Treatment for moderate to severe atopic dermatitis in alpine and moderate maritime climates differentially affects helper T cells and memory B cells in children.

BACKGROUND: Treatment of atopic dermatitis (AD) is focused on topical anti-inflammatory therapy, epidermal barrier repair and trigger avoidance. Multidisciplinary treatment in both moderate maritime and alpine climates can successfully reduce disease activity in children with AD. However, it remains unclear whether abnormalities in B cell and T cell memory normalize and whether this differs between treatment strategies. OBJECTIVE: To determine whether successful treatment in maritime and alpine climates normalizes B- and T lymphocytes in children with moderate to severe AD. METHODS: The study was performed in the context of a trial (DAVOS trial, registered at Current Controlled Trials ISCRTN88136485) in which eighty-eight children with moderate to severe AD were randomized to 6 weeks of treatment in moderate maritime climate (outpatient setting) or in the alpine climate (inpatient setting). Before and directly after treatment, disease activity was determined with SA-EASI and serum TARC, and T cell and B cell subsets were quantified in blood. RESULTS: Both treatment protocols achieved a significant decrease in disease activity, which was accompanied by a reduction in circulating memory Treg, transitional B cell and plasmablast numbers. Alpine climate treatment had a significantly greater effect on disease activity and was accompanied by a reduction in blood eosinophils and increases in memory B cells, CD8+ TemRO, CD4+ Tcm and CCR7+ Th2 subsets. CONCLUSIONS AND CLINICAL RELEVANCE: Clinically successful treatment of AD induces changes in blood B- and T cell subsets reflecting reduced chronic inflammation. In addition, multidisciplinary inpatient treatment in the alpine climate specifically affects memory B cells, CD8+ T cells and Th2 cells. These cell types could represent good markers for treatment efficacy.

Oral cholera vaccination promotes homing of IgA+ memory B cells to the large intestine and the respiratory tract.

Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin ß1 and ß7, CCR9, CCR10, CCR7, and CLA. After vaccination, antibody responses to cholera toxin B (CTB) and Dukoral® were detected in serum and nasal wash. CTB-specific memory B cells in peripheral blood and tissue homing profiles of memory B cells peaked at day 18. IgA+ memory B cells expressed markers that enable homing to the airways and colon, while IgA- memory B cells primarily expressed small-intestine-homing markers. These data show that oral cholera vaccination has a differential effect on immune responses in various mucosal sites, including the respiratory tract.

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.

Peanut allergy is common among hazelnut-sensitized subjects but is not primarily the result of IgE cross-reactivity.

BACKGROUND: Hazelnut and peanut are botanically unrelated foods, but patients are often sensitized and allergic to both, for reasons that are not well understood. METHODS: To investigate molecular cosensitization and cross-reactivity to peanut in hazelnut-sensitized individuals, children (n = 81) and adults (n = 80) were retrospectively selected based on sensitization to hazelnut. IgE to hazelnut extract, Cor a 1, 8, 9 and 14, to peanut extract, Ara h 1, 2, 3, 8 and 9, and to Bet v 1 was determined by ImmunoCAP. Allergy to hazelnut and peanut was established by DBPCFC and/or detailed clinical history. Patients were either tolerant or displayed subjective or objective symptoms to either food. IgE cross-reactivity between hazelnut and peanut storage proteins was assessed by reciprocal ImmunoCAP inhibition experiments. RESULTS: Of the 161 hazelnut-sensitized subjects, 109 (68%) were also sensitized to peanut, and 73 (45%) had clinical expression of allergy to peanut that was not associated with the presence or severity of hazelnut allergy. Instead, it was associated with IgE reactivity to peanut storage proteins, in particular Ara h 2. No cross-reactivity could be detected between Ara h 2 and Cor a 14, and 2 of 13 subjects displayed extensive cross-reactivity between 11S globulins; in plasma of both individuals, Ara h 3 almost completely inhibited IgE binding to Cor a 9. CONCLUSIONS: Peanut allergy is not primarily the result of IgE cross-reactivity to hazelnut storage proteins. IgE to Cor a 14 and Ara h 2 may serve as useful markers of primary sensitization to hazelnut and peanut, respectively.

Hazelnut allergy differs between children and adults in frequency of severity, aetiology and relevance of diagnostic parameters.

