key: cord-0689680-1b95kcac authors: Huang, Chenlu; Fei, Ling; Li, Weixia; Xu, Wei; Xie, Xudong; Li, Qiang; Chen, Liang title: Efficacy Evaluation of Intravenous Immunoglobulin in Non-severe Patients with COVID-19: A Retrospective Cohort Study Based on Propensity Score Matching date: 2021-01-09 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.01.009 sha: 55a1991899a3b98822a772ebb2550ab43124b1ac doc_id: 689680 cord_uid: 1b95kcac OBJECTIVES: At present, there is an absence of any proven effective anti-viral therapy for COVID-19 patients. This study aimed to assess the efficacy of intravenous immunoglobulin (IVIg) in non-severe patients with COVID-19. METHODS: A retrospective study based on propensity score matching (PSM) was designed. Primary outcomes included severity rate and mortality. Secondary outcomes included the duration of fever, virus clearance time, length of hospital stays, and use of antibiotics. RESULTS: 639 non-severe patients with COVID-19 were enrolled. 45 patients received IVIg therapy and 594 received non-IVIg therapy. After PSM (1:2 ration), the baseline characteristics were well balanced between IVIg (n = 45) and control group (n = 90). No statistically significant differences were found between IVIg group and control group in the duration of fever (median, 3 vs 3 days, p = 0.667), virus clearance time (median, 11 vs 10 days, p = 0.288), length of hospital stay (median, 14 vs 13 days, p = 0.469), and the use of antibiotics (40% vs 38.9%, p = 0.901). Meanwhile, compared to IVIg group, no more patients progressed to severe cases (3.3% vs 6.6%, p = 0.376) and died (0 vs 2.2%, p = 0.156) in control group. CONCLUSION: In non-severe patients with COVID-19, no benefit was observed with IVIg therapy beyond standard therapy. In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of coronavirus disease-2019 (COVID- 19) [1] . Person-to-person transmission of SARS-CoV-2 has been confirmed, and asymptomatic infection patients have been identified as potential infection sources [2, 3] . To date, the SARS-CoV-2 has spread to almost all countries worldwide, and the number of confirmed cases and death cases has been quickly growing due to the high rate of infectivity (Ro). As of September 25th, 2020, there have been 32,730,945 confirmed cases of COVID-19, including 991,224 deaths, reported to WHO globally [4] . So far, there is no antiviral drugs were approved for the treatment of COVID-19. Given rapid spread of SARS-CoV-2, there is an urgent need to explore pre-existing therapeutic options while novel therapies are being developed. Intravenous immunoglobulin (IVIg) is a blood product containing polyclonal immunoglobulin G isolated and pooled from healthy donors, which is usually used for treatment of immunodeficiencies, autoimmune diseases, and inflammatory conditions [5] . In addition, IVIg provides passive immune protection against abroad range of pathogens, and has been used in the treatment of severe infections [6] . Finally, IVIg has favorable clinical tolerability and safety for patients with viral infection. Therefore, IVIg does seem to be a promising candidate for the treatment of COVID-19. Nguyen et al reviewed the mechanism and utility of IVIg in viral infections, and consider its usage may be helpful in patients with COVID-19 through immune modulation [7] . Cao et al reported 3 patients with COVID-19 who received high-dose IVIg at the time of initiation of respiratory distress, with satisfactory clinical and radiographic recovery [8] . Mohtadi et al enrolled 5 severely ill COVID- 19 patients, and found that treatment with IVIg can improve the clinical condition and prevent the progression of pulmonary lesions [9] . However, the two case reports enrolled very small number of patients. Clear demonstration of therapeutic benefit of IVIg in COVID-19 patients will require more evidences. This study aimed to assess the efficacy of IVIg on non-severe patients with COVID-19 based on a large sample cohort study. Patients with COVID-19 were diagnosed following the WHO guideline [10] . Laboratory confirmation of SARS-CoV-2 infection were made by the Center for Disease Prevention and Control of China, using reverse transcription polymerase chain reaction (RT-PCR) method. According to the novel coronavirus pneumonia prevention and control program published by the National Health Committee of China, non-severe patients were defined as cases without any of the followings [11] : (1) Respiratory distress, respiratory rates ≥ 30/min; (2) Pulse oxygen saturation ≤ 93% in the resting state; (3) Oxygenation index ≤ 300 mmHg; (4) Require mechanical ventilation; (5) Shock; (6) Combined with other organ failures and needed treatment in ICU. The demographic characteristics, comorbidities, vital signs, laboratory parameters, chest CT results, treatments, and clinical outcomes were extracted from electronic medical records. The vital signs were monitored daily; laboratory tests were examined every 3-5 days; and chest CT scans were performed every 3-7 days. In this study, primary outcomes included severity rate and mortality rate. Secondary outcomes included the duration of fever, virus clearance time, length of hospital stays, and use of antibiotics. The virus clearance time was defined as the time from illness onset to twice continuous negative J o u r n a l P r