First-Line Antituberculosis Drug Challenge Reactions in Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome in an HIV Endemic Setting.

BACKGROUND: In high HIV prevalence settings, first-line antituberculosis drug (FLTD)-associated drug reaction with eosinophilia and systemic symptoms (DRESS) poses therapeutic challenges. A sequential and additive drug challenge (SADC) of FLTDs best identifies offending drug(s), avoids unnecessary exclusions, and optimizes reinitiation of nonoffending drugs. However, SADC-associated reaction complexities limit its utility. OBJECTIVE: We aimed to describe the characteristics of patients with FLTD-associated DRESS, their treatment-limiting SADC reactions, and related outcomes. METHODS: Patients hospitalized with FLTD-associated DRESS from 2013 to 2023 in a South African tertiary hospital and enrolled (retrospectively or prospectively) in an existing registry were eligible. RESULTS: SADC was undertaken in 41 patients. Overall, 47 classifiable reactions occurred. 34/47 (72%) reactions in 29/41 (71%) patients were treatment-limiting and 12 of 41(29%) patients reinitiated FLTDs uneventfully. Fifteen single and 8 multiple drug reactors were identified. Rifampicin in 13 of 23(57%) reactors was the most common individual offender. Ethambutol was most frequently involved in multiple drug reactors. The median (interquartile range) time to a detectable reaction was 24(12-120) hours, 6 of 34(18%) being immediate (<6 hours). Itch (65%), eosinophilia (56%), fever (41%), atypical lymphocytosis (41%), rash (38%), transaminitis (32%), and facial edema (18%) singly or in combination were the most common features. Three reactions, 1 epidermal necrolysis and 2 liver derangements, were Common Terminology Criteria for Adverse Events grade 4 (life-threatening) events. No predictors of multiple drug reactivity were identified, but multiple reactors were hospitalized significantly longer, 125(100-134) days versus 60(45-80) days. CONCLUSIONS: SADC optimizes FLTD reinitiation. However, timing, clinical presentation, and severity of SADC-associated reactions after FLTD-associated DRESS are markedly heterogeneous. Additionally, multiple drug reactors are a complex group that require longer hospitalization. There are no routine biomarkers available to distinguish true multiple drug hypersensitivity from nonspecific flare-ups and to guide long-term drug avoidance strategies.

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial.

PURPOSE: Critically ill patients are vulnerable to penicillin allergy labels that may be incorrect. The validity of skin testing in intensive care units (ICUs) is uncertain. Many penicillin allergy labels are low risk, and validated tools exist to identify those amenable to direct oral challenge. This pilot randomised controlled trial explored the feasibility, safety, and validity of direct enteral challenge for low-risk penicillin allergy labels in critical illness. METHODS: Consenting patients with a low-risk penicillin allergy label (PAL) (PEN-FAST risk assessment score < 3) in four ICUs (Melbourne, Australia) were randomised 1:1 to penicillin (250 mg amoxicillin or implicated penicillin) direct enteral challenge versus routine care (2-h post-randomisation observation for each arm). Repeat challenge was performed post -ICU in the intervention arm. Patients were reviewed at 24 h and 5 days after each challenge/observation. RESULTS: We screened 533 patients. 130 (24.4%) were eligible and 80/130 (61.5%) enrolled (age median 64.5 years (interquartile range, IQR 53.5, 74), PEN-FAST median 1 (IQR 0,1)), with 40 (50%) randomised to direct enteral challenge. A positive challenge rate of 2.5% was identified. No antibiotic-associated serious adverse events were identified. 32/40 (80%) received a repeat challenge (zero positive). Post-randomisation, 13 (32%) of the intervention arm and 4 (10%) of the control arm received penicillin (odds ratio, OR 4.33 [1.27, 14.78] p = 0.019). CONCLUSION: These findings support the safety, validity, and feasibility of direct enteral challenge for critically ill patients with PEN-FAST assessed low-risk penicillin allergy. The absence of false negative results was confirmed by subsequent negative repeat challenges. A relatively low recruitment to screened ratio suggests that more inclusive eligibility criteria and integration of allergy assessment into routine ICU processes are needed to optimise allergy delabelling in critical illness.

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.

Placebo-Controlled Histamine Challenge Disproves Suspicion of Histamine Intolerance.

