Standard Intravenous Immunoglobulin Research Articles

NAVIGATING THE UNCHARTED WATERS: MANAGING CONCURRENT CYTOMEGALOVIRUS MYOCARDITIS AND ALLOGRAFT REJECTION IN A PATIENT WITH HEART TRANSPLANTATION

Abstract A 49–year–old female with hypertrophic cardiomyopathy underwent orthotopic heart transplantation. She was cytomegalovirus(CMV)–positive and received a heart from a CMV–negative donor, so prophylaptic therapy was not administered. Initial immunosuppression included cyclosporine and induction with Basiliximab in a steroid–free regimen. The first routine biopsy (EMB) showed mild focal cellular rejection (grade 1A) and C4d positivity with granular aspect. Mycophenolate mofetil (MMF) was added. The second EMB, 7 days later, showed mild diffuse cellular rejection (grade 1B) and diffuse C4d positivity. Anti–HLA donor–specific antibodies (DSA) had increased anti–B13 levels (MFI=21298) compared to pre–transplantation tests. Echocardiography showed a normal ejection fraction (LVEF) and mild concentric hypertrophy (LVH). Treatment included pulse methylprednisolone therapy (1 g/day for three days) followed by oral prednisone with a slow tapering regimen, and increased MMF. CMV count weekly monitored was negative. The next two EMBs performed one week apart from each other described a grade 1A mild focal pattern while the 5th EMB (1 month and 2 weeks post–transplant) showed a grade 1A rejection together with focal mild fibrosis and eosinophils, so we replaced cyclosporine with tacrolimus, increased MMF and prednisone. At this time, the patient had no overt clinical signs of CMV infection but a CMV–PCR of 100847 IU/mL so ganciclovir 5 mg/Kg bid was started and CMV–PCR decreased to 42308 IU/mL after 1 week. Subsequently, she developed sinus tachycardia, mildly reduced LVEF, moderate LVH and diastolic dysfunction. Troponin was elevated. A new EMB revealed interstitial edema, diffuse ischemic injury, and eosinophilic inclusions suggesting CMV myocarditis. Treatment involved down–titrating MMF and Prednisone, administering standard intravenous immunoglobulin (IVIG), and high–dose Ganciclovir (7.5 mg/Kg bid). Leukopenia subsequently led to Ganciclovir down–titration. In the next days, the patient improved, CMV cleared, and leukocyte count normalized. She was discharged on Tacrolimus, MMF, Prednisone and Valganciclovir. Subsequent tests showed no cellular or antibody–mediated rejection (AMR), no CMV inclusions, recovered cardiac function, and markedly reduced anti–B13 DSA (MFI 3000). This case raises some concerns: in this context, the use of IVIG in the treatment of CMV infection and AMR appears reasonable, in support of antiviral and immunosuppressive therapy.

A Historical Perspective on Respiratory Syncytial Virus Prevention: A Journey Spanning Over Half a Century From the Setback of an Inactive Vaccine Candidate to the Success of Passive Immunization Strategy.

The efforts to prevent respiratory syncytial virus (RSV) infection in infants span over half a century. RSV vaccine development began in the 1960s, and it confronted a significant disappointment after testing a formalin-inactivated RSV (FI RSV) vaccine candidate. This inactivated RSV vaccine was not protective. A large number of the vaccinated RSV-naive children, when subsequently exposed to natural RSV infection from wild-type virus in the community, developed severe lung inflammation termed enhanced respiratory disease. This resulted in a halt in RSV vaccine development. In the 1990s, attention turned to the potential for passive protection against severe RSV disease with immunoglobulin administration. This led to studies on using standard intravenous immunoglobulins in high-risk infants, followed by high-titer RSV immunoglobulin preparation and, subsequently, the development of RSV monoclonal antibodies. Over the past 25 years, palivizumab has been recognized as a safe and effective monoclonal antibody as a prevention strategy for RSV in high-risk children. Its high cost and need for monthly administration, however, has hindered its use to ~2% of the birth cohort, neglecting the vast majority of newborns, including healthy full-term infants who comprise the largest portion of RSV hospitalizations and the greatest part of the burden of RSV disease. Still these efforts, helped pave the way for the present advances in RSV prevention that hold promise for mitigating severe RSV disease for all infants.

