Incidence of new-onset in-hospital and persistent diabetes in COVID-19 patients: comparison with influenza.

BACKGROUND: This study investigated the incidences and risk factors associated with new-onset persistent type-2 diabetes during COVID-19 hospitalization and at 3-months follow-up compared to influenza. METHODS: This retrospective study consisted of 8216 hospitalized, 2998 non-hospitalized COVID-19 patients, and 2988 hospitalized influenza patients without history of pre-diabetes or diabetes in the Montefiore Health System in Bronx, New York. The primary outcomes were incidences of new-onset in-hospital type-2 diabetes mellitus (I-DM) and persistent diabetes mellitus (P-DM) at 3 months (average) follow-up. Predictive models used 80%/20% of data for training/testing with five-fold cross-validation. FINDINGS: I-DM was diagnosed in 22.6% of patients with COVID-19 compared to only 3.3% of patients with influenza (95% CI of difference [0.18, 0.20]). COVID-19 patients with I-DM compared to those without I-DM were older, more likely male, more likely to be treated with steroids and had more comorbidities. P-DM was diagnosed in 16.7% of hospitalized COVID-19 patients versus 12% of hospitalized influenza patients (95% CI of difference [0.03,0.065]) but only 7.3% of non-hospitalized COVID-19 patients (95% CI of difference [0.078,0.11]). The rates of P-DM significantly decreased from 23.9% to 4.0% over the studied period. Logistic regression identified similar risk factors predictive of P-DM for COVID-19 and influenza. The adjusted odds ratio (0.90 [95% CI 0.64,1.28]) for developing P-DM was not significantly different between the two viruses. INTERPRETATION: The incidence of new-onset type-2 diabetes was higher in patients with COVID-19 than influenza. Increased risk of diabetes associated with COVID-19 is mediated through disease severity, which plays a dominant role in the development of this post-acute infection sequela. FUNDING: None.

COVID-19 and children.

There has been substantial research on adult COVID-19 and how to treat it. But how do severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections afflict children? The COVID-19 pandemic has yielded many surprises, not least that children generally develop less severe disease than older adults, which is unusual for a respiratory disease. However, some children can develop serious complications from COVID-19, such as multisystem inflammatory syndrome in children (MIS-C) and Long Covid, even after mild or asymptomatic COVID-19. Why this occurs in some and not others is an important question. Moreover, when children do contract COVID-19, understanding their role in transmission, especially in schools and at home, is crucial to ensuring effective mitigation measures. Therefore, in addition to nonpharmaceutical interventions, such as improved ventilation, there is a strong case to vaccinate children so as to reduce possible long-term effects from infection and to decrease transmission. But questions remain about whether vaccination might skew immune responses to variants in the long term. As the experts discuss below, more is being learned about these important issues, but much more research is needed to understand the long-term effects of COVID-19 in children.

Bell’s palsy and lip HSV-1 infection: importance of subcutaneous access

Although HSV-1 has been implicated in facial palsy for a long time, testing and treating for HSV is not routine. The lack of a meaningful demonstration of how HSV-1 would cause facial palsy has limited progress in this field. Herein we demonstrate that the depth of the lip HSV-1 infection defines the course of the disease, with deeper subcutaneous infection allowing virus access to the facial nerve and causing facial palsy. HSV-1 inoculated subcutaneously caused extensive facial paralysis in cotton rats Sigmodon hispidus, while virus inoculated in the same area of the lip by skin surface abrasion did not. Demyelination along the facial nerve (CN VII) accompanied subcutaneous HSV-1 infection and was identified as the possible underlying mechanism of the disease. This causality demonstration is particularly important in light of increased facial palsy outbreaks associated with SARS-CoV-2 infection and SARS-CoV-2 and influenza vaccinations.

Cell-impermeable staurosporine analog targets extracellular kinases to inhibit HSV and SARS-CoV-2.

Herpes simplex virus (HSV) receptor engagement activates phospholipid scramblase triggering Akt translocation to the outer leaflet of the plasma membrane where its subsequent phosphorylation promotes viral entry. We hypothesize that this previously unrecognized outside-inside signaling pathway is employed by other viruses and that cell-impermeable kinase inhibitors could provide novel antivirals. We synthesized a cell-impermeable analog of staurosporine, CIMSS, which inhibited outer membrane HSV-induced Akt phosphorylation and blocked viral entry without inducing apoptosis. CIMSS also blocked the phosphorylation of 3-phosphoinositide dependent protein kinase 1 and phospholipase C gamma, which were both detected at the outer leaflet following HSV exposure. Moreover, vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein (VSV-S), but not native VSV or VSV pseudotyped with Ebola virus glycoprotein, triggered this scramblase-Akt outer membrane signaling pathway. VSV-S and native SARS-CoV-2 infection were inhibited by CIMSS. Thus, CIMSS uncovered unique extracellular kinase processes linked to HSV and SARS-CoV-2 entry.

