1,25(OH)2VitD3 supplementation enhances suppression of grass pollen-induced allergic asthma by subcutaneous and sublingual immunotherapy in a mouse model.

Allergen specific immunotherapy (AIT) can provide long-term alleviation of symptoms for allergic disease but is hampered by suboptimal efficiency. We and others have previously shown that 1,25(OH)2-VitaminD3 (VitD3) can improve therapeutic efficacy of AIT. However, it is unknown whether VitD3 supplementation has similar effects in sublingual and subcutaneous immunotherapy. Therefore, we aimed to test VitD3 supplementation in both grass pollen (GP) subcutaneous-IT (SCIT) and sublingual-IT (SLIT) in a mouse model for allergic airway inflammation. To this end, GP-sensitized BALB/c mice received GP-SCIT or GP-SLIT with or without 10 ng VitD3, followed by intranasal GP challenges and measurement of airway hyperresponsiveness (AHR) and inflammation. VitD3 supplementation of GP-SCIT resulted in enhanced induction of GP-specific (sp)-IgG2a and suppression of spIgE after challenge. In addition, eosinophil numbers were reduced and levels of IL10 and Amphiregulin were increased in lung tissue. In GP-SLIT, VitD3 supplementation resulted in enhanced sp-IgG2a levels in serum, enhanced suppression of eosinophils and increased IL10 levels in lung tissue, as well as suppression of AHR to methacholine. These data show that VitD3 increases efficacy of both SCIT and SLIT, by enhancing induction of blocking antibodies and suppression of airway inflammation, underscoring the relevance of proficient VitD3 levels for successful AIT.

The feasibility of an allergy management support system (AMSS) for IgE-mediated allergy in primary care.

BACKGROUND: The allergy management support system (AMSS) was developed to assist general practitioners (GPs) to handle the increasing burden of allergic diseases and facilitates the diagnosis and management of allergy. The aim of this cluster-randomized controlled pilot study was to test the feasibility of this AMSS for primary care. METHODS: GPs received diagnostic and management recommendations generated by the AMSS in addition to sIgE-test results (intervention) or GPs received sIgE-test results only (control). The AMSS recommendations are based on the previously developed patient-completed AMSS questionnaire and sIgE-test results. The AMSS was considered feasible when > 70% of the AMSS recommendations were sent to the GP within ten working days of sIgE-testing. GPs completed a questionnaire on their diagnosis and management before (T1) and after (T2) receiving sIgE test results. Agreement and disagreement concerning diagnosis, medication and referrals between GPs and AMSS was investigated at T1 and T2. A total agreement score between GPs and AMSS was calculated. GPs in the intervention group completed a questionnaire to evaluate the utility of the AMSS. Semi-structured interviews were used to explore the motivation of GPs who did not include patients in this pilot study. RESULTS: Twenty-seven GPs included 101 patients. Forty-two patients (72%) completed the AMSS questionnaire in the intervention group. The majority of the AMSS recommendations (93%) were returned to the GP within 10 working days after sIgE-test results were known [mean (SD) 4.7 (4.0) working days]. GPs in the intervention group reported largely following the AMSS recommendations in 71% of cases. The total agreement scores concerning diagnosis were significantly higher (p < 0.001) in the intervention group than the control group [mean (SD); 0.9 (1.8) vs - 0.8 (1.0)]. The agreement concerning medication or referral between GPs and AMSS did not differ between the intervention and the control group. GPs in the intervention group were reasonably positive about the AMSS. Not enrolling patients was not caused by anticipated ineffectiveness of the AMSS. CONCLUSION: The AMSS can be considered to be feasible for primary care. GPs tend to follow the AMSS recommendations. The AMSS may contribute to the empowerment of GPs to better manage allergy patients in primary care.Trial registration ISRCTN ISRCTN36780877. Registered 23 November 2017 (retrospectively registered).

Fatal Anaphylaxis to Yellow Jacket Stings in Mastocytosis: Options for Identification and Treatment of At-Risk Patients.

