Detection of Salivary Tryptase Levels in Children following Oral Food Challenges.

BACKGROUND: Oral food challenge (OFC) is commonly used to diagnose food allergy. This test is time and resource intensive, and conclusions are not always unequivocal as this relies on the interpretation of symptoms. Therefore, an objective marker would improve the accuracy of the diagnostic workup of food allergy. OBJECTIVES: The aim of this study was to investigate whether tryptase can be detected in saliva of children following OFC. METHOD: Children from 3 to 18 years of age were eligible for inclusion if an OFC for peanut or tree nut had been recommended. Saliva samples were collected prior to the first dose and 5, 10, and 15 min following the last administered dose during OFC. Assay precision, spike-and-recovery, and assessment of lower limit of detection of the tryptase immunoassay were examined before analysis of tryptase in saliva was performed. RESULTS: A total of 30 children were included (median age 8 years, 63.3% male, 53.3% positive OFC outcome). Tryptase was detected in saliva samples. The mean of the change in baseline tryptase value to each saliva collecting time point was significantly different in patients with a positive OFC outcome compared to a negative outcome (p < 0.01). CONCLUSIONS: This study showed that tryptase can be detected in saliva of children following OFC. Increased levels of tryptase compared to baseline were found if the OFC outcome was positive, suggesting that measuring tryptase in saliva may be useful in the diagnosis of food allergy. Further research is needed to evaluate the potential association between tryptase levels and symptoms.

The dilemma of open or double-blind food challenges in diagnosing food allergy in children: Design of the ALDORADO trial.

BACKGROUND: It is of major importance to diagnose food allergy accurately. Current guidelines support the use of oral food challenges to do so. The double-blind placebo-controlled food challenge (DBPCFC) has been regarded as the 'gold standard' for decades. However, DBPCFCs are costly, and time- and resource-intensive procedures. Structural implementation of less demanding open food challenges will only find support if research demonstrates that their outcome is comparable to DBPCFC, yet this has been proven difficult to investigate. METHODS: We performed a literature review to investigate the diagnostic accuracy of oral food challenges and interviewed 19 parents of children with proven or suspected food allergy about the design of a trial to study this. RESULTS: An overview of the dilemma of diagnosing food allergy using oral food challenges, and the methodological issues and parents' opinions to study this. No comparative studies have been performed using the latest guidelines on oral food challenges. CONCLUSIONS: There is an urgent need to investigate the diagnostic accuracy of different oral food challenge protocols. We present the rationale and design of the ALDORADO trial (ALlergy Diagnosed by Open oR DOuble-blind food challenge) that has been set up to investigate whether the outcome of the open food challenge is comparable to DBPCFC.

Prevalence and early-life risk factors of school-age allergic multimorbidity: The EuroPrevall-iFAAM birth cohort.

BACKGROUND: Coexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan-European, population-based birth cohort study have been lacking. This study compares the prevalence and early-life risk factors of these diseases in European primary school children. METHODS: In the prospective multicentre observational EuroPrevall-iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC-based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these. RESULTS: From 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family-allergy-score, odds ratio (OR) 1.50 (95% CI 1.32-1.70) per standard deviation; early-life allergy symptoms, OR 2.72 (2.34-3.16) for each symptom; and caesarean birth, OR 1.35 (1.04-1.76). Female gender, OR 0.72 (0.58-0.90); older siblings, OR 0.79 (0.63-0.99); and day care, OR 0.81 (0.63-1.06) were protective factors. CONCLUSION: Allergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early-life factors are modifiable and may be considered for prevention strategies.

Frequency of food allergy in school-aged children in eight European countries-The EuroPrevall-iFAAM birth cohort.

