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.

Ulcerative colitis patients with an inflammatory response upon mesalazine cannot be desensitized: a randomized study.

BACKGROUND AND AIMS: Mesalazine is a key drug in the treatment of ulcerative colitis (UC). Intolerance to mesalazine has been described, including fever and gastrointestinal symptoms. Several case reports reported successful desensitization of patients with mesalazine intolerance. The aim was to assess the number of UC patients who are persistently intolerant to mesalazine after single-blinded rechallenge and to test the effectiveness of a rapid desensitization protocol in UC patients demonstrated mesalazine intolerance. METHODS: This is a prospective, single-blind randomized study in UC patients who discontinued mesalazine because of intolerance. Patients with severe reactions were excluded. Eligible patients underwent a skin patch test with mesalazine followed by a single-blinded randomized crossover rechallenge with 500 mg mesalazine or placebo. Patients with symptoms upon rechallenge were admitted to the hospital for 3 days oral desensitization. RESULTS: Nine of the 37 identified UC patients who discontinued mesalazine because of intolerance were included. All nine patients had negative patch tests, seven patients had symptoms (fever, nausea, vomiting and diarrhea) within 2 h upon rechallenge. Four of these seven patients participated in the desensitization protocol and in none a successful desensitization could be performed. All four had an inflammatory intolerance reaction with rise in C-reactive protein. There were no elevations in serum tryptase or urinary-methylhistamine levels observed and no signs of immediate type allergic reactions, like urticaria, bronchial obstruction or anaphylaxis. CONCLUSION: We recommend not to rechallenge UC patients with an inflammatory response upon mesalazine and these patients will not benefit from a rapid desensitization protocol.

Predictors of new fragility fractures after diagnosis of indolent systemic mastocytosis.

BACKGROUND: Fragility fractures (FFxs) and osteoporosis occur frequently in patients with indolent systemic mastocytosis (ISM), even before 50 years of age. OBJECTIVE: We sought to develop a prediction model to identify individual patients with ISM at risk of new FFxs. METHODS: Data on lifetime fractures and trauma circumstances were collected from vertebral morphometry, patients' records, and questionnaires. Clinical, lifestyle, and bone characteristics were measured. Patients receiving treatment for osteoporosis before ISM diagnosis or with missing bone data were excluded from FFx risk assessment. RESULTS: In total, 389 lifetime fractures occurred in 127 of the 221 patients with ISM (age, 19-77 years), including 90 patients with 264 FFxs. Median follow-up after diagnosis was 5.4 years (range, 0.4-15.3 years), with 5- and 10-year FFx risks of 23% ± 3% and 31% ± 4%, respectively. Male sex, high levels of bone resorption (serum type I collagen C-telopeptide), low hip bone mineral density, absence of urticaria pigmentosa, and alcohol intake at the time of ISM diagnosis were independent predictors of future FFxs. The MastFx score, a prediction model using these 5 characteristics, showed good accuracy (area under the curve, 0.80) to determine the risk of new FFxs. QFracture, a validated risk scoring tool for persons aged 30 to 99 years, was not useful in patients with ISM. CONCLUSION: The MastFx score distinguishes patients with ISM at high, intermediate, and low risk of new FFxs. The included characteristics sex, serum type I collagen C-telopeptide, hip bone mineral density, urticaria pigmentosa, and alcohol intake are easy to collect in clinical practice. The high occurrence of FFxs in patients with ISM underlines the importance of optimizing bone quality and early start of therapeutic prevention in patients at risk.

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.

Omalizumab protects against allergen- induced bronchoconstriction in allergic (immunoglobulin E-mediated) asthma.

BACKGROUND: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. METHODS: Asthmatic adults (18-65 years; body weight 40-150 kg) were divided into groups according to screening IgE (group 1: 30-300 IU/ml; group 2: 700-2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12-14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FE(NO)) was an exploratory endpoint. RESULTS: Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6-16. Omalizumab completely suppressed FE(NO) increases after ABP in both groups. CONCLUSIONS: Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.