BACKGROUND: Patients with indolent systemic mastocytosis (ISM) are at risk for severe anaphylactic reactions to yellow jacket (YJ) stings while demonstration of sensitization can be challenging because specific IgE (sIgE) levels are regularly below 0.35 kUA/L. The implication of missing YJ allergy is illustrated by a case of fatal anaphylaxis. OBJECTIVE: To explore the natural course of YJ venom allergy and the diagnostic accuracy and therapeutic consequence of YJ venom sIgE in patients with ISM. METHODS: All patients with ISM seen from 1981 to 2015 (n = 243) were evaluated on the number of YJ stings, reaction severity, and sensitivity and specificity of YJ venom sIgE. YJ venom allergic patients without mastocytosis served as control (n = 313). RESULTS: A total of 153 patients with ISM were stung during adult life. The first systemic reaction was more often severe in patients with ISM than in patients without mastocytosis (69.9% vs 22.0%) and reactions recurred in 40 of 41 re-stung patients with ISM. ISM reactors showed lower YJ venom sIgE levels than nonmastocytosis reactors (0.61 vs 4.83 kUA/L; P < .001) and asymptomatic sensitization was exceedingly rare. In ISM the current clinical threshold of 0.35 kUA/L yields a sensitivity and specificity of 77.6% and 87.5%, respectively. The optimal diagnostic accuracy is achieved at 0.17 kUA/L (sensitivity, 83.6%; specificity, 85.0%). CONCLUSIONS: The high rate of severe reactions and the fatal case underscore the importance of adequate diagnostic sensitivity of sIgE in patients with ISM. The sensitivity of sIgE can be ameliorated by lowering the threshold to 0.17 kUA/L, retaining good specificity. We recommend sIgE screening in all patients with ISM and discussing immunotherapy when YJ venom sIgE exceeds 0.17 kUA/L.

The minimal clinically important difference of the Control of Allergic Rhinitis and Asthma Test (CARAT): cross-cultural validation and relation with pollen counts.

BACKGROUND: The Control of Allergic Rhinitis and Asthma Test (CARAT) monitors control of asthma and allergic rhinitis. AIMS: To determine the CARAT's minimal clinically important difference (MCID) and to evaluate the psychometric properties of the Dutch CARAT. METHODS: CARAT was applied in three measurements at 1-month intervals. Patients diagnosed with asthma and/or rhinitis were approached. MCID was evaluated using Global Rating of Change (GRC) and standard error of measurement (s.e.m.). Cronbach's alpha was used to evaluate internal consistency. Spearman's correlation coefficients were calculated between CARAT, the Asthma Control Questionnaire (ACQ5) and the Visual Analog Scale (VAS) on airway symptoms to determine construct and longitudinal validity. Test-retest reliability was evaluated with intra-class correlation coefficient (ICC). Changes in pollen counts were compared with delta CARAT and ACQ5 scores. RESULTS: A total of 92 patients were included. The MCID of the CARAT was 3.50 based on GRC scores; the s.e.m. was 2.83. Cronbach's alpha was 0.82. Correlation coefficients between CARAT and ACQ5 and VAS questions ranged from 0.64 to 0.76 (P < 0.01). Longitudinally, correlation coefficients between delta CARAT scores and delta ACQ5 and VAS scores ranged from 0.41 to 0.67 (P < 0.01). Test-retest reliability showed an ICC of 0.81 (P < 0.01) and 0.80 (P < 0.01). Correlations with pollen counts were higher for CARAT than for ACQ5. CONCLUSIONS: This is the first investigation of the MCID of the CARAT. The CARAT uses a whole-point scale, which suggests that the MCID is 4 points. The CARAT is a valid and reliable tool that is also applicable in the Dutch population.

Diminished reliability of tryptase as risk indicator of mastocytosis in older overweight subjects.

BACKGROUND: Currently, measurement of serum tryptase level is the most commonly used test to estimate the need for bone marrow biopsy in patients suspected to have indolent systemic mastocytosis (ISM). Yet tryptase levels do not solely reflect the mast cell load and can be elevated by overweight, older age, and impaired renal function. The influence of these factors on urinary methylhistamine (MH) and methylimidazole acetic acid (MIMA) is still unknown. OBJECTIVE: We investigated the impact of age, body mass index (BMI), and kidney function on the diagnostic accuracy of tryptase, MH, and MIMA to select the most optimal test indicating the necessity of a bone marrow biopsy in ISM-suspected patients. METHODS: Retrospective data analysis of all adults in whom bone marrow investigations were performed because of high clinical suspicion and/or elevated tryptase, MH, or MIMA. RESULTS: 194 subjects were included. ISM was present in 112 and absent in 82 subjects (non-ISM). Tryptase was elevated by age and body weight in non-ISM subjects and by BMI in ISM subjects; however, these factors did not influence MH or MIMA. In the total study population, the diagnostic accuracy of tryptase, MH, and MIMA were comparable (area under the curve 0.80, 0.80, and 0.83). In subjects >50 years with a BMI >25 kg/m(2), the diagnostic accuracy of MIMA was higher compared with that of tryptase (area under the curve 0.93 vs 0.74; P = .011). CONCLUSION: In ISM-suspected patients >50 years with a BMI of >25 kg/m(2), MIMA has a greater value compared with tryptase in estimating the need for bone marrow biopsy.

