Placebo-controlled Provocation Test Research Articles

Non-celiac gluten/wheat sensitivity (NCGS)-acurrently undefined disorder without validated diagnostic criteria and of unknown prevalence: Position statement of the task force on food allergy of the German Society of Allergology and Clinical Immunology (DGAKI).

Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist’s and nutritionist’s point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.

Skin manifestations of a case of phenylbutazone-induced serum sickness-like reactions

Serum sickness consists of a systemic reaction resulting from the formation of soluble circulating immunocomplexes after the introduction of a foreign substance into the body We studied a 38-year-old woman diagnosed with anxiety, depression and right sacroileitis who was treated with phenylbutazone, ranitidine, clomipramine and levomepromazine. After taking this treatment for 1 month, she presented with fever, diarrhea, localized edemas, generalized pruritic papular and erythematous rash and lymphadenopathies. She presented the same symptoms after oral intake of metamizole. The diagnosis was confirmed following a single-blind, placebo-controlled provocation test with phenylbutazone and a biopsy of the affected skin.

Challenge-proven aspirin hypersensitivity in children with chronic spontaneous urticaria.

Nonsteroidal anti-inflammatory drug (NSAID) exacerbated cutaneous disease is defined as the exacerbation of wheals and/or angioedema in patients with a history of chronic spontaneous urticaria (CSU). The objective of this study was to define 'aspirin-hypersensitive' children and adolescents in a clearly defined group of patients with CSU and to describe their clinical features. Eighty-one children with a history of CSU were enrolled over a 3-year period. The daily or almost daily (>4days a week) presence of urticaria was defined as 'chronic persistent urticaria' (CPU), while the presence of urticaria for 2-4days a week was defined as 'chronic recurrent urticaria' (CRU). Single-blind, placebo-controlled provocation tests (SBPCPTs) with aspirin were performed for children with CSU. Patients with CRU had a longer duration of cutaneous symptoms [1.6 (0.5-4) vs 0.6 (0.3-1.5) years], and stress was less frequently experienced as an eliciting factor in patients with CRU compared with the patients with CPU (P<0.016, P=0.024, respectively). SBPCPTs with aspirin revealed that 14 of 58 patients (24%) with CPU and one of 10 patients with CRU (10%) were aspirin hypersensitive. Aspirin hypersensitivity rate was 26.5% in patients <12years of age. All of the 15 aspirin-hypersensitive patients (aged between 6.6 and 17.4years), except for three, experienced an unequivocal angioedema of the lips as a positive reaction in SBPCPT. Nearly a quarter of children and adolescents with CSU were hypersensitive to aspirin. For children with chronic urticaria, determination of NSAID hypersensitivity in a well-controlled clinical setting will help to avoid severe drug hypersensitivity reactions.

Letter to the Editor: Two Major Phenotypes of Sulfite Hypersensitivity: Asthma and Urticaria

