Suzanne G.M.A. Pasmans

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Background IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL−1) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients (P = 3.0 × 10−6; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10−5; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis. Conclusion Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa

The cytoplasmic plaque protein desmoplakin (DP), which is located in desmosomes, plays a major role in epithelial and muscle cell adhesion by linking the transmembrane cadherins to the cytoplasmic intermediate filament network. Mutations of DP may cause striate palmoplantar keratoderma, arrhythmogenic right ventricular dysplasia, skin fragility/woolly hair syndrome, Naxos-like disease, and Carvajal syndrome. DP must be indispensable, because DP-/- mice are early abortive. Here, we report a patient with severe fragility of skin and mucous membranes caused by genetic truncation of the DP tail. The new phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. The phenotype also comprised universal alopecia, neonatal teeth, and nail loss. Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes. Immunofluorescence staining of DP showed a distinct punctate intercellular pattern in the patients skin. Protein analysis revealed expression of truncated DP polypeptides. Mutational analysis of the patient demonstrated compound heterozygosity for two DP mutations, 6079C-->T (R1934X) and 6370delTT, respectively. Aberrant mRNA transcripts that predict premature termination of translation with loss of the three intermediate filament-binding subdomains in the DP tail were detected by RT-PCR. The new dramatic phenotype, which we named lethal acantholytic epidermolysis bullosa, underscores the paramount role of DP in epidermal integrity.

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

Background:u2002 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.

Peanut epitopes for IgE and IgG4 in peanut-sensitized children in relation to severity of peanut allergy

BACKGROUNDnBetter understanding of the relationship between antibody response to peanut and clinical sensitivity might lead to more accurate prognostication.nnnOBJECTIVEnWe sought to investigate peanut-specific IgE and IgG4 epitope diversity in relation to challenge-defined clinical sensitivity to peanut in a group of peanut-sensitized children.nnnMETHODSnClinical sensitivity was determined by means of double-blind, placebo-controlled peanut challenges in 24 sensitized children. Six atopic control subjects were included. Specific IgE and IgG4 binding to 419 overlapping 15-amino-acid peptides representing the sequence of recombinant Ara h 1, Ara h 2, and Ara h3 was analyzed by means of microarray immunoassay.nnnRESULTSnPeanut-sensitized patient sera bound significantly more IgE and IgG4 epitopes than control sera. This patient group reacted to the same Ara h 1, Ara h 2, and Ara h 3 epitopes as reported previously. There was a positive correlation between IgE epitope diversity (ie, number of epitopes recognized) and clinical sensitivity (r = 0.6), such that patients with the greatest epitope diversity were significantly more sensitive than those with the lowest diversity (P = .021). No specific epitopes were associated with severe reactions to peanut. IgG4 binding was observed to largely similar epitopes but was less pronounced than IgE binding and did not relate to the clinical sensitivity to peanut. IgE and IgG4 epitope-recognition patterns were largely stable over a 20-month period.nnnCONCLUSIONnClinical sensitivity, as determined by means of double-blind, placebo-controlled peanut challenge, is positively related to a more polyclonal IgE response, which remains stable over time.

Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants

BACKGROUNDnInfantile hemangioma (IH) is a frequently encountered tumor with a potentially complicated course. Recently, propranolol was discovered to be an effective treatment option.nnnOBJECTIVEnTo describe the effects and side effects of propranolol treatment in 28 children with (complicated) IH.nnnMETHODSnA protocol for treatment of IH with propranolol was designed and implemented. Propranolol was administered to 28 children (21 girls and 7 boys, mean age at onset of treatment: 8.8 months).nnnRESULTSnAll 28 patients had a good response. In two patients, systemic corticosteroid therapy was tapered successfully after propranolol was initiated. Propranolol was also an effective treatment for hemangiomas in 4 patients older than 1 year of age. Side effects that needed intervention and/or close monitoring were not dose dependent and included symptomatic hypoglycemia (n = 2; 1 patient also taking prednisone), hypotension (n = 16, of which 1 is symptomatic), and bronchial hyperreactivity (n = 3). Restless sleep (n = 8), constipation (n = 3) and cold extremities (n = 3) were observed.nnnLIMITATIONSnClinical studies are necessary to evaluate the incidence of side effects of propranolol treatment of IH.nnnCONCLUSIONSnPropranolol appears to be an effective treatment option for IH even in the nonproliferative phase and after the first year of life. Potentially harmful adverse effects include hypoglycemia, bronchospasm, and hypotension.

Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults

BACKGROUNDnComponent-resolved diagnosis has been shown to improve the diagnosis of food allergy.nnnOBJECTIVEnWe sought to evaluate whether component-resolved diagnosis might help to identify patients at risk of objective allergic reactions to hazelnut.nnnMETHODnA total of 161 hazelnut-sensitized patients were included: 40 children and 15 adults with objective symptoms on double-blind, placebo-controlled food challenges (DBPCFCs) and 24 adults with a convincing objective history were compared with 41 children and 41 adults with no or subjective symptoms on DBPCFCs (grouped together). IgE levels to hazelnut extract and single components were analyzed with ImmunoCAP.nnnRESULTSnIgE levels to hazelnut extract were significantly higher in children with objective than with no or subjective symptoms. In 13% of children and 49% of adults with hazelnut allergy with objective symptoms, only sensitization to rCor a 1.04 was observed and not to other water-soluble allergens. Sensitization to rCor a 8 was rare, which is in contrast to rCor a 1. Sensitization to nCor a 9, rCor a 14, or both was strongly associated with hazelnut allergy with objective symptoms. By using adapted cutoff levels, a diagnostic discrimination between severity groups was obtained. IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 5 kUA/L or greater (children) and IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 1 kUA/L or greater (adults) had a specificity of greater than 90% and accounted for 83% of children and 44% of adults with hazelnut allergy with objective symptoms.nnnCONCLUSIONnSensitization to Cor a 9 and Cor a 14 is highly specific for patients with objective symptoms in DBPCFCs as a marker for a more severe hazelnut allergic phenotype.

Effectiveness and Cost-Effectiveness of eHealth Interventions in Somatic Diseases: A Systematic Review of Systematic Reviews and Meta-Analyses

Background eHealth potentially enhances quality of care and may reduce health care costs. However, a review of systematic reviews published in 2010 concluded that high-quality evidence on the benefits of eHealth interventions was still lacking. Objective We conducted a systematic review of systematic reviews and meta-analyses on the effectiveness/cost-effectiveness of eHealth interventions in patients with somatic diseases to analyze whether, and to what possible extent, the outcome of recent research supports or differs from previous conclusions. Methods Literature searches were performed in PubMed, EMBASE, The Cochrane Library, and Scopus for systematic reviews and meta-analyses on eHealth interventions published between August 2009 and December 2012. Articles were screened for relevance based on preset inclusion and exclusion criteria. Citations of residual articles were screened for additional literature. Included papers were critically appraised using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement before data were extracted. Based on conclusions drawn by the authors of the included articles, reviews and meta-analyses were divided into 1 of 3 groups: suitable, promising, or limited evidence on effectiveness/cost-effectiveness. Cases of uncertainty were resolved by consensus discussion. Effect sizes were extracted from papers that included a meta-analysis. To compare our results with previous findings, a trend analysis was performed. Results Our literature searches yielded 31 eligible reviews, of which 20 (65%) reported on costs. Seven papers (23%) concluded that eHealth is effective/cost-effective, 13 (42%) underlined that evidence is promising, and others found limited or inconsistent proof. Methodological quality of the included reviews and meta-analyses was generally considered high. Trend analysis showed a considerable accumulation of literature on eHealth. However, a similar percentage of papers concluded that eHealth is effective/cost-effective or evidence is at least promising (65% vs 62%). Reviews focusing primarily on children or family caregivers still remained scarce. Although a pooled (subgroup) analysis of aggregate data from randomized studies was performed in a higher percentage of more recently published reviews (45% vs 27%), data on economic outcome measures were less frequently reported (65% vs 85%). Conclusions The number of reviews and meta-analyses on eHealth interventions in patients with somatic diseases has increased considerably in recent years. Most articles show eHealth is effective/cost-effective or at least suggest evidence is promising, which is consistent with previous findings. Although many researchers advocate larger, well-designed, controlled studies, we believe attention should be given to the development and evaluation of strategies to implement effective/cost-effective eHealth initiatives in daily practice, rather than to further strengthen current evidence.

