Diagnostic accuracy of Ara h 2 for detecting peanut allergy in children.

BACKGROUND: Specific IgE to Ara h 2 is a diagnostic test for peanut allergy which may reduce the need for double-blind placebo-controlled food challenges (DBPCFC); however, guidance for using Ara h 2 in place of DBPCFCs has not been validated. OBJECTIVE: To prospectively evaluate 1) diagnostic accuracy of previously published Ara h 2 cut-off levels to diagnose peanut allergy in children and 2) costs. METHODS: A consecutive series of 150 children age 3.5 to 18 years was evaluated in secondary and tertiary settings in the Netherlands. sIgE to Ara h 2 was the index test, and oral peanut ingestion was the reference test. Oral peanut ingestion was home or supervised introduction for Ara h 2 ≤ 0.1, DBPCFC for 0.1-5.0 and open food challenge for ≥5.0. Costs were calculated using financial healthcare data. RESULTS: A conclusive reference test was performed in 113 children (75%). Sixty-four children (57%) had peanut allergy, as confirmed by a DBPCFC (27/47) or an open challenge (37/50). Forty-nine children (43%) were considered peanut-tolerant after peanut introduction (19/19), a DBPCFC (20/47) or an open challenge (10/50). Area under the curve for Ara h 2 was 0.94 (95% CI 0.90-0.98). The diagnostic flow chart correctly classified 26/26 (100%; 84-100) of children with Ara h 2 ≤ 0.1 as peanut-tolerant and 34/35 (97%; 83-100) of children with Ara h 2 ≥ 5.0 as peanut-allergic. At a cut-off of ≤0.1 and ≥5.0, a sensitivity of respectively 100% (93-100) and 53% (38-67) was observed and a specificity of 53% (38-67) and 98% (87-100). Mean annual costs of the flow chart were estimated as €320-€636 per patient lower than following national allergy guidelines. CONCLUSIONS: In this diagnostic accuracy study, which did not take into account pretest probability, we have validated previously published Ara h 2 cut-off levels which are associated with peanut tolerance and allergy.

Safety and effectiveness of omalizumab for the treatment of chronic urticaria in pediatric patients.

BACKGROUND: Evidence on safety and effectiveness of omalizumab for treatment of chronic urticaria in pediatric patients is scarce and limited to case reports. In particular, drug survival of omalizumab has not yet been investigated, which is a key element in the evaluation of its clinical performance. The aim of this study was to investigate safety, effectiveness, and drug survival rates of omalizumab in a daily practice cohort of pediatric patients with chronic urticaria (CU). METHODS: This is a multicenter study including all pediatric patients from an academic center (Wilhelmina Children's Hospital) and a general center (Diakonessenhuis Hospital) in the Netherlands, who started omalizumab treatment before the age of 18 years. Data on safety, effectiveness, time to discontinuation, and reasons for discontinuation of treatment were assessed. Drug survival of omalizumab was estimated using the Kaplan-Meier survival analysis. RESULTS: A total of 38 patients, who started treatment between January 2014 and January 2020, were included. Most patients (68.4%) used omalizumab without reporting any side effects and a complete or good response to treatment was achieved in 76.3% of patients. The 1- and 2-year drug survival rates were 62% and 50%, respectively, with well-controlled disease activity as the most frequent reason for discontinuation in 69.2% of patients, followed by ineffectiveness in 23.1% and side effects in 7.7% of patients. CONCLUSIONS: This study demonstrates high safety and effectiveness of omalizumab treatment in pediatric patients with CU, which will aid clinical decision making and management of expectations when choosing omalizumab treatment for pediatric patients with CU.

Accurate Prediction of Peanut Allergy in One-Third of Adults Using a Validated Ara h 2 Cutoff.

BACKGROUND: The diagnostic value of peanut components is extensively studied in children, but to a lesser extent in adults with suspected peanut allergy. The use of peanut components in daily practice may reduce the need for double-blind placebo-controlled food challenges (DBPCFCs); however, validation studies are currently lacking. OBJECTIVE: To evaluate the diagnostic value of (combined) peanut components and validate a previously found Ara h 2 cutoff level with 100% positive predictive value (PPV) in adults with suspected peanut allergy. METHODS: Adults who underwent a peanut DBPCFC were included: 84 patients from a previous study (2002-2012) and 70 new patients (2012-2019). Specific IgE (sIgE) to peanut extract, Ara h 1, 2, 3, 6, and 8 was measured using ImmunoCAP. Diagnostic value was assessed with an area under the curve (AUC) analysis. RESULTS: In total, 95 (62%) patients were peanut allergic. sIgE to Ara h 2 and Ara h 6 were the best predictors with an AUC (95% confidence interval) of 0.85 (0.79-0.91) and 0.85 (0.79-0.92), respectively. The Ara h 2 cutoff level with 100% PPV (≥1.75 kUA/L) was validated in the 70 new patients. Thirty percent of all included patients could be classified correctly as peanut allergic using this validated cutoff level. CONCLUSION: sIgE to Ara h 2 and Ara h 6 have equally high discriminative ability. Peanut allergy can be predicted accurately in one-third of adults using a validated cutoff level of sIgE to Ara h 2.