e -p r o o f tests for SARSCoV-2 with at least 24 hours intervals. The duration of fever was defined as the time from fever onset to persistently normal temperature. Normal distribution variables, non-normal distribution continuous variables, and categorical variables, were showed as means±standard deviations (SD), medians (interquartile ranges, IQR), and counts (percentages), respectively. T-tests, Mann-Whitney-tests, and Chi-Square tests were applied to normal distribution variables, non-normal distribution continuous variables, and categorical variables, respectively. Propensity score matching (PSM) is a powerful tool for comparing groups with similar observed characteristics without specifying the relationship between confounders and outcomes [12] . In this study, PSM was used to adjust for differences in the baseline characteristics of patients between IVIg group and control group. Propensity scores for all patients were estimated according to the essential covariates that might have affected patients assignment to a IVIg group or control group, as well as clinical outcomes. The treatment effect of IVIg on clinical outcomes was analyzed with adjustment for variables that associated with clinical outcomes. A 1:2 exposed unexposed matched analysis was performed based on the estimated propensity scores of each patient and the caliper was set as 0.25 [13] . All statistical analyses were conducted with SPSS software version 15.0 (SPSS Inc. USA), and statistical significance set at 2-sided p < 0.05. As shown in Table 1 , patients who had higher age (56 vs. 36 years, p < 0.001), more common comorbidity (51.1% vs. 18.7%, p < 0.001), higher CRP (19.8 vs 0.5 mg/L, p < 0.001), LDH (272 vs 201 U/L, p < 0.001), and D-dimer (0.5 vs 0.3 ng/mL, p < 0.001) were more likely to be treated with IVIg. Moreover, cortcosteroids (20% vs 7.4%, p=0.003), Thymosin-α (88.9% vs 24.2%, p < 0.001), Arbidol (64.4% vs 18.2%, p < 0.001), and Lopinavir/Ritonavir (46.7% vs 15.5%, p < 0.001) were more frequently used in IVIg group, while Hydroxychloroquine (2.2% vs 44.6%, p < 0.001) was less common in IVIg group compared with control group. No statistically significant differences were found between IVIg group and control group in the rate of acute kidney injury during the hospitalization (8.9% vs 6.9%, p = 0.616). In this study, there were 45 patients who received IVIg therapy, and 594 patients who received Variables associated with primary outcomes are shown in Table p=0.015) as the independent variables associated with primary outcomes. Variables associated with secondary outcomes are shown in Table 3 suggested that all variables associated with primary and secondary outcomes were well balanced between IVIg and control group (Table 4) . Comparisons between patients treated with or without IVIg in propensity-matched groups are shown in Cox regression analysis showed that no significant differences were found in the duration of fever to widen therapeutic opportunities of IVIg [14] . The rationale for the use of IVIg in COVID-19 has been explained in previous review articles [7, 15] . IVIg may modulate the immune response via multiple mechanisms, including blocking a wide array of proinflammatory cytokines, Fc-gamma receptors (FcRs), and leukocyte adhesion molecules, suppressing pathogenic Th1 and Th17 subsets, and neutralizing pathogenic autoantibodies [15] . At present, the use of IVIg has been reported in the treatment of COVID-19. Cao et al reported on 3 severe patients with COVID-19 who received high-dose IVIg with satisfactory recovery [8] . Sheianov et al presented the cases of three severe patients with COVID-19 who had failed to achieve substantial improvement on intial treatment [16] . They subsequently received pulse therapy with methylprednisolone and IVIg (20g/day), which was associated with a prompt resolution of respiratory failure, elimination of clinical manifestations, and reversal of pulmonary CT changes [16] . However, confounding factors of the two studies include the lack of case-matched control patients. Thus, the field lacks strong evidence to better understand the efficacy of IVIg. In this retrospective cohort study, we found that IVIg therapy did not show a benefit in the treatment of non-severe patients with COVID-19. Our results were consistent with a review, which concluded that it is insufficient to support the efficacy of IVIg in the treatment of COVID-19 [17] . Based on previous cases reports [8, 16] , a high dose of IVIg administered at the appropriate point could successfully block the progression of the disease cascade and improve the outcome of severe or critically ill COVID-19 patients. Mohtadi et al also reported the effects of IVIg administration in severely ill COVID-19 patients [9] . Five severely ill COVID-19 patients in whom standard treatments failed were administrated with IVIg, and all the patients showed a desirable therapeutic response and were discharged from the hospital with a stable clinical condition [9] . Lanza et al J o u r n a l P r e -p r o o f describe a 42-year old woman, admitted to Monaldi Hospital after 15 days of persistence of respiratory failure and treated with infusion of IVIg with a successful outcome [18] . Xie et al included 58 patients diagnosed with severe COVID-19, and found that IVIg can reduce the use of mechanical