key: cord-0902338-x6eom6kh
authors: Zhang, Jingyi; Yang, Yinmei; Yang, Nan; Ma, Yanfang; Zhou, Qi; Li, Weiguo; Wang, Xia; Huang, Liping; Luo, Xufei; Fukuoka, Toshio; Ahn, Hyeong Sik; Lee, Myeong Soo; Luo, Zhengxiu; Chen, Yaolong; Liu, Enmei; Yang, Kehu; Fu, Zhou
title: Effectiveness of Intravenous Immunoglobulin for Children with Severe COVID-19: A Rapid Review
date: 2020-04-22
journal: nan
DOI: 10.1101/2020.04.17.20064444
sha: e3a80e7de600756dc0273af41fa0b10bf41232f9
doc_id: 902338
cord_uid: x6eom6kh

Background: Intravenous immunoglobulin (IVIG) is usually used as supportive therapy, but the treatment of COVID-19 by IVIG is controversial. This rapid review aims to explore the clinical effectiveness and safety of IVIG in the treatment of children with severe COVID-19. Methods: We systematically searched the literature on the use of IVIG in patients with COVID-19, Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS), including both adults and children. We assessed the risk of bias and quality of evidence and reported the main findings descriptively. Results: A total of 1519 articles were identified by initial literature search, and finally six studies, included one randomized controlled trial (RCT), four case series and one case report involving 198 patients. One case series showed the survival of COVID-19 patients with acute respiratory distress syndrome (ARDS) was not improved by IVIG. One case report showed high-dose IVIG could improve the outcome of COVID-19 adults. Three observational studies showed inconsistent results of the effect of IVIG on SARS patients. One RCT showed that IVIG did not reduce mortality or the incidence of nosocomial infection in adults with severe SARS. The quality of evidence was between low and very low. Conclusions: The existing evidence is insufficient to support the efficacy or safety of IVIG in the treatment of COVID-19. Keywords: COVID-19; children; intravenous immunoglobulin; rapid review.

Coronavirus disease 2019 (COVID- 19) , first reported in China on December, 2019, is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). SARS-CoV-2 belongs to the family of coronaviruses, which are enveloped viruses that can cause illnesses ranging from common cold to severe diseases such as SARS and MERS (2, 3) . The COVID-19 epidemic massively influences the public health and people's daily lives, and the disease was declared a pandemic on 11

March 2020 (4) . All populations are susceptible to infection and there is a research shows children are as likely to be infected as adults (5) . On February 11, 2020, there were 44672 confirmed cases in mainland China, of whom 416 were under the age of 10 years and 549 between the ages of 10 to 19 years (6) . The main symptoms in children are fever and cough, and the disease is on average less severe in children than adults (7) .

However, severe cases have been reported also in children (8) . So far, there has been no specific treatment for COVID-19, antiviral therapy and vaccination are currently under development (9, 10) .

IVIG is prepared from the plasma of healthy humans and usually used as supportive therapy. Its main component is immunoglobulin (Ig) G, which has dual therapeutic effects of immune-modulation effects and immune substitution (11) . IVIG is one of the alternative treatments for children with agammaglobulinemia, and an effective treatment of Kawasaki disease (12, 13) . IVIG was used to treat SARS patients during the SARS outbreak in 2003 (14, 15) , but there is no convincing evidence of its effectiveness. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . https://doi.org/10.1101/2020.04. 17.20064444 doi: medRxiv preprint According to recent reports, about 33% of patients with severe COVID-19 received IVIG in China (16) . Some published guidelines of COVID-19 have indicated that IVIG could be used to treat children with severe or critical disease (17) .

The purpose of this study is to perform a comprehensive rapid review to explore whether it is beneficial to treat children with severe COVID-19 with IVIG and provide supporting evidence support for COVID-19 guidelines. Because of the urgent situation, the review was not registered (18) .

