High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy.

BACKGROUND: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT. METHODS: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. RESULTS: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01). CONCLUSIONS: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Risk Factors for Hepatotoxicity Due to Paracetamol Overdose in Adults.

Background and Objectives: Over-the-counter availability and a good safety profile make paracetamol one of the most common analgesics in developed countries but also the leading cause of liver failure due to overdose. The objectives of the study were to identify modifiable risk factors for severe hepatotoxicity following paracetamol overdose in adults. Materials and Methods: A retrospective cohort study involved the consecutive adult patients hospitalized in a toxicological center over a period of seven years due to paracetamol overdose. Complete medical datasets of laboratory and anamnestic variables were analyzed and validated by means of logistic regression model. Results: A total of 185 patients entered the study, including 25 individuals who developed severe hepatotoxicity (plasma aminotransferases levels above 1000 UI/L) and 31 individuals with mild to moderate liver injury (plasma aminotransferases levels above upper normal range, but below 1000 UI/L). In the univariable analysis, significant hepatotoxicity risk factors were male gender, alcohol abuse, an ingested paracetamol dose, and a timespan from ingestion to hospital admission. The later one was the only significant risk factor in the multivariable model (adjusted odds ratio 1.08; 95% CI: 1.03-1.12). Conclusions: A delay in hospital admission, resulting in a delayed administration of disease-specific treatment outweighs any other known risk factors of paracetamol-induced hepatotoxicity.

Alpha-gal syndrome: the first report in Poland.

Alpha-gal syndrome is an immunoglobulin E (IgE)-dependent allergy to galactose-α-1,3-galactose, resulting in a delayed anaphylactic reaction to red meat. The syndrome is causally linked to bites from ticks and associated with cross-reactivity to some drugs, e.g. cetuximab. Although cases of alpha-gal allergy have already been reported in a few European countries, to our best knowledge, no cases have been reported so far in Central-Eastern Europe. In the current report, we describe a case of alpha-gal syndrome diagnosed in Poland, to highlight the fact that it may occur in new geographic areas. Within three months, the described patient underwent five anaphylactic reactions with typical clinical manifestations. They developed a few hours after ingestion of red meat (pork, beef or mutton) and were preceded by tick bites. The level of specific IgE antibodies to alpha-gal reached 72.6 kAU/l, whereas the levels of specific IgE antibodies to other food allergens were within the reference range. As the onset of symptoms in this syndrome is usually delayed, numerous cases may be identified as idiopathic anaphylaxis, while early diagnosis is indispensable to avoid potentially life-threatening complications.

A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency.

BACKGROUND: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. METHODS: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. RESULTS: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. CONCLUSIONS: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.

Angioedema. Interdisciplinary diagnostic and therapeutic recommendations of the Polish Dermatological Society (PTD) and Polish Society of Allergology (PTA).

Angioedema is a non-inflammatory oedema of the subcutaneous tissue and/or mucosal membranes. It most commonly coexists with urticaria wheals and is considered to be a deep form of urticaria. Less commonly, it occurs in isolation and can take two basic forms: acquired angioedema and hereditary angioedema. Currently, there are 4 defined types of acquired angioedema and 7 types of hereditary angioedema. Treatment of angioedema depends on its form and etiological factors. Especially the genetic form, i.e. hereditary angioedema, is a considerable challenge for medical specialists, particularly dermatologists and allergists.

In Vitro Assays in Severe Cutaneous Adverse Drug Reactions: Are They Still Research Tools or Diagnostic Tests Already?

Severe cutaneous adverse drug reactions (SCARs) represent life-threatening medical conditions and an appropriate causative diagnosis of these conditions is of the highest importance. Existing in vivo diagnostic methods are risky or are just contraindicated in these patients. Therefore, in vitro tests take on greater significance. In this survey, the studies on in vitro assays in SCARs were identified with a defined searching strategy and strict eligibility criteria. Different methods in the particular clinical manifestations and the groups of drugs were compared in respect to the diagnostic parameters obtained. The lymphocyte transformation test and IFNg-ELISpot (Interferon γ-Enzyme-linked immunospot assay) appeared to have the best evidence currently available. Further diagnostic assays, which are based mostly on distinct mechanisms of SCARs, may outdo previous assays but they still need confirmation in a larger group of patients and in more research centers. Data from pediatric populations and acute generalized exanthematous pustulosis (AGEP) patients are scarce. Some technical issues, limitations, and modifications of routine laboratory methods are also discussed.

