To our knowledge, this is the first study to evaluate the effect of oral corticosteroids on the long-term life prognosis of COPD patients in solid manner. The HR for death from LTOC estimated in the three models ranged from 1.50 to 1.73. LTOCs were generally prescribed for patients in a deteriorated condition (Table 1), as suggested in the old guideline . However, LTOC further deteriorated the life prognosis of these patients. We still believe that systemic corticosteroids are effective for acute exacerbation of COPD [6–10]. However, it should be discontinued after the acute phase. Discontinuation of LTOC has already been proven to be safe . We strongly support the current guidelines which do not recommend LTOC for stable COPD patients .
One of the most important side effect of LTOC is respiratory muscle deterioration. Decramer observed 21 patients with COPD or asthma who were admitted to hospitals due to exacerbations . The average daily dose of corticosteroids taken in the previous six months was significantly related to inspiratory and expiratory muscle strength. These relationships were independent of the degree of bronchial obstruction estimated by % predicted FEV1. In addition, glucocorticoids, which are the most potent anti-inflammatory and immunosuppressive agents, inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function . It is easily anticipated that patients who is taking oral corticosteroids have more chance to suffer from potentially life-threatening acute exacerbation due to the immunosuppressive states.
The results of some previous studies may appear to conflict with the current study [3–5]. Postma observed 79 patients with chronic airflow obstruction, i.e. COPD or asthma, whose FEV1 was less than 1000 ml for more than 14 years . The same author also observed 139 less severe patients with chronic airflow obstruction whose FEV1 was more than 1200 ml for more 11 years on average . Both studies concluded that oral prednisolone, in doses above 7.5 mg/d, may slow down the deterioration of FEV1[3, 4]. We should interpret the results carefully, because Postma’s study observed COPD patients together with asthma patients. Considering Decramer’s study  and Postma’s study [3, 4], LTOC may improve the respiratory function of asthma patients but may worsen that of COPD patients.
Callahan conducted a meta-analysis to evaluate oral corticosteroids therapy for patients with stable COPD . He scrutinized 10 placebo controlled randomized controlled trials and concluded that patients with stable COPD receiving oral corticosteroids therapy have a 20% or greater improvement in baseline FEV1 approximately 10% more often than similar patients receiving a placebo. The most important difference between Callahan’s meta-analysis and Decramer’s study  is the duration of observation. Among 10 randomized controlled trials in the meta-analysis, nine observed COPD patients for 14 days or less, and one observed COPD patients for eight weeks . Oral corticosteroids may improve FEV1 of COPD patients if prescribed for weeks. However, it may deteriorate FEV1, if prescribed for months or years. Another considerable limitation of Callahan’s study is a publication bias, which has a considerable impact on the result of the meta-analysis .
Our study had several limitations. First, it was an observational study, and not a randomized controlled trial. Since the current guidelines  do not recommend administering LTOC, a randomized controlled trial was not thought to be a feasible design. Our study design was the next best to a randomized controlled trial. Second, the dosage of oral corticosteroids in this study was not verified. Considering that the long − term dosages in previous studies were 5 mg/d , 7.5 mg/d , and 10 − 15 mg/d , a similar dosage might be prescribed for patients in our cohort. Third, our cohort contained only patients whose % predicted FEV1 ≤ 45% and this study did not explain whether LTOC worsens the life prognosis of COPD patients with % predicted FEV1 > 45. However, LTOC had been already regarded as the last option for patients with uncontrolled advanced COPD . There was no reason to recommend LTOC for patients with mild or moderate COPD. Together with other inclusion and exclusion criteria, the current cohort may have slight difference from “real-world” patients. Thus, we should interpret the result with caution. Fourth, as in other observational studies, oral corticosteroids before observation may cause some bias. Oral corticosteroids administered before randomization probably deteriorate baseline characteristics of LTOC(+) patients [12, 13]. But the LTOC(+) and (−) patients in the propensity-matched cohort were nearly equal (Table 2) by cancelling the harm from oral corticosteroids before randomization. The matched LTOC(+) cases would have better condition, if they had not been treated with oral corticosteroids. Nonetheless, they had poorer life prognosis than LTOC(−) cases. This bias made true impact of medication seem smaller. Fifth, it is not fully confirmed that LTOC(+) patients actually took oral corticosteroids during the entire follow-up period. The definition of LTOC(+) patients in the current study might reflect repeated short course oral corticosteroid. In addition, patient’s adherence to prescribed medication is not evaluated. This bias shift the observed HR toward the null, as drop-out cases in intentional-to-treat analysis do. Thus, oral corticosteroids may have stronger impact on mortality than we estimated in this study.