Prevalence and Predictors of Uncontrolled Asthma in Children Referred for Asthma and Other Atopic Diseases.

BACKGROUND: Uncontrolled asthma in children is still highly prevalent despite the availability of effective asthma treatment. We investigated 1) the prevalence of uncontrolled asthma among children referred for asthma and referred for atopic diseases other than asthma (ie food allergy, allergic rhinitis or atopic dermatitis) to secondary care; and 2) the predictors associated with uncontrolled asthma. METHODS: All children (4 to 18 years) referred for asthma or atopic diseases other than asthma to 8 secondary care centers in The Netherlands were invited to an electronic portal (EP). The EP is a web-based application with several validated questionnaires including the ISAAC questionnaires and the Asthma Control Test (ACT). Children were eligible for inclusion in this study when their parents reported in the EP that their child had asthma diagnosed by a physician. The ACT was used to assess asthma control. Multiple predictors of asthma control (patient, asthma and atopic characteristics) were evaluated by univariable and multivariable logistic regression analyses. RESULTS: We included 408 children: 259 children (63%) with asthma referred for asthma and 149 children (37%) with asthma referred for atopic diseases other than asthma. Thirty-nine percent of all children had uncontrolled asthma: 47% of the children referred for asthma and 26% of the children referred for atopic diseases other than asthma. Predictors associated with uncontrolled asthma were a family history of asthma (odds ratio [OR] 2.08; 95% confidence interval [95% CI] 1.34 to 3.24), and recurrent upper and lower respiratory tract infections in the past year (OR 2.40; 95% CI 1.52 to 3.81 and OR 2.00; 95% CI 1.25 to 3.23, respectively). CONCLUSION: Uncontrolled asthma is highly prevalent in children with asthma referred to secondary care, even if children are primarily referred for atopic diseases other than asthma. Thus, attention should be paid to asthma control in this population.

Predictors of treatment success in children with difficult to treat atopic dermatitis using a personalized integrative multidisciplinary (PIM) treatment programme.

BACKGROUND: A 6-week personalized integrative multidisciplinary treatment programme (PIM) was developed for children with difficult to treat AD who appeared unresponsive to treatment according to current guidelines. OBJECTIVE: The aim of the present study was to identify clinical and psychosocial characteristics that predict long-term treatment success after PIM. METHODS: Treatment was considered successful when there was a 75% reduction on the Self-Administered Eczema Area and Severity Index and/or little impact of AD on daily life, measured with the Children's Dermatology Life Quality Index (score ≤ 6), 6 months after the end of PIM. PIM is a personalized, integrative, multidisciplinary treatment programme with clearly defined goals and strategies, addressing atopic, paediatric, mental health comorbidities and general well-being, for children and adolescents aged 8- to 18 years. Multivariate logistic regression models were constructed using a backward selection procedure. Questionnaires were used to assess psychosocial characteristics; clinical data was extracted from medical records. RESULTS: In total, 79 children/adolescents with difficult to treat AD completed PIM and long-term treatment results were available for 74 children/adolescents. The majority (77%) of children/adolescents demonstrated long-term treatment success with PIM. Predictors of long-term treatment success (adjusted ORs) included maternal disease acceptance OR (95% CI) 1.84 (1.15-2.94). A group (23%) of mostly females OR (95% CI) 0.10 (0.02-0.54) with multiple somatic complaints OR (95% CI) 0.88(0.80-0.97), from families where the mother has anxiety for the use of topical corticosteroids OR (95% CI) 0.62(0.40-0.94), is less likely to obtain long-term treatment success. CONCLUSION: Most children and adolescents with difficult to treat AD, seemingly unresponsive to conventional treatment according to current guidelines, are able to improve with PIM. Psychosocial and family but not clinical variables, predicted long-term treatment success after participating in PIM.

Effectiveness of alpine climate treatment for children with difficult to treat atopic dermatitis: Results of a pragmatic randomized controlled trial (DAVOS trial).

