Drug reintroduction testing and beta-lactam hypersensitivity in children: Protocols and results, a 12-year experience.

Introduction: Oral provocation test (OPT) to beta-lactam antibiotics (BL) is a gold standard in allergology investigation. We aimed to demonstrate the contribution of OPT in BL hypersensitivity (HS) indicated as a first step in diagnosis. Methods: We conducted a retrospective study from 2007 to 2019, in a single Tunisian tertiary care academic center. It concerned children with presumed non-severe allergic manifestations to BL, with a reaction that has occurred at least 6 months before the OPT. Results: We identified 35 children for inclusion. After the first OPT, a second OPT with a different BL was performed in case of a positive result of the first one. In 12 cases (34.2%), the OPT elicited a reaction. In eight cases the allergy was to penicillin and in two cases to cephalosporins (cefixim). Cross-reactivity was noted in two cases. Conclusion: An OPT to BL indicated in the first instance in non-severe reaction in children will allow a rapid diagnosis in case of suspicion of HS to BL.

Recent Updates in Understanding NSAID Hypersensitivity.

PURPOSE OF REVIEW: To provide a review of available literature regarding nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with an emphasis on more recent findings. RECENT FINDINGS: Oral provocation tests with aspirin are important for diagnosis and management in adult and pediatric populations with reported NSAID hypersensitivity. Risk of cross-reactivity to COX-2 inhibitors varies by NSAID hypersensitivity phenotype. COX-2 inhibitors are tolerated in aspirin-exacerbated respiratory disease. Reported NSAID allergy is associated with a higher risk of a substance use disorder. Effective treatment of underlying chronic spontaneous urticaria can allow tolerance of NSAIDs in NSAID-exacerbated cutaneous disease. The pathophysiology, cross-reactivity, and appropriate diagnostic evaluation differ between the 5 distinct NSAID hypersensitivity phenotypes. Further research into the pathophysiology of NSAID hypersensitivity in patients with and without underlying disease is needed.

Beta-lactam hypersensitivity in children: Frequency and risk factors.

AIMS: To determine the frequency of an authentic ß-lactam (BL) hypersensitivity (HS) amongst a large number of children and to identify clinical risk factors that predict this hypersensitivity. METHODS: All children with suspected BL allergy were evaluated by skin tests (ST) with the suspected BL. A 1-day oral provocation test (OPT) was performed in children with negative ST. We defined an authentic BL-HS case if the child exhibited a positive ST or a positive OPT. Risk factors associated with BL-HS were assessed using a univariate analysis. Covariates showing a P-value <.2 were included in the multivariate logistic regression analysis to determine independent predictors. RESULTS: A total of 354 patients reporting 368 suspected BL reactions were included. The diagnosis of BL-HS was established in 24 children (6.7%). All these children had a positive ST. OPT was performed in 30 patients and was negative in all of them. In 110 children with a negative ST, BL was tolerated. In the risk factors analysis, 164 children were included. Older age (>5 years) at the reaction (odds ratio = 1.11; 95% confidence interval, 1.01-1.22; P = .02) and BL administered (odds ratio = 7.7; 95% confidence interval, 2.76-21.8; P < .001) were significantly associated with authentic BL-HS. CONCLUSION: BL-HS should be evaluated with an appropriate allergy work-up before strict prohibition is made. In addition, age of patient and BL involved can be used as predictive factors of developing BL-HS in this population.

[Provocation tests]. / Pruebas de provocación.

Oral provocation tests involve the supervised administration of suspected foods in increasing doses to evaluate a patient's allergic condition. Acknowledged as the superior method for diagnosing food allergies, it surpasses results from specific IgE serum or prick tests, which indicate sensitization but not necessarily allergy. The test is indicated in cases of diagnostic uncertainty, assessment of natural or induced tolerance, or cross-reactivity risks. Three types of tests exist: open, single-blind, and double-blind with a placebo. While the latter two reduce anxiety, open tests are more practical for children under three.

Las pruebas de provocación oral implican la administración supervisada de alimentos sospechosos en dosis crecientes para evaluar la condición alérgica del paciente. Reconocido como el mejor método para diagnosticar alergias alimentarias, supera los resultados de IgE sérica específica o pruebas de punción, que indican sensibilización pero no necesariamente alergia. La prueba se indica en casos de incertidumbre diagnóstica, evaluación de tolerancia natural o inducida, o riesgos de reacción cruzada. Existen tres tipos: abierta, simple ciega y doble ciega con placebo. Mientras que las dos últimas reducen la ansiedad, las pruebas abiertas son más prácticas para menores de tres años.

