GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway.

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.

The spectrum of side effects associated with COVID-19 vaccines in patients with inborn errors of immunity.

OBJECTIVE: COVID-19 immunization was implemented with emergency-use authorization. We had concerns/lack of information on mRNA vaccine side effects in different inborn errors of immunity (IEI) types. METHODS: We enrolled 141 patients (IEIP) and 151 healthy controls(HC) who received SARS-CoV-2 vaccine/s(Sinovac and/or Pfizer-BioNTech(mRNA vaccine), one to five doses), questioned them for side-effects, evaluated in three groups according to the vaccine/s they received; only Sinovac, only Pfizer-BioNTech, and both vaccines. RESULTS: Arm pain, generalized weakness, myalgia, and fever were common side effects in IEI-P and HC groups. Generalized weakness/fatigue, fever, and palpitation were significantly frequent in IEI-P who experienced COVID-19 compared to those who did not (p = 0.021, p = 0.047, and p = 0.024, respectively). Severe symptoms after vaccination, new-onset splenomegaly and pancytopenia, urticaria, herpes simplex virus (HSV), and varicella zoster virus (VZV) reactivation were seen in four IEI-P (2.8%). CONCLUSION: IEI-P mRNA vaccination is relatively safe compared to the conventional vaccine. Individuals who experience uncommon side effects should undergo immunological screening.

Genetic Evaluation of the Patients with Clinically Diagnosed Inborn Errors of Immunity by Whole Exome Sequencing: Results from a Specialized Research Center for Immunodeficiency in Türkiye.

Molecular diagnosis of inborn errors of immunity (IEI) plays a critical role in determining patients' long-term prognosis, treatment options, and genetic counseling. Over the past decade, the broader utilization of next-generation sequencing (NGS) techniques in both research and clinical settings has facilitated the evaluation of a significant proportion of patients for gene variants associated with IEI. In addition to its role in diagnosing known gene defects, the application of high-throughput techniques such as targeted, exome, and genome sequencing has led to the identification of novel disease-causing genes. However, the results obtained from these different methods can vary depending on disease phenotypes or patient characteristics. In this study, we conducted whole-exome sequencing (WES) in a sizable cohort of IEI patients, consisting of 303 individuals from 21 different clinical immunology centers in Türkiye. Our analysis resulted in likely genetic diagnoses for 41.1% of the patients (122 out of 297), revealing 52 novel variants and uncovering potential new IEI genes in six patients. The significance of understanding outcomes across various IEI cohorts cannot be overstated, and we believe that our findings will make a valuable contribution to the existing literature and foster collaborative research between clinicians and basic science researchers.

Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.

Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1 and RAG2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. The male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n = 25; 71.4%), OS (n = 5; 14.3%), and CID (n = 5; 14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% were in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 mo (4-13.5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.

A large single-center cohort of bare lymphocyte syndrome: Immunological and genetic features in Turkey.

Major histocompatibility complex class II (MHC-II) deficiency or bare lymphocyte syndrome (BLS) is a rare, early-onset, autosomal recessive, and life-threatening inborn error of immunity. We aimed to assess the demographic, clinical, laboratory, follow-up, and treatment characteristics of patients with MHC-II deficiency, together with their survival. We retrospectively investigated 21 patients with MHC-II deficiency. Female/male ratio was 1.63. The median age at diagnosis was 16.3 months (5 months-9.7 years). Nineteen patients (90.5%) had parental consanguinity. Pulmonary diseases (pneumonia, chronic lung disease) (81%), diarrhoea (47.6%), and candidiasis (28.6%) were common. Four (19%) had autoimmunity, two developed septic arthritis, and three (14%) developed bronchiectasis in the follow-up. Three patients (14%) had CMV viraemia, one with bilateral CMV retinitis. Eight (38.1%) had lymphocytopenia, and four (19%) had neutropenia. Serum IgM, IgA, and IgG levels were low in 18 (85.7%), 15 (71.4%), and 11 (52.4%) patients, respectively. CD4+ lymphocytopenia, a reversed CD4+/CD8+ ratio, and absent/low HLA-DR expressions were detected in 93.3%, 86.7%, and 100% of the patients, respectively. Haematopoietic stem cell transplantation (HSCT) was performed on nine patients, and four died of septicaemia and ARDS after HSCT. The present median age of patients survived is 14 years (1-31 years). Genetic analysis was performed in 10 patients. RFX5 homozygous gene defect was found in three patients (P1, P4 and P8), and RFXANK (P2 and P14) and RFXAP (P18 and P19) heterozygous gene defects were found in each two patients, respectively. This large cohort showed that BLS patients have severe combined immunodeficiency (SCID)-like clinical findings. Flow cytometric MHC-II expression study is crucial for the diagnosis, differential diagnosis with SCID, early haematopoietic stem cell transplantation (HSCT), and post-HSCT follow-up. Genetic studies are required first for matched family donor evaluation before HSCT and then for genetic counselling.

