Purpose: High-accuracy diagnostic screening tests for Mycobacterium tuberculosis (MTB) infection are required, primarily to detect patients with latent infections (LTBIs) in order to avoid their progression to active tuberculosis disease. The performance of the novel IGRA LIOFeron®TB/LTBI was evaluated in children. The originality of this test is the new MTB antigen contained (l-alanine dehydrogenase), identified as a tool to differentiate active TB from LTBI infection. Methods: From March 2022 to November 2023, a population of 90 children was enrolled and grouped into healthy, active TB or LTBI individuals, based on diagnostic guidelines. The blood of all these participants was tested with LIOFeron®TB/LTBI assay in comparison to diagnosis, as gold standard, and to the current used IGRA QuantiFERON®-TB Gold Plus. Results: The two assays demonstrated an excellent concordance of their results with patients’ diagnosis of MTB infection. The performance of LIOFeron®TB/LTBI assay in terms of accuracy of MTB infection diagnosis was high at ROC analysis (AUC = 0.997), and the test showed 100

The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels. Nowadays a geneticmolecular characterization is possible and allows the distinction in various monogenic pathologies, which share some clinical characteristics but also important differences. In addition to long-known STAT3 and DOCK8 gene mutations, in fact, also ZNF341, CARD11, ERBB2IP, IL6R and IL6ST genes mutations can cause the disease. The main clinical manifestations are represented by newborn rash, eczema similar to atopic dermatitis, bacterial and viral skin infections, cold abscesses, respiratory infections with possible pulmonary complications, allergies, gastrointestinal manifestations, malignancies and connective tissue abnormalities. Diagnosis is still a challenge because, especially in the early stages of life, it is difficult to distinguish from other pathologies characterized by eczema and high IgE, such as atopic dermatitis. Several scores and diagnostic pathways have been developed, but it is essential to seek a genetic diagnosis. Treatment is based on prevention and early treatment of infections, meticulous skincare, intravenous immunoglobulins and HSCT, which, in some HIES subtypes, can modify the prognosis. Prognosis is related to the affected gene, but also to early diagnosis, timely treatment of infections and early HSCT.

Sydenham's chorea (SC), an autoimmune disorder affecting the central nervous system, is a pivotal diagnostic criterion for acute rheumatic fever. Primarily prevalent in childhood, especially in developing countries, SC manifests with involuntary movements and neuropsychiatric symptoms. Predominantly occurring between ages 5 and 15, with a female bias, SC may recur, particularly during pregnancy or estrogen use. The autoimmune response affecting the basal ganglia, notably against dopamine, underlies the pathophysiology. Clinical management necessitates an integrated approach, potentially involving immunomodulatory therapies.To address discrepancies in SC management, a survey was conducted across Italy, targeting specialists in neurology, pediatrics, child neuropsychiatry, and rheumatology. Of the 51 responding physicians, consensus favored hospitalization for suspected SC, with broad support for laboratory tests and brain MRI. Treatment preferences showed agreement on oral prednisone and IVIG, while opinions varied on duration and plasmapheresis. Haloperidol emerged as the preferred symptomatic therapy. Post-SC penicillin prophylaxis and steroid therapy gained strong support, although opinions differed on duration. Follow-up recommendations included neuropsychological and cardiological assessments.Despite offering valuable insights, broader and more studies are needed in order to guide treatment decisions in this well-known yet challenging complication of acute rheumatic fever, which continues to warrant scientific attention and concerted clinical efforts.