BACKGROUND: The prevalence of food allergy (FA) among European school children is poorly defined. Estimates have commonly been based on parent-reported symptoms. We aimed to estimate the frequency of FA and sensitization against food allergens in primary school children in eight European countries. METHODS: A follow-up assessment at age 6-10 years of a multicentre European birth cohort based was undertaken using an online parental questionnaire, clinical visits including structured interviews and skin prick tests (SPT). Children with suspected FA were scheduled for double-blind, placebo-controlled oral food challenges (DBPCFC). RESULTS: A total of 6105 children participated in this school-age follow-up (57.8% of 10 563 recruited at birth). For 982 of 6069 children (16.2%), parents reported adverse reactions after food consumption in the online questionnaire. Of 2288 children with parental face-to-face interviews and/or skin prick testing, 238 (10.4%) were eligible for a DBPCFC. Sixty-three foods were challenge-tested in 46 children. Twenty food challenges were positive in 17 children, including seven to hazelnut and three to peanut. Another seventy-one children were estimated to suffer FA among those who were eligible but refused DBPCFC. This yielded prevalence estimates for FA in school age between 1.4% (88 related to all 6105 participants of this follow-up) and 3.8% (88 related to 2289 with completed eligibility assessment). INTERPRETATION: In primary school children in eight European countries, the prevalence of FA was lower than expected even though parents of this cohort have become especially aware of allergic reactions to food. There was moderate variation between centres hampering valid regional comparisons.

Prevalence estimates and risk factors for early childhood wheeze across Europe: the EuroPrevall birth cohort.

BACKGROUND: Preschool wheeze is an important problem worldwide. No comparative population-based studies covering different countries have previously been undertaken. OBJECTIVE: To assess the prevalence of early childhood wheeze across Europe and evaluate risk factors focusing on food allergy, breast feeding and smoke exposure. METHODS: Infants from nine countries were recruited into the EuroPrevall birth cohort. At 12 and 24 months, data on wheeze, allergic signs/symptoms, feeding, smoke exposure, infections and day care attendance were collected using questionnaires. Poisson regression was used to assess risk factors for wheeze. RESULTS: 12 049 infants were recruited. Data from the second year of life were available in 8805 (73.1%). The prevalence of wheeze in the second year of life ranged from <2% in Lodz (Poland) and Vilnius (Lithuania) to 13.1% (95% CI 10.7% to 15.5%) in Southampton (UK) and 17.2% (95% CI 15.0% 19.5%) in Reykjavik (Iceland). In multivariable analysis, frequent lower respiratory tract infections in the first and second years of life (incidence rate ratio (IRR) 1.9 (95% CI 1.3 to 2.6) and 2.5 (95% CI 1.9 to3.4), respectively), postnatal maternal smoking (IRR 1.6, 95% CI 1.1 to 2.4), day care attendance (IRR 1.6, 95% CI 1.1 to 2.5) and male gender (IRR 1.3, 95% CI 1.0 to 1.7) were associated with wheeze. The strength of their association with wheeze differed between countries. Food allergy and breast feeding were not independently associated with wheeze. CONCLUSION: The prevalence of early childhood wheeze varied considerably across Europe. Lower respiratory tract infections, day care attendance, postnatal smoke exposure and male gender are important risk factors. Further research is needed to identify additional modifiable risk factors that may differ between countries.

Physician's appraisal vs documented signs and symptoms in the interpretation of food challenge tests: The EuroPrevall birth cohort.

BACKGROUND: Blinded food challenges are considered the current gold standard for the diagnosis of food allergies. We used data from a pan-European multicenter project to assess differences between study centers, aiming to identify the impact of subjective aspects for the interpretation of oral food challenges. METHODS: Nine study centers of the EuroPrevall birth cohort study about food allergy recruited 12 049 newborns and followed them for up to 30 months in regular intervals. Intensive training was conducted and every center visited to ensure similar handling of the protocols. Suspected food allergy was clinically evaluated by double-blind, placebo-controlled food challenges using a nine dose escalation protocol. The primary challenge outcomes based on physician's appraisal were compared to documented signs and symptoms. RESULTS: Of 839 challenges conducted, study centers confirmed food allergy in 15.6% to 53.6% of locally conducted challenges. Centers reported 0 to 16 positive placebo challenges. Worsening of eczema was the most common sign when challenged with placebo. Agreement between documented objective signs and the challenge outcome assigned by the physician was heterogeneous, with Cohen's kappa spanning from 0.42 to 0.84. CONCLUSIONS: These differences suggest that the comparison of food challenge outcomes between centers is difficult despite common protocols and training. We recommend detailed symptom assessment and documentation as well as objective sign-based challenge outcome algorithms to assure accuracy and comparability of blinded food challenges. Training and supervision of staff conducting food challenges is a mandatory component of reliable outcome data.