Eosinophilia in children: characteristics, etiology and diagnostic algorithm.

Eosinophilia is common in children and may be caused by various disorders. Large-cohort studies, including mild cases, are limited in children. This study aimed to reveal underlying etiologies of childhood eosinophilia and to create a diagnostic algorithm. Children (< 18 years) with absolute eosinophil counts (AECs) ≥ 0.5 × 109/L were reviewed from medical files. Clinical characteristics and laboratory values were recorded. Patients were grouped based on the severity of eosinophilia as mild (0.5-1.5 × 109/L), moderate (≥ 1.5 × 109/L) and severe (≥ 5.0 × 109/L). An algorithm was formed to evaluate these patients. We included 1178 children with mild (80.8%), moderate (17.8%) and severe eosinophilia (1.4%). The most common reasons of eosinophilia were allergic diseases (80%), primary immunodeficiency (PID) (8.5%), infectious diseases (5.8%), malignancies (0.8%) and rheumatic diseases (0.7%). Only 0.3% of children presented with idiopatic hypereosinophilic syndrome. Allergic diseases and PIDs were the most common etiologies in mild/moderate and severe groups, respectively. The median duration of eosinophilia was 7.0 (3.0-17.0) months in the study population and was the shortest in severe cases (2.0 (2.0-5.0) months). Multiple logistic regression analysis demonstrated food allergy [OR:1.866, 95%CI:1.225-2.842, p = 0.004] and PIDs [OR:2.200, 95%CI:1.213-3.992, p = 0.009] as independent factors for childhood eosinophilia. A diagnostic algorithm including mild form was presented for childhood eosinophilia.    Conclusion: Eosinophilia was frequently determined due to secondary causes; allergic diseases in mild/moderate eosinophilia, PIDs in severe group. Etiology of eosinophilia was diverse, and an algorithm concerning the severity of eosinophilia would be practical and rational. What is Known: • In children, eosinophilia is common, and mild eosinophilia occurs frequently. • Malignancies presents frequently with severe eosinophilia. What is New: • Primary immunodeficiencies were not a rare cause of eosinophilia, especially in countries such as the Middle East and eastern Mediterranean countries, where the countries consanguineous marriages are common, and should be investigated in children with eosinophilia who do not have allergic or infectious diseases. • In literature, there are many algorithms about childhood hypereosinophilia. However, mild eosinophilia is extremely important in children. Because all patients with malignancy and most of the patients with rheumatic diseases presented with mild eosinophilia. Therefore, we proposed an algorithm for childhood eosinophilia that includes mild eosinophilia besides moderate and severe cases.

Different age groups present different clinics in anaphylaxis with children: one size does not fit all children.

BACKGROUND: Childhood anaphylaxis presents with a heterogeneous clinic. Elicitors and epidemiologic factors associated with anaphylaxis differ with age, geographic location and lifestyle. This study aimed to determine the clinical features and age-specific patterns of childhood anaphylaxis in a single referral center in Turkey. METHODS: We conducted a retrospective study of anaphylaxis in children aged between 0 and 18 years of age, attending an allergy department in a children's hospital. RESULTS: A total of 95 children diagnosed with anaphylaxis were analyzed. Among all, 35.8% of the first anaphylaxis episodes occurred ininfancy and 57.9% in preschool age. Foods were the most common culprits (57.9%) and followed by drugs (15.8%). Patients with foodinduced anaphylaxis were younger in age (p < 0.001). Food-related anaphylaxis was most common with cow's milk (36.4%) and followed by tree nuts (20%). Cow's milk played a significant role as a trigger in infancy, and tree nuts as a trigger in preschoolers and school-age children. Mucocutaneous manifestations were almost universally present (94.7%), followed by respiratory compromise (56.8%), with gastrointestinal (55.8%), cardiovascular (9.5%), and neurologic (4.2%) symptoms being less common. Respiratory and cardiovascular system-related symptoms were found more frequently in school-age children (p = 0.02 and p = 0.014, respectively). The severity of anaphylaxis was higher in school-age children (p = 0.015). DISCUSSION: Findings reveal that children diagnosed with anaphylaxis differ in terms of etiological and clinical findings according to age groups. This difference shows the dynamically changing clinic of anaphylaxis over time and the importance of evaluating childhood anaphylaxis according to age groups.

