Diagnosis Of Drug Hypersensitivity Research Articles

The importance of clinical history in the diagnosis of drug hypersensitivity in children.

In case of suspected hypersensitivity reactions (HRs) to drugs, a challenging area for pediatricians is detecting relevant elements in the parent-reported history, in order to reach a definite diagnosis. We analyzed the concordance between the description of the HR and the medical reports documented at the time of the event. Furthermore, we studied any correlation between clinical history variables and the prediction of true allergy. We retrospectively collected 50 charts of children referred to our Allergy Unit, after a previous access to the Emergency Department. We compared the description of the HR at acute phase to the history told by parents. Type and timing of the HR and culprit drug were classified as "known" or "unknown." The diagnosis was confirmed or excluded at the end of the investigations. Logistic regression analysis was performed to find any significant association. The type of the HR was known in 74%, the timing in 28%, and the culprit drug in 98%. We showed that having had a severe HR had an increased odds of remembering the timing; being older >6 years and having had an immediate HR had an increased odds of remembering the type; time to diagnostic was lower in patients whose parents remembered the type of HR. Our paper underlines the importance of an accurate anamnesis at the time of the event. Providing the physicians with a standardized Case Report Form could be a useful tool to simplify the diagnostic work-up and minimize mistakes due to lack of memory.

Drug hypersensitivity, in vitro tools, biomarkers, and burden with COVID-19 vaccines.

Hypersensitivity reactions to drugs are increasing worldwide. They display a large degree of variability in the immunological mechanisms involved, which impacts both disease severity and the optimal diagnostic procedure. Therefore, drug hypersensitivity diagnosis relies on both in vitro and in vivo assessments, although most of the methods are not well standardized. Moreover, several biomarkers can be used as valuable parameters for precision medicine that provide information on the endotypes, diagnosis, prognosis, and prediction of drug hypersensitivity development, as well on the identification of therapeutic targets and treatment efficacy monitoring. Furthermore, in the last 2 years, the SARS‐CoV‐2 (severe acute respiratory syndrome‐coronavirus) pandemic has had an important impact on health system, leading us to update approaches on how to manage hypersensitivity reactions to drugs used for its treatment and on COVID‐19 (Coronavirus disease) vaccines used for its prevention. This article reviews recent advances in these 3 areas regarding drug hypersensitivity: in vitro tools for drug hypersensitivity diagnosis, recently identified biomarkers that could guide clinical decision making and management of hypersensitivity reactions to drugs and vaccines used for COVID‐19.

In vitro basophil activation test for drug hypersensitivity diagnosis

According to the definition of the World Health Organization, drug allergy is one of the types of adverse reactions to drugs, and is defined as any harmful or unintended reaction that occurs in doses used for prevention, diagnosis or treatment (Astakhova A. V., 2008). In accordance with the studies data, patients with an adverse drug reaction (ADR) account for approximately 6.5 % of all hospitalizations, and the incidence of fatal ADRs is 0.32 %. This explains why drug allergy is an important clinical problem (Kostyleva M. N., 2014, Verlan N. V., Rybalko M. V., 2013). Purpose of the study: to conduct a CAST (drug intolerance test) in children with a positive result on the Naranjo scale.

Psychiatric comorbidity and quality of life in patients with drug hypersensitivity

Background: Compared with advances in a drug hypersensitivity diagnosis and management, little is known about the mental health status of patients with drug hypersensitivity and the impact of this psychological distress on their quality of life (QoL). Objective: The objectives were to evaluate anxiety, depression, and QoL levels in patients with drug hypersensitivity, assess how some related factors may affect them, and determine the impact of disease on their QoL. Methods: A total of 203 patients with drug hypersensitivity and 80 healthy controls were evaluated with the Beck Anxiety (BAI) and the Depression Inventory (BDI), and the short version of the World Health Organization Quality of Life (WHOQOL-BREF) scale. Results: The mean ± standard deviation (SD) BAI scores of the patients and the controls were 13.46 ± 11.78 and 1.94 ± 1.93, respectively (p < 0.0001). The mean ± SD BDI scores were higher in the patient group (9.23 ± 6.36) than in the control group (2.18 ± 2.02) (p < 0.0001). The patients had significantly increased risk of anxiety versus the controls (48.8% versus 7.5%) (odds ratio [OR] 11.74 [95% confidence {CI}, 4.88-28.20]; p < 0.0001) and depression versus the controls (31.5% versus 6.2%) (OR 6.90 [95% CI, 2.66-17.90]; p = 0.0001). The comparison of patients' BAI and BDI scores showed that those with more severe reactions had higher scores than those with moderate and mild reactions. A negative correlation was found among all WHOQOL-BREF scale domain scores and the BAI and BDI scores. Conclusion: Anxiety and depressive symptoms have a high prevalence in patients with confirmed drug hypersensitivity, which leads to a notable decrease in QoL. Self-administered psychological questionnaires were shown to be useful in the psychological examination and management of patients with drug hypersensitivity. Therefore, we found that psychological support is critical to reducing the negative outcomes of hypersensitivity reactions in patients.