The sulfites are widely used as anti-browning agents and preservatives in food, cosmetics and medicine. The use and amount of sulfites in products have recently been regulated by the Food and Drug Administration (FDA) and the Korean FDA; however, sulfite hypersensitivity reactions, ranging from bronchoconstriction,1 urticaria,2 contact dermatitis3 to life threatening anaphylaxis,4 are still being reported.5 To date, this is the first study to compare two major phenotypes of sulfite hypersensitivity, asthma and urticaria, in this country. Moreover, we carefully analyzed the clinical features of sulfite sensitive asthma, and compared them with those of sulfite tolerant asthma. We retrospectively analyzed the medical records of 26 sulfite hypersensitivity subjects confirmed by a sulfite oral provocation test (OPT). As a control group, 61 asthmatic patients negative to sulfite OPT were enrolled from Ajou University Hospital, Suwon, Korea. We performed sulfite oral provocation test on the subjects who were resistant to conventional treatment of asthma/urticaria or who had histories of allergy to sulfite containing food such as wine, dried fruits, or salads from buffet. To confirm sulfite sensitivity, we conducted single blind placebo controlled provocation test. After the asthmatic patients showed no response to gelatin capsule (EMBO CAPS lot. 051A51-22306, Suheung Capsule, Seoul, Korea) with 2 hours observation, they were administered sodium metabisulfite (Na2S2O5; Sigma Co., St. Louis, MO, USA) starting from 40 mg and increasing to 100-200 mg via gelatin capsule vehicle. The reactions were observed for 2 hours each until the hypersensitivity reactions developed,1 maximally 6 hours. Especially for bronchoconstriction reaction, 1) a decline in FEV1 of 20% or greater, or 2) a decline in FEV1 of 15% to 20% compared to the baseline with definite symptoms/signs of sulfite hypersensitivities (such as wheezing, cough or dyspnea) were considered positive. Pulmonary function tests were repeated at 30 minute intervals.6 In the case of urticarial reaction, sulfite OPT was defined as positive when hives arise; however, it was classified as negative if subjective pruritus developed. Subjects were classified into group I: sulfite sensitive asthma, group II: sulfite sensitive urticaria and group III: sulfite tolerant asthma according to their sulfite OPT reaction. In addition, group I included two patients with concurrent sulfite anaphylaxis. Sulfite sensitive asthma was a more common phenotype of sulfite hypersensitivity than sulfite sensitive urticaria (69.2% vs. 30.8%). Chronic asthma was more common in group I, as previously reported;6 however, chronic urticaria was more common in group II. Group II subjects required significantly higher provocative dosage of sulfite (187.5±35.4 mg vs. 114.4±60.0 mg, p=0.006) and a longer time (100±37.4 min vs. 54.2±34.8 min, p=0.008) to induce hypersensitivity reactions compared with group I subjects. A previous history of adverse reactions was found in 44.4% of group I and 62.5% of group II, being different from previous studies that enrolled subjects with a history of sulfite hypersensitivities (Table 1).1,7 Table 1 Comparison of Clinical Characteristics between Group I and II There were no significant differences in asthma-related parameters-such as atopic status, total IgE level, peripheral eosinophil count, FEV1% and metacholine PC20 level when the clinical characteristics were compared between group I and group III. The prevalence of severe asthma according to American Thoracic Society guidelines was significantly higher in group I than as previously reported in group III (44% vs. 16%, p=0.023).1,8 The asthma exacerbation related hospitalization rate (≥1 times/yr), emergency room visit (≥1 times/yr) and oral steroid burst (≥3 times/yr) were significantly higher in group I than in group III (66.7% vs. 24.6%, p=0.001; 66.7% vs. 24.6%, p=0.001; 55.6% vs. 17.3%, p=0.003). Many potential mechanisms of sulfite hypersensitivity have been postulated. Sulfite oxidase deficiency has been suggested as one of the mechanisms.5 Most asthmatic patients could show a sensitivity to SO2 exposure due to bronchial hypersensitivity.9 However, not all asthmatic patients with severe clinical symptoms presented sulfite hypersensitivity in this study, due to their higher prevalence of severe asthma and more frequent episodes of acute exacerbation compared to sulfite tolerant asthma. We speculate that these findings are due to individual variability of sulfite oxidase inactivity.1 It would, therefore, be helpful to investigate individual factors, including genetic factors, in order to better understand the mechanism of sulfite hypersensitivity. We report herein two major phenotypes of sulfite hypersensitivity, asthma and urticaria in Korea. Considering high prevalence of severe asthma and frequent health care utilization rate in patients with sulfite sensitive asthma, sulfite OPT can be considered as a screening test to identify exacerbating factors for severe asthma patients regardless of history of hypersensitivity reaction.