We carried out a comprehensive search in the following electronic databases: the Data, by using the terms "COVID-19", "SARS-CoV-2", "Novel coronavirus", "2019-novel coronavirus", "2019-nCoV", "SARS", "MERS", "IVIG", "intravenous immunoglobulin"

and their derivatives. The search covered the time from each database's inception to March 31, 2020 . The search strategies are determined by multiple pre-searches and will be discussed with the clinicians about the appellation of disease and IVIG. We also searched the World Health Organization Clinical Trials Registry Platform, ISRCTN Registry, ClinicalTrials, Google Scholar, three preprint services, including medRxiv (https://www.medrxiv.org/), bioRxiv (https://www.biorxiv.org/) and SSRN All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The primary outcomes were the risk of death and severity of the disease. Secondary outcomes included the incidence of nosocomial infection, the duration of hospitalization, clinical symptoms, absorption of lung lesions, improvement in abnormal biochemical indicators, and adverse effects. We excluded duplicates, conference abstracts, comments and letters, studies published in languages other than English or Chinese, and studies where we could not access the full text.

After eliminating duplicates by EndNote software and manual check, two reviewers (J Zhang and Y Yang) independently reviewed the titles and abstracts of records retrieved All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . https://doi.org/10.1101/2020.04. 17.20064444 doi: medRxiv preprint from the search and selected all potentially relevant studies according to the pre-defined inclusion and exclusion criteria. After this, the same reviewers screened the full texts and made the final selection. A pilot search was conducted before the full screening of the literature to ensure that each researcher understood the screening criteria and process. Disagreements about selection of studies were resolved by consulting a third party (N Yang). The process of study selection was documented using a PRISMA flow diagram (19) .

Two reviewers (J Zhang and Y Yang) independently extracted the following data from included trials using a standardized extraction sheet: 1) basic information (year of publication, first author and affiliation, journal, funding, conflict of interest); 2) study details (type of study, sample size, research purpose, research population characteristics, interventions; and 3) outcome data. A pre-test was conducted before formal extraction to ensure that each researcher agreed with the extraction criteria and process.

Disagreements were solved through discussion with a third researcher (N Yang).

Two reviewers (J Zhang and Y Ma) assessed the quality of the included studies independently. We used the Cochrane bias risk assessment tool (Risk of bias) to assess the randomized controlled trials and clinical controlled trials (20) , the criteria recommended by the National Institute of Health and Clinical Optimization (NICE) for case series to assess the risk of bias (21) , the Joanna Briggs Institute'(JBI) case report All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . https://doi.org/10.1101/2020.04. 17.20064444 doi: medRxiv preprint quality appraisal tool for case reports (22) Newcastle-Ottawa Quality Assessment Scale (NOS) for the quality of cohort studies and case-control studies (23) , and Agency for Healthcare Research and Quality (AHRQ) tool for cross-sectional studies (24) .

For dichotomous outcomes we calculated the risk ratio (RR) and the corresponding 95% confidence interval (CI) and P value. For continuous outcomes, we calculated the mean difference (MD) and its corresponding 95% CI when means and standard deviations (SD) were reported. If sufficient data were available, we considered examined the robustness of meta-analyses in a sensitivity analysis.When effect sizes could not be pooled, we reported the study effectives narratively.

The quality of the body of evidence was graded using the GRADE method (25, 26) . Evidence from randomized trials could be downgraded by the following five factors: risk of bias, inconsistency of results, indirectness of evidence, imprecision of results, and publication bias. The quality of evidence for each outcome was graded as high, medium, low, or very low. The results of the grading were presented in "GRADE evidence profile" (27) (28) (29) (30) .

We identified 1519 articles in the initial literature search (Figure 1 ). After removing duplicates, we screened the titles and abstracts of 1405 records. Thirty-one articles were retrieved for full-text reviewing. Finally, one RCT, four case series and one case report involving a total of 198 patients were included for rapid review (31) (32) (33) (34) (35) (36) .

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . https://doi.org/10.1101/2020.04. 17.20064444 doi: medRxiv preprint The studies were published between 2004 and 2020, and all studies were from China ( Table 1 and Table 3 ). We found one case series on IVIG in COVID-19 adults with ARDS, one case report in COVID-19 adults, one randomized controlled trial of 44 adults with severe SARS, which included 25 adults with acute lung injury (ALI) and 19 adults with ARDS), one case series involving children with SARS, and two case series also involving adults with SARS. The outcomes of the studies were the duration of fever, total peripheral blood WBC, time of the lung lesions subsided obviously, adverse effects, WBC counts, platelet counts, serum globulin, the incidence of nosocomial infection, the risk of death, survival probability and the progression of disease cascade. In all studies IVIG was used before or in combination with other drugs and treatment (such as antibiotics, glucocorticoids, antivirals, oxygen therapy). The IVIG dose and duration of use differed across studies.

