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Background: Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and iymphoproliferative disorders. Objective: This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. Methods: Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. Results: Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. Conclusion: Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome. [ABSTRACT FROM AUTHOR]

Background: The influence of cat allergen exposure in early childhood on the development of sensitization and allergic diseases is complex. Little is known about the natural course of the sensitization development within individuals. Objective: We investigated the association between cat allergen exposure in infancy and cat ownership and cat contact during childhood and the development of cat sensitization and allergic diseases up to age 6 years using a longitudinal analysis approach. Methods: Overall, 2166 children from an ongoing birth cohort study were included in the analysis. House dust samples were collected 3 months after birth. Cat allergen levels were extracted. Blood samples were collected when the children were 2 and 6 years old. Information on the allergic symptoms of children and doctor-diagnosed allergic disease were collected at each follow-up using questionnaires. Results: Cat allergen exposure in infancy was positively associated with sensitization at age 2 years but not at age 6 years. No associations existed between cat allergen exposure in infancy and allergic symptoms and diseases up to age 6 years. Cumulative allergen exposure from cat ownership and regular cat contact increased the risk of cat sensitization up to age 6 years. Conclusion: Cat allergen exposure in infancy increases the risk of sensitization development in early childhood but not in school-age children. Cumulative allergen exposure from cat ownership and regular cat contact during childhood contribute to sensitization development up to school age. Clinical implications: Cat allergen avoidance at home alone might be not effective to prevent the development of allergic sensitization in young children. [Copyright &y& Elsevier]

Background: There is evidence that microRNAs (miRNAs) are sensitive to environmental stressors, including tobacco smoke. On the other hand, miRNAs are involved in immune regulation, such as regulatory T (Treg) cell differentiation. The aim of the present study was to investigate the association between prenatal tobacco smoke exposure, miRNAs, and Treg cell numbers. Methods: Within a prospective mother-child study (Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk), we analyzed the expression of miR-155 and miR-223 together with Treg cell numbers in maternal blood during pregnancy, as well as in cord blood (n = 441). Tobacco smoke exposure was assessed based on questionnaire answers and maternal urine cotinine levels. Additionally, the concentration of smoking-related volatile organic compounds was measured in dwellings of study participants. Results: Both maternal and cord blood miR-223 expressions were positively correlated with maternal urine cotinine levels. An association was also found between maternal miR-223 expression and indoor concentrations of benzene and toluene. High miR-223 expression was associated with lower Treg cell numbers in maternal and cord blood. Furthermore, children with lower Treg cell numbers at birth had a higher risk of atopic dermatitis during the first 3 years of life. The concentration of the toluene metabolite S-benzylmercapturic acid in maternal urine was associated with decreased cord blood, but not maternal blood, miR-155 expression. A relationship between miR-155 expression and Treg cell numbers was not found. Conclusions: For the first time, we show that maternal tobacco smoke exposure during pregnancy correlates with the level of miRNA-223 expression in blood, with an effect on children's cord blood Treg cell numbers and subsequent allergy risk. [Copyright &y& Elsevier]

Background: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)–HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis. Objective: To facilitate early diagnosis of AD-HIES to initiate appropriate therapy. Methods: The clinical phenotype (suggested by a National Institutes of Health [NIH] score of ≥40 points), STAT3 genotype, and TH17 cell counts were compared in a cohort of 78 patients suspected of having HIES. Results: Heterozygous STAT3 missense mutations and in-frame deletions were identified in 48 patients, all but 2 with an NIH score ≥40 points. Patients with STAT3 mutations with HIES showed significantly lower TH17 cell counts compared with patients with wild-type STAT3 and control subjects. Only 1 patient with wild-type STAT3 had both an NIH score ≥40 points and abnormal TH17 cell counts (≤0.2% of CD4+ cells), with this exception being identified with a homozygous dedicator of cytogenesis 8 protein (DOCK8) mutation. Pathologic shedding of primary teeth was present in 3 patients with wild-type STAT3 and 33 patients with STAT3 mutations. Internal abscesses and severe infections were exclusively seen in patients with STAT3 mutations, who also had increased pneumatocele formation and skeletal or connective tissue manifestations compared with patients with wild-type STAT3. Conclusion: We expanded the number of STAT3 mutations and validated that the NIH score sensitively identifies patients with HIES. Based on our patient cohort, we propose key findings that, when combined with TH17 cell numbers, predict patients with AD-HIES with STAT3 mutations, supporting early diagnosis of AD-HIES. [Copyright &y& Elsevier]

Background: Several studies showed a protective effect of elder siblings on eczema development, which is in line with the hygiene hypothesis. However, findings are not consistent, and there might exist different causal pathways for the development of eczema. Especially barrier disturbances as found in children with mutations in the filaggrin gene (FLG) seem to play an important role. Objectives: To investigate the interaction between FLG mutations and the presence of elder siblings on the development of eczema in 2 independent birth cohorts. Methods: We used data from 2 German birth cohorts (LISAplus, GINIplus) up to the age of 6 years. Genotyping for FLG mutations (R501X, 2282del4) was performed in 1039 (LISAplus) and 1828 (GINIplus) children. Data on eczema (diagnosis and symptoms) and elder siblings were obtained by parental questionnaires. The association among eczema, FLG mutations, and elder siblings was analyzed longitudinally by using generalized estimating equations. Results: We found no protective effect of elder siblings on eczema development. On the contrary, children with FLG mutations had a significantly higher risk for eczema if they had elder siblings. Attending day care centers lessened this effect. After excluding 303 children who attended early day care, the odds ratio for interaction between FLG mutations and elder siblings was 3.27 (95% CI, 1.14-9.36) in LISAplus and 2.41 (95% CI, 1.06-5.48) in GINIplus. Conclusion: Our findings did not confirm a protective sibling effect. The prevalence of eczema in children with filaggrin deficiency was higher if elder siblings were present. Our results give evidence for complex skin-driven pathogenic mechanisms that might be different depending on children''s genetic backgrounds. [Copyright &y& Elsevier]