Faculty Bibliography

BACKGROUND:The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. OBJECTIVE:To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. DESIGN:Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. SETTING:A national collaboration of pediatric health systems (PEDSnet). PARTICIPANTS:77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase. INTERVENTION:First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine. MEASUREMENTS:Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification. RESULTS:During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period. LIMITATION:Observational study design and potentially undocumented infection. CONCLUSION:This study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. PRIMARY FUNDING SOURCE:National Institutes of Health.

BACKGROUND:PD-1 marks exhausted T cells, with weak effector functions. Adults living with HIV have increased levels of PD-1+ CD8 T cells that correlate with HIV disease progression, yet little is known about the role of PD-1+ CD8 T cells in children with perinatal HIV. METHODS:We enrolled 76 Kenyan children with perinatal HIV and 43 children who were HIV unexposed and quantified PD-1 levels on CD8 T cells, their coexpression with immune checkpoints (IC) 2B4, CD160 and TIM3, correlates with immune activation and HIV disease progression and HIV-specific and non-specific proliferative responses. RESULTS:PD-1+ CD8 T cell frequencies are elevated in children with perinatal HIV and associated with disease progression. The majority of PD-1+ CD8 T cells coexpress additional ICs. ART initiation lowers total PD-1 levels and coexpression of multiple ICs. The frequency of PD-1 + 2B4+CD160+TIM3- in PD-1+ CD8 T cells, predicts weaker HIV-specific proliferative responses, suggesting this subset is functionally exhausted. CONCLUSION/CONCLUSIONS:Children with perinatal HIV have high PD-1+ CD8 T cells that are a heterogeneous population differentially coexpressing multiple ICs. Understanding the complex interplay of ICs is essential to guide the development of PD-1 directed immunotherapies for pediatric HIV remission and cure.

OBJECTIVES/OBJECTIVE:We sought to describe the presentation, course, and outcomes of hospitalized pediatric coronavirus disease 2019 patients, with detailed description of those requiring mechanical ventilation, and comparisons between critically ill and noncritical hospitalized pediatric patients. DESIGN/METHODS:Observational cohort study. SETTING/METHODS:Riley Hospital for Children at Indiana University Health in Indianapolis in the early weeks of the coronavirus disease 2019 pandemic. PATIENTS/METHODS:All hospitalized pediatric patients with confirmed coronavirus disease 2019 as of May 4, 2020, were included. INTERVENTIONS/METHODS:Patients received therapies including hydroxychloroquine, remdesivir, tocilizumab, and convalescent serum and were managed according to an institutional algorithm based on evidence available at the time of presentation. MEASUREMENTS AND MAIN RESULTS/RESULTS:Of 407 children tested for severe acute respiratory syndrome-coronavirus 2 at our hospital, 24 were positive, and 19 required hospitalization. Seven (36.8%) were critically ill in ICU, and four (21%) required mechanical ventilation. Hospitalized children were predominantly male (14, 74%) and African-American or Hispanic (14, 74%), with a bimodal distribution of ages among young children less than or equal to 2 years old (8, 42%) and older adolescents ages 15-18 (6, 32%). Five of seven (71.4%) of critically ill patients were African-American (n = 3) or Hispanic (n = 2). Critical illness was associated with older age (p = 0.017), longer duration of symptoms (p = 0.036), and lower oxygen saturation on presentation (p = 0.016); with more thrombocytopenia (p = 0.015); higher C-reactive protein (p = 0.031); and lower WBC count (p = 0.039). Duration of mechanical ventilation averaged 14.1 days. One patient died. CONCLUSIONS:Severe, protracted coronavirus disease 2019 is seen in pediatric patients, including those without significant comorbidities. We observed a greater proportion of hospitalized children requiring mechanical ventilation than has been reported to date. Older children, African-American or Hispanic children, and males may be at risk for severe coronavirus disease 2019 requiring hospitalization. Hypoxia, thrombocytopenia, and elevated C-reactive protein may be useful markers of critical illness. Data regarding optimal management and therapies for pediatric coronavirus disease 2019 are urgently needed.