Reintroduction failure after negative food challenges in adults is common and mainly due to atypical symptoms.

BACKGROUND: Reintroduction of a food after negative food challenge (FC) faces many obstacles. There are no studies available about this subject in adults. OBJECTIVE: To investigate the frequency, reasons and risk factors of reintroduction failure in adults. METHODS: In this prospective study, adult patients received standardized follow-up care after negative FCs including a reintroduction scheme and supportive telephone consultations. Data were collected by telephone interview (2 weeks after FC) and questionnaires (at baseline and 6 months after FC(s)): food habits questionnaire, State-Trait Anxiety Inventory, Food Allergy Quality of Life Questionnaire-Adult Form and Food Allergy Independent Measure. Frequency and reasons of reintroduction failure were analysed using descriptive statistics and risk factors with univariate analyses. RESULTS: Eighty patients were included with, in total, 113 negative FCs. Reintroduction failed on short-term (2 weeks after FC) in 20% (95% CI: 13%-28%). Common reasons were symptoms upon ingestion during the reintroduction scheme (50%) and no need to eat the food (23%). On the long-term (5-12 months after FC(s)), reintroduction failure increased to 40% (95% CI: 28%-53%). Common reasons were atypical symptoms after eating the food (59%) and fear for an allergic reaction (24%). Five risk factors for long-term reintroduction failure were found: if culprit food was not one of the 13 EU regulated allergens, reintroduction failure at short-term, atypical symptoms during FC, a lower quality of life and a higher state anxiety. CONCLUSIONS AND CLINICAL RELEVANCE: Reintroduction failure after negative FCs in adults is common, increases over time, and is primarily due to atypical symptoms. This stresses the need for more patient-tailored care before and after negative food challenges.

Perceived triggers of asthma impair quality of life in children with asthma.

BACKGROUND: Data on the impact of the number and nature of perceived asthma triggers on health-related quality of life (HRQL) in children are scarce. OBJECTIVE: To investigate the impact of perceived asthma triggers on both asthma-specific and generic HRQL in children. METHODS: A cross-sectional study was conducted among children (7-18 years) with asthma in secondary and tertiary care. Children were screened with electronic questionnaires regarding respiratory and allergic symptoms. Asthma-specific HRQL was assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) (score range 1-7) and generic HRQL using the RAND questionnaire (score range 7-32). The Kruskal-Wallis test and one-way ANOVA were used to test the difference of, respectively, the PAQLQ and RAND scores across the number of perceived asthma triggers (0, 1-2, 3-4, or ≥ 5). Univariable and multivariable linear regression analyses were performed to evaluate the association between individual triggers and HRQL. RESULTS: A total of 527 children with a mean (SD) age of 12.1 (2.9) years were included. Children with a higher number of perceived triggers had significantly lower PAQLQ and RAND scores (ie poorer HRQL). The difference in PAQLQ scores was clinically relevant between children with 0 versus 3-4 or ≥ 5 triggers and 1-2 versus ≥ 5 triggers (mean difference 0.66, 1.02 and 0.63, respectively). Especially, non-allergic triggers (physical exercise, the weather, (cigarette) smoke and emotions) were significantly associated with reduced PAQLQ scores. Emotions and food/drinks were associated with reduced RAND scores. CONCLUSION AND CLINICAL RELEVANCE: A higher number of perceived triggers of asthma were associated with reduced HRQL in children with asthma. Especially, non-allergic triggers were associated with reduced HRQL.

The impact of oral food challenges for food allergy on quality of life: A systematic review.

