Immunomodulatory Therapy for MIS-C
CONTEXT Studies comparing initial therapy for multisystem inflammatory syndrome in children (MIS-C) provided conflicting results. OBJECTIVE To compare outcomes in MIS-C patients treated with intravenous immunoglobulin (IVIG), glucocorticoids, or the combination thereof. DATA SOURCES Medline, Embase, CENTRAL and WOS, from January 2020 to February 2022. STUDY SELECTION Randomized or observational comparative studies including MIS-C patients <21 years. DATA EXTRACTION Two reviewers independently selected studies and obtained individual participant data. The main outcome was cardiovascular dysfunction (CD), defined as left ventricular ejection fraction < 55% or vasopressor requirement ≥ day 2 of initial therapy, analyzed with a propensity score-matched analysis. RESULTS Of 2635 studies identified, 3 nonrandomized cohorts were included. The meta-analysis included 958 children. IVIG plus glucocorticoids group as compared with IVIG alone had improved CD (odds ratio [OR] 0.62 [0.42-0.91]). Glucocorticoids alone group as compared with IVIG alone did not have improved CD (OR 0.57 [0.31-1.05]). Glucocorticoids alone group as compared with IVIG plus glucocorticoids did not have improved CD (OR 0.67 [0.24-1.86]). Secondary analyses found better outcomes associated with IVIG plus glucocorticoids compared with glucocorticoids alone (fever ≥ day 2, need for secondary therapies) and better outcomes associated with glucocorticoids alone compared with IVIG alone (left ventricular ejection fraction < 55% ≥ day 2). LIMITATIONS Nonrandomized nature of included studies. CONCLUSIONS In a meta-analysis of MIS-C patients, IVIG plus glucocorticoids was associated with improved CD compared with IVIG alone. Glucocorticoids alone was not associated with improved CD compared with IVIG alone or IVIG plus glucocorticoids.
Benefits of high-dose intravenous immunoglobulin on mortality in patients with severe COVID-19: An updated systematic review and meta-analysis
Frontiers in Immunology. 2023;14:1116738
BACKGROUND The clinical benefits of high-dose intravenous immunoglobulin (IVIg) in treating COVID-19 remained controversial. METHODS We systematically searched databases up to February 17, 2022, for studies examining the efficacy of IVIg compared to routine care. Meta-analyses were conducted using the random-effects model. Subgroup analysis, meta-regression, and trial series analysis w ere performed to explore heterogeneity and statistical significance. RESULTS A total of 4,711 hospitalized COVID-19 patients (1,925 IVIg treated and 2786 control) were collected from 17 studies, including five randomized controlled trials (RCTs) and 12 cohort studies. The application of IVIg was not associated with all-cause mortality (RR= 0.89 [0.63, 1.26], P= 0.53; I(2) = 75%), the length of hospital stays (MD= 0.29 [-3.40, 6.44] days, P= 0.88; I2 = 96%), the needs for mechanical ventilation (RR= 0.93 ([0.73, 1.19], P= 0.31; I2 = 56%), or the incidence of adverse events (RR= 1.15 [0.99, 1.33], P= 0.06; I2 = 20%). Subgroup analyses showed that overall mortality among patients with severe COVID-19 was reduced in the high-dose IVIg subgroup (RR= 0.33 [0.13, 0.86], P= 0.02, I(2) = 68%; very low certainty). CONCLUSIONS Results of this study suggest that severe hospitalized COVID-19 patients treated with high-dose IVIg would have a lower risk of death than patients with routine care. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021231040, identifier CRD42021231040.
Intravenous immunoglobulins (IVIG) in severe/critical COVID-19 adult patients
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;163:114851
The coronavirus disease 2019 (COVID-19) pandemic has become a huge obstacle to the health system due to the high rate of contagion. It is postulated that intravenous immunoglobulins (IVIG) can lower the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related inflammation and prevent the development of acute respiratory distress syndrome (ARDS). The main advantages of IVIG treatment might be targeting cytokine storm in severe and critical COVID-19 by influences on complement, innate immune cells, effector T-cells, and Tregs. Randomized clinical trials (RCTs) and non-RCTs evaluating the safety and efficacy of IVIG in patients with severe/critical COVID-19 were performed. It seems that early administration of high-dose IVIG (in the acceleration phase of the disease) in severe or especially critical COVID-19 may be an effective therapeutic option, but there are no strong data to use it routinely. The results regarding mortality reduction are inconclusive. Additionally, IVIG treatment carries a risk of complications that should be considered when initiating treatment. However, given the COVID-19 mortality rate and limited therapeutic options, the use of IVIG is worth considering. This review summarizes the development and highlights recent advances in treatment with IVIG of severe/critically ill COVID-19 patients.