Allergy clinic patients' drug hypersensitivity.

Drug hypersensitivity reaction (DHR) is a common reason for an allergology con- sultation, during which it is not only necessary to gather a thorough medical history, but also to propose and perform diagnostic tests. The aim of the study was to retrospectively assess the patients with a profile of preliminary drug hypersensitivity diagnosis, the usefulness of NSAID hypersensitivity classifica- tion in outpatient practice, and to analyze the results of skin, provocation, and drug tolerance tests performed in Immunology and Allergy Clinic patients. Around 501 medical records of patients referred to the academic allergy outpatient clinic from 2011 to 2019, and had a preliminary drug hypersensitivity diagnosis were analyzed. The diagnostic and drug tolerance tests results carried out in 269 patients of the Clinic from 2009 to 2019 were then evaluated. Among the patients referred due to suspected drug hypersensitivity, the majority (n=338, 67.5%) were believed to be hypersensitive to NSAIDs and antibiotics (n=272, 54.3%). In patients with hypersensitivity to NSAIDs, the mixed pattern was the most prevalent (n=73, 21.6%), followed by NECD (n=64, 18.9%) and NIUA (n=55, 16.3%). The second most common drug causing DHR were the antibiotics, mainly β-lactams (n=160, 58.8%), followed by macrolides (n=35, 12.9%). In hypersensitivity caused due to β-lactams, the delayed form was predominant (n=24, 15%) with manifested skin symptoms (n=74, 46.3%). Non-steroidal anti-inflammatory drugs (n=21, 42.9%), followed by antibiotics (n=11, 22.5%) were the commonest causes of ana- phylaxis, as reported by 49 patients. The study shows that a majority of patients with suspected drug hypersensitivity can be classified under the hypersensitivity umbrella based on their medical history, which is the basis for further diagnostic process.

Advances and novel developments in drug hypersensitivity diagnosis.

A correct diagnosis of drug hypersensitivity reactions (DHRs) is very important for both the patient and health system. However, DHRs diagnosis is complex, time consuming, requires trained personnel, is not standardized for many drugs, involves procedures not exempt of risk, and in most cases lacks standardized in vivo and in vitro tests. Thus, there is an urgent need for improving the different approaches to diagnose patients with suspected DHRs. In this review, we have analyzed the advances performed in immediate and nonimmediate DHRs diagnosis during the last two years and obtained several conclusions: the significant heterogeneity in current practice among centers illustrates the need to re-evaluate, update, and standardize in vivo tests and protocols for the diagnosis and management of patients with suspected drug allergy. Regarding in vitro tests, the latest studies have focused on increasing their sensitivity or on establishing the sensitivity and specificity for the tests performed with new drugs. There seems to be a consensus about combining in vivo and in vitro tests as the best way to increase the diagnostic accuracy.

Drug Allergy in children: focus on beta-lactams and NSAIDs.

Drug hypersensitivity reactions (DHRs) are adverse reactions to a drug. In children, most common drugs inducing such reactions include beta-lactams (BLs) and non-steroidal anti-inflammatory drugs (NSAIDs). The aim of the present work was to provide current knowledge on the management of DHRs in the pediatric population, focusing on BLs and NSAIDs hypersensitivity. The clinical feature of DHRs include immediate and non-immediate (delayed and accelerated) reactions, that may be severe or non-severe. A systematic approach to the patient based on the reported clinical history is essential to organize a safe and adapted allergy work-up. Skin tests are the first step to assess a possible DHRs, especially in immediate reactions to BLs. Drugs concentrations for these tests are standardized and validated. The drug provocation test remains the gold standard to reach a firm diagnosis. In selected cases, a therapeutic desensitization protocol may be proposed in children with a confirmed diagnosis of drug hypersensitivity. Clinicians should be aware of the diagnostic and therapeutic options, to provide the best management in children having experienced a history of DHR. (www.actabiomedica.it)

Drug Allergy in Children: What Should We Know?