An Observational Study on Factors Causing Variable Response to Therapeutic Doses of Intravenous Immunoglobulin in Acute Immune-Mediated Polyneuropathy: A Tertiary Care Center Experience

Context: Immune-mediated neuropathies, notably Guillain–Barré syndrome (GBS) and its subtypes, exhibit diverse clinical presentations. Intravenous immunoglobulin (IVIG) is a standard treatment for these conditions, but the variable clinical course complicates outcome prediction. Despite standard IVIG dosing, some patients continue to deteriorate. Aim: The aim of this study was to assess the factors responsible for variable response to therapeutic doses of immunoglobulins in acute immune-mediated polyneuropathy. Settings and Design: This was a prospective, observational study. Materials and Methods: Acute immune-mediated polyneuropathy cases within 14 days of symptom onset and receiving IVIG were recruited. Hughes disability score (HDS), modified Erasmus GBS outcome score (mEGOS), and modified Rankin score (mRS) were assessed before IVIG, immediately after IVIG, and 4 weeks thereafter. Statistical Analysis Used: Categorical variables are expressed as percentages, and continuous variables are presented as mean ± standard deviation. Relationships between parameters were assessed using analysis of variance and multivariate analysis of covariance. Correlations were measured using Pearson’s correlation, and proportions were compared using the Chi-square test or Fisher’s exact test. Results: Among 60 GBS patients, the median age was 38 years, with upper respiratory tract infection as the most common antecedent infection (60%). The most common variant was pure motor type, while demyelinating (88.33%) was the most common electrophysiological subtype. Outcome correlated with post-IVIG scores of HDS and mRS. Linear regression analysis showed a positive correlation between onset-to-treatment duration and HDS and mEGOS scores after 4 weeks of IVIG, while mRS showed minimal correlation. No significant correlations were found between antecedent infection, gender, nerve conduction study pattern, GBS variant, and scores of HDS, mEGOS, and mRS. Conclusions: The study highlights the significance of onset-to-treatment duration. Factors with unfavorable course were age, delay in receiving IVIG, respiratory involvement, dysautonomia, cranial nerve involvement, and those with higher mEGOS scores at the 7th day of admission. Seasonal trends should not be overlooked. Serial evaluation of disability scores can predict the varying response to IVIG.

Population Pharmacokinetic Modelling of Intravenous Immunoglobulin Treatment in Patients with Guillain-Barré Syndrome.

Background and ObjectiveIntravenous immunoglobulin (IVIg) at a standard dosage is the treatment of choice for Guillain–Barré syndrome. The pharmacokinetics, however, is highly variable between patients, and a rapid clearance of IVIg is associated with poor recovery. We aimed to develop a model to predict the pharmacokinetics of a standard 5-day IVIg course (0.4 g/kg/day) in patients with Guillain–Barré syndrome.MethodsNon-linear mixed-effects modelling software (NONMEM®) was used to construct a pharmacokinetic model based on a model-building cohort of 177 patients with Guillain–Barré syndrome, with a total of 589 sequential serum samples tested for total immunoglobulin G (IgG) levels, and evaluated on an independent validation cohort that consisted of 177 patients with Guillain–Barré syndrome with 689 sequential serum samples.ResultsThe final two-compartment model accurately described the daily increment in serum IgG levels during a standard IVIg course; the initial rapid fall and then a gradual decline to steady-state levels thereafter. The covariates that increased IgG clearance were a more severe disease (as indicated by the Guillain–Barré syndrome disability score) and concomitant methylprednisolone treatment. When the current dosing regimen was simulated, the percentage of patients who reached a target ∆IgG > 7.3 g/L at 2 weeks decreased from 74% in mildly affected patients to only 33% in the most severely affected and mechanically ventilated patients (Guillain–Barré syndrome disability score of 5).ConclusionsThis is the first population-pharmacokinetic model for standard IVIg treatment in Guillain–Barré syndrome. The model provides a new tool to predict the pharmacokinetics of alternative regimens of IVIg in Guillain–Barré syndrome to design future trials and personalise treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01136-z.