OBJECTIVES/OBJECTIVE:CD163 is a hemoglobin scavenger receptor on monocytes and macrophages, cleaved to soluble CD163 (sCD163) in the plasma following activation. In HIV+ adults, sCD163 is linked to non-AIDS morbidity and predicts mortality, but there is limited data in children. We investigated sCD163 levels in HIV+ children and their correlations with disease progression, immune activation and gut mucosal damage. DESIGN AND METHODS/METHODS:We quantified sCD163 levels in Kenyan children aged 0-20 years with perinatal HIV infection, including 74 ART-naive (ART-) and 64 virally suppressed on ART (ART+), and 79 HIV unexposed-uninfected controls (HIV-). The cohort was divided into age groups 0-5 (younger) and 5-20 (older) years. Correlations between sCD163 and HIV viral load, %CD8, CD4:CD8 ratio, markers of T cell activation and proliferation, and gut mucosal damage were also assessed. RESULTS:ART- children have higher sCD163 levels compared to HIV- and ART+ children (p ≤ 0.01); ART+ have equivalent sCD163 levels to HIV- children. In a prospective analysis, sCD163 levels decreased in older ART- children after 12 months of treatment (p < 0.0001). Regardless of age, sCD163 levels correlate with clinical disease progression measured by %CD4 T cells, CD4:CD8 T cell ratios and HIV viral load. Soluble CD163 levels directly correlate with T cell activation markers CD38, HLA-DR, and Ki67 (p ≤ 0.01). CONCLUSIONS:High plasma sCD163 levels in HIV+ children correlate with advancing disease and T cell activation. ART initiation normalizes sCD163 levels and may alleviate HIV-related morbidities and improve long-term pediatric outcomes.

During the COVID-19 pandemic, children have had markedly different clinical presentations and outcomes compared to adults. In the acute phase of infection, younger children are relatively spared the severe consequences reported in adults. Yet, they are uniquely susceptible to the newly described Multisystem Inflammatory Syndrome in Children (MIS-C). This may result from the developmental "immunodeficiency" resulting from a Th2 polarization that starts in utero and is maintained for most of the first decade of life. MIS-C may be due to IgA complexes in a Th2 environment or a Th1-like response to COVID-19 antigens that developed slowly. Alternatively, MIS-C may occur in vulnerable hosts with genetic susceptibilities in other immune and non-immune pathways. Herein, we present a brief overview of the host immune response, virologic and genetic factors, and comparable inflammatory syndromes that may explain the pathophysiology leading to drastic differences in clinical presentation and outcomes of COVID-19 between children and adults.

Invasive community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections disproportionately affect children, but there are few pediatric reports of pericarditis and mediastinitis caused by CA-MRSA in previously healthy children. Here we report a severe case of CA-MRSA pericarditis with extension to the mediastinum and carotid sheath in a previously healthy 8-month-old infant who was successfully treated with surgical interventions and with a combination of daptomycin and vancomycin. The relatively indolent clinical course in this patient was notable given the significant extent of infection. This case highlights the potential virulence of CA-MRSA in previously healthy children and the importance of early diagnosis, prompt drainage, and appropriate antibiotic coverage.

Background: CD163 is a hemoglobin scavenger receptor on monocytes and macrophages, cleaved to soluble CD163 (sCD163) in the plasma following activation. In HIV+ adults, sCD163 is linked to non-AIDS morbidity and predicts mortality, but there is limited data in children. We investigated sCD163 levels in HIV+ children and their correlations with intestinal damage, immune activation and disease progression. Methods: In a Kenyan cohort aged 5-20 years of 77 perinatally-infected HIV+ children, with 44 ART-naive (ART-) and 33 virally suppressed on ART (ART+), and 45 HIV unexposeduninfected (HIV-) controls, we measured sCD163 and intestinal fatty acid binding protein (I-FABP) plasma levels by ELISA (R&D Systems). T cell activation and proliferation cytokine IL-2 were analyzed by flow cytometry on PBMCs with markers CD4, CD8, CD45RO, CD38, HLA-DR, and IL-2. Statistical analysis was performed on GraphPad Prism with Kruskall-Wallis, Spearman's correlation, and Wilcoxon tests. Results: ART- children have high sCD163 levels compared to HIV- (p=0.004) and ART+ (p=0.01) children, that decrease after 12 months of ART (p=0.02) to levels similar to HIV- controls. ART+ and HIV- children have equivalent sCD163 levels. In HIV+ children, sCD163 levels correlate with HIV disease progression indicated by %CD4 T cells, (p=0.0002, r=-0.41), HIV viral load (p<.0001, r=0.65), and CD4:CD8 T cell ratios (p=0.001, r=-0.36). sCD163 also associates with I-FABP, a marker of gut mucosal disruption (p=0.005, r=0.32). sCD163 correlates with CD4 and CD8 T-cell activation measured by CD38 and HLA-DR coexpression (CD4: p<0.0001, r=0.50; CD8: p=0.001, r=0.36) in HIV+ but not in HIV- children. Finally, there is an indirect correlation between sCD163 and IL-2+ memory CD4 T cells (p=0.0003, r=-0.42). Conclusion: Untreated HIV+ children have elevated sCD163 levels that normalize with ART. Elevated sCD163 levels correlate with advancing HIV disease, marked by increasing viral load and decreasing %CD4 and CD4:CD8 ratios. Compromised gut barriers and microbial translocation may trigger sCD163 release, as sCD163 directly associates with I-FABP. In HIV+ children, sCD163 strongly correlates with T cell activation, linking inflammation in the innate and adaptive immune systems. Last, the inverse correlation between sCD163 and IL-2 suggests a potential inhibitory role for sCD163 on T cell proliferation. Overall, high sCD163 levels in HIV+ children reflect gut mucosal disruption, global inflammation and disease progression