Increase in vesicular hand eczema after house dust mite inhalation provocation: a double-blind, placebo-controlled, cross-over study.

BACKGROUND: It is unclear whether the respiratory tract is involved in eliciting or aggravating eczematous lesions in patients with vesicular hand eczema. Objectives. To investigate the effect of inhalation of house dust mite (HDM) on vesicular hand eczema. METHODS: Eighteen patients with vesicular hand eczema and HDM allergy received inhalation challenges with four concentrations of HDM in a randomized, double-blind, placebo-controlled, cross-over study. Early asthmatic reactions and late asthmatic reactions were defined as a placebo-corrected fall of 15% or more from baseline of forced expiratory volume in 1 second. Hand eczema was scored according to the Dyshidrotic Eczema Area and Severity Index (DASI) at baseline, and 1, 6, 24 and 48 hr. RESULTS: The median DASI increased significantly as compared with baseline at 6 and 48 hr after HDM inhalation. This increase was significantly different between the provocations at 6 hr. The median vesicles score increased significantly from baseline at 24 and 48 hr. Patients with a placebo-corrected increase in the number of vesicles at 24 hr and 48 hr had significantly more often late asthmatic reactions than those without an increase in the number of vesicles. Patients with a placebo-corrected increase of the DASI score at 24 hours had as a group a higher mean total IgE level than those without an increase of the DASI score. CONCLUSION: Hand eczema increased significantly more after HDM provocation than after placebo provocation. An increase in the number of vesicles was preceded by late asthmatic reactions. The group patients with an increase of hand eczema tended to have a higher mean total IgE level.

SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial.

BACKGROUND: The main aim of specific immunotherapy is sustained effect due to changes in the immune system that can be demonstrated only in long-term trials. OBJECTIVE: To investigate sustained efficacy and disease modification in a 5-year double-blind, placebo-controlled trial, including 2 years of blinded follow-up after completion of a 3-year period of treatment, with the SQ-standardized grass allergy immunotherapy tablet, Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU,(∗) ALK, Denmark) or placebo. METHODS: A randomized, double-blind, placebo-controlled, multinational, phase III trial included adults with a history of moderate-to-severe grass pollen-induced allergic rhinoconjunctivitis, with or without asthma, inadequately controlled by symptomatic medications. Two hundred thirty-eight participants completed the trial. End points included rhinoconjunctivitis symptom and medication scores, combined scores, asthma symptom and medication scores, quality of life, days with severe symptoms, immunologic end points, and safety parameters. RESULTS: The mean rhinoconjunctivitis daily symptom score was reduced by 25% to 36% (P ≤ .004) in the grass allergy immunotherapy tablet group compared with the placebo group over the 5 grass pollen seasons covered by the trial. The rhinoconjunctivitis DMS was reduced by 20% to 45% (P ≤ .022 for seasons 1-4; P = .114 for season 5), and the weighted rhinoconjunctivitis combined score was reduced by 27% to 41% (P ≤ .003) in favor of active treatment. The percentage of days with severe symptoms during the peak grass pollen exposure was in all seasons lower in the active group than in the placebo group, with relative differences of 49% to 63% (P ≤ .0001). Efficacy was supported by long-lasting significant effects on the allergen-specific antibody response. No safety issues were identified. CONCLUSION: The results confirm disease modification by SQ-standardized grass allergy immunotherapy tablet in addition to effective symptomatic treatment of allergic rhinoconjunctivitis.

Changes in gene expression caused by insect venom immunotherapy responsible for the long-term protection of insect venom-allergic patients.