We found a high risk of bias in random sequencing, allocation concealment and blinding in the only included RCT. All case series had a moderate risk (score 4 to 5 out of 8), one case report meeting 8 of the 8 items of the JBI quality appraisal tool ( Table   1) .

The quality of evidence for all outcomes assessed in the only included RCT was graded low ( Table 2) , primarily due to serious risk of bias and imprecision. As we included four case series, we judged that reporting a 'GRADE evidence profile' would not be meaningful. Overall, the quality of evidence was very low for most outcomes and cannot thus provide a reliable indication of any likely effect across outcomes. All rights reserved. No reuse allowed without permission.

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A case series of 109 adults with COVID-19 reported that most patients used antibiotics and antiviral treatment, and over half of the patients were given glucocorticoid therapy and IVIG. The survival probability of patients with ARDS could not be improved by antiviral, glucocorticoid, or immunoglobulin treatment. The risk of death was not associated with the use of IVIG in the patients with ARDS (31) .A case report of three adults with COVID-19 reported that a high dose IVIG (25 g/d for 5 days) administered at the appropriate point could successfully block the progression of disease cascade (result of the clinical symptoms, laboratory inspection indicators and chest CT scan), and finally improve the outcome of COVID 19 (32) .

The randomized controlled trial of 44 adults with severe SARS found no significant difference in the risk of death (18.1% vs. 23.8%) or the incidence of nosocomial infection (65.2% vs. 52.4%) between adults treated either with IVIG or with conventional treatment. And there was no significant difference in the incidence of nosocomial infection between ALI (50.0% vs. 38.5%) and ARDS (81.8% vs. 75.0%) patients (36) .

One case series reported the patients with SARS who did not receive steroids for severe hemocytopenia had increased WBC counts and platelet counts after undergoing IVIG (34) . Another case series reported the children with persistent fever who were given All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted April 22, 2020. . https://doi.org/10.1101/2020.04. 17.20064444 doi: medRxiv preprint IVIG had significantly improved total peripheral blood WBC after undergoing IVIG (33) . The included RCT showed the serum globulin increased slightly in the IVIG group, but decreased in the conventional treatment group, the difference was not significant (36) .

One case series included ten children with persistent fever who were given IVIG. The body temperature ranged between 38.4℃ and 40℃ at baseline and the duration of fever was 1 to 4 days after IVIG (33) .

One case series reported that chest radiographs in children who were given IVIG showed more patchy focal asymmetric infiltrative shadows, more rapid time of the lung lesions subsided obviously than in a randomly selected, age-and sex-matched control group of 20 children without IVIG (33) .

One case series reported no adverse effects associated with IVIG , when IVIG was used in the patients who had high fever or other obvious poisoning symptoms, who were in the early stage of the disease, who were treated with glucocorticoids, or whose white blood cell counts below 3.0 ×10 9 /L (35).

We only found limited evidence about the use of IVIG to treat children or adults with severe COVID-19. Since SARS and COVID-19 belong to the same family of viruses, All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . we used IVIG treatment of SARS as indirect evidence, even though the quality of the included studies was generally low. The results were also inconsistent, and no benefit was found in the only identified randomized controlled trial. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. infection, compared with placebo or no intervention (41) .

IVIG is prepared from pools of plasma obtained from several thousand healthy blood donors. Unlike convalescent plasma from patients with COVID-19, IVIG does not contain SARS-Cov-2 neutralizing antibody (42, 43) . The review showed that there was no evidence that IVIG has an effect on anti-MERS-CoV, or that IVIG would cause kidney failure or thrombosis in patients with MERS (44) . IVIG could increase the risk of vaccination delay. A study by National Advisory Committee on Immunization and the American Advisory Committee on Immunization showed a delay of five months of varicella vaccine in patients who received IVIG and varicella immune globulin (VZIG) (45) . IVIG may increase the risk of infections transmitted by transfusion (42) . Some adverse effects, such as thrombosis, aseptic meningitis, hemolysis, and renal failure, are mainly associated with the use of high-dose IVIG (46) .