Safety and efficacy of rapid drug desensitization in children.

BACKGROUND: Any drug taken at the recommended dosage may cause hypersensitivity reactions (DHR). Rapid drug desensitization (RDD) protocols have been developed in the case of a confirmed or highly suspected HSR to allow safe administration of the medicine when there is no alternative drug or in the presence of a less effective or more toxic alternative. The aim of this study was to evaluate the characteristics of children who underwent desensitization, the safety and efficacy of RDD in children, as well as, the characteristics and management of breakthrough reactions. METHOD: This retrospective study concerned children who underwent RDD due to physician-diagnosed HSRs during or up to 48 hours after the infusion of various drugs between February 2010-February 2021. Patients with a chronic disease needing chronic drug usage and acute infections seen in patients with chronic diseases were included. The results of RDD were documented. RESULTS: The study included 48 patients [8.1(IQR = 3.32-13.4) years, 60.4% male] with 58 HSRs of which 62.1% were classified as moderate and 5.2% as severe. Most of the patients were being treated for leukemia (41.7%), solid tumors (29.2%), and infections (6.3%). Skin tests were done for 41 out of 58 HSRs in 35 patients, and twenty of them were positive. A total of 269 RDDs were performed for 18 different drugs. Ninety percent of desensitizations were achieved with no reaction, and 3.7% and 5.6% with mild and moderate reactions, respectively. In multivariate analysis, skin test positivity was the only risk factor for breakthrough reactions (OR = 8.5, CI = 1.72-42.15, p = .009). CONCLUSION: We demonstrated the safety and efficacy of RDD in childhood, thereby offered the first line treatment options to children with chronic diseases with hypersensitivity reactions (HSRs).

Psychological burden of asthma in adolescents and their parents.

INTRODUCTION: Asthma, a common chronic disease in adolescents is impacted by factors affecting quality of life. This study aimed to determine the psychosocial factors of adolescents with asthma and their parents. METHODS: The study included 122 adolescents with asthma, 82 healthy controls, and their parents who completed the Asthma Control Test (ACT), Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Brief Symptom Inventory (BSI). RESULTS: The mean age was 14.2 ± 1.9 years. ACT score was high and depression was low in patients with good treatment compliance. As the age of the first asthma symptoms/diagnosis increased, somatization, anxiety, hostility and general psychopathology scores increased, as did the somatization score of parents. Parental anxiety score was not related with adolescent BSI scores in the controls but in the study group when it was higher, the anxiety, depression, somatization, and general psychopathology scores were higher. PAQLQ showed that anxiety, negative self-esteem, somatization, depression, and general psychopathology were higher in patients concerned about asthma. Depression and somatization scores were higher in the parents of patients who perceived that "Treatment does not contribute to asthma control." Somatization scores were higher among parents of patients who noted: "Asthma will not pass in the long-term" and "I cannot control asthma." CONCLUSION: Higher scores of asthma patients who were anxious about the disease and families who were despondent about treatment demonstrate that health care providers should spend more time informing patients and caregivers. Increasing patient treatment compliance during early adolescence will lessen the psychological burden of the disease.

Nutritional status of children with primary immunodeficiency: A single center experience.