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

BACKGROUND: Precautionary 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. OBJECTIVE: We sought to define threshold dose distributions for 5 major allergenic foods in the European population. METHODS: Patients 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 common matrices. Dose distributions were modeled by using interval-censoring survival analysis with 3 parametric approaches. RESULTS: Of 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. CONCLUSION: This 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.

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.

Remaining symptoms in half the children treated for milk allergy.

UNLABELLED: The aim of this study was to investigate the cumulative incidence and predictive variables of treatment failure with a whey-based extensively hydrolyzed formula (w-eHF) in children with cow's milk allergy (CMA). All children were diagnosed with CMA, using double-blind placebo-controlled food challenge (DBPCFC) with amino acid-based formula as placebo, and receive w-eHF treatment after diagnosis. Forty-nine children with CMA were included. w-eHF treatment failure was defined as incomplete resolution of original CMA symptoms upon w-eHF treatment and disappearance of these symptoms upon replacement of w-eHF with amino acid-based formula. A multiple logistic regression model was used to investigate which variables could predict treatment failure. Twenty-five (51%; 95% confidence interval (CI) 38-64%) of the children with CMA failed on w-eHF. Only "gastrointestinal discomfort" was found to contribute independently to the probability of failing w-eHF, odds ratio (95% CI) 8.994 (1.007-79.457). CONCLUSIONS: In half of the children with proven CMA, there is incomplete resolution of symptoms upon w-eHF treatment. This study needs to be repeated including DBPCFC with w-eHF to provide more definitive diagnosis, especially since gastrointestinal discomfort seems to be the sole predictive variable for treatment failure. In the meantime, a change in formula should be considered in children with incomplete symptom resolution upon w-eHF treatment.

From knemometry to final adult height: inhaled corticosteroids and their effect on growth in childhood.

Growth impairment in children with asthma, as a consequence of inhaled corticosteroids (ICS), is a major issue. Adverse systemic effects of ICS have been reviewed extensively, but no clinically relevant effects are reported if they are used in an appropriate dose as advocated in most guidelines. Growth studies can be divided into knemometry studies, intermediate term studies, and long term studies up to final adult height. These different studies provide different information. Knemometry demonstrates a dose dependent systemic effect, while all intermediate term studies demonstrate growth reduction of approximately one cm after one year of treatment. Most reassuring is that this delay seems to be temporary. The one study with a follow-up to final height shows no differences between the ICS and non-ICS treated children. The studies suggest that the use of ICS with respect to growth is safe if these drugs are used in a low to medium dose.

Towards better triage of infants suspected of cow's milk allergy: development of a preliminary multivariable diagnostic index.

The double-blind placebo-controlled food challenge (DBPCFC) is currently the gold standard to diagnose cow's milk allergy (CMA). However, DBPCFCs are burdensome, expensive and require specialised facilities. For primary care physicians, selective and consistent referral to DBPCFC of infants suspected of CMA may be difficult. The objective of this study was to assess the predictive value of clinical parameters for a positive DBPCFC in infants suspected of CMA. Clinical data from 124 infants suspected of CMA that had undergone a DBPCFC were collected. Out of a total of 23 parameters, nine candidate predictors were selected on clinical grounds. We used bootstrapped logistic regression analysis to find a more parsimonious and practical model. The prevalence of a positive DBPCFC was 34.7 % (95 % CI from 27 to 43). A well-calibrated diagnostic model containing as predictors abdominal cramps, inconsolable crying and the objective SCORAD index discriminated moderately well between infants with and without a positive DBPCFC. The area under the ROC curve was 0.68 (95 % CI from 0.58 to 0.78). The fifth and 95th percentiles of the positive DBPCFC predictive probability distribution were 17 and 73 % (17 and 59 % after correction for over-optimism). We conclude that a diagnostic model with three clinical parameters may be used for better referral of children suspected of CMA and the decision to either initially perform an open food challenge or directly perform a DBPCFC. Large prospective studies are needed to validate these findings and provide additional precision.