BACKGROUND: Alpine climate treatment has historically been used in Europe to treat atopic dermatitis (AD), but no randomized trials have been conducted to provide evidence for its effectiveness. OBJECTIVE: To investigate the long-term effectiveness of alpine climate treatment for children with difficult to treat AD. MATERIALS & METHODS: A pragmatic, open, randomized controlled trial was conducted. Children diagnosed with AD that was considered difficult to treat, aged between 8 and 18 years and willing to be treated in Switzerland were randomized to a six-week personalized integrative multidisciplinary treatment period in a clinical setting in the alpine climate (Switzerland) or an outpatient setting in moderate maritime climate (Netherlands). Study assessments were conducted at the Wilhelmina Children's Hospital; an electronic portal was used for the collection of questionnaire data. Primary outcomes were disease activity (SAEASI), quality of life (CDLQI) and catastrophizing thoughts (JUCKKI/JU) 6 months after intervention. Other assessments were immediately and 6 weeks after intervention. Subgroup analyses concerned asthma-related outcomes. Children were randomly assigned to either the intervention or control group using a covariate adaptive randomization method, taking age and asthma diagnosis into account. Children, parents and healthcare professionals involved in treatment were not blinded to group assignment. Data were analysed according to intention-to-treat with linear mixed-effects models for continuous outcomes. The trial is registered at Current Controlled Trials ISCRTN88136485. RESULTS: Between 14 September 2010 and 30 September 2014, 88 children were enrolled in the trial, 84 children were randomized (41 assigned to intervention, 43 to control) of whom 77 completed the intervention (38 of 41 (93%) intervention, 39 of 43 (91%) control) and 74 completed follow-up (38 of 41 (93%) intervention, 36 of 43 (84%) control). Six months after intervention there were no significant differences between the groups on disease activity (SAEASI mean difference -3.4 (95%CI -8.5 to 1.7)), quality of life (CDLQI mean difference -0.3 (95%CI -2.0 to 1.4)) and catastrophizing thoughts (JUCCKI/JU subscale mean difference -0.7 (95%CI -1.4 to -0.0)). Immediately and 6 weeks after intervention, disease activity and quality of life were significantly different in favour of alpine climate treatment. Mean differences on SAEASI were -10.1 (95%CI -14.5 to -5.8) and -8.4 (95%CI -12.2 to -4.6) and on CDLQI -1.9 (95%CI -3.3 to -0.5) and -1.5 (95%CI -2.8 to -0.3) immediately and 6 weeks after the intervention, respectively. There were no long-term differences on asthma-related outcomes. Five serious adverse events occurred during the study period, which were not thought to be related to the treatment. CONCLUSIONS & CLINICAL RELEVANCE: For children with difficult to treat AD, there was no additional long-term benefit of alpine climate treatment, in contrast to the short-term, compared to an outpatient treatment programme in moderate maritime climate, using a personalized integrative multidisciplinary treatment approach.

Using Component-Resolved Diagnostics in the Management of Peanut-Allergic Patients.

Instead of relying on crude peanut extract, component-resolved diagnostics (CRD) uses sensitization to allergenic proteins within peanut. In this review, we describe the recent advances and future perspectives of the use of CRD in the management of peanut-allergic patients. There is strong evidence that sensitization to Ara h 2 is the best predictor for clinically relevant peanut allergy in children and adults. Isolated sensitization to other peanut components is only rarely present in patients with systemic reactions to peanut. It is, however, important to remark that cut-off points of sIgE to Ara h 2 that predict tolerance or allergy vary between different study populations, different age groups and geographical regions, and validation studies performed in different settings are necessary to implement cut-offs in daily practice. Future studies should focus on the role of CRD in risk-assessment early in life, predicting long-term tolerance and monitoring treatment responses following immunotherapy.

Objective eliciting doses of peanut-allergic adults and children can be combined for risk assessment purposes.

