The many faces of pediatric urticaria.

Urticaria is a common disease that can affect individuals of all age groups, with approximately one-quarter of the population experiencing it at least once in their lifetime. Lesions characterized by erythema and itchy hives can appear anywhere on the body. These can vary in size ranging from millimeters to centimeters, and typically clear within 24 h. About 40% of patients with urticaria have accompanying angioedema, which involves localized deep tissue swelling. Urticaria usually occurs spontaneously and is classified into acute and chronic forms, with the latter referring to a condition that lasts for more than 6 weeks. The prevalence of chronic urticaria in the general population ranges from 0.5% to 5%, and it can either be inducible or spontaneous. The most common form of pediatric urticaria is acute and is usually self-limiting. However, a broad differential diagnosis should be considered in children with urticaria, particularly if they also have accompanying systemic complaints. Differential diagnoses of pediatric urticaria include chronic spontaneous urticaria, chronic inducible urticaria, serum sickness-like reaction, urticarial vasculitis, and mast cell disorders. Conditions that can mimic urticaria, including but not limited to cryopyrinopathies, hyper IgD syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPs), and Schnitzler syndrome should also be considered. The many faces of pediatric urticaria can be both easy and confusing. A pragmatic approach relies on clinical foresight and understanding the various forms of urticaria and their potential mimickers. This approach can pave the way for an accurate and optimized diagnostic approach in children with urticaria.

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.

A case-control study of the effects of Aspergillus clinical phenotypes on pulmonary functions in patients with cystic fibrosis.

INTRODUCTION: There are no precise data about the effect of Aspergillus infection on lung function other than allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (pwCF). Here, we aimed to determine clinical phenotypes caused by Aspergillus spp. using laboratory and immunologic parameters and to compare Aspergillus phenotypes in terms of pulmonary function tests (PFT) prospectively. METHODS: Twenty-three pwCF who had Aspergillus isolation from respiratory cultures in the last year (case group) and 20 pwCF without Aspergillus isolation in sputum (control group) were included. Aspergillus immunoglobulin (Ig)-G, Aspergillus IgE, Aspergillus polymerase chain reaction (PCR), galactomannan, total IgE from blood samples, and Aspergillus PCR and galactomannan from sputum, and skin prick test reactivity to Aspergillus antigen were used to distinguish different Aspergillus phenotypes. Pulmonary functions and frequency of pulmonary exacerbations were evaluated during a 1-year follow-up. RESULTS: Of 23 pwCF, 11 (47.8%) had Aspergillus colonization, nine (39.1%) had Aspergillus bronchitis, and three (13%) had ABPA. Aspergillus infection was not associated with worse z-scores of forced expiratory volume in the first second (FEV1) (p = 0.612), forced vital capacity  (p = 0.939), and the median FEV 1% decline (0.0%/year vs. -4.7%/year, p = 0.626). The frequency of pulmonary exacerbations in the Aspergillus infected and noninfected groups was similar. CONCLUSION: Although Aspergillus spp. Isolation in pwCF was not associated with decreased lung function, a further decline was seen in the ABPA subgroup, and frequent pulmonary exacerbations during the 1-year follow-up.

The miRNA-24, miRNA-21 expressions and matrix metalloproteinase-7 level in exhaled breath condensate of children with primary spontaneous pneumothorax.

Bullous lung diseases may cause primary spontaneous pneumothorax (PSP) in children. The microRNAs (miRNAs) are non-coding RNAs that participate in regulation of inflammation and cancer. We hypothesized that children with bullous lung disease and PSP may have altered miRNA expressions in their exhaled breath condensates (EBCs). Therefore, a prospective study was performed to evaluate the miRNA-24 and 21 expression, and the matrix metalloproteinase-7 (MMP-7) levels in EBC of children with PSP. Children with PSP were evaluated for age, gender, clinical features and results of surgical treatment. EBC samples (500-1000 ml) were collected to evaluate the miRNA-21, 24 expressions, and MMP-7, and tissue-inhibitor-MMP-1 (TIMP-1) levels. miRNA expressions and MMP levels of patients were compared with healthy controls (control group (CG),n= 12). Subjects (n= 16) with a mean age of 15 years (10-19 years), and a male-to-female ratio of 14:2 were enrolled in this study. The most common presenting symptom was sudden chest pain (n= 14). In 62.5% of the cases an underlying bullous lung disease were detected. During an average of 16.6 months (1-60 months) follow up period, four subjects relapsed. The mean MMP-7 (1.74-1.57 ng ml-1), and TIMP-1 (1.92-1.84 ng ml-1) levels were similar between both groups (p> 0.05). miRNA-24 expression was significantly decreased in the PSP group, when compared to the CG (0.16-1 2-ΔΔCT,p< 0.05). In addition, the miRNA-21 expression was not different between the two groups (p> 0.05). In conclusion, the miRNA-24 levels were significantly decreased in children with PSP. Taken together, children with PSP, especially those with bullous disease, should be closely monitored in the long-term period.