CD30 in systemic mastocytosis.

CD30 is a transmembrane receptor, normally not expressed by mast cells, which regulates proliferation/apoptosis and antibody responses. Aberrant expression of CD30 by mastocytosis mast cells and interaction with its ligand CD30L (CD153) appears to play an important role in the pathogenesis and clinical presentation of systemic mastocytosis. This article highlights the expression profile and role of CD30 and CD30L in physiologic and pathologic conditions, the applicability of CD30 as a marker for systemic mastocytosis, the consequences of mast cell-expressed CD30, and the possibility of future anti-CD30 based cytoreductive therapies.

Epidemiology, diagnosis, and treatment of Hymenoptera venom allergy in mastocytosis patients.

Hymenoptera venom allergy is a typical IgE-mediated reaction caused by sensitization to 1 or more allergens of the venom, and accounts for 1.5% to 34% of all cases of anaphylaxis. Patients suffering from mastocytosis are more susceptible to the anaphylactic reactions to an insect sting. This article aims to answer the most important clinical questions raised by the diagnosis and treatment of insect venom allergy in mastocytosis patients. Total avoidance of Hymenoptera is not feasible, and there is no preventive pharmacologic treatment available, although venom immunotherapy reduces the risk of subsequent systemic reactions.

Higher mast cell load decreases the risk of Hymenoptera venom-induced anaphylaxis in patients with mastocytosis.

BACKGROUND: Increased basal serum tryptase (bsT) levels are a well-described risk factor for Hymenoptera venom-induced anaphylaxis (HVAn) in patients allergic to Hymenoptera venom. Increased bsT levels might also indicate the presence of mastocytosis. In this study we evaluated whether the risk of HVAn increases with increasing mast cell load in patients with mastocytosis. METHODS: Consecutive patients with different subtypes of mastocytosis (n = 329) admitted to the University Medical Center Groningen were retrospectively assessed. As markers for mast cell load, levels of both bsT and the urinary histamine metabolites methylhistamine and methylimidazole acetic acid (MIMA) were used. RESULTS: In the entire patient group, irrespective of disease subtype and Hymenoptera venom exposure, HVAn prevalence gradually increased with increasing marker levels to a maximum of 36% to 47% at a bsT level of 28.0 µg/L, a methylhistamine level of 231.0 µmol/mol creatinine, and a MIMA level of 2.7 mmol/mol creatinine but decreased thereafter with a further increase in these levels. In patients with indolent systemic mastocytosis with a history of Hymenoptera venom exposure after age 15 years or greater (n = 152), MIMA and age at the most recent Hymenoptera sting were independent predictors for HVAn (odds ratios of 0.723 [P = .001] and 1.062 [P < .001], respectively). CONCLUSIONS: In patients with mastocytosis, HVAn prevalence does not increase constantly with increasing levels of mast cell load parameters: after a gradual increase to a maximum of near 50%, it decreases with a further increase in these levels. In the indolent systemic mastocytosis population, all mast cell load markers were independent negative predictors of HVAn. These findings suggest a complex pathophysiologic association between mast cell load and HVAn risk in patients with mastocytosis.

Food allergy-related quality of life after double-blind, placebo-controlled food challenges in adults, adolescents, and children.

BACKGROUND: Currently, the longitudinal validity (validity over time) and responsiveness (ability to measure change over time) of the Food Allergy Quality of Life Questionnaire-Adult Form (FAQLQ-AF), the Food Allergy Quality of Life Questionnaire-Teenager Form (FAQLQ-TF), and the Food Allergy Quality of Life Questionnaire-Child Form (FAQLQ-CF) are unknown. Additionally, the self-reported impact of a double-blind, placebo-controlled food challenge (DBPCFC) on health-related quality of life (HRQL) in adults (≥18 years of age), adolescents (13-17 years of age), and children (8-12 years of age) is unknown. OBJECTIVE: The aims of this study were to assess the longitudinal validity and responsiveness of the FAQLQ-AF, FAQLQ-TF, and FAQLQ-CF and to assess the impact of a DBPCFC on HRQL. METHODS: Two hundred twenty-one participants suspected of food allergy were included from Dutch allergy centers. Participants undergoing a DBPCFC (experimental group) completed the FAQLQ and Food Allergy Independent Measure (FAIM) 1 month before (baseline) and 6 months after (follow-up) a DBPCFC. Participants not undergoing a DBPCFC (control group) completed the questionnaire package twice with a 7-month interval. RESULTS: HRQL scores improved after a DBPCFC, with greater improvements in HRQL scores after a negative outcome (food allergy ruled out) than a positive outcome (food allergy confirmed), demonstrating responsiveness of the FAQLQs. Significant correlations were shown between the change (follow-up minus baseline) in FAQLQ and FAIM scores supporting longitudinal validity of these questionnaires: FAQLQ-AF (Pearson correlation coefficient = 0.71, P < .001), FAQLQ-TF (Pearson correlation coefficient = 0.35, P = .018), and FAQLQ-CF (Pearson correlation coefficient = 0.51, P < .001). CONCLUSIONS: Our findings demonstrate the longitudinal validity and responsiveness of the FAQLQs. Greater improvements in HRQL scores were shown after a negative outcome than after a positive outcome.

