Improvements in an oral aspirin challenge protocol for the diagnosis of aspirin hypersensitivity

Oral aspirin challenge (OAC) is used to confirm aspirin hypersensitivity (AHs) but there is no consensus on a standardized protocol. As a prior clinical history of adverse reactions to aspirin is poorly predictive of a positive result from formal aspirin challenge, many patients have an OAC performed. We retrospectively identified and prospectively validated how a 1-day OAC protocol could be modified, and patient selection improved, to deliver a safe and more efficient service. In a retrospective audit of 45 OACs using a 2 h dose interval, all reactions occurred within 90 min of the threshold dose. Forty OACs were then performed using a 90-min dose interval. This reduced the mean duration of a positive and negative OAC from 6 to 5 h and from 8 to 6 h, respectively. Histories of multiple manifestations of AHs were found in 91.6% (11) of those with asthma, 87.5% (7) with angiooedema, 70.6% (12) with rhinosinusitis, 63.6% (7) with chronic non-vasculitic urticaria and all with anaphylaxis, who developed a positive OAC. None of those with anaphylaxis, 8.3% (1) with asthma and 12.5% (1) with angiooedema, with a positive OAC, had a history of a single manifestation of AHs. The efficiency of an OAC service can safely be improved by reduction of the dose interval from 2 to 1 (1/2) h, and more targeted patient selection, as the likelihood of a positive OAC increases among patients with a history of asthma, angiooedoema or anaphylaxis with multiple manifestations of AHs.     

EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common causes of adverse drug reactions. Majority of them are of the hypersensitivity type. The two frequent clinical presentations of aspirin hypersensitivity are: aspirin-induced bronchial asthma/rhinosinusitis (AIA/R) and aspirin-induced urticaria/angioedema (AIU). The decisive diagnosis is based on provocation tests with aspirin, as the in vitro test does not hold diagnostic value as yet. Detailed protocols of oral, bronchial and nasal aspirin provocation tests are presented. Indications, contraindications for the tests, the rules of drug withdrawal and equipment are reviewed. Patient supervision and interpretations of the tests are proposed.     

Decreased apoptosis and distinct profile of infiltrating cells in the nasal polyps of patients with aspirin hypersensitivity

BACKGROUND: Patients with aspirin-hypersensitive rhinosinusitis/asthma suffer from a severe form of hyperplastic rhinosinusitis with recurrent polyposis. We aimed to assess the presence of apoptotic cells in nasal polyps from aspirin-hypersensitive (AH) and aspirin-tolerant (AT) patients with rhinosinusitis as related to the characteristics of local inflammation. METHODS: Nasal polyps obtained from 16 AH patients and 36 AT patients (17 atopic and 19 nonatopic) were stained for eosinophils and metachromatic cells, and in parallel immunocytochemistry was performed to detect CD45RO+, HLA-DR+, CD8+ and CD68+ positive cells. Apoptotic cells were detected by a nick-end labelling technique, TUNEL. RESULTS: The density of apoptotic cells in AH polyps (5.5 + 1.5 cells/mm2) was significantly lower as compared to both atopic (18.7 + 3.8 cells/mm2; P < 0.02;) and nonatopic (21.3 + 5.2 cells/mm2; P < 0.01) AT polyps. The number of eosinophils, mast cells, and CD45RO+ cells were significantly increased in AH compared to AT polyps (P < 0.001), and the density of HLA-DR+ cells in AH patients was higher than in nonatopic (P < 0.02), but not in atopic AT patients. While in AH patients the duration of rhinosinusitis correlated inversely with the number of apoptotic cells (r = - 0.67; P < 0.04), in contrast, in AT atopic patients the duration of rhinosinusitis showed positive correlation with apoptosis (r = 0.89; P < 0.003). CONCLUSIONS: We conclude, that decreased apoptosis of inflammatory cells in nasal polyps from ASA-hypersensitive patients, reflects a distinct mechanisms of local inflammation and may be related to persistence and severity of the disease in these patients.     

Delayed hypersensitivity reaction to paracetamol (acetaminophen)

We are reporting three patients who experienced delayed cutaneous reactions after treatment with paracetamol (acetaminophen). These reactions were confirmed in controlled challenge tests. Patch tests with paracetamol were positive in all patients. A biopsy performed of the case 1 patch test confirmed that the lesion was compatible with delayed hypersensitivity reaction-type allergic contact dermatitis.     