The drug allergy “label” may have a lifetime of consequences for a child. Many children with alleged drug allergies are proven to be tolerant to the culprit medication when challenged. The field of drug hypersensitivity is a recently evolving field of research, but studies on its epidemiology and diagnostic tools are lacking in children. Clinical history is significant in the diagnosis and classification of drug hypersensitivity in children. Diagnostic tools have been evaluated in a limited number of children; therefore, the guidelines are mainly in line with those for adults. Here, we review the clinical characteristics, main drugs, risk factors, and diagnosis of drug hypersensitivity to aid in its accurate diagnosis in children.

Cutaneous drug hypersensitivity: developments and controversies.

Cutaneous drug hypersensitivity reactions (CDHRs) are a complicated area with multiple clinical manifestations and differential diagnoses, requiring differentiated diagnostic measurements and optimized therapeutic management. Disseminated CDHRs to classical drugs can be classified by a simple algorithm, whereas chemotherapeuticals or biopharmaceuticals may show drug-specific and atypical clinical presentations. Controversies in drug hypersensitivity diagnosis exist about the benefit and accuracy of in-vitro tests. Although skin tests are the best means of detecting sensitization to drugs, methods have not been sufficiently standardized. The necessity for skin tests before performing drug provocation test (DPT) and of prolonged DPTs is discussed in selected patients. If a suspicion has been documented, β-lactam allergy should be excluded. The standard allergy diagnosis is done by an allergist. In case of urgent need because of an infection and low risk according to history, faster delabeling pathways have been developed. There is weak evidence that patients with mastocytosis may have a slightly increased risk of developing immediate-type drug hypersensitivity; however, if considerations are taken, drugs do not have to be withheld for this patient group. There is particular need for improved diagnostic measurements in patients with drug-induced severe cutaneous adverse reactions (SCARs), both identifying the offending drug and detecting individuals at risk. Further challenges encompass appropriate treatments during the acute as well as chronic phase of SCARs. Recent literature has contributed to our understanding of clinical manifestations and existing controversies and future needs in this area.

Mild to moderate hypersensitivity reactions to beta-lactams in children: a single-centre retrospective review

ObjectiveBeta-lactam (BL) antibiotics are the most reported drugs in hypersensitivity reactions in children. More than 90% of these children tolerate the suspected drug after diagnostic work-up. Skin tests (STs) show...

Penicillin allergy – recommendations for diagnostic work up and patient management

Allergy to penicillins or cephalosporins manifests either within a few minutes after intake or infusion in the form of acute anaphylaxis symptoms, or several hours to days later as exanthematous skin reactions. Exanthematous skin eruptions caused by amoxicillin or ampicillin are currently the most frequently diagnosed clinical reaction pattern within the spectrum of penicillin allergy. Certain single cephalosporins such as cefazolin, ceftriaxone, and cefuroxime are gaining in relevance as triggers of β‑lactam antibiotic-induced IgE(Immunglobulin E)-mediated anaphylaxis reactions. This article provides an overview of selected scientific articles and is based on research in PubMed, studies, and specialist databases. Penicillin allergy work-up is based on patient history and documented medical findings; serological IgE determinations, as well as skin and provocation testing, are routinely performed. While the determination of IgE directed to certain penicillin determinants is one of the few reliable laboratory tests for the diagnosis of drug hypersensitivity, the basophil activation test or the lymphocyte transformation test are reserved for experienced laboratories which are able to critically evaluate their test results. Wheal-and-flare reactions in skin prick and intradermal testing suggest IgE-mediated allergy, while infiltrated erythematous or exanthematous plaques in patch or intradermal testing point to delayed-type hypersensitivity. The overall predictive value of combined in vitro and in vivo allergy testing with β‑lactam antibiotics is approximately 90%. However, subsequent controlled provocation testing is recommended in order to reliably exclude allergic hypersensitivity.