Chronic infantile neurological cutaneous articular (CINCA) syndrome is an autoinflammatory disease encompassed in the group of cryopyrin-associated periodic syndromes (CAPS). Patients suffering from CINCA have an elevated risk of developing chronic sequelae, including deforming arthropathy, chronic meningitis, neurodevelopmental delay, and neurosensorial hearing loss. The diagnosis of CINCA presents several difficulties, as the clinical phenotype could be difficult to recognize, and almost half of the patients have negative genetic testing. In this paper, we describe the case of a patient presenting with the typical phenotype of neonatal-onset CINCA who resulted negative for NLRP3 mutations. Based on the clinical judgment, the patient underwent treatment with anti-interleukin-1 (IL-1) agents (anakinra and, later, canakinumab) resulting in a complete clinical and laboratory response that allowed confirmation of the diagnosis. Additional genetic investigations performed after the introduction of anti-IL-1 therapy revealed a pathogenic mosaicism in the NLRP3 gene. After a 12-year follow-up, the patient has not experienced chronic complications. Although genetics is rapidly progressing, this case highlights the importance of early diagnosis of CINCA patients when the clinical and laboratory picture is highly suggestive in order to start the appropriate anti-cytokine treatment even in the absence of a genetic confirmation.

Introduction We studied the cellular immune response in a patient infected since 10 months (along with other 51 people) during a trichinellosis outbreak caused by Trichinella spp. Methods A 46 years old female resulted serologically positive for trichinellosis. We isolated peripheral blood mononuclear cells (PBMCs) and incubated them with excretory/secretory antigens (ESA) of Trichinella spiralis (T1) or Trichinella pseudospiralis (T4) to produce antigen specific T cell lines and clones, analysed for the phenotype (T helper or cytotoxic cells), for their T4 or T1 antigens specificity and for their cytokine profile (IFNγ, IL-17A, IL-4) by flow cytometry, thymidine incorporation assay and ELISpot. Results The test performed using ESA from T1 or T4 has identified the species responsible for infection as T. pseudospiralis since the proliferative responses (evaluated by CFSE, Carboxyfluorescein succinimidyl ester, FACS analysis) was higher for T4 (72,8%) than T1 (23.6 %) antigen. The cell lines produced significant levels of IFNγ, IL-4 and IL-17A after stimulation. From the T cell line obtained in response to T1 ESA, as regards CD4 + cells, 12 % Th2, 22.8 % Th1, 6.6 % Th17, 6 % Th0, 2.2 % Th1/Th17 and 0.7 % Th2/Th17, were obtained. From the T1-specific TCL we generated 15 clones. From the TCL specific for T4 ESA, as regards CD4+, 15.2 % Th2, 27.1 % Th1, 3 % Th17, 10.3 %Th0, 1.9 % Th1/Th17 and 1 % Th2/ Th17 were obtained. From such TCL 4 clones were isolated, 1Th2, 1 Th1, 1 Th17, 1 Th1/Th17 and no Th0 nor Th2/Th17. Conclusions By cellular immunology techniques the species responsible of the infection resulted T. pseudospiralis, confirming the results previously obtained by serology. For the first time it was revealed in a human chronic infection the presence of Th17 cells.

The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels. Nowadays a genetic-molecular characterization is possible and allows the distinction in various monogenic pathologies, which share some clinical characteristics but also important differences. In addition to long-known STAT3 and DOCK8 gene mutations, in fact, also ZNF341, CARD11, ERBB2IP, IL6R and IL6ST genes mutations can cause the disease. The main clinical manifestations are represented by newborn rash, eczema similar to atopic dermatitis, bacterial and viral skin infections, cold abscesses, respiratory infections with possible pulmonary complications, allergies, gastrointestinal manifestations, malignancies and connective tissue abnormalities. Diagnosis is still a challenge because, especially in the early stages of life, it is difficult to distinguish from other pathologies characterized by eczema and high IgE, such as atopic dermatitis. Several scores and diagnostic pathways have been developed, but it is essential to seek a genetic diagnosis. Treatment is based on prevention and early treatment of infections, meticulous skincare, intravenous immunoglobulins and HSCT, which, in some HIES subtypes, can modify the prognosis. Prognosis is related to the affected gene, but also to early diagnosis, timely treatment of infections and early HSCT.