Efficacy of intravenous immunoglobulins (IVIG) in COVID-19 patients: a systematic review and meta-analysis
Research in pharmaceutical sciences. 2023;18(4):346-357
BACKGROUND AND PURPOSE Though controversial, many clinical trials have been conducted to evaluate the efficacy of intravenous immunoglobulins (IVIG) in COVID-19 cases. Therefore, a systematic review and meta-analysis have been performed to evaluate the efficacy of IVIG in the treatment of COVID-19 patients. EXPERIMENTAL APPROACH A systematic search was performed in electronic databases and preprint servers up to November 20, 2021. Since substantial heterogeneity was expected, a random-effects model was applied to pool effect size from included studies to calculate the standardized mean differences (SMDs) for the continuous variables and relative risks (RRs) for the dichotomous variable with 95% confidence intervals (CIs). FINDINGS/RESULTS Five randomized clinical trials and seven cohort studies were analyzed among the 12 eligible studies with a total of 2,156 patients. The pooled RR of mortality was 0.77 (CI 0.59-1.01, P-value = 0.06), and of mechanical ventilation was 1.50 (CI 0.29-7.83; P-value = 0.63) in the IVIG group compared with the standard care group. The pooled SMD of hospital length of stay was 0.84 (CI -0.43-2.11; P-value = 0.20) and of ICU length of stay was -0.07 (CI -0.92-0.78; P-value = 0.86) in the IVIG group compared with the standard care group. CONCLUSION AND IMPLICATIONS This meta-analysis found that the IVIG therapy was not statistically different from the standard care group. Mortality, ICU admission, mechanical ventilation, length of hospital stay, and length of ICU stay were not significantly improved among IVIG recipients. However, statistical indifference is not equal to clinical indifference.
Characteristics and conflicting recommendations of clinical practice guidelines for COVID-19 management in children: A scoping review
Travel medicine and infectious disease. 2022;48:102354
BACKGROUND Clinical practice guidelines (CPGs) are statements that should be rigorously developed to guide clinicians' decision-making. However, given the scarce evidence for certain vulnerable groups like children, CPGs' recommendations formulation could be challenging. METHODS We conducted a scoping review of CPGs for COVID-19 management in children. Documents were included if they claimed to be a "clinical practice guideline", published between January and October 2021, and described the process followed to issue their recommendations. We assessed the quality using the "Appraisal of Guidelines for Research and Evaluation II" (AGREE-II) and described how the recommendations were reached. RESULTS We found five CPGs that fulfilled our inclusion criteria. The median score on the overall AGREE-II evaluation was 61% (range: 49%-72%), and the score on the third domain referred to the rigor of methodological development was 52% (range: 25%-88%). Recommendations for remdesivir, tocilizumab, and intravenous immunoglobulin were heterogeneous across CPGs (in favor, against, no recommendation), as well as the methodologies used to present the evidence, perform the benefits/harms balance, and issue the recommendation. CONCLUSIONS Heterogeneous recommendations and justifications across CPGs were found in the three assessed topics. Future CPGs should describe in detail their evidence-to-decision process to issue reliable and transparent recommendations.