Diagnostic Value of Oral Provocation Tests in Drug Hypersensitivity Reactions Induced by Nonsteroidal Anti-Inflammatory Drugs and Paracetamol.

Oral drug provocation tests (DPT) are the basic diagnostic tool for the detection of hypersensitivity to non-opioid analgesics and for selecting a safe alternative for a patient. They are of great practical importance due to their common use, but the data on the follow-up of patients after negative DPT are still very scarce. We examined the further fate of 164 such adult patients after negative NSAID or paracetamol tests and analyzed which excipients in the studied drugs they could be exposed to after the diagnostic workup. A structured medical interview was performed 32.9 months (mean) after the provocation tests. Of the 164 patients, 131 (79.9%) retook the tested drug and 12 developed another hypersensitivity reaction, giving the estimated negative predictive value of 90.8%. These reactions were induced by acetylsalicylic acid, paracetamol, meloxicam, and diclofenac, and were clinically similar to the initial ones (most commonly urticaria and angioedema). There are 93 generics of these drugs on the local market, containing a total of 33 excipients for which hypersensitivity reactions have been reported. All available generics contain such excipients. Thirty-one patients (20.1%) did not take the previously tested drug again, most often because it was not needed or because they were afraid of another reaction. DPT with analgesics has a high diagnostic performance. A minority of patients had relapsed after reexposure. One of the underestimated reasons for this may be drug excipients provoking a reaction, so it is advisable to use exactly the same medical product that has been negatively tested. Many patients avoid reexposure to a given drug, despite negative tests, therefore very reliable patient education in connection with DPT is highly needed.

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: does age matter?

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are reported to be the leading cause of drug hypersensitivity reactions. The aim of this study was to characterize a cohort of patients with NSAID hypersensitivity and establish if there are any differences between two groups of adult patients, under 55 years old and over 55 years old, and identify safe alternative options. METHODS: Patients with NSAID hypersensitivity who were referred to a single tertiary Allergy center from January 2019 to December 2021 were included. Clinical information was obtained from a review of medical records. RESULTS: A total of 135 patients with a history of NSAID-induced hypersensitivity reactions were included, 80 patients under 55 years old and 55 patients older than 55. Most of the patients enrolled were female (80.74%) and the mean age was 50.21 years, ranging from 18 to 78 years old. The time interval between the first reaction and the allergy work-up was longer in the older group (average timeframe 6.87 years) than in the younger group (average timeframe 3.77 years). The main culprit was metamizole in both groups. An oral provocation test to paracetamol was performed in most of the patients who tolerated the intake of 1000 mg, except for 2 patients who developed angioedema. CONCLUSION: Angioedema was the most encountered symptom in our population. Age does not influence the allergy work-up of patients with a history of NSAID-induced hypersensitivity reactions. The drug provocation challenge remains the gold standard for finding a suitable alternative in patients with NSAID-induced hypersensitivity.

Antibiotic oral provocation challenge in children.

AIM: The main objective of this study was to see how many of the children, with a suspected antibiotic allergy, developed an allergic or adverse reaction to a drug provocation test. METHODS: Data on children that had undergone a drug provocation test for a suspected antibiotic allergy were compiled retrospectively for the period from 2007-2018. The median age at the first provocation was 2.25 years (1.5-5.7). Standardised questionnaires, the children's parents had answered before the provocation, were used to evaluate the originally suspected allergic reaction, previous health, atopic diseases and family history. RESULTS: Ninety-two (6.4%) of the 1440 children showed a possible mild allergic reaction. Sixty-four of the 92 children underwent a second drug provocation test 1-2 years later. At that time, only eleven developed a positive- or a possible-delayed reaction. CONCLUSION: An immediate moderate or severe allergic reaction was excluded in all cases of suspected antibiotic allergy in this study. Our study indicates that an oral drug provocation test is safe. It may be appropriate to wait for 6 months or more after the initial event of ADR before these tests are performed. A second oral provocation 1-2 years after the first one shows that ADRs are outgrown in most children.

Clarithromycin hypersensitivity in children: Is there a link with ß-lactam hypersensitivity?