Abstract Objectives To review available health and nutrition claims for infant formula products in multiple countries and to evaluate the validity of the evidence used for substantiation of claims. Design International cross sectional survey. Setting Public facing and healthcare professional facing company owned or company managed formula industry websites providing information about products marketed for healthy infants delivered at full term in 15 countries: Australia, Canada, Germany, India, Italy, Japan, Nigeria, Norway, Pakistan, Russia, Saudi Arabia, South Africa, Spain, the United Kingdom, and the United States in 2020-22. Main outcome measures Number and type of claims made for each product and ingredient. References cited were reviewed and risk of bias was assessed for registered clinical trials using the Cochrane risk of bias tool, and for systematic reviews using the Risk Of Bias in Systematic reviews tool. Results 757 infant formula products were identified, each with a median of two claims (range from 1 (Australia) to 4 (US)), and 31 types of claims across all products. Of 608 products with ≥1 claims, the most common claim types were “helps/supports development of brain and/or eyes and/or nervous system” (323 (53%) products, 13 ingredients), “strengthens/supports a healthy immune system” (239 (39%) products, 12 ingredients), and “helps/supports growth and development” (224 (37%) products, 20 ingredients). 41 groups of ingredients were associated with ≥1claims, but many claims were made without reference to a specific ingredient (307 (50%) products). The most common groups of ingredients cited in claims were long chain polyunsaturated fatty acids (278 (46%) products, 9 different claims); prebiotics, probiotics, or synbiotics (225 (37%) products, 19 claims); and hydrolysed protein (120 (20%) products, 9 claims). 161/608 (26%) products with ≥1 claims provided a scientific reference to support the claim—266 unique references were cited for 24 different claim types for 161 products. The reference types most frequently cited were clinical trials (50%, 134/266) and reviews (20%, 52/266). 28% (38/134) of referenced clinical trials were registered, 14% (19/134) prospectively. 58 claims referred to 32 registered clinical trials, of which 51 claims (27 trials) related to a randomised comparison. 46 of 51 claims (90%) referenced registered clinical trial outcomes at high risk of bias, and all cited systematic reviews and pooled analyses, carried a high risk of bias. Conclusions Most infant formula products had at least one health and nutrition claim. Multiple ingredients were claimed to achieve similar health or nutrition effects, multiple claims were made for the same ingredient type, most products did not provide scientific references to support claims, and referenced claims were not supported by robust clinical trial evidence.

Ataxia telangiectasia (AT) is a rare disease characterized by the early onset and slow progression of neurodegenerative defects, mainly affecting the cerebellum, associated with immunodeficiency and teleangiectasias. Ataxia is the hallmark of the disease and usually its first manifestation. Overt cerebellar ataxia usually becomes evident between 16 and 18 months of age, after the onset of walking, and is characterized by frequent falls and an ataxic gait with an enlarged base. We report the case of a child who first presented with serious recurrent infectious, without exhibiting neurological symptoms. The patient was initially diagnosed with combined immunodeficiency (CID) of unknown etiology for nearly 3 years, before he was definitively diagnosed with ataxia telangiectasia.

Psoriasis is a multisystemic inflammatory disorder mainly involving the skin and joints, whose etiopathogenesis is still not completely understood. An association with streptococcal throat infection has been suggested. We aim to investigate a correlation between IL-17A and IFN-γ production by T cells infiltrating skin lesions and PASI in 313 patients with psoriasis, compared with that in 252 healthy controls. The phenotype of β-hemolytic Streptococci-specific infiltrating T cells in skin lesions was evaluated and characterized for IFN-γ, IL-4, and IL-17A production. In addition, PBMCs were tested by ELISpot for IFN-γ and IL-17A after streptococcal antigen exposure. A total of 64 of 313 (20.4%) patients with psoriasis had throat streptococcal infection. Of the 3,868 skin-derived T-cell clones from psoriasis with streptococcal infection, 66% proliferated in response to β-hemolytic Streptococci antigens. Most β-hemolytic Streptococci-specific T cells displayed T helper 17 and T helper 1 phenotypes. The levels of IFN-γ and IL-17A secreted by skin-infiltrating T cells of patients with psoriasis significantly correlated with PASI score. In β-hemolytic Streptococci-positive patients, IFN-γ and IL-17A production by peripheral blood T cells after stimulation with streptococcal antigens was quantified by ELISpot. The results obtained may suggest ELISpot as a useful diagnostic tool to identify patients with psoriasis that may deserve antibiotic treatment.

