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1.  Perceived Food Hypersensitivity Relates to Poor Asthma Control and Quality of Life in Young Non-Atopic Asthmatics 
PLoS ONE  2015;10(4):e0124675.
The relationship between perceived food hypersensitivity in asthmatics, food allergen sensitization, asthma control and asthma-related quality of life has not been studied.
Our aim was to study the prevalence of perceived food hypersensitivity in a cohort of young asthmatics, its relation to food allergen sensitization, and any correlation to asthma control and asthma-related quality of life.
Perceived food hypersensitivity, as well as IgE sensitization to common food allergens, levels of exhaled nitric oxide (FeNO), and blood eosinophil counts (B-Eos) were assessed in 408 subjects (211 women) with asthma, aged (mean ± SEM) 20.4 ± 0.3 years. Subjects filled out the Asthma Control Test (ACT) and the Mini Asthma Quality of Life Questionnaire (Mini-AQLQ). Inflammation was assessed by means of FeNO and B-Eos.
Fifty-three per cent of subjects reported food hypersensitivity. A corresponding food allergen sensitization was found in 68% of these subjects. Non-atopic subjects with perceived food hypersensitivity (n = 31) had lower ACT (19 (15 - 22) vs. 21 (20 - 23), p < 0.001) and Mini-AQLQ -scores (5.3 (4.3 - 6.1) vs. 6.1 (5.5 - 6.5), p < 0.001) than subjects with no food hypersensitivity (n = 190), despite lower levels of FeNO and B-Eos (p < 0.05).
Conclusions and Clinical Relevance
Food hypersensitivity was commonly reported among young asthmatics. In a majority of cases, a corresponding food allergen sensitization was found. A novel and clinically important finding was that non-atopic subjects with perceived food hypersensitivity were characterized by poorer asthma control and asthma-related quality of life.
PMCID: PMC4414584  PMID: 25923451
2.  Evaluation of basophil allergen threshold sensitivity (CD-sens) to peanut and Ara h 8 in children IgE-sensitized to Ara h 8 
Diagnosing peanut allergy properly is important and can be achieved by combining clinical history with various diagnostic methods such as IgE-antibody (IgE-ab) measurements, skin-prick test, basophil allergen threshold sensitivity (CD-sens) and food challenge. We aimed to evaluate CD-sens to peanut, Ara h 8 and Gly m 4 in relation to an oral peanut challenge in children IgE-sensitized to birch, peanut and Ara h 8 avoiding peanuts.
Twenty children IgE-sensitized to birch pollen and Ara h 8, but not to Ara h 1, Ara h 2 or Ara h 3 were challenged orally with roasted peanuts. Blood samples were drawn for IgE-ab and CD-sens analysis. To measure CD-sens, basophils were stimulated in vitro with decreasing doses of allergens until threshold sensitivity was reached.
All children passed challenge without objective symptoms, but mild oral allergy syndrome (OAS) symptoms were reported in 6/20 children. Nineteen of twenty children were negative in CD-sens to peanut but 17/20 were positive to rAra h 8. Eleven of twenty children were positive in CD-sens to rGly m 4.
Positive CD-sens to rAra h 8 show that the Ara h 8 IgE-ab sensitized basophils can be activated by a rAra h 8 allergen and initiate an allergic inflammation despite a negative challenge. Hence, children sensitized to Ara h 8 but not to peanut storage proteins may be at risk for systemic allergic reaction when eating larger amounts of peanuts but most likely don’t have to fear smaller amounts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12948-014-0007-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4397898  PMID: 25878561
rAra h 8; Basophils; Birch pollen allergy; CD63; CD-sens; Children; Cross-reactivity; Flow cytometry; Peanut allergy; Pediatrics
3.  Natural History of Perceived Food Hypersensitivity and IgE Sensitisation to Food Allergens in a Cohort of Adults 
PLoS ONE  2014;9(1):e85333.
No longitudinal studies exist on the natural history of food hypersensitivity and IgE sensitisation to food allergens in adults.
To examine the natural history of food hypersensitivity, the natural history of IgE sensitisation to food allergens and to investigate the risk factors for new onset food hypersensitivity.
Food hypersensitivity was questionnaire-assessed in 2307 individuals (aged 20–45 years) from Iceland and Sweden during the European Community Respiratory Health Survey both at baseline and follow-up 9 years later. IgE food and aeroallergen sensitisation were assessed in a subgroup of these individuals (n = 807). Values of 0.35 kU/L and above were regarded as positive sensitisation.
