Betul Karaatmaca

Different Phenotypes of Non-Steroidal Anti-Inflammatory Drug Hypersensitivity during Childhood

Background: Although non-steroidal anti-inflammatory drug hypersensitivity (NSAID-H) has been widely studied in adults, there is still a lack of data regarding the features and phenotypes of NSAID-H in children. Our aim was to define risk factors and different phenotypes according to clinical patterns. Methods: Patients with a history of reaction to any NSAIDs referred between January 2012 and October 2014 were included. After completing a European Network for Drug Allergy (ENDA) questionnaire, initial skin and/or oral provocation tests (OPTs) were performed for the offending drug. Additional OPTs were done with aspirin in case of NSAID-H to determine cross-reactivity. NSAID-hypersensitive patients were defined as being either a selective responder (SR) or cross-intolerant (CI) and further categorized according to either the ENDA/GA2LEN classification or an alternative scheme by Caimmi et al. [Int Arch Allergy Immunol 2012;159:306-312]. Results: Among 121 patients [58.7% male, average age 7.8 years (4.7-10.8)] with 161 NSAID-related reactions, 110 patients with 148 reactions were assessed. NSAID-H was diagnosed in 30 (27%) patients with 37 (25%) reactions. Multivariate regression analysis revealed that an immediate-type reaction and respiratory symptoms during the reaction increased the risk of a reproducible NSAID-related reaction (OR 3.508, 95% CI 1.42-8.7, p = 0.007; OR 3.951, 95% CI 1.33-11.77, p = 0.014, respectively). Additional OPTs revealed 13 SRs and 14 CIs. A family history of allergic disease was more frequent in CIs compared to SRs (57.1 vs. 15.4%, p = 0.031). Reactions belonging to CIs were more frequently characterized by angioedema compared to those of SRs (81.3 vs. 46.2%, p = 0.019). SRs and CIs were further classified as single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 13), NSAID-induced urticaria/angioedema (n = 7), NSAID-exacerbated cutaneous disease (n = 2) and NSAID-exacerbated respiratory disease (n = 1). Four CIs could not be categorized according to either classification system. One SR could not be categorized according to ENDA/GA2LEN. Conclusion: During childhood, NSAID-H exhibits different phenotypes and the majority of them can be categorized with current classification systems; however, classifications based on adult data may not exactly fit NSAID-H in paediatric patients.

The persistence of chronic spontaneous urticaria in childhood is associated with the urticaria activity score.

BACKGROUND There is little information regarding the etiology and natural course of chronic spontaneous urticaria (CSU) in childhood. OBJECTIVE To investigate the etiology, prognosis, and the factors associated with the prognosis of CSU in children. METHOD Data from children with CSU who had been diagnosed between 1992 and 2015 were analyzed. A telephone interview was done to assess the current status of these patients. Remission was defined as the disappearance of urticaria for >6 months. RESULTS A total of 222 children with CSU were evaluated. The median age of symptom onset was 8.8 years (interquartile range [IQR], 4.6-12.3 years), median duration of urticaria was 23 months (IQR, 7-48 months), and the median sum of the daily urticaria activity score of 7 consecutive days (UAS7) was 28 (IQR, 21-42). Accompanying angioedema was reported by 107 patients (48.2%), whereas 27.1% of the study population had autoantibody positivity. Autologous serum skin testing results were positive in 43 (34.1%); skin-prick testing results revealed atopy in 55 children (27.9%). Parasites (4.8%), pollen sensitization (1.5%), food allergy (0.9%), urinary tract infection (0.9%), and Hashimoto thyroiditis (0.5%) were determined as etiologic factors of CSU. The patients were followed up for a median time of 15 months (IQR, 5-36.5 months). Remission was observed in 10.6, 29.3, and 44.5% of the patients in 1, 3, and 5 years, respectively. In multivariate regression analysis, a UAS7 of >28 at admission was found to be a risk factor for persistence of urticaria (odds ratio 6.22 [95% confidence interval, 1.54-25.15; p = 0.010). CONCLUSION The etiology of CSU in children was mostly idiopathic despite detailed investigation. In childhood, the natural course of CSU was favorable, and nearly half of the patients recovered after 5 years of disease duration. A high UAS7 at admission seemed to be a significant risk factor for the persistence of symptoms.

