Intravenous Gammaglobulin Research Articles

Multisystem Inflammatory Syndrome Temporally Related to COVID-19 in Children From Latin America and the Caribbean Region: A Systematic Review With a Meta-Analysis of Data From Regional Surveillance Systems.

BackgroundWith the emergence of the COVID-19 pandemic, increasing numbers of cases of the multisystem inflammatory syndrome in children (MIS-C) have been reported worldwide; however, it is unclear whether this syndrome has a differential pattern in children from Latin America and the Caribbean (LAC). We conducted a systematic review and meta-analysis to analyze the epidemiological, clinical, and outcome characteristics of patients with MIS-C in LAC countries.MethodsA systematic literature search was conducted in the main electronic databases and scientific meetings from March 1, 2020, to June 30, 2021. Available reports on epidemiological surveillance of countries in the region during the same period were analyzed.ResultsOf the 464 relevant studies identified, 23 were included with 592 patients with MIS-C from LAC. Mean age was 6.6 years (IQR, 6–7.4 years); 60% were male. The most common clinical manifestations were fever, rash, and conjunctival injection; 59% showed Kawasaki disease. Pool proportion of shock was 52%. A total of 47% of patients were admitted to the pediatric intensive care unit (PICU), 23% required mechanical ventilation, and 74% required vasoactive drugs. Intravenous gamma globulin alone was administered in 87% of patients, and in combination with steroids in 60% of cases. Length of hospital stay was 10 days (IQR, 9–10) and PICU stay 5.75 (IQR, 5–6). Overall case fatality ratio was 4% and for those hospitalized in the PICU it was 7%.ConclusionLimited information was available on the clinical outcomes. Improvements in the surveillance system are required to obtain a better epidemiologic overview in the region.

Pathogenic TNF-α drives peripheral nerve inflammation in an Aire-deficient model of autoimmunity

Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may, therefore, reveal new therapeutic targets for switching immune cells from an inflammatory role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-α signaling induced macrophage expression of multiple genes (Clec4e, Marcksl1, Cxcl1, and Cxcl10) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies.

Treatment of Acute Antibody-Mediated Rejection in Children Post-Kidney Transplantation: A Single Center’s Experience

Introduction Acute antibody-mediated rejection (aAMR) can negatively impact renal allografts outcomes. To date, there has not been a consistent therapeutic approach to manage aAMR. The aim of the study is to evaluate the tolerance and efficacy of an institutional protocol of methylprednisolone, intravenous gamma globulin (IVIG), rituximab, and bortezomib used to treat aAMR in pediatric renal transplant recipients (pRTRs). Methods A retrospective chart review was performed on 10 pediatric renal transplant recipients (pRTRs) who were diagnosed with aAMR on a renal biopsy performed between January 2014 and November 2015. Results Over the study period, 9.5% of pRTRs had aAMR. Sixty percent of whom had concurrent acute cellular rejection (ACR). Renal allografts survival was 100% during the the first post-aAMR. At the time of diagnosis of aAMR, estimated glomerular filtration rate (eGFR) had decreased by 42% (mean at baseline eGFR=67.2±19.5 mL/min/1.73 m2 vs mean at aAMR eGFR=38.9±14.2 mL/min/1.73 m2; p=0.002). At 1-year post rejection, eGFR had increased by 26% as compared eGFR at the time of rejection (mean eGFR=49.0±13.2 mL/min/1.73 m2; p=0.006). Immuno-dominant donor-specific anti-HLA antibody titers (iDSAs) class I and class II decreased by 69% and 15% at 6-month follow-up visit. No serious opportunistic infections nor malignancy were reported in our subjects. Conclusion Our study suggests that our protocol improved kidney function with 100% graft survival at 1-year post aAMR episode. The percentage decline in iDSAs class I titers was more significant than class II. Furthermore, our treatment protocol was well-tolerated with no life threatening complications.