The accuracy of the diagnosis of suspected paracetamol (acetaminophen) hypersensitivity: results of a single-blinded trial

BACKGROUND: Hypersensitivity to paracetamol (acetaminophen) is rare and very few clinical data are available in the literature. MATERIALS AND METHODS: Eighty-four patients (28 males and 56 females, 5-70 years old) with a suspicion of paracetamol hypersensitivity were referred to our drug allergy clinic between May 1996 and May 2000. The reaction had occurred 1-96 months prior to the consultation. Single-blinded placebo-controlled oral challenges were carried out in 82 patients, under strict hospital surveillance. RESULTS: Most of the patients experienced skin eruptions 82/84 (97.6%), with 10 cases of anaphylactic shock (11.9%). Twenty-six (30.9%) reactions were immediate (occurring within the first hour after drug intake), 53 (63.1%) non-immediate and five could not remember. Oral provocation tests (OPT) demonstrated drug hypersensitivity in 11 patients only. The two patients not tested (due to a history of life-threatening reaction) were included in the positive group. Thus, 13 (15.5%) patients had paracetamol hypersensitivity and 71 (84.5%) had not. All the 13 positive patients had skin eruptions, five with anaphylactic shock. 9/13 had immediate reactions. Using OPT, 10 out of 11 had the same clinical reaction but more delayed. In both groups, whether hypersensitive to paracetamol or not: atopy was similar (7/13-53.8% and 31/71-43.7%), sex ratio was not different (M/F 0.3 and 0.5), 3/13 (23.1%) and 0/71 (0%) had aspirin/ibuprofen hypersensitivity. CONCLUSION: The clinical history of paracetamol (acetaminophen) hypersensitivity is rarely sufficient to set a firm diagnosis and only OPT can confirm this. Careful OPT reproduces the same symptoms (not more severe in our hands) with the same or slightly more delayed chronology. Atopy and sex are not risk factors.     

Ethanol as a cause of hypersensitivity reactions to alcoholic beverages

BACKGROUND: Adverse reactions after ingestion of alcoholic beverages are common. Metabolic differences in individuals and also the histamine content in alcoholic beverages have been implicated. By contrast pure ethanol has rarely been reported as a cause of hypersensitivity reactions and its mechanism has not been clarified yet. OBJECTIVE: To determine whether ethanol itself accounts for alcohol hypersensitivity in patients with anaphylactic reactions after alcohol intake. In search of possible pathomechanisms all patients were analysed by skin prick testing and sulfidoleukotriene production of peripheral leucocytes using ethanol and its metabolites. METHODS: Double-blind, placebo-controlled food challenges with a cumulated amount of 30 mL ethanol were performed in 12 adult patients with a positive history of adverse reactions after consumption of different alcoholic beverages. Skin prick tests and measurement of sulfidoleukotriene production were performed using different concentrations of ethanol and acetaldehyde from 50 to 1000 mm. RESULTS: Oral challenges with pure ethanol were positive in six out of eleven patients. All challenge-positive patients, but also four out of five challenge-negative patients, showed an increased sulfidoleukotriene production in-vitro compared with healthy controls. Skin prick tests using alcoholic beverages, ethanol, acetaldehyde and acetic acid were negative in all patients (12/12). CONCLUSION: Our study shows that ethanol itself is a common causative factor in hypersensitivity reactions to alcoholic beverages. These reactions occur dose-dependent and a non-IgE-mediated pathomechanism is likely, because skin prick tests were negative in all cases. Increased sulfidoleukotriene production was determined in some patients, but is no reliable predictor. Therefore oral provocation tests remain indispensable in making the diagnosis of ethanol hypersensitivity.     

Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland

BACKGROUND: Acetylsalicylic acid (ASA) and other nonsteroid anti-inflammatory drugs (NSAIDs) are reported to account for 21-25% of all adverse drug reactions. Some asthmatics may react to ASA and other NSAIDs with acute bronchoconstriction, profuse rhinorrhea and skin flushing. This is a distinct clinical syndrome called aspirin-induced asthma (AIA). The prevalence of AIA among asthmatic patients in Poland has not been previously assessed. METHODS: A questionnaire survey of 12,970 adults of both sexes, randomly selected from the population of Poland. RESULTS: The prevalence of AIA in the general population of Poland was estimated as 0.6%. Thirty patients (4.3%; 95% CI: 2.8-5.8) of 703 asthmatics (5.4% of general population) reported symptoms attesting to hypersensitivity to aspirin. In 27% of them the reactions were precipitated by aspirin, whereas in the remaining subjects by other NSAIDs. CONCLUSIONS: The prevalence of AIA in Poland is 4.3%, being somewhat lower than in Finland and Australia, where it was recently reported to account for 8.8 and 10.9% of the adult asthmatics, respectively. These figures indicate that aspirin hypersensitivity might be a significant community problem.     

Hypersensitivities to non-steroidal anti-inflammatory drugs

NSAIDs are the most commonly used medications worldwide and are responsible for almost 25% of adverse drug reactions. Such reactions can have different manifestations and can be immunologic or non-immunologic. The diagnosis is primarily based on the medical history, which can be difficult in patients receiving multiple medications. Because skin testing and blood tests are not valid for NSAIDs reactions, confirmation requires an appropriately-designed challenge. The latter could be avoided when the history is obvious and the reaction is life-threatening. The challenge route can be oral, nasal, or bronchial. Avoidance of the causative NSAID, often associated with the avoidance of the cross-reacting preparations, is the cornerstone of management. In most cases, a safe substitute can be used. When treatment with the causative NSAID is necessary, titrated desensitization can be performed. This review discusses the classes of NSAIDs, mechanisms of their adverse reactions, manifestations, diagnosis, and management.     

Characteristics of subjects experiencing hypersensitivity to non‐steroidal anti‐inflammatory drugs: patterns of response

Background Non‐steroidal anti‐inflammatory drugs (NSAIDs) are one of the most frequently involved groups of medicines in hypersensitivity drug reactions. Two mechanisms can induce the reaction: immunological (sensitization) due to a specific IgE or T cell response and pharmacological (cyclooxygenase inhibition). The contribution of each of these mechanisms to the reactions is not well known. Objective To analyse a large group of subjects with confirmed hypersensitivity reactions to NSAIDs. Methods The drugs involved, the clinical entities induced and the time interval between drug intake and appearance of the reaction were studied. In cases where the diagnosis was not confirmed, a drug provocation test was carried out. Atopy status was also assessed with prick test and total IgE in serum. Results A total of 659 patients were finally considered to have had hypersensitivity reactions to NSAIDs; 76% had cross‐intolerance (CI) and 24% were selective responders (SR). The most important drugs involved in CI were propionic acid derivatives, in most cases ibuprofen, and in SR pyrazolones. In CI, the most frequent clinical entity was urticaria and angio‐oedema and to a lesser extent airway involvement. The skin and airways were both involved in an important proportion of cases. The most frequent entities in SR were urticaria and/or angio‐oedema followed by anaphylaxis. Atopy was significantly associated in the CI group (P<0.005). Conclusion and Clinical Relevance Cutaneous hypersensitivity reactions by CI to NSAIDs are the most frequent entities induced by these compounds. In addition to aspirin, other NSAIDs are taking on a predominant role. Atopy can be a predisposing factor in patients with CI. Cite this as: I. Doña, N. Blanca‐López, J. A. Cornejo‐García, M. J. Torres, J. J. Laguna, J. Fernández, A. Rosado, C. Rondón, P. Campo, J. A. Agúndez, M. Blanca and G. Canto, Clinical & Experimental Allergy, 2011 (41) 86–95.     

Cross-reactivity between human adenoviruses in delayed-type hypersensitivity

The aim of this study was to determine the antigen responsible for the induction of delayed-type hypersensitivity (DTH) by human adenoviruses (Ads). The estimation of DTH was based on measurement of the extent of swelling of the hind footpads of mice. CsCl density gradient-purified human Ad serotype 6 (Ad6) induced DTH in a dose-dependent manner. In Ad6-sensitized mice, DTH could be elicited by serotypes belonging to the same species of human Ads (types 1 and 5) and by a serotype (type 3) belonging to another species. Latex particles coated with purified hexon antigen prepared from Ad5 had the capacity to sensitize mice and elicit a DTH reaction. We suggest that, for serotypes belonging to species C, the cross-reactive highly conserved T cell epitope of the hexon protein might be responsible for the DTH induction, and furthermore the same epitope might result in the cross-reactivity between serotypes 3 and 6. The possible importance of these data is discussed in relation to human gene therapy through the application of Ad vectors.     