[Recent advances in the in vitro diagnosis of drug allergy].

Allergic reactions to drugs are a matter of great concern, both for patients and health care professionals. The diagnosis is primarily based on a clinical history and in vivo tests, but they have some significant limitations in a range of clinical situations. This review presents currently available in vitro methods for the identification of the culprit drug in drug-induced immediate reactions (specific IgE determination, basophil activation test), T-cell-mediated drug allergy (lymphocyte transformation test, enzyme-linked immunosorbent spot assay, cell activation markers and cytokine release) and in nonallergic hypersensitivity to nonsteroidal anti-inflammatory drugs. Perspectives for further improvement of the in vitro diagnosis of drug allergy are also discussed.

Drug-specific in vitro secretion of IFNγ in the diagnosis of drug-induced exanthemas: electrochemiluminescence assay versus previously used diagnostic methods.

The in vitro diagnosis of delayed drug hypersensitivity reactions remains a research problem. We measured drug-specific IFNγ release in peripheral blood mononuclear cells sampled from patients with drug-induced maculopapular exanthema and the age- and sex-matched control group. This is the first study to directly cross-compare an ultrasensitive assay based on an emerging electrochemiluminescence technology (ECL), the standard lymphocyte proliferation assay and three following tests detecting IFNγ at different steps of its production: intracellular in CD3+CD4+ cells (flow cytometry), secretion at the single cell level (enzyme-linked immunospot assay), bulk content in cell culture supernatant (enzyme-linked immunosorbent assay, ELISA). The highest rate of drug-positive responses were recorded for ELISA and ECL tests (56.25%). No false-positive responses were observed--all tests were negative in the control group. We demonstrated that IFNγ-detecting ELISA is not less efficient than ECL test, however, it is easily available and cheap, which makes it a potential method of choice in the future.

[Prevalence of drug allergy claims in school children]. / Czestosc zglaszania alergii na leki u dzieci szkolnych.

BACKGROUND: Adverse drug reactions, especially drug hypersensitivity reactions (DHR) are common problem, which impacts on prescription choices. In general pediatric populations data on the epidemiology of DHRs are scarce compared to in-patient and adult populations. In the current study, we assess the prevalence of parental-reported drug allergy in school children. METHODS: We performed a cross-sectional survey of a general 6- to 7-yr-old children population from Krakow. The life occurrence of drug allergy along with basic data on sensitization to common environmental allergens was assessed using a self-administered questionnaire. Four thousand eighty questionnaires were collected. RESULTS: The prevalence of drug allergy according to answers given by parents was 3.38% (138/4080). The most common reported drugs were penicillin and its derivatives (39%), followed by sulphonamides (25%), cephalosporins (9%) and non-steroidal anti-inflammatory drugs (8%). Sensitization to inhalant allergens, food allergens or haptens was not significant risk factor for drug allergy. CONCLUSIONS: The study showed that drug allergy claims in children are highly prevalent. Although results are based on parental perception, they point out how many patients need complete diagnostic work-up to confirm or exclude drug allergy. Otherwise they are treated with alternative drugs, which are usually less effective and/or more expensive.

[Basophil activation test--a practical approach to diagnosis of common respiratory allergy]. / Test aktywacji bazofilów--praktyczne aspekty cytometrycznej diagnostyki alergii oddechowych.

BACKGROUND: The diagnosis of immediate allergy is based on clinical data, skin prick tests (SPT), and measurements of allergen-specific IgE (sIgE). Basophil activation test (BAT) can supplement these methods and obviate their disadvantages, and possibly replace allergen challenge tests, such as a nasal provocative test (NPT). In this study, we assessed the influence of different storage times on BAT results. Futhermore, we compared the results of SPT, sIgE and NPT against BAT for common aeroallergens. METHODS: BAT was performed in twelve patients with allergic rhinitis sensitized to birch pollen or mites 1, 4 and 24 hours after blood sampling. CD63 was used as an activation marker. Three serial 10-fold dilutions (1:1, 1:10, 100) of allergen extract were employed. The further 10 individuals allergic to mites undergone complete diagnostic evaluation including SPT, sIgE measurements, NPT and BAT. Receiver operating characteristic (ROC) curves were used to compare the diagnostic techniques and tests conditions. RESULTS: Basophil activation expressed as stimulation index did not decline significantly up to 24h. Exposure to causal allergens resulted in a dose-dependent increase in expression of CD63 on peripheral blood basophils in tested individuals. We did not observed substantial differences in results of the investigated diagnostic methods determined by a ROC analysis. CONCLUSIONS: Flow-assisted diagnosis of common respiratory allergy relies upon allergen-induced activation of blood basophils can be a useful approach to determine the clinically relevant allergen in sensitized individuals. BAT with inhaled allergens can be performed within 24 hours after blood collecting into a tube with EDTA. Allergen suitable for NPT in appropriate dilutions is a good reagent for use in BAT.

