Pulmonary dysfunction severity may impact optimal dexamethasone dosing in patients with COVID-19
Authors: Kuo-Chuan Hung, I-Wen Chen, Cheuk-Kwan Sun
Journal: Journal of Infection (2024)

Dear Editor, We read with interest the article by Snow et al. titled "Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis" published in the Journal of Infection1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar. The authors performed a systematic review and meta-analysis of eight randomized controlled trials comparing high-dose (12-24 mg daily) and low-dose (6-8 mg daily) dexamethasone for the treatment of COVID-191Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar. They found no significant difference in 28-day mortality between the high-dose and low-dose groups (OR 1.20, 95% confidence interval: 0.86-1.67, p=0.29; I2=63%)1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar. This finding is critical as it challenges the assumption that higher doses of steroids might be more effective in severe cases. The significance of this topic cannot be overstated considering the widespread impact of COVID-19 and the urgent need for identifying optimal treatment protocols. Their analysis1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar contributes significantly to our understanding of COVID-19 treatment and will undoubtedly influence future clinical practice. One concern in their findings1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar was that the observed heterogeneity for the primary outcome (i.e., 28-day mortality risk) was notably high (I2 = 63%). While subgroup analysis is a typical method to address such heterogeneity, the author chose to perform meta-regression1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar that ruled out significant influences of factors such as the proportion of male patients, mean age, percentage of patients needing invasive ventilation, and dosage of dexamethasone on the study outcome. However, this approach does not fully clarify the source of the heterogeneity. The article by Snow et al.1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar encompassed a diverse patient population with varying levels of pulmonary dysfunction, including those needing only oxygen via a nasal cannula or open mask, those requiring noninvasive ventilation methods (e.g., the use of Continuous Positive Airway Pressure), and those deemed necessary for invasive ventilation. Considering that acute respiratory distress syndrome (ARDS) remains a significant cause of COVID-19-related mortality, we conducted a subgroup analysis based on the severity of pulmonary dysfunction to explore the source of heterogeneity. We categorized the studies included in the original meta-analysis by Snow et al.1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar into two groups: those involving patients with mild pulmonary dysfunction (i.e., requiring only oxygen through nasal cannula or open mask) and those with mixed pulmonary dysfunction (i.e., requiring oxygen via nasal cannula, noninvasive or invasive ventilation). Our subgroup analysis aimed at determining the impact of pulmonary dysfunction severity on the heterogeneity of the primary outcome (i.e., 28-day mortality). Using the raw data from the original meta-analysis1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar, we performed a subgroup analysis using Review Manager (version 5.4; Cochrane Collaboration, Oxford, UK). As illustrated in Fig. 1, for the mild pulmonary dysfunction subgroup, a high dose of dexamethasone was associated with an increased risk of mortality compared with a low dose (odds ratio: 1.65, 95% confidence interval: 1.24 to 2.2, p=0.0005, I2=0%). Conversely, in the mixed pulmonary dysfunction subgroup, there was no significant difference in the risk of 28-day mortality between the high and low doses of dexamethasone (odds ratio, 0.92; 95% confidence interval: 0.7 to 1.21, p=0.55; I2=21%). The difference in the outcomes between these subgroups was statistically significant (p=0.003). Furthermore, the heterogeneity was markedly lower in these subgroup analyses, at 0% and 21%, respectively, suggesting that variability in pulmonary dysfunction severity was a primary contributor to the overall heterogeneity observed in the meta-analysis by Snow et al.1Snow T.A.C. Arulkumaran N. Singer M. Choi S.H. Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis.The Journal of infection. 2023; 87: 490-497Abstract Full Text Full Text PDF Scopus (0) Google Scholar. In conclusion, our findings suggest that high doses of dexamethasone may be deleterious to patients with mild pulmonary dysfunction in terms of survival, while it offers no survival benefit to those with relatively severe pulmonary problems compared with low doses. Therefore, our results support the use of low-dose dexamethasone for patients diagnosed with COVID-19 regardless of the severity of pulmonary dysfunction. No external funding was received for this study.