Summary
Background
Data‐driven methods such as hierarchical clustering (HC) and principal component analysis (PCA) have been used to identify asthma subtypes, with inconsistent results.
Objective
To ...develop a framework for the discovery of stable and clinically meaningful asthma subtypes.
Methods
We performed HC in a rich data set from 613 asthmatic children, using 45 clinical variables (Model 1), and after PCA dimensionality reduction (Model 2). Clinical experts then identified a set of asthma features/domains which informed clusters in the two analyses. In Model 3, we reclustered the data using these features to ascertain whether this improved the discovery process.
Results
Cluster stability was poor in Models 1 and 2. Clinical experts highlighted four asthma features/domains which differentiated the clusters in two models: age of onset, allergic sensitization, severity, and recent exacerbations. In Model 3 (HC using these four features), cluster stability improved substantially. The cluster assignment changed, providing more clinically interpretable results. In a 5‐cluster model, we labelled the clusters as: “Difficult asthma” (n = 132); “Early‐onset mild atopic” (n = 210); “Early‐onset mild non‐atopic: (n = 153); “Late‐onset” (n = 105); and “Exacerbation‐prone asthma” (n = 13). Multinomial regression demonstrated that lung function was significantly diminished among children with “Difficult asthma”; blood eosinophilia was a significant feature of “Difficult,” “Early‐onset mild atopic,” and “Late‐onset asthma.” Children with moderate‐to‐severe asthma were present in each cluster.
Conclusions and clinical relevance
An integrative approach of blending the data with clinical expert domain knowledge identified four features, which may be informative for ascertaining asthma endotypes. These findings suggest that variables which are key determinants of asthma presence, severity, or control may not be the most informative for determining asthma subtypes. Our results indicate that exacerbation‐prone asthma may be a separate asthma endotype and that severe asthma is not a single entity, but an extreme end of the spectrum of several different asthma endotypes.
Background
Indoleamine 2,3‐dioxygenase (IDO), which degrades tryptophan (Trp) to kynurenine (Kyn), has been demonstrated to contribute to modulation of allergic responses. However, the role of IDO in ...food allergy has not yet been elucidated.
Methods
Serum Trp and Kyn concentrations were analyzed by high‐pressure liquid chromatography. Expression of IDO gene was measured by real‐time PCR. The levels of interleukin (IL)‐4, IL‐10, and interferon (IFN)‐γ in cell culture supernatants were measured by ELISA.
Results
Kyn/Trp (IDO activity) was significantly lower in subjects with food allergy (n = 100) than in aged‐matched healthy controls (n = 112) (P = 0.004). Kyn/Trp was decreased from healthy through completely tolerant, partially tolerant, and reactive ones LN transformation (mean ± SEM) healthy: 3.9 ± 0.02 μM/mM; completely tolerant: 3.83 ± 0.04; partially tolerant: 3.8 ± 0.06; reactive: 3.7 ± 0.04 (P = 0.008). The frequency of genetic polymorphisms of IDO did not reveal a significant association with Trp, Kyn, and Kyn/Trp in healthy and food‐allergic cases. Culture of PBMC experiments yielded that IDO mRNA expression was not different between tolerant and reactive groups. IL‐4 synthesis when stimulated with casein increased significantly in subjects who are reactive and tolerant to foods (P = 0.042, P = 0.006, respectively). Increase in IL‐10 synthesis was observed only in children tolerant to milk, but not in reactive ones. IFN‐γ synthesis, when stimulated with IL‐2 and β‐lactoglobulin in cell culture, was significantly higher in subjects tolerant to milk than in the reactive ones (P = 0.005 and P = 0.029, respectively).
Conclusion
Our results imply the probability of involvement of IDO in development of tolerance process, and we presume that high IDO activity is associated with nonresponsiveness to food allergens despite allergen sensitization.
