Flow-based basophil activation test in immediate drug hypersensitivity. An EAACI task force position paper.

Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus-based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug-specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti-inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory.

Local anesthetics allergy: who should be tested?

Summary: Objective. To document the test results of patients referred to our clinic for testing with local anesthetics (LAs) in real life conditions and provide data related to the necessity of these tests. Methods. All consecutive subjects who were referred to be evaluated for LA allergy during a two-year follow up were included in the analysis. All subjects underwent skin prick / intradermal tests followed by a subcutaneous provocation test with the LAs tested. Results. A total of 228 subjects were included. The main referral reason was the presence of a history of drug hypersensitivity reaction (DHR) to drugs other than LAs (n = 128; 56%), whereas a history of LA allergy constituted the second most common referral reason (n = 64, 28.1%). In the majority of cases (n = 39; 60.9%), the culprit LA was not known by the patients. Asthma was the third most common referral reason, presented in 49 cases (21.5%). Ten cases had positivity to the tested LA in skin testing / challenges. Nine out of 10 patients had a history of DHR to drugs other than LA, whereas 5 of them had also a history of DHR to LA. Six of the 10 patients had a history of multiple DHR. None of the asthma patients without any DHR history were positive in the LA tests. Eight out of 10 cases who underwent skin testing / challenge with an alternative LA, tolerated the alternative LA. Conclusion. The most common referral reason for testing with LA was a history of DHR to drugs other than LAs, whereas asthma was the third most common referral reason. Patients with a history of multiple DHR may be considered for testing with LAs. Asthmatics and those with other allergic diseases without a history of drug / LA allergy do not need to be tested with LA.

How do patients with asthma and COPD behave during fasting?

BACKGROUND-OBJECTIVE: Several factors might affect the adherence to treatment in patients with asthma and COPD. Among these factors, the effect of religious beliefs and behaviours has been less studied so far. In this study, the effect of fasting on drug use behaviours of patients with asthma and COPD were comparatively analysed. METHODS: A total of 150 adult patients with asthma and 150 adult patients with COPD were consecutively enrolled into this cross-sectional study. The patients were asked whether they fast during Ramadan and if the answer was yes, they were kindly asked to respond to further questions related to use of inhaled medications during that particular time. RESULTS: The majority of the cases from both groups [98 (65.3%) of asthma patients and 139 (92.6%) of COPD] were fasting during Ramadan. The majority of the patients with COPD (n = 126; 90.6%) reported that they quitted their regular therapy basis during Ramadan. On the other hand, the majority of asthma patients used their controller inhaled medications during Ramadan and preferred to use them on iftar and sahur times (n = 81, 82.6%). CONCLUSION: Our results showed that in a Muslim population, the patients with asthma and COPD do not feel their diseases to be an inhibitory factor for fasting during Ramadan. However, fasting seems to be an important determining factor in medication compliance by modifying the drug use behaviours in each group in a different way. Therefore, the patients should be informed about the effects of fasting on their disease and the allowed drugs during fasting

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How do patients with asthma and COPD behave during fasting?

BACKGROUND-OBJECTIVE: Several factors might affect the adherence to treatment in patients with asthma and COPD. Among these factors, the effect of religious beliefs and behaviours has been less studied so far. In this study, the effect of fasting on drug use behaviours of patients with asthma and COPD were comparatively analysed. METHODS: A total of 150 adult patients with asthma and 150 adult patients with COPD were consecutively enrolled into this cross-sectional study. The patients were asked whether they fast during Ramadan and if the answer was yes, they were kindly asked to respond to further questions related to use of inhaled medications during that particular time. RESULTS: The majority of the cases from both groups [98 (65.3%) of asthma patients and 139 (92.6%) of COPD] were fasting during Ramadan. The majority of the patients with COPD (n=126; 90.6%) reported that they quitted their regular therapy basis during Ramadan. On the other hand, the majority of asthma patients used their controller inhaled medications during Ramadan and preferred to use them on iftar and sahur times (n=81, 82.6%). CONCLUSION: Our results showed that in a Muslim population, the patients with asthma and COPD do not feel their diseases to be an inhibitory factor for fasting during Ramadan. However, fasting seems to be an important determining factor in medication compliance by modifying the drug use behaviours in each group in a different way. Therefore, the patients should be informed about the effects of fasting on their disease and the allowed drugs during fasting.

