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.

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 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.

Background Prevention of nosocomial coronavirus disease 2019 (COVID-19) infection for patients undergoing flap-based reconstructive surgery is crucial to providing care and maintaining operative volume and income to support plastic surgery programs. We conducted this study to (1) determine the postoperative incidence of COVID-19 among patients undergoing flap reconstruction from December 1, 2019 to November 1, 2020 and (2) compare 30-day outcomes between patients who underwent surgery before and during the early pandemic. Methods We conducted an 11-month retrospective cohort study of all patients who underwent flap reconstruction across our institution. We abstracted patient demographics, intraoperative management, COVID-19 testing history, and 30-day postoperative complications from electronic health records. Nosocomial COVID-19 infection was defined as reverse transcription polymerase chain reaction (RT-PCR) viral ribonucleic acid detection within 30 days of patients' postoperative course or during initial surgical admission. We used chi-squared tests to compare postoperative outcomes between patients who underwent surgery before (prior to March 12, 2021, when our institution admitted its first COVID-19 patient) versus during (on/after March 12, 2021) the pandemic. Results Among the 220 patients (mean [standard deviation] age = 53.8 [18.1] years; female = 54.8%) who underwent flap reconstruction, none had nosocomial COVID-19 infection. Five (2%) patients eventually tested COVID-19 positive (median time from surgery to diagnosis: 9 months, range: 1.5–11 months) with one developing partial flap loss while infected. Between patients who underwent free flap surgery before and during the pandemic, there were no significant differences in 30-day takebacks (15.6% vs. 16.6%, respectively; p > 0.999), readmissions (9.4% vs. 12.6%, respectively; p = 0.53), and surgical complications (e.g., total flap loss 1.6% vs. 2.1%, p = 0.81). Conclusion Robust precautions can ensure the safety of patients undergoing flap surgeries across an academic medical institution, even during periods of high COVID-19 admission rates. Further studies are needed to generate evidence-based guidelines that optimize infection control and flap survival for patients undergoing reconstruction.

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 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.