Immunoglobulin-Induced Aseptic Meningitis in Juvenile Dermatomyositis: A Case Report

Background: Aseptic meningitis is a known but unusual serious adverse effect of intravenous immunoglobulin (IVIG). It usually resembles infectious meningitis which makes diagnosis challenging. Case presentation: We report a five-and-a-half-year-old Chinese girl with juvenile dermatomyositis presented with signs of meningismus 21 hours after the initiation of IVIG infusion. Her blood work at diagnosis showed neutrophilia and lymphopenia. The cerebrospinal fluid analysis demonstrated neutrophilic pleocytosis, hyperproteinorrachia and normoglycorrhachia. All microbiological tests were negative. The child recovered fully within 72hours without neurological sequelae.Conclusion: IVIG-induced aseptic meningitis remains a diagnosis of exclusion. Although it is rare, paediatricians should be aware of this complication and avoid unnecessary investigation or treatment.

Premedication with Hydrocortisone Increases Risk of Adverse Drug Events and Return to Medical Care Among Pediatric Patients with ITP Treated with IVIG

Immune Thrombocytopenia (ITP) is one of the most common acquired bleeding disorders affecting children. While 75-80% of these children will develop only mild bleeding symptoms, others can experience more severe bleeding, including rare intracranial hemorrhage (ICH), and may require platelet-directed therapy. Intravenous immunoglobulin (IVIG), a commonly utilized and effective first-line therapy, may be associated with adverse drug events (ADEs). The most commonly reported ADEs include headache (approximately 30% of treated patients) and nausea/vomiting, however the exact rates of these events and relationship to premedication strategies are poorly classified. These ADEs often result in emergent medical evaluation and additional diagnostic testing, including computed tomography (CT) of the head, to evaluate for ICH in children with severe thrombocytopenia. In order to identify rates of IVIG-associated ADEs and subsequent emergent medical evaluations in pediatric patients with ITP, we completed an retrospective observational cohort study of all pediatric patients with ITP who were treated with one-time IVIG infusion utilizing Gamunex-C ® 10% at a dose of 1g/kg across 4 large pediatric centers from 2010 to 2019. Included patients were between the ages of 0 and 21 years. Among the 563 patients receiving single IVIG infusions across all 4 centers, patients reported headache, nausea/vomiting, or both following 203 infusions (36%). Excluding those patients who remained hospitalized at the time of symptom development, 16% (84 of 513) of all patients returned for urgent medical evaluation following IVIG infusion. Nine percent of all patients receiving a single IVIG infusion underwent head CT to rule out ICH. All 51 CTs were negative for ICH. In order to determine if specific patient characteristics were associated with the development of IVIG-associated ADEs and return to medical care, univariable logistic regression was performed. Multiple logistic regression was used to determine whether the associations identified in the univariable analysis persisted after adjusting for other significant factors. Older age at administration (Adjusted Odds Ratio [adj OR] 1.07 for each additional year of age; 95% Confidence Interval [CI] 1.03, 1.11; p<0.001) and premedication with hydrocortisone (adj OR 2.36; 95% CI 1.38, 4.07; p=0.002) were associated with increased odds of IVIG-associated ADEs. Patients who received premedication with hydrocortisone were more likely to re-present for medical evaluation than patients who did not receive hydrocortisone (OR 1.90; 95% CI 0.98, 3.54; p=0.049). No associations were identified between ADEs and gender, race/ethnicity, premedication with diphenhydramine or ondansetron, pre-treatment serum IgG levels, or concurrent glucocorticoid administration. In summary, the rate of ADEs among pediatric patients with ITP treated with IVIG is remarkably high. Thirty-six percent of patients in our multi-institutional cohort reported headache, nausea/vomiting, or both following single IVIG infusion, consistent with our previous single institution experience. This again highlights the need for proper balance of risks and benefits when considering treatment for children with ITP. Patients who received premedication with acetaminophen were less likely to develop IVIG-associated ADEs, but those who received premedication with diphenhydramine or concurrent glucocorticoid therapy were no more or less likely to develop ADEs. Interestingly, however, patients who received premedication with hydrocortisone were more likely to develop IVIG-associated ADEs. Despite only a small subset of our cohort being premedicated with hydrocortisone (12%, n=66), this premedication strategy was significantly associated with an increased rate of return to medical care following IVIG infusion. Patients returning for emergent medical evaluation frequently underwent repeat laboratory studies or CT imaging, resulting in unnecessary radiation exposure and increased healthcare-related costs. These findings will help to inform IVIG premedication strategies in an attempt to reduce both ADEs and re-presentation to medical care among pediatric patients with ITP receiving IVIG therapy. Figure 1 Figure 1. Disclosures Kirk: Biomarin: Honoraria. Grace: Novartis: Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding. Neunert: Novartis: Research Funding. Lambert: Bayer: Consultancy; ClinGen, ISTH, ASH, GW University: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PDSA: Research Funding; Sysmex: Research Funding; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Despotovic: UpToDate: Patents & Royalties: Royalties; Apellis: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy.

