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Epstein-Barr Virus (EBV) diseases, including EBV-associated post-transplant lymphoproliferative disorder (PTLD) remain important causes of morbidity and mortality in children undergoing solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Despite progress in the prevention of EBV disease including PTLD (EBV/PTLD) in HCT, key questions in the prevention, and management of these infectious complications remain unanswered. The goal of this manuscript is to highlight key points and recommendations derived from the consensus guidelines published by the International Pediatric Transplant Association and the European Conference on Infections in Leukemia for children undergoing SOT and HCT, respectively. Additionally, we provide background and guidance on the use of EBV viral load measurement in the prevention and management of these children. [ABSTRACT FROM AUTHOR]

Background Recently, cases of multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) have been reported worldwide. Negative polymerase chain reaction (RT-PCR) testing associated with positive serology in most of the cases suggests a postinfectious syndrome. Because the pathophysiology of this syndrome is still poorly understood, extensive virological and immunological investigations are needed. Methods We report a series of 4 pediatric patients admitted to Geneva University Hospitals with persistent fever and laboratory evidence of inflammation meeting the published definition of MIS-C related to COVID-19, to whom an extensive virological and immunological workup was performed. Results RT-PCRs on multiple anatomical compartments were negative, whereas anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin A (IgA) and immunoglobulin G (IgG) were strongly positive by enzyme-linked immunosorbent assay and immunofluorescence. Both pseudoneutralization and full virus neutralization assays showed the presence of neutralizing antibodies in all children, confirming a recent infection with SARS-CoV-2. The analyses of cytokine profiles revealed an elevation in all cytokines, as reported in adults with severe COVID-19. Although differing in clinical presentation, some features of MIS-C show phenotypic overlap with hemophagocytic lymphohistiocytosis (HLH). In contrast to patients with primary HLH, our patients showed normal perforin expression and natural killer (NK) cell degranulation. The levels of soluble interleukin (IL)-2 receptor (sIL-2R) correlated with the severity of disease, reflecting recent T-cell activation. Conclusion Our findings suggest that MIS-C related to COVID-19 is caused by a postinfectious inflammatory syndrome associated with an elevation in all cytokines, and markers of recent T-cell activation (sIL-2R) occurring despite a strong and specific humoral response to SARS-CoV-2. Further functional and genetic analyses are essential to better understand the mechanisms of host–pathogen interactions. [ABSTRACT FROM AUTHOR]

In 208 children seeking medical care, the seropositivity rate of anti–SARS-CoV-2 IgG antibodies was 8.7%, suggesting an infection rate similar to that observed in adults but >100-fold the incidence of RT-PCR–confirmed pediatric cases. Compared with the gold-standard combined ELISA + immunofluorescence, the MEDsan IgG rapid diagnostic test performed accurately. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 viral load (VL) can serve as a correlate for infectious virus presence and transmission. Viral shedding kinetics over the first week of illness for symptomatic children (n = 279), adolescents (n = 639), and adults (n = 7109) show VLs compatible with infectious virus presence, with slightly lower VL in children than adults. [ABSTRACT FROM AUTHOR]

Background: Despite annual immunization, solid organ transplant (SOT) patients remain at increased risk for severe influenza infection because of suboptimal vaccine immunogenicity. We aimed to compare the CD4+ and CD8+ T-cell responses of the high-dose (HD) and the standard-dose (SD) trivalent inactivated vaccine.Methods: We collected peripheral blood mononuclear cells pre- and postimmunization from 60 patients enrolled in a randomized trial of HD versus SD vaccine (30 HD; 30 SD) during the 2016-2017 influenza season.Results: The HD vaccine elicited significantly greater monofunctional and polyfunctional CD4+ and CD8+ T-cell responses against influenza A/H1N1, A/H3N2, and B. For example, median vaccine-elicited influenza-specific polyfunctional CD4+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza A/H1N1 (1193 vs 0 per 106 CD4+ T cells; P = .003), A/H3N2 (1154 vs 51; P = .008), and B (1102 vs 0; P = .001). Likewise, vaccine-elicited influenza-specific polyfunctional CD8+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza B (367 vs 0; P = .002).Conclusions: Our study provides novel evidence that HD vaccine elicits greater cellular responses compared with the SD vaccine in SOT recipients, which provides support to preferentially consider use of HD vaccination in the SOT setting. [ABSTRACT FROM AUTHOR]

Influenza is responsible for significant morbidity after transplantation. We evaluated T-helper 1/T-helper 2 (Th2) cytokines and interleukin (IL) 10 levels during influenza infection in the posttransplant setting. Serum samples from 277 transplant recipients were analyzed at influenza diagnosis and 28 days later for interferon gamma (IFN-γ), IL-4, IL-13, and IL-10. IL-13 levels were associated with protection against pneumonia and intensive care unit (ICU) admission, whereas the IFN-γ/IL-13 ratio and IL-10 levels were associated with an increased risk of pneumonia and ICU admission. This association was independent of viral load. A skewing of immune responses toward Th2 in transplant patients appears to confer protection from severe influenza infection, independent of viral load. [ABSTRACT FROM AUTHOR]

The factors that contribute to transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by children are unclear. We analyzed viral load at the time of diagnosis in 53 children and 352 adults with coronavirus disease 2019 (COVID-19) in the first 5 days post symptom onset. No significant differences in SARS-CoV-2 RNA loads were seen between children and adults. [ABSTRACT FROM AUTHOR]

Background: An influenza A(H1N1)pdm09 infection was diagnosed in a hematopoietic stem cell transplant recipient during conditioning regimen. He was treated with oral oseltamivir, later combined with intravenous zanamivir. The H275Y neuraminidase (NA) mutation was first detected, and an E119D NA mutation was identified during zanamivir therapy.Methods: Recombinant wild-type (WT) E119D and E119D/H275Y A(H1N1)pdm09 NA variants were generated by reverse genetics. Susceptibility to NA inhibitors (NAIs) was evaluated with a fluorometric assay using the 2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid (MUNANA) substrate. Susceptibility to favipiravir (T-705) was assessed using plaque reduction assays. The NA affinity and velocity values were determined with NA enzymatic studies.Results: We identified an influenza A(H1N1)pdm09 E119D mutant that exhibited a marked increase in the 50% inhibitory concentrations against all tested NAIs (827-, 25-, 286-, and 702-fold for zanamivir, oseltamivir, peramivir, and laninamivir, respectively). The double E119D/H275Y mutation further increased oseltamivir and peramivir 50% inhibitory concentrations by 790- and >5000-fold, respectively, compared with the WT. The mutant viruses remained susceptible to favipiravir. The NA affinity and velocity values of the E119D variant decreased by 8.1-fold and 4.5-fold, respectively, compared with the WT.Conclusions: The actual emergence of a single NA mutation conferring pan-NAI resistance in the clinical setting reinforces the pressing need to develop new anti-influenza strategies. [ABSTRACT FROM AUTHOR]