The condition, dose and duration of IVIG were inconsistent between studies, the efficacy, and the associated adverse effects remain unclear. The first severe case of COVID-19 in children in China took IVIG with a dose of 400 mg/kg for a duration of five days (8) . The recommended dosage of IVIG for children with severe COVID-19 was also inconsistent in different guidelines, including 1.0g/kg/d for 2 days, or 400mg/kg/d for 5 days, 0.2g/kg/d for 3~5 days, or 1~2g/kg for 2~3 days (47) (48) (49) .

Therefore, it is particularly important and urgent to study the benefits and disadvantages of IVIG treatment in children with COVID-19. It is promising that a trial addressing efficacy and safety of IVIG therapy in patients with severe or critical COVID-19 All rights reserved. No reuse allowed without permission.

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This is the first systematic review of IVIG treatment for children with COVID-19.

There are several limitations in this systematic review. First, the use of glucocorticoids or a combination of a variety of broad-spectrum antibiotics before IVIG may lead to changes in the microecology of the body, affect the immune regulation function, and thus also affect the effect of IVIG. Second, the total sample size of this study was insufficient to make strong conclusions, and the quality of the methodology was generally low which affect the certainty of the results. Finally, we may have missed some studies as we only included studies published in Chinese and English.

There is no direct evidence for IVIG in children with COVID-19, current evidence is insufficient to assess the effectiveness and safety of IVIG for children with severe COVID-19. Therefore, we cannot suggest use of IVIG for the treatment of COVID-19 in children. More clinical studies to address this topic are needed. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . 

We thank Janne Estill, Institute of Global Health of University of Geneva for providing guidance and comments for our review. We thank all the authors for their wonderful collaboration. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. explode all trees #4 "COVID-19":ti,ab,kw #5 "SARS-COV-2":ti,ab,kw #6 "Novel coronavirus":ti,ab,kw #7 "2019-novel coronavirus":ti,ab,kw #8 "Novel CoV":ti,ab,kw #9 "2019-nCoV":ti,ab,kw #10 "2019-CoV":ti,ab,kw #11 "coronavirus disease-19":ti,ab,kw #12 "coronavirus disease 2019":ti,ab,kw #13 "COVID 19":ti,ab,kw #14 "Wuhan-Cov":ti,ab,kw #15 "Wuhan Coronavirus":ti,ab,kw #16 "Wuhan seafood market pneumonia virus":ti,ab,kw #17 "Middle East Respiratory Syndrome":ti,ab,kw All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted April 22, 2020. . #8 TOPIC: "Novel CoV" #9 TOPIC: "2019-nCoV" #10 TOPIC: "2019-CoV" #11 TOPIC: "Wuhan-Cov" #12 TOPIC: "Wuhan Coronavirus" #13 TOPIC: " Wuhan seafood market pneumonia virus" #14 TOPIC: " Middle East Respiratory Syndrome" #15 TOPIC: " MERS" #16 TOPIC: " MERS-CoV" #17 TOPIC: "Severe Acute Respiratory Syndrome" #18 TOPIC: "SARS" #19 TOPIC: "SARS-CoV" #20 TOPIC: "SARS-Related" #21 TOPIC: "SARS-Associated" #22 #1-#21 /OR #23 TOPIC: "Intravenous Immunoglobulin*" #24 TOPIC: "Intravenous IG" #25 TOPIC: "immune globulin*" #26 TOPIC: "IVIG" #27 TOPIC: "IV Immunoglobulin*" #28 TOPIC: "Intravenous Antibodies" #29 TOPIC: "gamma globulin*" #30 TOPIC: "gamma-globulin*" #31 TOPIC: "Flebogamma DIF" #32 TOPIC: "Gamune" #33 TOPIC: "Globulin-N" #34 TOPIC: "Globulin N" #35 TOPIC: "Intraglobin" #36 TOPIC: "Gammagard" #37 TOPIC: "Gamimune" #38 TOPIC: "Gamimmune" #39 TOPIC: "Privigen" #40 TOPIC: "Sandoglobulin" #41 TOPIC: "Venoglobulin" #42 TOPIC: "Iveegam" #43 TOPIC: "Endobulin" #44 TOPIC: "Gammonativ" #45 #23-#44 /OR #46 #22 AND #45 CBM #1 "新型冠状病毒"[常用字段:智能] All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. #18 #13-#17/ OR #19 #13 AND #18 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 2.Using other drugs (such as interferon, hormone, etc.) before intervention 3.The value of square I above 50%.

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