Anstrengungsinduzierte Anaphylaxie

Exercise-induced anaphylaxis is a mast cell dependent reaction, which is induced by allergen exposure in combination with physical activity. Typically, the reaction occurs within 2 hours after allergen exposure followed by physical activity. Not only food allergens but all kinds of allergens including drugs can induce this form of anaphylaxis. The clinical symptoms of exercise-induced anaphylaxis are the same as in any other type of anaphylaxis. Thus not only the skin and mucosa but also other organ systems like the lungs, cardiovascular system and gastrointestinal tract can be affected. The diagnostic work up should cover a detailed clinical history including the assessment of symptoms and possible trigger factors including suspected allergens. Besides classical allergy diagnostics like skin prick tests and specific IgE determination, tryptase should be measured for the differential diagnosis to exclude mast cell dependent diseases. The diagnosis of exercise-induced anaphylaxis is made by the means of a double-blind placebo-controlled provocation test. Both, a sufficient amount of allergen and of physical activity must be achieved for a valid test. After the diagnosis is made, patients should be extensively counseled and provided with an emergency kit including an epinephrine auto injector.

Skin Prick Test Reactivity to Supplemental Enzymes in Cystic Fibrosis and Pancreatic Insufficiency

Patients with cystic fibrosis and pancreatic insufficiency take supplemental pancreatic enzymes of porcine or plant origin on a daily basis. The frequency of immediate skin prick hypersensitivity reactions to such enzymes and the correlations to gastrointestinal symptoms and nutritional status were assessed in a single center prospective descriptive study. Skin prick tests using five different freshly prepared porcine pancreatic enzyme preparations, one enzyme preparation of fungal origin, porcine meat and cat epithelia were performed in patients with cystic fibrosis and pancreatic insufficiency and in healthy control subjects. Positive skin tests in the 48 patients with cystic fibrosis were no more frequent than in 21 control subjects. No correlations with the frequency of gastrointestinal symptoms, nutritional status and lung function were found. Although immediate hypersensitivity reactions to pancreatic enzyme preparations in subjects with cystic fibrosis are not common, individuals with possible allergic reactions to supplemental enzymes should be identified by skin prick tests and in unclear cases by double-blind placebo-controlled provocation tests.

Multiple NSAID intolerance in chronic idiopathic urticaria is correlated with delayed, pronounced and prolonged autoreactivity.

Autologous serum skin test (ASST) reactivity is positive in up to 60% of patients with chronic idiopathic urticaria (CIU). About 21 to 30% of patients with CIU have intolerance to acetyl salicylic acid (ASA) and/or other chemically unrelated non-steroidal anti-inflammatory drugs (NSAIDs). To investigate the relationship between ASA/NSAID intolerance and ASST reactivity, a case-control study was performed in 110 patients with CIU and 60 healthy controls. A positive ASST was defined as an erythematous wheal with a diameter of > 5 mm more than the saline-induced response. Patients were assessed at 10-minute intervals for a minimum of three hours. ASA/NSAID intolerance was ascertained by a placebo controlled-provocation test with offending drug (s). Forty-two patients with CIU (38.2%) had autoreactivity whereas only two of the controls (3.3%) displayed early and weak skin responses (P<.0001). ASA/NSAID intolerance was demonstrated in 30 (27.3%) patients with CIU. The prevalences of autoreactivity were 93.3% (28/30) and 17.5% (14/80) in patients with and without ASA/NSAID intolerance, respectively (P<.001). Thirteen of the 25 ASST-positive patients (52%) who had single (n: 7) or multiple (n: 6) NSAID intolerance showed early (before or at 30 min) and mild autoreactivity of short duration, whereas 15 of the remaining 17 ASST-positive patients (88.2%) who all had multiple NSAID intolerance showed delayed (later than 30 min) and prolonged autoreactivity (P<.05). These findings suggest that a common mechanism may be responsible for the pathogeneses of both delayed autoreactivity and multiple NSAID intolerance in CIU. It might be further speculated that delayed, prolonged, and pronounced autoreactivity may be a possible predictor for multiple NSAID sensitivity in CIU.