BACKGROUND: Insect venom immunotherapy (VIT) is the only causative treatment of insect venom allergy (IVA). The immunological mechanism(s) responsible for long-term protection achieved by VIT are largely unknown. A better understanding is relevant for improving the diagnosis, prediction of anaphylaxis, and monitoring and simplifying treatment of IVA. OBJECTIVE: To find genes that are differentially expressed during the maintenance phase of VIT and after stopping, to get clues about the pathways involved in the long-term protective effect of immunotherapy. METHODS: Whole genome gene expression analysis was performed on RNA samples from 50 patients treated with VIT and 43 healthy controls. Patients were divided into three groups: (1) before the start of VIT; (2) on maintenance phase of VIT for at least 3 years still receiving injections; and (3) after VIT. RESULTS: Of all 48,804 probes present in the array, 48,773 transcripts had sufficient data for further analysis. The list of genes that were differentially expressed (at least log2 FC > 2; P < .05 corrected for multiple testing) during the maintenance phase of VIT as well as after successful VIT contains 89 entities. The function of these genes affects cell signaling, cell differentiation, and ion transport. CONCLUSION: This study shows that a group of genes is differentially expressed both during and after VIT in comparison with gene expression in patients before VIT. Although the results of this study should be confirmed prospectively, the relevance of these findings is supported by the fact that they are related to putative mechanisms of immunotherapy.

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.

Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet.

BACKGROUND: Sustained and disease-modifying effects of sublingual immunotherapy have never before been confirmed in a large-scale randomized, double-blind, placebo-controlled trial. OBJECTIVE: We sought to investigate sustained efficacy 1 year after a 3-year period of daily treatment with the SQ-standardized grass allergy immunotherapy tablet Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU; ALK-Abelló, Hørsholm, Denmark). METHODS: A randomized, double-blind, placebo-controlled, phase III trial including adults with a history of moderate-to-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications. The analysis set comprised 257 subjects at the follow-up. Efficacy end points were rhinoconjunctivitis symptom and medication scores, quality of life, and percentages of symptom and medication free days. Immunologic end points included grass pollen-specific serum IgG4 and IgE-blocking factor. Safety was assessed based on adverse events. RESULTS: Significant improvements in efficacy were consistently shown during 3 years' treatment. One year after treatment, the active group showed sustained reductions in mean rhinoconjunctivitis symptom scores (26%, P < .001) and medication scores (29%, P = .022) when compared with placebo. This level was similar to the efficacy observed during the 3-year treatment period. The differences in percentages of symptom- and medication-free days were significant during and 1 year after treatment. The active group also reported sustained and significant improvements in quality of life. Sustained clinical benefit was accompanied by immunologic changes. No safety issues were identified. CONCLUSION: Three years of treatment with the SQ-standardized grass allergy immunotherapy tablet resulted in consistent clinical improvement and accompanying immunologic changes that were sustained 1 year after treatment, which is indicative of disease modification and associated long-term benefits.

Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years.

BACKGROUND: This is an interim analysis of a randomized, double-blind, placebo-controlled phase III trial with 3 years of daily treatment with grass tablet immunotherapy (GRAZAX; ALK-Abelló A/S, Hørsholm, Denmark) or placebo, followed by 2 years of follow-up to assess the persistent efficacy. OBJECTIVE: We sought to evaluate the efficacy and safety of specific immunotherapy with grass allergen tablets compared with placebo after treatment covering 2 consecutive grass pollen seasons. METHODS: The interim analyses included 351 adult participants with moderate-to-severe allergic rhinoconjunctivitis caused by grass pollen. Participants were treated with active (n = 189) or placebo (n = 162) tablets for an average of 22 months. All participants were allowed to use symptomatic rescue medication. RESULTS: The primary efficacy analysis showed highly significant mean reductions of 36% in rhinoconjunctivitis symptom score (P < .0001; median reduction, 44%) and 46% in rhinoconjunctivitis medication score (P < .0001; median reduction, 73%) in the active group relative to the placebo group. Mean rhinoconjunctivitis quality of life was 33% better (P < .0001; median, 40%). Clinical improvements were paralleled by significant changes in allergen-specific immunoglobulins. The treatment was well tolerated, and adverse events led to withdrawal in less than 1% of participants. There were no serious adverse events related to treatment. CONCLUSION: Grass allergen tablet immunotherapy showed progressive immunologic changes and highly significant efficacy over 2 years of continued treatment.

Biochemical markers predictive for bone marrow involvement in systemic mastocytosis.

