Our results showed that IVIg could improve clinical outcomes in COVID-19 patients with severe respiratory system involvement. Previously, Prohaska et al. showed that IVIg could not reduce the mortality of patients with ARDS undergoing extracorporeal membrane oxygenation (ECMO) therapy. In this study, patients with bacterial and fungal infection also included, and only 54% of patients in the IVIg group and 28% of patients in the control group had viral infection (13). Recently, a randomized controlled trial studied the hyperimmune IVIg (hIVIg) effect on patients with confirmed influenza A or B infection. This study showed that hIVIg was not superior to placebo in treating patients with influenza A or B. In this study the mortality rates of patients in hIVIg and control groups were 4% and 3% respectively (14). The two mentioned studies have investigated IVIg effect in very high-risk and very low-risk patients for mortality, and it is possible that the effectiveness of IVIg in our study could be due to using the drug in patients with intermediate-risk of mortality.
Xie et al. studied the IVIg treatment’s timing effect on mortality of patients with critical illness due to COVID-19 infection. In this study, 58 patients were included, and 28 patients died during 28 days of admission (total mortality = 48.2%). The mortality rate of patients who received IVIg during 48 hours of admission to ICU and those who received IVIg after 48 hours of admission were 23.3% vs 57.1%, respectively (p = 0.009) (15). The mortality rate of Xie et al. study is close to our results, which shows that early IVIg treatment could significantly reduce the mortality of critically ill COVID-19 patients. Cao et al. also reported desirable results in the treatment of 3 patients with COVID-19 and severe disease with IVIg 25 gr/day continued for five days (16). Our results showed that IVIg 20 g/day for three days could be effective and safe.
Very recently, a multicenter retrospective cohort study conducted on 325 patients including 222
(68%) patients with severe type and 103 (32%) with critical type of confirmed COVID-19. In 174 patients, IVIg was administered and 151 patients did not take IVIg. Two groups had significantly different bassline characteristics, and the IVIg group were in more severe condition. This study showed a 28 days mortality rate of 13% in both groups. The primary analysis showed no difference between the IVIg group and control group in reducing in-hospital mortality. However, after adjusting the outcomes of two groups with the severity of illness, results showed that administration of IVIg significantly decreased the 60-day mortality. This study also showed that IVIg dosage > 15 g/d and starting the drug ≤ 7 days could be more effective (17). A meta-analysis showed that IVIg could be effective in patients with severe sepsis or septic shock and its efficacy in mortality reduction could be better in patients with higher baseline risk and those with lower plasma immunoglobulins (18). Justel et al. studied patients admitted with severe pandemic influenza showed that lower level of IgG and IgM was associated with higher early mortality (19).
Our study showed that higher age, lower diastolic blood pressure, and higher LDH were also associated with higher mortality in COVID-19 patients with severe disease. Correspondingly, Du et al. also showed that age ≥ 65 years was associated with higher mortality in patients with COVID-19 pneumonia (20). Moreover, Henry et al. reported that elevated LDH was associated with 16 fold higher mortality among patients with COVID-19 infection (21).
To the best of our knowledge, our study is the first randomized double-blinded control trial that suggests the effectiveness of IVIg in reducing mortality in patients with severe COVID-19 pneumonia. However, some limitations existed in our study. The study was conducted as a pilot study and included a relatively small sample size. Therefore, further multicenter studies with larger samples size should be conducted in this regard. Moreover, it was better to follow the patients for evaluation of intermediate and long term effects of IVIg treatment. However, due to the pressing requirement of physicians and health care systems for providing evidence-based medications for patients with COVID-19, we decided to report the follow-up data in future updates of the study. Furthermore, it should be noted that the cost of IVIg treatment is relatively high, and it may not be widely available, particularly in low and middle-income countries.