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Histaminergic urticaria-angiodema is a common complaint in children. According to clinical criteria, it is classified as acute and chronic urticaria. A further clinical classification relies on triggering factors. We focus on diagnosis and therapeutic strategies. We report the main progresses in the field and issues that remain to be understood. (www.actabiomedica.it)

Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper-IgE syndromes, Omenn syndrome, Wiskott-Aldrich syndrome, IPEX-linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.

IgE-mediated food allergy (FA) is a potentially life-threatening condition with a negative impact on quality of life and an increasing prevalence in westernized countries in the recent two decades. A strict avoidance of the triggering food(s) represents the current standard approach. However, an elimination diet may be difficult and frustrating, in particular for common foods, (eg, milk, egg, and peanut). Food allergy immunotherapy (FA-AIT) may provide an active treatment that enables to increase the amount of food that the patient can intake without reaction during treatment (ie, desensitization), and reduces the risk of potential life-threatening allergic reaction in the event of accidental ingestion. However, several gaps need still to be filled. A memorable Latin orator stated: "Est modus in rebus" (Horace, Sermones I, 1, 106-07). This sentence remembers that there is a measure in everything to a proper proportion of therapy. The common sense of measure should find application in each stage of treatment. A personalized approaching should consider the specific willing and features of each patient. Efforts are devoted to improve the efficacy, the safety but also the quality of life of patients suffering from FA. In the near future, it will be important to clarify immunologic pathways of FA-AIT, and to identify reliable biomarkers in order to recognize the most suitable candidates to FA-AIT and algorithms for treatments tailored on well-characterized subpopulations of patients.

We described a 5-year-old male with hypodontia, hypohidrosis, and facial dysmorphisms characterized by a depressed nasal bridge, maxillary hypoplasia, and protuberant lips. Chromosomal analysis revealed a normal 46,XY male karyotype. Due to the presence of clinical features of hypohidrotic ectodermal dysplasia (HED), the EDA gene, located at Xq12q13.1, of the patient and his family was sequenced. Analysis of the proband's sequence revealed a missense mutation (T to A transversion) in hemizygosity state at nucleotide position 158 in exon 1 of the EDA gene, which changes codon 53 from leucine to histidine, while heterozygosity at this position was detected in the slightly affected mother; moreover, this mutation was not found in the publically available Human Gene Mutation Database. To date, our findings indicate that a novel mutation in EDA is associated with X-linked HED, adding it to the repertoire of EDA mutations.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that commonly presents during early childhood. In the last decades the prevalence of AD has increased, especially in western societies. This frequently relapsing inflammatory condition has a strong impact on the quality of life of patients and families. The recent advances in the understanding of this disease have paved the way for the development of new strategies for the prevention and treatment of AD. Among the new therapeutic options, there is increasing interest in the potential benefit of probiotic supplementation. It has been widely demonstrated that the human microbiota plays a fundamental role not only in the maintenance of intestinal homeostasis through the interaction between microorganisms and the innate immune system, but also in the microbiota-mediated development of adaptive immunity. In addition, several studies have demonstrated that probiotics are able to influence the composition of gut microbiota and may exert immunomodulatory effects. According to these promising results, the possible application of probiotics in the therapeutic management of allergic diseases has been investigated in many studies. In particular, a considerable body of literature has been published analyzing the effects of probiotics on patients with AD. In order to shed light on frequently conflicting results, we reviewed the data regarding the application of probiotics in AD, with the aim to provide a state-of-the-art assessment of the most important studies exploring the role of probiotics both in the prevention and treatment of AD.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3-kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients’ quality of life and prognosis.

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as “COVID toes”, remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.SummaryNET formation and degradation are dysregulated in pediatric and symptomatic adult patients with various complications of COVID-19, in association with disease severity. NET degradation impairments are multifactorial and associated with natural inhibitors of DNase 1, G-actin and anti-DNase1L3 and anti-NET antibodies. Infection with the Omicron variant is associated with decreased levels of NETs when compared to other SARS-CoV-2 strains.

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.