Systemic mastocytosis is characterized by bone marrow involvement, which requires a bone marrow biopsy for diagnostic work-up. We questioned whether bone marrow involvement could be predicted using biochemical markers. We selected patients with various symptoms suggestive of indolent systemic mastocytosis, of whom 63 ultimately had bone marrow involvement. Patients suspected of aggressive mastocytosis, or mastocytosis associated with other hematologic diseases were excluded. Evaluation of 115 patients and 15 patient controls demonstrated a test accuracy for serum tryptase, urinary N(-) methylhistamine and N(-) methylimidazole acetic acid of 96%, 88% and 95% respectively. These markers provide an excellent pre-test probability of indolent systemic mastocytosis.

Effect of ciclesonide treatment on allergen-induced changes in T cell regulation in asthma.

BACKGROUND: The allergen-induced release of CCL17/thymus and activation-regulated chemokine (TARC) may be crucial in asthmatic airway inflammation by recruitment of Th2 cells. In addition, it might lead to aberrant Th2 cell activity through impairment of beta2-adrenergic receptor (beta2-AR) control. We questioned how chemokine patterns change upon allergen challenge and whether treatment with the inhaled steroid ciclesonide can reduce chemokine release and subsequently prevent allergen-induced changes in Th2 cell regulation and migration. METHODS: Asthma patients were double-blindly treated with placebo or 80 microg ciclesonide for 7 days. We studied allergen-induced changes in sputum chemokines, migration of peripheral blood T cells and control of beta2-agonist fenoterol over T cell migration and alpha-CD3/alpha-CD28-induced cytokine production. RESULTS: Treatment with 80 microg ciclesonide significantly diminished the late asthmatic response. The late asthmatic response was associated with increased sputum levels of CCL17 and CCL4 (but none of the other chemokines measured) and loss of beta2-AR control over T cell migration and Th2-type cytokine production. Although ciclesonide treatment did not prevent chemokine release nor altered beta2-AR function in circulating T cells, it exerted an inhibitory effect on TARC-induced T cell migration and alpha-CD3/alpha-CD28-induced cytokine production. CONCLUSION: Our data support the hypothesis that CCL17 is involved in allergen-induced dysregulation of Th2 cell migration and cytokine production. Ciclesonide treatment inhibits T cell migration and cytokine production upon allergen inhalation, which is regulated independently from reducing CCL17 release, but may contribute to beneficial effects of ciclesonide on Th2-mediated airway inflammation.

Mastocytosis in children: a protocol for management.

Mastocytosis is characterized by an increased number of mast cells with an abnormal growth and accumulation in one or more organs. In most children mastocytosis is limited to the skin (cutaneous mastocytosis) and often transient as compared with that in adults in whom mastocytosis is usually progressive and systemic. Generally, we recognize three more common forms of cutaneous mastocytosis: maculopapulous mastocytosis (formerly urticaria pigmentosa), mastocytoma of skin, and diffuse cutaneous mastocytosis. Childhood mastocytosis can further be divided into cutaneous mastocytosis (nonpersisting and persisting) and systemic mastocytosis (extremely rare). An approach to management using a set protocol is described in table form. In most cases of mastocytosis, only yearly checkups are necessary and no treatment is required; preventive recommendations are warranted in those individuals with systemic disease and constitutional symptoms. Symptomatic therapy is advised in only a minority of cases. This article is meant as a guideline for physicians involved in the care of children with mastocytosis and their parents.

Evaluation of impermeable covers for bedding in patients with allergic rhinitis.

