This is the first large cohort study to evaluate the association between IVIG treatment and mortality among a well-defined cohort of patients with severe COVID-19. The results suggest that use of IVIG treatment was not associated with 28-day mortality or the time to SARS-CoV-2 RNA clearance from respiratory specimens. However, after propensity score matching, the logistic regression suggested that high-dose IVIG treatment (> 10 g/day) was associated with reduced 28-day mortality among patients with severe COVID-19. Moreover, use of IVIG treatment was independently associated with the APACHE II score, APTT, lymphocyte count, platelet count, leukocyte count, and SOFA score.
The use of IVIG has been reported in the treatment of other coronaviruses. Studies of SARS and MERS infection have suggested that IVIG led to significant improvement in leukocyte and platelet counts although the lack of control group and patient’s overall clinical course (16, 17). The present study revealed that although IVIG treatment overall was not associated with a significant reduction in 28-day mortality in severe COVID-19 patients, patients who received IVIG were less likely to experience shock or to require invasive mechanical ventilation and prone position ventilation, suggesting that IVIG treatment may provide some clinical benefits for treating severe COVID-19. In Wuhan, China, the use of high-dose IVIG treatment (25 g/day for 5 days) plus antivirals (lopinavir/ritonavir) and methylprednisolone for severe COVID-19 resulted in increased lymphocyte counts, lower concentrations of inflammatory markers, partial/complete resolution of specific lung findings, and negative nasal and oropharyngeal swab test results within a few days of starting the treatment (18). Moreover, Rodriguez et al reported that IVIG treatment plus adequate antibiotic treatment improved survival among surgical ICU patients with intra-abdominal sepsis (19). Therefore, until a vaccine or other specific treatment is available, IVIG plus antiviral drugs may be an alternative therapeutic strategy for COVID-19.
The use of IVIG as an adjunctive treatment for sepsis and septic shock has been studied for decades. Lizuka et al. found that low-dose IVIG (5 g/day for 3 days) did not reduce mortality among patients with sepsis and septic shock (20). Tagami et al. reported that IVIG treatment (5 g/day for 3 days) was not significantly associated with the survival among mechanically ventilated patients with pneumonia and septic shock (9), or among ventilated patients with septic shock after emergency laparotomy (21). Moreover, Davey Jr. et al. reported that h-IVIG was not superior to placebo for adults who were hospitalized because of influenza A and B viral infections (22). The lack of a relationship between use of IVIG treatment and reduced mortality may be related to the use of only a low dose that was approved by the Japanese Ministry of Health, Labor, and Welfare (20). This dose was lower than the IVIG dose that used in international studies and may be insufficient for patients with severe sepsis (23, 24). We found in the present study that high-dose (> 10 g/day) IVIG treatment may help reduce the 28-day mortality rate. Consistently, a meta-analysis of IVIG treatment for sepsis revealed survival benefits at a total dose of ≥ 1 g/kg or at a treatment duration of ≥ 2 days (25), indicating the beneficial effects of high dose IVIG treatment.
IVIG treatment carries a risk of complications, which include thromboembolic events, renal dysfunction, aseptic meningoencephalitis, and anaphylaxis (26). It is possible that these complications might compromise the effectiveness of IVIG treatment in critically ill patients. Nevertheless, IVIG remains widely used for patients with sepsis, despite a lack of strong evidence supporting this application (26–28). The use of high dose of IVIG is effective in the treatment of COVID-19, possibly through immune modulation, saturating Fc𝛾 receptor, and reducing antibody-dependent enhancement of inflammatory response (29). Therefore, well controlled studies are needed to confirm the clinical and survival benefits of IVIG treatment.
Our study revealed that IVIG treatment influenced immune cell counts (leukocytes, neutrophils, and lymphocytes) and CRP concentrations in patients with severe COVID-19. These results may reflect the ability of IVIG to regulate the inflammatory response by modulating complement and cytokine production, as well as neutralizing superantigens and antibodies (30). These mechanisms are used to justify the widespread use of IVIG for treating inflammatory and autoimmune diseases. We also found that IVIG treatment was associated with increased platelet counts, which suggests an improvement in coagulation function. In consistent with our finding, Ishikura et al. have reported that IVIG treatment significantly decreased the disseminated intravascular coagulation score for septic patients (31). In this context, IVIG treatment ameliorates hemostatic abnormalities via the intrinsic and extrinsic coagulation pathways, and IVIG treatment induces anti-inflammatory and anti-coagulation effects which may benefit the hemostasis in patients.
The present study involved a large and well-defined group of patients with severe COVID-19. However, several limitations should be considered. First, retrospective studies are prone to bias and we were unable to compare the results to those from a placebo control group. We cannot clearly indicate why some patients received IVIG and other did not. The decision was left at the discretion of the physician in charge of the patient. Second, there was some heterogeneity in the patient population, such as critically ill patients who were treated outside the ICU due to a shortage of ICU beds. Third, we did not have access to long-term follow-up data or information regarding secondary infections that were related to the IVIG treatment.