BACKGROUND: Hazelnut allergy in adults is often birch pollen related, whereas in children, non-pollen-related hazelnut allergy is more frequent. OBJECTIVE: To compare the differences in hazelnut allergy between children and adults with regard to severity, aetiology and diagnostic value of routinely available data. METHODS: Adults (n = 120) who underwent a double-blind placebo-controlled food challenge (DBPCFC) for hazelnut were selected and compared to 151 hazelnut-challenged children from a previous study. Univariate and multivariate logistic regression analyses were performed to build a prediction model. The area under the curve (AUC) of the ROC curve was determined for level of hazelnut-specific IgE, skin prick test (SPT) and the prediction model. RESULTS: Hazelnut allergy was confirmed by DBPCFC in 95/120 (79%) adults, 77% had only subjective and 23% objective symptoms, whereas in children, 63% had objective symptoms to hazelnut. Within the group of children, the frequency of severe hazelnut allergy was higher in younger than in older children. A concomitant birch pollen allergy was more common in adults (82%) than in children (39%) with a hazelnut allergy. A detailed history with allergic symptoms to previous ingestion of hazelnut had the highest diagnostic value in adults, while in children, SPT to hazelnut extract showed the highest level of discrimination between clinical reactivity and tolerance to hazelnut. CONCLUSIONS AND CLINICAL RELEVANCE: Hazelnut allergy differs between children and adults with respect to frequency of severity, aetiology and relevance of diagnostic parameters. Therefore, age has to be taken into account in the diagnostic work-up of a hazelnut allergy.

Chemical modification of peanut conglutin reduces IgE reactivity but not T cell reactivity in peanut-allergic patients.

BACKGROUND: Specific immunotherapy for peanut allergy is associated with significant side-effects. Chemically modified allergens may provide a safer alternative. OBJECTIVE: This study aimed to analyse the immunogenicity and allergenicity of modified peanut conglutin. METHODS: Native peanut conglutin and two modifications thereof were generated (RA and RAGA). Conglutin-specific T cell lines from 11 peanut-allergic patients were analysed for proliferation and cytokine production. Sera from 14 patients were analysed for IgE/IgG1/IgG4 binding by immunoblot and ELISA. IgE reactivity was analysed by direct and indirect basophil activation test (BAT), in presence and absence of patient plasma or CD32-blocking antibodies. RESULTS: T cell proliferation to RA was unchanged, and proliferation to RAGA was reduced compared to native conglutin. Cytokine profiles remained unchanged. IgE, IgG1 and IgG4 binding to RA and RAGA was significantly reduced. In the direct BAT, the relative potency of modified conglutin was decreased in 67% and increased/similar in 33% of the patients. In the indirect BAT, RA and RAGA were 10-100 times less potent than native conglutin. Addition of plasma to the indirect BAT increased the relative potency of modified conglutin in patients with high peanut-specific IgG levels. This was mediated via blocking of the response to native conglutin, most likely by soluble IgG, and not via CD32. CONCLUSION AND CLINICAL RELEVANCE: Chemical modification of peanut conglutin by RA retains immunogenicity and reduces allergenicity and may be a promising approach for development of a curative treatment for peanut allergy. In a subgroup of patients, where the reactivity of native conglutin is already partially blocked by IgG, the effect of the modification of conglutin is less pronounced.

The degree of whey hydrolysis does not uniformly affect in vitro basophil and T cell responses of cow's milk-allergic patients.

BACKGROUND: Several studies investigated whether hydrolysed proteins can induce tolerance to cow's milk (CM) in children at risk of developing CM allergy. Due to methodological problems and inconsistent findings, the evidence for a tolerogenic effect is limited. A major problem is that different hydrolysates may give different outcomes due to variations in their production and composition. OBJECTIVE: The aim of the study was to investigate the effect of the degree of hydrolysis on the allergenicity and immunogenicity of whey hydrolysates. METHODS: The hydrolysis of whey was stopped at different time-points between 1 and 60 min. In 18 CM allergic patients, the allergenicity of the hydrolysates was determined by immunoblot and the basophil activation test. To test immunogenicity, CM-specific T cell lines were generated. RESULTS: In most patients, increasing time of hydrolysis decreased IgE recognition and basophil activation. However, in five patients, hydrolysed proteins induced more basophil activation than non-hydrolysed proteins. The immunoblot data indicated that these patients recognized either a 25- to 30-kDa degradation product of casein or a 10-kDa degradation product of whey. Although T cell activation was decreased in all patients over time, half of them still showed a positive response to the proteins after 60 min of hydrolysis. CONCLUSION: Increasing the time of hydrolysis reduces both allergenicity and immunogenicity of whey hydrolysates in most but not all patients. This indicates that not the degree of hydrolysis is decisive but the presence and stability of IgE and T cell epitopes in the hydrolysate recognized by individual patients.