Intravenous Immunoglobulin Use In Critically Ill Children

Purpose: The use of intravenous immunoglobulins (IVIG) has increased significantly in the last decade causing challenges for blood suppliers to respond to the demand. Indications for which IVIG infusion should be given to critically ill children remain unclear. The objective of this study is to characterize the epidemiology of IVIG use in this population. Methods: We performed a single-center retrospective cohort study of all patients aged between 3 days and 18 years who received at least one IVIG infusion while hospitalized in the pediatric intensive care unit of the Centre hospitalier universitaire (CHU) Sainte-Justine, Montréal Quebec (Canada) between January 1, 2013 and December 31, 2018. Results: One hundred and seventy-two patients received a total of 342 IVIG infusions over the study period. Most common indications for IVIG infusions were staphylococcal or streptococcal toxic shock syndrome (n=53/342, 15.5%), immunoglobulin replacement in chylothorax (n=37/342, 10.9%), prophylaxis following bone marrow transplantation (n=31/342, 9.1%), myocarditis (n=25/342, 7.3%) and post-solid organ transplant complications (n=21/342, 6.1%). The median dose of IVIG per infusion was 0.95 g/kg (IQR 0.5-1.0) and median number of IVIG infusions per patient was one (IQR: 1-2). Seventy-nine percent of IVIG infusions given were administrated for off-label indications with regards to Health Canada recommendations. Conclusion: This study identified the most common indications for IVIG infusion in critically ill children in a tertiary care pediatric intensive care unit. Given the costs, the known adverse events associated with IVIG and the pressure that blood suppliers are facing to meet the demands, clinical trials are needed to evaluate the efficacy and safety of IVIG in conditions where use is significant.

Transfusion-Associated Circulatory Overload (Taco) Presentations In Pediatric Patients

Introduction/Objective Limited literature exists regarding Transfusion Associated Circulatory Overload(TACO) in children. Its clinical expressions compared to those in adults remains to be fully explored. We report two TACO cases in children <18 months of age describing their clinical presentations compared to those in older patients. Methods/Case Report Case series Results (if a Case Study enter NA) Case 1: 1.13 kg 18 day old male neonate (27 weeks premature) with anemia requiring hemotherapy(HT). He received 35 ml aliquot of Red Blood Cells(RBCs) which he tolerated well on postoperative day(POD) 1 after bowel surgery. On POD 2, he was transfused RBCs(18 mls). Within 15 minutes of HT initiation, marked elevations in blood pressure(BP) were noted. Workup for a suspected transfusion reaction(STR) was initiated. Blood Bank studies revealed vital sign value(VSV) changes similarly seen in adults with TACO(Transfusion: 52; 2311, 2012). NT-proBNP levels post HT were markedly elevated (8,000 and 64,000 pg/ml).Case 2: 17 month old(11 kg) female with a three weeks prior history of COVID-19 admitted with fever/dehydration and subsequently diagnosed with multisystem inflammatory syndrome in children (MIS-C). Intravenous immunoglobulin(IVIG) infusion ordered and within 20 minutes of starting IVIG, she developed grunting. STR workup showed post HT BP/temperature elevations/chest X-ray with increased interstitial markings. Of note she had also received 1070 ml of intravenous fluids within 48 hours prior to HT. Elevated NT-proBNP levels pre/post HT were measured(17,121 pg/ml and 19, 824 pg/ml respectively). Symptoms improved with diuretics. Conclusion Children experiencing TACO can clinically manifest similarly as in adults with respect to BP elevations and pulmonary changes. Grunting may be an underappreciated manifestation of TACO in pts < 18 months of age. IVIG infusions used in the treatment of patients with MIS-C may present problematic fluid challenges. Recognition of and mitigation strategies for TACO risk factors in such patients may enhance HT safety in this vulnerable patient population.

