Clinical Efficacy of Early Administration of Human Immunoglobulin on Children with Severe Hand-foot-mouth Disease
Wu H, Li L
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2023;33(2):234-236
The objective of this study was to investigate the clinical effect of early administration of human immunoglobulin in children with severe hand, foot and mouth disease (HFMD) and its influence on serum c-reactive protein (CRP), creatine kinase (CK), and creatine kinase isoenzyme (CK-MB). One hundred and forty children with severe HFMD were randomly divided into Group A (n=70) and Group B (n=70) according to the random number table method. Group A was treated with routine treatment. Group B was treated with routine treatment, and an early intravenous injection of human immunoglobulin. Serum CRP, CK, and CK-MB in Group B were lower than those in Group A after treatment (all p <0.001). The total clinical effective rate of Group B was 92.9%, which was higher than that of Group A (80.0%, p=0.026). Early administration of human immunoglobulin may reduce the levels of serum markers CRP, CK, and CK-MB in children with severe HFMD. Key Words: Human immunoglobulin, Children, HFMD (Hand, foot and mouth disease).
Children with severe hand, foot and mouth disease (n= 140).
Routine treatment + early intravenous injection of human immunoglobulin (n= 70).
Routine treatment (n= 70).
Serum c-reactive protein, creatine kinase, and creatine kinase isoenzyme in children who received routine treatment were lower than those who received the routine treatment + human immunoglobulin after treatment. The total clinical effective rate of routine treatment + human immunoglobulin was 92.9%, which was higher than that of routine treatment (80.0%).
Intravenous immunoglobulin in the management of neonatal sepsis: A randomised controlled trial
Rizvi MQ, Singh MV, Mishra N, Shrivastava A, Maurya M, Siddiqui SA
Tropical doctor. 2023;:494755221138689
Sepsis is a leading cause of neonatal mortality and morbidity in low and middle-income countries. We designed a double-blinded randomised controlled trial in a neonatal intensive care unit (NICU) of a tertiary care teaching hospital to determine the role of intravenous immunoglobulin (IVIG) in decreasing hospital stay. Eighty neonates with clinical features of sepsis were enrolled in the study and placebo groups to receive 500 mg/kg of IVIG for three consecutive days or a placebo. The primary outcome measure was duration of hospital stay in days. The babies in both groups were comparable in terms of birth weight, gestation and sex distribution. There was no significant difference in duration of hospital stay (days) in the study and placebo groups. We found that treatment with IVIG did not shorten the duration of hospital stay in our setting.
Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial
Welzel T, Atkinson A, Schöbi N, Andre MC, Bailey DGN, Blanchard-Rohner G, Buettcher M, Grazioli S, Koehler H, Perez MH, et al
The Lancet. Child & adolescent health. 2023
BACKGROUND The emergence of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) led to the widespread use of anti-inflammatory treatments in the absence of evidence from randomised controlled trials (RCTs). We aimed to assess the effectiveness of intravenous methylprednisolone compared with intravenous immunoglobulins. METHODS This is an open-label, multicentre, two-arm RCT done at ten hospitals in Switzerland in children younger than 18 years hospitalised with PIMS-TS (defined as age <18 years; fever and biochemical evidence of inflammation, and single or multiorgan dysfunction; microbiologically proven or putative contact with SARS-CoV-2; and exclusion of any other probable disease). Patients were randomly assigned 1:1 to intravenous methylprednisolone (10 mg/kg per day for 3 days) or intravenous immunoglobulins (2 g/kg as a single dose). The primary outcome was length of hospital stay censored at day 28, death, or discharge. Secondary outcomes included proportion and duration of organ support. Analyses were done by intention-to-treat. The study was registered with Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS Between May 21, 2021, and April 15, 2022, 75 patients with a median age of 9·1 years (IQR 6·2-12·2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulins group). The median length of hospital stay was 6·0 days (IQR 4·0-8·0) in the methylprednisolone group and 6·0 days (IQR 5·0-8·8) in the intravenous immunoglobulins group (estimated effect size -0·037 of the log(10) transformed times, 95% CI -0·13 to 0·065, p=0·42). Fewer patients in the methylprednisolone group (ten [27%] of 37) required respiratory support compared with the intravenous immunoglobulin group (21 [55%] of 38, p=0·025). Need and duration of inotropes, admission to intensive care units, cardiac events after baseline, and major bleeding and thrombotic events were not significantly different between the study groups. INTERPRETATION In this RCT, treatment with methylprednisolone in children with PIMS-TS did not significantly affect the length of hospital stay compared with intravenous immunoglobulins. Intravenous methylprednisolone could be an acceptable first-line treatment in children with PIMS-TS. FUNDING NOMIS Foundation, Vontobel Foundation, and Gaydoul Foundation.