BACKGROUND: Food allergy significantly impairs health-related quality of life (HRQL). Currently, it is still unknown whether diagnostic interventions for food allergy improve HRQL. We aim to assess the impact of diagnostic interventions for food allergy on HRQL. METHODS: A systematic search was performed in MEDLINE, Embase, Cochrane Library, and CINAHL focused on patients with a (suspected) food allergy who underwent diagnostic interventions (ie, skin prick test, specific IgE, or oral food challenges [OFC]) and in whom HRQL was assessed. The mean difference between HRQL before and after the diagnostic intervention was calculated. A minimal clinically important difference of 0.5 was considered clinically relevant for the food allergy quality of life questionnaire. RESULTS: Seven of 1465 original identified publications were included in which the impact of an OFC on HRQL was investigated (total patients n = 1370). No other diagnostic interventions were investigated. Food allergy-specific parent-reported HRQL improved significantly after an OFC irrespective of the outcome in children with a suspected food allergy in two publications. The change was considered clinically relevant in one of two publications. In addition, parent-reported HRQL improved after an OFC to assess the eliciting dose in children with a confirmed food allergy. The parental burden was significantly reduced after an OFC to assess resolution of food allergy. A meta-analysis could not be performed due to the limited numbers of, and considerable heterogeneity between, eligible publications. CONCLUSION: An OFC is associated with an improved food allergy-specific HRQL and a reduced parental burden of food allergy.

Fecal Microbiome and Food Allergy in Pediatric Atopic Dermatitis: A Cross-Sectional Pilot Study.

BACKGROUND: Exposure to microbes may be important in the development of atopic disease. Atopic diseases have been associated with specific characteristics of the intestinal microbiome. The link between intestinal microbiota and food allergy has rarely been studied, and the gold standard for diagnosing food allergy (double-blind placebo-controlled food challenge [DBPCFC]) has seldom been used. We aimed to distinguish fecal microbial signatures for food allergy in children with atopic dermatitis (AD). METHODS: Pediatric patients with AD, with and without food allergy, were included in this cross-sectional observational pilot study. AD was diagnosed according to the UK Working Party criteria. Food allergy was defined as a positive DBPCFC or a convincing clinical history, in combination with sensitization to the relevant food allergen. Fecal samples were analyzed using 16S rRNA microbial analysis. Microbial signature species, discriminating between the presence and absence food allergy, were selected by elastic net regression. RESULTS: Eighty-two children with AD (39 girls) with a median age of 2.5 years, and 20 of whom were diagnosed with food allergy, provided fecal samples. Food allergy to peanut and cow's milk was the most common. Six bacterial species from the fecal microbiome were identified, that, when combined, distinguished between children with and without food allergy: Bifidobacterium breve, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Escherichia coli, Faecalibacterium prausnitzii, and Akkermansia muciniphila (AUC 0.83, sensitivity 0.77, specificity 0.80). CONCLUSIONS: In this pilot study, we identified a microbial signature in children with AD that discriminates between the absence and presence of food allergy. Future studies are needed to confirm our findings.

Usefulness of open mixed nut challenges to exclude tree nut allergy in children.

BACKGROUND: To minimize the risk of accidental reactions, atopic children with multiple sensitizations to tree nuts are advised to avoid all nuts. Multiple food challenges would be needed to confirm the clinical relevance, but are too burdensome to be practical. The usefulness of open mixed nut challenges in terms of safety, reactions during challenge, tolerance of the challenge material, effect on the elimination diet and satisfaction of the parents was evaluated. FINDINGS: Open mixed nut challenges were performed in 19 children with a previous negative hazelnut challenge and long term elimination diet for tree nuts. Challenges were negative in 13 (68 %) children, in four (21 %) children (non-severe) allergic symptoms were observed. The challenges were well accepted, safe and efficient. We were able to avoid multiple nut challenges in 15 (79 %) children. CONCLUSIONS: Open mixed nut challenge can efficiently exclude multiple tree nut allergies in children with a lifelong nut free diet and low suspicion of clinical allergy.

Standardized food challenges are subject to variability in interpretation of clinical symptoms.

BACKGROUND: Food challenge tests are the gold standard in diagnosing food allergy. Guidelines provide scoring systems to classify symptoms during challenge and typically recommend that challenges are considered positive when objective symptoms occur. However, currently no standard criteria for the definition of a positive challenge outcome exists and interpretation of food challenges mainly depends on clinical judgment. This study aims to assess inter- and intra-observer variability in outcomes of routinely performed peanut challenges in children. METHODS: All complete food challenge score sheets of double blind placebo controlled peanut challenges performed in 2008-2010 in an academic hospital were included. Score sheets were reassessed independently by three clinical experts including double reassessment in a subset of score sheets. Inter- and intra-observer variability was evaluated using kappa statistics. RESULTS: We included 191 food challenge score sheets. Inter-observer agreement on overall challenge outcome was moderate (κ = 0.59-0.65) and was fair (κ = 0.31-0.46) on challenges with symptoms. Intra-observer agreement on overall challenge outcome was good (κ = 0.63-0.77) but was moderate (κ = 0.50-0.60) on challenges with symptoms. Subjective symptoms (oral symptoms, abdominal complaints, food aversion) were significantly associated with disagreement between observers. CONCLUSIONS: We demonstrate that, despite strict adherence to guidelines, there is a considerable amount of variability in reassessment of symptoms recorded on food challenges sheets between and within well trained clinicians, especially when subjective symptoms occur.