Hazelnut allergy: from pollen-associated mild allergy to severe anaphylactic reactions

Purpose of reviewHazelnut allergy can vary between mild oral symptoms and potentially dangerous anaphylaxis. There is a need to predict which subjects are at risk for severe reactions. In this study, possibilities for ‘component-resolved diagnosis’, based on sensitization to different allergens in hazelnut, are discussed. Recent findingsOne type of hazelnut allergy can be associated with sensitization to homologues of pollen allergens, predominantly birch, in hazelnut: Cor a 1 (Bet v 1) and Cor a 2 (profilin). These allergens account for relatively mild symptoms. However, subjects can also be sensitized to several other allergens in hazelnut that are related to more severe symptoms. These allergens are homologues of allergens in other nuts and peanut: Cor a 8 (lipid transfer protein) and Cor a 9 (11S globulin) and perhaps Cor a 11 (7S globulin). The clinical relevance of these and other potential hazelnut allergens has to be further defined. The diagnosis of hazelnut has to be confirmed by oral double-blind placebo-controlled food challenge. SummarySensitization to hazelnut can either be associated with mild oral symptoms, depending on sensitization to pollen, or with more serious allergic symptoms, related to sensitization to homologues of nut and peanut allergens.

The diagnostic value of specific IgE to Ara h 2 to predict peanut allergy in children is comparable to a validated and updated diagnostic prediction model.

BACKGROUNDnA diagnostic prediction model for peanut allergy in children was recently published, using 6 predictors: sex, age, history, skin prick test, peanut specific immunoglobulin E (sIgE), and total IgE minus peanut sIgE.nnnOBJECTIVESnTo validate this model and update it by adding allergic rhinitis, atopic dermatitis, and sIgE to peanut components Ara h 1, 2, 3, and 8 as candidate predictors. To develop a new model based only on sIgE to peanut components.nnnMETHODSnValidation was performed by testing discrimination (diagnostic value) with an area under the receiver operating characteristic curve and calibration (agreement between predicted and observed frequencies of peanut allergy) with the Hosmer-Lemeshow test and a calibration plot. The performance of the (updated) models was similarly analyzed.nnnRESULTSnValidation of the model in 100 patients showed good discrimination (88%) but poor calibration (P < .001). In the updating process, age, history, and additional candidate predictors did not significantly increase discrimination, being 94%, and leaving only 4 predictors of the original model: sex, skin prick test, peanut sIgE, and total IgE minus sIgE. When building a model with sIgE to peanut components, Ara h 2 was the only predictor, with a discriminative ability of 90%. Cutoff values with 100% positive and negative predictive values could be calculated for both the updated model and sIgE to Ara h 2. In this way, the outcome of the food challenge could be predicted with 100% accuracy in 59% (updated model) and 50% (Ara h 2) of the patients.nnnCONCLUSIONSnDiscrimination of the validated model was good; however, calibration was poor. The discriminative ability of Ara h 2 was almost comparable to that of the updated model, containing 4 predictors. With both models, the need for peanut challenges could be reduced by at least 50%.

Probiotics Have a Different Immunomodulatory Potential in vitro versus ex vivo upon Oral Administration in Children with Food Allergy

Background: Previous studies suggest that administration of probiotics in vitro can stimulate regulatory and Th1 immune responses. We studied both the in vitro immunological effects of probiotics and the ex vivo immunological effects after oral administration of probiotics in children with food allergy, a Th2-mediated disease. Methods: Thirteen children were enrolled. Probiotics (n = 7) or placebo (n = 6) were orally administered during 3 months. At baseline and after 1 and 3 months, peripheral blood mononuclear cells were stimulated with crude peanut extract, anti-CD3, or anti-CD40 and IL-4 in the presence (in vitro response) or absence (ex vivo response) of probiotics. The proliferation and production of IFN-γ, IL-5, IL-13, IL-10, TNF-α, IL-6 and IgE were analyzed. Sensitization to peanut, cow’s milk and hen’s egg was determined before and after treatment. Results: The in vitro addition of probiotics to peripheral blood mononuclear cell cultures resulted in enhanced proliferation and production of IFN-γ, IL-10 and TNF-α. After oral treatment, proliferation in the presence of probiotics increased, whereas in vitro IgE production decreased in the probiotics group compared to baseline. The ex vivo production of IL-10, TNF-α and IL-6 tended to decrease. Th1 and Th2 cytokines were not altered. Sensitization remained unchanged. Conclusion: Probiotics enhanced the production of Th1 and regulatory cytokines in vitro. Oral administration of probiotics resulted in a slightly decreased ex vivo production of IL-10, TNF-α and IL-6. This indicates that probiotics have a different potential to modulate the immune response in vitro versus ex vivo.