IPINeT Ped-unPAD Study: Goals, Design, and Preliminary Results.

Background: An unclassified primary antibody deficiency (unPAD) is a widely heterogeneous clinical entity, recently identified within the spectrum of Inborn Errors of Immunity (IEIs). Since unPAD has been traditionally considered as a mild condition, it has incorrectly received little attention, resulting in the paucity of extensive and comparable studies describing its natural history. To address the gaps in characterizing, understanding, and managing pediatric unPAD patients, the Italian Primary Immunodeficiency Network (IPINet) Ped-unPAD study has recently been launched. Methods: Seventeen IPINeT Centers have expressed interest to participate, and data collection is still on-going. Hereby, we anticipate preliminary key issues emerging from the first 110 enrolled patients, attending three IPINet Centers. Results: A proportion of unPAD patients have experienced a severe infectious phenotype, which required hospitalization in a quarter of patients and antibiotic prophylaxis or Immunoglobulin Replacement Therapy in approximately 10% of patients. In this partial cohort, a mean follow-up (FU) of 5 years confirmed unPAD diagnosis in fifty percent of cases, with the remaining being reclassified as the Transient Hypogammaglobulinemia of Infancy (25%) and other IEIs (25%), such as a Common Variable Immunodeficiency, Selective IgA deficiency, Selective IgM deficiency, and IgG3 subclass deficiency. Conclusions: Despite a phenotype overlap at diagnosis, clinicians should be aware that unPAD is a mutable condition that deserves comprehensive evaluation and long-term monitoring to dissect the final diagnosis for optimal treatment.

The Evolutionary Scenario of Pediatric Unclassified Primary Antibody Deficiency to Adulthood.

BACKGROUND: Unclassified primary antibody deficiency (unPAD) is a relatively novel inborn error of immunity (IEI) condition that can vary with time to more defined entities. Since long-term follow-up (FU) studies are scarce, we aimed to provide insight into the evolutionary clinical and immunological scenario of unPAD children to adulthood and identification of biomarkers of primary immune deficiency (PID) persistence. METHODS: A total of 23 pediatric unPAD patients underwent clinical and immunological FU for a mean time of 14 years (range 3-32 years, median 16 years). RESULTS: UnPAD diagnosis may change over time. At the last FU, 10/23 (44%) children matched the diagnosis of transient hypogammaglobulinemia of infancy and 13/23 (56%) suffered from a persistent PID. In detail, an unPAD condition was confirmed in 7/23 (30%) patients, whereas 3/23 (13%), 2/23 (9%), and 1/23 (4%) were reclassified as common variable immunodeficiency, selective IgA deficiency, and isolated IgM deficiency, respectively. Low IgA, low specific antibody response to pneumococcus, and lower respiratory tract infections at diagnosis were independently associated with IEI persistence. CONCLUSIONS: Long-term monitoring of unPAD patients is required to define their outcome and possible evolution towards a definitive IEI diagnosis.

Dupilumab Treatment in Children Aged 6-11 Years With Atopic Dermatitis: A Multicentre, Real-Life Study.

BACKGROUND: The management of paediatric atopic dermatitis (AD) is challenging, mostly relying on emollients and topical corticosteroids. Dupilumab, a fully human monoclonal antibody, has been recently approved for the treatment of children aged 6-11 years with moderate-to-severe AD not adequately controlled with topical therapies or when those therapies are not advisable. OBJECTIVES: The aim of this study was to evaluate in real life the effectiveness and safety of dupilumab in the treatment of children aged from 6 to 11 years. METHODS: Demographic and clinical data of children aged 6-11 years, affected by moderate-to-severe AD and treated with dupilumab, were retrospectively collected from 24 dermatological and paediatric referral centres. Dupilumab was administered subcutaneously at an induction dose of 300 mg on day (D) 1, followed by 300 mg on D15 and 300 mg every 4 weeks. Disease severity was assessed at baseline and after week 2 (W2), W4 and W16 of dupilumab therapy using Eczema Area Severity Index (EASI), Pruritus Numerical Rating Scale (P-NRS) and Sleep NRS (S-NRS) and Children's Dermatology Life Quality Index (c-DLQI) score. RESULTS: A total of 55 AD children (24 males [43.64%], 31 females [56.36%]; mean age 9.35 ± 1.75 years) were included. A significant improvement in EASI score, P-NRS, S-NRS and c-DLQI was observed from baseline to W16 of treatment with dupilumab. In particular, at W16 the proportion of patients achieving EASI75 was 74.54%. Moreover, at the same timepoint a significant mean percentage reduction for P-NRS, S-NRS and c-DLQI was also observed (68.39%, 70.22% and 79.03%, respectively). CONCLUSIONS: Our real-life data seem to confirm the effectiveness of dupilumab in paediatric patients on all disease aspects, including extent and severity of signs, intensity of symptoms, sleep and QoL, with a good safety profile.

Fatty-Acid-Based Membrane Lipidome Profile of Peanut Allergy Patients: An Exploratory Study of a Lifelong Health Condition.

