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1.
Efficacy of IVIG therapy for patients with sepsis: a systematic review and meta-analysis
Pan, B., Sun, P., Pei, R., Lin, F., Cao, H.
Journal of translational medicine. 2023;21(1):765
Abstract
BACKGROUND Sepsis is an overwhelming reaction to infection that comes with high morbidity and mortality. It requires urgent interventions in order to improve outcomes. Intravenous immunoglobulins (IVIG) are considered as potential therapy in sepsis patients. Results of trials on IVIG as adjunctive therapy for sepsis have been conflicting due to the variability in population characteristics, country geography and drug dosage form in different studies. METHODS A systematic article search was performed for eligible studies published up to January, 31, 2023, through the PubMed, Embase, Cochrane Library and Chinese National Knowledge Infrastructure database. The included articles were screened by using rigorous inclusion and exclusion criteria. Subgroup analyses were conducted according to different IVIG types, ages and economic regions. All analyses were conducted using Review Manager 5.4. Quality of studies and risk of bias were evaluated. RESULTS In total, 31 randomized controlled trials were included with a sample size of 6,276 participants. IVIG could reduce the mortality (RR 0.86, 95% CI: 0.77-0.95, p = 0.005), the hospital stay (MD - 4.46, 95% CI: - 6.35 to - 2.57, p = 0.00001), and the APACHE II scores (MD - 1.65, 95% CI: - 2.89 to - 0.63, p = 0.001). Additionally, the results showed that IgM-enriched IVIG was effective in treating sepsis (RR 0.55, 95% CI: 0.40 - 0.76; p = 0.0003), while standard IVIG failed to be effective (RR 0.91, 95% CI: 0.81-1.02, p = 0.10). And the effect of IVIG in reducing neonatal mortality was inconclusive (RR 0.93, 95% CI: 0.81-1.05, p = 0.24), but it played a large role in reducing sepsis mortality in adults (RR 0.70, 95% CI: 0.57-0.86, p = 0.0006). Besides, from the subgroup of different economic regions, it indicated that IVIG was effective for sepsis in high-income (RR 0.89, 95% CI: 0.79-0.99, p = 0.03) and middle-income countries (RR 0.49, 95% CI: 0.28-0.84, p = 0.01), while no benefit was demonstrated in low-income countries (RR 0.56, 95% CI: 0.27-1.14, p = 0.11). CONCLUSIONS There is sufficient evidence to support that IVIG reduces sepsis mortality. IgM-enriched IVIG is effective in both adult and neonatal sepsis, while standard IVIG is only effective in adult sepsis. IVIG for sepsis has shown efficacy in high- and middle-income countries, but is still debatable in low-income countries. More RCTs are needed in the future to confirm the true clinical potential of IVIG for sepsis in low-income countries.
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2.
Interventions for reducing late-onset sepsis in neonates: an umbrella review
Razak A, Alhaidari OI, Ahmed J
Journal of perinatal medicine. 2022
Abstract
OBJECTIVES Neonatal sepsis is one of the leading causes of neonatal deaths in neonatal intensive care units. Hence, it is essential to review the evidence from systematic reviews on interventions for reducing late-onset sepsis (LOS) in neonates. METHODS PubMed and the Cochrane Central were searched from inception through August 2020 without any language restriction. Cochrane reviews of randomized clinical trials (RCTs) assessing any intervention in the neonatal period and including one or more RCTs reporting LOS. Two authors independently performed screening, data extraction, assessed the quality of evidence using Cochrane Grading of Recommendations Assessment, Development and Evaluation, and assessed the quality of reviews using a measurement tool to assess of multiple systematic reviews 2 tool. RESULTS A total of 101 high-quality Cochrane reviews involving 612 RCTs and 193,713 neonates, evaluating 141 interventions were included. High-quality evidence showed a reduction in any or culture-proven LOS using antibiotic lock therapy for neonates with central venous catheters (CVC). Moderate-quality evidence showed a decrease in any LOS with antibiotic prophylaxis or vancomycin prophylaxis for neonates with CVC, chlorhexidine for skin or cord care, and kangaroo care for low birth weight babies. Similarly, moderate-quality evidence showed reduced culture-proven LOS with intravenous immunoglobulin prophylaxis for preterm infants and probiotic supplementation for very low birth weight (VLBW) infants. Lastly, moderate-quality evidence showed a reduction in fungal LOS with the use of systemic antifungal prophylaxis in VLBW infants. CONCLUSIONS The overview summarizes the evidence from the Cochrane reviews assessing interventions for reducing LOS in neonates, and can be utilized by clinicians, researchers, policymakers, and consumers for decision-making and translating evidence into clinical practice.
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3.