Corticosteroids for the treatment of Kawasaki disease in children.

Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in high-income countries. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids. This is an update of the review first published in 2017. To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and two trials registers to 8 February 2021. We searched the reference lists of relevant articles for additional studies. We selected randomised controlled trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroids, different durations of treatment, and where corticosteroids were used alone or in conjunction with other accepted KD treatments. We included trials using corticosteroids for both first- and second-line treatment. Two review authors independently selected studies, assessed study quality and extracted data using standard Cochrane methods. We performed fixed-effect model meta-analyses with odds ratios (ORs) or mean difference (MD) with 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity. We assessed the certainty of the evidence using GRADE. The outcomes of interest were incidence of coronary artery abnormalities, serious adverse events, mortality, duration of acute symptoms (such as fever), time for laboratory parameters to normalise, length of hospital stay and longer-term coronary morbidity. This update identified one new study, therefore the analysis included eight trials consisting of 1877 participants. Seven trials investigated the use of corticosteroids in first-line treatment and one investigated second-line treatment. The trials were all of good methodological quality. On pooled analysis, corticosteroid treatment reduced the subsequent occurrence of coronary artery abnormalities (OR 0.32, 95% CI 0.14 to 0.75; 8 studies, 986 participants; moderate-certainty evidence), without resultant serious adverse events (0 events; 6 studies, 737 participants; moderate-certainty) and mortality (0 events; 8 studies, 1075 participants; moderate-certainty evidence). In addition, corticosteroids reduced the duration of fever (MD -1.34 days, 95% CI -2.24 to -0.45; 3 studies, 290 participants; low-certainty evidence), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD -2.80 days, 95% CI -4.38 to -1.22; 1 study, 178 participants; moderate-certainty evidence), and length of hospital stay (MD -1.01 days, 95% CI -1.72 to -0.30; 2 studies, 119 participants; moderate-certainty evidence). None of the included studies reported long-term (greater than one year after disease onset) coronary morbidity. Moderate-certainty evidence shows that use of steroids in the acute phase of KD can be associated with reduced coronary artery abnormalities, reduced inflammatory markers and shorter duration of hospital stay when compared to no corticosteroids. There were no serious adverse events or deaths reported with or without corticosteroid use. Low-certainty evidence shows use of corticosteroids can reduce duration of clinical symptoms (fever and rash). None of the included studies reported on long-term (greater than one year after disease onset) coronary morbidity. Evidence presented in this systematic review agrees with current clinical guidelines on the use of corticosteroids in the first-line treatment in KD.

Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy

Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published.The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomized, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (Panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomized 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary end point was the response rate in the 1.0 g/kg group, defined as an improvement ≥1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary end points included dose response and safety. This trial was registered with EudraCT (Number 2015–005443-14) and clinicaltrials.gov (NCT02638207).Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post-infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) [95% confidence interval (CI): 69–88%] in the 1.0 g/kg group, 65% (22/34; CI: 48–79%) in the 0.5 g/kg group, and 92% (33/36; CI: 78–97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six per cent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths.Intravenous immunoglobulin (1.0 g/kg) was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.

Polyvalent Immunoglobulin Preparations Inhibit Pneumolysin-Induced Platelet Destruction.