Components in soy allergy diagnostics: Gly m 2S albumin has the best diagnostic value in adults.

BACKGROUND: Thus far, four soy allergens have been characterized. Their diagnostic value was assessed only using a case-control design with controls not suspected of soy allergy or in a soy-allergic population without controls. Our objective was to analyze the diagnostic value of specific immunoglobulin E (sIgE) to Gly m 2S albumin, Gly m 4, 5, and 6, and their possible relation with severity or culprit soy product. METHODS: Adult patients suspected of soy allergy were included (n = 46). Allergy was confirmed by challenge (n = 19) or history (n = 16) and excluded by challenge in 11 patients. Soy components were analyzed by ImmunoCAP. Diagnostic value was assessed in the challenged patient group by an area under receiver operating characteristic (ROC) curve (AUC). RESULTS: Specific immunoglobulin E to Gly m 2S albumin had the highest AUC (0.79), comparable to skin prick test (SPT) and sIgE to soy extract (0.76 and 0.77, respectively). All patients were sensitized to either soy extract or Gly m 4 (sIgE ≥ 0.35 kU/l). sIgE to soy extract, Gly m 5, and Gly m 6 was significantly higher in patients with mild symptoms (P = 0.04, 0.02 and 0.02, respectively). Patients only reacting to soy milk had higher sIgE levels to Gly m 4 (median 9.8 vs 1.1 kU/l, P = 0.01). CONCLUSION: Specific immunoglobulin E to Gly m 2S albumin had the best accuracy in diagnosing soy allergy. Gly m 5 and 6 were related to mild symptoms. Higher levels of Gly m 4 were related to allergy to soy milk.

Management of acute food allergic reactions by general practitioners.

BACKGROUND: Food is one of the leading causes of anaphylaxis. In the Netherlands, patients visit a general practitioner (GP) as often as an emergency department (ED) in case of an acute food allergic reaction. So far, the management of food allergic reactions by GPs has not been investigated. Therefore, we explored the management of acute food allergic reactions by GPs regarding specific treatment, observation period, prescription of emergency medication to treat new episodes, diet advices and referral to a specialist. METHODS: A questionnaire containing three hypothetical cases (two anaphylactic and one mild case) with questions about their management was sent to 571 GPs. RESULTS: Overall, treatment choice was dependent on the severity of the reaction (mild vs. anaphylaxis, P < .001). However, epinephrine was used for treatment of anaphylaxis with mainly respiratory symptoms in only 27% and for anaphylaxis with mainly cardiovascular symptoms in 73%. At discharge, the percentages for prescription of self-injectable epinephrine were 53% and 77%, respectively. A short observation period of <2 hours was advised by 42% of general practitioners in case of anaphylaxis. CONCLUSIONS: Treatment of food induced anaphylaxis by GPs appears to be suboptimal: a considerable number of patients would not be treated with epinephrine for the acute reaction (especially anaphylactic cases with respiratory symptoms), the observation period chosen by GPs was often too short and self-injectable epinephrine was not always prescribed at discharge to treat possible new episodes. Education programs are needed to increase the awareness of GPs to recognize and treat anaphylactic reactions.

Anaphylactic versus mild reactions to hazelnut and apple in a birch-endemic area: different sensitization profiles?.

