Material and Methods
Patients and data: This study was conducted in a tertiary center with diagnosis of COVID-19 patients. Study population consisted of patients with positive polymerase chain reaction and computer tomography findings compatible with COVID-19 as well as critical illness requiring high flow nasal oxygen supplement, or its equivalent defined according to National Institute of Health (NIH) COVID-19 disease severity scale (5). Clinical and laboratory features of patients were obtained from their medical cards and hospital software system and evaluated by retrospectively. All laboratory results were recorded at patients’ admission and inflammatory parameters such as C-reactive protein (CRP), ferritin, d-dimer, lactate dehydrogenase (LDH) also on the highest levels and last day of hospitalization. Hyperinflammatory state of the patients were evaluated and scored according to COVID-19 hyperinflammatory syndrome score (cHIS score) (6).
Treatment protocol and outcome: All patients received background glucocorticoid treatment with methylprednisolone 80 mg/day intravenously or equivalent concomitant anticoagulant prophylaxis with enoxaparin 0.4 mg/day subcutaneously. Anakinra was initiated in patients who did not respond to two days of corticosteroid treatment or concomitantly in high risky patients with 400 mg/day intravenously in two divided dose and gradually increased to 1600 mg/day if necessary. The dose adjustment was performed by daily for each patient according to current clinical and laboratory findings by the same rheumatologist (MB). In combination group, baricitinib was started in 8 mg/day in two divided dose (4 mg/day in chronic renal failure) in addition to steroid and anakinra in patients with unresponsive to anakinra 1600 mg/day at least three days, thereafter dose reduction was performed according to clinical and laboratory results of the patients. Drug tapering was performed in anakinra doses initially when clinical and laboratory response achieved thereafter treatment was stopped when the patients were oxygen free and/or had normal inflammatory parameters such as CRP and ferritin. Treatment failure was defined as no reduction in oxygen support and/or inflammatory parameters as well as need for intensive care unit (ICU) admission and/or invasive mechanical ventilation and/or development of mortality. Age, gender, disease severity (NIH score 4, critically ill patients) and inflammatory burden according to cHIS score matched patients who receiving steroid and anakinra defined as control group. Steroid and anakinra treatment protocol were similar between two groups. Individual patient consent and ethical committee approval were obtained for this study (date/number: 24.02.2022, 2022/04-09).
Statistical analysis : In our study, 21.0 version (IBM, Armonk, NY, USA) of the SPSS (Statistical Package for the Social Sciences) program was used for statistical analysis of data. Descriptive statistics, discrete​ ​and continuous numerical variables were expressed as mean, ± standard deviation or median and interquartile range (IQR). Categorical variables were expressed as number of cases and (%). Cross table statistics were used to compare categorical variables (Chi-Square, Fisher exact test). Normally distributed parametric data were compared with Student’s t-test and Paired t-test; non-parametric data that did not meet normal distribution were compared with Mann Whitney U and Kruskal Wallis tests. Multiple intergroup comparisons were made by Post Hoc Tukey analysis.​ ​Kaplan-Meier and log-rank methods were used for survival analysis. Multivariable analysis was performed by using logistic regression. Correlation analysis was performed with Pearson or Spearman method according to normality distribution.  p<0.05 value was considered statistically significant.