A. B. Sprikkelman

The multinational birth cohort of EuroPrevall: background, aims and methods

To cite this article: Keil T, McBride D, Grimshaw K, Niggemann B, Xepapadaki P, Zannikos K, Sigurdardottir ST, Clausen M, Reche M, Pascual C, Stanczyk AP, Kowalski ML, Dubakiene R, Drasutiene G, Roberts G, Schoemaker A‐FA, Sprikkelman AB, Fiocchi A, Martelli A, Dufour S, Hourihane J, Kulig M, Wjst M, Yazdanbakhsh M, Szépfalusi Z, van Ree R, Willich SN, Wahn U, Mills ENC, Beyer K. The multinational birth cohort of EuroPrevall: background, aims and methods. Allergy 2010; 65: 482–490.

How much is too much? Threshold dose distributions for 5 food allergens

BACKGROUNDnPrecautionary labeling is used to warn consumers of the presence of unintended allergens, but the lack of agreed allergen thresholds can result in confusion and risk taking by patients with food allergy. The lack of data on threshold doses below which subjects are unlikely to react is preventing the development of evidence-based allergen management strategies that are understood by clinician and patient alike.nnnOBJECTIVEnWe sought to define threshold dose distributions for 5 major allergenic foods in the European population.nnnMETHODSnPatients with food allergy were drawn from the EuroPrevall birth cohort, community surveys, and outpatient clinic studies and invited to undergo a food challenge. Low-dose, double-blind, placebo-controlled food challenges were undertaken with commercially available food ingredients (peanut, hazelnut, celery, fish, and shrimp) blinded into commonxa0matrices. Dose distributions were modeled by using interval-censoring survival analysis with 3 parametric approaches.nnnRESULTSnOf the 5 foods used for challenge, 4 produced similar dose distributions, with estimated doses eliciting reactions in 10% of the allergic population (ED10), ranging from 1.6 to 10.1 mg of protein for hazelnut, peanut, and celery with overlapping 95% CIs. ED10 values for fish were somewhat higher (27.3 mg of protein), although the CIs were wide and overlapping between fish and plant foods. Shrimp provided radically different dose distributions, with an ED10 value of 2.5 g of protein.nnnCONCLUSIONnThis evidence base will contribute to the development of reference doses and action levels for allergens in foods below which only the most sensitive subjects might react.

Birch pollen sensitization with cross-reactivity to food allergens predominates in adults with eosinophilic esophagitis

EoE patients show variable sensitization patterns to food and aeroallergens. The value of allergy testing in adult EoE patients is unclear. Component‐resolved diagnosis (CRD) may offer additional insights into sensitization patterns. The aim of this study was to characterize sensitization patterns in adult EoE patients using CRD. Serum from 76 patients (17 female), age 38.6 ± 1.5 years, was analyzed for reactivity to 112 different allergen components using an immuno‐solid‐phase allergen chip (ISAC). We observed any sensitization in 59 patients (78%), of which 54 patients were polysensitized. Aeroallergen sensitization, mostly against components of grass or tree pollen, or house dust mite, was observed in 74% of the patients. Birch pollen (rBet v 1) sensitization with cross‐reactivity to food allergen components was observed in 30 patients (39%). In conclusion, food sensitizations in EoE patients are mainly caused by cross‐reactivity to food allergens after primary birch pollen sensitization. Pollen and food sensitizations may cause or maintain esophageal inflammation in EoE patients. CRD provides more insight into sensitization patterns, identifies additional food allergen sensitizations and might be useful to direct dietary therapy in EoE.

Long-term effects of prednisolone in the acute phase of bronchiolitis caused by respiratory syncytial virus

Follow‐up studies have demonstrated that bronchiolitis caused by respiratory syncytial virus (RSV) is strongly associated with wheezing in the ensuing years. During the acute infection the immune response may induce long‐lasting detrimental effects, thereby contributing to post‐bronchiolitis wheezing (PBW). Therefore, immune‐modulating drugs like corticosteroids, administered in the acute phase of RSV bronchiolitis, may prevent PBW and asthma. To evaluate this, we performed a controlled prospective follow‐up study after a randomized double‐blind placebo‐controlled intervention in the acute phase with oral prednisolone. Fifty‐four patients under 2 years of age and hospitalized for RSV bronchiolitis between 1992 and 1995 were randomly assigned to prednisolone 1 mg/kg/day for 7 days or placebo. At the mean age of 5 years, 47 patients had completed their follow‐up. Patients were divided into four groups: no wheezing, transient wheezing (wheezing during the first year of life); persistent wheezing (wheezing during the first year of life and asthma at the age of 5); and late‐onset wheezing (no wheezing during the first year of life but asthma at the age of 5). Prevalence of wheezing and asthma were investigated through an interview by telephone, using a standardized questionnaire.