Reintroduction failure after negative peanut challenges in children.

BACKGROUND: A negative double-blind placebo-controlled food challenge (DBPCFC) should normally be followed by reintroduction of the food. However, reintroduction fails in a subset of children. The observed reintroduction problems could be due to refusal of the food that long has been avoided, to other behavioural/psychological factors or to false negative DBPCFC outcome. This study analyses the frequency, causes and risk factors for reintroduction failure in children after negative peanut DBPCFC. METHODS: A retrospective study of children with a negative DBPCFC for peanut was performed. During follow-up after DBPCFC, parents were systematically interviewed about the current diet, symptoms and problems during reintroduction, and reactions to peanut after the reintroduction period. Successful reintroduction was defined as eating peanut or products containing peanut as ingredient on a regular basis. RESULTS: Follow-up data were obtained in 103 children with a negative peanut challenge. In 70 (68%) children, reintroduction was successful (54 children tolerated peanut, 16 children tolerated peanut as ingredient). Reintroduction failed in 33 (32%) children. Food refusal (45%) and peanut-related symptoms (33%) were the most reported reasons. Risk factors for reintroduction failure were an elimination diet for more than three other foods (p = 0.019), a long elimination diet for peanut (p = 0.048) and peanut-related symptoms at home (p = 0.002). CONCLUSION: Reintroduction failure is a common problem in children after negative peanut challenge. To guide reintroduction and identify potential peanut-related symptoms at home, careful follow-up after negative DBPCFC is advised. When symptoms occur or persist, food challenge outcome needs to be reconsidered.

Suspected cow's milk allergy in everyday general practice: a retrospective cohort study on health care burden and guideline adherence.

BACKGROUND: Cow's milk allergy (CMA) is the most common food allergy among infants. No data are available on the health care burden of suspected CMA in general practice. This study was conducted to evaluate the burden of suspected CMA in general practice (GP): (a) prevalence, (b) presenting symptoms, (c) diagnostic process, (d) guideline adherence, and (e) dietary measures. METHODS: A retrospective cohort study was carried out in four Julius Healthcare Centers (JHCs). These JHCs form the core primary care academic network of the department of general practice of the University Medical Center of Utrecht. Electronic records of the first year of infants born May 2009 - April 2010 registered in the JHCs were screened for possible CMA suspicion. Preventive child healthcare (PCH) records were reviewed for additional information. Clinical presentation, diagnostic strategies and dietary measures were extracted. RESULTS: Of 804 infants evaluated, 55 presented with symptoms fitting the suspicion of CMA (prevalence of 7%). Presenting complaints involved the skin (71%); the gastrointestinal tract (60%); the respiratory tract (13%) or other symptoms (36%) and 23 infants presented with symptoms of two or more organ systems. In 31 children (56%) a food challenge was performed (n = 28 open and n = 3 double-blind). Open challenge test results were difficult to interpret due to inadequate implementation or reporting. None had confirmed CMA after an adequate challenge test. Long term milk substitute formulas were prescribed in 39 (71%) infants. CONCLUSION: On a yearly basis seven percent of children visit their GP for suspected CMA. A positive CMA diagnosis was rarely established after adequate implementation and reporting of diagnostics, yet long term dietary measures were prescribed in >70% of patients. There is definitely need for improvement of diagnosing CMA in primary care.

Comparing high altitude treatment with current best care in Dutch children with moderate to severe atopic dermatitis (and asthma): study protocol for a pragmatic randomized controlled trial (DAVOS trial).