The therapeutic window of intravenous immunoglobulin (IVIG) and its correlation with clinical outcomes in Kawasaki disease: a systematic review and meta-analysis
Li Z, Cai J, Lu J, Wang M, Yang C, Zeng Z, Tang Q, Li J, Tang W, Luo H, et al
Italian journal of pediatrics. 2023;49(1):45
BACKGROUND The optimal therapeutic window to start intravenous immunoglobulin (IVIG) for Kawasaki disease (KD) is highly debatable. We aimed to summarize the existing literature to evaluate the therapeutic window of IVIG treatment and its correlation with clinical outcomes in KD patients. METHODS We searched the databases from inception to August 26, 2022, without language restrictions. The primary outcomes were initial IVIG resistance and coronary artery lesions (CALs) in acute phase. Secondary outcome was CALs during 1-2 months of follow-up. RESULTS 27 studies involving 41,139 patients were included in this study. Very low-quality evidence showed that the earlier IVIG treatment within 4 days had a higher IVIG-resistance rate (RR, 1.80; 95% CI, 1.50-2.15; Pâ€‰<â€‰.00001; I(2)â€‰=â€‰75%) than the late treatment. Very low-quality evidence showed that IVIG treatment for more than 7 days was associated with a higher risk of CALs in acute phase(RR, 0.57; 95% CI, 0.40-0.80; Pâ€‰=â€‰.001; I(2)â€‰=â€‰76%). There was a lower risk of CALs during 1-2 months follow-up for those who started IVIG administration within 10 days from the onset. CONCLUSIONS Overall, IVIG treatment within 7 days of illness seems to be the optimal therapeutic window of IVIG. IVIG treatment within 7 days is found to be effective for reducing the risk of coronary artery lesions and cardiac sequelae in KD patients. The early IVIG treatment within 4 days should be vigilant for the IVIG resistance although large multi-center randomized trials with well design are needed.
Prediction Models for Intravenous Immunoglobulin Resistance in Kawasaki Disease: A Meta-analysis
Kuniyoshi Y, Tsujimoto Y, Banno M, Taito S, Ariie T, Takahashi N, Tokutake H, Takada T
CONTEXT Approximately 10% to 20% of patients with Kawasaki disease (KD) are refractory to initial intravenous immunoglobulin (IVIG) therapy. KD is mainly associated with coronary artery abnormalities. OBJECTIVES To identify and evaluate all developed prediction models for IVIG resistance in patients with KD and synthesize evidence from external validation studies that evaluated their predictive performances. DATA SOURCES PubMed Medline, Dialog Embase, the Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from inception until October 5, 2021. STUDY SELECTION All cohort studies that reported patients diagnosed with KD who underwent an initial IVIG of 2 g/kg were selected. DATA EXTRACTION Study and patient characteristics and model performance measures. Two authors independently extracted data from the studies. RESULTS The Kobayashi, Egami, Sano, Formosa, and Harada scores were the only prediction models with 3 or more external validation of the161 model analyses in 48 studies. The summary C-statistics were 0.65 (95% confidence interval [CI]: 0.57-0.73), 0.63 (95% CI: 0.55-0.71), 0.58 (95% CI: 0.55-0.60), 0.50 (95% CI: 0.36-0.63), and 0.63 (95% CI: 0.44-0.78) for the Kobayashi, Egami, Sano, Formosa, and Harada models, respectively. All 5 models showed low positive predictive values (0.14-0.39) and high negative predictive values (0.85-0.92). LIMITATIONS Potential differences in the characteristics of the target population among studies and lack of assessment of calibrations. CONCLUSIONS None of the 5 prediction models with external validation accurately distinguished between patients with and without IVIG resistance.
