Clinical outcomes of intravenous immunoglobulin therapy in COVID-19 related acute respiratory distress syndrome: a retrospective cohort study

Background Intravenous immunoglobulin (IVIG) has been used as an immunomodulatory therapy to counteract severe systemic inflammation in coronavirus disease 2019 (COVID-19). But its use in COVID-19 related acute respiratory distress syndrome (ARDS) is not well established. Methods We conducted a retrospective analysis of electronic health records of COVID-19 patients admitted to intensive care units (ICUs) at Hazm Mebaireek General Hospital, Qatar, between March 7, 2020 and September 9, 2020. Patients receiving invasive mechanical ventilation for moderate-to-severe ARDS were divided into two groups based on whether they received IVIG therapy or not. The primary outcome was all-cause ICU mortality. Secondary outcomes studied were ventilator-free days and ICU-free days at day-28, and incidence of acute kidney injury (AKI). Propensity score matching was used to adjust for confounders, and the primary outcome was compared using competing-risks survival analysis. Results Among 590 patients included in the study, 400 received routine care, and 190 received IVIG therapy in addition to routine care. One hundred eighteen pairs were created after propensity score matching with no statistically significant differences between the groups. Overall ICU mortality in the study population was 27.1%, and in the matched cohort, it was 25.8%. Mortality was higher among IVIG-treated patients (36.4% vs. 15.3%; sHR 3.5; 95% CI 1.98–6.19; P < 0.001). Ventilator-free days and ICU-free days at day-28 were lower (P < 0.001 for both), and incidence of AKI was significantly higher (85.6% vs. 67.8%; P = 0.001) in the IVIG group. Conclusion IVIG therapy in mechanically ventilated patients with COVID-19 related moderate-to-severe ARDS was associated with higher ICU mortality. A randomized clinical trial is needed to confirm this observation further. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01717-x.

human cases of COVID-19 were reported in Wuhan City, China, in December 2019. Since then, the disease has rapidly spread worldwide, with World Health Organization (WHO) formally declaring it a pandemic on March 11, 2020 [2]. Over 4.8 million deaths have been reported worldwide due to COVID-19 [3]. The leading cause of death is respiratory failure due to acute respiratory distress syndrome (ARDS). In addition, almost half of the patients with COVID-19 receiving invasive mechanical ventilation died, based on the case fatality rates reported in a recent meta-analysis [4]. There is increasing evidence that a hyperinflammatory response to SARS-CoV-2 contributes to disease severity and death in COVID-19. Patients with severe disease have increased serum levels of proinflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ [5,6]. Therefore, an effective therapy that modulates inflammatory response, prevents clinical deterioration and improves mortality is urgently needed.
Intravenous immunoglobulin (IVIG) is a blood product prepared from the serum pooled from thousands of healthy donors. The main component of IVIG is the serum IgG fraction with traces of IgA and IgM. IVIG exerts an immunomodulatory action, involving both innate (phagocytic leukocytes, natural killer cells, and cytokines) and adaptive (B cells, T cells, and antibodies) immunity [7]. It has been successfully used to treat dermatomyositis, Guillain-Barre syndrome, immune cytopenia, post-bone marrow transplantation, vasculitis, and Kawasaki disease [8]. Due to its anti-inflammatory effect, IVIG may suppress the hyperactive immune response associated with severe COVID-19 pneumonia and improve clinical outcomes. However, only a few studies with inconsistent results have investigated the use of IVIG in critically ill SARS-CoV-2 infected patients [9,10]. Moreover, none of the available literature reports outcomes of IVIG therapy in COVID-19 related ARDS. This prompted us to conduct a retrospective study to evaluate the efficacy and safety of IVIG in COVID-19 pneumonia patients requiring invasive mechanical ventilation for moderate-to-severe ARDS.