BACKGROUND: About 10 to 20% of children in West European countries have atopic dermatitis (AD), often as part of the atopic syndrome. The full atopic syndrome also consists of allergic asthma, allergic rhinitis and food allergy. Treatment approaches for atopic dermatitis and asthma include intermittent anti-inflammatory therapy with corticosteroids, health education and self-management training. However, symptoms persist in a subgroup of patients. Several observational studies have shown significant improvement in clinical symptoms in children and adults with atopic dermatitis or asthma after treatment at high altitude, but evidence on the efficacy when compared to treatment at sea level is still lacking. METHODS/DESIGN: This study is a pragmatic randomized controlled trial for children with moderate to severe AD within the atopic syndrome. Patients are eligible for enrolment in the study if they are: diagnosed with moderate to severe AD within the atopic syndrome, aged between 8 and 18 years, fluent in the Dutch language, have internet access at home, able to use the digital patient system Digital Eczema Center Utrecht (DECU), willing and able to stay in Davos for a six week treatment period. All data are collected at the Wilhelmina Children's Hospital and DECU. Patients are randomized over two groups. The first group receives multidisciplinary inpatient treatment during six weeks at the Dutch Asthma Center in Davos, Switzerland. The second group receives multidisciplinary treatment during six weeks at the outpatient clinic of the Wilhelmina Children's Hospital, Utrecht, the Netherlands. The trial is not conducted as a blind trial. The trial is designed with three components: psychosocial, clinical and translational. Primary outcomes are coping with itch, quality of life and disease activity. Secondary outcomes include asthma control, medication use, parental quality of life, social and emotional wellbeing of the child and translational parameters. DISCUSSION: The results of this trial will provide evidence for the efficacy of high altitude treatment compared to treatment at sea level for children with moderate to severe AD. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88136485.

Plasma IL-25 is elevated in a subgroup of patients with clinical reactivity to peanut.

BACKGROUND: One of the IL-17 family members, IL-25, has been implicated with the initiation and amplification of Th2 responses in animal models and has been associated with airway hyper-reactivity. The involvement of IL-25 and also IL-17 in food allergic disease remains to be investigated. FINDINGS: In this study thirty children suspected of peanut allergic disease underwent a double-blind placebo controlled food challenge (DBPCFC) and IL-25 and IL-17 plasma levels were determined before and after challenge. IL-25 was highly elevated only in subgroup of children with a positive DBPCFC outcome. Plasma IL-25 was absent in children with a negative DBPCFC outcome and in healthy controls. CONCLUSIONS: This study shows that IL-25, an IL-17 family member, is highly elevated only in children with a clinical response to peanut. This suggests a role for IL-25 in the pathogenesis of peanut allergy and elevated plasma IL-25 may be a sign of a severe atopic phenotype.

[One guideline for diagnosing cow milk allergy; for primary, secondary and tertiary care in the Netherlands]. / 1 richtlijn voor diagnostiek van koemelkallergie; voor de eerste, tweede en derde lijn in Nederland.

The aims of the new Dutch guideline 'Diagnosing Cow Milk Allergy in Children in the Netherlands' are to provide an evidence-based instrument for the reliable and safe diagnosis of cow milk allergy and to improve the collaboration between health care professionals at well-baby clinics, general practices and hospitals. The double-blind, placebo-controlled cow-milk provocation test is the only test available for establishing an allergy to cows' milk. The double-blind provocation test in children at a low risk of severe reactions may be performed at the better-equipped well-baby clinics and at all general practices, thereby shifting care from secondary to primary care. The use of extensively hydrolysed formulas based on whey protein as well as on casein can be advised for a cow-milk-free diet. The general practitioner and well-baby physician should collaborate in designating responsibilities during the diagnostic phase of cow milk allergy in primary care.

Can we predict severe reactions during peanut challenges in children?

BACKGROUND: Limited and contrasting data are available about risk factors for severe reactions during double-blind, placebo-controlled food challenge (DBPCFC). Knowing these risk factors would help to improve safety precautions and choosing the best setting for challenge. We assessed whether we could determine predictors for positive and severe food challenge outcome (FCO) with regular available patient data in children suspected for peanut allergy. METHODS: A retrospective study in children referred for DBPCFC with peanut was performed during a 3-year period. Reactions during challenge were classified as mild/moderate (Sampson's grade 1-3) and severe (Sampson's grade 4-5). We performed uni- and multivariable logistic regression to determine predictors for positive and severe FCO. RESULTS: A group of 225 children with a median age of 6.7 (IQR 5.0-9.5) years were studied. In 109 (48%) children, food challenge outcome was positive and 24 (11%) children developed a severe reaction. The level of sIgE for peanut OR 1.14 (1.08-1.20), male gender OR 0.40 (0.20-0.81), having another food allergy OR 0.43 (0.20-0.88), were independently related to positive FCO. No significant differences were found between children with severe and non-severe FCO with respect to age, gender, asthma, sIgE, or previous reaction to peanut. CONCLUSIONS: Although predictors of positive FCO could be identified, none of the studied risk factors could predict a severe reaction during peanut challenge. When challenging a child sensitized to peanut, clinicians should be prepared and equipped to handle any reaction in all cases.