Tolerance Induction in Cow's Milk Allergic Children by Heated Cow's Milk Protein: The iAGE Follow-Up Study.

Accelerating the induction of tolerance to cow's milk (CM) reduces the burden of cow's milk allergy (CMA). In this randomised controlled intervention study, we aimed to investigate the tolerance induction of a novel heated cow milk protein, the iAGE product, in 18 children with CMA (diagnosed by a paedriatric allergist). Children who tolerated the iAGE product were included. The treatment group (TG: n = 11; mean age 12.8 months, SD = 4.7) consumed the iAGE product daily with their own diet, and the control group (CG: n = 7; mean age 17.6 months, SD = 3.2) used an eHF without any milk consumption. In each group, 2 children had multiple food allergies. The follow-up procedures consisted of a double-blind placebo-controlled food challenge (DBPCFC) with CM t = 0, t = 1 (8 months), t = 2 (16 months), and t = 3 (24 months). At t = 1, eight (73%) of 11 children in the TG had a negative DBPCFC, versus four out of seven (57%) in the CG (BayesFactor = 0.61). At t = 3, nine of the 11 (82%) children in the TG and five of seven (71%) in the CG were tolerant (BayesFactor = 0.51). SIgE for CM reduced from a mean of 3.41 kU/L (SD = 5.63) in the TG to 1.24 kU/L (SD = 2.08) at the end of intervention, respectively a mean of 2.58 (SD = 3.32) in the CG to 0.63 kU/L (SD = 1.06). Product-related AEs were not reported. CM was successfully introduced in all children with negative DBPCFC. We found a standardised, well-defined heated CM protein powder that is safe for daily OIT treatment in a selected group of children with CMA. However, the benefits of inducing tolerance were not observed.

The Dutch Working Party on Antibiotic Policy (SWAB) guideline for the approach to suspected antibiotic allergy.

OBJECTIVES: Prudent handling of reported antibiotic allergies is an important aspect of antibiotic stewardship. The Dutch Working Party on Antibiotic Policy (SWAB) constituted a multidisciplinary expert committee to provide evidence-based recommendations for bedside decision-making in antibiotic therapy in patients that report an antibiotic allergy. METHODS: The guideline committee generated 12 key questions, most of which were population, intervention, comparison, and outcome questions relevant to both children and adults with suspected antibiotic allergies. For each question, a systematic literature search was performed and reviewed for the best available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The quality of evidence was graded from very low to high, and recommendations were formulated in structured discussions as strong or weak. RESULTS: Sixty recommendations were provided for suspected allergy to ß-lactam antibiotics (BLAs) and non-ß-lactam antibiotics. Owing to the absence of randomized controlled trials in this field, the underlying evidence was predominantly graded as low or very low. Available data support that a detailed allergy history should always be performed and critically appraised. When cross-allergy between BLA groups is not to be expected due to the absence of molecular similarity of the side chains, the patient can be safely exposed to the alternative BLA. An exception to this rule is severe delayed-type reactions in which re-exposure to a BLA should only be considered after consultation with a multidisciplinary team. CONCLUSIONS: Accumulated scientific data now support a more liberal approach that better balances the benefits of treatment with first choice and usually smaller spectrum antibiotics with appropriate avoidance of antibiotics in case of a truly high risk of a (severe) allergic reaction. In The Netherlands, a formal guideline was developed that provides recommendations for the approach toward suspected allergy to BLA and frequently used non-ß-lactam antibiotics, thereby strongly supporting antimicrobial stewardship.

Relevance of Early Introduction of Cow's Milk Proteins for Prevention of Cow's Milk Allergy.