BACKGROUND: To improve food labelling strategies, information regarding eliciting doses (EDs) and the effect of patient characteristics on these EDs is necessary. OBJECTIVE: To establish EDs for objective and subjective symptoms and analyse the effect of sensitization levels and other patient characteristics on threshold distribution curves (TDCs). METHODS: Threshold data from 100 adults and 262 children with a positive food challenge were analysed with interval-censoring survival analysis (ICSA) and fitted to a TDC from which EDs could be extracted. Possible influencing factors were analysed as covariates by ICSA. A hazard ratio (HR) was calculated in case of a significant effect. RESULTS: TDCs for both objective and subjective symptoms were significantly different between adults and children (P < 0.001). Objective ED05 values, however, were comparable (2.86 mg peanut protein in adults and 6.38 mg in children). Higher levels of sIgE to Ara h 2 and peanut extract were associated with a larger proportion of patient groups reacting to a dose increase with objective symptoms (adults and children) or subjective symptoms (adults, in children a trend). Age had a similar effect in children (HR 1.05 for objective symptoms and 1.09 for subjective symptoms). Gender had no effect on TDCs. CONCLUSION AND CLINICAL RELEVANCE: Subjective and objective TDCs were different between adults and children, but objective ED05 values were comparable, meaning that threshold data from children and adults can be combined for elaboration of reference doses for risk assessment. Higher sIgE levels to Ara h 2 and peanut extract were associated with a larger proportion of both patient groups to react to a certain dose increase.

A systematic review of the effect of thermal processing on the allergenicity of tree nuts.

BACKGROUND: Allergenicity of foods can be influenced by processing. Tree nuts are an important source of nutrition and increasingly consumed; however, processing methods are quite variable and data are currently lacking on the effects of processing on allergenicity. OBJECTIVE: To perform a systematic literature review on the effects of food processing on the allergenicity of tree nuts. METHODS: A systematic literature search of PubMed and Embase databases was performed, with screening of references, related articles and citations. Studies were included if they assessed the allergenicity or immunogenicity of processed nuts. RESULTS: The search resulted in 32 articles suitable for analysis. Clinical studies indicate that roasting reduces the allergenicity of hazelnut in individuals with a birch pollen allergy and reactivity to raw hazelnut. Thermal processing may reduce the allergenicity of the PR-10 protein in hazelnut and almond in vitro. The majority of the in vitro studies investigating the allergenicity of nonspecific lipid transfer proteins (nsLTPs) and seed storage proteins in hazelnut, almond, cashew nut, Brazil nut, walnut, pecan nut and pistachio nut show heat stability towards different thermal processing methods. CONCLUSION: Thermal processing may reduce allergenicity of PR-10 proteins in hazelnut and almond, in contrast to nsLTPs and seed storage proteins. This has important implications for source materials used for IgE testing and food challenges and diet advice.

Moving from peanut extract to peanut components: towards validation of component-resolved IgE tests.

BACKGROUND: Replacement of peanut extracts by recombinant peanut components is an important step in allergy serologic testing. Criteria are needed for the unbiased inclusion of patients into a study to validate such a replacement. METHODS: Plasma samples from 64 peanut-positive children (42 reactors, 22 nonreactors in a double-blind, placebo-controlled food challenge) were used to compare IgE reactivity to six recombinant peanut allergens with reactivity to natural peanut proteins extracted at neutral or low pH. We tested the hypothesis that poor extractability of Ara h 9 and other basic allergens at neutral pH leads to under-representation of patients with such sensitization. RESULTS: IgE reactivity to the components did not fully explain IgE reactivity to peanut extract in 5 of 32 reactors with IgE to peanut extract ≤100 kUA /l. IgE reactivity to components was stronger than to the extract in 11 plasma samples, which was largely due to a low Ara h 8 reactivity of the extract. IgE reactivity to Ara h 9 was much lower than reactivity to other basic proteins, some of which bound IgE well in the RAST, but lost IgE reactivity upon immunoblotting. CONCLUSIONS: Conventional peanut extracts are deficient in significant IgE-binding components. The inclusion of patients for a validation study should be based on serology performed with improved peanut reagents to avoid a bias against these under-represented, potentially important allergens. To judge clinical relevance of an allergen, the reagent used for inclusion of patients needs to be efficient in detecting IgE to this component.

