High soluble CD163 levels correlate with disease progression and inflammation in Kenyan children with perinatal HIV-infection

Objectives: 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: We quantified sCD163 levels in Kenyan children aged 0–20 years with perinatal HIV infection, including 74 antiretroviral treatment (ART)-naïve (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 with 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. sCD163 levels directly correlate with T-cell activation markers CD38, human leukocyte antigen-DR isotype, and Ki67 (P ≤ 0.01). Conclusion: 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

COVID-19 in Children: A Review and Parallels to Other Hyperinflammatory Syndromes

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

Clinical Features of Critical Coronavirus Disease 2019 in Children

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Objectives: 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: Observational cohort study. Setting: Riley Hospital for Children at Indiana University Health in Indianapolis in the early weeks of the coronavirus disease 2019 pandemic. Patients: All hospitalized pediatric patients with confirmed coronavirus disease 2019 as of May 4, 2020, were included. Interventions: 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: 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.This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (grant numbers K23 HD095778, T32 HD069047); and by the National Institute of Allergy and Infectious at the National Institutes of Health Diseases (grant number T32 AI07637). Drs. Bhumbra, Malin, Khaitan, John, Rowan, and Enane disclosed off-label use of remdesivir, convalescent plasma, hydroxychloroquine, and tocilizumab. Drs. Kirkpatrick and Enane are supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (grant numbers K23 HD095778, T32 HD069047). Dr. Bhumbra is supported by the National Institute of Allergy and Infectious at the National Institutes of Health Diseases (grant number T32 AI07637)

COVID-19 and hereditary spherocytosis: A recipe for hemolysis

We describe a patient infected with COVID-19 in the setting of a known chronic illness, HS, and the resulting presentation and medical complications

Low Peripheral T Follicular Helper Cells in Perinatally HIV-Infected Children Correlate With Advancing HIV Disease.

Background: 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: 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: 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: 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

Low Peripheral T Follicular Helper Cells in Perinatally HIV-Infected Children Correlate With Advancing HIV Disease

BackgroundT 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.MethodsIn 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.ResultsART− 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.ConclusionLow 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

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children.

Regulatory T cells (Tregs) are functionally suppressive CD4 T cells, critical for establishing peripheral tolerance and controlling inflammatory responses. Previous reports of Tregs during chronic HIV disease have conflicting results with higher or lower levels compared with controls. Identifying true Tregs with suppressive activity proves challenging during HIV infection, as traditional Treg markers, CD25 and FOXP3, may transiently upregulate expression as a result of immune activation (IA). Helios is an Ikaros family transcription factor that marks natural Tregs with suppressive activity and does not upregulate expression after activation. Coexpression of FOXP3 and Helios has been suggested as a highly specific marker of bona fide Tregs. We evaluated Treg subsets by FOXP3 coexpressed with either CD25 or Helios and their association with HIV disease progression in perinatally infected HIV-positive children. Identifying Tregs by FOXP3 coexpression with Helios rather than CD25 revealed markedly higher Treg frequencies, particularly in HIV+ children. Regardless of antiretroviral therapy, HIV-infected children had a selective expansion of memory FOXP3+Helios+ Tregs. The rise in memory Tregs correlated with declining HIV clinical status, indicated by falling CD4 percentages and CD4:CD8 ratios and increasing HIV plasma viremia and IA. In addition, untreated HIV+ children exhibited an imbalance between the levels of Tregs and activated T cells. Finally, memory Tregs expressed IA markers CD38 and Ki67 and exhaustion marker, PD-1, that tightly correlated with a similar phenotype in memory CD4 T cells. Overall, HIV-infected children had significant disruptions of memory Tregs that associated with advancing HIV disease. J Acquir Immune Defic Syndr 2016 Aug 15; 72(5):474-84

Immune activation despite preserved CD4 T cells in perinatally HIV-infected children and adolescents

<div><p>Background</p><p>HIV disease progresses more rapidly in children than adults with mortality rates exceeding 50% by 2 years of age without antiretroviral therapy (ART) in sub-Saharan Africa. Recent World Health Organization (WHO) guidelines recommend universal treatment for all living persons with HIV, yet there is limited supporting evidence in pediatric populations. The objective of this study was to determine whether CD4 cell counts reflect immunological markers associated with disease progression in ART naïve perinatally-infected HIV+ children and adolescents and their response to ART.</p><p>Methods</p><p>PBMC and plasma samples were collected from 71 HIV negative and 132 HIV+ children (65 ART naïve and 67 on ART) between ages 1–19 years from Mombasa, Kenya. Untreated HIV+ subjects were sub-categorized by high or low CD4 T cell counts. Immune activation markers CD38, HLA-DR and Ki67 were analyzed by flow cytometry. Plasma soluble CD14 (sCD14) was quantified by ELISA.</p><p>Results</p><p>HIV-infected children and adolescents with preserved CD4 cell counts had depleted CD4 percentages and CD4:CD8 ratios, and high immune activation levels. ART initiation rapidly and persistently reversed T cell activation, but failed to normalize CD4:CD8 ratios and plasma sCD14 levels.</p><p>Conclusions</p><p>Diminished CD4 percentages and CD4:CD8 ratios along with profound immune activation occur independent of CD4 cell count thresholds in ART naïve HIV+ children and adolescents. Immediate ART initiation, as recommended in the most recent WHO guidelines may protect them from pathologic sequelae associated with persistent inflammation.</p></div