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).

The controversy of drug hypersensitivity in patients with cystic fibrosis and review of the literature.

BACKGROUND: Cystic fibrosis (CF) is reported to be a risk factor for drug hypersensitivity. However, there are conflicting data about true prevalence of drug hypersensitivity in children with CF. METHODS: The suspicious drug hypersensitivity reactions (DHRs) of children with CF were enquired by the European Network for Drug Allergy (ENDA) questionnaire, and skin tests and/or drug provocation tests were performed according to the established guidelines. RESULTS: Two hundred and nineteen children (48.9% boys; median [IQR] age, 8.4 years [4.8-12.4 years]) with cystic fibrosis were included in the study, among which 22 patients with 24 suspected DHRs were evaluated. Most of the suspected DHRs were of non-immediate (n = 16, 66.6%) type, and the offending drugs were amoxicillin-clavulanic acid (n = 7), macrolides (n = 4), trimethoprim-sulfamethoxazole (TMP/SMX) (n = 2), piperacillin-tazobactam (n = 1), pancrelipase (n = 1), and ursodeoxycholic acid (n = 1). Eight (33.3%) of the DHRs were classified as immediate (ceftriaxone [n = 2], ceftazidime [n = 2], meropenem [n = 1], AmBisome [n = 2], and vancomycin [n = 1]). The main clinical presentations were maculopapular eruption (41.6%) and urticaria (37.5%), accompanied by angioedema (8.3%), flushing (12.5%), and vomiting (8.3%). Nine skin tests (with beta-lactam protocol in 6 patients) and 24 DPTs were performed, and none of the skin tests revealed a positive result; however, 2 DPTs with TMP/SMX were positive. CONCLUSION: Actual drug hypersensitivity was demonstrated in 2 of 219 patients (0.9%) with non-beta-lactam antibiotics. These results conflict with previous researches that showed higher drug hypersensitivity rates but are consistent with some recent studies. Allergological diagnostic workup is mandatory in patients with cystic fibrosis in case of a suspicious DHR.

Hypersensitivity Reactions to Biologicals: from Bench to Bedside.

PURPOSE OF REVIEW: Biologic agents are new treatment options for chronic inflammatory diseases and cancers. As a result of their unique mechanism of action, they are more effective and less toxic treatment option and their clinical usage is increasing. While they are more commonly used, various adverse effects have been observed including life-threatening ones, including anaphylaxis. The aim of this review is to distinguish the anaphylaxis from other hypersensitivity reactions (HSR) and provide a management algorithm for the anaphylactic reactions induced by biological agents. RECENT FINDINGS: Many case reports and series have been published regarding anaphylaxis and other hypersensitivity reactions (concerning cytokine release syndrome, acute infusion-related reactions) due to biologic agents. Although acute treatment of HSR varies according to the clinical presentation, desensitization with the drug is the major management option for subsequent administrations in the case of anaphylactic reactions. SUMMARY: Anaphylaxis and other immediate onset hypersensitivity reactions are occasionally difficult to differentiate from each other, and mixed-type reactions may be observed. Immediate management of anaphylaxis includes discontinuation of infusion, immediate administration of adrenaline, antihistamines, corticosteroids, and other treatment options depending on the symptoms. After 30-120 min of the reaction, a blood sample for serum tryptase levels should be obtained and after 4-6 weeks skin testing with the culprit drug should be performed for decision of long-term management via either graded challenge or desensitization.

A Rare Case of Pediatric Bullous Spontaneous Acute Urticaria.