ventilation, and shorten the hospital length of stay [19] . Based on the above studies, although our results did not support the use of IVIg in non-severe patients with COVID-19, IVIg can be considered for use in severe and critically ill patients. Besides COVID-19, there is a debate on the use of IVIg in the treatment of SARS-CoV. Stockman et al performed a review of treatment options in SARS patients, including IVIg [20] . Despite 5 studies of the use of IVIg or convalescent plasma were evaluated, these studies were deemed inconclusive since the effects of IVIg could not be distinguished from other factors that included comorbidities, stage of illness, and the effect of other treatments [20] . Therefore, it was not possible to determine whether IVIg benefited patients during the SARS outbreak. Wang et al conducted a prospective study on SARS patients with pneumonia, in which IVIg was administered for leukopenia or thrombocytopenia, or if there was rapid progression of disease on radiography [21] . The study found that IVIg led to significant improvement in leukocyte and platelet counts, but acknowledges that there was no control group to objectively evaluate responses. In this study, we analyzed the effect of IVIg in non-severe patients with COVID-19 with adjustment for variables that associated with primary and secondary outcomes and comparison with control group. In this study, although Lopinavir/Ritonavir (46.7% vs 15.5%, p < 0.001) were more common, while Hydroxychloroquine (2.2% vs 44.6%, p < 0.001) was less common in IVIg group, compared with control group. We have reason to believe that Hydroxychloroquine and Lopinavir/Ritonavir had no effect on hospitalized patients with COVID-19. Solidarity is an international clinical trial launched by the World Health Organization and partners. The results of Solidarity Trial reported that Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon regimens had little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay [22] . study, the PSM method has been used to balance the differences between IVIg group and control group. However, the PSM method is limited by adjusting for observed variables only, it cannot account for residual confounding of many of variables. That is to say, the PSM method that has been used is still subject to biais. Therefore, our results need confirmation in a perspective randomized clinical trial. Fourth, no children were enrolled in this study, because children with COVID-19 hospitalized at another designated hospital in Shanghai. In conclusion, in non-severe patients with COVID-19, no benefit was observed with IVIg treatment beyond standard therapy. Our results did not support the use of IVIg in the treatment of non-severe patients with COVID-19. Randomised controlled trials or at least non-randomised prospective trials with a control group are needed to confirm the findings of this study. Liang Chen. All authors read and approved the manuscript. This study was supported by grant NO.17411969700 from Shanghai Association for Science and Technology and grant NO.19YF1441200 from Shanghai Sailing Plan Program. The funding organizations are public institutions and had no role in the design and conduct of the study; collection, management, and analysis of the data; or preparation, review, and approval of the manuscript. We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality. The supporting data can be accessed from Qiang Li (corresponding author), E-mail: liqiang66601@163.com The J o u r n a l P r e -p r o o f A new coronavirus associated with human respiratory disease in China A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany IVIG-mediated effector functions in autoimmune and inflammatory diseases Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga(R)) in Patients with Primary Immunodeficiency Diseases: a Two-Stage, Multicenter, Prospective, Open-Label Study Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution! High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease Recovery of severely ill COVID-19 patients by intravenous immunoglobulin (IVIG) treatment: A case series Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV) infection is suspected: interim guidance National Health Commision of China The Propensity Score Statistical primer: propensity score matching and its alternatives Editorial -High dose intravenous immunoglobulins as a therapeutic option for COVID-19 patients Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients? Pulse Therapy With Corticosteroids and Intravenous Immunoglobulin in the Management of Severe Tocilizumab-Resistant COVID-19: A Report of Three Clinical Cases Effectiveness of intravenous immunoglobulin for children with severe COVID-19: a rapid review Successful intravenous immunoglobulin treatment in severe COVID-19 pneumonia Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19 SARS: systematic review of treatment effects Clinical manifestations, laboratory findings, and treatment outcomes of SARS patients Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results We thank all doctors who work in Shanghai Public Health Clinical Center for their efforts in the diagnosis and treatment of patients with COVID-19.J o u r n a l P r e -p r o o f accordance with the declaration of Helsinki. The authors declare no competing interests.