Drug-induced Adverse Reactions Research Articles

Frequencies of HLA-B alleles in Indonesian Malay Ethnic

BackgroundThe HLA-B alleles have been used as a marker to predict drug-induced adverse reactions and as a major contributor to hypersensitivity reactions. We examined the feasibility of HLA-B alleles as pharmacogenomic markers of drug-induced hypersensitivity in an Indonesian Malay Ethnic. MethodsFifty-eight Indonesian individuals of Malay ethnicity were enrolled in this study. HLA-B alleles were determined using reverse sequence-specific oligonucleotide probe coupled with xMAP technology. ResultsHLA-B*15:02 (15.52%), HLA-B*35:05 (9.48%), and HLA-B*07:05 (7.76%) were frequent alleles in the Indonesian Malay ethnic populations. We discovered at least eight pharmacogenomics markers of drug-induced hypersensitivity: HLA-B*15:02, HLA-B*15:21, HLA-B*13:01, HLA-B*35:05, HLA-B*38:02, HLA-B*51:01, HLA-B*57:01, and HLA-B*58:01. HLA-B*15:02 was in the same serotype group with HLA-B*15:21, which is a B-75 serotype associated with genetic predisposition for carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis. The Indonesian population, represented by Malay, Javanese, and Sundanese ethnicities, was similar to South East Asian, Han Chinese, and Taiwanese populations based on HLA-B*15:02 frequency as the most common allele found in Malay ethnics. ConclusionWe provided valuable information on the frequency of drug hypersensitivity-associated HLA-B alleles in Indonesian Malay ethnic population, which can improve treatment safety.

СЛОЖНОСТЬ ВЕДЕНИЯ ПАЦИЕНТА С ШЛУ ТУБЕРКУЛЕЗОМ ПРИ ЛЕЧЕНИИ КОРОТКИМ РЕЖИМОМ, ВКЛЮЧАЮЩИМ ЛИНЕЗОЛИД (BPaL)

The article describes a clinical observation illustrating a rational approach to the correction of adverse drug-induced reaction – severe toxic polyneuropathy in a patient with extensively-drug resistant (XDR) infiltrative pulmonary TB with cavities and dissemination – during administration of a new 24-week chemotherapy regimen containing bedaquiline (Bq), pretomanid (Pa) and linezolid (Lzd) (BPaL).

Drug-induced cardiac toxicity and adverse drug reactions, a narrative review

Drug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity.

Indirect and Direct 65+ Patient Reporting of Non-Steroidal Anti-Inflammatory Drug-Induced Adverse Drug Reactions as a Source of Information on Polypharmacy and Polypharmacy-Related Risk.

Background and Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs), which have anti-inflammatory and analgesic properties, are commonly used in the treatment of various, particularly frequent, as well as chronic, conditions in older patients. Due to common polypragmasia in these patients and a high risk of adverse drug reactions (ADRs) and drug interactions, pain management poses a therapeutic challenge. This study describes the importance of ADR reports in the identification of polypharmacy and the ensuing interactions. Materials and Methods: Both healthcare professionals (HPs) and non-healthcare professionals (non-HPs) reports collected in the EudraVigilance database of NSAIDs, including most commonly co-reported medications and reported reactions, were analysed and differences between HPs and non-HPs reports were identified. Results: In the analysed period and group, non-HPs reported more reactions but indicated fewer drugs as suspect or concomitant. The outcomes of our analysis indicate more HP engagement and more detailed reports of serious ADRs when compared to non-serious individual case safety reports (ICSRs) by non-HPs, which appeared more detailed. Such reactions as kidney failure and increased risk of bleeding are known adverse reactions to NSAIDs and common symptoms of their interactions, which were described in the available literature. They were much more frequently reported by HPs than by non-HPs. Non-HPs more frequently reported reactions that may have been considered less significant by HPs. Conclusions: The differences between healthcare professionals' (HPs) and non-healthcare professionals' (non-HPs) reports may result from the fact that the reports from patients and their caregivers require a professional medical diagnosis based on symptoms described by the patient or additional diagnostic tests. This means that when appropriately classified, medically verified, and statistically analysed, the data may provide new evidence for the risks of medication use or drug interactions.