Which drug is it? Utility of lymphocyte transformation testing in the diagnosis of drug hypersensitivity in a university teaching hospital

Which drug is it? Utility of lymphocyte transformation testing in the diagnosis of drug hypersensitivity in a university teaching hospital

Modified tests basophil degranulation and leukocyte migration inhibition factor in drug allergy. Study 2009-2014

Adverse reactions to drugs are increasing and there are few studies for the diagnosis. To determine the utility of modified basophil degranulation (MBD) test and modified leukocyte migration inhibition factor (MLMIF) test to prove drug hypersensitivity. 177 patients of both sexes were studied with the diagnosis of drug hypersensitivity, determining MBD, MLMIF, or both, between 2009 and 2014. They were matched with positive and negative controls and the non-allergic population. Applications are issued according to the type of hypersensitivity, considering type I MBD and type IV MLMIF. 170 patients (96.04%) were positive to at least one drug (RR = 4.71). 561 MBD (73.62%) and 201 MLMIF (26.37%) were performed. Female sex was more frequent (64.41%); the average age was 38.5. MBD was positive in 70.23% and MLMIF in 67.16%. The test sensitivity was increased complementarily and with two dilutions. The correlation of MBD and MLMIF was positive and highly significant. Women have more drug reactions. Modified MBD test is useful at any age. Since medications can activate one or other hypersensitivity mechanism, it is important to request the tests simultaneously.

Development of nanostructures in the diagnosis of drug hypersensitivity reactions

This article provides an overview of novel nanoscale structures potentially applicable to the field of allergy, and to discuss the required properties, advantages, and disadvantages of those nanostructures for clinical application focusing on diagnosis of drug hypersensitivity reactions. Advances in the development of different nanostructures are favoring their biomedical applications. One area of interest is the interaction between nanostructures and the immune system, including their ability to emulate carrier molecules and their potential use for the diagnosis of allergic reactions. Immunoassays are the most widely used in-vitro test for evaluating immunoglobulin E (IgE)-mediated drug hypersensitivity reactions. However, they have important technical limitations affecting their sensitivity. A wide variety of nanostructures have been designed to quantify specific IgE, with the aim of diagnosing different kinds of allergies. Nanoparticles-based colloidal immunoassay employed in microdevices and/or miniaturized systems are improving IgE detection sensitivity. Dendrimers have shown immense potential for the design and development of sensor platforms for evaluating IgE-mediated drug hypersensitivity reactions, due to the increase in hapten density and IgE accessibility. In this sense, a variety of dendritic structures as well as their hybridization to different solid supports have been shown to be successful when applied in the diagnosis of drug allergy. Moreover, the knowledge of the complete antigenic determinants would allow their inclusion and therefore further improvement of the sensitivity.

Drug provocation tests in the diagnosis of drug hypersensitivity reactions

Drug provocation tests (DPTs)are considered to be not only a gold standard for the diagnosis and exclusion of drug hypersensitivity, but also a safe and efficient approach to seeking alternative medicines. The operation procedures for DPTs have not yet been internationally unified. At present, consensus has been reached that prolonged successive provocation in addition to routine daily oral provocation can improve the positive rate of DPTs. DPTs have a high negative predictive value of more than 90%, and are fairly safe. Almost all positive reactions to DPTs, even long-term DPTs in children, manifest as skin eruptions or urticaria/angioedema, which are mild and easily controlled. Many studies on the diagnostic value, safety and acceptance of SPTs among patients indicate that further researches are required to develop safer and more accurate operation procedures. Key words: Pharmaceutical preparations; Hypersensitivity; Diagnosis; Methods; Drug provocation tests