Evaluation of the Effect of Intravenous Immunoglobulin Dosing on Mortality in Patients with Sepsis: A Network Meta-analysis
Yang Y, Yu X, Zhang F, Xia Y
Clinical therapeutics. 2019
Abstract
PURPOSE Intravenous immunoglobulin (IVIG) has been proposed as an adjunctive therapy for sepsis. Related systematic reviews and meta-analyses of IVIG in sepsis indicate that IVIG can reduce the mortality of sepsis in adults. However, the effective dose of IVIG has not been clearly determined to date. We aimed to conduct an updated meta-analysis and use a network meta-analysis to elucidate the efficacy of IVIG dosing regimens in sepsis treatment. METHODS We searched PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE for articles published on or before February 14, 2019. We performed a direct meta-analysis to update a previous meta-analysis of the effects of IVIG therapy on mortality in adult patients with septic shock and a network meta-analysis to evaluate the efficacy of IVIG dosing regimens in sepsis treatment. FINDINGS Compared with the control treatment, the IVIG treatment reduced the all-cause mortality of patients with sepsis (odds ratio = 0.61; 95% CI, 0.41-0.92; P = 0.018), but significant heterogeneity was found across the studies (I(2) = 45.0%; P = 0.04). Regarding the IVIG dosage regimens, the highest total dose range (1.5-2 g/kg) was the optimal dose of administration (surface under the cumulative ranking curve = 84.7%). IMPLICATIONS On the basis of the available data, IVIG treatment is likely to reduce the all-cause mortality of patients with sepsis, and the highest total dose range (1.5-2 g/kg) is likely the optimal dose of administration.
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4.
Intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clinical effectiveness
Busani S, Damiani E, Cavazzuti I, Donati A, Girardis M
Minerva Anestesiologica. 2016;82((5)):559-72.
Abstract
INTRODUCTION Sepsis is characterized by a complex immune response. In this study we aimed to provide a review of the mechanisms of action of immunoglobulin (Ig) related to sepsis and an updated meta-analysis of the clinical effectiveness of the Ig use in septic patients. EVIDENCE ACQUISITION We performed two separate searches of Medline and other databases with the keywords Ig, sepsis, septic shock, septicemia, septicemia with no language restrictions in order to review the mechanisms of action of Igs in sepsis and to update the previous meta-analysis on the effects of the Ig therapy on the mortality of adult patients with septic shock. EVIDENCE SYNTHESIS Pathogens and toxin clearance, anti-inflammatory effects and anti-apoptotic effects on immune cells seems to be the main mechanisms of action of Ig therapy in sepsis. The meta-analysis of 18 RCTs indicated that the use of intravenous Ig reduces the mortality risk of septic patients (odds ratio=0.50 [95% CI 0.34-0.71], I2=44.68%). Low study quality, heterogeneous dosing regimens and type of Ig preparations, and different control interventions (placebo or albumin) may have influenced our results. CONCLUSIONS Our study showed that the use of intravenous Ig therapy in adult septic patients may have a rationale and seems to be associated with a reduced mortality. Anyway, the treatment effect generally tended to be smaller or less consistent if considering only those studies that were deemed adequate on each indicator. So, the available evidence is not clearly sufficient to support the widespread use of Ig in the treatment of sepsis.
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5.
Meta-analysis of mortality in adults, newborns and older children with bacterial infections and sepsis when treated by Igm-enriched intravenous immunoglobulins and standard schemes
Fedyaeva VK, Rebrova OY
Value in Health. 2015;18((7)):A578.
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6.
Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock
Alejandria MM, Lansang MA, Dans LF, Mantaring JB
Cochrane Database of Systematic Reviews. 2013;9:CD001090.
Abstract
BACKGROUND Mortality from sepsis and septic shock remains high. Results of trials on intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have been conflicting. This is an update of a Cochrane review that was originally published in 1999 and updated in 2002 and 2010. OBJECTIVES To estimate the effects of IVIG as adjunctive therapy in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1966 to December 2012), and EMBASE (1988 to December 2012). We contacted investigators in the field for unpublished data. The original search was performed in 1999 and updated in 2002 and 2008. SELECTION CRITERIA We included randomized controlled trials comparing IVIG (monoclonal or polyclonal) with placebo or no intervention in patients of any age with bacterial sepsis or septic shock. DATA COLLECTION AND ANALYSIS Two authors independently assessed the studies for inclusion and undertook methodologic quality assessment and data abstraction. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation. MAIN RESULTS We included 43 studies that met our inclusion criteria in this updated review out of 88 potentially eligible studies. The studies included a large polyclonal IVIG trial in neonates that was concluded in 2011 and classified as ongoing in the 2010 version of this review. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality in adults with sepsis compared to placebo or no intervention (relative risk (RR) 0.81; 95% confidence interval (CI) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates, which now includes the recently concluded large polyclonal IVIG trial, showed no significant reduction in mortality for standard IVIG (RR 1.00; 95% CI 0.92 to 1.08; five trials, n = 3667) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; three trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; five trials, n = 945) and neonates (RR 1.01; 95% CI 0.93 to 1.09; three trials, n = 3561). Mortality was not reduced among patients (eight trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (nine trials, n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97). AUTHORS' CONCLUSIONS Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.
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7.