Causes of Drug-Induced Severe Cutaneous Adverse Reaction Epidermal Necrolysis (EN): An Analysis Using FDA Adverse Event Reporting System (FAERS) Database.

The purpose of the study is to analyze FAERS data to identify drugs associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), determine demographics, drug classes involved, most likely resulted in death, and highlight emerging trends in SJS/TEN reactions. We reviewed the publicly available FAERS database from 2004-2021. Using search terms "Stevens-Johnson syndrome" or "Toxic epidermal necrolysis", we identified the reports of SJS/TEN or SJS/TEN followed by death that might associated with specific drugs. Then the amounts and trends were counted analyzed. During the study period of 2004-2021, the Food and Drug Administration (FDA) received a total of 14,363,139 reports of adverse reactions, among which 24,976 were linked to SJS or TEN. After excluding the cases with incomplete or insufficient information on age, gender, or country of origin, the median median age of patients was 53.82 (IQR = 57.52), the females accounted for 56.59% (12,827 cases) and 8,507 (38.34%) originated in the United States. The top 50 drugs were associated with 15,149 cases (60.65%). The subsequent fatal outcome occurring in 4878 out of 24,976 cases (19.53%). Top 3 drug classes associated with SJS/TEN in FAERS were antiepileptics, non-steroidal anti-inflammatory drugs (NSAIDs) and others. Top drug classes associated with SJS/TEN deaths were antineoplastic agents and cephalosporins. Linear regression showed that the annual percentage of monoclonal antibody-related SJS/TEN reactions increased at an average rate of 0.25% (95% confidence interval: 0.18, 0.32) from 0.00% in 2004 to 4.79% in 2021, faster than any other drug class except antigout drug (allopurinol). By using the publicly available FAERS data, we have identified some important themes and trends in drug-related SJS/TEN reactions. Monoclonal antibodies and proton pump inhibitors are drugs with emerging trends causing SJS/TEN. Additionally, cephalosporin antibiotics have a higher mortality rate following SJS/TEN.

Acute Phase Reactants: Relevance in Dermatology.

Acute phase reactants (APRs) are a heterogeneous group of plasma proteins whose concentration either increases or decreases by at least 25% during an inflammatory process. The conditions that commonly lead to acute phase response are infection, trauma, burns, tissue infarction, inflammatory conditions, and advanced malignancy. APRs are elevated in all infective conditions. In skin and soft tissue infection, the levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) help to predict the severity of infection. Procalcitonin can be used to differentiate between viral and bacterial infections. During active stages of systemic lupus erythematosus (SLE), ESR is elevated, but CRP either remains normal or shows only moderate elevation. In the case of superadded bacterial infection in SLE, CRP is elevated. In SLE, ferritin levels are elevated during the active stage of the disease. Serum amyloid antigen (SAA) and CRP levels are significantly higher in patients with early and late stages of diffuse systemic sclerosis. Elevated levels of serum ferritin are seen in rheumatoid arthritis and adult-onset Still's disease. CRP, SAA, and α2-macroglobulin (α 2M) are elevated in active psoriasis. In severe psoriasis, the ferritin-iron ratio is elevated. In drug-induced maculopapular rash, drug-induced hyperaemic vasculitis, and severe drug-induced cutaneous adverse reactions, CRP levels are elevated during the active stages. Neoplastic diseases in general are accompanied by increased serum ferritin. Further detailed studies are required to explore the clinical significance of APRs in dermatology and the scope of their possible application as a diagnostic tool.