Gene expression analysis in predicting the effectiveness of insect venom immunotherapy.

BACKGROUND: Venom immunotherapy (VIT) enables longtime prevention of insect venom allergy in the majority of patients. However, in some, the risk of a resystemic reaction increases after completion of treatment. No reliable factors predicting individual lack of efficacy of VIT are currently available. OBJECTIVE: To determine the use of gene expression profiles to predict the long-term effect of VIT. METHODS: Whole genome gene expression analysis was performed on RNA samples from 46 patients treated with VIT divided into 3 groups: (1) patients who achieved and maintained long-term protection after VIT, (2) patients in whom insect venom allergy relapsed, and (3) patients still in the maintenance phase of VIT. RESULTS: Among the 48.071 transcripts analyzed, 1401 showed a >2 fold difference in gene expression (P < .05); 658 genes (47%) were upregulated and 743 (53%) downregulated. Forty-three transcripts still show significant differences in expression after correction for multiple testing; 12 of 43 genes (28%) were upregulated and 31 of 43 genes (72%) downregulated. A naive Bayes prediction model demonstrated a gene expression pattern characteristic of effective VIT that was present in all patients with successful VIT but absent in all subjects with failure of VIT. The same gene expression profile was present in 88% of patients in the maintenance phase of VIT. CONCLUSION: Gene expression profiling might be a useful tool to assess the long-term effectiveness of VIT. The analysis of differently expressed genes confirms the involvement of immunologic pathways described previously but also indicates novel factors that might be relevant for allergen tolerance.

Test-retest reliability of the Food Allergy Quality of Life Questionnaires (FAQLQ) for children, adolescents and adults.

OBJECTIVE: The self-administered Food Allergy Quality of Life Questionnaire-Child Form (FAQLQ-CF), -Teenager Form (FAQLQ-TF) and -Adult Form (FAQLQ-AF) were recently developed within EuroPrevall, a multi-centred study of food allergy in Europe. The primary aim of this study was to evaluate the test-retest reliability of the FAQLQ-CF, -TF and -AF. METHODS: One hundred and one Dutch patients (31 children, 34 adolescents and 36 adults) completed the FAQLQ twice with a 10-14 day interval. The intraclass correlation coefficient (ICC), Lin's concordance correlation coefficient (CCC) and Bland-Altman plots were used to assess test-retest reliability. RESULTS: Test-retest reliability was excellent with ICCs and CCCs above 0.907, 0.975 and 0.951 for the FAQLQ-CF, -TF and -AF, respectively. Bland-Altman plots showed that the mean differences of the test and re-test were all close to zero for the FAQLQs. CONCLUSIONS: The FAQLQs are reliable over a short time interval. The FAQLQs are not only excellent tools for group comparison studies, but also for monitoring individual patients.

Development and validation of the self-administered Food Allergy Quality of Life Questionnaire for adolescents.

BACKGROUND: Food allergy can affect health-related quality of life (HRQL). Currently, no validated, self-administered, disease-specific HRQL questionnaire for adolescents with food allergy exists. OBJECTIVE: We sought to develop and validate the Food Allergy Quality of Life Questionnaire-Teenager Form (FAQLQ-TF) in the Dutch language. METHODS: Ten adolescents (13-17 years) with food allergy were interviewed and generated 166 HRQL items. The most important items were identified by 51 adolescents with food allergy by using the clinical impact method, resulting in the FAQLQ-TF containing 28 items (score range: 1 "no impairment" to 7 "maximal impairment"). The FAQLQ-TF, the Food Allergy Independent Measure, and a generic HRQL questionnaire (CHQ-CF87) were sent to 98 adolescents with food allergy for cross-sectional validation of the FAQLQ-TF. RESULTS: Construct validity was assessed based on the correlation between the FAQLQ-TF and the Food Allergy Independent Measure (rho = 0.57, P < .001). The FAQLQ-TF had excellent internal consistency (Cronbach alpha = .92) and discriminated between adolescents who differed in number of food allergies (1 vs >2 food allergies: total FAQLQ-TF score, 4.3 vs 3.5; P = 0.037) but did not discriminate between those who did or did not have reported anaphylaxis. The FAQLQ-TF correlated weakly with 6 of the 11 CHQ-CF87 scales, demonstrating convergent/discriminant validity. CONCLUSION: The FAQLQ-TF is the first self-administered, disease-specific HRQL questionnaire for adolescents with food allergy. It has good construct validity and excellent internal consistency and discriminates between adolescents who differ in the number of food allergies. The FAQLQ-TF is short and easy to use and might therefore be a useful tool in clinical research.