The emerging threat of multisystem inflammatory syndrome in adults (MIS-A) in COVID-19: A systematic review
Heart & lung : the journal of critical care. 2022;54:7-18
BACKGROUND The exact prevalence of Multisystem Inflammatory Syndrome in Adults (MIS-A) is largely unknown. Vague and multiple definitions and treatment options often add to the confusion on how to label the diagnosis with certainty. OBJECTIVES The objective of the study was to determine the demographic profile, clinical presentation, laboratory findings and outcomes of MIS-A in COVID-19. METHODS A systematic review was conducted after registering with PROSPERO. Multiple databases were systematically searched to encompass studies characterizing MIS-A from 1st January 2020 up to 31st August 2021. The inclusion criteria were- to incorporate all published or in press peer-reviewed articles reporting cases of MIS-A. We accepted the following types of studies: case reports, case-control, case series, cross-sectional studies and letters to the editors that incorporated clinical, laboratory, imaging, as well as the hospital course of MIS-A patients. The exclusion criteria for the review were- articles not in English, only abstracts published, no data on MIS-A and articles which have focus on COVID-19, and not MIS-A. Two independent authors screened the articles, extracted the data, and assessed the risk of bias. RESULTS A total of 53 articles were included in this review with a sample size of 79 cases. Majority of the patients were males (73.4%) with mean age of 31.67±10.02 years. Fever (100%) and skin rash (57.8%) were the two most common presenting symptoms. Echocardiographic data was available for 73 patients of whom 41 (73.2%) had reduced left ventricular ejection fraction. Cardiovascular system was most frequently involved (81%) followed by gastrointestinal (73.4%) and mucocutaneous (51.9%) involvement. Anti-inflammatory therapies used in treatment included steroids (60.2%), intravenous immunoglobulin (37.2%) and biologics (10.2%). Mean duration of the hospital stay was 11.67±8.08 days. Data regarding the outcomes was available for all 79 subjects of whom 4 (5.1%) died during course of hospital stay. CONCLUSIONS Emergence of MIS-A calls for further large-scale studies to establish standard case definitions and definite treatment guidelines.
IVIG plus Glucocorticoids versus IVIG Alone in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Systematic Review and Meta-Analysis
The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale. 2022;2022:9458653
BACKGROUND There is limited information available regarding the management of multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2. We performed a systematic review and meta-analysis to evaluate the optimal treatment using IVIG alone versus IVIG plus glucocorticoids. METHODS PubMed, Google Scholar, EMBASE, and Cochrane databases were searched along with other secondary searches. Studies published within the time frame of January 2020 to August 2021 were included. We screened records, extracted data, and assessed the quality of the studies using NOS. Studies that directly compare the two treatment groups were included. Analyses were conducted using the random-effects model (DerSimonian-Laird analysis) if I (2) > 50% and fixed-effects model was used if I (2) < 50%. RESULTS We included three studies in the final quantitative analysis. The initial therapy with the IVIG plus glucocorticoids group significantly lowered the risk of treatment failure (OR 0.57, 95% CI (0.42, 0.79), I (2) 45.36%) and the need for adjunctive immunomodulatory therapy (OR 0.27, 95% CI (0.20, 0.37), I (2) 0.0%). The combination therapy showed no significant reduction in occurrence of left ventricular dysfunction (OR 0.79, 95% CI (0.34, 1.87), I (2) 58.44%) and the need for inotropic support (OR 0.83, 95% CI (0.35, 1.99), I (2) 75.40%). CONCLUSION This study supports the use of IVIG with glucocorticoids compared to IVIG alone, as the combination therapy significantly lowered the risk of treatment failure and the need for adjunctive immunomodulatory therapy.
Intravenous immunoglobulin (IVIg) therapy in hospitalised adult COVID-19 patients: A systematic review and meta-analysis
Reviews in medical virology. 2022;:e2397
Intravenous immunoglobulin (IVIg) therapy has been suggested as a potential treatment option for hospitalised COVID-19 patients. The aim of this systematic review and meta-analysis was to investigate the potential impact of IVIg on mortality and length of hospitalisation in adult COVID-19 patients. PubMed, Scopus, Web of Science and medRxiv were searched in the week of 20.12.2021 for English language, prospective trials, and retrospective studies with control groups, reporting on the use of intravenous immunoglobulin therapy in adult hospitalised COVID-19 patients. Exclusion criteria were: studies evaluating the use of IVIg in paediatric COVID-19 cases, trials using convalescent anti-SARS-CoV-2 plasma or immunoglobulins derived from convalescent anti-SARS-CoV-2 plasma. A random effects meta-analysis with subgroup analyses regarding study design and patient disease severity according to WHO criteria was also performed. A total of 13 studies were included, of which 6 were prospective, on a total of 2313 (IVIg = 1104, control = 1209) patient outcomes. Meta-analysis results indicated that IVIg therapy had no statistically significant effect on mortality (RR 0.91 [0.59; 1.39], p = 0.65, I(2) = 69% [46%; 83%]) or length of hospital stay (MD 0.51 [-2.80; 3.81], p = 0.76, I(2) = 96% [94%; 98%]). Subgroup analyses indicated no statistically significant impact on either outcome, but prospective studies' results suggested that IVIg may increase the length of hospitalisation in the severe COVID-19 patient group (MD 2.66 [1.43; 3.90], p < 0.01, I(2) = 0% [0%; >90%]). The results of this meta-analysis do not support use of IVIg in hospitalised adult COVID-19 patients.