Food hypersensitivity was reported by 21% of the subjects and this proportion remained unchanged at follow-up (p = 0.58). Fruits, nuts and vegetables were the three most common causes of food hypersensitivity, with a similar prevalence at baseline and follow-up. The prevalence IgE sensitisation to food allergens decreased in general by 56% (p<0.001) and IgE sensitisation to peanut decreased in particular by 67% (p = 0.003). The prevalence of timothy grass IgE sensitisation decreased by 15% (p = 0.003) while cat, mite and birch IgE sensitisation did not decrease significantly. Female sex, rhinitis, eczema and presence of IgE sensitisation to aeroallergens were independently associated with new onset food hypersensitivity.
The prevalence of food hypersensitivity remained unchanged while the prevalence of IgE sensitisation to food allergens decreased in adults over a 9-year follow-up period. The decrease in prevalence of IgE sensitisation to food allergens was considerably larger than the change in prevalence of IgE sensitisation to aeroallergens.
PMCID: PMC3888405  PMID: 24427301
4.  Oral Peanut Challenge Identifies an Allergy but the Peanut Allergen Threshold Sensitivity Is Not Reproducible 
PLoS ONE  2013;8(1):e53465.
Double-blind placebo-controlled food challenge, DBPCFC, the gold standard for diagnosing food allergy, is time-consuming and potentially dangerous. A basophil allergen threshold sensitivity test, CD-sens, has shown promising results as a diagnostic tool in food allergy.
To evaluate the reproducibility of oral peanut challenge and compare the outcome to CD-sens in peanut-sensitized children.
Twenty-seven children (4–19 years) underwent a DBPCFC followed by a single-blind oral food-challenge. The peanut challenges (1 mg to 5 g) were evaluated by severity scoring. Blood samples were drawn for CD-sens before the two first challenges.
Thirteen children (48%) did not react at any of the challenges. Fourteen reacted at both peanut challenges but not to placebo. Only two of these children reacted at the same threshold dose and with the same severity score. All other children scored differently or reacted at different doses. For children with a positive challenge the geometric mean of the ratio of the doses was 1.834 (p = 0.307) and the arithmetic mean of the difference between the severity scores was 0.143 (p = 0.952). No association was obtained between the two peanut challenges regarding severity score (rs = 0.11, p = 0.71) or threshold dose (rs = 0.35, p = 0.22). Among the children positive in peanut challenge, 12 were positive in CD-sens. Two were low-responders and could not be evaluated. Geometric mean of the ratio of CD-sens values in children with a positive challenge was 1.035 (p = 0.505) but unlike for the severity score and the threshold dose the association between the two CD-sens values was strong (rs = 0.94, P<0.001).
For a positive/negative test the reproducibility is 100% for both peanut challenge and CD-sens. However, a comparison of the degree of allergen threshold sensitivity between the two tests is not possible since the threshold dose and severity scoring is not reproducible.
PMCID: PMC3541227  PMID: 23326435
5.  Exploring the temporal development of childhood IgE profiles to allergen components 
Children often develop allergies that may or not persist into adulthood. Although the different allergic symptoms over time have been well documented, the underlying pattern of sensitization to various proteins and subsequent allergy development is unexplored.
The aim was to study the sensitization pattern to allergen components over time from infancy to adulthood in a group of infants with heredity for allergic diseases.
IgE profiles were monitored in a group of 67 children from 6 months to 18 years using a microarray chip (ImmunoCAP® ISAC) containing 103 allergen components derived from 47 allergen sources. The chip IgE profile was compared with clinical history, skin prick test results and diagnoses (atopic dermatitis, asthma and allergic rhinoconjunctivitis) at each time point for each child.
IgE profiles were unique for each child and showed broad agreement with the results of skin prick tests and doctors’ diagnoses. In addition, close examination of the IgE profiles often revealed early indication of subsequent allergies. IgE profiles also facilitated the examination of cross-reactivity contra co-sensitization, thereby greatly enhancing the possibility for managing patients.
This explorative description indicates that sensitization pattern to allergen components differs over time as well as among allergic individuals when examined with microarray technology.