Severity Scoring of Atopic Dermatitis

Hanifin and Rajka (1980) outlined the diagnostic criteria of atopic dermatitis (AD) in order to apply uniform criteria in diagnosing the disease. At the present time a pathognomonic diagnostic laboratory test is still lacking, and the diagnosis of AD continues to be based on the presence or absence of a combination of signs and symptoms. The significance and validity of the major and minor diagnostic criteria they proposed have constituted a topic of interest in several studies, and adjustments have been made in order to improve the reliability of diagnoses (Kanwar et al., 1991; Kapp et al., 1991; Diepgen and Fartasch, 1992; Williams et al., 1994; Tada et al., 1994; Rudzki et al., 1994; Williams and Pembroke, 1996; Nagaraja et al., 1996). Although, the outline of diagnostic criteria proved useful for practitioners and investigators, a more objective, quantitative, and accurate assessment of the severity of AD was needed, so different methods have been developed over the last years, including laboratory techniques and clinical scoring systems

Altered exhaled biomarker profiles in children during and after rhinovirus-induced wheeze

Preschool rhinovirus-induced wheeze is associated with an increased risk of asthma. In adult asthma, exhaled volatile organic compounds (VOC) are associated with inflammatory activity. We therefore hypothesised that acute preschool wheeze is accompanied by a differential profile of exhaled VOC, which is maintained after resolution of symptoms in those children with rhinovirus-induced wheeze. We included 178 children (mean±sd age 22±9 months) from the EUROPA cohort comparing asymptomatic and wheezing children during respiratory symptoms and after recovery. Naso- and oropharyngeal swabs were tested for rhinovirus by quantitative PCR. Breath was collected via a spacer and analysed using an electronic nose. Between-group discrimination was assessed by constructing a 1000-fold cross-validated receiver operating characteristic curve. Analyses were stratified by rhinovirus presence/absence. Wheezing children demonstrated a different VOC profile when compared with asymptomatic children (p<0.001), regardless of the presence (area under the curve (AUC) 0.77, 95% CI 0.07) or absence (AUC 0.81, 95% CI 0.05) of rhinovirus. After symptomatic recovery, discriminative accuracy was maintained in children with rhinovirus-induced wheeze (AUC 0.84, 95% CI 0.06), whereas it dropped significantly in infants with non-rhinovirus-induced wheeze (AUC 0.67, 95% CI 0.06). Exhaled molecular profiles differ between preschool children with and without acute respiratory wheeze. This appears to be sustained in children with rhinovirus-induced wheeze after resolution of symptoms. Therefore, exhaled VOC may qualify as candidate biomarkers for early signs of asthma. Children with rhinovirus-induced wheeze have altered exhaled biomarkers both during symptoms and after resolution http://ow.ly/C6vWT

Use of tracheal auscultation for the assessment of bronchial responsiveness in asthmatic children

BACKGROUND: It can be difficult to assess bronchial responsiveness in children because of their inability to perform spirometric tests reliably. In bronchial challenges lung sounds could be used to detect the required 20% fall in the forced expiratory volume in one second (FEV1). A study was undertaken to determine whether a change in lung sounds corresponded with a 20% fall in FEV1 after methacholine challenge, and whether the occurrence of wheeze was the most important change. METHODS: Fifteen children with asthma (eight boys) of mean age 10.8 years (range 8-15) were studied. All had normal chest auscultation before the methacholine challenge test. Lung sounds were recorded over the trachea for one minute and stored on tape. They were analysed directly and also scored blindly from the tape recording by a second investigator. Wheeze, cough, increase in respiratory rate, and prolonged expiration were assessed. RESULTS: The total cumulative methacholine dose causing a fall in FEV1 of 20% or more (PD20) was detected in 12 children by a change in lung sounds - in four by wheeze and in eight by cough, increased respiratory rate, and/or prolonged expiration. In two subjects altered lung sounds were detectable one dose step before PD20 was reached. In three cases in whom no fall in FEV1 occurred, no change in lung sounds could be detected at the highest methacholine dose. CONCLUSION: Changes in lung sounds correspond well with a 20% fall in FEV1 after methacholine challenge. Wheeze is an insensitive indicator for assessing bronchial responsiveness. Cough, increase in respiratory rate, and prolonged expiration occurs more frequently.