Peanut allergy is a lifelong, increasingly prevalent, and potentially life-threatening disease burdening families and communities. Dietary, particularly polyunsaturated fatty acids (PUFAs), intakes can exert positive effects on immune and inflammatory responses, and the red blood cell (RBC) membrane lipidome contains stabilized metabolic and nutritional information connected with such responses. The fatty-acid-based membrane lipidome profile has been exploratorily evaluated in a small cohort of patients (eight males and one female, age range 4.1−21.7 years old, body mass index BMI < 25) with angioedema and/or anaphylaxis after peanut ingestion. This analysis was performed according to an ISO 17025 certified robotic protocol, isolating mature RBCs, extracting membrane lipids, and transforming them to fatty acid methyl esters for gas chromatography recognition and quantification. Comparison with a group of age- and BMI-matched healthy individuals and with benchmark interval values of a healthy population evidenced significant differences, such as higher levels of ω-6 (arachidonic acid), lower values of ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), together with an increased ω-6/ω-3 ratio in allergic patients. A significant inverse correlation was also found between specific immunoglobulin E (IgE) levels and ω-6 di-homo-gamma-linolenic acid (DGLA) and total PUFAs. Results of this preliminary study encourage screenings in larger cohorts, also in view of precision nutrition and nutraceuticals strategies, and stimulate interest to expand basic and applied research for unveiling molecular mechanisms that are still missing and individuating treatments in chronic allergic disorders.

Case Report: Crossing a rugged road in a primary immune regulatory disorder.

Over the last decades, Inborn Errors of Immunity (IEI) characterized by an immune dysregulatory picture, isolated or combined with infections, have been increasingly identified and referred as Primary Immune Regulatory Disorders (PIRD). PIRD diagnosis may be difficult due to heterogeneity of time onset, sequence of clinical manifestations and laboratory abnormalities. Moreover, the dissection of a PIRD vs. a secondary immunodeficiency (SID) might be a real challenge since the same indications for immunosuppressant treatments might represent per se a PIRD clinical expression. Here we report a female patient with a history of recurrent respiratory and urinary tract infections since early infancy and a diagnosis of Rheumatoid Arthritis in adulthood. After poor response to several biologicals she was treated with Rituximab and sent to immunology referral for a severe hypogammaglobulinemia. Clinical and immunological features matched a diagnosis of common variable immunodeficiency and when IgG replacement therapy and antibiotic prophylaxis were added a good infectious control was obtained. Next generation sequencing analysis has revealed a novel heterozygous VUS in the IKBKB gene (c.1465A > G; p.Ser489Gly). Functional analysis has shown a reduced capacity of B lymphocytes and CD4 positive T cells in inducing IκBα degradation, with negative impact on NF-kB pathway. Due to recurrent infections attributed to a common condition in childhood and to an exclusive autoimmunity-centered approach in adulthood, both diagnosis and suitable treatment strategies have suffered a significant delay. To reduce the diagnostic delay, pediatricians, general practitioners and specialists should be aware of IEI and the challenges to differentiate them from SID. Furthermore, genetic characterization and functional analysis may contribute to a personalized approach, in a perspective of targeted or semi-targeted therapy.

Pediatric health care professionals' vaccine knowledge, awareness and attitude: a survey within the Italian Society of Pediatric Allergy and Immunology.

BACKGROUND: Physicians play a key role in driving vaccine acceptance and their recommendations are crucial to address vaccine hesitancy. The aim of the study was to assess knowledge, awareness and attitude of Italian Pediatric Health Care Professionals (pHCPs) on vaccinations. METHODS: An anonymous on-line questionnaire was developed within the Vaccine Committee of Italian Society of Pediatric Allergy and Immunology (SIAIP) and spontaneously completed by 231 Pediatricians and Pediatric Nurses (PN). RESULTS: An accurate vaccine education was reported by 70% of pediatricians and 13% of PN but 11% of pediatricians versus 26% of PN consult social media instead of scientific sources for their vaccine update. The investigation on the pHCPs attitudes to vaccination in a personal and family setting highlights poor adherence to vaccinations. Only 63% of pediatricians versus 16% of PN (p < 0.0001) annually received the Flu vaccine. In their family setting 93% of pediatricians versus 51% of PN recommended all vaccinations (p < 0.0001). Anti-flu, anti-rotavirus, anti-zoster and anti-pneumococcal vaccines were not regularly recommended by all pHCPs due to doubts of uselessness (55% of pediatricians versus 40% of PN) and preference for "natural immunity" (44% of pediatricians versus 40% of PN). CONCLUSIONS: Our results indicate that pHCPs' attitude and confidence in regards to vaccines remain suboptimal. Current COVID-19 pandemic and the rapid development of vaccines could increase vaccine hesitancy. Due to the documented pHCPs' influence in the parental decision, educational interventions are needed to improve their level of knowledge and counselling skills in order to address parental vaccine hesitancy and to maintain continuity of immunization services.

Genotypes of p53 codon 72 correlate with age at onset of type 1 diabetes in a sex-specific manner.

In type 1 diabetes mellitus (T1D) p53 pathways are up-regulated and there is an increased susceptibility to apoptosis. The hypothesis is that p53 codon 72 polymorphism could be associated with T1D. A total of 286 children with T1D and a control sample of 730 subjects were studied. p53 codon 72 polymorphism was analysed by polymerase chain reaction. A large increase of p53 *Arg/*Arg was observed in T1D patients with age at onset < 6 years. A strong linear correlation between *Arg/*Arg genotype and age at onset was observed in females. The involvement of the *Arg/*Arg genotype in apoptosis suggests that during the autoimmune process leading to T1D, genetic factors that favor apoptosis may contribute to the onset of overt disease.