BACKGROUND: Clarithromycin hypersensitivity is reported as the most common cause of non-ß-lactam antibiotic allergy in children. Clarithromycin is frequently prescribed in cases of suspected ß-lactam hypersensitivity. Oral provocation tests stand as the gold standard to confirm drug hypersensitivity as diagnostic value of skin tests is variable. We analyzed the frequency of true clarithromycin hypersensitivity ratio and its relationship with ß-lactam allergy among children with suspected clarithromycin hypersensitivity and evaluated the diagnostic value of skin tests. METHODS: The study included 160 children referred with suspected clarithromycin hypersensitivity. Clinical history and allergy workups including skin tests or/and oral provocation tests were retrieved from medical records. RESULTS: Oral provocation test confirmed clarithromycin hypersensitivity rate was 5.6% (n = 9/160). Skin tests with clarithromycin showed positivity in 32.6% (n = 29/89) of the tested patients. The sensitivity of clarithromycin skin tests was negligible, and specificity was 73.9% (95% confidence interval [CI], 64.7-81.8). Eighty-eight of the patients (55%) reported that they had previously tolerated a ß-lactam antibiotic. ß-lactam hypersensitivity was suspected in 40% (n = 64/160) of the patients (simultaneous [n = 10], sequential [n = 19], distant form [n = 35]) in relation with clarithromycin usage. ß-lactam hypersensitivity (95% CI, 2.1-70.6, p = .005) and sequential usage of clarithromycin after the development of a rash with amoxicillin-clavulanic acid (95% CI, 2.0-96.4, p = .007) were found as risk factors for confirmed clarithromycin hypersensitivity. CONCLUSION: The frequency of confirmed clarithromycin hypersensitivity was found low among suspected patients. Oral provocation test is crucial for definite diagnosis. Confirmed ß-lactam allergy may be attributed as a risk factor for clarithromycin hypersensitivity, particularly clarithromycin treatment after a developing rash with amoxicillin-clavulanic acid in sequential usage.

Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.

BACKGROUND: Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence. OBJECTIVE: To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity. METHODS: A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly. RESULTS: We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild. CONCLUSION: Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.

Meloxicam and/or Etoricoxib Could Be Administered Safely in Two Equal Doses during an Open Oral Challenge in Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity.

BACKGROUND: Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are common. These patients require an effective and safe analgesic alternative. OBJECTIVE: The aim of the study was to demonstrate the safety of meloxicam and etoricoxib administered by open oral challenge in 2 equal steps in patients with NSAID hypersensitivity. METHODS: A cross-sectional, descriptive study of patients with a diagnosis of NSAID hypersensitivity who underwent an oral drug provocation test (DPT) with meloxicam or etoricoxib between January 2011 and August 2017 was conducted. The analysis was performed from a database in BD Clinic. RESULTS: Two hundred and twenty-eight oral provocations were performed with an alternative NSAID (203 with meloxicam and 25 with etoricoxib) in 217 patients with hypersensitivity to NSAIDs. The median age was 38 years. Ninety-eight percent of meloxicam and 100% of etoricoxib DPTs were performed in 2 steps (without previous placebo), and 52% and 64% of meloxicam and etoricoxib DPTs, respectively, were performed with 50% of the therapeutic dose in each step. Tolerance to meloxicam was demonstrated in 192 patients (94.5%) and in 100% of patients receiving etoricoxib. CONCLUSIONS: Open oral provocation with meloxicam and etoricoxib carried out in 2 steps without placebo seems to be safe and implies less costs and less time expenditure. Also, it could be performed with 2 equal doses.

The first case of tegoprazan-induced urticaria.

WHAT IS KNOWN AND OBJECTIVE: Tegoprazan induces adverse drug reactions during clinical trials; however, tegoprazan-induced urticaria has not been reported. Here, we describe the first case of this. CASE DESCRIPTION: A 55-year-old woman presented with acute urticaria with pruritus after taking the gastro-oesophageal reflux disease medication, tegoprazan. Urticaria disappeared after tegoprazan discontinuation. In an oral provocation test, after taking 10% of tegoprazan, she developed pruritus, and after taking 30%, she developed urticaria on her back. WHAT IS NEW AND CONCLUSION: This is the first case of urticaria induced by tegoprazan. Physicians should understand the possibility of a tegoprazan-induced hypersensitivity reactions.

