Clinical and laboratory evaluation of Turkish children with IgG subclass deficiency

MakaleWOS:000922080700001PubMed ID: 36089538Background: IgG subclass deficiency is a laboratory diagnosis and becomes important with recurrent infections. This study aimed to examine the demographic, clinical, and laboratory results of pediatric cases with IgG subclass deficiency and to improve the understanding of the clinical significance of IgG subclass deficiency. Methods: In this study, the clinical and laboratory features of 111 pediatric patients, with at least one whose serum IgG subclasses was measured as lower than 2 standard deviation of healthy aged-matched control values, were evaluated. The clinical and laboratory features of the cases with isolated IgG subclass deficiency (Group 1) and those with low serum levels of any of IgG, IgA, and IgM in addition to the IgG subclass deficiency (Group 2) were compared. Results: A total of 55 (49.54%) and 56 (50.45 %) patients were included in Groups 1 and 2, respectively. Among our studied cases, 20 (18. 1%) had a history of hospitalization in the neonatal period, 61 (54.95 %) had at least one hospitalization due to infection, and 55 (49.54%) had a history of recurrent infection. The frequencies of these three conditions were statistically significantly higher in Group 2 (p < 0.05). The frequencies of infections in the last year in Groups 1 and 2 were 4.4 +/- 1.2 and 5.4 +/- 1.9, respectively (p < 0.05). As a result of recurrent infections, 43.24% (n = 48) of our patients received antibiotic prophylaxis, and 21.62% (n = 24) had immunoglobulin replacement therapy. Furthermore, the numbers of pa-tients who needed these treatments were higher in Group 2 (p < 0.05).Conclusion: In cases with IgG subclass deficiencies, concomitant main-group immunoglobulin deficiencies may increase the number and severity of infections, leading to hospitalizations, antibiotic prophylaxis, and immunoglobulin therapy. More attention should be paid to cases of immunoglobulin main-group deficiencies in the follow-up of these cases.Copyright (c) 2022, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/)

Chest Imaging Findings in Hospitalized Children with H1N1 Influenza

Objective: The aim was to review the radiological findings and to find new prognostic factors that determine the need for pediatric intensive care unit (PICU) in children with swine-origin influenza (H1N1) virus infection. Methods: Chest X-ray (CXR) and computed tomography (CT) findings of 18 children with laboratory-confirmed H1N1 infection (9 boys, 9 girls) with a median age of 34 (1–216) months were retrospectively evaluated. Results: CXRs were performed in 15 (83.3%) and thorax CT in 7 (38.8%) children. Abnormal findings were detected in 60% of the patients who underwent CXR and 85.7% of the patients who underwent thorax CT. Radiological findings were mostly diffuse, bilateral, and asymmetric. Ground-glass opacity (GGO) (66.6%) was the leading abnormality and was followed by reticulation (38.8%), nodules (27.7%), consolidation only (16.6%), tree-in-bud pattern (11.1%), consolidation with GGO (5.5%), and septal lines (5.5%). Lymphadenopathy (22.2%), air trapping (5.5%), and parenchymal band (5.5%) were other recorded findings. CXR was found to be insufficient to detect subpleural nodules, lymphadenopathies, and sometimes GGO. Only existence of nodules (p=0.04) affected the need for PICU admission. Conclusion: The most common radiological findings in children with H1N1 infection were bilateral, asymmetric GGO with or without associated multifocal areas of consolidation. CXR was insufficient to detect subpleural nodules, lymphadenopathies, and sometimes GGO. The existence of nodules is a bad prognostic factor in determining the need for PICU admission

Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

One of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling of peripheral T-cells. In contrast to the lymphopenia in most SCID patients, ZAP70-deficient patients have lymphocytosis, despite the selective absence of CD8+ T-cells. The clinical presentation is usually before 2 years of age with typical findings of SCID. Here, we present three new ZAP70-deficient patients who vary in their clinical presentation. One of the ZAP70-deficient patients presented as a classical SCID, the second patient presented as a healthy looking wheezy infant, whereas the third patient came to clinical attention for the eczematous skin lesions simulating atopic dermatitis with eosinophilia and elevated immunoglobulin E (IgE), similar to the Omenn syndrome. This study illustrates that awareness of the clinical heterogeneity of ZAP70 deficiency is of utmost importance for making a fast and accurate diagnosis, which will contribute to the improvement of the adequate treatment of this severe immunodeficiency

DOCK8 Functions as an Adaptor that Links TLR–MyD88 Signaling to B Cell Activation