Lipoxin A4 generation is decreased in aspirin-sensitive patients in lysine-aspirin nasal challenge in vivo model

Background: Lipoxins represent a group of lipoxygenase derived eicosanoids which, in contrast to leukotrienes, are potent anti‐inflammatory mediators. The aim of our study was to determine lipoxin A₄ (LXA₄) and leukotriene C₄ (LTC₄) levels in nasal lavages after intranasal challenge with aspirin in aspirin intolerant (AIA) in comparison to aspirin tolerant (ATA) asthmatics and after allergen challenge in patients suffering from allergic rhinitis. Methods: Twelve AIA, 8 ATA and 20 allergic patients were challenged with placebo, 16 mg of lysine‐aspirin (Lys‐ASA) or allergen (grasses). Nasal lavages were collected and eicosanoids’ levels were determined using ELISA. Results: Clinically positive Lys‐ASA challenge in AIA resulted in influx of leukocytes (eosinophils and basophils) to nasal secretions and increase of LTC₄ to 106.82 pg/ml (P < 0.05 vs baseline (26.58 pg/ml)) on first hour after the challenge. We did not observe any differences in LTC₄ level before and after ASA challenge in ATA. In AIA group the mean level of LXA₄ was 43 ± 21.5 pg/ml after placebo and decreased in 2 h after Lys‐ASA challenge (29 ± 17 pg/ml, P = 0.015). We found an increase in LXA₄ in ATA after ASA provocation as compared to placebo (33 ± 16 pg/ml vs 52 ± 31 pg/ml, P = 0.046). In atopic patients baseline level of LXA₄ was 33.49 ± 16.95 pg/ml with no difference after the clinically positive allergen challenge (36.22 ± 13.26 pg/ml, P = 0.23). Conclusions: Results of our study confirm that AIA have diminished LXs’ biosynthesis capacities in vivo after ASA challenge. Taking into consideration anti‐inflammatory properties of lipoxins this phenomenon may be partially responsible for the development of chronic inflammation in AIA patients.     

Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity

Purpose

Identification of tolerable alternative analgesics is crucial for management in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients. We investigated cross-reactivity of acetaminophen and celecoxib according to the type of aspirin/NSAID hypersensitivity and aimed to determine the risk factors for cross-intolerance.

Methods

We retrospectively reviewed the medical records of patients intolerant to aspirin and NSAIDs who had undergone an acetaminophen and/or celecoxib oral provocation test. Aspirin/NSAID hypersensitivity was classified into 4 types according to a recently proposed classification: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated chronic urticaria (AECU), aspirin-induced acute urticaria/angioedema (AIAU), and NSAID-induced blended reaction (NIRD).

Results

A total of 180 patients with hypersensitivity to aspirin and NSAIDs were enrolled; 149 acetaminophen provocation test results and 145 celecoxib provocation test results were analyzed. The overall cross-reaction rates to acetaminophen and celecoxib were 24.8% and 10.3%, respectively. There was a significant difference in the cross-reactivity to acetaminophen according to the type of NSAID hypersensitivity. Cross-reactivity to acetaminophen was highest in the AECU group (43.9%), followed by the AERD (33.3%), NIBR (16.7%), and AIAU (12.5%) groups. Underlying chronic urticaria was more prevalent in patients with cross-intolerance to both acetaminophen (P=0.001) and celecoxib (P=0.033). Intolerance to acetaminophen was associated with intolerance to celecoxib (P<0.001).

Conclusions

Acetaminophen and celecoxib may induce adverse reactions in a non-negligible portion of aspirin/NSAID-sensitive patients. Physicians should be aware of the possible cross-reactions of these alternative drugs and consider an oral challenge test to confirm their tolerability.     

