Autosomal Recessive IL-12p40 Deficiency due to a Mutation in the IL12B Gene: Report of a Brazilian Patient with Lymph Node Mycobacterial Infection.

Background: Autosomal recessive interleukin (IL)-12p40 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). It has been described in ∼50 patients, usually with onset at childhood with Bacille Calmette-Guérin (BCG) and Salmonella infections. Case Presentation: A male patient born to consanguineous parents was diagnosed with presumed lymph node MSMD at the age of 13 years after ocular symptoms. A positive history of inborn error of immunity was present: BCG reaction, skin abscess, and recurrent oral candidiasis. Abnormal measurements of cytokine levels, IL-12p40 and interferon-gamma (IFN-γ), lead to the diagnosis of MSMD. Genetic analysis showed a mutation in exon 7 of the IL12B gene. Currently, the patient is alive under prophylactic antibiotics. Conclusion: We report a rare case of IL-12p40 deficiency in a Latin American patient. Medical history was crucial for immune defect suspicion, as confirmed by precision diagnostic medicine tools.

Doença granulomatosa crônica: características clínicas, seguimento e terapêutica de cinco pacientes pediátricos / Chronic granulomatous disease: clinical characteristics, follow-up, and therapy of 5 pediatric patients

Introdução: A doença granulomatosa crônica (DGC) é caracterizada por um defeito na capacidade microbicida das células fagocíticas (monócitos e neutrófilos), com alta mortalidade se não diagnosticada precocemente. Os pacientes apresentam infecções recorrentes ou graves, suscetibilidade a granulomas em órgãos profundos, doenças autoimunes e doença inflamatória intestinal. Objetivo e Método: Relato de aspectos clínicos e do tratamento de cinco pacientes com doença granulomatosa crônica. Resultados: Cinco pacientes, três meninos, medianas de idade no início dos sintomas e diagnóstico de 8 meses e 48 meses, respectivamente, foram estudados por um período de 10 anos. Pneumonia (5/5) e doença micobacteriana (3/5) foram as manifestações iniciais mais comuns. Alterações pulmonares foram observadas em todos os casos. Mutações nos genes CYBB e NCF1 foram identificadas em três casos. Antibioticoprofilaxia foi instituída em todos os pacientes e três foram submetidos ao transplante de células tronco-hematopoiéticas (TCH), aos 7, 18 e 19 anos e com sobrevida atual entre 4 a 5 anos. Conclusão: O monitoramento cuidadoso de infecções graves com tratamento imediato foi crucial para a sobrevivência. O TCH, mesmo ao final da adolescência, promoveu a cura da DGC em três pacientes.

Introduction: Chronic granulomatous disease (CGD) is characterized by a defective microbicidal capacity of phagocytic cells (monocytes and neutrophils) with high mortality if not early diagnosed. Patients have recurrent or severe infections and are susceptible to granulomas in visceral organs, autoimmune diseases, and inflammatory bowel diseases. Objective and Method: To report the clinical features and treatment of 5 patients with CGD. Results: Five patients, 3 boys, with median ages at symptom onset and diagnosis of 8 months and 48 months, respectively, were followed for 10 years. Pneumonia (5/5) and mycobacterial disease (3/5) were the most common initial manifestations. Pulmonary changes were observed in all cases. Mutations in the CYBB and NCF1 genes were identified in 3 cases. All patients received antibiotic prophylaxis. Three patients underwent a hematopoietic stem cell transplant (HSCT) at 7, 18, and 19 years, with current survival of 4 to 5 years. Conclusion: Careful monitoring for severe infection with prompt treatment was crucial for survival. Even though HSCT was performed in late adolescence, it promoted the cure of CGD in 3 patients.

Immediate adverse events to intravenous immunoglobulin in pediatric patients with inborn errors of immunity: A longitudinal study with a pre-infusion protocol.