Rituximab and High-Dose Methylprednisolone for the Initial Treatment of Chronic Lymphocytic Leukemia Is Associated with Promising Clinical Activity and Minimal Hematologic Toxicity

Myelosuppression is associated with significant morbidity and mortality in chronic lymphocytic leukemia (CLL) and is often exacerbated by currently available treatments for this disease. Myelosuppression often requires dose reductions in cytotoxic agents, delays in therapy, truncated treatment courses, or the exclusion of elderly or infirmed individuals from receiving standard chemoimmunotherapy.High-dose methylprednisolone (HDMP) and the anti-CD20 mAb rituximab (Rituxan), each is non-myelotoxic and can induce partial remissions when used alone to treat patients with CLL. However, complete remissions (CRs) in CLL patients are rarely observed following treatment with either agent. Recently, we reported the use of the combination of HDMP and rituximab in fludarabine-refractory patients [Castro Leukemia 2008]. The promising clinical activity and tolerability of this regimen in the refractory setting led to the evaluation of this regimen for the initial treatment of patients with CLL. To mitigate toxicity associated with use of HDMP, we employed a 40% reduction in the dose of HDMP by administering solumedrol at 1 gm/m2 for 3 instead of 5 days during each 4-week treatment cycle. Rituximab was given weekly for 12 weeks at 375mg/m2 or at 750mg/m2 in 9 doses over the 12 weeks of treatment to chemotherapy na·ve CLL patients with an NCI-WG indication for treatment. Objectives were to determine the response rate, safety, and toxicity of this regimen. PFS, overall survival (OS), hematologic, and immune parameters were also evaluated. We enrolled 28 patients who had a median age 65 years (range 48–80), 29% of whom were at least 70 years old. Forty-six were high risk by modified Rai classification, 39% had unfavorable cytogenetic features, and 64% had CLL cells that used unmutated IgVH region genes or exhibited high expression levels of ZAP-70. Patients received the full course of treatment without dose reductions or delays and the treatment well tolerated. Overall response rate was 96% with complete remission achieved in 32% of patients, 22% of whom had no detectable minimal residual disease (MRD) by sensitive 4-color flow cytometry capable of detecting residual CLL cells when present in marrow mononuclear cells at levels of more than 0.01%. Those patients over age 70 had an ORR of 100% with 38% CR, and 11% MRD-negative CR. There was a non-significant trend towards those receiving rituximab at 750mg/m2 being more likely to achieve a CR to treatment (Odds Ratio (OR) = 4.3, p-value 0.09). Individually, both beta-2-microglobulin (p=0.04) and splenomegaly palpable to at least 5 cm below the left costal margin (p<0.01) were associated with failure to achieve a CR to HDMP and rituximab. However, multivariable logistic regression analysis identified only splenomegaly as being significantly associated with failure to achieve a CR (OR = 0.096, p value = 0.03) to this regimen.The majority of adverse events were grade I/ II (80%) and hematologic toxicity was minimal. During the course of treatment, we noted resolution of thrombocytopenia or anemia. (See Figure) A total of 81 cycles of treatment were administered and only one red cell transfusion and no platelet transfusions were required. Serum immunoglobulins decreased with therapy and a low threshold was used to initiate intravenous gammaglobulin for those patients with experiencing recurrent infections. Percent of CD4 T cell counts increased significantly from median 2% (+/−4% 95% CI) to 32% (+/−8%) (Student t-test p < 0.0001). All patients had a CD4 count of greater than 200 cells/μl (median 848 cells/ul) two months after the completion of treatment.Six patients received consolidation with alemtuzumab at least 4 months following initial therapy and 83% of these patients became MRD negative. The CR and MRD negative CR rate following HDMP and Rituximab with 6 patients receiving consolidation were 43% and 25% respectively. With over three years of follow-up (36.3 mo) median PFS and time to requiring additional therapy have not been reached and OS is 96%. Achieving a MRD negative response was associated with significantly prolonged PFS and time to requiring additional therapy over all other responses (log-rank test p= 0.036 and 0.016 respectively).In summary, the combination of HDMP and rituximab is an effective non-myelotoxic treatment regimen for patients with CLL. Treatment was well tolerated, notably in elderly patients and those with baseline cytopenias making this regimen an effective and safe alternative for frontline therapy. [Display omitted]

