Predictive factors for relapse of cryptogenic organizing pneumonia

Organizing pneumonia (OP) is pathologically defined by the presence of granulation tissue buds within distal pulmonary airspaces consisting of fibroblasts and myofibroblasts intermixed with loose connective matrix [1]. Clinically, OP is associated with a syndrome of acute or subacute onset that may include cough, fever, and progressive dyspnea, and radiographically, with multiple patchy alveolar opacities not responsive to antibiotics.

Organizing pneumonia is classified as either cryptogenic OP (COP), which has no specific etiology, or secondary OP caused by an inflammatory reaction to drugs, infection, collagen vascular disease, malignancy, or radiation therapy [2‐4]. One previous study [5] reported that secondary OP was less responsive to treatment and associated with worse prognosis than COP, while another [6] reported similar clinical and radiographic findings, treatment responses, relapse rates, and mortality for COP and secondary OP. Patients with OP sometimes relapse during or after steroid treatment, and several relapses increase the side effects of steroid treatment and may negatively influence prognosis. The frequency of relapse ranges from 9 to 33% [7‐9], and we sometimes encounter relapse when steroids are tapered or stopped. Therefore, it is important to identify predictive factors of relapse as possible aids to guide preventative treatment.

A relationship between relapse and steroid dose was identified [10, 11], and guidelines for steroid treatment have been proposed by Epler [3] and Schwartz and King [4]. Epler suggested starting with 1 mg/kg/day prednisone (60 mg/day) for 1–3 months, tapered to 40 mg/day for 3 months, and then 10–20 mg/day for 1 year. Schwartz and King suggested initiating therapy with 1–1.5 mg/kg/day prednisone for 4–8 weeks, tapering to 0.5–1 mg/kg/day for the ensuing 4–6 weeks. Although there is general consensus on steroid efficacy, the specifics of the steroid treatment regimen, such as initial dose and interval of tapering, have not been standardized. Several studies reported that relapse was associated with tapering or discontinue of steroid treatment [6, 12]. Other proposed predictive factors for relapse are severity of initial hypoxemia, traction bronchiectasis and architectural distortion on computed tomography (CT) scans with increased serum Krebs von den Lungen-6 (KL-6) levels, the presence of intra-alveolar fibrin in lung biopsy tissue, and the delay between first symptom and treatment onset [10, 12‐15]. However, the predictive factors for relapse remain uncertain.

The purpose of this study is to identify predictive factors for relapse of COP by comparing the clinical characteristics, laboratory data, radiographic findings, duration of steroid treatment, cumulative equivalent dose of prednisone, and response to steroid therapy between non-relapse and relapse groups.

Thirty-three patients fulfilled the selection criteria, of whom 10 (30.3%) relapsed and 23 (69.7%) did not (Fig. 3). The clinical characteristics of both groups are shown in Table 1, and there was no significant difference. The most common symptom in all patients was cough (81.8%), followed by fever (66.6%). One patient in the non-relapse group presented with chest pain. Physical findings included crackles in 60.6% and wheezing in 15.1% of all patients.

Four patients were still on steroid treatment (mean prednisone dose 6.8 ± 3.7 mg; range 2.5–12.5 mg/day) when the first relapse occurred. The mean time to first relapse was 476 ± 445 days (range, 70–1682 days). All patients were treated with increased steroid dose when relapse occurred, and the mean prednisone equivalent dose at that time was 24 ± 8 mg/day.

Comparisons of serum parameters (Table 2) revealed no significant differences between groups. Table 3 compared the radiological findings between groups. Chest radiographs revealed consolidation in 30 patients (90.9%), which was bilateral in 20 (60.6%). The proportion of patients with a bilateral shadow pattern was significantly higher in the relapse group (90% vs. only 47.8% in the non-relapse group, p = 0.02). Similarly, incidence of traction bronchiectasis was also significantly higher in the relapse group (60% vs. 17.3% in the non-relapse group, p = 0.02). Although there was no significant difference in the lesion pattern distribution between groups (consolidation, ground-glass attenuation, or nodules), the proportion of patients with partial remission after steroid treatment was significantly higher in the relapse group (90% vs. 43.3% in the non-relapse group, p = 0.01). Migratory infiltrative shadows were observed in five patients in the entire cohort (15.1%) and did not differ significantly between groups.