Platelets play an important role in the development and progression of respiratory distress. Functional platelets are known to seal inflammatory endothelial gaps and loss of platelet function has been shown to result in loss of integrity of pulmonary vessels. This leads to fluid accumulation in the pulmonary interstitium, eventually resulting in respiratory distress. Streptococcus pneumoniae is one of the major pathogens causing community-acquired pneumonia. Previously, we have shown that its major toxin pneumolysin forms pores in platelet membranes and renders them nonfunctional. In vitro, this process was inhibited by polyvalent intravenous immunoglobulins (IVIGs). In this study, we compared the efficacy of a standard IVIG preparation (IVIG, 98% immunoglobulin G [IgG]; Privigen, CSL Behring, United States) and an IgM/IgA-enriched immunoglobulin preparation (21% IgA, 23% IgM, 56% IgG; trimodulin, Biotest AG, Germany) to inhibit pneumolysin-induced platelet destruction. Platelet destruction and functionality were assessed by flow cytometry, intracellular calcium release, aggregometry, platelet viability, transwell, and flow chamber assays. Overall, both immunoglobulin preparations efficiently inhibited pneumolysin-induced platelet destruction. The capacity to antagonize pneumolysin mainly depended on the final IgG content. As both polyvalent immunoglobulin preparations efficiently prevent pneumolysin-induced platelet destruction and maintain platelet function in vitro, they represent promising candidates for clinical studies on supportive treatment of pneumococcal pneumonia to reduce progression of respiratory distress.

The outcome of using intravenous immunoglobulin (IVIG) in critically ill COVID-19 patients\u2019: a retrospective, multi-centric cohort study

BackgroundDuring the COVID-19 pandemic, different treatments have been used in critically ill patients. Using intravenous immunoglobulin (IVIG) has been suggested in various studies as an effective option. Our study aims to access the efficacy of IVIG in critically ill COVID-19 patients.MethodsIn this retrospective matched cohort study, records of three tertiary centers with a large number of COVID-19 admissions were evaluated and used. Based on treatment options, patients were divided into two groups, standard COVID-19 treatment (109 patients) and IVIG treatment (74 patients) patients. Also, the effect of IVIG in different dosages was evaluated. Patients with IVIG treatment were divided into three groups of low (0.25 gr/kg), medium (0.5 gr/kg), and high (1 gr/kg) dose. Data analysis was performed using an independent t test and one-way analysis of variance (ANOVA) to compare the outcomes between two groups, including duration of hospitalization, intensive care unit (ICU) length of stay, and mortality rate.ResultsThe duration of hospitalization in the IVIG group was significantly longer than standard treatment (13.74 days vs. 11.10 days, p < 0.05). There was no significant difference between the two groups in ICU length of stay, the number of intubated patients, and duration of mechanical ventilation (p > 0.05). Also, initial outcomes in IVIG subgroups were compared separately with the standard treatment group. The results indicated that only the duration of hospitalization in the IVIG subgroup with medium dose is significantly longer than the standard treatment group (p < 0.01).ConclusionOur data indicate that the use of IVIG in critically ill COVID-19 patients could not be beneficial, based on no remarkable differences in duration of hospitalization, ICU length of stay, duration of mechanical ventilation, and even mortality rate.

First-line corticosteroids for Kawasaki disease: Pulse versus multiple dose.

Kawasaki disease (KD) can result in severe coronary artery abnormalities (CAAs). Corticosteroids added to initial standard intravenous immunoglobulin (IVIG) treatment may decrease the risk for these complications. Different corticosteroid regimens (single-day high dose pulse vs multiple lower doses) may contribute to the discrepant results of prior studies. Using data from the 22nd, 23rd , and 24th Japanese nationwide KD surveys (2011-2016), we identified KD patients who did not have CAAs at first presentation and who were treated with either pulse or multiple-dose corticosteroids as part of their initial treatment. Occurrence of subsequent CAAs and treatment failure were compared between the treatment regimens and adjusted odds ratios were calculated controlling for sex, age group, illness day at first treatment, survey, and recurrent KD. There were 782 KD patients who received pulse corticosteroid treatment and 4,817 who received multiple dose treatment. Patients receiving multiple dose treatment were less likely to develop CAAs (5.5% vs 8.3%, OR 0.64; 95% CI: 0.48-0.85) or treatment failure (21.4% vs 41.6%; OR: 0.38; 95% CI: 0.33-0.45). Adjusted analyses showed similar protective effects of multiple-dose treatment against CAAs (OR: 0.67, 95% CI: 0.51-0.90) and treatment failure (OR: 0.39, 95% CI: 0.33-0.46). Multiple-dose corticosteroid combination treatment resulted in substantially improved outcomes in KD patients compared to pulse treatment. For patients who may be at elevated risk of treatment failure or CAA, use of multiple-dose corticosteroids in conjunction with IVIG is likely to provide considerable clinical benefit.

