Effect of weekly vitamin D supplementation on the severity of atopic dermatitis and type 2 immunity biomarkers in children: A randomized controlled trial.

BACKGROUND: Vitamin D (VD) deficiency is common among patients with atopic dermatitis (AD) and often associated with severity. However, randomized trials of VD supplementation in AD have had equivocal results, and there is little information regarding the effect of VD supplementation on type 2 immunity in AD patients. OBJECTIVES: To investigate the efficacy of VD supplementation to decrease severity of AD and to alter type 2 immunity biomarkers. METHODS: We performed a randomized, double-blind, placebo-controlled trial. We randomly assigned 101 children with AD to weekly oral vitamin D3 (VD3) or placebo for 6 weeks. The primary outcome was the change in the Severity Scoring of AD (SCORAD). RESULTS: Mean age of subjects was 6.3 ± 4.0 years, and baseline SCORAD was 32 ± 29. At baseline, 57% of children were VD deficient, with no difference between groups. Change in 25(OH)D was significantly greater with VD3 than placebo (+43.4 ± 34.5 nmol/L vs. +2.3 ± 21.2 nmol/L, p < 0.001). SCORAD change at 6 weeks was not different between VD and placebo (-5.3 ± 11.6 vs. -5.5 ± 9.9, p = 0.91). There were no significant between-group differences in change of eosinophil counts, total IgE, Staphylococcal enterotoxin specific IgE, CCL17, CCL22, CCL27, LL-37 or Staphylococcus aureus lesional skin colonization. Vitamin D receptor (VDR) gene single nucleotide polymorphisms FokI, ApaI and TaqI did not modify subjects' response to VD supplementation. CONCLUSIONS: Among children with AD, weekly VD supplementation improved VD status but did not modify AD severity or type 2 immunity biomarkers compared to placebo (ClinicalTrials.gov NCT01996423).

Association between obesity and atopic dermatitis in children: A case-control study in a high obesity prevalence population.

BACKGROUND/OBJECTIVE: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Research suggests an association between obesity and AD, although evidence is lacking from Latin American populations. This study evaluated the association of obesity with AD in children from Chile, a country with high obesity prevalence. METHODS: A case-control study was performed in children with active AD (cases) and healthy controls (HCs) from Santiago, Chile. Body mass index was evaluated by z-score (z-BMI), with overweight defined as z-BMI ≥+1 and <+2, and obesity as z-BMI ≥+2. Abdominal obesity was defined by a waist circumference-to-height ratio (WHR) ≥0.5. AD severity was evaluated by Scoring AD (SCORAD) index. RESULTS: A total of 174 children with AD and 101 controls were included. AD patients had similar overweight (27% vs. 28%) and obesity (21% vs. 26%) rates as HCs (p = .65). Abdominal obesity rates were also comparable (64% vs. 62%, p = .81). In sex-specific analyses, girls with AD had higher abdominal obesity rates than HCs (71% vs. 53%, p < .05) while boys with AD had lower abdominal obesity rates than HCs (53% vs. 75%, p = .03). Among children with AD, higher z-BMI or WHR did not correlate with higher SCORAD, eosinophil counts or total IgE. CONCLUSION: In our study, Chilean children with AD had high but similar rates of obesity as HCs, but showed sex-specific associations of abdominal obesity and AD. Further research is needed to evaluate these associations and the roles that weight excess and weight loss could play in the pathogenesis and treatment of AD.

Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation.

BACKGROUND: The gene AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival. OBJECTIVE: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection. METHODS: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function. RESULTS: We identified 2 different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function. CONCLUSIONS: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.

Autoimmunity and immunodeficiency.