Comparison of IVIg and TPE efficacy in the treatment of neurological disorders: a systematic literature review
Pinto, A. A., De Seze, J., Jacob, A., Reddel, S., Yudina, A., Tan, K.
Therapeutic Advances in Neurological Disorders. 2023;16:17562864231154306
BACKGROUND Intravenous immunoglobulin (IVIg) and therapeutic plasma exchange (TPE) are among the main immunotherapies for neurological disorders. Their benefit is greatest in immune-mediated conditions, but their distinct efficacy cannot be simply explained. OBJECTIVES This review aimed to systematically identify studies comparing the efficacy of TPE and IVIg treatments for selected autoimmune neurological disorders and identify optimal therapies for each condition. DATA SOURCES AND METHODS PubMed, MEDLINE and Embase databases were searched for original publications from 1990 to 2021. Additional publications were identified via expert recommendations. Conference abstracts older than 2017, review articles and articles without information on TPE and IVIg comparison in title and abstract were excluded. Risks of bias were descriptively addressed, without a meta-analysis. RESULTS Forty-four studies were included on Guillain-Barré syndrome (20 studies - 12 adult, 5 paediatric, 3 all ages), myasthenia gravis (11 studies -8 adult, 3 paediatric), chronic immune-mediated polyradiculoneuropathy (3 studies -1 adult, 2 paediatric), encephalitis (1 study in adults), neuromyelitis optica spectrum disorders (5 studies -2 adult, 3 all ages) and other conditions (4 studies - all ages). TPE and IVIg were mostly similarly efficacious, measured by clinical outcomes and disease severity scores. Some studies recommended IVIg as easy to administer. TPE procedures, however, have been simplified and the safety has been improved. TPE is currently recommended for management of neuromyelitis optica spectrum disorder relapses and some myasthenia gravis subtypes, in which rapid removal of autoantibodies is crucial. CONCLUSION Despite some limitations (e.g. the low evidence levels), this review provides an extensive 30-year-long overview of treatments for various conditions. Both IVIg and TPE are usually comparably efficacious options for autoimmune neurological disorders, with few exceptions. Treatment choices should be patient-tailored and based on available clinical resources. Better designed studies are needed to provide higher-level quality of evidence regarding clinical efficacy of TPE and IVIg treatments.
Meta-analysis of the effectiveness of relapse prevention therapy for myelin-oligodendrocyte glycoprotein antibody-associated disease
Chang X, Zhang J, Li S, Wu P, Wang R, Zhang C, Wu Y
Multiple sclerosis and related disorders. 2023;72:104571
BACKGROUND Approximately 40% of adults and 30% of children with Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) experience a relapsing course, but the optimal relapse prevention therapy remains unclear. A meta- analysis was conducted to investigate the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), maintenance intravenous immunoglobulin (IVIG), and tocilizumab (TCZ) in prevention of attacks in MOGAD. METHODS English and Chinese-language articles published from January 2010 to May 2022 were searched in PubMed, Embase, Web of Science, Cochrane, Wanfang Data, China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (CQVIP). Studies with fewer than three cases were excluded. Meta-analysis of the relapse-free rate, the change of annualized relapse rate (ARR)and Expanded Disability Status Scale (EDSS) scores before and after treatment, and an age subgroup analysis was performed. RESULTS A total of 41 studies were included. Three were prospective cohort studies, one was an ambispective cohort study, and 37 were retrospective cohort studies or case series. Eleven, eighteen, eighteen, eight, and two studies were included in the meta-analysis for relapse-free probability after AZA, MMF, RTX, IVIG, and TCZ therapy, respectively. The proportions of patients without relapse after AZA, MMF, RTX, IVIG, and TCZ were 65% [95% confidence interval (CI):49%-82%]), 73% (95%CI:62%-84%), 66% (95%CI:55%-77%), 79% (95%CI:66%-91%), and 93% (95%CI:54%-100%), respectively. The relapse-free rate did not significantly differ between the children and adults treated with each medication. Six, nine, ten, and three studies were included in the meta-analysis for the change of ARR before and after AZA, MMF, RTX, and IVIG therapy, respectively. ARR was significantly decreased after AZA, MMF, RTX, and IVIG therapy with a mean reduction of 1.58 (95%CI: [-2.29--0.87]), 1.32 (95%CI: [-1.57--1.07]), 1.01 (95%CI: [-1.34--0.67]), and 1.84 (95%CI: [-2.66--1.02]), respectively. The change in ARR did not significantly differ between children and adults. CONCLUSIONS AZA, MMF, RTX, maintenance IVIG, and TCZ all reduce the risk of relapse in both pediatric and adult patients with MOGAD. The literatures included in the meta-analysis were mainly retrospective studies, so large randomized prospective clinical trials are needed to compare the efficacy of different treatments.