Diagnostic value of hazelnut allergy tests including rCor a 1 spiking in double-blind challenged children.

BACKGROUND: The diagnostic value of hazelnut allergy tests in double-blind challenged children is largely unknown. The aim of this study was to analyze the performance of current diagnostic tests for hazelnut allergy in children and the effect of spiking. METHODS: Data of 151 children who underwent a double-blind placebo-controlled food challenge for hazelnut were analyzed. The positive predictive value and negative predictive value (PPV/NPV) of level of specific IgE (sIgE) for hazelnut, the influence of rCor a 1 spiking of the ImmunoCAP, and size of the skin prick test (SPT) for hazelnut were determined, also in relation to the severity of the hazelnut allergy. Reported accidental ingestion leading to an allergic reaction to hazelnut was also analyzed in relation to hazelnut allergy. RESULTS: Specific IgE ≥0.35 kU(A) /l for hazelnut was a moderate predictor for hazelnut allergy. The spiking decreased the PPV from 41% to 38% and increased the NPV from 91% to 100% for sIgE ≥0.35 kU(A) /l. The maximum reached PPV was 73% for sIgE cutoff of 26 kU(A) /l. Level of sIgE before spiking was significantly different between different grades of severity and was lost after spiking. Skin prick test was a better predictor for hazelnut allergy and severity than the level of sIgE. A history of accidental ingestion leading to an allergic reaction to hazelnut had a predictive value of 59% for hazelnut allergy. CONCLUSIONS: This study showed a good NPV of diagnostic tests for hazelnut allergy in children which further improved by rCor a 1 spiking. However, the PPVs are moderate and decreased by spiking.

Evaluation of the child with atopic dermatitis.

Atopic dermatis (AD) is a very common inflammatory skin disease in childhood. Various doctors such as paediatricians, general practitioners, allergologists and dermatologists are regularly consulted by these children and their parents, but there is no clear consensus on the diagnostic work-up that should be performed when evaluating a child with eczema. A careful history, clinical examination and adequate documentation of disease severity are essential in all children with eczema, irrespective of their disease severity. AD is a clinical diagnosis; diagnostic criteria, such as the UK diagnostic criteria, can be helpful for an accurate definition of the disease. A careful history, including alarm symptoms, respiratory symptoms and the impact of the disease on psychosocial functioning is important. Clinical scoring lists such as SCORAD and EASI are well validated for clinical studies; they are, however, not very suitable tools in clinical practice. More simple scoring systems, such as Three Item Severity Score (TIS) and Investigator Global Assessment (IGA), are more easy to use for clinical record keeping in daily practice. Allergen testing in children with AD without a history of acute non-eczematous reactions after allergen exposure is not necessary. In very young children with eczema, not yet exposed to foods, routine allergen testing is not necessary. If in individual cases, the decision is made to perform allergen tests, oral challenges should performed to confirm the diagnoses of food allergy.

Effect of excipients on the encapsulation efficiency and release of human growth hormone from dextran microspheres.