PURPOSE OF REVIEW: Advances in genomics and animal models of human disease have enabled the discovery of mechanisms important for host immunity and self-tolerance. Here, we summarize conceptual and clinical discoveries identified from 2018 to 2019 in the field of primary immunodeficiencies and autoimmunity. RECENT FINDINGS: Three new primary immunodeficiencies with autoimmunity were identified and the clinical phenotypes of NFKB1 haploinsufficiency and RASGRP1 deficiency were expanded. A diversity of novel mechanisms leading to autoimmunity associated with primary immunodeficiencies (PIDs) was reported, including pathways important for the metabolism and function of regulatory T cells and germinal B cells, the contribution of neutrophil extracellular traps to plasmacytoid dendritic cell activation and the influence of commensal bacteria on the generation of autoantibodies. With regard to therapeutic developments in the field, we highlight the use of janus kinase inhibitors for immune dysregulation associated with gain-of-function variants in STAT1 and STAT3, as well as the risks of persistent hypogammaglobulinemia associated with rituximab treatment. SUMMARY: Mechanistic studies of PIDs with autoimmunity elucidate key principles governing the balance between immune surveillance and self-tolerance.

Early origins of allergy and asthma (ARIES): study protocol for a prospective prenatal birth cohort in Chile.

BACKGROUND: Growing evidence shows that atopic dermatitis (AD), food allergy (FA), allergic rhinitis, and asthma are largely determined during the first 1000 days (time elapsed from conception to the 2nd birthday). The ARIES birth cohort aims to determine prenatal and perinatal conditions, as well as genetic and epigenetic factors, that participate in the early setting of immune responses, and the role of these in the later determination of the risk of allergic diseases and asthma in the offspring. METHODS: We have designed a birth cohort of 250 families with prenatal recruitment (~ 14 weeks). We will genotype relevant allergy/asthma-associated variants in trios and will perform immunophenotyping and evaluation of allergy biomarkers in cord blood. At 1 and 2 years of age we will assess if infants have developed allergic sensitization, AD, FA, as well as biomarkers of asthma including the asthma predictive index. We will also evaluate how maternal conditions modify immune programming through epigenetic modifications and will then depict newborn epigenetic cues of allergy/asthma risk. Next, we will assess composition/diversity of maternal gut, placenta, breastmilk and infant gut microbiome and their association with immunophenotype and biomarkers at birth, and clinical outcomes at age 1 and 2. Finally, we plan to assess how environmental exposures (perinatal outdoor and indoor pollution, allergens and endotoxin) affect the incidence of allergic sensitization, AD, FA, and risk of asthma. DISCUSSION: The in-depth study of the ARIES birth cohort shall provide crucial information to understand the rising incidence of allergies and asthma in developing countries, and hopefully provide cues on how to prevent and treat these diseases. TRIAL REGISTRATION: clinicaltrials.gov NCT04186949, retrospectively registered on December 5, 2019.

[Severe combined immunodeficiency, report of chilean patients diagnosed during the 1999-2020 period]. / Inmunodeficiencia Combinada Severa, reporte de pacientes chilenos diagnosticados durante el período 1999-2020.

INTRODUCTION: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency. To date, there is little local information about this disease. OBJECTIVE: To describe the epidemiology, complications, prognosis, and use of the BCG vaccine in Chilean patients with SCID. PATIENTS AND METHOD: Retrospective review of the clinical records of patients diagnosed with SCID by clinical immunologists between 1999 and 2020 throughout Chile. SCID was diagnosed according to the cri teria proposed by Shearer: T lymphocytes (CD3+) < 300 cells/µL and proliferation 10% of the limit of normality in response to phytohemagglutinin or presence of T lymphocytes of maternal origin. Data collected from the clinical records were: sex, age at diagnosis, consanguinity, region of origin, lymphocyte subpopulations, genetic diagnosis, infectious and non-infectious complications, BCG vaccination and its complications, age at referral to the bone marrow transplant (BMT) center, and cause of non-BMT-related mortality. RESULTS: Between 1999 and 2020, 25 patients were diagnosed with SCID. 78% of them were male, mean age at first manifestation of the disease was 2.3 months (0-7), while the mean age at diagnosis was 3.4 months (0-7). 16% of patients had a family history of SCID. 40% of cases were diagnosed within the Metropolitan Region. The most frequent immuno- phenotype was T-B-NK+ SCID (48%). Genetic studies were done in 69.5% of cases, mutations in the RAG2 gene were the most common etiology of SCID (39%). 88% of SCID patients received the Bacillus Calmette-Guerin (BCG) vaccine before diagnosis, including 2 cases with a known family history of SCID. 36% of those who received the vaccine had BCG-related complications. The mean age at referral to a bone marrow transplant center was 7.4 months (5-16). 11/25 patients died before being transferred to a transplant center. DISCUSSION: There is a clinically significant delay between the first manifestations and the diagnosis of SCID in Chilean patients, as well as an important time gap between the diagnosis of SCID and referral to a center for BMT. Most SCID cases in Chile receive the BCG vaccine, despite a known family history of the disease, and frequently develop vaccine-related complications.