A relationship between serum basal tryptase (sBT) levels, anaphylactic reactions, and clonal mast cell diseases was shown recently in adults with venom allergy, but the relationship between sBT ...levels and IgE‐mediated food allergy and anaphylaxis is not known. In this study, children with food allergy (FA; n = 167) were analyzed in two groups according to the presence (FA+/A+; n = 79) or absence of anaphylaxis (FA+/A−; n = 88) and were compared with a control group (n = 113). Median sBT values in FA+/A+, FA+/A−, and control groups were 4.0 ng/ml (2.8–5.8), 3.6 (2.3–4.5), and 3.3 (2.4–4.4), respectively (P = 0.022). sBT measurements higher than the cutoff values of 5.7 and 14.5 were associated with 50% and 90% predicted probabilities, respectively, of moderate to severe anaphylaxis. Children with tree nuts/peanut allergies had significantly higher levels of sBT than children with milk and egg allergy (P = 0.022). Results suggest that sBT levels may predict moderate to severe anaphylaxis in children with food allergy, which may follow a particular pattern according to the food allergy phenotype.
Omalizumab is useful as an add-on treatment in patients unresponsive to high doses of second-generation antihistamines. This study aimed to evaluate the efficacy and safety of omalizumab treatment in ...adolescents with refractory chronic spontaneous urticaria (CSU).
CSU patients aged 12–18 years old with the diagnosis of symptomatic CSU and unresponsive to classical treatment were included in the study. All patients had an urticaria-activity-score (UAS7) of ≥16 or and were treated with 300mg omalizumab every four weeks. The degree of response was classified into complete, partial and non-responders due to UAS7.
A total of 29 patients were evaluated. The median age and symptom onset age of the patients was 15.2 (IQR, 12.8–16.5) years and 14.0 (IQR, 11.8–15.9) years, respectively. The median duration of urticaria was eight (IQR, 4–24) months at admission. Eleven (37.9%) patients had angioedema and ten (34.5%) patients had concomitant allergic diseases. The median age at the beginning of treatment with omalizumab was 15.4 (IQR, 12.9–16.9) years. The median symptom duration was 12 (IQR, 6.5–27.5) months before the omalizumab treatment. Twenty-eight (96.5%) of the patients (89.6% complete, 6.9% partial) achieved response; however, one patient was a non-responder (3.5%). The adverse effect was observed in one (3.4%) patient as angioedema after the third dose. Twenty-three patients were followed up for a median of 18 (IQR, 13–27) months. Relapse was observed in three (13%) patients.
Omalizumab is considered as an effective and safe treatment for CSU in adolescents. Relapses mostly occur within the first year after the cessation of treatment.
Background
The importance of serum basal tryptase (sBT) levels on patients with venom allergy is highlighted in recent adulthood studies. The aim of this study was to evaluate the sBT levels of ...venom‐allergic children with varying severity of clinical reactions. We also aimed to document the association between sBT levels and severe systemic reactions (SR).
Methods
Serum basal tryptase levels were estimated by UniCAP (Pharmacia & Upjohn, Uppsala, Sweden). Children who suffered from large local reaction (LLR) or SR after insect stings were included along with healthy control subjects without a history of any local or SR after insect stings.
Results
A total of 128 children (55 with SR, 18 with LLR, and 55 age and sex‐matched control subjects) with a median age of 8.9 years (range 3.2–17.4) were enrolled. Severe SR was encountered in 24 (44%) patients with SRs. The median level of sBT in children with SRs (median, interquartile range) 4.2 μg/l (3.6–4.9) was significantly higher than in children with LLRs 3.1 μg/l (2.5–4.0) and healthy control subjects 2.9 μg/l (2.3–3.4) (P < 0.001). Logistic regression analysis revealed sBT ≥ 4.8 μg/l as a significant risk factor for severe SR (5.7 1.5–21.4; P = 0.01) in children with venom allergy.