The Role of NLRP3 Inflammasome in the Pathogenesis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) are mainly drug-induced severe cutaneous adverse reactions with increased mortality. It also involves the eyes causing ocular surface disease leading to visual impairment and blindness. The role of NLRP3 Inflammasome in causing ocular surface disease and keratinocyte apoptosis is not fully explored. This study is focused on determining the role of NLRP3 Inflammasome in the pathogenesis of SJS/TEN. The NLRP3 Inflammasome plays a crucial role in the pathogenesis of SJS/TEN and may correlate with the degree of severity of skin detachment and ocular surface disease. This study looked at the expression of the NLRP3 Inflammasome in the skin of patients with biopsy confirmed SJS/TEN compared to the lichen planus and normal controls by immunohistochemistry as well as observing the mitochondrial function of platelets challenged with plasma from patients with SJS/TEN and Normal Human Plasma using Agilent Seahorse XF Analyzer. Under a current, Loyola IRB approved protocol, 12 collected and archived unstained slides of skin and blood plasma samples from patients with biopsy confirmed SJS/TEN was used for this study. Immunohistochemical analysis was performed using anti-NLRP3 antibodies followed by imaging on a Delta Vision microscope. The precise roles of cytokines and chemokine receptors in severity of skin detachment has not been completely studied. The identification of the roles of NLRP3 in SJS/TEN would bridge the gaps in the basic understanding regarding the pathogenesis of this disease spectrum, especially skin detachment seen in SJS/TEN. NLRP3 Inflammasome is a potential therapeutic target and its inhibition by phytochemicals may be appropriate effective treatment strategies in the management of this condition.

Association of Human Leukocyte Antigen Alleles with Carbamazepine- or Lamotrigine-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in an Iranian Population: A Case-control Study.

Genetic diversity in human leukocyte antigen (HLA) alleles across populations is a significant risk factor for drug-induced severe cutaneous adverse reactions (SCARs), e.g., carbamazepine (CBZ)- and lamotrigine (LTG)-induced Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The present study aimed to investigate the frequency of different HLA alleles in Iranian patients with CBZ- and LTG-induced SJS/TEN. A case-control study was conducted from 2011 to 2018 at various hospitals affiliated with Shiraz University of Medical Sciences (Shiraz, Iran). A total of 31 patients receiving anticonvulsant drugs (CZB or LTG) were recruited and divided into two groups. The drug-induced group (n=14) included hospitalized patients due to CBZ- or LTG-induced SJS/TEN. The drug-tolerant group (n=17) included individuals receiving CBZ or LTG for at least three months with no adverse effects. In addition, 46 healthy individuals (control group) were recruited. The frequency of HLA-A, -B, and -DRB1 alleles in patients with CZB- or LTG-induced SJS/TEN was investigated. HLA typing was performed using the allele-specific polymerase chain reaction method. The Chi square test and Fisher's exact test were used to determine a potential association between SJS/TEN and HLA alleles. P<0.05 was considered statistically significant. CBZ- or LTG-induced SJS/TEN was not significantly associated with HLA alleles. However, HLA-DRB1*01 showed a significantly higher frequency in patients with CBZ-induced SJS/TEN than the CBZ-tolerant patients (30% vs. 9%, P=0.07). Overall, no significant association was found between CBZ- or LTG-induced SJS/TEN and HLA alleles. Further large-scale studies are required to substantiate our findings.

Patient Preferences for Rescue Medications in the Treatment of Breakthrough Cancer Pain.

