EAACI/ENDA position paper on drug provocation testing.

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low-risk patients. The task force suggests a strict definition of such low-risk patients in children and adults. Based on experience and evidence from studies of allergy to beta-lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non-steroidal anti-inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources.

Desensitization in children allergic to drugs: Indications, protocols, and limits.

Any drug can potentially induce a hypersensitivity reaction. If after the allergological work-up the drug hypersensitivity reaction is confirmed, in most cases, the simple avoidance of the culprit drug and a suggestion of an unrelated alternative is enough. However, there are circumstances where the choice to stop the treatment affects the survival, the safety and/or the quality of life of the patient and the global outcome of the disease in question. When this occurs, drug desensitization can be the answer and should not be viewed as an extravagance, nor the pediatric age should be considered a contraindication. Drug desensitization in children can be safely and successfully performed, having a positive impact on the survival and overall prognosis. In general, the indications for DDS are the same in adults as in children. However, in this age group there are specificities that this paper aimed to describe, reviewing the mechanisms behind drug hypersensitivity and rapid drug desensitization, types of protocols, indications, and contraindications, as well as several technical aspects that are specific to the pediatric age.

Dietary parameters in patients with drug allergy: Assessing dietary inflammatory index.

BACKGROUND: Research on the increasing incidence of allergic diseases evidenced the role of diet as a potential key factor. Diet can modulate the low-grade systemic inflammation related to obesity and several diseases. There are no published data on drug allergy. AIM: To investigate a potential association between diet, including dietary inflammatory index (DII), and drug allergy. Also, to evaluate correlations between diet and obesity, inflammatory and metabolic parameters in patients with drug allergy. METHODS: Ninety consecutive patients studied for suspected drug allergy were evaluated in terms of dietary parameters, anthropometric measurements, bioimpedance and biochemical analysis. DII was calculated based on information collected from a food frequency questionnaire. RESULTS: After diagnostic work-up, 39 patients had confirmed drug allergy and 45 excluded, representing the study group and the control group, respectively. The majority (79%) were female, with mean age of 39.58±13.3 years. The 84 subjects revealed an anti-inflammatory diet pattern. No significative difference was found in DII scores between drug allergic patients and controls (-3.37±0.95 vs -3.39±0.86, p = 0.985). However, the patients with drug allergy revealed higher obesity and inflammatory parameters. A significative negative correlation was found between DII and adiponectin levels, in the control group (r = -0.311, p = 0.040). In the patient group, a significative positive correlation was observed between DII and triglycerides (r = 0.359, p = 0.032). No other correlations were found between DII and the assessed parameters. Patients with drug allergy presented a significative higher intake of mono-unsaturated fatty-acids comparing to controls (19.8±3.7 vs 17.8 ± 4.0, p = 0.021). No other statistically significant differences were achieved in dietary parameters, between patients and controls. CONCLUSION: The population assessed in this study revealed an anti-inflammatory diet profile. Although we have found in a previous work that the same patients with drug allergy revealed higher obesity and inflammatory parameters, the DII did not allow to distinguish between patients with drug allergy or controls. The DII scores correlated with triglycerides levels in the drug allergy patients and inversely with adiponectin levels in the control group. Larger studies are needed to clarify the potential role of the diet in drug allergy and its outcomes.

Management of adverse reactions induced by chemotherapy drugs.

PURPOSE OF REVIEW: There is a broad spectrum of chemotherapy-induced adverse reactions. Hypersensitivity reactions are being extensively studied as they can affect the ideal treatment. The goal of this review is to describe the current management of adverse reactions to chemotherapy, focusing on hypersensitivity events. RECENT FINDINGS: The range of possible desensitization protocols is increasing, as well as the delabeling algorithms and diagnostic tools. One-bag desensitization protocols, omalizumab use in immediate hypersensitivity reactions, slow desensitization protocols in nonimmediate hypersensitivity reactions and standardization of skin tests for platinum drugs, are some examples. SUMMARY: The handling of adverse reactions to chemotherapy is evolving, with the increasing identification of hypersensitivity reactions and the development of strategies for their management, to maintain the culprit drug.

Allergies and COVID-19 vaccines: An ENDA/EAACI Position paper.

BACKGROUND: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized. METHOD: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed. RESULTS: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable. CONCLUSIONS: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated.

Hypersensitivity reactions to chemotherapy: an EAACI Position Paper.