BACKGROUND: Nutritional status in primary immunodeficiencies (PID) is a major factor influencing immune defense. We aimed to evaluate the nutritional status of patients with PID. METHODS: Demographic findings and anthropometric measurements of 104 patients were recorded for this cross-sectional study. RESULTS: Combined immunodeficiencies (n = 49), predominantly antibody deficiencies (n = 28) and phagocytic system disorders (n = 17), were the major disease groups. In total, 44 (42.3%) patients had at least one anthropometric measurement below -2 standard deviations. Chronic, acute, and mixed-type malnutrition were detected in 18.3%, 16.3%, and 7.7% of the patients, respectively. No significant difference was detected among groups regarding anthropometric measurements however higher malnutrition rates were observed in 'combined immune deficiency less profound than severe combined immuno deficiency' (52%), chronic granulomatous disease (66.6%), and X-linked agammaglobulinemia (50%) patients. Severe malnutrition was present in 22 (21.2%) of the patients, although it was not significant. It was more common in the phagocytic system disorder group. All patients in the severe combined immunodeficiency group had undergone hematopoietic stem cell transplantation and 50% of them had malnutrition. There was also no significant difference regarding age, sex, anthropometric indexes (Weight for age, lenght/height for age body mass index Z-scores), malnutrition types, and prevalence of malnutrition among three major disease groups. Only the hospitalization history inversely related to body mass index and weight for age Z-scores (P < 0.0001). In patients with malnutrition, daily caloric intake was at least 20% or more below the requirement. CONCLUSIONS: Regardless of the type of immunodeficiency, nutritional status was poor in PID and hospitalization is the most important determinant of nutritional status. Even after hematopoietic stem cell transplantation, nutritional support should be continued.

In case of recurrent wheezing and bronchiolitis: Think again, it may be a primary immunodeficiency.

BACKGROUND: Wheezing, starting early in life, is a heterogeneous medical condition caused by airway obstruction due to different underlying mechanisms. Primary immunodeficiencies are also among the risk factors that cause wheezing and recurrent bronchiolitis. ADA deficiency is a primary immunodeficiency, also a rare metabolic disease associated with multisystemic clinical findings. OBJECTIVE: This report will be helpful for adressing the importance of thinking primary immunodeficiency in case of wheezing and recurret bronchiolitis. METHODS: The patient was diagnosed by using a targeted next generation sequencing PID panel. Lymphocyte subsets were measured by flow-cytometry. RESULTS: Here we present an infant with ADA deficiency who admitted with wheezing and recurrent bronchiolitis as the first presentation. He was found to have wheezing, relative CD4+ T cell deficiency, and prolonged neutropenia. CONCLUSIONS: Primary immunodeficiencies including ADA deficiency should be considered in infants with wheezing, recurrent bronchiolitis, lymphopenia and neutropenia.

Clinical and Immunological Characteristics of 63 Patients with Chronic Granulomatous Disease: Hacettepe Experience.

BACKGROUND: Chronic granulomatous disease (CGD), one of the phagocytic system defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex which generates reactive oxygen species (ROS), which are essential for killing pathogenic microorganisms, especially catalase-positive bacteria and fungi. OBJECTIVE: The objective of our study was to assess the clinical and laboratory characteristics, treatment modalities, and prognosis of patients with CGD. METHODS: We retrospectively reviewed 63 patients with CGD who have been diagnosed, treated, and/or followed-up between 1984 and 2018 in Hacettepe University, Ankara, in Turkey, as a developing country. RESULTS: The number of female and male patients was 26/37. The median age at diagnosis was 3.8 (IQR: 1.0-9.6) years. The rate of consanguinity was 63.5%. The most common physical examination finding was lymphadenopathy (44/63), growth retardation (33/63), and hepatomegaly (27/63). One adult patient had squamous cell carcinoma of the lung. The most common infections were lung infection (53/63), skin abscess (43/63), and lymphadenitis (19/63). Of the 63 patients with CGD, 6 patients had inflammatory bowel disease (IBD). Twelve of the 63 patients died during follow-up. CYBA, NCF1, CYBB, and NCF2 mutations were detected in 35%, 27.5%, 25%, and 12.5% of the patients, respectively. CONCLUSION: We identified 63 patients with CGD from a single center in Turkey. Unlike other cohort studies in Turkey, due to the high consanguineous marriage rate in our study group, AR form of CGD was more frequent, and gastrointestinal involvement were found at relatively lower rates. The rate of patients who treated with HSCT was lower in our research than in the literature. A majority of the patients in this study received conventional prophylactic therapies, which highlight on the outcome of individuals who have not undergone HSCT.

Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: A multicenter study in Turkey.

Leukocyte adhesion deficiency type I is a rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type 1 (LAD-1). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1-48) months. Eleven (73%) of the 15 patients had a LAD-1 diagnosis in their first 6 months and 14 (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n = 12) of the patients in our cohort, whereas omphalitis was observed in 53% (n = 8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n = 11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-1 were characterized, two of which (c.305_306delAA and c.779_786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305_306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent hematopoietic stem cell transplantation. Two patients died because of HSCT complications and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling.