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 7, 2020 and September 9, 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 (PaO 2 /FiO 2 ≤ 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 routine care or IVIG plus routine care during their ICU stay. All patients received steroid and antiviral therapy as per the hospital's policy for COVID-19 management unless contraindicated. Prophylactic-, intermediate-or therapeutic-dose of anticoagulation was administered based on the patient's risk stratification as low-, intermediateor high-risk for thromboembolic disease (anticoagulation protocol in Additional file 1: Fig. S1). IVIG was given to patients at the treating physician's discretion if there was a persistent increase in oxygen requirement and worsening laboratory parameters (C-reactive protein and serum ferritin level), suggestive of disease progression. The IVIG treatment group received a minimum one dose of 0.4 g/ kg of IVIG. Further doses of IVIG were given on consecutive days, to a maximum of 5 doses, based on the treating physician's decision. 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, PaO 2 /FiO 2 ratio, vasopressor use, sequential organ failure assessment (SOFA) score, immune-modulating, and antiviral 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 ≥ 0.3 mg/dl (≥ 26.5 μmol/L) within 48 h or increase in serum creatinine to ≥ 1.5 times baseline [12]. Sub-group analysis was done for patients based on PaO 2 /FiO 2 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, PaO 2 /FiO 2 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. We included the treatment with IVIG as a discrete time-dependent covariate to minimize the risk of immortal time bias. 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 procedure was used to deal with missing data (BMI, seven values; D-dimer, nine values; and 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.

Characteristics of patients
During the study period (between March 7, 2020 and September 9, 2020), 1417 patients were admitted to ICUs at Hazm Mebaireek General Hospital with the diagnosis of COVID-19. Seven hundred eighty-seven patients received invasive mechanical ventilation, of which 595 (75.6%) had moderate-to-severe ARDS. We excluded three patients who received IVIG for other indications from the treated group and two patients admitted to the ICU post-cardiac arrest from the control group. The remaining cohort of 590 patients comprised 190 treated with IVIG and 400 in the routine care group (Fig. 1).
A comparison between unmatched and propensity score-matched groups is shown in Table 1. Before matching, the patients in the IVIG group were older, had a higher prevalence of hypertension, dyslipidemia, and hemodialysis, had lower PaO 2 /FiO 2 ratio, lesser vasopressor use, lower SOFA score, raised alanine transaminase (ALT), more use of dexamethasone and lesser use of methylprednisolone, hydrocortisone, tocilizumab, lopinavir-ritonavir, and oseltamivir. In the IVIG group, the median time from ICU admission to initiation of IVIG therapy was 6.28 days (IQR 2.1-11.9 days). The median cumulative dose of IVIG received was 150 g (IQR 105-235 g), and the median number of doses received was 4 (IQR 3-5).  Data are presented as count (%) or median (interquartile range) unless otherwise indicated Laboratory data and SOFA score were obtained at baseline on ICU admission BMI, body mass index; PaO 2 /FiO 2 ratio, ratio of partial pressure arterial oxygen and fraction of inspired oxygen; SOFA score, sequential organ failure assessment score; CRP, C-reactive protein; ALT, alanine transaminase; AST, aspartate aminotransferase Propensity score matching generated 118 matched sets. Post matching, the two groups did not have any statistically significant differences (Table 1). In the matched cohort, the median time from ICU admission to initiation of IVIG therapy was 6 days (IQR 2.2-11.1 days). The median cumulative dose of IVIG received was 152.0 g (IQR 108.0-235.0 g), and the median number of doses received was 5.0 (IQR 3.0-5.0).

Outcomes
The all-cause ICU mortality for COVID-19 pneumonia patients admitted with respiratory failure requiring invasive mechanical ventilation for moderate-severe ARDS was 27.1%, and for the matched cohort, it was 25.8%. ICU mortality was significantly higher in the IVIG group (36.4% vs. 15.3% for IVIG and routine care, respectively; sHR 3.5; 95% CI 1.98-6.19; P < 0.001). In the propensity score-matched and propensity score-adjusted survival analysis, there was an increased risk of death in the IVIG group compared to the routine care group (Table 2). Results were similar, with an increased risk of death in the IVIG-treated patients for the subgroups based on PaO 2 /FiO 2 ratio and serum ferritin level. Association of IVIG with increased ICU mortality was significant regardless of the time from ICU admission to IVIG therapy and the number of doses received (Table 3).