INTRODUCTION: Immunoglobulin represents the main therapy for patients with inborn errors of immunity (IEI) and it is a safe procedure, but adverse events (AEs) can occur with variable frequencies. OBJECTIVE: To evaluate the frequency of immediate AEs to intravenous immunoglobulin (IVIG) regular therapy in a pediatric cohort with IEI after a pre-IVIG infusion protocol. METHODS: This was a longitudinal study from 2011 to 2019 at a tertiary pediatric hospital in Brazil. RESULTS: A total of 1736 infusions were studied in 70 patients with IEI, 46 (65.7%) of whom were males and whose median age was 5.8 years old (range: 6 mo - 18 yo). Seven different brands of IVIG were used with the median loading dose of 0.57g/kg (range: 0.23 - 0.88g/Kg). According to the protocol, pre-medication and step-up infusion rate, were performed in 1305 (75.2%) infusions. Immediate AEs were noted in 10 children (14.3%) and in 22 (1.2%) infusions. Skin reactions (rash or urticaria) were the most common AE with 14 episodes (0.8% of all infusions). Almost all AEs were mild (19/86.4%), with no severe ones being observed. The majority of the AEs (81.8%) was identified at a 0.04ml/kg/min infusion rate. Gender, age at first infusion, presence of infection on the infusion day and change of the IVIG brand were evaluated and none of them were associated with AEs. CONCLUSION: The low frequency of immediate AEs in children with IEI highlights the safety and tolerability of intravenous immunoglobulin replacement with the procedures established at our center.

Immediate adverse events to intravenous immunoglobulin in pediatric patients with inborn errors of immunity: A longitudinal study with a pre-infusion protocol

Introduction Immunoglobulin represents the main therapy for patients with inborn errors of immunity (IEI) and it is a safe procedure, but adverse events (AEs) can occur with variable frequencies. Objective To evaluate the frequency of immediate AEs to intravenous immunoglobulin (IVIG) regular therapy in a pediatric cohort with IEI after a pre-IVIG infusion protocol. Methods This was a longitudinal study from 2011 to 2019 at a tertiary pediatric hospital in Brazil. Results A total of 1736 infusions were studied in 70 patients with IEI, 46 (65.7%) of whom were males and whose median age was 5.8 years old (range: 6 mo - 18 yo). Seven different brands of IVIG were used with the median loading dose of 0.57g/kg (range: 0.23 - 0.88g/Kg). According to the protocol, pre-medication and step-up infusion rate, were performed in 1305 (75.2%) infusions. Immediate AEs were noted in 10 children (14.3%) and in 22 (1.2%) infusions. Skin reactions (rash or urticaria) were the most common AE with 14 episodes (0.8% of all infusions). Almost all AEs were mild (19/86.4%), with no severe ones being observed. The majority of the AEs (81.8%) was identified at a 0.04ml/kg/min infusion rate. Gender, age at first infusion, presence of infection on the infusion day and change of the IVIG brand were evaluated and none of them were associated with AEs. Conclusion The low frequency of immediate AEs in children with IEI highlights the safety and tolerability of intravenous immunoglobulin replacement with the procedures established at our center.

One-year intravenous immunoglobulin replacement therapy: efficacy in reducing hospital admissions in pediatric patients with Inborn Errors of Immunity

Abstract Objectives: To compare the frequency of hospitalization in children with Inborn Errors of Immunity with antibody deficiency previous to intravenous immunoglobulin (pre- IVIG) with a one-year period after initial IVIG (post-IVIG). Methods: Medical reports of 45 patients during an eight-year period were reviewed from 2018 to 2019. Wilcoxon-test was used for related samples. Results: Forty-five children were included in the study, aged 29-249 months of age, and most of them (64.4%) were males. Median ages at onset symptoms and at diagnosis were 6 and 73 months old, respectively. Specific antibody deficiency and unclassified hypogammaglobulinemia were the predominant diagnoses (31.1% and 17.8%, respectively). X-linked agammaglobulinemia, Hyper IgE syndrome, Hyper IgM, transient hypogammaglobulinemia of infancy, and Common Variable Immunodeficiency (CVID) were also reported, in a low frequency. Forty-four (97.8%) patients were hospitalized before IVIG, and 10 patients (22.2%) after. Annual mean hospital admission reduced from 2.5 to 0.5, pre and post-IVIG, respectively (p < 0.0001). Mean length of stay (LOS) reduced from 71 to 4.7 days/year (p < 0.0001) in general ward and in the PICU from 17.2 days/year to zero (p < 0.0002). Pneumonia was the main cause of hospital admission with a reduction in the number of episodes per patient from an average of 2.2-0.1 per year (p < 0.001). Concomitant use of antibiotic prophylaxis did not influence the number of hospital admission. Conclusion: One-year intravenous IVIG significantly decreased the number of hospitalizations and length of stay in children with impaired antibody production. Social and economic impacts would be required.

One-year intravenous immunoglobulin replacement therapy: efficacy in reducing hospital admissions in pediatric patients with Inborn Errors of Immunity.

