Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Aquagenic wrinkling of the palms (AWP) is a cutaneous phenomenon marked by the transient formation of edematous, translucent papules and plaques on the palms and fingertips within minutes of water exposure. AWP is anecdotally reported in patients with cystic fibrosis (CF) and several studies have recently confirmed this association. The primary aim of this study was to determine the prevalence of aquagenic wrinkling of the palms in subjects with cystic fibrosis (CF) compared to controls, and secondarily to evaluate for genotype-phenotype correlations among CF subjects found to have AWP. Fifty-one children with CF and 25 control children who were being treated for asthma underwent a 5-minute hand immersion in lukewarm water. The test for AWP was positive if subjects demonstrated >30% wrinkling over the palm. Secondary analyses explored associations with genotype, pancreatic and pulmonary function, body mass index (BMI), and sweat chloride levels. Palmar transepidermal water loss (TEWL) was also measured for all subjects with and without AWP. Forty-three of the subjects (84%) with CF demonstrated aquagenic wrinkling, in contrast to none (0%) of the controls. These results remained statistically significant when stratified for by age and race. TEWL was significantly higher in CF subjects with AWP compared to CF subjects without AWP and controls. No genotype-phenotype correlations were detected in patients with AWP, nor were there associations of AWP with other phenotypic features of CF, although these analyses were likely underpowered. Aquagenic wrinkling of the palms is prevalent in children with CF and is associated with increased TEWL.

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Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1 , OAS2 , or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Monocytic cell lines and primary myeloid cells with OAS1 , OAS2 , or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV-2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1- but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Object The authors conducted a phase I study of late infantile neuronal ceroid lipofuscinosis using an adenoassociated virus serotype 2 (AAV2) vector containing the deficient CLN2 gene (AAV2CUhCLN2). The operative technique, radiographic changes, and surgical complications are presented. Methods Ten patients with late infantile neuronal ceroid lipofuscinosis disease each underwent infusion of AAV2CUhCLN2 (3 × 1012 particle units) into 12 distinct cerebral locations (2 depths/bur hole, 75 minutes/infusion, and 2 μl/minute). Innovative surgical techniques were developed to overcome several obstacles for which little or no established techniques were available. Successful infusion relied on preoperative stereotactic planning to optimize a parenchymal target and diffuse administration. Six entry sites, each having 2 depths of injections, were used to reduce operative time and enhance distribution. A low-profile rigid fixation system with 6 integrated holding arms was utilized to perform simultaneous infusions within a practical time frame. Dural sealant with generous irrigation was used to avoid CSF egress with possible subdural hemorrhage or altered stereotactic registration. Results Radiographically demonstrated changes were seen in 39 (65%) of 60 injection sites, confirming localization and infusion. There were no radiographically or clinically defined complications. Conclusions The neurosurgical considerations and results of this study are presented to offer guidance and a basis for the design of future gene therapy or other clinical trials in children that utilize direct therapeutic delivery.