BACKGROUND: Hazelnut and apple are common causes of food allergy in Europe. In northern Europe, symptoms are usually mild and associated with cross-reactivity to the birch pollen allergen, Bet v 1. In the Mediterranean area, symptoms are more frequently severe and associated with sensitization to lipid transfer protein (LTP). This study compared patients with anaphylactic versus mild reactions to hazelnut and apple in The Netherlands, a birch-endemic area, with respect to sensitization to Bet v 1-homologues (i.e. PR10-proteins) and LTP. METHODS: Twenty-one patients fulfilling the criteria for anaphylaxis and 21 with only mild symptoms (oral allergy) to hazelnut and/or apple were recruited. Specific immunoglobulin E to birch pollen, apple, hazelnut and PR10-proteins (rBet v 1, rPru p 1, rMal d 1 and rCor a 1) and recombinant LTP (rPru p 3 and rCor a 8) was measured by ImmunoCAP. RESULTS: Both mild and anaphylactic apple-allergic patients were sensitized to PR10-proteins, whereas only 1/7 of the mild and none of the anaphylactic apple-allergic patients was sensitized to LTP. In contrast, anaphylactic hazelnut-allergic patients displayed no such clear sensitization pattern: some were sensitized to both PR10-proteins and hazelnut LTP (1/9), and others to only LTP (2/9) or to only PR10-proteins (4/9) or to neither PR10-proteins nor LTP (2/9). CONCLUSION: This study shows that in a birch-endemic area, the sensitization profile to PR10-proteins and LTP in anaphylactic patients may differ between different plant foods. In this patient group, anaphylaxis to hazelnut can be LTP-associated, whereas anaphylaxis to apple is not.

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.

T cell responses to major peanut allergens in children with and without peanut allergy.

BACKGROUND: T cell responses involved in peanut allergy are poorly understood. OBJECTIVE: To investigate T cell responses towards major peanut allergens in peanut-allergic (PA) subjects compared with peanut-sensitized (PS) non-allergic children and non-atopic (NA) controls. METHODS: Eighteen PA children, seven non-allergic PS children and 11 NA adults were included. Peripheral blood mononuclear cells were stimulated with a crude peanut extract (CPE). Short-term T cell lines were generated and subsequently stimulated with CPE and purified Ara h 1, Ara h 2, Ara h 3 and Ara h 6. The proliferation and production of IL-13, IFN-gamma, IL-10 and TNF-alpha were analysed. RESULTS: Proliferation to CPE and major allergens was enhanced in PA subjects. The primary response to CPE was comparable with PS subjects, with increased production of IL-13 and IFN-gamma compared with NA. Production of IL-10 was not observed. In short-term T cell lines, the response to CPE was stronger in PA than in PS and NA subjects. Only PA children had a detectable response to major peanut allergens, characterized by IL-13 production. The response was the highest after Ara h 3 stimulation, and the lowest after Ara h 2 stimulation. No significant correlation was observed between peanut-specific IgE levels and T cell responses to CPE. CONCLUSION: T cell responses to CPE in PA and PS children were characterized by Th1 and Th2 cytokines. Only PA children showed enhanced Th2 responses to Ara h 1, Ara h 3 and Ara h 6.

Suboptimal management of acute food-allergic reactions by patients, emergency departments and general practitioners.

Suboptimal food allergy management by patients and doctors.

Clinical relevance of sensitization to lupine in peanut-sensitized adults.

BACKGROUND: The use of lupine in food has been increasing during the last decade and allergic reactions to lupine have been reported, especially in peanut-allergic patients. The frequency and the degree of cross-reactivity to other legumes are not known. The aim of the study was to investigate the frequency of sensitization to lupine, and in addition to pea and soy, and its clinical relevance, in peanut-sensitized patients. Furthermore, to determine the eliciting dose (ED) for lupine using double-blind placebo-controlled food challenges (DBPCFC). METHODS: Thirty-nine unselected peanut-sensitized patients were evaluated by skin prick tests (SPT) and ImmunoCAP to lupine, pea, and soy. Clinical reactivity was measured by DBPCFC for lupine, and by history for pea and soy. RESULTS: Eighty-two percent of the study population was sensitized to lupine, 55% to pea, and 87% to soy. Clinically relevant sensitization to lupine, pea, or soy occurred in 35%, 29%, and 33% respectively of the study population. None of the patients was aware of the use of lupine in food. The lowest ED for lupine, inducing mild subjective symptoms, was 0.5 mg, and the no observed adverse effect level (NOAEL) was 0.1 mg. No predictive factors for lupine allergy were found. CONCLUSION: In peanut-sensitized patients, clinically relevant sensitization to either lupine or to pea or soy occurs frequently. The ED for lupine is low (0.5 mg), which is only fivefold higher than for peanut. Patients are not aware of lupine allergy and the presence of lupine in food, indicating that education is important to build awareness.

A specific mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides induces a beneficial immunoglobulin profile in infants at high risk for allergy.

