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Background: The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy, in the treatment of IEI-related immune dysregulation disorders, according to labelled and off-label indications. Recent years have been dominated by a progressive imbalance between the gradual but constant increase in the use of immunoglobulins and their availability, exacerbated by the SARS-CoV-2 pandemic., Objectives: To provide pragmatic indications for a need-based application of high-dose immunoglobulins in the pediatric context., Sources: A literature search was performed using PubMed, from inception until 1st August 2023, including the following keywords: anti-inflammatory; children; high dose gammaglobulin; high dose immunoglobulin; immune dysregulation; immunomodulation; immunomodulatory; inflammation; intravenous gammaglobulin; intravenous immunoglobulin; off-label; pediatric; subcutaneous gammaglobulin; subcutaneous immunoglobulin. All article types were considered., Implications: In the light of the current imbalance between gammaglobulins' demand and availability, this review advocates the urgency of a more conscious utilization of this medical product, giving indications about benefits, risks, cost-effectiveness, and administration routes of high-dose immunoglobulins in children with hematologic, neurologic, and inflammatory immune dysregulation disorders, prompting further research towards a responsible employment of gammaglobulins and improving the therapeutical decisional process.

Multisystem inflammatory syndrome (MIS-C) is a rare condition associated with COVID-19 affecting children, characterized by severe and aberrant systemic inflammation leading to nonspecific symptoms, such as gastrointestinal, cardiac, respiratory, hematological, and neurological disorders. In the last year, we have experienced a progressive reduction in the incidence and severity of MIS-C, reflecting the worldwide trend. Thus, starting from the overall trend in the disease in different continents, we reviewed the literature, hypothesizing the potential influencing factors contributing to the reduction in cases and the severity of MIS-C, particularly the vaccination campaign, the spread of different SARS-CoV-2 variants (VOCs), and the changes in human immunological response. The decrease in the severity of MIS-C and its incidence seem to be related to a combination of different factors rather than a single cause. Maturation of an immunological memory to SARS-CoV-2 over time, the implication of mutations of key amino acids of S protein in VOCs, and the overall immune response elicited by vaccination over the loss of neutralization of vaccines to VOCs seem to play an important role in this change.

Background: Pyogenic bacteria are associated with a wide range of clinical manifestations, ranging from common and relatively mild respiratory and cutaneous infections to life-threatening localized or systemic infections, such as sepsis and profound abscesses. Despite vaccination and the widespread use of effective antibiotic treatment, severe infection is still observed in a subset of affected patients., Objectives: We aim to summarize the available data regarding inborn errors of immunity that result in a high risk of severe pyogenic infections., Sources: Case series, as well as review and original articles on human genetic susceptibility to pyogenic infections were examined., Content: We review host-associated factors resulting in inborn errors of immunity and leading to a susceptibility to pyogenic infections, including deficiency in major components of the immune system (e.g., neutrophils, complement, immunoglobulin, and spleen function) and novel monogenic disorders resulting in specific susceptibility to pyogenic infection. Specifically, innate immune system deficiency involving toll-like receptors and associated signaling typically predispose to a narrow spectrum of bacterial diseases in otherwise healthy people, making a diagnosis more difficult to suspect and confirm. More complex syndromes, such as hyper IgE syndrome, are associated with a high risk of pyogenic infections due to an impairment of the interleukin-6 or -17 signaling, demonstrating the pivotal role of these pathways in controlling bacterial infections., Implications: In clinical practice, awareness of such conditions is essential, especially in the pediatric setting, to avoid a potentially fatal diagnostic delay, set the most proper and prompt treatment, and ensure prevention of severe complications., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Inborn errors of intrinsic and innate immunity constitute the focus of a growing research field that investigates the molecular mechanisms underlying susceptibility to infections previously not considered part of the spectrum of inborn errors of immunity. These so-called nonconventional inborn errors of immunity often occur as infections caused by a narrow spectrum of microorganisms in otherwise healthy subjects., Objectives: This review aimed to provide a framework for identifying and evaluating patients with viral, bacterial, mycobacterial, and fungal infection needing further assessment for inborn errors of intrinsic and innate immunity., Sources: A literature search was performed using PubMed, from inception until 1 May 2022. The search included the following keywords: "inborn errors of immunity"; "inborn errors of innate immunity"; "primary immune deficiency"; "primary immunodeficiency"; "infections"; "infectious susceptibility"; "virus"; "pyogenic bacteria"; "mycobacteria"; "fungi". All article types were considered., Content: We review the definition of what can be considered an inborn error of immunity and how the definition changed over the last ∼25 years. We further provide criteria to rule out secondary immunodeficiencies, identify patients needing further clinical and laboratory immunological assessment, and suspect and diagnose an inborn error of intrinsic and innate immunity. These steps are proposed as part of an algorithm., Implications: Patients with unexplained life-threatening infections, including otherwise healthy subjects, should be systematically screened for known inborn errors of immunity. The early diagnosis can prevent recurrence of life-threatening infections in the patients and reduce the total burden of infectious diseases., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Sickle cell disease (SCD) is a condition of functional hypo-/a-splenism in which predisposition to bacterial infections is only a facet of a wide spectrum of immune-dysregulation disorders forming the clinical expression of a peculiar immunophenotype. The objective of this study was to perform an in-depth immunophenotypical characterization of SCD pediatric patients, looking for plausible correlations between immunological biomarkers, the impact of hydroxyurea (HU) treatment and clinical course. This was an observational case−control study including 43 patients. The cohort was divided into two main groups, SCD subjects (19/43) and controls (24/43), differing in the presence/absence of an SCD diagnosis. The SCD group was split up into HU+ (12/19) and HU− (7/19) subgroups, respectively receiving or not a concomitant HU treatment. The principal outcomes measured were differences in the immunophenotyping between SCD patients and controls through chi-squared tests, t-tests, and Pearson’s correlation analysis between clinical and immunological parameters. Leukocyte and neutrophil increase, T-cell depletion with prevalence of memory T-cell compartment, NK and B-naïve subset elevation with memory and CD21low B subset reduction, and IgG expansion, significantly distinguished the SCD HU− subgroup from controls, with naïve T cells, switched-memory B cells and IgG maintaining differences between the SCD HU+ group and controls (p-value of <0.05). The mean CD4+ central-memory T-cell% count was the single independent variable showing a positive correlation with vaso-occlusive crisis score in the SCD group (Pearson’s R = 0.039). We report preliminary data assessing plausible clinical implications of baseline and HU-related SCD immunophenotypical alterations, which need to be validated in larger samples, but potentially affecting hypo-/a-splenism immuno-chemoprophylactic recommendations.