Basal serum tryptase is not a risk factor for immediate-type drug hypersensitivity during childhood.

High serum basal tryptase (sBT) levels have been identified as a risk factor for both venom‐ and food‐induced severe allergic reactions. The aim of this study was to compare sBT levels in children with different severity of actual drug hypersensitivity reactions (DHRs) with those of age‐ and sex‐matched controls without any history of DHRs.

Characteristics of children with food protein-induced enterocolitis and allergic proctocolitis.

BACKGROUND The aim of this study was to determine and compare the clinical and laboratory features of food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP), and to provide information about the short-term prognoses. METHOD Children diagnosed with FPIES or FPIAP between 2010 and 2015 were enrolled in this study. RESULTS Overall, 64 infants (37 FPIAP, 27 FPIES) were evaluated, with the average age at the onset of symptoms being significantly lower in the patients with FPIAP than in the patients with FPIES (2 months [1-3 months] versus 4 months [1.5-6 months]; p = 0.043). Fifteen of the patients with FPIAP (40.5%) and six of the patients with FPIES (22.2%) were exclusively breast-fed at the time of the onset of symptoms. Cows milk was the most frequent trigger (100% FPIAP, 74% FPIES); solid foods caused FPIES more frequently. Forty-eight of the 64 patients were followed up until at least 2 years of age, with the resolution rates being 91.3% for FPIAP and 60% for FPIES. The solid food-induced cases of FPIES (27.3%) had a significantly lower rate of resolution than the liquid food-induced FPIES (83.3%) (p = 0.003). CONCLUSION Cows milk is the most common trigger of both FPIAP and FPIES. The symptom onset age seemed to be earlier in FPIAP. The resolution age was similar, however, the recovery in FPIES may be later if the trigger food is solid. To our knowledge, this was the first clinical study to compare the clinical and laboratory characteristics of patients with FPIAP and FPIES.

Parasitic Infections in Children with Chronic Spontaneous Urticaria

Background: Parasites have been proposed to be an underlying cause of chronic spontaneous urticaria (CSU) in childhood, but a clear causal relationship between them has not been established. This study aimed to investigate the prevalence of parasitic infection-related CSU (PIRCSU) in children and to determine the factors associated with PIRCSU. Method: Data from 211 children with CSU were analyzed. Information on stool examination, antiparasitic medications received, and response to treatment was recorded. The disappearance of urticaria for more than 6 months is defined as remission, and remission of urticaria after antiparasitic treatment is defined as PIRCSU. Results: Parasites were detected in 21 (10%) patients. Blastocystis hominis was the most common parasite. After antiparasitic medication, all samples became normal; urticaria continued in 5, was reduced in 6, and disappeared in 10 patients. The latter 10 patients were considered as cases of PIRCSU (4.7%). The erythrocyte sedimentation rate was significantly higher in patients with PIRCSU than in those without [8.5 mm/h (3.5-14.5) vs. 2 (0-7), p = 0.011]. Gastrointestinal complaints were significantly more frequent in patients with PIRCSU than in those without. The occurrence of abdominal pain was a significant risk factor that increased the probability of PIRCSU [OR = 6.60, 95% CI = 1.35-32.23, p = 0.020]. Conclusion: Parasites may cause CSU even in nontropical countries, and remission may only be possible with the treatment of the parasitic infection. The occurrence of abdominal pain points to parasitic infection in patients with CSU. Therefore, we suggest that parasites should be investigated routinely, especially if the patient has gastrointestinal symptoms of CSU in childhood.

ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome

IntroductionAdenosine deaminase (ADA) deficiency is an autosomal recessive primary immunodeficiency. It results in the intracellular accumulation of toxic metabolites which have effects particularly on lymphocytes and the brain. The aim of this study was to evaluate the outcome of 13 ADA-deficient patients. We planned to evaluate their clinical and laboratory findings before and after enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (aHSCT), and hematopoietic stem cell gene therapy (HSCGT).MethodsMeasurement of ADA enzyme activity and metabolites and sequencing of the ADA gene were performed in most of the patients with ADA deficiency. One of the patients with late-onset ADA deficiency was diagnosed by the help of primary immunodeficiency panel screening.ResultsTen out of 13 patients were diagnosed as SCID, while 3 out of 13 were diagnosed as delayed-/late-onset ADA deficiency. Late-onset ADA deficiency patients had clinical and laboratory findings of combined immunodeficiency (CID). Eight patients with ADA-SCID were found to have higher levels of ADA metabolite (dAXP%) (62.1% (34.6–71.9)) than 3 patients with delayed-/late-onset ADA deficiency (6.9% (2.1–8.9). All but one patient with SCID had T-B-NK− phenotype, one had T-B-NK+ phenotype. Genetic defect was documented in 11 patients. Four out of 11 patients had compound heterozygous defects. Three out of 4 patients with compound heterozygous defects had delayed-onset/late-onset ADA deficiency. Seven out of 11 patients with SCID had homozygous defects. Five out of 7 had the same homozygous indel frameshift mutation (c.955-959delGAAGA) showing a founder effect. There were two novel splice site defects: one (IVS10+2T>C) was heterozygous in a patient with late-onset ADA deficiency, and the other was homozygous (IVS2delT+2) in a SCID patient. Other defects were missense defects. Nine out of 13 patients were put on pegylated ADA ERT. Four out of six patients were transplanted without using a conditioning regimen. HSCGT was performed to one of the patients.ConclusionThe genetic diagnosis of SCID is utmost important. There is a chance to give ERT before the definitive therapy if the patient with SCID/CID has ADA deficiency. Although ERT was insufficient to restore a normal immune function in ADA-SCID patients, it was useful to improve and stabilize the clinical status before curative therapy (aHSCT/HSCGT). Enzyme replacement therapy was successful in patients with late-/delayed-onset ADA deficiency who presented with the features of combined immunodeficiency. Gastrointestinal polyposis in a patient with late-onset ADA deficiency may be an association or a coincidental finding. Intermittent neurodevelopmental evaluation especially for hearing impairment should be performed in most of the ADA-deficient patients. This may alleviate the speech delay and cognitive abnormalities which may be observed in the follow-up.

Selective loss of function variants in IL6ST cause Hyper-IgE Syndrome with distinct impairments of T cell phenotype and function

Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T-helper 17-enriched subsets) and non-conventional CD8+T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.

Two siblings with PRKDC defect who presented with cutaneous granulomas and review of the literature

V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.

Repeated doses of salbutamol and aeroallergen sensitisation both increased salbutamol-induced hypoxia in children and adolescents with acute asthma

We aimed to identify the frequency, magnitude and risk factors of salbutamol‐induced hypoxia in children with acute asthma.

Characteristics of drug-induced anaphylaxis in children and adolescents

BACKGROUND Although data on anaphylaxis in the general population exist for different allergens, there is still lack of detailed etiologic data on drug-induced anaphylaxis (DIA), particularly in children. OBJECTIVE To define the etiology of DIA, to determine the accuracy of drug-related anaphylaxis histories, along with the severity and culprit drug associations among individuals <18 years old. METHODS Patients with a history of drug hypersensitivity reaction (DHR) referred to our center between January 2012 and February 2016 were included. After the collection of European Network for Drug Allergy questionnaire results, initial skin tests and/or provocation tests were performed for the offending drug. RESULTS Among 561 children and adolescents referred due to a suspected DHR, 113 (19%) (median age [interquartile range], 9.6 years [5.4-13.8 years]; 55% boys) had anaphylaxis in their history. At the end of diagnostic evaluation of the patients, 84 (74% of the patients with a history of DIA) were actually hypersensitive to the offending drug. Major drugs that resulted in DIA were antibiotics (33%), nonsteroidal anti-inflammatory drugs (25%), and chemotherapeutics (19%). The majority of patients reported grade 2 (moderate) (45%) and grade 3 (severe) (33%) anaphylactic reactions. A history of systemic illness (41.7 versus 7.1%; p = 0.001), concomitant intake of other drugs regularly (36.9 versus 10.3%; p = 0.007), and the use of chemotherapeutics as the culprit drug (19 versus 0%; p = 0.011) were more frequent, whereas the use of antibiotics was less frequent (34.5 versus 75.9%; p < 0.001) among patients with actual DIA compared to drug tolerant patients. CONCLUSION Three-fourths of the children and adolescents referred due to a suspected history of DIA were found to actually be drug hypersensitive. Prediagnosed systemic illness and different types of drugs would have an impact on the risk of DIA; however, atopic disease or a family history of drug hypersensitivity did not have an impact on actual DIA.