Development of a Complement-Mediated Hemolysis Assay for Immune Globulin Intravenous Products and Characterization of Lots Associated with Clinical Hemolysis

Introduction: Immune Globulin Intravenous (Human) (IGIV), as known as Intravenous Gamma-Globulin (IVIg), are therapeutic polyclonal immunoglobulin preparations manufactured from pooled human plasma. Initially licensed for replacement therapy of primary immune deficiencies, IGIV indications have expanded to include various autoimmune and inflammatory conditions. Hemolytic reactions associated with IGIV infusion were historically considered as uncommon, but seem to be more frequent over the past 5-6 years, coinciding with widespread manufacturing changes to increase IgG yield, and use of higher dosages. Anti-A and anti-B IgG isoagglutinins in the IGIV preparations are believed to mediate these events. In 2014, FDA co-organized a workshop to discuss strategies to address hemolytic complications of IGIV infusions (Scott 2015). Although US products all comply with an anti-A and anti-B specification of ≤1:64, using the European Pharmacopoeia direct hemagglutination test (DHAT) (Thorp 2010), hemolytic events have persisted. The DHAT is semi-quantitative, imprecise, and does not measure hemolytic function. However, hemolysin tests have been difficult to standardize, especially for highly concentrated IGIV products (Scott 2015).This study reports development of a complement-dependent hemolysis assay (CDHA) suitable for testing IGIV products. We also tested a positive control preparation that is available from NIBSC (code 14/160), consisting of an IGIV lot that caused clinical hemolysis. Finally, we demonstrated differences among IGIV brands with respect to hemolytic activity.Methods: To provide consistent reagents, serum from whole blood donations were frozen as a large volume source of complement and a droplet-freezing method was used to store Red Blood Cells (Schmid 2011; Figure 1). Critical assay conditions were studied, including enzymatic treatment of RBC, removal of unbound IgG, complement source and concentration, divalent cation concentrations, and pH. Hemolytic activities of IGIV products and a positive control IGIV preparation were compared to the hemagglutination results tested using DHAT method. The CDHA was also used to evaluate hemolytic activity of IgG subclasses.Results: The most critical parameters for reproducible CDHA were complement source and preparation method, and assay pH. A pH of 6.5 (0.1M Tri-BIS buffer) was the most suitable condition for all of the tested IGIV analytes. Intra-laboratory variation was minimized by use of frozen RBCs and a consistent highly active complement preparation. The DHAT and CDHA results correlated with each other for most IGIV product lots (Figure 2). Hemolytic activity in IGIV lots varied among, in some cases within, brands. Enrichment of IgG subclass fractions from NIBSC 14/160 showed the highest hemolytic activity was present in IgG2 (Figure 3). In contrast, studies of recombinant anti-A monoclonal antibodies expressing the same anti-A F(ab'), but subclass-specific Fc receptors showed greatest activity of IgG3, consistent with evidence that IgG3 is the most potent complement-activating subclass. The role of IgG2 in hemolysis is not entirely surprising, as saccharide antigens often elicit IgG2 responses, and IgG2 can mediate complement activation (Diebolder 2014). Further subclass studies are planned.Conclusion: Hemolytic activity of IGIV products mediated by anti-A isoagglutinins can be reproducibly measured in IGIV products (Figure 4). Compared to the DHAT method, CDHA provides a continuous readout, is less variable, amenable to use of a standard curve, and more precise. Historical challenges to reproducibility are addressed through biological reagent standardization and attention to critical conditions. Studies comparing the CDHA and DHAT methods across a wider range of products and hemolytic lots will discern whether the CDHA provides a better measure of product safety than the current DHAT lot release assay. The CDHA can be helpful for characterization of new manufacturing methods and products, and investigation of hemolytic events. Studies of hemolysis-implicated lots may provide a basis for improvements in product safety. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diagnosis and Treatment Protocol for COVID-19 Patients (Tentative 8th Edition): Interpretation of Updated Key Points.

Diagnosis and Treatment Protocol for COVID-19 Patients (Tentative 8th Edition): Interpretation of Updated Key Points.