BACKGROUND: It has been suggested that human breast milk oligosaccharides play a role in the development of the immune system in infants, and may consequently inhibit the onset of allergy. A specific prebiotic mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (GOS/FOS) has been shown to reduce the incidence of atopic dermatitis (AD) at 6 months of age in infants at risk for allergy. AIM OF THE STUDY: This study was aimed to analyze the effect of GOS/FOS on the immune response in these infants. METHODS: In a double-blind randomized placebo-controlled study, infants received a hypoallergenic whey formula with either 8 g/l GOS/FOS in a 9 : 1 ratio (IMMUNOFORTIS) or 8 g/l maltodextrine (placebo) for 6 months. At 3 months of age, children were vaccinated with Hexavac against a.o. diphteria, tetanus, polio (DTP). At 6 months of age, plasma samples were collected from 84 infants (verum group n = 41, placebo group n = 43). Levels of total immunoglobulins (Ig) and of cow's milk protein (CMP-) and DTP-specific Ig were measured. RESULTS: GOS/FOS supplementation led to a significant reduction in the plasma level of total IgE, IgG1, IgG2 and IgG3, whereas no effect on IgG4 was observed. CMP-specific IgG1 was significantly decreased. DTP-specific Ig levels were not affected. CONCLUSIONS: This study shows that GOS/FOS supplementation induces a beneficial antibody profile. GOS/FOS reduces the total Ig response and modulates the immune response towards CMP, while leaving the response to vaccination intact. This suggests that oral GOS/FOS supplementation is a safe method to restrain the atopic march.

Reported food allergy to peanut, tree nuts and fruit: comparison of clinical manifestations, prescription of medication and impact on daily life.

BACKGROUND: Peanut (PN), tree nuts (TN) and fruits are frequent causes of food allergy (FA). Peanut and TN are believed to cause more severe reactions than fruits. However, there are no studies comparing the severity of PN, TN and fruit allergy within one patient group. METHODS: Four-hundred and eleven adult patients referred to our tertiary allergy center with suspicion of FA completed a standardized questionnaire. Patients with a typical history of immunoglobulin E (IgE)-mediated allergy, e.g. oropharyngeal symptoms to PN, TN (hazelnut, walnut, cashew nut) or fruit (apple, kiwi, peach, pear and cherry) were recruited (218/411). The objective was to evaluate differences in clinical severity between PN, TN and fruit allergy and how this was reflected by prescription of emergency medication and impact on daily life. RESULTS: Eighty-two percent of the included 218 patients were sensitized to the respective foods. The percentages of severe symptoms (i.e. respiratory or cardiovascular symptoms) in PN, TN and fruit allergic patients were respectively 47%, 39% and 31% (respiratory) and 11%, 5.0% and 3.4% (cardiovascular). Prescription and use of emergency medication (epinephrine, antihistamines and steroids) did not differ among the three groups. The majority of patients with a PN or TN allergy (72%) and fruit allergy (62%) reported that FA influences their daily life considerably. CONCLUSIONS: Fruit allergy causes less severe symptoms than TN and especially PN allergy. However, this is not reflected in the prescription or use of emergency medication. This may indicate that physicians are not fully acquainted with the guidelines for prescription of emergency medication. A high impact on daily life was found both in PN, TN and in fruit allergy.

Cow's milk allergy in adults is rare but severe: both casein and whey proteins are involved.

BACKGROUND: Studies on cow's milk allergy (CMA) in adults are scarce. Little is known about the clinical symptoms, eliciting doses (ED), and allergens involved. OBJECTIVE: The aim of this study was to analyse the clinical symptoms, ED and allergen recognition in adult CMA patients, compared with cow's milk (CM)-sensitized, but tolerant controls. METHODS: Adult CMA patients were evaluated by standardized questionnaires (n=30), skin prick tests (SPTs) and specific IgE for CM allergens (n=18), and a double-blind placebo-controlled food challenge (DBPCFC, n=10). A control group (n=25) of CM-sensitized, but tolerant adults was included. RESULTS: The majority of CMA patients (20/30, 67%) reported severe symptoms. In all patients participating in DBPCFC, CMA was confirmed. ED for subjective symptoms (0.3-300 mg CM protein) were significantly lower than that for objective symptoms (300-9000 mg CM protein). The severity of CMA by history and ED was not correlated with SPT or IgE. Patients had higher SPT reactivity than controls for CM, alpha-lactalbumin and beta-lactoglobulin (P=0.002, P=0.014 and P=0.004) but not for casein. Specific IgE to CM tended to be higher (P=0.068) and IgE to casein was higher in patients than that in controls (P=0.016). No difference was observed for IgE to alpha-lactalbumin and beta-lactoglobulin. CONCLUSION: Adult CMA is severe in nature. ED are low, starting from 0.3 mg CM protein. Patients with CMA recognize the same major allergens (casein and whey proteins) as controls, but display a stronger SPT and IgE reactivity.