Immediate-Type Hypersensitivity Cross-Reactions to Proton Pump Inhibitors: A Descriptive Study of Data from the French National Pharmacovigilance Database.

BACKGROUND: Proton pump inhibitors (PPIs) can trigger immediate-type hypersensitivity reactions (HSRs). Three main patterns of cross-reactivity have been identified: reactions to a single PPI, selective cross-reactions, and cross-reactions with all PPIs. Several hypotheses have been advanced, but no consensus has been reached. OBJECTIVE: We sought to identify immediate-type hypersensitivity cross-reactions to PPIs using real-world data about hypersensitivity testing from French pharmacovigilance cases. METHODS: Potentially relevant immediate-type HSRs reported from January 1985 to February 2015 were extracted from the French pharmacovigilance database using a standardized MedDRA query (SMQ). Cases describing skin tests or oral provocation tests (OPTs) performed with several PPIs that yielded at least one positive result were included. RESULTS: The SMQ extracted 2,119 cases, 38 of which were included in our study. Data collected from skin tests and OPTs indicated cross-reactions with all PPIs (n = 1), reactions to a single PPI (n = 14), or selective cross-reactions (n = 23). Esomeprazole, omeprazole, and pantoprazole concerned 78% of all selective cross-reactions. In more than half of the cases (55.3%), only 2 PPIs were tested. CONCLUSION: To the best of our knowledge, this PPI cross-reactivity study is the largest to date in terms of population size, describing 38 immediate-type HSRs to PPIs explored by skin tests or OPTs. This paucity of data belies the lack of standardized procedures for PPI hypersensitivity testing. It is likely that PPI HSR workups in everyday clinical practice are often incomplete. Further research to gain insight into selective cross-reactions between PPIs is needed. In the meantime, thorough workups should be completed when a PPI is suspected to have triggered an HSR, instead of routine contraindication to all PPIs.

The Oral Provocation Test for Raw Egg in Patients with Hen Egg Allergy.

BACKGROUND: Many researchers have made efforts to develop diagnostic tools for predicting the outcome of oral food challenges (OFCs). The aim of this study was to assess the diagnostic value of the skin prick test (SPT) and blood-specific IgE concentrations based on the outcome of the OFCs for heated and raw hen egg. METHODS: This study included 103 children with suspected hen egg allergy (HEA; median age 23 months, range 10-155; 72 boys, 31 girls). Forty-three patients were diagnosed with HEA by OFC. Of 60 patients who tolerated heated egg white (HEW), 22 underwent the OFC for raw hen egg and 7 developed adverse reactions after ingesting raw egg. Their wheal diameters and specific IgE levels for egg white and ovomucoid were determined. RESULTS: Wheal diameters as well as blood-specific IgE levels for egg white and ovomucoid were significantly larger in children with positive OFC results for HEW than in those with negative results. However, there were no significant differences between the positive and negative test results for raw hen egg white (REW) in wheal diameter or blood-specific IgE levels. CONCLUSIONS: The SPT and blood-specific IgE can be used to diagnose HEA. However, the provocation test for REW in children without HEW allergy is important because the values of SPT and specific IgE were not significantly different between children with and without raw egg allergy.

[Is celecoxib a safe alternative for the Fernand Widal syndrome?] / Célécoxib, une alternative sûre pour les syndromes de Fernand Widal ?

The Fernand Widal syndrome is a set of associations between asthma, nasal polyposis and aspirin sensitivity. Selective cyclo-oxygenase 2 (COX 2) inhibitors are recognized as being a therapeutic alternative in cases needing analgesic or anti-inflammatory treatment. In a retrospective study, we have compiled data concerning oral provocation tests (OPT) undertaken with celecoxib, one of most the selective COX 2 inhibitors, in eight patients with the Fernand Widal syndrome. They were compared with twenty-seven control patients with sensitivity to aspirin or non-steroidal anti-inflammatories, manifesting as asthma, urticaria or rhino-conjunctivitis. Four patients with the Fernand Widal syndrome developed bronchospasm after taking the usually recommended daily dose of celecoxib while all the control patients tolerated it. The Fernand Widal patients who reacted during the OPT had a lower threshold of reactivity to aspirin, a more severe reaction with aspirin, and/or more severe asthma. In patients with the Fernand Widal syndrome, celecoxib is not always a possible alternative to non-steroidal anti-inflammatory drugs. Its introduction must be carried out in a hospital environment under medical supervision.