Evans syndrome in child with sudden blindness

A 3-year-old girl presented with sudden onset of bilateral vision loss on waking up from sleep. There had been no associated eye pain, eye redness, fever or history of trauma in the days leading up to the presentation. She had been diagnosed with Evans syndrome at the age of 18 months and started on a regular dose of oral prednisolone under regular follow-up at the paediatric clinic. Upon presentation, her visual acuity was light perception bilaterally, with relative afferent pupillary defect in the right eye and sluggish pupils bilaterally. Bilateral fundus examination showed normal macula and pink optic discs without papilloedema. Other systemic examinations were unremarkable. The provisional diagnosis was severe bilateral retrobulbar optic neuritis, prompting further investigations to rule out infectious or vasculitic causes. Extensive investigations were carried out during admission including infective screenings of blood and urine, all of which were negative. A contrasted magnetic resonance image of the brain showed both orbital segments were swollen and appeared hyperintense, with involvement of the intracanalicular and intracranial segments, suggesting an inflammatory or demyelinating aetiology. A visual evoked potential test to rule out demyelination disease was also normal. As intravenous methylprednisolone treatment appeared to have a slow effect, the treatment was switched to intravenous gammaglobulin. The patient responded well to treatment, and her latest visual acuity assessment 1 month after presentation showed bilateral vision of 6/24. This is the first-ever Evans syndrome patient to be reported worldwide with bilateral optic nerve sterile inflammation.

Infliximab and Intravenous Gammaglobulin in Hospitalized Severe COVID-19 Patients in Intensive Care Unit.

Severe coronavirus disease 2019 (COVID-19) may lead to the cytokine storm syndrome which may cause acute respiratory failure syndrome and death. Our aim was to investigate the therapeutic effects of infliximab, intravenous gammaglobulin (IVIg) or combination therapy in patients with severe COVID-19 disease admitted to the intensive care unit (ICU). In this observational research, we studied 104 intubated adult patients with severe COVID-19 infection (based on clinical symptoms, and radiographic or CT scan parameters) who were admitted to the ICU of a multispecialty hospital during March 2020 in Tehran, Iran. All cases received standard treatment regimens as local protocol (Oseltamivir + hydroxychloroquine + lopinavir/ritonavir or sofosbuvir or atazanavir ± ribavirin). The cases were grouped as controls (n = 43), infliximab (n = 27), IVIg (n = 23) and combination (n = 11). There was no significant difference between controls and treatment groups in terms of underlying diseases or the number of underlying diseases. The mean age (SD) of cases was 72.42 (16.06) in the control group, 64.52 (12.965) in IVIg, 63.40 (17.57) in infliximab and 64.00 (11.679) in combination therapy; (P = 0.047, 0.031 and 0.11, respectively). Also, 37% in the infliximab group, 26.1% in IVIg, 45.5% in combination therapy, and 62.8% in the control group expired (all P < 0.05). Hazard ratios were 0.31 in IVIg (95% CI: 0.12-0.76, P = 0.01), 0.30 in infliximab (95% CI: 0.13-0.67, P = 0.004), 0.39 in combination therapy (95% CI: 0.12-1.09, P = 0.071). According to the findings of this study, it seems that infliximab and IVIg, alone or together, in patients with severe COVID-19 disease can be considered an effective treatment.

Clinical analysis of adenovirus pneumonia with pulmonary consolidation and atelectasis in children.

ObjectiveTo assess the clinical characteristics of 168 children with adenovirus pneumonia complicated by pulmonary consolidation and atelectasis.MethodsWe retrospectively studied patients with adenovirus pneumonia complicated by pulmonary consolidation and atelectasis admitted to Xiamen Children’s Hospital from March 2019 to August 2019. In total, 168 patients were recruited and divided into a severe group and non-severe group according to disease severity. Clinical results were assessed.ResultsAll children had fever and cough, 29 had wheezing, and 82 had dyspnea. Pleural effusion was found in 53 patients. Mixed infections were present in 95 patients. A total of 105 patients received hormone therapy, 72 received intravenous gamma globulin, and 103 underwent bronchoscopy, among whom 6 were found to have bronchial casts. Of the 168 children, 166 were cured and two died. The patients were divided by disease severity, with 82 in the severe group and 86 in the non-severe group. The two groups showed significant differences in the fever course, pleural effusion, mixed infections, hemoglobin concentration, procalcitonin concentration, and lactate dehydrogenase concentration.ConclusionA long fever course, mixed infection, pleural effusion, decreased hemoglobin concentration, and increased procalcitonin and lactate dehydrogenase concentrations may be associated with more severe adenovirus pneumonia.