PMCID: PMC3574828  PMID: 23254184
Children; Atopic march; Specific IgE; ImmunoCAP ISAC; CRD; Allergen components
6.  Psychosomatic problems and countermeasures in Japanese children and adolescents 
In Japan there are a number of children and adolescents with emotion-related disorders including psychosomatic diseases (orthostatic dysregulation, anorexia nervosa, recurrent pains), behavior problems and school absenteeism. According to our previous report, the Japanese children had significantly higher score of physical symptoms and psychiatric complaints than did the Swedish children, and these were more strongly influenced by school-related stress than by home-related stress. To enforce countermeasures for psychosomatic problems in children, the Japanese Society of Psychosomatic Pediatrics (established in 1982) have started several new projects including multi-center psychosomatic researches and society-based activities. In this article, we present an outline of our study on mental health in Japanese children in comparison with Swedish children. Countermeasures including clinical guidelines for child psychosomatic diseases are reviewed and discussed.
PMCID: PMC3362750  PMID: 22433184
Psychosomatic disease; Orthostatic dysregulation; Anorexia nervosa; School absenteeism; Migraine
7.  Clara cell protein in nasal lavage fluid and nasal nitric oxide - biomarkers with anti-inflammatory properties in allergic rhinitis 
Clara cell protein (CC16) is ascribed a protective and anti-inflammatory role in airway inflammation. Lower levels have been observed in asthmatic subjects as well as in subjects with intermittent allergic rhinitis than in healthy controls. Nasal nitric oxide (nNO) is present in high concentrations in the upper airways, and considered a biomarker with beneficial effects, due to inhibition of bacteria and viruses along with stimulation of ciliary motility. The aim of this study was to evaluate the presumed anti-inflammatory effects of nasal CC16 and nNO in subjects with allergic rhinitis.
The levels of CC16 in nasal lavage fluids, achieved from subjects with persistent allergic rhinitis (n = 13), intermittent allergic rhinitis in an allergen free interval (n = 5) and healthy controls (n = 7), were analyzed by Western blot. The levels of nNO were measured by the subtraction method using NIOX®. The occurrences of effector cells in allergic inflammation, i.e. metachromatic cells (MC, mast cells and basophiles) and eosinophils (Eos) were analyzed by light microscopy in samples achieved by nasal brushing.
The levels of CC16 correlated with nNO levels (r2 = 0.37; p = 0.02) in allergic subjects.
The levels of both biomarkers showed inverse relationships with MC occurrence, as higher levels of CC16 (p = 0.03) and nNO (p = 0.05) were found in allergic subjects with no demonstrable MC compared to the levels in subjects with demonstrable MC. Similar relationships, but not reaching significance, were observed between the CC16 and nNO levels and Eos occurrence. The levels of CC16 and nNO did not differ between the allergic and the control groups.
The correlation between nasal CC16 and nNO levels in patients with allergic rhinitis, along with an inverse relationship between their levels and the occurrences of MC in allergic inflammation, may indicate that both biomarkers have anti-inflammatory effects by suppression of cell recruitment. The mechanisms behind these observations warrant further analyses.
PMCID: PMC3395834  PMID: 22309677
CC16; nasal nitric oxide; allergic rhinitis; anti-inflammatory effects; metachromatic cells; mast cells; basophils; eosinophils; nasal lavage fluid; upper airways
8.  The usefulness of casein-specific IgE and IgG4 antibodies in cow's milk allergic children 
Cow's milk allergy is one of the most common food allergies among younger children. We investigated IgE antibodies to milk, and IgE and IgG4 antibodies to casein, α-lactalbumin and β-lactoglobulin in cow's milk allergic (CMA) and non-allergic (non-CMA) children in order to study their clinical usefulness.
Eighty-three children with suspected milk allergy (median age: 3.5 years, range: 0.8-15.8 years) were diagnosed as CMA (n = 61) or non-CMA (n = 22) based on an open milk challenge or convincing clinical history. Their serum concentrations of allergen-specific (s) IgE and IgG4 antibodies were measured using ImmunoCAP®. For the sIgG4 analysis, 28 atopic and 31 non-atopic control children were additionally included (all non-milk sensitized).
The CMA group had significantly higher levels of milk-, casein- and β-lactoglobulin-sIgE antibodies as compared to the non-CMA group. The casein test showed the best discriminating performance with a clinical decision point of 6.6 kUA/L corresponding to 100% specificity. All but one of the CMA children aged > 5 years had casein-sIgE levels > 6.6 kUA/L. The non-CMA group had significantly higher sIgG4 levels against all three milk allergens compared to the CMA group. This was most pronounced for casein-sIgG4 in non-CMA children without history of previous milk allergy. These children had significantly higher casein-sIgG4 levels compared to any other group, including the non-milk sensitized control children.