The “Intermediate” CD14 + CD16 + monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease

Background Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children. Materials and methods The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry. Results The numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p < 0.0001). After infusion, intermediate monocytes decreased in the responsive group, while a trend of increase was observed in the resistant group. Only intermediate monocytes were significant in logistic regression with adjusted OR of 0.001 and p value of 0.03. Conclusions CD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.

Case Report: Successful Response to Intravenous Immunoglobulin and Steroid Pulses in a Renal Transplant Recipient With Severe Covid-19 Disease and Associated Acute Allograft Failure

The impact of Covid-19 pneumonia caused by SARS-CoV-2 on transplanted populations under chronic immunosuppression seems to be greater than in normal population. Clinical management of the disease, particularly in those patients worsening after a cytokine storm, with or without allograft impairment and using available therapeutic approaches in the absence of specific drugs to fight against the virus, involves a major challenge for physicians. We herein provide evidence of the usefulness of high-dose intravenous immunoglobulin (IVIG) combined with steroid pulses to successfully treat a case of Covid-19 pneumonia in a single-kidney transplanted patient with mechanical ventilation and hemodialysis requirements in the setting of a cytokine storm. A rapid decrease in the serum level of inflammatory cytokines, particularly IL-6, IL-8, TNF-α, MCP-1 and IL-10, as well as of acute-phase reactants such as ferritin, D-dimer and C-reactive protein was observed after the IVIG infusion and methylprednisolone bolus administration with a parallel clinical improvement and progressive allograft function recovery, allowing the patient’s final discharge 40 days after the treatment onset. The immunomodulatory effect of IVIG together with the anti-inflammatory and immunosuppressive potential of steroids could be an alternative strategy to treat severe cases of Covid-19 pneumonia associated with an uncontrolled inflammatory response in transplanted populations.

Predictive Value of Albumin-Bilirubin Grade For Intravenous Immunoglobulin Resistance In A Large Cohort Of Patients With Kawasaki Disease: A Prospective Study

Background: Intravenous immunoglobulin (IVIG) resistance, which defined that Kawasaki disease (KD) patients have recrudescence fever more than 36 hours after IVIG infusion, and its prediction is one of the primary clinical issues and study hotspots in KD. This study aimed to prospectively investigated the value of albumin-bilirubin grade (ALBI) in predicting IVIG resistance in KD, and assessed whether ALBI has more predictive value or accuracy than either ALB or TBil alone in predicting IVIG resistance.Methods: A total of 823 patients with KD were prospectively enrolled. The clinical and laboratory data were compared between IVIG-response group (n=708) and IVIG-resistance group (n=115). Multivariate logistic regression analysis was performed to identify the independent risk factors of IVIG resistance. Receiver operating characteristic (ROC) curves analysis was applied to assess the validity of ALBI, ALB, and TBil in predicting IVIG resistance. Results: ALBI was significantly higher in patients with IVIG resistance and was identified as an independent risk factor for IVIG resistance in KD. The parameter of ALBI ≥ –2.57 (AUC: 0.705, 95%CI: 0.672–0.736), ALB ≤ 33.0g/L (AUC: 0.659, 95%CI: 0.626–0.692), and TBil ≥16.0μmol/L (AUC: 0.626, 95%CI: 0.592–0.659), produced a sensitivity, specificity, PPV, and NPV of 0.617, 0.657, 0.226, 0.914, and 0.651; 0.374, 0.850, 0.289, 0.893, and 0.783; 0.269, 0.941, 0.425, 0.888, and 0.847, respectively.Conclusion: A higher ALBI was an independent risk factor for IVIG resistance. It yielded better predictive ability than ALB and TBil alone for initial IVIG resistance.