[Food allergy in adulthood]. / Nahrungsmittelallergie im Erwachsenenalter.

Food allergies can newly arise in adulthood or persist following a food allergy occurring in childhood. The prevalence of primary food allergy is basically higher in children than in adults; however, in the routine practice food allergies in adulthood appear to be increasing and after all a prevalence in Germany of 3.7 % has been published. The clinical spectrum of manifestations of food allergies in adulthood is broad. Allergy symptoms of the immediate type can be observed as well as symptoms occurring after a delay, such as indigestion, triggering of hematogenous contact eczema or flares of atopic dermatitis. The same principles for diagnostics apply in this group as in childhood. In addition to the anamnesis, skin tests and in vitro tests, as a rule elimination diets and in particular provocation tests are employed. Molecular allergy diagnostics represent a major step forward, which allow a better assessment of the risk of systemic reactions to certain foodstuffs (e.g. peanuts) and detection of cross-reactions in cases of apparently multiple sensitivities. Current German and European guidelines from 2015 are available for the practical approach to clarification of food allergies. The most frequent food allergies in adults are nuts, fruit and vegetables, which can cross-react with pollen as well as wheat, shellfish and crustaceans. The therapy of allergies involves a consistent avoidance of the allogen. Detailed dietary plans are available with avoidance strategies and instructions for suitable food substitutes. A detailed counseling of affected patients by specially trained personnel is necessary especially in order to avoid nutritional deficiencies and to enable patients to enjoy a good quality of life.

Direct oral provocation tests in non-immediate mild cutaneous reactions related to beta-lactam antibiotics.

BACKGROUND: Skin testing has a limited role in the diagnosis of non-immediate beta-lactam hypersensitivity in children. The aim of this study was to report the results of oral provocation tests performed without skin tests in children with non-immediate mild cutaneous reactions without systemic symptoms caused by beta-lactam antibiotics. METHODS: Oral provocation tests with suspected antibiotics were performed to patients with non-immediate mild cutaneous reactions without systemic symptoms caused by beta-lactam antibiotics. Skin tests were not performed before provocation tests. A total of five doses were administered with half-an-hour intervals in increasing doses. Provocation was continued for 5 days. RESULTS: A total of 119 patients with a median age of 4.3 (IQR: 2-7.5) years, of whom 58% were males, were included in the study. Amoxicillin-clavulanic acid was the most frequently responsible agent in 87 (73.1%) patients, and most common type of rash was maculopapular in 74 (62.2%) patients. Four patients (3.4%) had an urticarial reaction during the provocation test. CONCLUSION: We did not experience any severe reactions during oral provocation test without previous skin tests performed to children with non-immediate mild cutaneous reactions without systemic symptoms. Omitting skin tests before oral provocation test in this group of children can help decreasing the burden of allergy clinics and alleviating the discomfort of children.

Fixed drug eruption to sitagliptin.

Fixed drug eruption is a common adverse effect seen with various drugs notably antibiotics, antiepileptics and non-steroidal anti-inflammatory drugs. Herein we report a case of Sitagliptin induced fixed drug eruption in a 46 year old female who developed circumscribed, erythematous macules all over the body within one week of initiation of Sitagliptin. The lesions resolved with residual hyperpigmentation on cessation of the drug. The diagnosis was confirmed by an oral provocation test which led to a reactivation of the lesions. To the best of our knowledge, this is the first case of fixed drug eruption to Sitagliptin reported in the literature.

Fixed drug eruption due to clarithromycin.

Fixed drug eruption (FDE) is an unusual adverse effect of any drug, especially antibiotics like clarithromycin. Herein we report a case of clarithromycin induced FDE in a 30-year-old man who presented with recurrent erythematous and pruritic cutaneous lesions on the lower lip, right hand and left thigh. The lesions were initially misdiagnosed as lichen planus and treated with topical steroids. Each recurrence was at the same site and the lesions faded within 2 weeks leaving behind violacceous pigmentation. All the cutaneous lesions were reproduced following an oral provocation test thus confirming the diagnosis of clarithromycin induced FDE, which is a rare occurrence. When it does occur, it is often misdiagnosed, so physicians should be aware of this condition in order to prevent future recurrences as it causes a lot of cosmetic and physical discomfort to the patient.