[Pharmacogenomics of severe drug hypersensitivity reactions--from bench to bedside]. / Farmakogenomika ciezkich polekowych reakcji nadwrazliwosci--miedzy laboratorium a lózkiem chorego.

Recent remarkable findings of pharmacogenomics and basic scientific research provided insights in the pathogenesis of severe drug hypersensitivity reactions such as drug rush with eosinophilia and systemic symptoms (DRESS), abacavir hypersensitivity syndrome or blistering reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis). There is increasing evidence for the strong associations of certain human leukocyte antigen (HLA) alleles with hypersensitivity to particular drugs. HLA genes may serve as genomic biomarkers of predisposition to severe adverse drug reactions and enable to prevent them. In this paper we review essentials and advances in this area.

Clinical Characteristics and Quality of Life in a Cohort of Polish Pediatric Patients with Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare genetic disease. It is characterized by recurrent attacks of angioedema. Evidence to what extent it affects patient functioning is limited in the pediatric population. We aimed to determine the clinical characteristics and management of Polish children with HAE and to measure the health-related quality of life (HRQoL) of these patients. This cross-sectional study was conducted among 21 pediatric patients and their caregivers, as well as 21 respective controls randomly selected from the general population. During routine follow-up visits, standardized pediatric quality of life questionnaires (PedsQLTM 4.0) were administered to all caregivers and adolescents (≥13 years). Caregivers also completed a structured medical interview regarding the clinical characteristics and treatment of children with HAE during the previous six months. During this period, 57% of patients had low (group I), 24% moderate (group II), and 19% high (group III) HAE activity, corresponding to ≥10 attacks per 6 months. None of the patients received long-term prophylaxis. The children in group III had a lower HRQoL than other groups and controls on all dimensions of the PedsQLTM 4.0. The lowest scores in all groups were observed in the emotional functioning domain. Our data demonstrate that the burden of HAE on the quality of life of pediatric patients and their families encompasses a wide range of daily functioning.

Modulation of the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2) by Xenobiotic Compounds and Its Relevance to Human Diseases.

Mast cells (MCs) are immune cells that reside in tissues; particularly in the skin, and in the gastrointestinal and respiratory tracts. In recent years, there has been considerable interest in the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2), which is present on the surface of MCs and can be targeted by multiple exogenous and endogenous ligands. It is potentially implicated in non-IgE-mediated pseudoallergic reactions and inflammatory conditions such as asthma or atopic dermatitis. In this paper, we review natural products and herbal medicines that may potentially interact with MRGPRX2. They mainly belong to the classes of polyphenols, flavonoids, coumarins, and alkaloids. Representative compounds include rosmarinic acid, liquiritin from licorice extract, osthole, and sinomenine, respectively. While evidence-based medicine studies are still required, these compounds have shown diverse effects, such as antioxidant, analgesic, anti-inflammatory, or neuroprotective. However, despite potential beneficial effects, their use is also burdened with risks of fatal reactions such as anaphylaxis. The role of MRGPRX2 in these reactions is a subject of debate. This review explores the literature on xenobiotic compounds from herbal medicines that have been shown to act as MRGPRX2 ligands, and their potential clinical significance.

Mast cell degranulation and bradykinin-induced angioedema - searching for the missing link.

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema.

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

[Desensitization in drug hypersensitivity]. / Desensytyzacja w nadwrazliwosci na leki.

