Background Genetic deficiencies of immune system, referred to as inborn errors of immunity (IEI), serve as a valuable model to study human immune responses. In a multicenter prospective cohort, we evaluated the outcome of SARS‐CoV‐2 infection among IEI subjects and analyzed genetic and immune characteristics that determine adverse COVID‐19 outcomes. Methods We studied 34 IEI patients (19M/15F, 12 [min: 0.6‐max: 43] years) from six centers. We diagnosed COVID‐19 infection by finding a positive SARS‐CoV‐2 PCR test ( n = 25) and/or a lung tomography scoring (CORADS) ≥4 ( n = 9). We recorded clinical and laboratory findings prospectively, fitted survival curves, and calculated fatality rates for the entire group and each IEI subclass. Results Nineteen patients had combined immune deficiency (CID), six with predominantly antibody deficiency (PAD), six immune dysregulation (ID), two innate immune defects, and one in the autoinflammatory class. Overall, 23.5% of cases died, with disproportionate fatality rates among different IEI categories. PAD group had a relatively favorable outcome at any age, but CIDs and IDs were particularly vulnerable. At admission, presence of dyspnea was an independent risk for COVID‐related death (OR: 2.630, 95% CI; 1.198–5.776, p < .001). Concerning predictive roles of laboratory markers at admission, deceased subjects compared to survived had significantly higher CRP, procalcitonin, Troponin‐T, ferritin, and total‐lung‐score ( p = .020, p = .003, p = .014, p = .013, p = .020; respectively), and lower absolute lymphocyte count, albumin, and trough IgG ( p = .012, p = .022, p = .011; respectively). Conclusion Our data disclose a highly vulnerable IEI subgroup particularly disadvantaged for COVID‐19 despite their youth. Future studies should address this vulnerability and consider giving priority to these subjects in SARS‐Cov‐2 therapy trials.

The exact rate of prevalence of pediatric angioedema is not well known, and any reported rate will change with the presence of urticaria, or due to a specific cause of angioedema. The lifetime prevalence of non-hereditary angioedema was shown to be 4.9%-7.4% in two large nationwide studies. 1,2 However, information about the prevalence of recurrent histaminergic angioedema (HA) and its clinical presentation in children is limited. Considering only patients with hereditary angioedema (HAE), it has been reported that approximately 1 in 50 000 individuals is affected, with a range of 1:10 000-1:150 000 worldwide. 3 Hereditary angioedema is a rare genetic disease characterized by recurrent episodes of submucosal or subcutaneous swelling. The clinical manifestations are highly variable, from asymptomatic cases to life-threatening attacks. The more common forms, HAE type I (85% of patients) and type 2 are caused by autosomal dominant mutations in the gene encoding the C1 inhibitor (C1-INH), leading

The molecular programs involved in regulatory T (T reg ) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in T reg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4–NF-κB p65–Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in T reg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased T reg cell p65 expression and nuclear translocation, impaired NF-κB p65–Foxp3 complex formation, and defective T reg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3 S418E in Stk3/4-deficient T reg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3–dependent transcription that promotes T reg cell–mediated immune tolerance.

Objective Significant concerns for patients with hereditary angioedema (HAE) include hormonal fluctuations and drug safety during pregnancy. The impact of the disease on childbearing in multiparous women remains to be elucidated. We aimed to investigate the clinical course and impacts of multiparity on HAE patients. Study design This observational study included 15 multiparous women with HAE; a total of 88 pregnancies were assessed using a questionnaire and the patient's medical records. Results The median age was 36 (IQR, 33–39). Of 72 resulted in healthy babies without any congenital abnormalities. In sixteen pregnancies, 12 (13.6%) ended with spontaneous abortion; three resulted in stillbirth and one neonatal death. Two‐thirds of the patients (n = 10) enounced a worsening in the frequency of angioedema attacks during pregnancy. There was no statistically significant difference compared with the nonpregnant period (p = 0.283). One‐fifth of the patients (n = 3) reported alleviation in attacks. While most deliveries were vaginally (n = 57 babies), 19 deliveries in six patients were by cesarean section. None of the patients were aware of the diagnosis of HAE prior to their first pregnancies. After the diagnosis was made, eight patients received 263 vials of plasma‐derived C1‐inhibitor concentrate during a total of 13 pregnancies. No adverse events were reported. Conclusion We conclude that our results on clinical course and outcomes of HAE in multiparous patients are consistent with the literature. A greater focus on multiparous HAE patients could produce exciting findings.

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