High levels of casein-sIgE antibodies are strongly associated with milk allergy in children and might be associated with prolonged allergy. Elevated casein-sIgG4 levels in milk-sensitized individuals on normal diet indicate a modified Th2 response. However, the protective role of IgG4 antibodies in milk allergy is unclear.
PMCID: PMC3398319  PMID: 22212305
casein; cow's milk allergy; IgE; IgG4; ImmunoCAP
9.  Health-care cost reduction resulting from primary-care allergy testing in children in Italy 
Allergy places a considerable cost burden on society. Specific immunoglobulin E (spIgE) testing may improve the management of allergy patients. There is therefore a reason to quantify the economic consequences of the use of spIgE testing in the diagnosis of allergic conditions.
The expected costs of spIgE testing versus no-testing were calculated using a clinical decision model based on a prospective clinical trial performed in primary care.
The expected costs per patient over 2 years decreased from 802 euros in the "no-test strategy" to 560 euros in the spIgE "test strategy". Cost savings persisted even after assumptions about the prevalence of allergy and the prices of medications were changed. The "test strategy" increased the percentage of patients correctly diagnosed from 54 to 87%.
spIgE testing of children with respiratory and/or skin problems in primary care in Italy reduces overall costs to society. These cost savings mostly result from a reduction in the use of medications, particularly corticosteroids. The study indicates that spIgE testing of all children with respiratory and/or skin symptoms would be a cost-effective strategy.
PMCID: PMC2945355  PMID: 20836868
10.  Phadiatop Infant in the Diagnosis of Atopy in Children with Allergy-Like Symptoms 
Background and Objective. Allergy-like symptoms such as wheezing and eczema are common in young children and an early diagnosis is important to initiate correct management. The objective of this study was to evaluate the diagnostic performance of Phadiatop Infant, an in vitro test for determination of early sensitisation to food and inhalant allergens. Patients and Methods. The study was conducted, retrospectively, using frozen sera from 122 children (median age 2.7 years) admitted to the hospital with suspected allergic symptoms. The doctor's diagnosis atopic/nonatopic was based on routinely used procedures such as clinical evaluation, SPT, total and allergen-specific IgE antibodies. The performance of Phadiatop Infant was evaluated in a blinded manner against this diagnosis. Results. Eighty-four of the 86 children classified as atopic showed a positive Phadiatop Infant test. Thirty-six were classified as nonatopic, 32 of who had a negative test. With a prevalence of atopy of 70% in this population, this gives a sensitivity of 98%, a specificity of 89%, and a positive and negative predictive value of 95% and 94%, respectively. Conclusion. The results from the present study suggest that Phadiatop Infant could be recommended as a complement to the clinical information in the differential diagnosis on IgE-mediated disease in young children with allergy-like symptoms.
PMCID: PMC2778347  PMID: 20041015
11.  Allergy Diagnosis in Children and Adults: Performance of a New Point-of-Care Device, ImmunoCAP Rapid 
Allergy is a serious problem affecting approximately 1 of 4 individuals. The symptoms with and without allergy etiology are often difficult to distinguish from each other without using an IgE antibody test. The aim of this study was to investigate the performance of a new point-of-care (POC) test for IgE antibodies to relevant allergens in Europe.
IgE antibodies from children and adults with allergies recruited from allergy clinics in Sweden and Spain were analyzed for 10 allergens, suitable for the age groups, using the new POC test and ImmunoCAP laboratory test. The IgE antibody level best discriminating between positive and negative results (the cutoff point) for the different allergens of the POC test and the efficacy of the POC and the ImmunoCAP laboratory tests for diagnosing allergy compared with that of clinical diagnosis were investigated.
The estimated cutoffs for the different allergens in the POC test ranged from 0.70 to 2.56 kUA/L. Taking into account all positive allergen results in a given patient, the POC test could identify 95% of the patients with allergies. Seventy-eight percent of the allergen-specific physicians' diagnoses were identified and 97% of the negative ones. Most allergens exhibited good performance, identifying about 80% of clinically relevant cases. However, dog, mugwort, and wall pellitory would benefit from improvement.
The POC test will be a valuable adjunct in the identification or exclusion of patients with allergies and their most likely offending allergens, both in specialist and general care settings.
PMCID: PMC3651003  PMID: 23283063
IgE antibody allergy diagnosis; point-of-care test

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