Vitamin D modulates the allergic phenotype of dendritic cells in children with atopic dermatitis.

Vitamin D (VD) deficiency has been associated with increased incidence and severity of atopic dermatitis (AD), but the mechanisms through which VD may ameliorate AD are unclear. We compared the phenotypic characteristics of circulating myeloid and plasmacytoid dendritic cells (mDCs and pDCs, respectively) of children with AD vs healthy controls (HC) and evaluated if VD can modulate the allergic phenotype of circulating DCs in AD patients. Although there was no difference in frequency of circulating DCs between groups, among children with AD there was an inverse correlation between SCORAD and circulating total DCs and mDCs. In AD, serum IgE concentration correlated with FcεRI and surface-bound IgE expression on mDCs and pDCs; pDCs expressing FcεRI and IgE were significantly increased compared to HC. Ex vivo, 1,25(OH)2 D3 significantly decreased FcεRI expression on mDCs and surface-bound IgE on mDCs and pDCs. Oral VD supplementation reduced expression of surface-bound IgE on pDCs in children with AD. In summary, VD decreases the allergic phenotype of circulating DCs in children with AD, a potential mechanism for how VD supplementation may improve AD severity. Future studies are needed to further assess the role of VD supplementation as an immunomodulatory therapy for AD.

[Severe combined immunodeficiency: The time for newborn screening has come]. / Inmunodeficiencia combinada severa: Es tiempo de su detección precoz.

Primary immunodeficiencies (PIDs) are a set of about 350 genetic disorders that affect the normal function of the immune system. Advances in genetic diagnosis have allowed the description of new defects in the immune system, broadening the clinical spectrum of PIDs' manifestations beyond susceptibility to infection. Although most PIDs present with recurrent or opportunistic infections, a subgroup of them may be recognized by the early development of auto-inflammatory events, tumors and, paradoxically, the coexistence of autoimmunity and immunodeficiency in the same patient. As their clinical manifestations, the severity of PIDs is highly variable. Severe combined immunodefi ciency (SCID), a PID that affects cellular and humoral immunity, is one of the most severe forms of PIDs and the only available curative treatment in Latin America is hematopoietic stem cells trans plantation. All patients affected by SCID die during the first two years of life if they are not diagnosed and treated opportunely. In contrast, early transplantation of patients with SCID can lead to excellent survival outcomes. Despite recent advances in the diagnosis of PIDs in Chile, diagnostic resources are not available throughout the country, making the early diagnosis of SCID and other forms of PID difficult in big areas of Chile. The objective of this article is to review general concepts on the patho physiology, diagnosis, and initial management of SCID and raise the need for the implementation of neonatal screening for SCID in Chile.

Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1.

RASGRP1 is a guanine-nucleotide-exchange factor essential for MAP-kinase mediated signaling in lymphocytes. We report the second case of RASGRP1 deficiency in a patient with a homozygous nonsense mutation in the catalytic domain of the protein. The patient had epidermodysplasia verruciformis, suggesting a clinically important intrinsic T cell function defect. Like the previously described patient, our proband also presented with CD4+ T cell lymphopenia, impaired T cell proliferation to mitogens and antigens, reduced NK cell function, and EBV-associated lymphoma. The severity of the disease and the development of EBV lymphoma in both patients suggest that hematopoietic stem cell transplantation should be performed rapidly in patients with RASGRP1 deficiency.

Solar radiation is inversely associated with inflammatory bowel disease admissions.