Benefits of high-dose intravenous immunoglobulin on mortality in patients with severe COVID-19: An updated systematic review and meta-analysis
Liu, X., Zhang, Y., Lu, L., Li, X., Wu, Y., Yang, Y., Li, T., Cao, W.
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.
Adverse Reactions Associated with Intravenous Immunoglobulin Administration in the Treatment of Neurological Disorders: A Systematic Review
Jiang, M., Kimber, J. S., Gupta, A., Kovoor, J., Stretton, B., Ravindran, J., Hissaria, P., Smith, W. B., Bacchi, S.
International Archives of Allergy and Immunology. 2023;:1-16
Intravenous immunoglobulin (IVIg), which is used to treat multiple neurological conditions, may be associated with serious adverse reactions. The individual neurological disease characteristics associated with adverse reactions, along with strategies to prevent and treat adverse reactions, are uncertain. A systematic review was conducted of the databases PubMed, Embase, and Cochrane Library to summarise studies that report adverse reactions of IVIg therapy in patients with neurological disease. There were 65 studies included in the review. The reported rates of adverse reactions vary widely, but the best evidence suggests rates between 25 and 34% per patient. Common adverse reactions include headache and laboratory abnormalities. Less common but serious adverse reactions included thromboembolic complications and anaphylaxis. Overall, there is a lack of high-quality comparative data to definitively determine if any specific neurological indications are associated with a higher risk of adverse reactions. However, individual neurological disease characteristics possibly associated with an increased likelihood of adverse reactions include limited mobility (as in certain neuromuscular conditions), paraproteinaemia (as in certain peripheral neuropathies), and cardiomyopathy (as in certain myopathies). There is limited evidence to support the effectiveness of prevention and treatment strategies, which may include modification to dose, reduced infusion rate, and premedication. Further studies regarding methods to prevent and treat IVIg-ARs in neurology patients are required.
Intravenous immunoglobulin for the treatment of Kawasaki disease
Broderick, C., Kobayashi, S., Suto, M., Ito, S., Kobayashi, T.
The Cochrane Database of Systematic Reviews. 2023;1(1):Cd014884
BACKGROUND Kawasaki disease (KD) is an acute systemic vasculitis (inflammation of the blood vessels) that mainly affects children. Symptoms include fever, chapped lips, strawberry tongue, red eyes (bulbar conjunctival injection), rash, redness, swollen hands and feet or skin peeling; and enlarged cervical lymph nodes. High fevers and systemic inflammation characterise the acute phase. Inflammation of the coronary arteries causes the most serious complication of the disease, coronary artery abnormalities (CAAs). The primary treatment is intravenous immunoglobulin (IVIG) and acetylsalicylic acid (ASA/aspirin), with doses and regimens differing between institutions. It is important to know which regimens are the safest and most effective in preventing complications. OBJECTIVES To evaluate the efficacy and safety of IVIG in treating and preventing cardiac consequences of Kawasaki disease. SEARCH METHODS The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 26 April 2022. SELECTION CRITERIA We included randomised controlled trials (RCTs) investigating the use of IVIG for the treatment of KD. We included studies involving treatment for initial or refractory KD, or both. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were incidence of CAAs and incidence of any adverse effects after treatment. Our secondary outcomes were acute coronary syndromes, duration of fever, need for additional treatment, length of hospital stay, and mortality. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS We identified 31 RCTs involving a total of 4609 participants with KD. Studies compared IVIG with ASA, another dose or regimen of IVIG, prednisolone, or infliximab. The majority of studies reported on primary treatment, so those results are reported below. A limited number of studies investigated secondary or tertiary treatment in IVIG-resistant patients. Doses and regimens of IVIG infusion varied between studies, and all studies had some concerns related to risk of bias. Primary treatment with IVIG compared to ASA for people with KD Compared to ASA treatment, IVIG probably reduces the incidence of CAAs in people with KD up to 30 days (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.41 to 0.87; 11 studies, 1437 participants; moderate-certainty evidence). The individual studies reported a range of adverse effects, but there was little to no difference in numbers of adverse effects between treatment groups (OR 0.57, 95% CI 0.17 to 1.89; 10 studies, 1376 participants; very low-certainty evidence). There was limited evidence for the incidence of acute coronary syndromes, so we are uncertain of any effects. Duration of fever days from treatment onset was probably shorter in the IVIG group (mean difference (MD) -4.00 days, 95% CI -5.06 to -2.93; 3 studies, 307 participants; moderate-certainty evidence). There was little or no difference between groups in need for additional treatment (OR 0.27, 95% CI 0.05 to 1.57; 3 studies, 272 participants; low-certainty evidence). No study reported length of hospital stay, and no deaths were reported in either group. Primary treatment with IVIG compared to different infusion regimens of IVIG for people with KD Higher-dose regimens of IVIG probably reduce the incidence of CAAs compared to medium- or lower-dose regimens of IVIG up to 30 days (OR 0.60, 95% CI 0.40 to 0.89; 8 studies, 1824 participants; moderate-certainty evidence). There was little to no difference in the number of adverse effects between groups (OR 1.11, 95% CI 0.52 to 2.37; 6 studies, 1659 participants; low-certainty evidence). No study reported on acute coronary syndromes. Higher-dose IVIG may reduce the duration of fever compared to medium- or lower-dose regimens (MD -0.71 days, 95% CI -1.36 to -0.06; 4 studies, 992 participants; low-certainty evidence). Higher-dose regimens may reduce the need for additional treatment (OR 0.29, 95% CI 0.10 to 0.88; 4 studies, 1125 participants; low-certainty evidence). We did not detect a clear difference in length of hospital stay between infusion regimens (MD -0.24, 95% CI -0.78 to 0.30; 3 studies, 752 participants; low-certainty evidence). One study reported mortality, and there was little to no difference detected between regimens (moderate-certainty evidence). Primary treatment with IVIG compared to prednisolone for people with KD The evidence comparing IVIG with prednisolone on incidence of CAA is very uncertain (OR 0.60, 95% CI 0.24 to 1.48; 2 studies, 140 participants; very low-certainty evidence), and there was little to no difference between groups in adverse effects (OR 4.18, 95% CI 0.19 to 89.48; 1 study; 90 participants; low-certainty evidence). We are very uncertain of the impact on duration of fever, as two studies reported this outcome differently and showed conflicting results. One study reported on acute coronary syndromes and mortality, finding little or no difference between groups (low-certainty evidence). No study reported the need for additional treatment or length of hospital stay. AUTHORS' CONCLUSIONS The included RCTs investigated a variety of comparisons, and the small number of events observed during the study periods limited detection of effects. The certainty of the evidence ranged from moderate to very low due to concerns related to risk of bias, imprecision, and inconsistency. The available evidence indicated that high-dose IVIG regimens are probably associated with a reduced risk of CAA formation compared to ASA or medium- or low-dose IVIG regimens. There were no clinically significant differences in incidence of adverse effects, which suggests there is little concern about the safety of IVIG. Compared to ASA, high-dose IVIG probably reduced the duration of fever, but there was little or no difference detected in the need for additional treatment. Compared to medium- or low-dose IVIG, there may be reduced duration of fever and reduced need for additional treatment. We were unable to draw any conclusions regarding acute coronary syndromes, mortality, or length of hospital stay, or for the comparison IVIG versus prednisolone. Our findings are in keeping with current guideline recommendations and evidence from long-term epidemiology studies.