Drug allergy in tertiary care in Turkey: results of a national survey. The ADAPT study: adult drug allergy perception in Turkey.

BACKGROUND: No data are available on the incidence of drug hypersensitivity (DH) reactions in outpatient settings of tertiary allergy/immunology clinics. Our aims were to document the frequency of outpatient hospital admissions due to DH reactions to allergy/immunology clinics in adults and the management of these reactions in real life. We also investigated whether drug allergy affected social and medical behaviours of the patients. METHODS: This multi-centre study was performed for one year with the participation of 11 out of 16 tertiary allergy/clinical immunology clinics in Turkey. The study group consisted of the patients with DH reactions. Results of a questionnaire including drug reactions and management were recorded. RESULTS: Among 54,863 patients, 1000 patients with DH were enrolled with a median of 2.1% of all admissions. In real life conditions, the majority of approaches were performed for finding safe alternatives (65.5%; 1102 out of 1683) with 11.7% positivity. Diagnostic procedures were positive in 27% (154/581) of the patients. The majority of the patients had higher VAS scores for anxiety. A total of 250 subjects (25%) reported that they delayed some medical procedures because of DH. CONCLUSION: Our results documented the frequency of admissions due to DH reactions to allergy/clinical immunology clinics for the first time. Although physicians mostly preferred to perform drug tests in order to find safe alternatives, considering the fact that DH was confirmed in 27% of the patients, use of diagnostic tests should be encouraged, if no contraindication exists in order to avoid mislabelling patients as DH.

Challenge-proven nonsteroidal anti-inflammatory drug hypersensitivity in children.

BACKGROUND: Few studies investigated hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) in children. The objective was to determine the frequency of true NSAID hypersensitivity (NSAID-H) and whether there were any parameters in the history of children that would predict NSAID-H. Secondly, an investigation was conducted into whether NSAID-hypersensitive children could tolerate safe alternatives. Differing from previous studies, the researchers followed the recent diagnostic algorithm proposed for acute reactions in NSAID-H. METHODS: Children with a history suggesting NSAID-H were evaluated by an allergist. The patients with a single NSAID in history were tested first with a skin prick test and if negative challenged with the culprit NSAID. The patients who had reactions with multiple NSAIDs were directly challenged with their culprit drugs. Safe alternatives in children with a confirmed NSAID-H were found by oral provocation tests (OPTs). RESULTS: Fifty-eight of 61 patients participated in the study. Thirty-eight patients (65.5%) described a reaction to a single NSAID and 20 mentioned reactions with ≥2 different NSAIDs. Single-drug-induced and cross-reactive NSAID-Hs were proven in 5 of 36 (14%) and 8 of 18 (44%) of patients, respectively. Acetaminophen and nimesulide were tolerated in 60% and 88.8% of the study patients as safe alternatives, respectively. Family history of NSAID-H was found as the only significant predictor of OPT (OR: 5.4; 95% CI: 1.02-28.6). CONCLUSION: Histories of both single and multiple NSAID-Hs are poor predictors of actual drug hypersensitivity. Therefore, diagnostic tests should be performed in all children if no contraindication exits. Family history of NSAID-H is the only significant parameter predicting OPT results.

Are drug provocation tests still necessary to test the safety of COX-2 inhibitors in patients with cross-reactive NSAID hypersensitivity?

Background: COX-2 inhibitors are safe alternatives in patients with cross-reactive non-steroidal anti-inflammatory drug (NSAID) hypersensitivity. These drugs are recommended to these patients after negative drug provocation tests (DPTs). However, cumulative data on encouraging results about the safety of COX-2 inhibitors in the majority of these patients bring the idea as to whether a DPT is always mandatory for introducing these drugs in all patients with cross-reactive NSAID hypersensitivity. Objective: To document the safety of COX-2 inhibitors currently available and to check whether or not any factor predicts a positive response. Methods: This study included the retrospective analysis of cases with cross-reactive NSAID hypersensitivity who underwent DPTs with COX-2 inhibitors in order to find safe alternatives. DPTs were single-blinded and placebo controlled. Results: The study group consisted of 309 patients. COX-2 inhibitors were well tolerated in the majority of the patients [nimesulide: 91.9%; meloxicam: 90.2%; rofecoxib: 94.9%; and celecoxib: 94.9%)]. Twenty-five patients (30 provocations) reacted to COX-2 inhibitors. None of the factors were found be associated with positive response. Conclusion: Our results suggest to follow the traditional DPT method to introduce COX-2 inhibitors for finding safe alternatives in all patients with cross-reactive NSAID hypersensitivity before prescription as uncertainty of any predictive factor for a positive response continues. However, these tests should be performed in hospital settings in which emergency equipment and experienced personnel are available (AU)