Effects of immunoglobulin plus prednisolone in reducing coronary artery lesions in patients with Kawasaki disease: study protocol for a phase III multicenter, open-label, blinded-endpoints randomized controlled trial

BackgroundKawasaki disease (KD) is an acute systemic vasculitis of unclear etiology that mainly affects infants and young children. Strategies to reduce the incidence and severity of coronary artery lesions (CALs), the determinant factor in the long-term prognosis of KD, are currently a focus of studies on KD. Corticosteroids, preferred in the treatment of the majority of vasculitides, are controversial in the treatment of acute KD. In this trial, we will evaluate whether the addition of prednisolone to standard intravenous immunoglobulin (IVIG) plus aspirin therapy can reduce the occurrence of CAL in Chinese patients with KD.MethodsThis is a multicenter, prospective, open-label, randomized controlled trial, which is expected to be conducted in more than 20 hospitals in China and aims to assess the efficacy and safety of IVIG + prednisolone treatment versus standard treatment. Patients with KD who fulfill the inclusion and exclusion criteria will be recruited and randomized (1:1) to receive either a large dose of IVIG (2 g/kg over 12–24 h with a maximum dose of 60 g) + aspirin 30 mg/kg/d or IVIG (2 g/kg over 12–24 h) + aspirin 30 mg/kg/d + prednisolone (2 mg/kg/d with a maximum dose of 60 mg tapered over 15 days after normalization of C-reactive protein concentration). The primary outcome will be the occurrence of CAL at 1 month of illness. The follow-up duration for each participant will be set as 1 year. Patients and treating physicians will be unmasked to group allocation.DiscussionThis will be the first multicenter randomized controlled trial to evaluate the efficacy of IVIG + aspirin + prednisolone in Chinese pediatric patients with KD, which may provide high-level evidence for improving the initial treatment for acute KD.Trial registrationClinicalTrials.govNCT04078568. Registered on 16 August 2018.

Association Between the Rate of Treatment Response and Short-Term Outcomes in Childhood Guillain-Barré Syndrome.

Introduction: Few studies have examined the association between the rate of treatment response and the outcome of pediatric Guillain-Barré syndrome (GBS). Therefore, our study aimed to identify treatment response in relation to the short-term outcomes of GBS. Further, we investigated its potential predictive value for prognosis.Methods: Our retrospective study included children diagnosed with GBS in the Pediatric Neurology Department of the Children's Hospital of Hebei Province from 2016 to 2020. According to the rate of response from the standard intravenous immunoglobulin (IVIg) treatment, patients were divided into two groups: rapid-response GBS (initial response within 7 days) and slow-response (initial response within 8–30 days). The GBS disability score (Hughes Functional Grading Scale) was used to assess the children's functional disability at nadir, 1 month, and 6 months after onset.Results: Among the 36 children included in the study, 18 (50%) and 18 (50%) were rapid and slow responders, respectively. Time from IVIg treatment to the initial response was significantly shorter in the rapid-response group (5 [3–6.25] days vs. 10.5[8.75–15] days in slow-response GBS, p < 0.001). Hughes score at 1 month was worse than the rapid responders (Fisher's exact test, p = 0.006). Survival analysis (Kaplan–Meier) with respect to regaining the ability to walk independently (Hughes Functional Grading Scale of 2) within 1 month after onset was significantly different among the two groups (log-rank test for trend, p = 0.024). The abnormal levels of cerebral spinal fluid proteins and autonomic dysfunction were more frequent in the slow-response group than those in the rapid group (p < 0.05).Conclusion: The rate of response to IVIg treatment was correlated with short-term outcomes in children with GBS and had predictive value for prognosis. The role of patient's initial responses to treatment could be significantly valuable in developing more effective and efficient treatment options.