The discrete choice experiment (DCE) is conducted in this study to discuss Chinese cancer patients' risk-benefit preferences for rescue medications (RD) and their willingness to pay (WTP) in the treatment of breakthrough cancer pain (BTcP). Through literature reviews, specialist consultation, and patient surveys, this work finally included five attributes in the DCE questionnaire, i.e., the remission time of breakthrough pain, adverse reactions of the digestive system, adverse reactions of the neuropsychiatric system, administration routes, and drug costs (estimating patients' WTP). The alternative-specific conditional logit model is used to analyze patients' preferences and WTP for each attribute and its level and to assess the sociodemographic impact and clinical characteristics. A total of 134 effective questionnaires were collected from January, 1 to April, 5 in 2022. Results show that the five attributes all have a significant impact on cancer patients' choice of "rescue medications" (P<0.05). Among these attributes, the remission time after drug administration (10.0; 95%CI 8.5-11.5) is the most important concern for patients, followed by adverse reactions of the digestive system (8.5; 95%CI 7.0-10.0), adverse reactions of the neuropsychiatric system (2.9; 95%CI 1.4-4.3), and administration routes (0.9; 95%CI 0-1.8). The respondents are willing to spend 1182 yuan (95%CI 605-1720 yuan) per month for "rescue medications" to take effect within 15 minutes and spend 1002 yuan (95%CI 605-1760 yuan) per month on reducing the incidence of drug-induced adverse reactions in the digestive system to 5%. For Chinese cancer patients, especially those with moderate/severe cancer pain, the priority is to relieve the BTcP more rapidly and reduce adverse drug reactions more effectively. This study indicates these patients' expectations for the quick control of breakthrough pain and their emphasis on the reduction of adverse reactions. These findings are useful for doctors, who are encouraged to communicate with cancer patients about how to better alleviate the BTcP.

054 Combination of thymus and activation-regulated chemokine and soluble OX40 as a diagnostic biomarker for DIHS/DRESS

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe drug-induced adverse reaction with fever, cutaneous eruptions, hematological abnormalities, organ dysfunction, and reactivation of human herpesvirus 6 (HHV-6). Although rapid diagnosis is necessary for the management of DIHS/DRESS, it is difficult to distinguish the early phase of DIHS/DRESS from other drug eruptions. We have previously reported that thymus and activation-regulated chemokine (TARC), which plays an important role in Th2-mediated immune-inflammatory processes such as atopic dermatitis, and serum soluble OX40 (CD134), which has an important role in allergic inflammation and functions as a cellular receptor for HHV-6 entry, can be a useful diagnostic marker for DIHS/DRESS. The sensitivity and specificity of sOX40 (cut-off value 213 pg/ml) for the diagnosis of DIHS/DRESS were 67% and 80%, respectively. Those of TARC (cut-off value 4000 pg/ml) were 72% and 77%, respectively. In this study, in order to reveal the relationship between serum soluble OX40 and TARC levels in the acute phase of DIHS/DRESS as well as the sensitivity and specificity of serological test using both soluble OX40 and TARC for diagnosis of DIHS/DRESS, we analyzed the sera of DIHS/DRESS patients presenting to our department. We found that the two markers were significantly correlated, and the combination of sOX40 and TARC significantly increased sensitivity to 85% but decreased specificity to 73%. The combined determination using sOX40 and TARC levels may be useful to increase the detection rate of DIHS/DRESS.

PSAT239 Pregnant Patient With a History of Methimazole-Induced Agranulocytosis Presenting With Hyperthyroidism: A Case Report