Conclusions
Our results indicate that sBT levels are associated with a higher risk of severe SR in children with insect venom hypersensitivity. Determination of sBT levels may help clinicians to identify patients under risk of severe SRs and optimal and timely use of therapeutic interventions in children with venom allergy.
Anaphylaxis is a sudden, severe, and potentially life-threatening allergic reaction, affecting a portion of allergic patients. Adrenaline is the first-line medication for anaphylaxis and available in ...many parts of the world as adrenaline autoinjectors (AAIs).
Aim of this study was to determine attitudes and knowledge levels of patients/parents regarding the use of AAIs, frequency, and rate of appropriate AAI use and to give a standardized and better education by improving on mistakes during administration.
190 patients aged 1–18 years who were prescribed AAIs for any reason between 2012 and 2017 in Hacettepe University Pediatric Allergy Unit. Demographic data were collected during face-to-face interview or by telephone. Parents completed a mini-survey regarding use, carriage, and storage of AAI.
Some 190 patients (64.7% male) aged 7.83 (4.99–12.08) years, median (inter-quartile), were included in the study. The indications for AAI prescription were food allergy (78.9%); venom allergy (14.2%); idiopathic anaphylaxis (3.7%); mastocytosis (2.1%); and drug allergy (1.0%). One-fourth of AAI-prescribed patients experienced anaphylaxis requiring the use of AAI within the past five years. However, only 30% of the patients dared to use AAI; only three-quarters of whom had managed to use it correctly.
After prescription of AAI and initial training, patients and parents’ concerns and fears should be taken into consideration and necessary support should be provided. At every opportunity and each clinical visit, not only should training sessions be repeated but also the patients and parents should be psychologically supported.
Atrial fibrosis has been found to be associated with recurrent atrial fibrillation (AF) following catheter ablation. Autoantibodies against M2-muscarinic receptors (anti-M2-R) may play a role in the ...development of AF by inducing left atrial (LA) fibrosis. In this study, we aim to compare anti-M2-R levels between paroxysmal lone AF patients and healthy control subjects and to investigate the relationship between pre-ablation anti-M2-R level, LA fibrosis quantified by delayed enhancement magnetic resonance imaging (DE-MRI), and AF recurrence following cryoablation.
Thirty-one patients with paroxysmal lone AF (53.4 ± 8.0 years, 61% male), who underwent cryoballoon-based ablation, along with 31 healthy control subjects were included. Enzyme-linked immunosorbent assay tests to measure serum anti-M2-R levels were performed in both groups and DE-MRI was done to quantify LA fibrosis prior to the ablation in the patients. Anti-M2-R levels were higher in the study population when compared with control subjects 212.4 (103.2-655.5) vs. 73.0 (39.5-299.1) ng/mL, P < 0.001. Anti-M2-R level predicted moderate-extensive LA fibrosis independent of other measures odds ratio: 1.26 (95% confidence interval (CI): 1.04-1.53), P = 0.017. At a mean follow-up of 35.2 ± 3.5 months, nine patients (29.0%) had AF recurrence. In the Cox regression model including pre-ablation anti-M2-R level, LA diameter, LA volume index, and moderate-extensive LA fibrosis, only moderate-extensive LA fibrosis predicted late AF recurrence independent of other measures hazard ratio: 29.41 (95% CI: 3.52-250.00), P = 0.002.
Serum anti-M2-R levels may be associated with the severity of LA fibrosis and may be implicated in the pathophysiology of AF recurrence following cryoablation. Detection of anti-M2-R levels may help select appropriate patients for the procedure.