Frequency of HLA Class I and Class II Alleles in Patients with CVID from Turkey.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Certain gene loci are pointed out in several studies in CVID patients. Until now, monogenic defects have been identified in only 2-10% of CVID patients; therefore, association of the disease with HLA alleles may be important for elucidating immunological and genetic mechanisms behind CVID. The aim of this study is to investigate the relationship between CVID and HLA alleles. METHODS: HLA class I/II alleles were analyzed in 65 patients with CVID and alleles that may be related to disease susceptibility were determined by comparing with 300 healthy controls. We also evaluated HLA allele frequencies in CVID patients with gastrointestial system (GIS) involvement and autoimmune manifestations. RESULTS: When compared with controls, frequencies of B*27, B*35, C*04, and DRB1*04 alleles were significantly different in patients with CVID (p < .05). Frequencies of C*12, DRB1*13, and DRB1*15 alleles were more frequent in controls, indicating protective alleles (p < .05). There was a statistically significant difference for DQ2 and DQ8 haplotypes between patients with GIS involvement and controls. CONCLUSION: In comparison with literature, distinctive HLA alleles found in our study may originate from the diversity in gene pool between the populations. These data may provide clues for disease susceptibility.

Infantile atopic dermatitis: Serum vitamin D, zinc and TARC levels and their relationship with disease phenotype and severity.

BACKGROUND: Several markers that influence the clinical course of atopic dermatitis (AD) have been investigated so far. Thymus and activation regulated chemokine (TARC) - a Th2-related cytokine - increase in various atopic diseases. It has been shown that vitamin D affects Treg cells and immune responses. Zinc as an essential trace element for cell-cell interactions, cellular differentiation, and proliferation. However, the effect of these markers on infantile AD and disease severity are mostly unknown. OBJECTIVE: The aim of this study was to investigate the relationship between TARC, vitamin D, zinc levels, and the disease severity in infants with AD. METHOD: AD patients (n = 160) with age and sex that matched healthy controls (n = 79) were included in the study. The diagnosis of AD was made based on the Hanifin-Rajka criteria. The objective SCORAD index was used for the assessment of disease severity. RESULTS: A total of 160 patients (male 71.9%) with AD were included in the study. The median age of onset of symptoms was 2 (1.0-3.5) months. The lesions initially started on face 76.9%, neck 6.9%, extremities 7.5%, and body 8.8%. Nearly 40% of the patients were found to be atopic. Food allergy was found in 39.4%. The median of objective SCORAD index was 27.5 (17.5-40) in the study group. The TARC levels of AD patients were higher than control group [1803 pg/ml (1006- 3123) vs 709 pg/ml (504-1147), p < 0.001] There was a significant correlation between objective SCORAD scores and TARC values in subjects with AD (r = 0.363, p < 0.001). As the severity of AD increased, vitamin D levels decreased (p for trend 0.015) and TARC values increased (p for trend < 0.001). Serum zinc levels did not change with the severity of the disease. The presence of atopy did not have an influence on serum TARC, zinc, and vitamin D levels. CONCLUSION: In infants with AD, disease severity is positively related with TARC levels; and inversely proportional to vitamin D levels. TARC levels differ between patients and healthy controls. The presence of atopy has not been shown to affect these markers. © 2021 Codon Publications. Published by Codon Publications.

Pistachio and cashew nut allergy in childhood: Predictive factors towards development of a decision tree.

BACKGROUND: Pistachio and cashew nut, which belong to the same botanical family, are tree nuts that induce serious allergic reactions. OBJECTIVE: We aimed to determine the predictive factors for pistachio and cashew nut reactivity during oral food challenge (OFC). METHODS: A total of 112 pistachio and/or cashew nut sensitized children, aged 58.45 (IQR:40.38-88.32) months, were included. Cutoff values and probability curves for skin prick test (SPT), sIgE, sIgE/Total IgE that predict reactivity were determined for pistachio and cashew nut. Additionally, a diagram was created that can be useful while making a decision for OFC based on SPT and sIgE values. RESULTS: A total of 73 patients underwent OFC with pistachio and/or cashew nut. Twelve children with current anaphylaxis history were not challenged and accepted as allergic. SPT was the only predictive factor for positive pistachio/ cashew nut OFC. According to area under curve (AUC) analysis, SPT was more predictive than sIgE and sIgE/Total IgE both for pistachio and cashew nut. Optimal cutoff values according to "Youden index" for pistachio SPT, sIgE, and sIgE/ Total IgE were 7.25 mm, 4.14 kUA/L, and 1.32%, respectively. And those values for cashew nut SPT, sIgE, and sIgE/Total IgE were 6.25 mm, 1.125 kUA/L, and 3.30%, respectively. The diagram showed that SPT predicted the reactivity together with sIgE better than only the SPT values. CONCLUSION: SPT was the best predictor for reactivity both for pistachio and cashew nut. Combined use of SPT and sIgE may improve the prediction of reactivity at pistachio and cashew nut OFCs in children.