Внутривенные иммуноглобулины: механизм действия и возможности клинического применения в педиатрии

Данный обзор посвящен анализу доступных клинических исследований и сообщений, касающихся оценки эффективности и безопасности применения внутривенных иммуноглобулинов (ВВИГ) при различных заболеваниях у детей. Внутривенные иммуноглобулины являются препаратами со строго регламентированными показаниями и доказанной эффективностью и безопасностью. Наиболее часто их применяют для коррекции гипогаммаглобулинемии, являющейся результатом первичного или вторичного иммунодефицитного состояния (ИДС).На сегодняшний день накоплена обширная, однако неоднородная доказательная база эффективности применения стандартных ВВИГ при сепсисе у детей различных возрастных групп.Потребление ВВИГ растет в связи с тем, что во многих случаях препараты назначают вне регламентированных показаний. ВВИГ стали чаще применяться при аутоиммунных и системных воспалительных заболеваниях. Однако в рандомизированных клинических исследованиях хороший эффект был достигнут только при болезни Кавасаки и иммунной тромбоцитопенической пурпуре. Современные клинические руководства сузили показания к назначению ВВИГ, ограничивают их применение при сепсисе. Заместительная терапия иммуноглобулинами рекомендуется детям с физиологической задержкой производства своего иммуноглобулина только при наличии повторных инфекций, которые нельзя проконтролировать или предотвратить с помощью антибиотиков. При вторичном ИДС заместительную терапию разрешается проводить, если причина гипогаммаглобулинемии не может быть устранена или устранение противопоказано, а также при ассоциации с β-клеточными онкозаболеваниями, при которых тяжелые инфекции, вызванные инкапсулированными бактериями, персистируют, несмотря на проведение профилактической антибиотикотерапии.

Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial

Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barré syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barré syndrome with a predicted poor outcome. In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barré syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barré syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barré syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barré syndrome disability score at 4 weeks was 1·4 (95% CI 0·6-3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). Our study does not provide evidence that patients with Guillain-Barré syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barré syndrome. Prinses Beatrix Spierfonds and Sanquin Plasma Products.

Functional benefits of corticosteroid and IVIG combination therapy in a coronary artery endothelial cell model of Kawasaki disease

BackgroundKawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD.MethodsHCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities.ResultsDEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1 s (IL-1α and IL-1β) was resistant to high-dose IgG.ConclusionsA corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.

Corticosteroids Added to Initial Intravenous Immunoglobulin Treatment for the Prevention of Coronary Artery Abnormalities in High-Risk Patients With Kawasaki Disease.

BACKGROUNDRandomized controlled trials previously provided different conclusions about the superiority of adding corticosteroids to initial intravenous immunoglobulin treatment for the prevention of coronary artery abnormalities in patients with Kawasaki disease (KD). To further assess this issue, we analyzed large‐scale data from nationwide KD surveys in Japan, where combination treatment (corticosteroids added to initial standard intravenous immunoglobulin treatment) has become commonly used for patients at high risk for KD.METHODS AND RESULTSStandard intravenous immunoglobulin treatment and combination treatment were compared using data from time periods with and without combination treatment. Outcome measures were coronary artery abnormalities and initial intravenous immunoglobulin treatment failure. Hospitals where ≥20% of patients received combination treatment were identified, and treatment and control groups were selected via matching by age, sex, illness day at initial treatment, and KD recurrence. Matched group selection and subsequent analyses were conducted 1000 times to minimize sampling bias and potential confounders (bootstrapping). From 115 hospitals, 1593 patients with KD in the treatment group and 1593 controls were selected for each of the 1000 sample iterations. The median proportion of patients who developed coronary artery abnormalities among the treatment group and controls were 4.6% (95% CI, 3.8%–5.8%) and 8.8% (95% CI, 7.5%–10.0%), respectively: an estimated risk ratio of 0.53 (0.41–0.67). A median of 14.1% (95% CI, 12.4%–15.9%) of the patients in the treatment group and 21.7% (95% CI, 19.8%–23.4%) in the controls had treatment failure: an estimated risk ratio of 0.65 (0.56―0.75).CONCLUSIONSCombination treatment reduced coronary artery abnormality risk by an estimated 47% and treatment failure by 35%. Multiple‐dose corticosteroids may provide benefit in selected patients at high risk for KD.