Potentially effective drugs for the treatment of COVID-19 or MIS-C in children: a systematic review
European journal of pediatrics. 2022;:1-12
The purpose of this systematic review is to evaluate the efficacy and safety of using potential drugs: remdesivir and glucocorticoid in treating children and adolescents with COVID-19 and intravenous immunoglobulin (IVIG) in treating MIS-C. We searched seven databases, three preprint platform, ClinicalTrials.gov, and Google from December 1, 2019, to August 5, 2021, to collect evidence of remdesivir, glucocorticoid, and IVIG which were used in children and adolescents with COVID-19 or MIS-C. A total of nine cohort studies and one case series study were included in this systematic review. In terms of remdesivir, the meta-analysis of single-arm cohort studies have shown that after the treatment, 54.7% (95%CI, 10.3 to 99.1%) experienced adverse events, 5.6% (95%CI, 1.2 to 10.1%) died, and 27.0% (95%CI, 0 to 73.0%) needed extracorporeal membrane oxygenation or invasive mechanical ventilation. As for glucocorticoids, the results of the meta-analysis showed that the fixed-effect summary odds ratio for the association with mortality was 2.79 (95%CI, 0.13 to 60.87), and the mechanical ventilation rate was 3.12 (95%CI, 0.80 to 12.08) for glucocorticoids compared with the control group. In terms of IVIG, most of the included cohort studies showed that for MIS-C patients with more severe clinical symptoms, IVIG combined with methylprednisolone could achieve better clinical efficacy than IVIG alone.Conclusions: Overall, the current evidence in the included studies is insignificant and of low quality. It is recommended to conduct high-quality randomized controlled trials of remdesivir, glucocorticoids, and IVIG in children and adolescents with COVID-19 or MIS-C to provide substantial evidence for the development of guidelines. What is Known: • The efficacy and safety of using potential drugs such as remdesivir, glucocorticoid, and intravenous immunoglobulin (IVIG) in treating children and adolescents with COVID-19/MIS-C are unclear. What is New: • Overall, the current evidence cannot adequately demonstrate the effectiveness and safety of using remdesivir, glucocorticoids, and IVIG in treating children and adolescents with COVID-19 or MIS-C. • We are calling for the publication of high-quality clinical trials and provide substantial evidence for the development of guidelines.
The effect of intravenous immunoglobulins on the outcomes of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials
Expert review of anti-infective therapy. 2022;:1-8
OBJECTIVES Severe-to-critical COVID-19 has been associated with exaggerated immune responses, and anti-inflammatory agents including corticosteroid and interleukin-6 antagonist have been repurposed as the treatment modality against severe SARS-CoV-2 infections. However, the clinical efficacy and safety of intravenous immunoglobulin (IVIG) in the treatment of patients with COVID-19 was controversial. METHODS This meta-analysis of randomized controlled trials (RCTs) investigated the effectiveness of IVIG in patients with COVID-19. Electronic databases were searched for RCTs that compared the clinical efficacy of IVIG with standard of care or placebo in the hospitalized patients with COVID-19 were included. RESULTS Six RCTs involving 472 patients were included. Patients who received IVIG had a similar mortality rate to the controls (25.3% vs 27.0%, odds ratio [OR], 0.60; 95% confidence interval [CI], 0.27-1.31). Compared with the control group, the study group demonstrated a similar incidence of receiving mechanical ventilation (OR, 0.70; 95% CI, 0.45-1.11), intensive care unit (ICU) admission (OR, 0.58; 95% CI, 0.22-1.53), length of hospital stay (mean difference [MD], -1.81 days; 95% CI, -8.42 to 4.81) and ICU stay (MD, -0.61 days; 95% CI, -2.80 to 1.58). CONCLUSIONS The administration of IVIG in hospitalized patients with COVID-19 does not improve clinical outcomes.
Hospitalised patients with COVID-19 (6 studies, n= 472).
Intravenous immunoglobulin IVIG (Study group).
Standard care or placebo (Control group).
Patients who received IVIG had a similar mortality rate compared to patients receiving standard care or placebo (25.3% vs. 27.0%). Compared with the Control group, the Study group demonstrated a similar incidence of receiving mechanical ventilation, intensive care unit (ICU) admission, length of hospital stay (mean difference (MD) -1.81 days) and ICU stay (MD -0.61 days).