IgE-mediated food allergy diagnosis: Current status and new perspectives.

In June 2005, the work of the EU Integrated Project EuroPrevall was started. EuroPrevall is the largest research project on food allergy ever performed in Europe. Major aims of the project are to generate for the first time reliable data on the prevalence of food allergies across Europe and on the natural course of food allergy development in infants. Improvement of in vitro diagnosis of food allergies is another important aim of the project. The present review summarizes current knowledge about the clinical presentation of food allergy and critically reviews available diagnostic tools at the beginning of the project period. A major problem in diagnosis is a relatively poor 'clinical specificity', i. e. both positive skin tests and in vitro tests for specific IgE are frequent in sensitized subjects without food allergy symptoms. So far, no in vitro test reliably predicts clinical food allergy. EuroPrevall aims at improving the predictive value of such tests by proceeding from diagnosis based on allergen extracts to purified allergen molecules, taking into account the affinity of the IgE-allergen interaction, and evaluating the potential of biological in vitro tests such as histamine release tests or basophil activation tests including assays performed with permanently growing cell lines.

Analysis of the burden of treatment in patients receiving an EpiPen for yellow jacket anaphylaxis.

BACKGROUND: Venom immunotherapy (VIT) is a treatment with established efficacy for the prevention of repeated anaphylactic reactions in patients with Hymenoptera allergy, which also allows patients to discontinue carrying an EpiPen. Despite their merits, both treatments can have negative aspects potentially important to patients. OBJECTIVE: We examined possible negative aspects of the EpiPen in comparison with VIT as perceived by patients. METHODS: Positive and negative aspects of both treatments were measured by using a burden of treatment questionnaire together with statements about the EpiPen. RESULTS: One hundred ninety-three patients were included, of whom 94 consented to randomization: 47 received VIT, and 47 received the EpiPen. Of the remaining 99, 75 chose VIT, and 26 chose the EpiPen. Of the patients receiving VIT, 91.5% were (extremely) positive about their treatment, and 85% would choose VIT again. Of the patients receiving the EpiPen, only 48% were positive about their treatment, and even of these patients, 68% preferred to be treated with VIT after 1 year of carrying the EpiPen. Although most patients indicated that it is reassuring to carry an EpiPen and makes them feel safe, many patients also indicated that it is inconvenient and troublesome. Especially patients who were negative about the EpiPen indicated that they would not dare use the EpiPen if necessary and were afraid at possible side effects. CONCLUSION: In contrast to VIT, the EpiPen is perceived as burdensome by most patients with venom allergy. For most patients, an EpiPen is an unsuitable definitive treatment. CLINICAL IMPLICATIONS: As VIT enables patients with venom allergy to get rid of the EpiPen, patients should be offered VIT.

Significance and rationale of studies of health-related quality of life in anaphylactic disorders.

PURPOSE OF REVIEW: Until recently, quality-of-life measures were only used in allergic diseases with ongoing symptoms, such as asthma and rhinoconjunctivitis. Anaphylaxis is a chronic disease without ongoing physical symptoms, but the problems concerning quality of life are related to the continuous vigilance required to prevent accidental exposure. This raises specific issues concerning the validation of quality-of-life instruments. RECENT FINDINGS: The preferred independent measure for validation generally is an objective measurement of the severity of disease (e.g. spirometry in asthma). In patients suffering from anaphylaxis, the perceived expectation of what will happen following exposure can be used as the key independent measure. Recently, a specific instrument measuring this expectation (the 'Expectation of outcome' questionnaire) has been developed, and successfully used in insect-venom anaphylaxis. SUMMARY: Also, in diseases without ongoing symptoms like anaphylaxis, quality of life can be measured and the disease-specific instrument validated. It is to be expected that many new instruments will be developed in the coming years to address important issues in anaphylaxis. They may provide a better understanding of the major problems of certain patient subgroups and may give direction to the kind of information that should be addressed and what kind of interventions could be important and whether they are useful or not.