Neurological involvement in Kawasaki disease: a retrospective study

BackgroundKawasaki disease (KD) is an acute, self-limiting systemic vasculitis that predominately affects children. Neurological involvement is a known complication of KD, however, its association with KD severity remains elusive. We aimed to systematically describe the general manifestations of neurological involvement in KD, determine whether neurological involvement is a marker of disease severity in patients with KD, and assess the relationship of such involvement with intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs).MethodsWe retrospectively reviewed data from 1582 patients with KD between January 2013 and December 2017. Profiles of patients with neurological symptoms (group A, n = 80) were compared to those of gender- and admission date-matched patients without neurological involvement (group B, n = 512). Multivariate logistic regression analyses were performed to determine whether neurological involvement was significantly associated with IVIG resistance.ResultsNeurological involvement was observed in 5.1% (80/1582) of patients with KD. The neurological manifestations were diffuse, presenting as headache (13/80, 16.3%), convulsions (14/80, 17.5%), somnolence (40/80, 50.1%), extreme irritability (21/80, 26.3%), signs of meningeal irritation (15/80, 18.8%), bulging fontanelles (7/80, 8.8%), and facial palsy (1/80, 1.3%). Neurological symptoms represented the initial and/or predominant manifestation in 47.5% (38/80) of patients with KD. The incidence of IVIG resistance and levels of inflammatory markers were higher in group A than in group B. However, neurological involvement was not an independent risk factor for IVIG resistance or CALs.ConclusionRates of neurological involvement were relatively low in patients with KD. Neurological involvement was associated with an increased risk of IVIG resistance and severe inflammatory burden. Our results highlight the need for pediatricians to recognize KD with neurological involvement and the importance of standard IVIG therapy.Trial registrationRetrospectively registered.

Lack of Efficacy of High-Titered Immunoglobulin in Patients with West Nile Virus Central Nervous System Disease.

West Nile Virus (WNV) can result in clinically severe neurologic disease. There is no treatment for WNV infection, but administration of anti-WNV polyclonal human antibody has demonstrated efficacy in animal models. We compared Omr-IgG-am, an immunoglobulin product with high titers of anti-WNV antibody, with intravenous immunoglobulin (IVIG) and normal saline to assess safety and efficacy in patients with WNV neuroinvasive disease as part of a phase I/II, randomized, double-blind, multicenter study in North America. During 2003-2006, a total of 62 hospitalized patients were randomized to receive Omr-IgG-am, standard IVIG, or normal saline (3:1:1). The primary endpoint was medication safety. Secondary endpoints were morbidity and mortality, measured using 4 standardized assessments of cognitive and functional status. The death rate in the study population was 12.9%. No significant differences were found between groups receiving Omr-IgG-am compared with IVIG or saline for either the safety or efficacy endpoints.

Role of pentamer complex-specific and IgG subclass 3 antibodies in HCMV hyperimmunoglobulin and standard intravenous IgG preparations.

HCMV hyperimmunoglobulin-preparations (HIG) contain high concentrations of HCMV-specific IgG. The reduced maternofetal-HCMV-transmission rate of IgG may be due to HCMV-specific neutralizing antibodies against the HCMV pentameric complex (PC). In contrast to HIG, standard intravenous immunoglobulin (IVIG) may have more neutralization (NT) capacity than HIG due to higher IgG subclass 3 levels (Planitzer et al., 2011). We investigated the HCMV-specific NT-capacity of HIG Cytotect®, using a recombinant pentameric complex (gHgLUL128-131A) for specific antibody-depletion. We used a modified UL130-peptide (TANQNPSPPWSKLTYSKPH) based on original-sequence of Saccoccio et al. (Vaccine 29(15):2705-2711, 2011) (SWSTLTANQNPSPPWSKLTY) as neutralization target. Both UL130-peptides and the PC were bound via sixfold HisTag and anti-HisTag mAbs to magnetic beads to deplete HCMV-specific IgGs from HIG (Cytotect®). Modifying this depletion strategy, we analyzed the role of IgG subclass 3 in both HIG and IVIG. After CMV IgG-normalization of HIG and IVIG, we found a significant trend towards a decrease (16%) of neutralization-capacity for the UL130 TAN-peptide, but not for the original UL130 SWS-peptide. However, highly significant loss of NT-capacity could be only observed by PC depletion (42%). The IgG subclass 3 depletion revealed no significant reduction of NT-capacity in both HIG and IVIG. Via specific antibody depletion, we could demonstrate that pentameric complex-specific antibodies are present in HIG and bind to the recombinant PC resulting in a highly significant reduction of NT-capacity compared to the UL130 TAN-and SWS-peptides. We could not confirm the functional role of IgG subclass 3 neutralizing antibodies in IgG-preparations.