Food allergy incidence has increased worldwide over the last 20 years. For prevention of food allergy, current guidelines do not recommend delaying the introduction of allergenic foods. Several groundbreaking studies, such as the Learning Early About Peanut Allergy study, showed that the relatively early introduction of this allergenic food between 4-6 months of age reduces the risk of peanut allergy. However, less is known about the introduction of cow's milk, as many children already receive cow's-milk-based formula much earlier in life. This can be regular cow's milk formula with intact milk proteins or hydrolyzed formulas. Several recent studies have investigated the effects of early introduction of cow's-milk-based formulas with intact milk proteins on the development of cow's milk allergy while breastfeeding. These studies suggest that depending on the time of introduction and the duration of administration of cow's milk, the risk of cow's milk allergy can be reduced (early introduction) or increased (very early introduction followed by discontinuation). The aim of this narrative review is to summarize these studies and to discuss the impact of early introduction of intact cow's milk protein-as well as hydrolyzed milk protein formulas-and the development of tolerance versus allergy towards cow's milk proteins.

The utility of glucose area under the curve from the oral glucose tolerance test as a screening tool for cystic fibrosis-related diabetes.

BACKGROUND: Consistently abnormal glucose levels on oral glucose tolerance test (OGTT) are the most effective screening tool for cystic fibrosis-related diabetes (CFRD). However, some cystic fibrosis (CF) patients demonstrate abnormal glucose profiles not reaching levels required for CFRD diagnosis and are, therefore, left untreated. Since CFRD is associated with disease deterioration, early diagnosis and treatment are desirable. AIM: To explore the association between the area under the curve of glucose (G-AUC) obtained during a five-point 2-h standard OGTT and CF disease severity parameters. METHODS: All CF patients referred for an annual routine OGTT at the Hadassah CF Center between 2002 and 2018, were included. Disease severity parameters were correlated with the G-AUC. RESULTS: Two hundred forty-two OGTTs were performed in 81 patients (mean age 19.7 ± 9.0 years); 54% were normal, 14% showed impaired glucose tolerance (IGT), 5% had values in the indeterminate range (INDET), 11% had both IGT and INDET and 16% were diagnosed with CFRD. A gradual increase in mean G-AUC was observed among the groups. In multivariate regression models, G-AUC ≥ 295 mg h/dl was independently associated with an increased number of pulmonary exacerbations (PEx). Not all the patients having this value met the CFRD definition. CONCLUSION: Patients who do not fulfill the criteria for CFRD may have abnormal glucose metabolism identifiable by abnormally high G-AUC values, which may be associated with more PEx. The potential advantage of treating these patients with insulin and the subsequent reduction in PEx needs further investigation.

Introduction of Heated Cow's Milk Protein in Challenge-Proven Cow's Milk Allergic Children: The iAGE Study.

The introduction of baked milk products in cow's milk (CM) allergic children has previously been shown to accelerate induction tolerance in a selected group of children. However, there is no standardized baked milk product on the market. Recently, a new standardized, heated and glycated cow's milk protein (HP) product was developed. The aim of this study was to measure safety and tolerability of a new, well characterized heated CM protein (HP) product in cow's milk allergic (CMA) children between the age of 3 and 36 months. The children were recruited from seven clinics throughout The Netherlands. The HP product was introduced in six incremental doses under clinical supervision. Symptoms were registered after introduction of the HP product. Several questionnaires were filled out by parents of the children. Skin prick tests were performed with CM and HP product, sIgE to CM and α-lactalbumin (Bos d4), ß-lactoglobulin (Bos d5), serum albumin (Bos d 6), lactoferrin (Bos d7) and casein (Bos d8). Whereas 72% percent (18 out of 25) of the children tolerated the HP product, seven children experienced adverse events. Risk factors for intolerance to the HP product were higher skin prick test (SPT) histamine equivalent index (HEP) results with CM and the HP product, higher specific IgE levels against Bos d4 and Bos d8 levels and Bos d5 levels. In conclusion, the HP product was tolerated by 72% of the CM allergic children. Outcomes of SPT with CM and the HP product, as well as values of sIgE against caseins, α-lactalbumin, and ß-lactoglobulin may predict the tolerability of the HP product. Larger studies are needed to confirm these conclusions.