OBJECTIVE: To explore the associations between latitude and solar radiation with inflammatory bowel disease admission rates in Chile, the country with the largest variation in solar radiation in the world. PATIENTS AND METHODS: This is an ecological study, which included data on all hospital-admitted population for inflammatory bowel disease between 2001 and 2012, according to different latitudes and solar radiation exposures in Chile. The data were acquired from the national hospital discharge database from the Department of Health Statistics and Information of the Chilean Ministry of Health. RESULTS: Between 2001 and 2012 there were 12,869 admissions due to inflammatory bowel disease (69% ulcerative colitis, 31% Crohn's disease). Median age was 36 years (IQR: 25-51); 57% were female. The national inflammatory bowel disease admission rate was 6.52 (95% CI: 6.40-6.63) per 100,000 inhabitants with increasing rates over the 12-year period. In terms of latitude, the highest admission rates for pediatric ulcerative colitis and Crohn's disease, as well as adult ulcerative colitis, were observed in the southernmost region with lowest annual solar radiation. Linear regression analysis showed that regional solar radiation was inversely associated with inflammatory bowel disease admissions in Chile (ß: -.44, p = .03). CONCLUSIONS: Regional solar radiation was inversely associated with inflammatory bowel disease admission rates in Chile; inflammatory bowel disease admissions were highest in the southernmost region with lowest solar radiation. Our results support the potential role of vitamin D deficiency on inflammatory bowel disease flares.

Higher latitude and lower solar radiation influence on anaphylaxis in Chilean children.

BACKGROUND: Recent studies suggest an association between higher latitude, a proxy of vitamin D (VD) status, and allergic diseases. Chile provides an ideal setting to study this association due to its latitude span and high rates of VD deficiency in southern regions. The aim of this study is to explore the associations of latitude and solar radiation with anaphylaxis admission rates. METHODS: We reviewed anaphylaxis admissions in Chile's hospital discharge database between 2001 and 2010 and investigated associations with latitude and solar radiation. RESULTS: 2316 anaphylaxis admissions were registered. Median age of patients was 41 yr; 53% were female. National anaphylaxis admission rate was 1.41 per 100,000 persons per year. We observed a strong north-south increasing gradient of anaphylaxis admissions (ß 0.04, p = 0.01), with increasing rates south of latitude 34°S. A significant association was also observed between solar radiation and anaphylaxis admissions (ß -0.11, p = 0.009). Latitude was associated with food-induced (ß 0.05, p = 0.02), but not drug-induced (ß -0.002, p = 0.27), anaphylaxis. The association between latitude and food-induced anaphylaxis was significant in children (ß 0.01, p = 0.006), but not adults (ß 0.003, p = 0.16). Anaphylaxis admissions were not associated with regional sociodemographic factors like poverty, rurality, educational level, ethnicity, or physician density. CONCLUSIONS: Anaphylaxis admission rates in Chile are highest at higher latitudes and lower solar radiation, used as proxies of VD status. The associations appear driven by food-induced anaphylaxis. Our data support a possible role of VD deficiency as an etiological factor in the high anaphylaxis admission rates found in southern Chile.

Agreement between dermatologic and pediatric researchers in scoring of atopic dermatitis in children.

The Scoring of Atopic Dermatitis (SCORAD) index is a widely applied instrument for measuring the severity of atopic dermatitis (AD), but few studies have evaluated the interobserver agreement between different disciplines. A cross-sectional study of 21 children with AD evaluated by dermatology and pediatric researchers found excellent agreement between the SCORAD, the objective SCORAD, and the Three Item Severity score, confirming the applicability of these scores by nondermatologists.

Universal Access to On-Demand Treatment of Patients with Hereditary Angioedema, the Chilean Experience.

Background: In Chile, patients with hereditary angioedema (HAE) type I and type II are protected under Ley Ricarte Soto (LRS), which guarantees access to on demand plasma-derived C1-INH (pdC1-INH) since 2018. We aimed to analyze the first 3 years of LRS. Methods: Review of the LRS database between 2018 and 2021. Results: During the study period, 154 patients were covered by LRS, with an estimated prevalence of HAE in Chile at 0.8:100,000 inhabitants. A delay in diagnosis of 22 years was noted, 50 patients received epinephrine during an attack before the diagnosis of HAE. Mean number of attacks per year was 8, with 50% of adults and 42% of children experiencing more than 1 attack per month. Conclusion: Disease awareness must improve to reduce the diagnostic delay of HAE. Long-term prophylactic medications should be included in LRS to treat patients with high attack rates and control the costs of frequent on-demand treatment with pdC1-INH.