Study population, design, and setting:
We retrospectively analyzed electronic health record data of patients admitted to ICUs at Hazm Mebaireek General Hospital, Qatar, between March 07, 2020, and September 09, 2020. The Medical Research Center (MRC) at Hamad Medical Corporation, Qatar, approved this study and waived the requirement for informed consent (protocol ID MRC-01-20-853). Inclusion criteria were: COVID-19 positivity as determined by reverse-transcription polymerase chain reaction (RT-PCR) of nasopharyngeal swabs, age above 18 years, respiratory failure requiring invasive mechanical ventilation, and moderate-to-severe ARDS (PaO2/FiO2 £200 mm Hg) as defined by the Berlin criteria [11]. Patients who received IVIG for indications other than COVID-19 related ARDS or had cardiac arrest before ICU admission were excluded. The study population was divided into two groups based on receiving either routine care or IVIG plus routine care during their ICU stay. All patients received steroid and anti-viral therapy based on the hospital's policy for COVID-19 management unless contraindicated. IVIG was given to patients if there was a persistent increase in oxygen requirement, hemodynamic instability, and worsening laboratory parameters (C-reactive protein and serum ferritin level), suggesting disease progression. The IVIG treatment group received a minimum of one dose of 0.4 gram/kg of IVIG. Further doses of IVIG were given on consecutive days, to a maximum of 5 doses, based on the treating physician's discretion. Patients were closely monitored for immediate adverse effects like skin rash, arrhythmias, hypotension, and anaphylaxis.
Data collection:
Baseline data were collected at the time of ICU admission. Information collected were demographic characteristics, comorbid conditions, blood test results, PaO2/FiO2 ratio, vasopressor use, sequential organ failure assessment (SOFA) score, immune-modulating, and anti-viral drugs received.
Outcomes:
The primary outcome studied was all-cause ICU mortality. Secondary outcomes included ventilator-free days and ICU-free days at day-28, and incidence of acute kidney injury (AKI) defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria as an increase in serum creatinine level by ³0.3 mg/dl (³26.5 mmol/L) within 48 hours or increase in serum creatinine to ³1.5 times baseline [12]. Sub-group analysis was done for patients based on PaO2/FiO2 ratio, serum ferritin level, time from ICU admission to IVIG therapy, and doses of IVIG received.
Statistical Analysis:
We used propensity score matching to account for the non-random treatment allocation and to adjust for confounders. Propensity scores were generated based on age, sex, body mass index (BMI), comorbidities, SOFA score, PaO2/FiO2 ratio, baseline laboratory results, and other drug therapies. The propensity score overlap was assessed graphically. One-to-one matching with a caliper width of 0.2 of the standard deviation of the logit of the propensity score and no replacement was used to select a matching control group [13]. The post-matching covariate balance was assessed using the standardized differences. The primary outcome was compared using survival analysis. To minimize the risk of immortal time bias, we included the treatment with IVIG as a discrete time-dependent covariate. Because the discharge from ICU does not fulfill the assumption of non-informative censoring, Fine-and-Gray's competing risk model was used for the primary outcome with ICU discharge as a competing event. The treatment effect on the primary outcome was described as a sub-distribution hazard ratio (sHR) with a 95% confidence interval. A robust variance estimator was used to account for correlations resulting from matching. Multiple imputation procedures were used to deal with missing data (BMI, seven values; D-dimer, nine values; ferritin, three values). P values of less than 0.05 were considered statistically significant. All statistical analyses were conducted using Stata /MP 16.0 for Windows.