Defining low-dose corticosteroid: the pendulum still oscillates

From the authors:

We would like to thank P.R. Mohapatra and colleagues for their comments and interest in our study [1]. We also appreciate the editors of the European Respiratory Journal for giving us the opportunity to reply. The points made by P.R. Mohapatra and colleagues regard the following: 1) the corticotrophin test, 2) the dosage of corticosteroid, and 3) comorbidities as confounding factors for the use of corticosteroid.

We agree that some patients with community-acquired pneumonia (CAP) in the present study [1] might have had adrenal insufficiency. However, we possessed no data on how many patients were responders or nonresponders to the adrenocorticotropic hormone stimulation test, which was suggested for the evaluation of septic shock patients a decade ago (grade E recommendations in the Surviving Sepsis Campaign international guidelines for management of severe sepsis and septic shock, from 2004 [2]). Meanwhile, this stimulation test is no longer recommended (rather, is recommended not to be performed) for the identification of septic shock patients who should receive corticosteroid, in the revised guidelines (grade 2B recommendations in the Surviving Sepsis Campaign guidelines from 2008 [3] and 2012 [4]). Thus, we do not necessarily agree with the opinion that “the role of corticosteroids in management of severe CAP should be based on the assessment for adrenal reserve”, as far as the recent evidence is concerned [3, 4].

Although the current guidelines for severe sepsis and septic shock recommend hydrocortisone at a dose of 200 mg·day⁻¹ [4], the present study [1] evaluated CAP patients with mechanical ventilation. Most of the major studies and systematic review studies on CAP (with acute lung injury) have used the criteria of methylprednisolone 0.5–2.5 mg·kg⁻¹·day⁻¹ (or an equivalent dose of other steroids) [5–8]. Therefore, we defined low-dose corticosteroid use as intravenous infusion of methylprednisolone 0.5–2.5 mg⁻¹·kg⁻¹·day⁻¹ (or an equivalent dose of dexamethasone, hydrocortisone, prednisolone or betamethasone), and any higher dose was defined as high-dose corticosteroid use in the present study [1].

We strongly agree that comorbidities may work as important confounding factors for the treatment of CAP with corticosteroid. In particular, the comorbidities would include asthma and chronic obstructive pulmonary disease (COPD), because these diseases are also often treated by corticosteroid administration. Therefore, we implemented these factors in the estimation of the propensity scores, and these confounders were well balanced after propensity score matching. Moreover, we performed an instrumental variable analysis as a confirmatory analysis of the propensity score analyses. Using hospitals' preference as an instrumental variable, we computed the differences in the 28-day mortality risk between the groups with and without corticosteroid, using a two-stage least-squares method adjusted for the patient characteristics (i.e. all variables listed in tables 1 and 2 of our study [1], including asthma and COPD). We believe that these analyses are appropriate and useful for treating measured and unmeasured confounders.

We cannot yet draw robust conclusions regarding the effect of low-dose corticosteroid for CAP patients in general, at least from our retrospective analysis [1]. We believe that further studies are required to evaluate the optimal doses and types of corticosteroids for treating CAP. Our results provide basic data for future prospective trials to lead to the “end of the story” [9] and stop the “pendulum”.