BACKGROUND: Encasing bedding in impermeable covers reduces exposure to house-dust mites, but the clinical benefit of this intervention as part of mite-avoidance measures for patients with allergic rhinitis is not known. We performed a multicenter, randomized, placebo-controlled trial of one year of use of impermeable bedding covers in the bedrooms of patients with rhinitis who were sensitized to house-dust mites to determine the effects on the signs and symptoms of disease. METHODS: Three participating university medical centers enrolled 279 patients with allergic rhinitis who were randomly assigned to receive impermeable or non-impermeable (control) covers for their mattress, pillow, and duvet or blanket. At the start of the study, all participants received information on general allergen-avoidance measures. The severity of rhinitis was measured on a rhinitis-specific visual-analogue scale and by means of a daily symptom score and nasal allergen provocation testing. We also measured the concentrations of Dermatophagoides pteronyssinus (Der p1) and D. farinae (Der f1) in dust from patients' mattresses, bedroom floors, and living-room floors at base line and after 12 months as a measure of the efficacy of the intervention. RESULTS: A total of 232 patients completed the study. There was a significant reduction in Der p1 and Der f1 concentrations in the mattresses of the impermeable-cover group, whereas there was no significant reduction in the control group. However, there was no significant effect on the clinical outcome measures. Analyses of subgroups defined according to age, level of exposure, type and severity of sensitization, or characteristics of the patient's home had similar results. CONCLUSIONS: Mite-proof bedding covers, as part of a structured allergy-control program, reduced the level of exposure to mite allergens. Despite the success of the intervention, this single avoidance measure did not lead to a significant improvement of clinical symptoms in patients with allergic rhinitis.

Acute generalized exanthematous pustulosis caused by morphine, confirmed by positive patch test and lymphocyte transformation test.

Morphine, an opium alkaloid, frequently causes side effects such as hyperhidrosis and facial flushing, but serious cutaneous adverse drug reactions are seldom observed. Best known are urticaria, erythema, and pruritus; sometimes pseudoallergic anaphylactoid reactions, and blisters are reported.

Assessment of exposure to wheat flour and the shape of its relationship with specific sensitization.

OBJECTIVES: Dust and wheat-allergen exposure were assessed among bakers, flour millers, and bakery-ingredient producers, and the risk for sensitization was studied. METHODS: About 520 inhalable dust and wheat-allergen measurements were made among 270 Dutch workers. Data on sensitization to wheat and common allergens (atopy) were also available. Exposure was estimated according to the sector of industry, job title, and tasks. The shape of the relationship between sensitization and exposure was studied using a two-stage modeling approach: semi-parametric generalized additive modeling and, consequently, a simple description of the relationship using a parametric logistic model. To reduce the effect of exposure measurement errors (attenuation), a combination of the actual measured exposure and variance-weighted estimates of exposure was used. Results The effect of exposure to both inhalable dust and wheat allergens on sensitization was described best by a linear relationship in three industries and a quadratic relationship in one industry. The relation for the whole study population was best described as quadratic, and the probability of sensitization increased with exposure up to -2.7 mg/m3 for inhalable dust and approximately 25.7 microg EQ/m3 for wheat allergens. The risk decreased at higher exposures (P = 0.0121 and P = 0.0731 for dust and wheat, respectively). Atopy and sector of industry modified the sensitization risk significantly in all the analyses. Using a variant-weighted estimator to calculate exposures corrected for the bias and resulted in almost the same point risk estimators. Conclusions Exposure-response relationships for allergens may be nonlinear and differ between industries. A threshold is not indicated on which to base occupational exposure standards; alternatively, other approaches, such as benchmarking, seem warranted.

[Desensitisation to circumvent hypersensitivity reactions; treatment with docetaxel still possible]. / Desensitisatie om overgevoeligheid te omzeilen. Behandeling met docetaxel toch mogelijk gemaakt.

A 57-year-old woman with advanced non-small cell lung carcinoma developed hypersensitivity reactions to docetaxel. Measures taken to attempt the re-administration of docetaxel failed. For the differential diagnosis, an IgE specific to docetaxel (in terms of cross-reactivity with Taxus baccata), the solubilizing agent polysorbate 80, as well as the possibility of the reaction being non-IgE-mediated, were all considered. The latter was thought to be most likely. Desensitisation has been reported to be safe and effective in protecting patients from severe hypersensitivity reactions in both IgE- and non-IgE-mediated reactions. Desensitisation in this context means the induction of temporary clinical unresponsiveness to the culprit drug. The gradual reintroduction of small doses of the drug at fixed time intervals eventually allows delivery of full therapeutic doses. Desensitisation to docetaxel was successfully carried out in a supervised setting a total of three times in this patient.