COP who refractory to steroid. Generally, steroid in COP showed rapid resolution within several days or a few weeks and dramatic effect of majority patients. But, both of patients were not response to steroid 2 or 3 months, thus we used alternative therapy, macrolides.
The failure of treatment with clarithromycin was rarely reported. Almost all reports described good response to clarithromycin in patients with COP
4,5,6,7. Therefore we believe clarithromycin is good alternative drugs without failure in treatment of COP. Radzikowska et al.
8 reported that the response rate of clarithromycin was 75% in 12 patients with organizing pneumonia; however, the population of patients in this study was mixed with COP and secondary organizing pneumonia (OP). One patient failed to respond to intravenous erythromycin, but the duration of treatment was only 3 days
9. Therefore, we don't know yet the failure rate of macrolides in the treatment of COP.
The mechanism of macrolides in the treatment of COP is anti-inflammatory effects rather than antibiotic effects. Although the underlying mechanisms of anti-inflammatory effects are unknown,
in vitro and
in vivo studies suggest anti-inflammatory effects of macrolides may be related with the effect on polymorphonuclear cells and their products but also effect on T cells. Erythromycin decrease the number of neutrophils and the neutrophil-derived elastolytic-like activity in BAL fluid decreased significantly after treatment with erythromycin in patients with bronchiolitis
10. Macrolides treatment for 1-24 months significantly reduced BAL fluid levels of interleukin (IL) 1β and IL-8 in parallel with BAL fluid neutrophils in patients with diffuse panbronchiolitis
11. Furthermore, erythromycin decreased significantly the number of neutrophils recovered from lungs of mice responding to bacterial challenge
12. Erythromycin was capable of inhibiting expression of the IL-8 genes in T cells through transcriptional inhibition
13. In the presents cases, the level of neutrophils and lymphocyte in BAL fluid were not different between clarithromycin- responsive (case 1) and -nonresponsive (case 2) cases. These findings suggested the level of neutrophils and lymphocytes do not affect the response to clarithromycin, although only two cases were analyzed.
The discrepancy between cellular profiles in BAL fluid and histologic finding of lung biopsy was found in present cases. The level of neutrophils in BAL fluid was 13% and 15% in case 1 and 2, respectively, but, neutrophils in histology of lung biopsy were not observed as the level of BAL finding. This discrepancy may be explained by proximal bronchial airway obstruction preventing normal saline reaching diseased lung during BAL procedure.
Cohen et al.
14 reported OP with rapidly progressive clinical course and poor outcome. The majority of these patients had secondary OP associated with autoimmune disorders. This finding suggested the presence of autoimmune and connective tissue disorders were important predictor of rapidly progressive OP. However, also, in case of COP, rapidly progressive and fatal patients were reported
9. In our cases, both patients did not show any evidences of associated diseases.
The duration of macrolides in patients with COP was unknown yet. However, the majority of cases were successfully treated more than 3 months of macrolides without relapse
3,4,7. One case of patient showed relapse of COP after a 3-week course was discontinued
7, and the other case showed no improvement of clinical condition
9. These finding suggested long-term use more than three months of macrolides are needed for treatment and prevention of relapse. In our cases, case 1 showed significant clinical improvement after 3-month course of medication and no relapse after discontinuation, but case 2 showed no clinical responses in spite of 3 months of clarithromycin. Further studies are needed to decide when we should stop macrolides in case of no-responsive to these drugs.
Laboratory abnormalities, such as severe anemia (Hb less than 11 g/dL), high ESR (more than 60 mm/hr), and low serum albumin (less than 3.5 g/dL) could be associated with worse prognosis in 61 patients with COP and secondary OP
1. And paucity of lymphocytes in BAL fluid was suggested as a risk factor for relapse. In present case, case 2 showed no abnormalities in anemia, ESR, and albumin level, and also lymphocytes in BAL fluid were similar level as case 1. Therefore, case 2 showed no risk factor for worsening of COP.
Generally, the disease severity of idiopathic pulmonary fibrosis is assessed on the basis of symptoms, pulmonary function test, and radiologic findings
15. We applied these parameters to response to treatment in both two cases. We regarded improvement of disease in case of at least two of the above three parameters improved. In case 1, after use of clarithromycin showed improvement of every parameter, FVC, mMRC, and HRCT (
Figure 4). But, in case 2, any drugs could not improve these parameters (
Figure 8).
There is remarkable point that the age of the two patients was quite different. So, we suggest that age of patient may affect the results because of both patient's underlying immunological condition, lung biopsy setting, HRCT, initial FVC, and mMRC were similar.
In conclusion, we herein report clarithromycin-responsive and -resistant patients with COP who refractory to steroid. This clarithromycin-resistant case indicates that there is a need to evaluate the failure rate of macrolides including clarithromycin in treatment of COP.