Triggers of asthma and COPD: are they different?

BACKGROUND: Asthma symptoms can be triggered by a variety of factors commonly referred to as "triggers". Some of these factors can also induce severe asthma exacerbations. Thus, it can be assumed that actions taken against such triggers may prevent the progression of the disease. However, limited data exist on the clinical importance of these triggers in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To compare the effect of triggers on symptoms and actions taken against certain modifiable triggers in patients with asthma and COPD. METHODS: The study was conducted in a university hospital between June 2009 and June 2010. Patients with asthma and COPD were asked to complete a questionnaire in which both the factors triggering symptoms and the actions taken against several triggers were assessed. RESULTS: Three hundred consecutive adult patients (150 asthma, 150 COPD) were enrolled to the study. The frequency of triggering factors was similar in both groups. Vaccination rates for influenza and pneumococcus were significantly higher in patients with COPD. However, such anti-allergic approaches as the use of strategies to decrease dust exposure, the use of anti-mite bed sheets, and the removal of pets from the home were more commonly employed by asthmatic patients. CONCLUSION: This study revealed that certain triggers affected COPD and asthma patients to the same degree. Therefore, triggers and strategies for controlling modifiable triggers should be more concentrated on during education in both groups. However, the preventive effect of these strategies on disease progression, particularly in patients with COPD, needs clarification.

Are drug provocation tests still necessary to test the safety of COX-2 inhibitors in patients with cross-reactive NSAID hypersensitivity?

BACKGROUND: COX-2 inhibitors are safe alternatives in patients with cross-reactive non-steroidal anti-inflammatory drug (NSAID) hypersensitivity. These drugs are recommended to these patients after negative drug provocation tests (DPTs). However, cumulative data on encouraging results about the safety of COX-2 inhibitors in the majority of these patients bring the idea as to whether a DPT is always mandatory for introducing these drugs in all patients with cross-reactive NSAID hypersensitivity. OBJECTIVE: To document the safety of COX-2 inhibitors currently available and to check whether or not any factor predicts a positive response. METHODS: This study included the retrospective analysis of cases with cross-reactive NSAID hypersensitivity who underwent DPTs with COX-2 inhibitors in order to find safe alternatives. DPTs were single-blinded and placebo controlled. RESULTS: The study group consisted of 309 patients. COX-2 inhibitors were well tolerated in the majority of the patients [nimesulide: 91.9%; meloxicam: 90.2%; rofecoxib: 94.9%; and celecoxib: 94.9%)]. Twenty-five patients (30 provocations) reacted to COX-2 inhibitors. None of the factors were found be associated with positive response. CONCLUSION: Our results suggest to follow the traditional DPT method to introduce COX-2 inhibitors for finding safe alternatives in all patients with cross-reactive NSAID hypersensitivity before prescription as uncertainty of any predictive factor for a positive response continues. However, these tests should be performed in hospital settings in which emergency equipment and experienced personnel are available.