Drug hypersensitivity can occur with almost any drug and may range widely in clinical severity from mild pruritus, acute urticaria or angioedema to life-threatening anaphylaxis. Affected patients usually avoid the suspected drug in the future, but in selected cases the particular drug is essential for optimal therapy due to unavailable or ineffective alternative therapy. Under these circumstances, desensitization may be performed. Desensitization protocols have been developed and are used for antibiotics, sulfonamides, non-steroidal antiinflammatory drugs, insulins, biologic agents, and many others. Desensitization procedure is based on the induction of a temporary state of tolerance of a substance responsible for a hypersensitivity reaction. Gradually increasing doses of the drug are administered to the patient over several hours to a few days, until the total cumulative therapeutic dose is achieved and tolerated. Hypersensitivity to acetylsalicylic acid is a common indication to desensitization in a daily practice. A few protocols for this drug have been described. Recently, 7 patients hypersensitive to acetylsalicylic acid have been desensitized in our department due to cardiologic and rheumatologic reasons. In this group, desensitization procedures were performed successfully and the patients could continue pharmacotherapy with aspirin.

[The benefits of using basophil activation test as a diagnostic tool prior to specific immunotherapy with inhalant allergens]. / Korzysci z wykonywania testu aktywacji bazofilów w kwalifikacji do immunoterapii swoistej w alergii wziewnej.

BACKGROUND: Routine qualification for specific immunotherapy (SIT) is based on clinical history and skin prick tests (SPT) or specific IgE (sIgE). In cases of discordance between these two, basophil activation test (BAT) may be decisive. The aim of the present study was to determine the specificity and sensitivity of BAT, sIgE, and SPT, and to analyse cases, in which clinical data and SPT alone would result in wrongful qualification for SIT. PATIENTS AND METHODS: BAT results and sIgE levels to Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) were determined in 52 pediatric patients qualified for SIT based on clinical history and positive SPT. The group included 21 children qualified for SIT with birch or timothy grass, used as reference for specificity and sensitivity calculations for BAT, sIgE and SPT. RESULT: The sensitivity and specificity of BAT, using SPT as "gold standard" was 96.9% and 88.9% for Dp, and 89.3% and 100% for Df, respectively and the sensitivity and specificity of sIgE were 89.7%, 88.9% for Dp, and 92.9% and 94.4% for Df. When using BAT as "gold standard", the sensitivity and specificity of SPT was 90% and 90.5% for Dp, 92% and 84,6% for Df, and these indices for sIgE were 87.1% and 90.5% for Dp, 100% and 87.5% for Df. BAT did not confirm the initial qualification for SIT in 2 patients, revealing an unspecific basophil activation. Negative nasal provocation test ultimately confirmed the false-positive SPT, which could be explained by the co-existence of urticaria in those children. In further 2 children qualified for SIT with timothy and birch, BAT revealed lack of reactivity to respective allergens. Altogether BAT helped in avoiding unnecessary SIT in 4 out of 52 children (7.7%). CONCLUSIONS: In most cases, SPT, sIgE and BAT provide comparable information, however, SPT results care is advised in patients with co-existing urticaria. BAT is useful in verifying the actual relevance of allergens selected for SIT and helps in avoiding long-lasting, arduous, costly, and ineffective immunotherapy of wrongly qualified cases.

In Vitro Assays for Diagnosis of Drug-Induced Nonsevere Exanthemas: A Systematic Review and Meta-Analysis.

Frequent mislabelled causal relationship between drug hypersensitivity reactions and culprit drugs reinforces the need for an accurate diagnosis. The systematic reviews and meta-analyses of in vitro assays published so far focused on immediate reactions and the most severe delayed reactions, while the most frequent drug-induced delayed reactions-nonsevere exanthemas-have been underestimated. We aim to fill this gap. A systematic review of studies on in vitro assays used in the diagnosis of nonsevere drug-induced delayed reactions was conducted following the methodology of Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies Statement. The EMBASE and PubMed databases were searched. We have included 33 studies from which we extracted the data, then performed meta-analysis where possible, or synthesised the evidence narratively. The quality of the analysed studies was assessed with the QUADAS-2 tool. The tests identified the most frequently were lymphocyte transformation test (LTT), ELISpot, and ELISA. In the meta-analysis carried out for LTT in reactions induce by beta-lactams, the pool estimate of sensitivity and specificity amounted to 49.1% (95% CI: 14.0%, 85.0%) and 94.6% (95% CI: 81.7%, 98.6%), respectively. The studies showed heterogeneity in study design and laboratory settings, which resulted in a wide range of specificity and sensitivity of testing.

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.