DRESS à l’allopurinol compliqué d’un syndrome d’activation macrophagique

Drug hypersensitivity syndrome is among the most severe drug hypersensitivity reactions and in rare cases it may progress to hemophagocytic lymphohistiocytosis. Herein, we report a case of allopurinol-induced drug reaction with eosinophilia and systemic symptoms complicated by hemophagocytic lymphohistiocytosis. An 18-year-old girl presented with maculopapular rash associated with cervical lymphadenopahy appearing 3 weeks after treatment with allopurinol. Her hemodynamic status at admission was unstable. Cutaneous examination revealed an itchy maculopapular rash, which was purpuric at certain sites, together with facial edema. The diagnosis of drug hypersensitivity was suggested and was confirmed by histological examination of a skin biopsy. Allopurinol was stopped. Two weeks later, however, eosinophilia was noted. Further, four days after discontinuation of allopurinol, in view of the laboratory signs of bicytopenia, hyponatremia, hypertriglyceridemia and hyperferritinaemia, as well as the presence of hemophagocytosis in bone marrow, a diagnosis was made of lymphohistiocytosis hemophagocytic syndrome complicating a drug reaction with eosinophilia and systemic symptoms. Moreover, viral serology tests were negative. The patient was given intravenous immunoglobulin and the outcome was good. The literature contains only very few reports of drug reaction with eosinophilia and systemic symptoms complicated by hemophagocytic lymphohistiocytosis. The incriminated drugs were vancomycin, lamotrigine and phenobarbital. To our knowledge, there has only been one report of allopurinol-induced drug reaction with eosinophilia and systemic symptoms complicated by hemophagocytic lymphohistiocytosis.

Skin Testing with Betalactam Antibiotics for Diagnosis of Betalactam Hypersensitivity in Children

RationaleBetalactam antibiotics are the most common causes of drug hypersensitivity reported in children. Penicilloyl polylysine (PPL) and minor determinant were used for skin test but PPL is not commonly available. This study was to determine negative predictive value (NPV) of skin testing with betalactam antibiotics for diagnosis of betalactam hypersensitivity.MethodsPatients age 1-18 years old with history of betalactam hypersensitivity were evaluated by skin test (skin prick test, intradermal test) with culprit drugs (penicillin G, ampicillin, amoxicillin-clavulonic acid, cloxacillin and cephalosporin). Patients who have negative skin test were performed drug provocation test (DPT) in 3 dose graded challenge. The hypersensitivity reactions was classified into immediate and delay reactions.Results86 patients were evaluated for drug allergy. Only 18 patients (20%) were confirmed allergic to culprit drugs. 11 (61 %) of them confirmed by skin test. Among 75 patients with negative skin test were performed DPT, 7 patients (9.3%) were reacted providing NPV 90.7%. The most common culprit drug was amoxicillin (66.7%), followed by amoxicillin-clavulonic acid (16.7%). The history of immediate reaction was associated with true drug allergy (p value= 0.01). There were no serious systemic reaction in our study. There was only minor reactions which were response to symptomatic treatments.ConclusionsAmong children with history of betalactam hypersensitivity, skin testing with culprit drugs was safe and providing a good NPV when PPL was unavailable. However, skin test with betalactam antibiotics did not provide high sensitivity, thus DPT is necessary to confirm the diagnosis of drug hypersensitivity. RationaleBetalactam antibiotics are the most common causes of drug hypersensitivity reported in children. Penicilloyl polylysine (PPL) and minor determinant were used for skin test but PPL is not commonly available. This study was to determine negative predictive value (NPV) of skin testing with betalactam antibiotics for diagnosis of betalactam hypersensitivity. Betalactam antibiotics are the most common causes of drug hypersensitivity reported in children. Penicilloyl polylysine (PPL) and minor determinant were used for skin test but PPL is not commonly available. This study was to determine negative predictive value (NPV) of skin testing with betalactam antibiotics for diagnosis of betalactam hypersensitivity. MethodsPatients age 1-18 years old with history of betalactam hypersensitivity were evaluated by skin test (skin prick test, intradermal test) with culprit drugs (penicillin G, ampicillin, amoxicillin-clavulonic acid, cloxacillin and cephalosporin). Patients who have negative skin test were performed drug provocation test (DPT) in 3 dose graded challenge. The hypersensitivity reactions was classified into immediate and delay reactions. Patients age 1-18 years old with history of betalactam hypersensitivity were evaluated by skin test (skin prick test, intradermal test) with culprit drugs (penicillin G, ampicillin, amoxicillin-clavulonic acid, cloxacillin and cephalosporin). Patients who have negative skin test were performed drug provocation test (DPT) in 3 dose graded challenge. The hypersensitivity reactions was classified into immediate and delay reactions. Results86 patients were evaluated for drug allergy. Only 18 patients (20%) were confirmed allergic to culprit drugs. 11 (61 %) of them confirmed by skin test. Among 75 patients with negative skin test were performed DPT, 7 patients (9.3%) were reacted providing NPV 90.7%. The most common culprit drug was amoxicillin (66.7%), followed by amoxicillin-clavulonic acid (16.7%). The history of immediate reaction was associated with true drug allergy (p value= 0.01). There were no serious systemic reaction in our study. There was only minor reactions which were response to symptomatic treatments. 86 patients were evaluated for drug allergy. Only 18 patients (20%) were confirmed allergic to culprit drugs. 11 (61 %) of them confirmed by skin test. Among 75 patients with negative skin test were performed DPT, 7 patients (9.3%) were reacted providing NPV 90.7%. The most common culprit drug was amoxicillin (66.7%), followed by amoxicillin-clavulonic acid (16.7%). The history of immediate reaction was associated with true drug allergy (p value= 0.01). There were no serious systemic reaction in our study. There was only minor reactions which were response to symptomatic treatments. ConclusionsAmong children with history of betalactam hypersensitivity, skin testing with culprit drugs was safe and providing a good NPV when PPL was unavailable. However, skin test with betalactam antibiotics did not provide high sensitivity, thus DPT is necessary to confirm the diagnosis of drug hypersensitivity. Among children with history of betalactam hypersensitivity, skin testing with culprit drugs was safe and providing a good NPV when PPL was unavailable. However, skin test with betalactam antibiotics did not provide high sensitivity, thus DPT is necessary to confirm the diagnosis of drug hypersensitivity.