OBJECTIVE: Acute spontaneous bullous urticaria is an extremely rare entity, and there are few reports with blister formation in acute urticaria patients. CLINICAL PRESENTATION AND INTERVENTION: We present a 2-year-old girl who was admitted for bullous spontaneous acute urticaria; the underlying reason for this was not detected. Nikolsky's sign and Darier's sign were negative. Lesions were not compatible with erythema multiforme. However, biopsy was not allowed to be performed. Because of this, the underlying pathogenesis could not be clarified. The patient recovered by a short course of antihistamine and systemic steroid treatment, and the lesions did not recur during a 2-year follow-up. CONCLUSION: Short-term systemic steroid in addition to oral antihistamines resulted in prompt recovery in a patient with acute urticaria complicated by bullae.

Use of serial rigid bronchoscopy in the treatment of plastic bronchitis in children.

AIM: Plastic bronchitis (PB) is a rare disorder characterized by formation of bronchial casts (BC) in the tracheobronchial tree with partial or complete airway obstruction. Although lysis of casts with several fibrinolytic agents has been reported, removal of BC with bronchoscope provides better clearance of airways. A retrospective study was performed to evaluate the use of serial rigid bronchoscopy (RB) in the treatment of PB in children. PATIENTS AND METHODS: Between 2011 and 2015, children with partial or complete airway obstruction with PB were evaluated for age, gender, underlying disease, clinical findings, results of bronchoscopic interventions and histopathologic findings. RESULTS: Five patients with 14 RB interventions were evaluated. The mean age of the patients was 7.8years (min: 3years - max: 14years) and male-female ratio was 4:1. All of the patients were diagnosed as asthma and none of them had underlying cardiac disease. Suction of mucus plaques and bronchoalveolar lavage were performed in all patients with flexible bronchoscopy. Also, aerosolized tissue plasminogen activator was used in two patients. During follow-up serial RB was indicated in patients with persistent atelectasis and severe airway obstruction. The most common localization of BC was left main stem bronchus and bilateral cast formation was detected in 7 interventions. Although, removal of BC was challenging in two patients because of cast friability and fragmentation, most of the plugs were successfully removed with optical forceps and rigid suctioning. Two patients underwent repeated RB (min: 3 - max: 8) for recurrent symptoms. Histopathologic evaluation of BC revealed Charcot-Leyden crystals with inflammatory cells in all patients. The time interval between RB interventions was one to five months. CONCLUSION: BC are tenacious mucus plugs which are firmly wedged to the tracheobronchial tree. The use of optical forceps with rigid suction provides adequate removal of BC during RB. Because of underlying disease, it is difficult to cure cast formation. Therefore, most of the patients require serial RB when they become unresponsive to standard therapy or develop partial or complete airway obstruction.

The spectrum of aeroallergen sensitization in children diagnosed with asthma during first 2 years of life.

Aeroallergens may trigger symptoms in sensitized children with asthma. Documentation of sensitization is crucial to enable effective implementation of measures to prevent asthma exacerbations. To document the sensitization patterns of very young children (≤2 years) with asthma, we retrospectively analyzed the skin-prick test (SPT) results of the largest referral center in the country. During a 4-year period, 432 children (median age, 1.21 years; male/female, 2.35) were referred. All patients had recurrent wheezing attacks and good response to inhaled bronchodilators and were diagnosed with asthma by their referring physician. SPT with eight aeroallergens (grass mix, weed mix, tree mix, mold mix, house-dust mite, cockroach, cat, and dog) was performed in 209 patients (full panel group) and the remaining 223 were tested only with a mixture of two house-dust mites (Dermatophagoides pteronyssinus and Dermatophagoides farinae; house-dust mite group). The sensitization rates in house-dust mite and full panel groups were 3.2% (7/223) and 3.3% (7/209), respectively. Univariate and multivariate modeling was unable to identify a predictor for the presence of aeroallergen sensitization. During first 2 years of life, low rates of aeroallergen sensitization and lack of predictors of sensitization in children with asthma suggest that skin testing for aeroallergens may not be a routine procedure. When there is a high index of suspicion, testing only for indoor aeroallergens including house-dust mites, molds, and pets may identify the majority of sensitized children.

Recurrent wheezing in the first three years of life: short-term prognosis and risk factors.