Background: A steady increase in the international production and consumption of fish has positioned aquaculture as a development option. Previous literature has highlighted the potential of aquaculture to improve economic, nutritional and gender equality outcomes, however, the evidence on the effectiveness of these programmes remains unclear., Objectives: The review assessed whether aquaculture interventions increase the productivity, income, nutrition, and women's empowerment of individuals. We additionally aimed to identify barriers and facilitators that could affect the effectiveness of these interventions, and the cost-effectiveness of such programmes., Methods: We searched for experimental and quasi-experimental studies focused on low- and middle-income countries. We used standard methodological procedures expected by The Campbell Collaboration for the data collection and analysis., Results: We identified 21 impact evaluations assessing the effect of 13 aquaculture interventions in low- and lower-middle income countries. Twelve of these studies have a high risk of bias. Aquaculture interventions lead to a small increase in the production value, income, total expenditures and food consumption of participants. The limited availability of evidence prevented us from assessing other nutritional and women's empowerment outcomes. We identified barriers and facilitators affecting the programmes' set up, the participation of beneficiaries, and the level of productive activities. Insufficient cost data hindered full comparisons across programmes., Conclusions: The review suggests a lack of rigorous evidence assessing the effectiveness of aquaculture programmes. Future research could focus on evaluating nutrition and women's empowerment impacts, promoting reporting standards, and the use of cost data to continue building quality evidence around aquaculture interventions., (© 2021 International Initiative for Impact Evaluation (3ie). Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

The review aims to examine and synthesise the state of the evidence around what works to improve productivity, income, nutrition and women's empowerment outcomes of households involved in aquaculture in low- and middle-income countries. We are particularly interested in addressing the following research questions: (1) Do aquaculture interventions increase the productivity, income, nutrition and empowerment of individuals engaged in aquaculture and their households in low- and middle-income countries? (2) Do aquaculture interventions generate income and nutrition spillover effects beyond the farmers' households? (3) To what extent do the effects of aquaculture interventions vary by intervention type, population group, and location? In particular, to what extent do effects vary by gender? (4) What are the potential barriers and facilitating factors that impact the effectiveness of aquaculture interventions? (5) What is the cost-effectiveness of different aquaculture interventions focused on productivity, income, nutrition and empowerment outcomes?, (© 2021 International Initiative for Impact Evaluation (3ie). Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

Background: Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms., Objective: Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation., Methods: We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0-18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into two groups (IEI+ and IEI-), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19)., Results: IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T-cells%, switched memory B-cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T-cells% and CD21low B-cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn., Conclusion: The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI-related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted-gene variants responsible for IEI phenotype., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)