Effect of in vitro aspirin stimulation on basophils in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Basophil activation has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). However, a comprehensive analysis of basophil responses to aspirin in terms of mediator release, cytokine secretion and increased expression of surface activation markers has not been performed. OBJECTIVE: To study the in vitro effects of aspirin on the concurrent release of histamine, leukotriene C4 (LTC4) and IL-4 from human basophils and to also evaluate changes in surface activation markers (CD63, CD69 and CD203c) expressed by these cells. METHODS: Basophil-enriched cell suspensions from 10 patients with AERD and 10 healthy volunteers were incubated with lysine-aspirin for up to 3 h. Cells were analysed for expression of CD63, CD69 and CD203c using flow cytometry. Cell-free supernatants were evaluated for histamine, and LTC4 release and for IL-4 secretion. RESULTS: Aspirin-induced expression of CD63, CD69 and CD203c yielded 30%, 80% and 70% sensitivity, respectively, but with poor specificity. There was no significant difference in LTC4 synthesis between groups. None of the patients with AERD (or controls) released IL-4 in response to aspirin. A higher dose of 5 mg/mL aspirin-mediated non-specific effects on basophils. CONCLUSION: Basophil responses to in vitro aspirin challenge are poor indicators of clinical sensitivity. Aspirin activates some basophils by means of mechanisms that differ from the classical IgE-mediated pathway. Our study also shows that the use of 27 mm of aspirin (5 mg/mL) by previous investigators causes non-specific basophil activation, thereby eliminating its usefulness in a cell-based diagnostic test for AERD. Evaluation of in vitro basophil activation has low clinical value in identifying aspirin-induced respiratory reactions.

Regional pollen load: effect on sensitisation and clinical presentation of seasonal allergic rhinitis in patients living in Ankara, Turkey.

BACKGROUND: Although Gramineae pollens are the main reason for seasonal allergy in many parts of Europe, the influence of regional flora on sensitisation and symptoms has always been a topic of interest. The aim of this study was to document the sensitisation to pollens and to evaluate their clinical importance in patients with seasonal allergic rhinitis living in Ankara/central Anatolia. METHODS: The study included those subjects with seasonal allergic rhinitis living in Ankara. Skin prick testing with a panel of common aeroallergens as well as grass, individual tree and weed pollens predominant in the region was performed. The patients were followed by symptom-medication scores during the same season in which regional pollens were also counted. RESULTS: The final eligible study consisted of 54 subjects (F/M: 26/28; mean age: 29.4 years). Trees were the most common pollen source consisting of 95 % of the total amount, followed by grasses (3 %) and weeds (2 %). Sensitisation to Gramineae, to at least one weed; and to tree pollens were 100 %, 85.2 % and 94.4 %, respectively. The most common positive skin tests among tree pollens were to Oleaceae (59.2 %), Aesculus (57.4 %); and Tilia (42.5 %) despite low pollen counts. Chenopodiaceae (88 %) and Plantago (63 %) were the most sensitised weed pollens, with high pollen counts. All patients had significant symptoms during May and June. CONCLUSION: Although Gramineae pollens seem to be major allergens for seasonal allergic rhinitis in Ankara, the particular role of tree pollens and weed pollens cannot be discarded on symptom development in sensitised patients.

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity.

BACKGROUND: Lipoxin (LX) A4, an endogenous anti-inflammatory eicosanoid, has been found to be low in patients with severe asthma. However, few studies also suggested more diminished LX A4 levels in aspirin-exacerbated respiratory disease (AERD) when compared with aspirin-tolerant asthma (ATA). It is, therefore, currently not clear whether the asthma severity or the presence of AERD has a primary role in the disturbed LX metabolism. OBJECTIVE: To detect LX A4 and 15-epi-LX A4 levels in asthma patients with and without AERD of comparable severity. METHODS: The study groups consisted of 22 subjects with AERD, 22 subjects with ATA and 10 volunteers without asthma and aspirin sensitivity. Whole-blood samples were stimulated with calcium ionophore, A23187 (5 x 10(-5) m) and A23187 (5 x 10(-5) m)+aspirin (10(-4) m). LX A4 and 15-epi-LX A4 levels were analysed by the enzyme immune assay method. RESULTS: Severe asthma patients in both AERD [0.5 (0.8)] ng/mL and ATA [0.5 (0.45) ng/mL] groups showed diminished generation for LX A4 to stimulation with A23187 in comparison with other severity degrees in their groups (P=0.02 and 0.046, respectively). LX A4 generation in both severe groups was comparable with each other (P>0.05). Although severe cases with AERD showed a diminished capacity to generate 15-epi-LX A4, this did not reach statistical significance. CONCLUSION: This study indicated that diminished LX A4 generation was unique to severe asthma phenotype regardless of comorbid aspirin sensitivity. Clinical Implications Lower LX A4 levels in severe asthma would suggest a possibility for LX analogues as future treatment options in these patients.