Systemic and large local reactions during subcutaneous grass pollen immunotherapy in children.

BACKGROUND: Subcutaneous immunotherapy (SCIT) is the allergen-specific curative treatment of allergic rhinitis. Adverse effects, most of which are local, can be observed during the immunotherapy. These adverse effects have been reported more frequently during the pollen season. The purpose of this study was to estimate the rate of local, large local, and systemic reactions during the treatment, to determine the relationship between adverse reactions and the season in which these reactions occur, as well as the risk factors for adverse reactions during the grass pollen-specific SCIT treatment in children. METHODS: We retrospectively collected and analyzed the data of 261 children who administered grass pollen SCIT between 2008 and 2018. RESULTS: A total of 261 children (177, 67.8% male), who received grass pollen SCIT, with a mean (±SD) age of 12.0 ± 3.0 years at the initiation of SCIT were enrolled to the study. The number of the patients who experienced local and large local reactions was 109 and 30, respectively. In addition, the number of the patients with systemic reactions was 35. After the 12 284 injections, local reactions occurred in 357 (2.9%), and this was followed by systemic reaction as 55 (0.4%) and large local reactions as 40 (0.3%). Frequency of local (P < .001) and systemic reactions (P = .003) was higher during grass pollen season than out of the grass pollen season. In multivariate analysis, initiation of SCIT during the grass pollen season [OR:7.351, 95%CI:1.532-35.279, P = .013] and experiencing local reactions [OR:4.214, 95%CI:2.159-8.224, P < .001] were independent predictors for the development of large local and systemic reactions. CONCLUSION: SCIT, in which only mild-to-moderate systemic reactions occurred, is safe for the treatment of allergic rhinitis in children. Our study revealed that previous local reactions and initiation of immunotherapy during the grass pollen season were the predictors for large local and systemic reactions during SCIT in children.

Predictors for late tolerance development in food protein-induced allergic proctocolitis.

Background: Food protein-induced allergic proctocolitis (FPIAP) is a non-immunoglobulin E (IgE) mediated food allergy that typically presents with blood-mixed mucoid stool. Objective: To identify the predictors that affect the tolerance development in infants with FPAIP and laboratory as well as clinical differences between patients with early and with late tolerance. Methods: A total of 185 infants with FPIAP were included. The patients were grouped and analyzed based on laboratory tests and clinical characteristics. Results: The median (interquartile range [IQR]) age of onset of symptoms was 2.0 months (1.0-3.0 months). Symptoms began in severe cases in patients (n = 23) at a younger median (IQR) age (1.5 months [0.7-2.0 months]) than the group with nonsevere presentation (median 2.0 months [IQR 1.5-3.0 months]) (p < 0.001). The frequency of neutropenia (<1500/mm³) (p = 0.045) and eosinophilia (450 mm³) (p = 0.018) was increased in severe cases. Concomitant IgE-related food allergy (odds ratio [OR] 3.595 [95% confidence interval {CI}, 1.096-11.788], p = 0.035), non-IgE-mediated multiple food allergy (OR 3.577 [95% CI, 1.595-8.018], p = 0.002), feeding with cow's milk-based formula (at least once during infancy) (OR 2.517 [95% CI, 1.188-5.333], p = 0.016), and late complementary feeding (OR 5.438 [95% CI, 2.693-10.981], p < 0.001) were the predictors for late tolerance development. The estimated optimal cutoff value for introduction of complementary foods for the resolution of allergy was 5.5 months, with 69.4% sensitivity, 74.4% specificity, and an area under the curve of 0.737 (95% CI, 0.626-0.812) (p < 0.001). Conclusion: This study showed that the early introduction of complementary feeding accelerates tolerance development in FPAIP. A longer duration of an elimination diet has no impact on the resolution of allergy. Physicians should consider conservative avoidance measures and earlier introduction of complementary feeding in FPIAP.

A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects.

INTRODUCTION: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. METHODS: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). RESULTS: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαß+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. CONCLUSION: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.