OBJECTIVE: It is difficult to determine if preschool children with recurrent wheezing are suffering from asthma or will suffer from asthma in the future. The aim of this study was to investigate the prognosis and risk factors of recurrent wheezing in children, beginning in the first 3 years of life. METHOD: Children who were referred because of recurrent wheezing episodes during the first 3 years of life were evaluated for the presence of asthma over a 4-year period. A child without any symptoms within the last 12 months was considered to be in remission. RESULTS: The study included 529 (male/female: 2.17) children with a median (inter-quartile) age of 0.6 years (0.3-1.0) at symptom onset. The median follow-up and symptom durations were 2.93 years (1.74-4.76) and 4.30 years (2.91-5.97), respectively. Remission/recovery was achieved in 1.7%, 8.0%, and 14.4% of the children within 12, 24, and 36 months, respectively. A negative "stringent asthma predictive index" (API) significantly shortened the time to recovery of wheezing compared to the positive API (p = .036). Maternal smoking during pregnancy (OR = 4.35; 95% CI = 1.29-14.63); p = .018) and the number of emergency room admissions within the first 3 years of life (OR = 1.10; 95% CI = 1.01-1.19); p = .031) were found to be independent risk factors for the persistence of wheezing symptoms. CONCLUSION: Most of the children who were referred with frequent wheezing remain symptomatic 3 years after the initial wheezing episodes. A negative API is related to a shorter wheezing duration. Maternal smoking during pregnancy and the severity of the wheezing episodes appeared to be significant risk factors for the persistence of wheezing symptoms.

Determinants of allergic signs and symptoms in 24- 48-month-old Turkish children.

The expression of asthma and allergic diseases depends upon an interaction of genetic and environmental factors and thus may differ between populations. This study was performed to document the factors determining allergic signs and symptoms in early childhood in a group of Turkish children. Children followed at the Well-Baby Clinic who were 2 to 4 years were invited and re-evaluated. In addition to face-to-face questionnaire for allergic signs and symptoms and review of files, skin prick test was performed. The associations between risk factors and different aspects of atopy were analyzed. One hundred and nine patients (mean age: 31.6 +/- 3.5 months) were included in the study. All had been breast-fed with mean exclusive and total breastfeeding durations of 3.3 +/- 2.7 and 13.3 +/- 7.2 months, respectively. Eight children had physician-diagnosed allergic diseases (4 atopic eczema, 3 bronchial asthma and 1 food allergy) and the overall prevalence of sensitization was 13%. Introduction of cow's milk before 12 months appeared to be a significant risk factor for atopy. Smoking during lactation and having an older sibling showed a trend towards an increase while regular yoghurt consumption showed a trend to decrease the risk for atopy. No significant risk factor could be defined for ever wheezing. It was concluded that in young Turkish children, early introduction of cow's milk, passive smoking and having an older sibling may predict atopy whereas regular yoghurt consumption may decrease the risk of atopy. These results also support the concept that variability may exist between populations.

Alternative algorithm for L-asparaginase allergy in children with acute lymphoblastic leukemia.

BACKGROUND: L-asparaginase is a crucial chemotherapeutic agent for the treatment of acute lymphoblastic leukemia. The alternatives to L-asparaginase are not available in many parts of the world, including Turkey. OBJECTIVE: We sought to evaluate the utility of premedication with or without a desensitization protocol in children with acute lymphoblastic leukemia and systemic hypersensitivity reactions to Escherichia coli-asparaginase. METHODS: In this prospective study patients with systemic hypersensitivity reactions to E coli-asparaginase for whom we were unable to ascertain/provide other alternatives to asparaginase were either premedicated, desensitized, or both to receive their chemotherapy as E coli-asparaginase according to the severity of the hypersensitivity reaction. RESULTS: Nineteen patients (13 male patients) with a mean age of 7.4 +/- 4.7 years experienced a systemic hypersensitivity reaction to E coli-asparaginase during a 4-year period. Polyethylene glycol-asparaginase could be used for 3 patients. Eight of the remaining 16 children, who had experienced anaphylaxis, were premedicated and desensitized with E coli-asparaginase, and in 7 patients treatment was tolerated. The other 8 patients, with acute allergic reactions to E coli-asparaginase, were premedicated first, and 5 of them showed no reaction subsequently. Three of them demonstrated systemic hypersensitivity reactions again (anaphylaxis, n = 3), and premedication and desensitization with E coli-asparaginase resulted in anaphylaxis. Polyethylene glycol-asparaginase was administered uneventfully to the patients who could be provided it. CONCLUSION: E coli-asparaginase could be administered to more than half of the patients who had a hypersensitivity reaction, and all of these patients were able to receive their planned doses of asparaginase. In countries with shortages of alternative asparaginase preparations, our approach might be a suitable option.