There was no significant difference in the mean period of steroid treatment or cumulative equivalent dose of prednisone between groups (Table 4). All patients underwent antibiotic therapy before starting the steroid treatment. Eleven patients with severe respiratory disorder at onset received high-dose pulse intravenous steroid treatment with 1 g methylprednisolone for 3 days (30.4% in the non-relapse group vs. 40% in the relapse group, NS).

Thus, the relapse group included a significantly higher proportion of patients with bilateral shadow pattern, traction bronchiectasis, and partial remission as indicated by univariate analysis. However, there were no significant differences by multivariate Cox regression analysis.

This result that radiographic findings may be more important factor than clinical findings, and therapeutic passage is worth investigating further in the large-scale trials. As a result, we identified the three radiographic features, such as bilateral shadow pattern, traction bronchiectasis, and signs of partial remission (residual shadow), may have possibility the predictive factors of relapse. Four of the 10 patients (40%) in the relapse group exhibited all these three radiographic factors, far higher than that in the non-relapse group (8.7%), and three of the four patients had multiple relapses. Okada et al. [14] reported that CT findings of traction bronchiectasis and architectural distortion in COP patients were associated with serum KL-6 levels. In the present study, however, there was no significant difference in serum KL-6 between groups, but 3 of the 10 relapse patients had both serum KL-6 > 500 U/ml and traction bronchiectasis on chest images.

As regards steroid treatment of COP, there was no significant difference in the mean period of steroid treatment or cumulative equivalent dose between groups. There was a possibility that some patients with COP might have unnecessary and excessive steroid treatment. We need to comprehensively analyze clinical, and radiological findings to avoid the risk of side effects by unnecessary steroid treatment, and we should decide therapeutic dose and treatment period of steroid for each patient.

The present study has some limitations. First, the period of treatment and the timing of steroid tapering were not unified because of retrospective study. Although we statistically found no difference in the duration of steroid treatment or cumulative dose of prednisone, we do occasionally encounter COP relapse during tapering or after steroid treatment is stopped. In addition to the guidelines of steroid treatment proposed by Epler [3] and Schwarz and King [4], Lazor et al. [12] proposed the following standardized GERM“O”P protocol: 0.75 mg/kg/day prednisone for 4 weeks, 0.5 mg/kg/day for 4 weeks, 20 mg/day for 4 weeks, 10 mg/day for 6 weeks, and finally 5 mg/day for 6 weeks. Using GERM“O”P, patients received a significantly lower accumulated corticosteroid dose without higher relapse rate, morbidity, or mortality. It was also reported that treatment of first relapse with high-dose corticosteroids was associated with a higher rate of treatment side effects without objective benefit. Although severe adverse events due to steroid treatment were not observed in the present study, we expect that protocol as describes above will be proposed in the future by large prospective clinical trials. Second, we could not evaluate the results of pulmonary function tests such as lung volume and diffusion capacity for carbon monoxide because of the lack of available records for review. Third, the number of registered patients in the present study was small because this was conducted in one hospital. Despite the above limitations, we believe this study has valuable implications for clinical practice.

We identified several clinical factors that differed significantly in frequency between relapse and non-relapse COP patients. Although there were no significant differences by multivariate Cox regression analysis, we suggest that chest CT scans at initial episode are strong candidate predictive factors for relapse. Identification of such factors could be used to guide preventative treatments, thereby preventing patient distress, avoiding unnecessary steroid treatment, and possibly improving long-term prognosis. We hope that the recurrence factors will be clarified by a long-term study in the future.