Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature.

INTRODUCTION: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. METHODS: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. RESULTS: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. CONCLUSIONS: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

Proposal to Screen for Zinc and Selenium in Patients with IgA Deficiency.

The increase in life expectancy can be a consequence of the world's socioeconomic, sanitary and nutritional conditions. Some studies have demonstrated that individuals with a satisfactory diet variety score present a lower risk of malnutrition and better health status. Zinc and selenium are important micronutrients that play a role in many biochemical and physiological processes of the immune system. Deficient individuals can present both innate and adaptive immunity abnormalities and increased susceptibility to infections. Primary immunodeficiency diseases, also known as inborn errors of immunity, are genetic disorders classically characterized by an increased susceptibility to infection and/or dysregulation of a specific immunologic pathway. IgA deficiency (IgAD) is the most common primary antibody deficiency. This disease is defined as serum IgA levels lower than 7 mg/dL and normal IgG and IgM levels in individuals older than four years. Although many patients are asymptomatic, selected patients suffer from different clinical complications, such as pulmonary infections, allergies, autoimmune diseases, gastrointestinal disorders and malignancy. Knowing the nutritional status as well as the risk of zinc and selenium deficiency could be helpful for the management of IgAD patients. OBJECTIVES: to investigate the anthropometric, biochemical, and nutritional profiles and the status of zinc and selenium in patients with IgAD. METHODS: in this descriptive study, we screened 16 IgAD patients for anthropometric and dietary data, biochemical evaluation and determination of plasma and erythrocyte levels of zinc and selenium. RESULTS: dietary intake of zinc and selenium was adequate in 75% and 86% of the patients, respectively. These results were consistent with the plasma levels (adequate levels of zinc in all patients and selenium in 50% of children, 25% of adolescents and 100% of adults). However, erythrocyte levels were low for both micronutrients (deficiency for both in 100% of children, 75% of adolescents and 25% of adults). CONCLUSION: our results highlight the elevated prevalence of erythrocyte zinc and selenium deficiency in patients with IgAD, and the need for investigation of these micronutrients in their follow-up.

Administration of an excessive dosage of covid-19 pfizer vaccine in an infant: Case report of clinical and immune responses.

Introduction/Case report: We describe the case of a 6-month-old female infant who received the equivalent of 6 adult doses of the COVID-19 Pfizer vaccine due to an immunization error. The patient underwent clinical and laboratory evaluations from the time of vaccination error (January 2022) until November 2022. In the first three days after immunization, she presented with low-grade fever (38 °C) and mild pain and induration at the injection site. She showed no other symptoms afterwards. Laboratory tests were within normal limits for age, except for an elevated D-dimer (3.71 ug/mL; normal: up to 0.5 ug/mL) and as the echocardiogram and electrocardiogram were within normal limits as well, no interventions were instituted at that moment. On the tenth day, immune response evaluation showed a strong expression of cytokines related to the Th2 profile and a well-controlled inflammatory state. Forty-three days after the vaccine administration inflammation status remained, with a predominance of cellular immune response, IFN-γ expression increased compared to the previous evaluation, and a robust antiviral state was in place. After 90 days, immune response evaluation showed a significant reduction in the inflammatory state, still with a predominance of the cellular immune response. Clinically, the patient remained well, with no other noteworthy intercurrences, until the last appointment in November 2022. This child has had no evidence of a severe adverse effect associated to the vaccine overdose. Conclusion: The close follow-up of this case of vaccination error demonstrated that the COVID-19 Pfizer was safe and immunogenic in this individual, noting careful monitoring and followup of these vaccine administration errors is crucial.