Do the leukotriene receptor antagonists work in children with grass pollen-induced allergic rhinitis?

Although cysteinyl-leukotriene receptor antagonists were recently approved for use in allergic rhinitis (AR), there has been no study to date investigating their application in children. The aim was to evaluate whether montelukast provides any benefit in nasal allergen challenge-induced symptoms in children, and whether it could improve the control provided by an antihistamine during pollen season. Two randomized studies, one a double-blind, placebo-controlled, nasal allergen challenge study and one an open-label, cross-over, parallel-group clinical study, were performed in 18 (11.7+/-0.7 years) and 32 children (10.5+/-0.5 years), respectively, with grass pollen allergy. In the first study, the effect of a single dose of montelukast and its combination with loratadine were compared with placebo on nasal responses induced by allergen challenge. In the second study, the additive effect of montelukast to loratadine was tested in an open-label cross-over clinical study. In the challenge study, early-phase and late-phase nasal reactions peaked at 15 min and 4 h after the challenge respectively. During the early phase, combination improved total nasal symptoms (p=0.004) during the first hour and sneezing (p=0.012) at 15 min compared with placebo group. During the late phase, montelukast (p=0.017) and combination (p=0.011) caused less nasal obstruction at 4 h and combination caused less sneezing at 6 h (p=0.015). In the clinical trial, montelukast provided protection on seasonal increase in pulmonary symptoms [0 (0, 14) vs. 6.5 (0, 27.7); p=0.016] and on the decrease in FEF25-75 [-0.09 (-0.34, 0.17) vs. -0.28 (-0.66, 0.02); p=0.002]. However, there was no improvement in nasal symptoms and flows. Although we showed protection against nasal challenge-induced congestion with montelukast, we were not able to show the same in the clinical study possibly because of low pollen counts and mildness of the symptoms of the patients with AR. However, montelukast provided better control of pulmonary symptoms and protection from seasonal decrease in lung function, indicating its potential therapeutic benefit in children with AR.

Determinants of atopic sensitization in Turkish school children: effects of pre- and post-natal events and maternal atopy.

Emergence of new environmental risk factors, and/or loss of protective factors of a traditional lifestyle may explain the increase, or variations in prevalence of allergic diseases. The aim of this study was to delineate the prevalence and spectrum of, and to reveal the causal and/or protective factors for atopic sensitization among a heterogeneous cohort of Turkish children, for the first time in our country. The study design adhered to International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol. A self-administered parental questionnaire about demographic characteristics and detailed risk factors, and skin-prick test with 13 allergens were employed in a clustered random sample of 8-11-yr-old Turkish school children. Atopy was defined as the presence of at least one positive skin reaction to any allergen tested. The association between a total of 78 risk factors and different aspects of atopy were analyzed in 1144 children with multivariate logistic regression analysis. The overall prevalence of atopy was 20.6%. Most common sensitizations were to grass pollens, Dermatophagoides pteronyssinus and Blatella germanica. Day care attendance, high paternal education level, male gender and maternal asthma were significant risk factors for atopy. Breastfeeding more than 6 months (compared with 0-6 months), maternal smoking during pregnancy and a birth weight under 2500 g were inversely related to (or protective factors for) atopic sensitization. Maternal atopic disease had significant effects on risk factors pattern. In children with a maternal atopy history a low birth weight, day care attendance and maternal smoking during the first year of life independently increased the risk of atopic sensitization. Gender, breastfeeding and paternal education did not show any association with atopy in this group of children. A history of measles and low gestational age were significant protective factors for mite sensitization. This study showed that children of atopic mothers showed a different profile of risk factors associated with atopic sensitization, when compared with other children. Prenatal and early childhood events had important associations with atopic sensitization.