To cite this article: Sackesen C, Birben E, Soyer OU, Sahiner UM, Yavuz TS, Civelek E, Karabulut E, Akdis M, Akdis CA, Kalayci O. The effect of CD14 C159T polymorphism on in vitro IgE synthesis and ...cytokine production by PBMC from children with asthma. Allergy 2011; 66: 48-57. ABSTRACT: Background: Even though the genotype at the promoter region of the CD14 molecule is known to affect the atopic phenotypes, the cellular and molecular basis of this association is largely unknown. Objective: To investigate the effect of lipopolysaccharide (LPS) on IgE production and cytokine profile by peripheral blood mononuclear cells (PBMC) obtained from asthmatic children with the TT and the CC genotypes at position −159 of the CD14 gene. Methods: Peripheral blood mononuclear cells from asthmatic children with alternative genotypes at CD14 C159T locus were stimulated with 2 and 200 ng/ml LPS in vitro. The IgE, IgG and, IgM response was determined by ELISA and Ig έ-germline, IgG, and IgM transcription by real-time PCR. A cluster of cytokines was measured by cytometric bead array. Results: Asthmatic children with the TT genotype but not those with the CC genotype responded with increased IgE synthesis and germline transcription to LPS stimulation. There were no genotype-related differences in IgG and IgM. TT but not the CC genotype was associated with significantly increased interleukin (IL)-4/IL-12 and IL-4/interferon-gamma (IFN-γ) ratios in the culture supernatant. There were no genotype-related differences in IL-1β, IL-7, IL-10, IL-13, IL-17A, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, monocyte chemotactic protein, and tumor necrosis factor alpha. Conclusion: Peripheral blood mononuclear cells from asthmatic children with the TT genotype at position −159 of the CD14 gene make more IgE than those with the CC genotype following LPS stimulation because of increased germline transcription and have an augmented Th2 cytokine profile.
The second-generation cryoballoon (Arctic Front Advance™) (Arc-Adv-CB) has a redesigned injection system which distributes the refrigerant homogenously to the frontal balloon surface. The aim of this ...study was to compare the efficacy and safety of the Arc-Adv-CB and its predecessor (Arctic Front™) (Arc-CB) in patients who underwent pulmonary vein isolation (PVI) for atrial fibrillation (AF).
Three hundred and six patients (55.35 ± 10.60 years, 47.05% male) were included in the study. A total of 1205 pulmonary veins were attempted for PVI with either Arc-CB or Arc-Adv-CB. The follow-up durations were 30 (23-38) and 10 (8-13) months in Arc-CB and Arc-Adv-CB groups, respectively (P < 0.001). When the blanking period was considered, freedom from AF after a single ablation procedure was 68.53 and 90.83% in patients undergoing PVI with Arc-CB and Arc-Adv-CB, respectively. The most frequent complication was transient phrenic nerve palsy (PNP) which occurred in five(2.54%) and nine(8.26%) of patients undergoing PVI with Arc-CB and Arc-Adv-CB, respectively (P = 0.040). Left atrial (LA) diameter (hazard ratio, HR: 3.552, 95% CI: 2.034-6.201, P < 0.001), smoking history (HR:1.643, 95% CI: 1.011-2.671, P = 0.045), persistent AF (HR:1.725, 95% CI: 1.021-2.915, P = 0.041), duration of AF (HR:1.039, 95% CI: 1.000-1.080, P = 0.047), and early AF recurrence (HR:2.399, 95% CI: 1.443-3.989, P < 0.001) were associated with increased late AF recurrence. On the other hand, intraprocedural vagal reactions (HR: 0.550, 95% CI: 0.331-0.915, P = 0.021) and Arc-Adv-CB use (HR: 0.441, 95% CI: 0.225-0.866, P = 0.017) were associated with lower late AF recurrence. Left atrial diameter (HR: 3.072, 95% CI: 1.646-5.732, P < 0.001), early AF recurrence (HR: 1.906, 95% CI: 1.103-3.291, P = 0.021), and Arc-Adv-CB use (HR: 0.472, 95% CI: 0.239-0.931, P = 0.030) were independent predictors for late AF recurrence.
Our study has shown that Arc-Adv-CB use is associated with lower late AF recurrences at the cost of an increased risk for PNP.
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