Background: Helicobacter pylori infection is characterized by an inflammatory infiltrate that might be an important antecedent of gastric cancer. The purpose of this study was to evaluate whether interleukin (IL)-17 inflammation is elicited by gastric T cells in Helicobacter pylori patients with gastric intestinal metaplasia and dysplasia (IM/DYS). We also investigated the serum IL-17A levels in Helicobacter pylori patients with gastric intestinal metaplasia and dysplasia, and patients with Helicobacter pylori non-atrophic gastritis (NAG). Methods: the IL-17 cytokine profile of gastric T cells was investigated in six patients with IM/DYS and Helicobacter pylori infection. Serum IL-17A levels were measured in 45 Helicobacter pylori-infected IM/DYS patients, 45 Helicobacter pylori-infected patients without IM/DYS and in 45 healthy controls (HC). Results: gastric T cells from all IM/DYS patients with Helicobacter pylori were able to proliferate in response to Helicobacter pylori and to produce IL-17A. The Luminex analysis revealed that IL-17A levels were significantly increased in Helicobacter pylori IM/DYS patients compared to healthy controls and to Helicobacter pylori gastritis patients without IM/DYS (452.34 ± 369.13 pg/mL, 246.82 ± 156.06 pg/mL, 169.26 ± 73.82 pg/mL, respectively; p < 0.01, p < 0.05). Conclusions: the results obtained indicate that Helicobacter pylori is able to drive gastric IL-17 inflammation in IM/DYS Helicobacter pylori-infected patients, and that IL-17A serum levels are significantly increased in Helicobacter pylori-infected patients with IM/DYS.

Pernicious anemia (PA) is a megaloblastic anemia consisting of hematological, gastric and immunological alterations. The immunopathogenesis of PA is sustained by both autoantibodies (e.g. intrinsic factor (IFA) antibodies and anti parietal cell (PCA) antibodies and autoreactive T cells specific for IFA and the parietal cell proton pump ATPase. Iron deficient anemia (IDA) is a microcytic anemia and represents the most common cause of anemia worldwide. Our work aimed to investigate serum levels of several interleukins (IL) of the IL-20 cytokine subfamily in patients with PA, with IDA and in healthy subjects (HC). We compared serum levels of IL-19, IL-20, IL-26, IL-28A and IL-29 in 43 patients with PA and autoimmune gastritis, in 20 patients with IDA and no autoimmune gastritis, and in 47 HC. Furthermore, we analyzed the IL-19 cytokine production by gastric lamina propria mononuclear cells (LPMC) in eight patients with PA and four HC. We found that patients with PA have significantly higher serum levels of IL-19 (163.68 ± 75.96 pg/ml) than patients with IDA (35.49 ± 40.97 pg/ml; p<0.001) and healthy subjects (55.68 ± 36.75 pg/ml; p<0.001). Gastric LPMC from all PA patients were able to produce significantly higher levels of IL-19 (420.67 ± 68.14 pg/ml) than HC (53.69 ± 10.92 pg/ml) (p<0.01). Altogether, our results indicate that IL-19 serum levels are significantly increased in patients with PA but not with IDA and that IL-19 is produced in vivo in the stomach of PA patients. These data open a new perspective on PA pathogenesis and suggest that IL-19 may represent a novel important tool for the management of patients with PA.