Background/UNASSIGNED:T follicular helper (Tfh) cells are crucial for B cell differentiation and antigen-specific antibody production. Dysregulation of Tfh-mediated B cell help weakens B cell responses in HIV infection. Moreover, Tfh cells in the lymph node and peripheral blood comprise a significant portion of the latent HIV reservoir. There is limited data on the effects of perinatal HIV infection on Tfh cells in children. We examined peripheral Tfh (pTfh) cell frequencies and phenotype in HIV-infected children and their associations with disease progression, immune activation, and B cell differentiation. Methods/UNASSIGNED:In a Kenyan cohort of 76 perinatally HIV-infected children, comprised of 43 treatment-naïve (ART-) and 33 on antiretroviral therapy (ART+), and 42 healthy controls (HIV-), we identified memory pTfh cells, T cell activation markers, and B cell differentiation states using multi-parameter flow cytometry. Soluble CD163 and intestinal fatty acid-binding protein plasma levels were quantified by ELISA. Results/UNASSIGNED:ART- children had reduced levels of pTfh cells compared with HIV- children that increased with antiretroviral therapy. HIV+ children had higher programmed cell death protein 1 (PD-1) expression on pTfh cells, regardless of treatment status. Low memory pTfh cells with elevated PD-1 levels correlated with advancing HIV disease status, indicated by increasing HIV viral loads and T cell and monocyte activation, and decreasing %CD4 and CD4:CD8 ratios. Antiretroviral treatment, particularly when started at younger ages, restored pTfh cell frequency and eliminated correlations with disease progression, but failed to lower PD-1 levels on pTfh cells and their associations with CD4 T cell percentages and activation. Altered B cell subsets, with decreased naïve and resting memory B cells and increased activated and tissue-like memory B cells in HIV+ children, correlated with low memory pTfh cell frequencies. Last, HIV+ children had decreased proportions of CXCR5+ CD8 T cells that associated with low %CD4 and CD4:CD8 ratios. Conclusion/UNASSIGNED:Low memory pTfh cell frequencies with high PD-1 expression in HIV+ children correlate with worsening disease status and an activated and differentiated B cell profile. This perturbed memory pTfh cell population may contribute to weak vaccine and HIV-specific antibody responses in HIV+ children. Restoring Tfh cell capacity may be important for novel pediatric HIV cure and vaccine strategies.

Background: During human immunodeficiency virus (HIV) disease, chronic immune activation leads to T-cell exhaustion. PD-1 identifies "exhausted" CD8 T cells with impaired HIV-specific effector functions, but its role on CD4 T cells and in HIV-infected children is poorly understood. Methods: In a Kenyan cohort of vertically HIV-infected children, we measured PD-1+ CD4 T-cell frequencies and phenotype by flow cytometry and their correlation with HIV disease progression and immune activation. Second, in vitro CD4 T-cell proliferative and cytokine responses to HIV-specific and -nonspecific stimuli were assessed with and without PD-1 blockade. Results: HIV-infected children have increased frequencies of PD-1+ memory CD4 T cells that fail to normalize with antiretroviral treatment. These cells are comprised of central and effector memory subsets and correlate with HIV disease progression, measured by viral load, CD4 percentage, CD4:CD8 T-cell ratio, and immune activation. Last, PD-1+ CD4 T cells predict impaired proliferative potential yet preferentially secrete the Th1 and Th17 cytokines interferon-gamma and interleukin 17A, and are unresponsive to in vitro PD-1 blockade. Conclusions: This study highlights differences in PD-1+ CD4 T-cell memory phenotype and response to blockade between HIV-infected children and adults, with implications for potential immune checkpoint therapies.