Antibody function, antigenic target and glycans determine the transfer of herpes simplex virus (HSV) antibodies (Abs) from mothers to newborns and transfer is altered by SARS-CoV-2

OBJECTIVES/GOALS: Murine and clinical data suggest that antibody-dependent cellular cytotoxicity (ADCC) is associated with greater protection against disseminated neonatal HSV disease. To quantify the relative transfer of Abs with different functions and targets, we conducted a prospective study of mother-infant term and preterm dyads pre and during COVID-19 METHODS/STUDY POPULATION: Total and HSV lysate, glycoprotein D (gD) and glycoprotein B (gB)-specific IgG, IgG1 and IgG3 as well as HSV neutralizing Abs (nAbs) and ADCC were quantified in paired 3rd-trimester pregnant women and their newborns (cord) blood. Transfer ratios (TR) were defined as cord:maternal Ab levels. IgG1 and IgG3 subclass and gD or gB-specific Abs were isolated by column purification and glycan profiles were assessed by mass spectrometry. The study population included 21 term and 15 preterm dyads who were HSV-1 (+/- HSV-2) seropositive enrolled between 2018-2019 (pre-COVID) and 25 additional HSV-1 (+/- HSV-2) seropositive term dyads whose mothers were SARS-CoV-2 PCR and COVID Ab+ at delivery;14 were asymptomatic and 11 had mild-moderate COVID disease. None of the mothers had active genital HSV lesions during delivery RESULTS/ANTICIPATED RESULTS: Anti-HSV IgG, IgG1 and IgG3 TR were higher in term vs. preterm dyads (p<0.05). The nAb TR was 2.4 in term vs. 0.8 in preterm (p<0.001) but the ADCC TR was < 1.0 for both. To determine if the latter reflected antigenic target, subclass or glycans, we enriched for gD and gB specific and IgG1 and IgG3 Abs. The gD Abs were IgG1 and had only neutralizing activity. In contrast, gB Abs were polyfunctional and included IgG1 and IgG3 but only the IgG1 Abs had ADCC activity. The gD Abs were enriched for glycans associated with an affinity for the neonatal Fc receptor (FcRn);gB Abs expressed glycans associated with both FcRn and FcγRIIIa binding. There was no significant difference in total HSV-specific IgG TR in pre-COVID vs post-COVID dyads but the nAb TR was lower (p=0.018) and ADCC TR higher (p<0.001) in the COVID compared to pre-COVID cohort DISCUSSION/SIGNIFICANCE: HSV ADCC Abs, which may provide greater protection than nAbs against neonatal disease, transfer poorly particularly to preterm newborns. However, in the setting of SARS-CoV-2, the TR of HSV ADCC is significantly higher. This may reflect alterations in the placental architecture and/or glycan composition which is currently being investigated.

Natural mucosal barriers and COVID-19 in children.

BACKGROUNDCoronavirus disease 2019 (COVID-19) is more benign in children compared with adults for unknown reasons. This contrasts with other respiratory viruses where disease manifestations are often more severe in children. We hypothesize that a more robust early innate immune response to SARS coronavirus 2 (SARS-CoV-2) protects against severe disease.METHODSClinical outcomes, SARS-CoV-2 viral copies, and cellular gene expression were compared in nasopharyngeal swabs obtained at the time of presentation to the emergency department from 12 children and 27 adults using bulk RNA sequencing and quantitative reverse-transcription PCR. Total protein, cytokines, and anti-SARS-CoV-2 IgG and IgA were quantified in nasal fluid.RESULTSSARS-CoV-2 copies, angiotensin-converting enzyme 2, and TMPRSS2 gene expression were similar in children and adults, but children displayed higher expression of genes associated with IFN signaling, NLRP3 inflammasome, and other innate pathways. Higher levels of IFN-α2, IFN-γ, IP-10, IL-8, and IL-1ß protein were detected in nasal fluid in children versus adults. Children also expressed higher levels of genes associated with immune cells, whereas expression of those associated with epithelial cells did not differ in children versus adults. Anti-SARS-CoV-2 IgA and IgG were detected at similar levels in nasal fluid from both groups. None of the children required supplemental oxygen, whereas 7 adults did (P = 0.03); 4 adults died.CONCLUSIONThese findings provide direct evidence of a more vigorous early mucosal immune response in children compared with adults and suggest that this contributes to favorable clinical outcomes.FUNDINGNIH grants R01 AI134367, UL1 TR002556, T32 AI007501, T32GM007288, P30 AI124414; an Albert Einstein College of Medicine Dean's COVID-19 Pilot Research Award; and the Eric J. Heyer, MD, PhD Translational Research Pilot Project Award.

Severe Acute Respiratory Syndrome Coronavirus 2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth.

OBJECTIVE: To characterize the demographic and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes and identify admission variables predictive of disease severity. STUDY DESIGN: We conducted a multicenter, retrospective, and prospective study of pediatric patients hospitalized with acute SARS-CoV-2 infections and multisystem inflammatory syndrome in children (MIS-C) at 8 sites in New York, New Jersey, and Connecticut. RESULTS: We identified 281 hospitalized patients with SARS-CoV-2 infections and divided them into 3 groups based on clinical features. Overall, 143 (51%) had respiratory disease, 69 (25%) had MIS-C, and 69 (25%) had other manifestations including gastrointestinal illness or fever. Patients with MIS-C were more likely to identify as non-Hispanic black compared with patients with respiratory disease (35% vs 18%, P = .02). Seven patients (2%) died and 114 (41%) were admitted to the intensive care unit. In multivariable analyses, obesity (OR 3.39, 95% CI 1.26-9.10, P = .02) and hypoxia on admission (OR 4.01; 95% CI 1.14-14.15; P = .03) were predictive of severe respiratory disease. Lower absolute lymphocyte count (OR 8.33 per unit decrease in 109 cells/L, 95% CI 2.32-33.33, P = .001) and greater C-reactive protein (OR 1.06 per unit increase in mg/dL, 95% CI 1.01-1.12, P = .017) were predictive of severe MIS-C. Race/ethnicity or socioeconomic status were not predictive of disease severity. CONCLUSIONS: We identified variables at the time of hospitalization that may help predict the development of severe SARS-CoV-2 disease manifestations in children and youth. These variables may have implications for future prognostic tools that inform hospital admission and clinical management.