Human gastric autoimmunity [autoimmune gastritis (AIG)] is characterized by inflammation of the gastric mucosa and parietal cell loss. The gastric parietal cell proton pump H + /K + -adenosine triphosphatase (H + /K + -ATPase) is the major autoantigen in AIG. Our work aimed to investigate the gastric H + /K + -ATPase-specific T helper 17 (Th17) responses in AIG and serum interleukin (IL)-17 cytokine subfamily in AIG patients, in healthy subjects [healthy controls (HCs)], and in patients with iron deficiency anemia (IDA) without AIG. We analyzed the activation of gastric lamina propria mononuclear cells (LPMCs) by H + /K + -ATPase and the IL-17A and IL-17F cytokine production in eight patients with AIG and four HCs. Furthermore, we compared serum levels of IL-17A, IL-17F, IL-21, IL-17E, IL-22, and IL-23 in 43 AIG patients, in 47 HCs, and in 20 IDA patients without AIG. Gastric LPMCs from all AIG patients, but not those from HCs, were activated by H + /K + -ATPase and were able to proliferate and produce high levels of IL-17A and IL-17F. AIG patients have significantly higher serum IL-17A, IL-17F, IL-21, and IL-17E (393.3 ± 410.02 pg/ml, 394.0 ± 378.03 pg/ml, 300.46 ± 303.45 pg/ml, 34.92 ± 32.56 pg/ml, respectively) than those in HCs (222.99 ± 361.24 pg/ml, 217.49 ± 312.1 pg/ml, 147.43 ± 259.17 pg/ml, 8.69 ± 8.98 pg/ml, respectively) and those in IDA patients without AIG (58.06 ± 107.49 pg/ml, 74.26 ± 178.50 pg/ml, 96.86 ± 177.46 pg/ml, 10.64 ± 17.70 pg/ml, respectively). Altogether, our results indicate that IL-17A and IL-17F are produced in vivo in the stomach of AIG patients following activation with H + /K + -ATPase and that serum IL-17A, IL-17F, IL-21, and IL-17E levels are significantly elevated in AIG patients but not in patients without AIG. These data suggest a Th17 signature in AIG and that IL-17A, IL-17F, IL-21, and IL-17E may represent a relevant tool for AIG management.

Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.

Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.

Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T-cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28BR25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b 211 C > T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.

Abstract Objectives To identify a safe pathway for management and treatment of patients with X-linked hypophosphatemic rickets (XLH) during Covid-19 pandemic lockdown. Methods Twenty-six patients with XLH (age 3.1–25.7 years) were enrolled in Pediatric Endocrine Unit; nine of them were receiving human monoclonal anti-fibroblast growth factor 23 antibody (burosumab) and 17 (pediatric patients, age 9.5–17.9 years, n=7; young-adult patients, age 20.1–25.7 years, n=10) received conventional treatment with inorganic oral phosphate salts and active vitamin D metabolites. A Covid-19 free pathway was addressed for XLH patients receiving burosumab treatment in hospital. XLH patients receiving conventional treatment were followed by phone calls, e-mails, or telemedicine. Results All XLH patients receiving burosumab continued the scheduled follow-up and treatment; none of them was infected by Covid-19. Seven XLH patients out of 17 (41%) receiving conventional treatment showed some complication related to the disease itself or its treatment: periapical abscess with gingival fistula was diagnosed in five patients (three children and two young-adults) and treated with antibiotics with complete resolution; one child showed abdominal pain due to the administration of high doses of inorganic oral phosphate salts solved by reducing the dosage, and one child had severe legs pain during deambulation after orthopedic surgery solved with common analgesics. Conclusions Covid-19 free pathway was safe and effective to manage XLH patients receiving burosumab. E-health technologies were useful methods to follow XLH patients receiving conventional treatment during Covid-19 pandemic lockdown.