Distinct Cytokine and Chemokine Dysregulation in Hospitalized Children With Acute Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome With Similar Levels of Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 Shedding.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood. METHODS: Hospitalized children <18 years of age with suspected coronavirus disease 2019 (COVID-19) (N = 53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the US Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral ribonucleic acid (RNA) levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. RESULTS: The median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5-13.9) and 2.2 years (IQR, 1.1-10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1ß, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate <0.05; P < .05). CONCLUSIONS: The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Haemophilus influenzae Type b Vaccine Immunogenicity in American Indian/Alaska Native Infants.

OBJECTIVES: American Indian and Alaska Native (AI/AN) infants historically experienced a disproportionate burden of invasive Haemophilus influenzae type b (Hib) disease, especially early in life. PedvaxHIB vaccine is preferentially recommended for AI/AN infants because it elicits protective antibody levels postdose 1. Vaxelis, a hexavalent vaccine that contains the same Hib conjugate as PedvaxHIB but at lower concentration, is recommended for US children, but postdose 1 Hib immunogenicity data are needed to inform whether a preferential recommendation should be made for AI/AN infants. METHODS: We conducted a phase IV randomized, open-label, noninferiority trial comparing postdose 1 immunogenicity of Vaxelis to PedvaxHIB in AI/AN infants. Participants were randomized to receive a primary series of PedvaxHIB or Vaxelis. Serum samples collected 30 days postdose 1 were tested for anti-Hib immunoglobulin G antibody by enzyme-linked immunosorbent assay. The anti-Hib immunoglobulin G geometric mean concentration (GMC) ratio (Vaxelis/PedvaxHIB) was estimated by constrained longitudinal data analysis. Noninferiority was defined a priori as the lower bound of the 95% confidence interval (CI) of the GMC ratio ≥0.67. RESULTS: A total of 327 of the 333 infants enrolled in the study were included in the per-protocol analysis. The postdose 1 anti-Hib GMC was 0.41 µg/mL (95% CI 0.33-0.52) in the Vaxelis group (n = 152) and 0.39 µg/mL (95% CI 0.31-0.50) in the PedvaxHIB group (n = 146). The constrained longitudinal data analysis GMC ratio was 1.03 (95% CI 0.76-1.39). CONCLUSIONS: Postdose 1 immunogenicity of Vaxelis was noninferior to PedvaxHIB. Our findings support the use of Vaxelis in AI/AN children, a population with elevated risk of Hib disease.

Tuberculosis in Children.

Tuberculosis (TB) is one of the leading causes of mortality in children worldwide, but there remain significant challenges in diagnosing and treating TB infection and disease. Treatment of TB infection in children and adolescents is critical to prevent progression to TB disease and to prevent them from becoming the future reservoir for TB transmission. This article reviews the clinical approach to diagnosing and treating latent TB infection and pulmonary and extrapulmonary TB disease in children. Also discussed are emerging diagnostics and therapeutic regimens that aim to improve pediatric TB detection and outcomes.

Fatal SARS-CoV-2 Inflammatory Syndrome and Myocarditis in an Adolescent: A Case Report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an entity in children initially characterized by milder case presentations and better prognoses as compared with adults. Recent reports, however, raise concern for a new hyperinflammatory entity in a subset of pediatric COVID-19 patients. METHODS: We report a fatal case of confirmed COVID-19 with hyperinflammatory features concerning for both multi-inflammatory syndrome in children (MIS-C) and primary COVID-19. RESULTS: This case highlights the ambiguity in distinguishing between these two entities in a subset of pediatric patients with COVID-19-related disease and the rapid decompensation these patients may experience. CONCLUSIONS: Appropriate clinical suspicion is necessary for both acute disease and MIS-C. SARS-CoV-2 serologic tests obtained early in the diagnostic process may help to narrow down the differential but does not distinguish between acute COVID-19 and MIS-C. Better understanding of the hyperinflammatory changes associated with MIS-C and acute COVID-19 in children will help delineate the roles for therapies, particularly if there is a hybrid phenotype occurring in adolescents.

Ex-vivo cytoadherence phenotypes of Plasmodium falciparum strains from Malian children with hemoglobins A, S, and C.

Sickle hemoglobin (Hb) S and HbC may protect against malaria by reducing the expression of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of parasitized red blood cells (RBCs), thereby weakening their cytoadherence to microvascular endothelial cells (MVECs) and impairing their activation of MVECs to produce pathological responses. Therefore, we hypothesized that parasites causing malaria in HbAS or HbAC heterozygotes have overcome this protective mechanism by expressing PfEMP1 variants which mediate relatively strong binding to MVECs. To test this hypothesis, we performed 31 cytoadherence comparisons between parasites from HbAA and HbAS (or HbAC) Malian children with malaria. Ring-stage parasites from HbAA and HbAS (or HbAC) children were cultivated to trophozoites, purified, and then inoculated in parallel into the same wildtype uninfected RBCs. After one cycle of invasion and maturation to the trophozoite stage expressing PfEMP1, parasite strains were compared for binding to MVECs. In this assay, there were no significant differences in the binding of parasites from HbAS and HbAC children to MVECs compared to those from HbAA children (HbAS, fold-change  = 1.46, 95% CI 0.97-2.19, p = 0.07; HbAC, fold-change  = 1.19, 95% CI 0.77-1.84, p = 0.43). These data suggest that in-vitro reductions in cytoadherence by HbS and HbC may not be selecting for expression of high-avidity PfEMP1 variants in vivo. Future studies that identify PfEMP1 domains or amino-acid motifs which are selectively expressed in parasites from HbAS children may provide further insights into the mechanism of malaria protection by the sickle-cell trait.