DOCK8 and MyD88 have been implicated in serologic memory. Here we report antibody responses were impaired and $CD27^+$ memory B cells were severely reduced in DOCK8-deficient patients. Toll-like receptor 9 (TLR9)- but not CD40-driven B cell proliferation and immunoglobulin production were severely reduced in DOCK8-deficient B cells. In contrast, TLR9-driven expression of AICDA, CD23 and CD86, and activation of NF-κB, p38 and Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. Following TLR9 ligation, DOCK8 became tyrosine phosphorylated by Pyk2, bound the Src family kinase Lyn and linked TLR9 to a Src-Syk-STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021

IntroductionThe J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI.ResultsIn this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients’ data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174).Conclusions1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries

DiGeorge Syndrome

DiGeorge syndrome, which is caused by abnormal development and migration of neural crest cells, is the most common microdeletion syndrome. The phenotype is variable due to the existence of more than 35 genes in the typical deletion region. However, the genotypephenotype correlation is very weak in this patient group. Every patient with facial dysmorphism, delay in developmental milestones and macrothrombocytopenia should be questioned for the other specific findings of DGS, and tested if needed. All findings do not have to be together to make the diagnosis. It should be known that patients experience different problems at different stages of their lives, and genetic counseling should be provided to the patients and their families. Our aim in this review was to provide detailed information and raise awareness about DGS as it is common but rarely diagnosed, and presents many difficulties during follow-up

Successful Therapy with intravenous gamma globulin in two children with postinfectious bronchiolitis obliterans

Bronchiolitis obliterans (BO) is an infrequent clinical syndrome characterized by the chronic obstruction of small airways due to fibrosis [1]. Intravenous immunoglobulin (IVIG) could be used for treatment while underlying immune mechanisms in the pathogenesis of BO exist [2]. Here, we present two children with BO due to adenovirus infection whose complaints resolved after IVIG replacement

Co-Stimulatory and Inhibitory of T Cell: CD28 Family

Hücresel bağışıklıkta rol oynayan T lenfositlerin, immün yanıt oluşturabilmesi için aktive olmaları gerekmektedir. T lenfosit aktivasyonu için iki sinyal gereklidir. Bu sinyallerden birincisi antijen tarafından sağlanır. İkinci sinyal ise, eş uyaran moleküller tarafından sağlanmaktadır. Yıllar önce T hücrelerin aktivasyonu için herhangi bir eş uyarana ihtiyaç duymadığına inanılmaktaydı. Ancak yapılan in vitro ve in vivo çalışmalar T hücrelerin aktivasyonu ve büyümesi için eş uyaranlara ihtiyaç duyduklarını göstermişlerdir. T hücre aktivasyonu ve büyümesi gerekli eş uyarılar, CD28 ailesi ve tümör nekrosis faktör (TNF) ailesi üyelerine ait olan moleküller tarafından sağlanır. CD28 ailesine ait 4 adet eş uyaran molekül tanımlanmıştır. Bunlar CD28, indüklenebilir T hücre kostimulatör sistemi (ICOS), sitotoksik T lenfosit ilişkili protein 4 (CTLA-4, CD152) ve programlanmış hücre ölümü proteini 1 (PD-1) molekülleridir. CD28 ve ICOS T hücre aktivasyonunda pozitif etkili iken, CTLA-4 ve PD-1 molekülleri negatif etki göstermektedir. Bu derlemede CD28 ailesine ait eş uyaran moleküller, bu moleküllere ait ligandlar ve eş uyaran moleküllerin ligandlarla etkileşimleri tartışılmaktadır.T cells that play role in cell-mediated immunity must be activated in order to generate immune responses. The two signals are required for T cell activation. The first of these signals is provided by the antigen. The second signal is provided by the co-stimulatory molecules. For many years it was believed that T cells do not require co-stimulation for activation. However, in vitro and in vivo studies have shown that T cells need the co-stimulatory molecules for activation and expansion. Co-stimulation for T-cell activation and growth is provided by molecules of CD28 and the tumor necrosis factor (TNF) family members. Four co-stimulatory molecules belonging to the CD28 family have been identified. These family members are CD28, inducible co-stimulator (ICOS), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, CD152) and programmed cell death protein 1 (PD-1). Although CD28 and ICOS showed positive effects, CTLA4 and PD-1 molecule have a negative effect on T cell activation. In this review, we discussed co-stimulatory molecules belonging to the CD28 family, the ligands of these molecules, and the interactions of co-stimulatory molecules with ligands