Towards the development of mechanism-based biomarkers to diagnose drug hypersensitivity

T-cells are activated by different mechanisms in the presence of drugs, metabolites or haptens, and they release several molecules that can be used in the diagnosis of drug hypersensitivity.

T cell and basophil activation assays in the diagnosis of drug hypersensitivity

Drug hypersensitivity reactions (DHR) are defined as all drug reactions that clinically resemble allergic reactions. Drug allergies are those DHRs that are mediated by a definite immunological mechanism. Diagnostic pathways for suspected DHRs aim to identify drug allergy and define the immunological pathway involved, however, few such diagnostic tests are clinically available. DHRs are broadly divided into immediate and non-immediate reactions, this often implies that immediate reactions are Type I (IgE mediated) reactions, whereas non-immediate reactions are Type II (IgG and complement mediated), Type III (immune complex mediated) and Type IV cellular reactions (TH1, Th2, CTL or Neutrophil mediated). Hence, given the complexity of the pathophysiology involved in DHR, diagnostics need to be able to distinguish and interrogate all immunological pathways involved. Furthermore, such diagnostic assays are required to be highly sensitive and specific both at the time of reaction and for many years after the index DHR. To date, routine diagnostics have failed to match the complexity and diversity of DHRs seen in practice. As the clinical awareness of DHRs increases, novel approaches to aid rapid confirmation of DHR and the screening of alternative drugs that can be safely used are urgently needed. Two cellular based assays, namely T cell proliferation and the Basophil activation assay, are increasingly used in laboratory practice for a limited group of drugs. Current applications of these two assays as well as their limitations will be presented. Furthermore, novel diagnostics with potential for clinical laboratory use will be reviewed.

Aminopenicillin-associated exanthem: lymphocyte transformation testing revisited.

The lymphocyte transformation test (LTT) has been promoted as in-vitro test for diagnosis of drug hypersensitivity. For determination of statistical LTT sensitivity, series of patients with clinically uniform reactions followed by complete drug hypersensitivity work-up are mandatory. Assessment of LTT specificity requires control patients who tolerated exposure to the drug studied. To prospectively determine the diagnostic value of the LTT in a clinically and diagnostically well-defined series of patients. Patients with exanthematous skin eruptions after ampicillin (AMP) intake were included in this study. After exclusion or confirmation of delayed-onset allergic AMP hypersensitivity by skin and provocation testing, two independent LTTs were performed: one standard LTT and a modified LTT with additional anti-CD3/anti-CD28 monoclonal antibody stimulation. By testing, delayed-onset allergic AMP hypersensitivity was diagnosed in 11 patients and definitely ruled out in 26. The standard LTT reached a diagnostic sensitivity of 54.5% while the modified LTT yielded 72.7%. However, the methodical test modification resulted in a decline of specificity from 92.3% (standard LTT) to 76.9%. In cases of AMP-associated exanthems, the diagnostic value of the LTT compared with routine allergy testing is limited. When evaluating such exanthems, provocation testing remains the gold standard. Delayed reading of intradermal skin tests remains most useful to avoid positive provocation reactions.