Children with peanut allergy recognize predominantly Ara h2 and Ara h6, which remains stable over time.

BACKGROUND: In peanut-allergic adults, IgE is mainly directed to Ara h1 and Ara h2. More recently, a role for Ara h6 has been suggested. In contrast to adults, IgE in children can fluctuate over time. Therefore, children may have a more dynamic reactivity to peanut. OBJECTIVE: To examine the IgE reactivity to major peanut allergens in peanut-allergic children at two subsequent time-points. METHODS: Twenty children (3-15 years old) with peanut allergy, confirmed by a double-blind placebo-controlled food challenge (DBPCFC), were included. Just before and 20 months after DBPCFC, IgE reactivity to purified Ara h1, Ara h2, Ara h3 and Ara h6 was studied by immunoblots and skin prick tests (SPTs). RESULTS: Before DBPCFC, all peanut-allergic children showed IgE reactivity to Ara h2; Ara h6 was recognized by 16 children, and Ara h1 and Ara h3 by 10 children. After 20 months, peanut-specific IgE levels (median 23 kU/L) and the individual recognition of major allergens were comparable with the levels and recognition before challenge (median 28.2 kU/L). SPT with Ara h2 and Ara h6 was positive in most children, whereas SPT with Ara h1 and Ara h3 was positive in approximately half of the children. Ara h6 induced the largest weals. None of the parameters were related to the severity of peanut allergy. CONCLUSION: Ara h2 and Ara h6 are the most frequently recognized major peanut allergens in children. The individual reactivity to the major peanut allergens remained stable over time, despite DBPCFC.

Maintenance of tolerance to cow's milk in atopic individuals is characterized by high levels of specific immunoglobulin G4.

BACKGROUND: The central role of specific IgE in cow's milk allergy (CMA) is well documented. However, less is known about the function of other immunoglobulin isotypes in allergy and tolerance to cow's milk proteins (CMPs). OBJECTIVE: To determine differences in the antibody responses that are associated with allergy and tolerance to cow's milk in allergic, atopic and non-atopic individuals of different age groups. METHODS: Nineteen infants (<1 year), 18 children (6-14 years) and 41 adults (21-68 years) were included. Each age group was comprised of subjects with CMA, atopic individuals without a history of CMA and non-atopic subjects. Levels of specific IgE, IgG4, IgG1 and IgA to whole cow's milk and the six most abundant individual CMPs were determined in plasma by ELISA. For comparison, specific IgE and IgG4 were measured to ovomucoid and house dust mite (HDM) in individuals allergic for the respective allergens, and in atopic and non-atopic subjects without allergy. RESULTS: In infants and children with CMA, alphas1-casein and beta-lactoglobulin induced the highest specific IgE response, whereas alphas1-casein was the most allergenic CMP in adult patients. Specific IgG4 and IgG1 responses were the highest to alphas1-casein and beta-lactoglobulin in all age groups, while kappa-casein and alpha-lactalbumin induced the highest levels of IgA. CMP-specific IgG4 was higher in atopic children and adults without CMA, as compared with non-atopic individuals. A similar difference between tolerant atopic and non-atopic subjects was observed for IgG4 specific to ovomucoid, whereas HDM-specific IgG4 was not detectable in these subjects. CONCLUSION: Maintenance of tolerance to cow's milk in atopic children and adults without CMA is associated with elevated levels of specific IgG4, in combination with low specific IgE. The up-regulation of specific IgG4 in tolerant atopic individuals may be related to the type of allergen and its regular dose of exposure.

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-gamma, IL-5, IL-13, IL-10, TNF-alpha, 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-gamma, IL-10 and TNF-alpha. 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-alpha 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-alpha and IL-6. This indicates that probiotics have a different potential to modulate the immune response in vitro versus ex vivo.