COVID 19 infection: Pediatric perspectives.

The coronavirus disease 2019 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has rapidly spread across the globe, causing innumerable deaths and a massive economic catastrophe. Exposure to household members with confirmed COVID‐19 is the most common source of infection among children. Children are just as likely as adults to get infected with SARS‐CoV‐2. Most children are asymptomatic and when symptoms occur, they are usually mild. Infants <12 months old are at a higher risk for severe or critical disease. COVID‐19 is diagnosed the same way in pediatric population as adults by testing specimen obtained from upper respiratory tract for nucleic acid amplification test (NAAT) using reverse transcriptase viral polymerase chain reaction (RT‐PCR). The common laboratory findings in hospitalized patient include leukopenia, lymphopenia, and increased levels of inflammatory markers. Chest X‐ray findings are variable and computed tomography scans of the chest may show ground glass opacities similar to adults or non‐specific findings. Prevention is the primary intervention strategy. Recently the U.S. Food and Drug Administration (FDA) has provided emergency authorization of the Pfizer‐BioNTech COVID‐19 vaccine and many other vaccine candidates are in the investigational stage. There is limited data in children on the use of antivirals, hydroxychloroquine, azithromycin, monoclonal antibody, and convalescent plasma. Oxygen therapy is required in hypoxic children (saturation <92%). Similar to adults, other measures to maintain oxygenation such as high flow nasal cannula, CPAP, or ventilatory support may be needed. Ventilatory management strategies should include use of low tidal volumes (5–6 cc/kg), high positive expiratory pressure, adequate sedation, paralysis, and prone positioning. Recently, a new entity associated with COVID‐19 called multisystem inflammatory syndrome in children (MIS‐C) has emerged. Clinical, laboratory, and epidemiological criteria are the basis for this diagnosis. Management options include ICU admission, steroids, intravenous gamma globulin, aspirin, anakinra, and anticoagulants. Vasoactive‐inotropic score (VIS) is used to guide vasopressor support.

COVID-19: Imbalanced Immune Responses and Potential Immunotherapies.

The ongoing pandemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading and has resulted in grievous morbidity and mortality worldwide. Despite the high infectiousness of SARS-CoV-2, the majority of infected individuals are asymptomatic or have mild symptoms and could eventually recover as a result of their balanced immune function. On the contrary, immuno-compromised patients are prone to progress into severe or critical types underpinned by the entanglement of an overexuberant proinflammatory response and injured immune function. Therefore, well-coordinated innate and adaptive immune systems are pivotal to viral eradication and tissue repair. An in-depth understanding of the immunological processes underlying COVID-19 could facilitate rapidly identifying and choosing optimal immunotherapy for patients with severe SARS-CoV-2 infection. In this review, based on current immunological evidence, we describe potential immune mechanisms and discuss promising immunotherapies for COVID-19, including IL-6R blockades, convalescent plasma, intravenous gamma globulin, thymosin alpha1, corticosteroids, and type-I interferon, and recent advances in the development of COVID-19 vaccines.

Kawasaki disease in African American children

It is well known that Kawasaki disease has racial and ethnic variations in prevalence, response to intravenous gamma globulin, and outcomes. However, relatively little is known about African American children. In this volume of The Journal, Padilla et al report on comparisons between African American and white children with respect to Kawasaki Disease outcomes. They found that African American children were more likely to be refractory to IVIG treatment, have more severe inflammation, and had a greater proportion of persistent coronary artery abnormalities at follow-up compared with white children.