Aspirin Dose in Kawasaki Disease: The Ongoing Battle.

Kawasaki disease (KD) is an acute childhood vasculitis that may result in coronary aneurysms. Treatment of KD with a single infusion of 2 gm/kg intravenous immunoglobulin (IVIG) is well established, but acetylsalicylic acid (ASA) dose remains controversial. Our primary objective was to determine the difference in the incidence of IVIG resistance between 2 ASA doses. Our secondary objective was to compare the duration of hospital stay and the incidence of coronary artery aneurysm. We reviewed charts of patients with KD from 2 Canadian centers to assess the impact of ASA dose on IVIG resistance (operationally defined as administration of a second dose of IVIG). Both centers used standard IVIG dosing, but center 1 used low-dose ASA from diagnosis (3-5 mg/kg/day) while center 2 used initial high-dose ASA (80-100 mg/kg/day). There were no significant differences in baseline characteristics between the 2 centers. Retreatment with a second dose of IVIG was required in 28 of 122 patients (23%) treated with low-dose ASA, and in 11 of 127 patients (8.7%) treated with high-dose ASA in center 1 and center 2, respectively (P = 0.003). After adjusting for confounders, low-dose ASA was associated with higher odds of IVIG resistance (OR 3.2 [95% confidence interval 1.1, 9.1]). The mean duration of hospital stay was 4.1 and 4.7 days, respectively (P = 0.37). Coronary artery aneurysms were seen in 2 of 117 and 6 of 125 patients from centers 1 and 2, respectively (P = 0.28). Low-dose ASA was associated with 3-times higher odds of IVIG retreatment compared to high-dose ASA, with no significant difference in duration of hospital stay or incidence of coronary artery aneurysms.

Failure to Predict High-risk Kawasaki Disease Patients in a Population-based Study Cohort in Germany

Diverse scores on high-risk Kawasaki disease (KD) patients have proven a good prognostic validity in the Japanese population. However, data on non-Japanese have been inconclusive. Do the Kobayashi, Egami and Sano scores or application of up-to-date statistical methods (Random Forest) predict response to standard intravenous immunoglobulin (IVIG) therapy and the risk of persistent coronary artery aneurysm (CAA) in patients with KD in a mainly Caucasian population in Germany? Data on 442 children (German population-based survey, 2013 and 2014) were used to assess the prognostic validity of the Kobayashi, Egami and Sano scores for being refractory to IVIG treatment and for predicting the risk of persistent CAA. Additionally, an up-to-date statistical approach (Random Forest) was applied to identify a potentially more valid score. A total of 301 children were eligible for assessment of their response to IVIG treatment. Among those, 177 children were followed-up for 1 year to identify persistent CAA. Although all scores were significantly associated with being refractory to IVIG (relative risk range between 2.32 and 3.73), the prognostic properties were low (likelihood ratio positive: 1.83-4.57; sensitivity in the range of 0.28-0.53). None of the scores was a significant predictor of CAA 1 year after acute illness. Application of statistical analysis such as Random Forest did not yield a more valid score. None of the available scores appears to be appropriate for identifying high-risk Caucasian children with KD who might need intensified therapy.