OBJECTIVES: To compare the frequency of hospitalization in children with Inborn Errors of Immunity with antibody deficiency previous to intravenous immunoglobulin (pre- IVIG) with a one-year period after initial IVIG (post-IVIG). METHODS: Medical reports of 45 patients during an eight-year period were reviewed from 2018 to 2019. Wilcoxon-test was used for related samples. RESULTS: Forty-five children were included in the study, aged 29-249 months of age, and most of them (64.4%) were males. Median ages at onset symptoms and at diagnosis were 6 and 73 months old, respectively. Specific antibody deficiency and unclassified hypogammaglobulinemia were the predominant diagnoses (31.1% and 17.8%, respectively). X-linked agammaglobulinemia, Hyper IgE syndrome, Hyper IgM, transient hypogammaglobulinemia of infancy, and Common Variable Immunodeficiency (CVID) were also reported, in a low frequency. Forty-four (97.8%) patients were hospitalized before IVIG, and 10 patients (22.2%) after. Annual mean hospital admission reduced from 2.5 to 0.5, pre and post-IVIG, respectively (p < 0.0001). Mean length of stay (LOS) reduced from 71 to 4.7 days/year (p < 0.0001) in general ward and in the PICU from 17.2 days/year to zero (p < 0.0002). Pneumonia was the main cause of hospital admission with a reduction in the number of episodes per patient from an average of 2.2-0.1 per year (p < 0.001). Concomitant use of antibiotic prophylaxis did not influence the number of hospital admission. CONCLUSION: One-year intravenous IVIG significantly decreased the number of hospitalizations and length of stay in children with impaired antibody production. Social and economic impacts would be required.

Hypogammaglobulinemia in children: a warning sign to look deeply?

This study investigated phenotypic and functional characteristics of lymphocytes in children with common variable immunodeficiency (CVID) and unclassified hypogammaglobulinemia (UH), as well as B-cell subsets in non-consanguineous parents. Blood samples of 30 children, CVID (n = 9), UH (n = 9), healthy donors HD (n = 12), and 19 adults (parents and controls) were labeled by a combination of surface markers to identify CD4, CD8 T-cell and B-cell subpopulations. T-cell cytokine production in children was analyzed in vitro after stimulation with phytohemagglutinin (PHA) and tetanus toxoid. We observed low percentages of switched memory B cells in children with CVID, increase in total CD4+ T-cell counts, and high percentages of transitional B cells only in UH group. Analysis of T-cell immunity showed that CVID children had decreased percentages of CD8+ IFN-γ-producing cells after stimulation with PHA and tetanus toxoid. Parent of children with CVID had low percentages of naive B cell and increased percentages of memory B cells in comparison with controls. These results suggest that (i) early combined immune defect in children with CVID and (ii) a possible familial B-cell disturbance in pediatric CVID.

Increase of circulating α4ß7+ conventional memory CD4 and regulatory T cells in patients with common variable immunodeficiency (CVID).

This study investigated whether circulating α4ß7+ expressing T cells could serve as a potential marker for gastrointestinal (GI) disease activity in patients with CVID. The analysis of α4ß7+ T cells in the peripheral blood of 36 patients and 22 healthy donors (HD) revealed increased percentages of α4ß7+ conventional memory CD4 T cells and Tregs, but not among CD8 T-cell populations in patients with CVID compared to HD. No differences between patients with and without chronic or acute GI symptoms were observed. EUROClass smB- and 21lo patients, had higher percentages of α4ß7+ memory CD4 T cells compared to HD and smB+ or 21norm patients, respectively. In summary, the detection of α4ß7+ T cells in the peripheral blood did not correlate with active or chronic gastrointestinal disease. The increase of these cells in smB- and 21lo patients adds another piece to the immune dysregulation observed in these patients.

Health-Related Quality of Life and Health Resource Utilization in Patients with Primary Immunodeficiency Disease Prior to and Following 12 Months of Immunoglobulin G Treatment.