Megaloblastic Anemia with Systemic Lupus Erythematosus (SLE)-Induced Cold Agglutinin Syndrome (CAS): A Case Report and Literature Review

Cold agglutinin syndrome (CAS) is an uncommon disease of the blood system, and systemic lupus erythematosus (SLE)-induced cold agglutinin syndrome is also rare. Herein, we report a case of CAS with SLE induced by megaloblastic anemia. The onset of the disease for this patient was severe anemia, but the severity did not match the lack of raw material of the hematopoietic system. Moreover, peripheral blood assay revealed cold agglutinin. The patient was diagnosed with SLE, which was induced by infection and led to CAS. Anti-infection, blood transfusion, and fluid infusion, was administered with warmer S-line to ensure the infusion temperature was maintained at 30°C. Other treatments included an infusion of specially heated red blood cells with appropriate heating and correction of anemia with glucocorticoids, intravenous gamma globulin, cyclosporine, and hydroxychloroquine. Finally, the SLE recovered to the stationary phase. Although megaloblastic anemia is a common disease in the blood system, missed diagnosis is not rare if it is accompanied by other diseases that increase the severity of anemia. Thus, the primary cause of anemia should be explored and use targeted treatment employed.

A case of sporadic late‐onset nemaline myopathy without monoclonal gammopathy of unknown significance/human immunodeficiency virus successfully treated with intravenous gamma globulin

AbstractBackgroundSporadic late‐onset nemaline myopathy (SLONM) is an acquired form of nemaline myopathy developed in adulthood. Due to its rarity, standard treatment has not been established albeit some reports suggest treatment efficacy.Case presentationA 75‐year‐old woman developed progressive muscle weakness in her extremities 3 years previously. Muscle biopsy revealed nemaline bodies, which led to the diagnosis of SLONM. M protein, human immunodeficiency virus (HIV) antigen/antibody, and urine Bence‐Jones protein were all negative. Muscle strength gradually improved after receiving two courses of intravenous immunoglobulin (IVIg).ConclusionsIVIg may be effective in SLONM without monoclonal gammopathy of unknown significance or HIV infection by improving symptoms and suppressing the progression.

Practice Patterns and Outcomes of Hemophagocytic Lymphohistiocytosis in Adults: A Two-Decade Provincial Retrospective Review

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by uncontrolled immune activation, resulting in multi-organ dysfunction and a high risk of death. Due to scarcity of data in adults, the diagnosis remains challenging and has been historically associated with a delayed time to diagnosis and heterogeneous practice patterns. We examined the processes of care measures and outcomes in a large cohort of adults with HLH. Methods: This multicenter, retrospective cohort study examined the epidemiology, management, and outcomes of adult inpatients (≥18 years) diagnosed with HLH in the province of Alberta, Canada from January 1999 to December 2019. Patients were identified via International Classification of Diseases (ICD) codes, and those who met the HLH-2004 diagnostic criteria were included. Chart reviews were performed to collect demographics, clinical and laboratory characteristics, process of care measures, and outcomes. Overall survival (OS) was defined as the time from hospital presentation to death. Survival analysis was performed using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Cox proportional hazards regression was used to assess the association between time to diagnosis and the hazard of death, adjusting for patient and disease characteristics. Results: 83 patients met the HLH-2004 diagnostic criteria; 1 had a clear alternative diagnosis, hence 82 were included in the final data analysis. The median age of the cohort was 47 (interquartile range, IQR 32-62) years; 57 (70%) were male. The etiologies of HLH were as follows: malignancy (38%), infection (35%), autoimmune disease (16%), and idiopathic/others (11%). The most common clinical and laboratory findings were hyperferritinemia (100%), fever (99%), cytopenias (94%), hypofibrinogenemia and/or hypertriglycermidemia (91%), and hemophagocytosis on biopsy (89%). The median H-score was 244, with no significant difference across HLH etiologies. Interim data analysis showed that sCD25, natural killer (NK) cell activity, and molecular studies were ordered in 69%, 36%, and 29% of cases. The median length of hospitalization was 33 days (IQR 16-62), with a 30-day mortality rate of 25.6%. A majority of patients (55%) required admission to the intensive care unit (ICU) (Table 1). The median OS was 8.5 months. Patients with malignancy-associated HLH had a significantly worse median OS compared with those with non-malignancy-associated HLH (2.1 vs 54.5 months, p=0.0004; Figure 1). There were no differences in the median OS between B-cell (n=11) and T/NK lymphoproliferative disorders (n=13), or between new cancer diagnosis (n=27) and active cancer receiving chemotherapy (n=4). Age (adjusted hazards ratio, aHR 1.06, 95% CI 1.01-1.10), Charlson comorbidity index (aHR 1.4, 95% CI 1.2-1.8), and ICU admission (aHR 4.1, 95% CI 1.4-12.2) were associated with increased hazards of death on multivariable Cox proportional hazards model. Malignancy was associated with increased hazard of death on univariate analysis (HR 2.8, 95% 1.5-4.9), but did not remain as an independent prognostic factor on multivariable analysis (aHR 1.0, 95% 0.4-2.6). Sex, delayed diagnosis, or peak ferritin level were not significant predictors of mortality. The median times from presentation to diagnosis and from presentation to therapy were 10 days (IQR 2-19) and 14 days (IQR 6-25), respectively. Practice patterns varied significantly between centers without differences in survival outcome (log-rank p=0.8). Most patients (83%) received corticosteroids, whereas etoposide, intravenous gammaglobulin, and cyclosporine were administered in 38%, 34%, and 18%, respectively. Twelve (15%) patients did not receive any HLH-specific treatment, mostly in infection-associated HLH (n=8). Of the 31 patients receiving steroids and etoposide, 21 (68%), 12 (39%), and 20 (65%) receivedpneumocystis jirovecii, antiviral, and antifungal prophylaxis, respectively. Conclusion: In our two-decade provincial study, we observed that delayed diagnosis and treatment heterogeneity were common. Older age, comorbidities, and ICU admission were independent predictors of poor survival, whereas delayed diagnosis and malignant HLH were not. Development of a standardized provincial diagnostic and treatment protocol has the potential to improve the quality of care in adult HLH. Disclosures Sun: Sanofi:Other: Advisory board;Octapharma:Other: Advisory board;Pfizer:Other: Advisory board;Octapharma:Research Funding;Novo Nordisk:Other: Advisory board.

