key: cord-1018469-4tm4h47h authors: Arcani, Robin; Cauchois, Raphaël; Suchon, Pierre; Jean, Rodolphe; Jarrot, Pierre‐André; Gomes De Pinho, Quentin; Dalmas, Jean‐Baptiste; Jean, Estelle; Andre, Baptiste; Veit, Véronique; Koubi, Marie; Kaplanski, Gilles title: Factors associated with dexamethasone efficacy in COVID‐19. A retrospective investigative cohort study date: 2022-03-24 journal: J Med Virol DOI: 10.1002/jmv.27712 sha: 2b48faa890748efb4e6c07e253f4ad27395b2101 doc_id: 1018469 cord_uid: 4tm4h47h Dexamethasone has demonstrated efficacy in reducing mortality in COVID‐19. However, its practical use is badly defined. We aimed to investigate factors associated with dexamethasone efficacy in real life. Our retrospective study was conducted in two university hospitals between September and November 2020 and included all the consecutive hospitalized patients with a laboratory‐confirmed SARS‐CoV‐2 infection assessed by RT‐PCR, treated with intravenous dexamethasone (6 mg/day). Among 111 patients, 10.6% necessitated a transfer into the intensive care unit (ICU) and the 28‐day mortality rate was 17.1%. The 28‐day mortality rate was significantly lower in patients who demonstrated improvement at 48 h (hazard ratio [HR]: 0.17, 95% confidence interval [CI]: 0.04–0.78, p = 0.02) and 96 h (HR: 0.07, 95% CI: 0.02–0.31, p = 0.0005) after dexamethasone initiation. Apart from well‐known risk factors (age, hypertension, active cancer, severe lesions on chest computed tomography [CT] scan), we found that a high viral load in nasopharyngeal swab (Cycle threshold <30) at dexamethasone initiation was associated with higher 28‐day mortality (66.6% vs. 36.7%, p = 0.03). Patients who did not receive antibiotics at dexamethasone initiation had a higher rate of transfer into the ICU (55.6% vs. 23.5%, p = 0.045) with a trend towards higher mortality in case of severe or critical lesions on CT scan (75.0% vs. 25.0%, p = 0.053). Patients who did not improve within 2–4 days after steroid initiation have a bad prognosis and should receive additional anti‐inflammatory drugs. Our data suggest better efficacy of dexamethasone in patients with a low or negative viral load, receiving broad‐spectrum antibiotics. (ARDS), systemic inflammation, and disseminated coagulation, usually with a low viral load. Several drugs aiming at decreasing inflammation have been tried to treat moderate to severe COVID-19 pneumonia with conflicting results 4 and to date, only corticosteroids, especially dexamethasone, demonstrated a significant reduction of mortality in patients receiving oxygen in a large randomized controlled trial. 5 In France, dexamethasone is now the standard of care in patients hospitalized with moderate to severe COVID-19 pneumonia associated with excessive systemic inflammation. 6 However, corticosteroids in this context may be associated with delayed viral clearance such as observed in other coronavirus-induced severe pneumonia, [7] [8] [9] increased opportunistic infection, 9, 10 were not included if they have been previously hospitalized in the intensive care unit (ICU) or if they had an ongoing hematological malignancy. Clinical, biological, radiological, and follow-up data of these patients were collected from electronic medical records. We assessed the clinical status of patients using the National Early Warning Score (NEWS 2). 12, 13 We considered that the patients had a good clinical response to the treatment if they reached at least 2 of the following items: (1) decrease of the fraction of inspired oxygen This study was approved by the Institutional Review Board of Assistance Publique-Hôpitaux de Marseille (GDPR number PADS21-4). The study was conducted according to the Declaration of Helsinki. Quantitative variables were described using medians and interquartile range (IQR); categorical variables were described using numbers and percentages. Quantitative data were compared using the Student t or Mann-Whitney U test, while qualitative data were compared with the Chi-square or Fisher's exact test when appropriate. Survival and cumulative "survival or transfer into ICU" were estimated by means of the reverse Kaplan-Meier method and they were compared between groups using stratified log-rank tests. The tests were twosided. All p values <0.05 were considered significant. All analyses were performed with R software (R Foundation for Statistical Computing). Nine patients of the 85 eligible patients (10.6%) necessitated a transfer into the ICU, four of them (4.7%) requiring invasive mechanical ventilation. The 28-day mortality rate was 17.1%. The main characteristics of dexamethasone management and adverse events are presented in Table 2 . The patients received dexamethasone for a median of 7 days (IQR: After adjustment for risk factors such as age and hypertension, the 28-day mortality rate was significantly lower in patients who had a good response (as defined in the method section) at 48 h (hazard ratio The risk factors associated with mortality on dexamethasone vs. 36.7%, p = 0.03, Figure 3 ). The absence of antibiotics at the time of dexamethasone initiation seemed to be associated with a higher mortality in patients with severe or critical lesions on CT scan (75.0% vs. 25.0% death on antibiotics, p = 0.053). The risk factors associated with ICU requirement on dexamethasone were underlying immunosuppression (22.2% vs. 2.9%, p = 0.045) and the absence of antibiotics at D1 dexamethasone (55.6% vs. 23.5%, p = 0.045, Figure 4 ). In patients transferred to the ICU, 3 (33%) were diagnosed with a bacterial infection shortly after ICU admission ( In this study, we observed that the viral load, at the time of dexamethasone initiation, was associated with mortality. The higher the viral load, the higher the mortality, in accordance with previous reports. 15 We observed, however, that dexamethasone was associated with significant side effects that were not reported in the RECOVERY trial but were expectable and should be considered in patients with other comorbidities such as type 2 diabetes, hypertension, or cardiovascular diseases. Steroid treatment during COVID-19 has been controversial and in several hundred patients treated in China, no benefit was reported, initially leading the WHO to recommend against corticosteroid treatment. [16] [17] [18] [19] This may be due to heterogeneity in the doses and timing of the treatment. In the RECOVERY study, for example, no benefit and possibly detrimental effects were observed in patients who did not require oxygen treatment. 5 Conversely, the patients who mostly benefited from steroid treatment were those admitted into the ICU requiring invasive mechanical ventilation. 5 This may be expectable when considering that the severity of pneumonia parallels the severity of lung and systemic inflammation. 20 percentage of them will undergo invasive mechanical ventilation, prolonged disease, and death. 5, 31 One of the most important findings of this study is the fact that patients who did not have a good response to treatment 48 and 96 h after the initiation of dexamethasone (consisting in decreased oxygen requirement, CRP, or NEWS 2) had higher mortality and ICU transfer rates. Thus, a poor response to treatment appeared to be predictable very early, 2-4 days, after the initiation of dexamethasone. Patients may then necessitate the addition of other treatments, such as tocilizumab, baricitinib or anakinra, or completely different drug associations to control their disease. [32] [33] [34] [35] We acknowledge limitations to this study. First, it is retrospective, based on a limited number of patients which did not allow us to perform multivariate analysis. Second, the RT-PCR analysis was not quantitative as in another previous report, 15 however, this semiquantitative technique is routinely used in patient care and is easy to compare along time for each individual patient. In conclusion, our data suggest a better efficacy of dexamethasone in patients with a low or negative viral load, under antibiotics therapy. If the clinical condition does not improve within the 4 first days of treatment, additional therapy should be considered. 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