Discussion
Our single-center retrospective study revealed a significant association of IVIG therapy with higher ICU mortality in patients with COVID-19 pneumonia receiving invasive mechanical ventilation for moderate-to-severe ARDS. We confirmed these results after propensity score matching to account for the differences between the two groups.
Only a few randomized controlled studies have been conducted to evaluate the efficacy of IVIG therapy in COVID-19 pneumonia. Gharebaghi et al. have reported that administration of IVIG to 30 patients with severe COVID-19 infection who did not respond to initial treatment significantly reduced the in-hospital mortality (20.0% in the treatment group vs. 48.3% in the control group; P = 0.025). However, the authors did not report the severity of ARDS and the percentage of patients receiving invasive mechanical ventilation [14]. Another pilot randomized controlled trial showed that IVIG 0.5 g/kg daily for three days with concomitant methylprednisolone 40 mg significantly improved hypoxia and reduced progression to mechanical ventilation in COVID19 patients [15]. The clinical improvement found in this study cannot be generalized because of the small sample size and concomitant use of methylprednisolone therapy that may have confounded the results. Recently, Tabarsi et al. demonstrated that IVIG in combination with hydroxychloroquine and lopinavir/ritonavir for SARS-CoV-2 patients did not reduce mortality or need for mechanical ventilation, and did not improve radiological findings. However, the potential benefit of IVIG monotherapy couldn't be evaluated in this study due to the use of combination therapy with hydroxychloroquine and lopinavir/ritonavir [16].
The novelty of our work comes from exclusively studying critically ill COVID-19 pneumonia patients receiving invasive mechanical ventilation for moderate-to-severe  ARDS. Based on a global literature survey, the mortality rate in COVID-19 associated ARDS was 45%, and the incidence of ARDS among non-survivors of COVID-19 was 90%. In the same study, the mortality rate of patients who received invasive mechanical ventilation was 59% [17]. Overall ICU mortality of our patients with moderate-to-severe ARDS receiving invasive mechanical ventilation was lower (27.1%). This could be attributed to the younger age of our population (median age 53 years, Table 1) and is consistent with previous reports of higher mortality with increasing age [18]. The higher mortality observed in our patients who received IVIG could be related to multiple factors. Firstly, we observed a higher incidence of AKI in the IVIG group, and based on a recent report, the occurrence of AKI had increased the risk of death by 60% in patients with COVID-19 [19]. Secondly, IVIG was administered after ICU admission and receiving invasive mechanical ventilation for moderate-to-severe ARDS, which is late in the course of the disease. The median time from ICU admission to IVIG therapy was 6.28 days in our study. Xie et al. has reported that IVIG therapy for COVID-19 pneumonia within 48 h of ICU admission improved clinical outcomes [20]. Thirdly, thromboembolic events are high in SARS-CoV-2 infected individuals with significantly increased odds of mortality [21]. Also, previous studies have suggested an association between IVIG and increased risk of thromboembolic events [22,23]. Hence, initiating IVIG therapy in patients with predictive factors for thrombotic complications could have resulted in worse clinical outcomes in our cohort. Lastly, though the control and treatment groups were matched based on their baseline characteristics (including PaO 2 / FiO 2 ratio and SOFA score) at ICU admission, IVIG was administered mainly by physicians as salvage therapy to deteriorating patients who had not responded to initial management.
The dose and duration of IVIG administered to our patients were based on established practice in immune modulation therapy for other diseases [24], as there are no standardized guidelines for its use in COVID-19 patients. In a retrospective case series of 12 patients where IVIG appeared to improve the clinical course, the total dose administered ranged from 0.5 to 2.0 g/kg (median 1.25 g/kg) distributed over 1-4 daily doses [25]. Further studies are required to investigate the dose, duration, and appropriate time for initiation of IVIG therapy which might benefit COVID-19 patients without having adverse effects.
Our study has few limitations. We used propensity score matching to adjust for known confounders, but due to the retrospective design, we could not entirely exclude the possibility of unmeasured confounding factors that might have led to worse outcomes in the IVIG group. The study was conducted in a single center in Qatar, thereby limiting the generalization of these results to other institutions. Our hospital was a tertiary-care referral center for COVID-19 in the State of Qatar, receiving patients from numerous other healthcare facilities. Despite being rigorous in our data collection and analysis approach, there were missing data for some variables that could have affected the outcomes. We did not define the phenotype of our patients as hypo-or hyper-inflammatory based on the severity of systemic inflammation [26] and hence could not study the role of IVIG in modulating the immune response in hyper-inflammatory COVID-19 ARDS.