Fluctuations in Quality of Life and Immune Responses During Intravenous Immunoglobulin Infusion Cycles

Despite adequate infection prophylaxis, variation in self-reported quality of life (QOL) throughout the intravenous immunoglobulin (IVIG) infusion cycle is a widely reported but infrequently studied phenomenon. To better understand this phenomenon, immunodeficiency subjects receiving replacement doses of IVIG were studied over 3 infusion cycles. Questionnaire data from 6 time points spread over 3 IVIG infusions cycles (infusion day and 7 days after each infusion) was collected in conjunction with monitoring the blood for number of regulatory T-cells (Treg) and levels of 40 secreted analytes: primarily cytokines and chemokines. At day 7, self-reported well-being increased, and self-reported fatigue decreased, reflecting an overall improvement in QOL 7 days after infusion. Over the same period, percentage of Treg cells in the blood increased (p<0.01). Multiple inflammatory chemokine and cytokine levels increased in the blood by 1 hour after infusion (CCL4 (MIP-1b), CCL3 (MIP-1a), CCL2 (MCP-1), TNF-α, granzyme B, IL-10, IL-1RA, IL-8, IL-6, GM-CSF, and IFN-γ). The largest changes occurred in subjects initiated on IVIG during the study. A significant decrease in IL-25 (IL-17E) following infusion was seen in a majority of intervals among subjects already receiving regular infusions prior to study entry. These findings confirm IVIG “wear off” and provide a basis for the phenomenon. Secondary findings including differences between IVIG-experienced and IVIG-naïve subjects and the novel finding of suppression of IL-25 levels in the blood following IVIG are identified as novel immunomodulatory aspects of IVIG infusion in immunodeficient patients worthy of further exploration.

The interference of laboratory tests by immunoglobulin infusion: Problems and solutions

Intravenous Immunoglobulin (IVIG) has been increasingly used in managing a variety of immune-mediated conditions. While patients benefit from this treatment, the infusion of IVIG has transmitted large variety of antibodies and biological agents from donors to patients, and transiently interfered a broad spectrum of clinical laboratory tests covering the fields of infectious and autoimmune serology, biochemistry, haematology and blood bank, delivering spurious results that could potentially cause extensive evaluation and inappropriate clinical interventions. The medical practitioners and laboratory professionals must improve the awareness of test interferences caused by IVIG infusion. Proactive actions and appropriate strategy for investigating and interpreting the affected laboratory tests must be taken to avoid adverse impact on patient’s care.

Monocyte platelet aggregates in children with Kawasaki disease- a preliminary study from a tertiary care centre in North-West India

Background Platelet activation is an integral part of pathogenesis of Kawasaki disease (KD). However, there is paucity of literature on flow-cytometry based assessment of platelet activation in KD. We aimed to analyse monocyte-platelet aggregates (MPAs), one of the sensitive markers for platelet activation, by flow cytometry in children with KD. Findings In this single-centre prospective study, we have enrolled 14 children with KD and results were compared with age-matched febrile (n = 15) and healthy (n = 13) controls. After gating monocytes in side-scatter plot, MPAs were identified based on CD14 and CD41 expression. Two (2) ml of blood samples for children with KD were collected at 3 phases of illness- acute stage before start of intravenous immunoglobulin or aspirin, 24 h after completion of IVIg infusion, and 3 months after acute episode of KD. Children with KD had a significantly higher MPA% values [Median (IQR)- 41.3% (26.6, 52.7)] when compared with febrile [Median (IQR)- 5.98% (2.98-9.72)] and normal [Median (IQR)- 4.48% (2.57-5.59)] controls, p<0.01. On follow-up, the MPA% showed a gradual decline in children with KD, but even at 3 months, the value [Median (IQR)- 7.55% (4.15-14.6)] was higher compared to healthy controls [Median (IQR)- 4.48% (2.57-5.59)]. Conclusions Our results suggest that MPA% was significantly elevated in acute stages in children with KD and activated platelets may continue to persist even after systemic inflammation has subsided. Future studies are warranted whether objective evidence of platelet activation may guide the use of immunomodulatory and anti-platelet therapy in KD.