PURPOSE: Health-related quality of life (HRQOL) has not been examined in patients with predominant antibody deficiency both pre- and post-immunoglobulin G (IgG) treatment initiation. HRQOL and health resource utilization (HRU) were assessed in newly diagnosed patients with primary immunodeficiency disease (PIDD) pre- and 12 months post-IgG treatment initiation. METHODS: Adults (age ≥18 years) completed the 36-item Short Form Health Survey, version 2; pediatric patients (PP)/caregivers completed the Pediatric Quality of Life Inventory (PedsQL). Scores were compared with normative data from the US general population (GP) and patients with other chronic conditions (OCC). RESULTS: Seventeen adult patients (APs), 8 PPs, and 8 caregivers completed baseline assessments. APs had significantly lower baseline mean physical component summary scores versus GP (37.4 vs 50.5, p < 0.01) adults with chronic back pain (44.1, p < 0.05) or cancer (44.4, p < 0.05) and lower mental component summary scores versus GP (41.6 vs 49.2, p < 0.05). PPs had lower PedsQL total (63.1 vs 82.7), physical summary (64.5 vs 84.5), and psychosocial summary (62.5 vs 81.7) scores versus GP. Post-IgG treatment, 14 APs, 6 PPs, and 8 caregivers completed assessments. Hospital admissions (0.2 versus 1.8, p < 0.01), serious infections (3.3 versus 10.9, p < 0.01) and antibiotic prescriptions (3.0 versus 7.1; p < 0.01) decreased significantly overall. While APs reported significant improvement in role-physical (p = 0.01), general health (p < 0.01), and social functioning (p = 0.02) and caregivers in vitality (p < 0.01), PPs did not. CONCLUSIONS: Pre-IgG treatment, patients with PIDD experienced diminished HRQOL versus GP and patients with OCC; post-treatment, HRU decreased and certain HRQOL aspects improved for APs and caregivers.

Primary Immunodeficiency May Be Misdiagnosed as Cow's Milk Allergy: Seven Cases Referred to a Tertiary Pediatric Hospital.

Introduction. The presence of eczema and gastrointestinal manifestations are often observed in cow's milk allergy (CMA) and also in some primary immunodeficiency diseases (PID). Objective. To describe 7 patients referred to a tertiary allergy/immunology Center with a proposed diagnosis of CMA, who were ultimately diagnosed with PID. Methods. This was a retrospective study based on clinical and laboratory data from medical records. Results. Seven patients (6 males) aged between 3 mo and 6 y were referred to our clinic with a proposed diagnosis of CMA. They presented with eczema and/or gastrointestinal symptoms. Five were receiving replacement formula. All patients presented with other clinical features, including severe/recurrent infections unrelated to CMA, and two of them had a positive family history of PID. Laboratory tests showed immune system dysfunctions in all patients. Hyper-IgE and Wiskott-Aldrich syndromes, CD40L deficiency, severe combined immunodeficiency, X-linked agammaglobulinemia, transient hypogammaglobulinemia of infancy, and chronic granulomatous disease were diagnosed in these children. In conclusion, allergic diseases and immunodeficiency are a result of a different spectrum of abnormalities in the immune system and may be misdiagnosed. Educational programs on PID among clinical physicians and pediatricians can reduce the occurrence of this misdiagnosis.

Células T regulatórias: mecanismos de ação e função nas doenças humanas / T regulatory cell: mechanism of action and function

Objetivo: Revisar as principais características das células Tregulatórias (Tregs) e os estudos de suas funções nas doenças humanas. As Tregs são componentes da tolerância imunológica, e são moduladores essenciais na resposta imune à patógenos, alérgenos, células cancerígenas e antígenos próprios.Método: Levantamento bibliográfico nos bancos de dados PubMed, Medline, LILACS, SCIELO e capítulos de livros, nos últimos 10 anos.Resultados: Neste trabalho são descritas as principais características fenotípicas e funcionais das Tregs, as três hipótesesde mecanismos de ação das Tregs sobre as células T efetoras e estudos de Tregs em diversas doenças humanas.Conclusão: A identificação dos genes relacionados ao FOXP3 e o esclarecimento dos mecanismos de ação das Tregs, poderão melhorar a terapêutica nas doenças com desregulação imune.

Objective: To review the main characteristics of regulatory T cells (Tregs) and the studies of their function in human diseases. Treg cells are members of immune tolerance, and are essentia I modulators of immune response, including down-modulationof immune response to pathogens, allergens, cancer cells and self-antigens.Methods: Searches in MEDLINE, LILACS, SCIELO data base and book chapters, in the last 10 years.Results: This review describes the role of Tregs on immune regulation, the three current hypotheses of Tregs' action mechanisms on effector T cells, and some studies of Tregs in human diseases.Conclusion: The identification of genes related to FOXP3 and a better comprehension of Tregs' action mechanism, could improve the therapy in diseases with immune dysregulation.