An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis
Soares MO, Welton NJ, Harrison DA, Peura P, Shankar- Hari M, Harvey SE, Madan JJ, Ades AE, Palmer SJ, Rowan KM
Health Technology Assessment. 2012;16((7):):1-186.
Abstract
BACKGROUND Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. OBJECTIVES To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. DATA SOURCES Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. REVIEW METHODS Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. RESULTS Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control - as an indicator of proper blinding to treatment as a proxy for study quality - associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. LIMITATIONS As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. CONCLUSIONS Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would al
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8.
Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock
Kreymann KG, De Heer G, Nierhaus A, Kluge S
Critical Care Medicine. 2007;35((12):):2677-2685.
Abstract
OBJECTIVE There is ongoing debate about the efficacy of polyvalent immunoglobulins as adjunctive therapy for sepsis or septic shock. Two meta-analyses by the Cochrane collaboration calculated a significant reduction in mortality. However, data of the largest study were missing in one, and a subset of four high-quality studies failed to show an effect in the other. To broaden the database, we performed a meta-analysis of all randomized controlled studies published so far. DATA SOURCE MEDLINE, EMBASE, Cochrane Library of randomized trials, and personal files. STUDY SELECTION Meta-analysis of all published randomized controlled studies published on polyvalent immunoglobulins (Ig) for treatment of sepsis or septic shock in adults, children, or neonates. DATA EXTRACTION Twenty-seven trials with a total of 2,202 patients fulfilled the inclusion criteria. DATA SYNTHESIS As the immunologic state of neonates is different than that of adults or older children, data were evaluated separately for each group. Fifteen trials on 1,492 adults could be included. The pooled effect on mortality was a relative risk of death (RR) of 0.79 (95% confidence interval (CI) 0.69-0.90, p (less-than or equal to) .0003). There was a strong trend in favor of an immunoglobulin preparation enriched with IgA and IgM (IgGAM) (RR = 0.66, 95% CI 0.51-0.84, p (less-than or equal to) .0009) compared with preparations containing only IgG (RR = 0.85, 95% CI 0.73-0.99, p (less-than or equal to) .04). In 12 trials on 710 neonates, the pooled effect on mortality was 0.56 (95% CI 0.42-0.74, p (less-than or equal to) .0001). There was also a positive although less pronounced trend favoring the effect of IgGAM (RR = 0.50, 95% CI 0.34-0.73, p (less-than or equal to) .0003) compared with IgG (RR = 0.63, 95% CI 0.42-0.96, p (less-than or equal to) .03). A sensitivity analysis selecting eight trials in adults and ten in neonates of highest methodological quality confirmed these results. CONCLUSIONS Polyvalent immunoglobulins exert a significant effect on mortality in sepsis and septic shock, with a trend in favor of IgGAM. 2007 Lippincott Williams & Wilkins, Inc.
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9.
Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: A systematic review and meta-analysis*
Laupland KB, Kirkpatrick AW, Delaney A
Critical Care Medicine. 2007;35((12):):2686-2692.
Abstract
OBJECTIVES To systematically review the literature to assess whether adjunctive therapy with polyclonal intravenous immunoglobulin (ivIg) reduces mortality among critically ill adults with severe sepsis and septic shock. DATA SOURCE MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases; the meta-register of controlled trials; and the medical editors trial amnesty register. STUDY SELECTION Prospective randomized clinical trials (RCTs) evaluating ivIg treatment in critically ill adults with severe sepsis or septic shock were included. Two reviewers conducted assessment of suitability for inclusion. DATA EXTRACTION Two authors independently determined the validity of included studies and extracted data. DATA SYNTHESIS The effect of ivIg on all-cause mortality was quantified using a fixed-effect meta-analysis. RESULTS Fourteen RCTs published between 1988 and 2006 were included. Most were small, used relatively low doses of ivIg, and included predominantly surgical patients with Gram-negative infections. There was a significant reduction in mortality associated with use of ivIg treatment with a pooled odds ratio of 0.66 (95% confidence interval 0.53-0.83; p < .0005). In general, a greater treatment effect was seen among studies of lower methodological quality, studies using higher doses of ivIg, and studies that did not use albumin as a control. There was evidence of between-study heterogeneity (chi-square p = .009), and this was at least moderate as measured by the I value (I = 53.8%). When only high- quality studies were pooled, the odds ratio for mortality was 0.96 (95% confidence interval 0.71-1.3; p = .78). CONCLUSIONS This meta- analysis demonstrates an overall reduction in mortality with the use of ivIg for the adjunctive treatment of severe sepsis and septic shock in adults, although significant heterogeneity exists among the included trials and this result was not confirmed when only high- quality studies were analyzed. These data warrant a well-designed, adequately powered, and transparently reported clinical trial.
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10.
Effect of intravenous immunoglobulins in critically ill adults with sepsis: a meta-analysis
Turgeon AF, Hutton B, Fergusson D, Hebert PC, McIntyre L, Vandenberg S
Canadian Journal of Anaesthesia. 2006;53((4)):A415-6.