Development of allergic disorders in children with cow's milk protein allergy or intolerance in infancy

In 1995, the European Academy of Allergy and Clinical Immunology proposed a classi®cation of adverse reactions to foods based on mechanism [3]. `Adverse reaction to food, like cows milk, is de®ned as any aberant reaction following the ingestion of a food or food additive. Adverse reactions can be divided into toxic and nontoxic food reactions. A toxic reaction is an adverse reaction which will occur in every person provided that a suf®cient dose has been taken in. Nontoxic reactions can be divided in immune-mediated mechanisms (allergy), and nonimmunemediated mechanisms (intolerance), and the occurrence depends on the susceptibility of the person. Analogous, adverse reactions to cows milk protein can be divided in CMPA and CMPI. CMPA can be classi®ed according to the type of immune mechanisms, that is IgE-mediated (type I) reactions, and non-IgE-mediated reactions, as type II (cytotoxic), type III (immune complexes), and type IV (cellmediated) reactions. The de®nition of CMPI leads to some confusion. CMPI is de®ned as reproducible adverse reactions to cows milk which are not immunologically mediated, e.g. enzyme de®ciencies, absorption defects, pharmacological reactions, or infectious reactions. However, the term CMPI is also used in cases in which the immunological aetiology of a reaction to cows milk protein is not con®rmed, either due to a lack of immunological investigations, or negative results of the performed analyses. Therefore, the classi®cation of adverse reactions to cows milk proteins depends on the extensiveness, and the quality of the diagnostic tests that are used to investigate the immunological mechanisms. Since the immunological mechanism of the clinical reaction to cows milk protein is often not determined and no single laboratory test is diagnostic for CMPA or CMPI, and differentiation between CMPA and CMPI is often not possible on the basis of symptoms, adverse reactions to cows milk protein are indicated as CMPA/CMPI [1,2]. Several laboratory methods, including skin prick, scratch, and epicutaneous tests, determination of speci®c IgE antibodies, basophil-histamine release test, leucocyte migration inhibition assay, and lymphocyte transformation test are available as diagnostic tools in immunological mediated CMPA [4,5]. However, none of these tests have proved to be indicative of clinical disease, and none of them reaches suf®cient sensitivity, speci®city, and positive predictive accuracy. Because there is no reliable single laboratory test available to diagnose CMPA or CMPI, the diagnosis CMPA/CMPI has to be based on a cows milk protein elimination and challenge test, using strict well de®ned diagnostic criteria. In most recent studies [1,6±12], the diagnosis CMPA/CMPI is made according to criteria proposed by Savilahti, Bahna and Gandhi, and taken over by the European Society for Paediatric Gastroenterology and Nutrition Working Group for the diagnostic criteria for food Allergy, and the European Academy of Allergy and Clinical Immunology Subcommittee on Adverse reactions to foods [3,13±15]. These criteria include: a de®nite disappearance of symptoms after elimination of cows milk from the diet, recurrence of identical symptoms after one cows milk challenge, disappearance of symptoms after re-elimination of cows milk, and exclusion of lactose intolerance and coincidental infections. A strict well de®ned cows milk elimination and challenge procedure is needed to diagnose CMPA/CMPI [1]. In young infants of age 0±1 years, open controlled cows milk challenges are recommended, and have been shown to be reliable when performed under professional observation in a clinical setting [9,16,17]. In children older than 1±2 years, and in adults, double-blind placebocontrolled food challenges (DBPCFC) are recommended [7,18,19].

Prevalence of rhinoviruses in young children of an unselected birth cohort from the Netherlands

n Abstractn n Rhinovirus (RV) is a frequent pathogen in young children, eliciting symptoms ranging from common colds to wheezing illnesses and lower respiratory tract infections. The recently identified RV-C seems to be associated with asthma exacerbations and more severe disease, but results vary. We studied the prevalence and severity of infection with RV in an unselected birth cohort. Children with respiratory symptoms entered the symptomatic arm of the cohort and were compared with asymptomatic children. Severity of wheezing and other respiratory symptoms was registered. Respiratory viruses were evaluated using throat and nasopharyngeal swabs on first presentation and after recovery (wheezing children). RV genotyping was performed on RV-PCR positive samples. RV was the most prevalent respiratory virus and was found in 58/140 symptomatic children (41%), 24/96 (25%) control children and 19/74 (26%) wheezing symptomatic children after recovery (p <0.05) and did not differ between wheezing and non-wheezing symptomatic children—respectively, 42% (38/90) and 40% (20/50). RV-A was the most commonly detected species (40/68, 59%), followed by RV-C (22/68, 32%) and RV-B (6/68, 9%). RV-B was more frequently detected in asymptomatic children (5/6, p <0.05). There was no significant difference in the frequency of RV species between wheezing and non-wheezing symptomatic children. Children with RV mono-infection had more severe symptoms, but no association between RV species and severity of disease was seen. In an unselected birth cohort from the Netherlands with mild respiratory disease RV was the most prevalent respiratory virus. RV(-C) infection was not associated with more severe disease or wheezing.n n

A new framework for the documentation and interpretation of oral food challenges in population-based and clinical research.

The conduct of oral food challenges as the preferred diagnostic standard for food allergy (FA) was harmonized over the last years. However, documentation and interpretation of challenge results, particularly in research settings, are not sufficiently standardized to allow valid comparisons between studies. Our aim was to develop a diagnostic toolbox to capture and report clinical observations in double‐blind placebo‐controlled food challenges (DBPCFC).