The possibility was investigated to modulate the encapsulation efficiency and release of human growth hormone (hGH) from hydroxyl ethyl methacrylated dextran (dex-HEMA) hydrogel microspheres by using excipients. Microspheres were prepared by polymerization of dex-HEMA in an aqueous two-phase system of this polymer and PEG with or without excipients (Tween 80, pluronic F68, sucrose, NaCl, urea or methionine). High hGH encapsulation efficiencies (50-70%) were obtained for microspheres prepared without excipients and with Tween 80, NaCl or methionine. Substantially lower encapsulation efficiencies (27% and 19%, respectively) were obtained for microspheres prepared in the presence of sucrose and urea, which was attributed to the more favoured partitioning of hGH over the PEG-phase due to higher hydrophobicity of the (partly) denatured hGH. Likely, differences in precipitate size of the encapsulated hGH resulted in different release profiles between microspheres prepared without excipients (biphasic release: 2 days delay time followed by 6 days release) and the release profile for microspheres prepared with Tween 80, pluronic F68, sucrose, NaCl and urea (release over a period of 6-8 days (without a delay time)). Microspheres prepared with methionine showed a concentration-dependent delay time varying from 0 to 2 days followed by almost zero-order release over 6 days, attributed to the effect of methionine on the polymerization of dex-HEMA. Especially, Tween 80 and methionine are attractive excipients since hGH was encapsulated in high yield (60-70%) and the protein was released from the microspheres mainly in its monomeric form without a delay time and with an almost zero-order release over 6-8 days.

[Double-blind placebo-controlled cow's milk challenge for children in general hospitals]. / Dubbelblinde placebogecontroleerde koemelkprovocaties bij kinderen in een algemeen ziekenhuis.

Every child with possible food allergies has the right to a double-blind, placebo-controlled cow's milk challenge. This test can be performed in the paediatric ward of a non-academic hospital. Challenge with other foodstuffs can lead to more serious side effects and therefore should be considered in a general hospital setting only after extensive experience with double-blind, placebo-controlled challenge for cow's milk has been obtained. Other items of international discussion on double-blind, placebo-controlled challenge in children are: the natural development of tolerance for cow's milk, IgE- versus non-IgE-mediated cow's milk allergy, and the exacerbation of pre-existing eczema during and after double-blind, placebo-controlled challenge.

[Episodes of angioedema in children with C1 esterase inhibitor deficiency]. / Aanvallen van angio-oedeem bij kinderen door C1-esteraseremmerdeficiëntie.

A 6-year-old boy and a 3.5-year-old girl presented with unexplained episodes of angioedema without urticaria. Low serum C1 esterase inhibitor activity was found in both children. Family history revealed autosomal dominant inheritance in the girl. The boy had a negative family history for angioedema. C1 esterase inhibitor deficiency is a rare but serious condition that may cause oedema of the upper respiratory tract and death by asphyxiation. Episodes of angioedema occur spontaneously, usually subsiding within 48-72 h. Between episodes, the patients are symptom free. Treatment consists of substitution of synthetic C1 esterase inhibitor during episodes of edema carrying a risk of upper airway obstruction. In patients who have more than one episode of severe angioedema per month, daily treatment with tranexamic acid should be considered. Both of these patients were not receiving daily treatment.

Acute allergic reactions in children with AEDS after prolonged cow's milk elimination diets.

BACKGROUND: Food allergy is not always correctly diagnosed in children with atopic eczema dermatitis syndrome (AEDS) and treatment with an avoidance diet is not without danger. METHODS: After admission to our clinic, 11 children with a prolonged cow's milk (CM) elimination diet because of AEDS and sensitization underwent double-blind placebo-controlled food challenge (DBPCFC). Retrospectively, the exposure to CM, sensitization and reactions to accidental ingestion were carefully documented. The DBPCFC was used to evaluate the childrens' current status. RESULTS: Before the elimination period (median 2.3 years; started before the admission) all 11 children with AEDS were sensitized and had ingested CM (four bottle-fed; seven breast-fed without CM diet of the mother) without the development of acute reactions. The diagnosis of CM allergy was not confirmed by DBPCFC previously. After elimination the AEDS had not improved, but nevertheless the diet was continued. During the elimination period, eight of 11 children developed severe acute allergic reactions to CM after accidental ingestion. In evaluation, in our clinic all 11 children experienced acute allergic reactions to CM during DBPCFC. CONCLUSION: There is a considerable chance of developing acute allergic reactions to CM after elimination in children with AEDS without previous problems after CM intake.