消炎痛对醋氨酚所致小鼠肝脏损伤的保护作用

消炎痛预处理对醋氨酚所致小鼠肝损伤有明显的保护作用。300mg/kg剂量的醋氨酚引起严重的肝损伤,如果在给醋氨酚前24小时皮下一次注射消炎痛(10mg/kg),则损伤明显减轻。经消炎痛预处理动物的SGPT由对照的组1666±43下降到554±153 u/100ml,组织学检查也明显减轻,500mg/kg剂量的醋氨酚引起的死亡率由90％降到45％。小鼠经苯巴比妥钠(80mg/kg)处理三天,以增加细胞色素P_(450)含量,此时醋氨酚引起的肝损伤加重,且由消炎痛诱导的肝保护作用被消除。     

Confirmed prevalence of food allergy and non-allergic food hypersensitivity in a Mediterranean population

Background Until the present, no comprehensive studies evaluating the prevalence of food allergy and non‐allergic food hypersensitivity (FA/NAFH) in adults have been done in Turkey or its surrounding countries. Objective This large population‐based study was planned to identify the confirmed prevalence of adverse reactions to food in adults in Istanbul. Methods A total of 17 064 telephone numbers were randomly selected from both the European and Asian sides of Istanbul, and the 11 816 subjects who agreed to participate in the study were addressed with a questionnaire of eight items. Those who disclosed food‐related complaints in this survey were called again and a similar questionnaire was repeated. The respondents who were suspected of having food allergy or food hypersensitivity were invited for a personal clinical investigation that included double‐blind, placebo‐controlled food challenge tests. Results The lifetime prevalence of self‐reported FA/NAFH was found to be 9.5% [1118/11 816; 95% confidence interval (CI): 8.94–10.00%]. After the clinical investigations, the point prevalence of FA/NAFH, which also included the ‘possible FA/NAFH group’, was found to be as low as 0.3% (30/11 816; 95% CI: 0.17–0.36%), and the FA/NAFH rates assessed by double‐blind, placebo‐controlled food challenge tests were 0.1% (12/11 816; 95% CI: 0.05–0.18%) and 0.1% (11/11 816; 95% CI: 0.05–0.17%), respectively. The most significant factor influencing FA/NAFH was familial atopy (adjusted OR 4.3; 95% CI: 3.67–4.99), and the most related atopic disease was itching dermatitis/urticaria (adjusted OR: 3.9; 95% CI: 3.31–4.54). Conclusion We may conclude that FA/NAFH in the Turkish population seems to be low when compared with Northern and Western European countries. This may be due to genetic, cultural or dietary factors, and further studies evaluating the reasons for this low prevalence of FA/NAFH in our population are needed.     

Food allergy and non-allergic food hypersensitivity in children and adolescents

BACKGROUND: Previous studies have shown a 10-fold discrepancy of self-reported food-induced symptoms and physician-diagnosed food hypersensitivity. Little information is available on the prevalence of food hypersensitivity in unselected paediatric populations. No data were available for German children. OBJECTIVE: To study the perception of food-induced symptoms in the paediatric population, to investigate the allergens accused, to objectify patients' reports, and to identify subgroups at risk of having food-induced allergy (FA) or non-allergic food hypersensitivity (NAFH) reactions. METHODS: This paper presents the data of the paediatric group (0-17 years) of a representative, randomly sampled, cross-sectional population-based survey studying 13 300 inhabitants of the German capital city Berlin regarding food-related symptoms. Instruments included mailed questionnaires, structured telephone interviews, physical examination, skin-prick tests, specific serum IgE and standardized, controlled and blinded oral food challenges. RESULTS: Two thousand three hundred and fifty-four individuals were contacted by mailed questionnaire, 739 (31.4%) responses could be fully evaluated. Four hundred and fifty-five (61.5%) participants reported symptoms related to food ingestion, 284 (38.4%) affirmed reproducible symptoms in the standardized telephone interview. One hundred and eighty-four (24.8%) individuals were fully examined. Reproducible symptoms to food were found in 31 (4.2%) children and adolescents: 26 (3.5%) showed symptoms of FA and five (0.7%) of NAFH. The oral allergy syndrome was most often observed. Foods most commonly identified by oral challenges were apple, hazelnut, soy, kiwi, carrot and wheat. CONCLUSION: The perception of food-related symptoms is common among children and adolescents from the general population. Self-reports could be confirmed in around one out of 10 individuals, still resulting in 4.2% of proven clinical symptoms. However, most reactions were mild and mainly because of pollen-associated FA, while NAFH reactions were less common. Severe IgE-mediated FA was observed in individuals with pre-existing atopic disease, who should be fully investigated for clinically relevant FA.