BACKGROUND: Histamine intolerance (HIT) is frequently diagnosed in patients with polysymptomatic otherwise unexplained symptoms. OBJECTIVES: To exclude HIT by a single-blind placebo-controlled histamine challenge (SBPCHC), to study clinical features of patients with positive challenge, and to examine the predictability of HIT by biomarkers. METHODS: SBPCHC was performed in 59 patients with suspected HIT. History and clinical data, including serum diamine oxidase (DAO) and histamine skin test wheal size of patients with positive versus negative SBPCHC, were compared. RESULTS: Patients were predominantly middle-aged women (84.7%). Three-quarters reported improvement but never resolution of symptoms during a histamine-low diet. Histamine provocation was safe; only 1 patient was treated with antihistamines. Thirty-seven patients (62.7%) displayed symptoms to placebo. HIT was excluded in 50 patients (84.7%). Objective symptoms occurred in 4 of 59 cases (6.8%) after histamine but not after placebo challenge. These were diagnosed with "plausible HIT" because reactions occurring by chance could not be excluded. Another 5 patients (8.5%) were diagnosed with "possible HIT" after case-dependent detailed analysis. Patients with plausible/possible HIT had reported more gastrointestinal symptoms (P = .01), but comparable diet response and equal histamine skin prick test wheal sizes to those without HIT. Serum DAO activity tended to be lower in patients with HIT (P = .08), but was highly variable in those without, limiting its value as a biomarker. CONCLUSIONS: SBPCHC disproves HIT in the majority of patients. Placebo-controlled challenges are needed as placebo reactions were frequent. Gastrointestinal symptoms after food intake and reduced DAO levels are markers for HIT; however, specificity is not sufficient enough for making the diagnosis.

The Who, What, When, and Where of Inpatient Direct Oral Penicillin Challenge-Implications for Health Services Implementation.

Inpatient direct oral challenge programs are increasingly deployed as part of antimicrobial stewardship initiatives to reduce the burden and impacts of penicillin allergy labels on antibiotic prescribing. Using data from a prospective, multicenter cohort inpatient penicillin allergy program, we identify the key targets for delabeling to aid health service implementation.

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.

[Food Allergy in Childhood]. / Nahrungsmittelallergien im Kindesalter.

Food Allergy in Childhood Abstract. Food allergies in childhood are on the rise and are therefore a topical issue in practice. In this article, we describe the most common allergens and risk factors for the development of a food allergy. The classification of IgE- and non-IgE-mediated food allergies and their respective clinical manifestations are highlighted. The importance of a careful diagnosis with targeted history taking and allergy testing and finally the performance of oral provocation for the diagnosis will be presented in a practical manner. We will discuss the care of families of children with food allergies, whereby support through nutritional counselling as well as equipping families with an emergency kit, including appropriate instructions for use, are important. Finally, the latest therapeutic approaches of specific immunotherapy, which aims to induce tolerance, are presented and the prognosis of food allergies is discussed.

A Risk-Based Approach to Penicillin Allergy.

Penicillin allergy can be risk stratified in the hospital or outpatient setting to identify low-, moderate-, and high-risk phenotypes. Following ascertainment of risk, dedicated penicillin allergy testing strategies can be deployed successfully for each risk type-direct oral challenge (low risk), skin testing and oral challenge (moderate risk), and specialist review and/or skin testing (high risk).

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.

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.

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.

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.

Critically appraised topic on adverse food reactions of companion animals (9): time to flare of cutaneous signs after a dietary challenge in dogs and cats with food allergies.

BACKGROUND: At this time, elimination diets followed by oral food challenges (OFCs) represent the "gold standard" for diagnosing skin-manifesting food allergies (FA) in dogs and cats. Regrettably, there is no clear consensus on how long one should wait for clinical signs to flare after an OFC before diagnosing or ruling-out a FA in a dog or a cat. RESULTS: We searched two databases on October 23, 2019 to look for specific information on the time for a flare of clinical signs to occur during OFCs after elimination diets in dogs and cats with skin-manifesting FAs. Altogether, we reviewed the study results of nine papers that included 234 dogs and four articles containing data from 83 cats. As multiple OFCs could be done in the same patient and not all animals included were subjected to an OFC, we were able to compile 315 and 72 times to flare (TTF) after an OFC in dogs and cats, respectively. When regrouping all cases together, about 9% of dogs and 27% of cats exhibited a flare of clinical signs in the first day after an OFC; 21% of dogs and 29% of cats had such relapse by the end of the second day. The time needed for 50 and 90% of dogs to exhibit a deterioration of clinical signs (TTF50 and TTF90) was 5 and 14, respectively; in cats, these times were 4 and 7 days, respectively. By 14 days after an OFC, nearly all food-allergic patients from both species had had a relapse of clinical signs. These results are limited by the likely under-reporting of flares that occur on the first day immediately following an OFC, the time in which IgE-mediated acute allergic reactions typically develop. CONCLUSION: Veterinary clinicians performing an OFC need to wait for 14 and 7 days for more than 90% of dogs and cats with a skin-manifesting FA to have a flare of clinical signs, respectively.