Kawasaki Disease and Clinical Outcome Disparities Among Black Children

ObjectiveTo determine whether Black children with Kawasaki disease exhibit disparities in prevalence, sequelae, and response to intravenous gamma globulin (IVIG) treatment.Study designInternational Classification of Diseases codes were used to identify children with Kawasaki disease admitted to a tertiary center in the southeastern US. Subjects diagnosed and treated according to American Heart Association criteria were included. Demographic, laboratory, clinical, and echocardiographic data from the electronic medical record (2000-2015) were compared between Blacks and Whites.ResultsData from 369 subjects (52% Whites and 48% Blacks) were included in our analysis. No significant differences related to timely admission, IVIG treatment, or coronary artery (CA) abnormalities during hospitalization were observed. Blacks showed lower IVIG response rates than Whites for patients administered IVIG within 10 days of fever onset (86.6% vs 95.6%; P = .007). Blacks received more ancillary drugs (9.6% vs 2.6%; P = .003), and endured longer hospitalizations (mean, 5 ± 3.9 days vs 3.4 ± 2.2 days; P = .001). Blacks presented with higher C-reactive protein level and erythrocyte sedimentation rate and lower hemoglobin, albumin, and sodium levels. Blacks had a higher proportion of persistent CA abnormalities than Whites at second follow-up echocardiogram (14.5% vs 6.3%; P = .03), and at third follow-up echocardiogram (21.2% vs 6.9%; P = .01).ConclusionsCompared with White children, Black children with Kawasaki disease had higher IVIG refractory prevalence, more severe inflammation, more ancillary treatments, and longer hospitalizations. Despite no racial differences in time to diagnosis or initial treatment, there was greater CA abnormality persistence among Black children at follow-up.

The Natural History of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children: A Systematic Review.