Shedding consistency of strongyle-type eggs in Dutch boarding horses.

Faeces of 484 horses were sampled twice with an interval of 6 weeks while anthelmintic therapy was halted. Faecal eggs counts revealed that 267 (55.2%) horses had consistently low numbers of eggs per gram faeces (EPG) (EPG < 100 or = 100), 155 (32.0%) horses had consistently high EPGs (EPG > 100). Horses with consistently high EPGs were more often mares with access to pasture, aged less than 6 or more than 23 years, that were dewormed at intervals longer than 6 months, and were treated for the last time more than 3 months before the start of the study. Horses with consistently low EPGs were more often male horses with no or limited access to pasture, that were dewormed at maximally 6-month intervals, and were aged between 6 and 23 years. The results are an indication that some horses have consistently low EPGs and perhaps could be used as non-treated animals in a selective anthelmintic treatment scheme aimed at the prevention of the development of anthelmintic resistance.

[Double blind placebo controlled cow's milk provocation for the diagnosis of cow's milk allergy in infants and children]. / Dubbelblinde placebogecontroleerde koemelkprovocatie voor de diagnostiek van koemelkallergie bij zuigelingen en kinderen.

OBJECTIVE: To test a protocol for a double-blind placebo-controlled cow's milk provocation for the diagnosis of acute allergic reactions to milk in an outpatient setting. DESIGN: Prospective, descriptive. METHOD: During the period from June 1, 1999 to February 28, 2001 the protocol was tested on all infants and children who were referred to the Paediatric outpatient clinic of the University Medical Centre on Utrecht with symptoms indicative of cow's milk allergy. The protocol comprised of a phased administration of two test meals, one with a true feed and one with placebo, during the course of one day. In case of allergic symptoms the test was discontinued and the code was broken. A diagnosis of 'cow's milk allergy' was made if the symptoms appeared during the provocation with true feeding. RESULTS: The test group (n = 154) consisted of 85 boys and 69 girls with ages ranging from 0.25 to 14 years (median 1.5). Acute type reactions to cow's milk occurred in 21 of the children who underwent the provocation. These reactions mainly consisted of cutaneous symptoms (erythema and urticaria). In none of these cases the symptoms were severe enough to require a prolonged stay in the hospital. There were no reactions on placebo meals nor acute reactions during the reintroduction of milk at home. CONCLUSION: It is possible to perform double-blind placebo-controlled provocations routinely in the diagnostic work-up of children with a suspicion of cow's milk allergy.

Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.

Severe congenital neutropenia (Kostmann syndrome) is characterized by profound absolute neutropenia and a maturation arrest of marrow progenitor cells at the promyelocyte-myelocyte stage. Marrow cells from such patients frequently display a reduced responsiveness to granulocyte-colony-stimulating factor (G-CSF). G-CSF binds to and activates a specific receptor which transduces signals critical for the proliferation and maturation of granulocytic progenitor cells. Here we report the identification of a somatic point mutation in one allele of the G-CSF receptor gene in a patient with severe congenital neutropenia. The mutation results in a cytoplasmic truncation of the receptor. When expressed in murine myeloid cells, the mutant receptor transduced a strong growth signal but, in contrast to the wild-type G-CSF receptor, was defective in maturation induction. The mutant receptor chain may act in a dominant negative manner to block granulocytic maturation.

Acute hemiparesis as the presenting sign in a heterozygote for ornithine transcarbamylase deficiency.

Strokes in children occur in conjunction with cardiac disease, hematological disorders, trauma, intracranial infections and migraine. Recently several inborn errors of metabolism have been recognized as possible causes of stroke-like symptoms. We describe a female heterozygote of ornithine transcarbamylase deficiency, who presented with convulsions and right sided hemiplegia. MR-imaging of the brain demonstrated an acute ischemic lesion in the left hemisphere. In addition to other known metabolic causes of stroke like attacks urea cycle defects should be considered in the differential diagnosis of acute hemiplegia in childhood.