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug-induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work-up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section.

Obesity markers in patients with drug allergy and body fat as a predictor.

BACKGROUND: Obesity is a chronic low-grade inflammation state associated with several diseases. OBJECTIVE: To investigate a potential link between drug allergy and obesity, exploring whether the association depends on the type (immediate vs nonimmediate) or the severity of the reaction. METHODS: Anthropometric measurements, bioimpedance, and biochemical analysis, including serum adipokines, were performed in 90 consecutive adult patients studied for suspected drug allergy. Logistic regression models were developed to identify predictors of drug allergy. RESULTS: A total of 84 patients completed the diagnostic workup (78.6% women; mean age 39.58 ± 13.3 years). Drug allergy was confirmed in 39 patients and excluded in 45 (controls). Regarding body mass index, 42.2% had normal weight and 55.3% were overweight/obese. A total of 58% of women and 41% of men fulfilled the criteria for central obesity. Patients with drug allergy exhibited considerably higher body mass index, waist and hip circumferences, waist-hip ratio, fat mass, body fat percentage (BFP), trunk fat mass, leptin levels, and leptin-adiponectin ratio than controls. Similar results were obtained in the subgroup with immediate reactions, compared with the nonimmediate or unknown reactions. The higher the BFP and the number of reactions, the greater the odds of drug allergy (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01-1.14 and OR, 2.82; 95% CI, 1.31-6.10, respectively). An immediate reaction was also a predictor of drug allergy (OR, 3.81; 95% CI, 1.30-11.14, P = .02), compared with nonimmediate or unknown reactions. In patients with drug allergy, BFP was a predictor of having an immediate reaction (OR, 1.12; 95% CI, 1.02-1.24, P = .02). CONCLUSION: Our study illustrates, for the first time, evidence of a link between obesity and drug allergy, particularly immediate reactions. The BFP emerged as a potential predictor of drug allergy.

Practice parameters for diagnosing and managing iodinated contrast media hypersensitivity.

Immediate and nonimmediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5%-3% of patients receiving nonionic ICM. The diagnosis and management of these patients vary among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and nonimmediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Re-exposition or drug provocation test should only be done with skin test-negative ICMs. The decision for performing either re-exposition or drug provocation test needs to be taken based on a risk-benefit analysis. The role of in vitro tests for diagnosis and pretreatment for preventing reactions remains controversial.

Psychological profiles of patients with suspected drug allergy.

BACKGROUND: Several studies demonstrate an important association between allergic diseases and patients' psychological characteristics. OBJECTIVE: To evaluate any differences in the psychological characteristics of patients studied for suspected drug allergy in comparison with healthy controls. A secondary aim was to assess differences between patients with confirmed versus excluded drug allergy, with respect to the clinical aspects. METHODS: The psychological characteristics of 115 consecutive patients >16 years-old, studied for suspected drug allergy were assessed. They were compared with healthy controls. Four validated questionnaires were used to evaluate anxiety, depression, alexithymia, and personality type. RESULTS: Eighty-eight patients completed the evaluation: 34 had confirmed drug allergy and 33 excluded. Forty-eight healthy subjects filled the 4 questionnaires. Increased neuroticism was associated with increased odds of belonging to the excluded drug allergy group (odds ratio [OR], 1.374; 95% confidence interval [CI], 1.173-1.609). Increased neuroticism (OR, 1.244; 95% CI, 1.065-1.453) and increased anxiety (OR, 1.210; 95% CI, 1.084-1.351) were associated with increased odds of confirmed drug allergy. However, higher extraversion decreased this likelihood (OR, 0.755; 95% CI, 0.643-0.888). The odds of having confirmed drug allergy was reduced by 79.7% (OR, 0.203; 95% CI, 0.060-0.694) for patients with 2 suspected drugs and by 84.6% (OR, 0.154; 95% CI, 0.029-0.809) for those with ≥3 in comparison to those with only one. Patients with moderate to severe reactions were more likely to have confirmed drug allergy (OR, 4.295; 95% CI, 1.105-16.693) than those with milder manifestations. CONCLUSION: Our results highlight that patients with drug allergy have a distinctive psychological profile. Psychological assessment may help to identify patients that would benefit from a targeted intervention.

Genetic variants associated with T cell-mediated cutaneous adverse drug reactions: A PRISMA-compliant systematic review-An EAACI position paper.

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.