BackgroundThe clinical manifestations and natural history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related multisystem inflammatory syndrome in children (MIS-C) are poorly defined. Using a systematic review of individual cases and case series and collating elements of the clinical course, the objective of this study was to provide a detailed clinical description and natural history of MIS-C.MethodsCase reports and series of MIS-C were recovered from repeated MEDLINE searches, a single EMBASE search, and table of contents reviews of major general medicine and pediatric journals performed between June 3 and July 23, 2020. Fever, evidence of inflammation, and evidence of organ dysfunction were required for inclusion.ResultsMEDLINE and EMBASE searches produced 129 articles, and 10 articles were identified from journal contents or article bibliographies; 16 reports describing 505 children with MIS-C comprise this review. Thirty-two children (14.7%) had negative results for SARS-CoV-2 by nucleic acid and/or antibody testing. The weighted median age was 9 years (6 months to 20 years). Clinical findings included fever (100%), gastrointestinal symptoms (88.0%), rash (59.2%), conjunctivitis (50.0%), cheilitis/ “strawberry tongue” (55.7%), or extremity edema/erythema (47.5%). Median serum C-reactive protein, ferritin, fibrinogen, and D-dimer concentrations were above the normal range. Intravenous gammaglobulin (78.1%) and methylprednisolone/prednisone (57.6%) were the most common therapeutic interventions; immunomodulation was used in 24.3% of cases. Myocardial dysfunction requiring ionotropic support (57.4%) plus extracorporeal membrane oxygenation (5.3%), respiratory distress requiring mechanical ventilation (26.1%), and acute kidney injury (11.9%) were the major complications; anticoagulation was used commonly (54.4%), but thrombotic events occurred rarely (3.5%). Seven (1.4%) children died.ConclusionsMIS-C following SARS-CoV-2 infection frequently presents with gastrointestinal complaints and/or rash; conjunctivitis, cheilitis, and/or extremity changes also occur frequently. Serious complications occur frequently and respond to aggressive supportive therapy.

Coronavirus Disease 2019 in Neonates - What Is Known and What Needs to Be Known.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in Wuhan, China, and subsequently spread worldwide affecting all ages including newborns. The cases of coronavirus disease 2019 (COVID-19) are very less in neonates and they recover well with supportive treatment. Though the vertical transmission of infection is scarcely found, to get rid of acquiring infection by horizontal transmission one should screen all pregnant women and ensure standard infection control measures and monitoring of newborns at risk of COVID-19. Neonates may present as a refusal to feed, feeding intolerance, fever, pneumonia, shortness of breath, and lethargic. Based on available evidence, antivirals like lopinavir, ritonavir, remdesivir specific medication like chloroquine/hydroxychloroquine, azithromycin, corticosteroids, and intravenous gamma globulin, are not recommended, so early detection and supportive treatment is needed for an optimal outcome.

Multisystem Inflammatory Syndrome in Children and Kawasaki Disease: Two Different Illnesses with Overlapping Clinical Features

Multisystem Inflammatory Syndrome in Children and Kawasaki Disease: Two Different Illnesses with Overlapping Clinical Features

Neonatal Kawasaki disease with multiple arterial aneurysms: a case report

BackgroundKawasaki disease (KD) is a medium vessel vasculitis that typically occurs in children aged between 6 months and 5 years. It is extraordinarily rare in the neonatal period. KD-related systemic artery aneurysms (SAAs) have never been reported in neonates.Case presentationA male infant was transferred to our institution for persistent high-grade fever lasting 16 days. Symptoms started at day 14 of life, and he was admitted to a children’s hospital on the second day of fever. Physical examination at the time found no signs suggestive of KD. The only laboratory parameters which were of significance were values suggestive of systemic inflammation. However, his fever persisted and inflammatory markers continued to rise despite 2 weeks of antibiotic therapy. KD as a noninfectious cause of fever was considered when he came to our institution, and echocardiographic findings of left and right medium coronary artery aneurysms (CAAs) confirmed our suspicions. Full-body magnetic resonance angiography also revealed bilateral axillary artery aneurysms. Administration of intravenous gamma globulin resulted in rapid improvement. His fever resolved on the next day and CAAs and SAAs regressed to normal at 6 months and 3 months after diagnosis, respectively.ConclusionThis unique case of incomplete KD highlights the importance of considering KD in neonates with unexplained prolonged fever and reinforces the need to remain vigilant for SAAs in KD.