Abstract Background Pregnancy has a profound impact on the thyroid gland and its function. Severe thyrotoxicosis can lead to many complications and endanger the mother or fetus. Antithyroid drug (ATD), at its lowest possible dose, should be given. However, one of the complications of treatment include agranulocytosis which is a rare but serious allergic event with a prevalence of 0.1 to 0.5 percent. Thus, alternative treatment should be prescribed because a cross-reaction between ATDs was observed in 15.2% of patients in a study. Insufficient data is available regarding the use of these medications in pregnant patients with history of drug-induced adverse reactions. There are other feasible alternative treatments but are contraindicated in pregnancy. Case We report a 29-year old patient gravida 5 para 4 at 10 weeks age of gestation at the time of consult presenting with palpitations. She is a known case of Graves’ disease for 7 years and maintained on Methimazole. She was admitted a year prior consult as a case of impending thyroid storm; Methimazole-induced agranulocytosis. Initially, maintained on Lithium but shifted back to Methimazole without a physician's advice and later on, discontinued the medication upon knowledge of pregnancy. She presented on her first trimester of pregnancy with palpitations and elevated free thyroxine (T4) at 71.29 pM (normal range: 11-24 pM). She was started on Propylthiouracil 50 mg/tablet 1 tablet three times a day. On her second trimester, no reported symptoms of hyperthyroidism and/or agranulocytosis such as fever or sore throat. Thyroidectomy was offered at this time explaining the risks and benefits but she strongly refused. Free T4 was then maintained at a value slightly above the upper normal limit. Propylthiouracil was also shifted to Methimazole 5 mg/tablet 1 tablet once daily and revised to 1 tablet every other day on the third trimester of pregnancy. Delivery was uneventful and the newborn was evaluated by a pediatrician with unremarkable findings. Four weeks postpartum, no noted symptoms of hyperthyroidism and/or agranulocytosis. Free T4 was noted within the normal range at 18.84 pM. Alternative treatment was offered due to the risk of ATD-induced agranulocytosis. Conclusion Hyperthyroidism in pregnancy is associated with a variety of complications for the mother and fetus. Three effective treatment options include ATD, thyroidectomy or RAI therapy. But, not all are relatively safe for pregnancy. In initiating ATD, cross-reaction between medications should be considered especially for patients with history of adverse reaction, such as agranulocytosis, which can be life-threatening. However, there are limited studies in the management of this specific case. Treating physician and patient should discuss each of the options, including the benefits, drawbacks and side effects. Keywords: Hyperthyroidism, Graves’ disease, Pregnancy, Agranulocytosis Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Trovafloxacin drives inflammation-associated drug-induced adverse hepatic reaction by changing macrophage polarization

Drug-induced liver injury (DILI) is an adverse hepatic reaction and a serious concern for public healthcare systems and pharmaceutical companies. DILI is frequently caused by a combination of direct toxic stresses and subsequent immune damage to hepatocytes. However, little is known about the mechanism by which drugs facilitate the activation of the innate immune system. Here, we aimed to decipher the inflammatory events in trovafloxacin (TVX)-induced reactions using liver macrophages. We showed that proinflammatory M1-like macrophages mainly contributed to hepatotoxicity mediated by TVX, a DILI drug. Additionally, transcriptome results showed that the interferon type I pathway, cytokines, and apoptosis pathway were involved in the initiation of synergistic effects resulting in TVX-induced liver injury. We hypothesized that DILI drugs could drive liver injury by altering the activation and phenotype of hepatic macrophages. Furthermore, drug treatment-induced transcriptional changes such as Traf1 and 2, Socs3, and Hbegf in macrophage polarization could be used to assess drug-specific immune-mediated reactions. Therefore, we proposed that transcriptional change in the genes related to macrophage polarization index could be an indicator to reflect the severity of DILI in a preclinical setting during drug development.

Drug reaction with eosinophilia and systemic symptoms (DRESS): A tertiary care centre retrospective study.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, drug-induced severe adverse reaction that usually occurs 3-6weeks after initial exposure to certain drugs. It affects mainly adults and children to a lesser extent. Clinical features include fever, facial oedema, generalized skin rash, lymphadenopathy, haematological abnormalities and internal organ involvement. The objective was to investigate the clinical and laboratory features of patients with DRESS in our centre. We retrospectively describe and analyse 19 cases of DRESS whose diagnosis was based on the RegiSCAR criteria (≥6 points) that occurred from January 2009 to December 2019. Patient age ranged from 4 to 76 years (4 children/15 adults); 10 were female (52.3%). The most common culprit drugs were antibiotics (74%) and anticonvulsants (21%). The most common comorbidities were epilepsy (26%) and hypertension (26%). All patients developed cutaneous manifestations and of those, 58% presented facial oedema. Liver function tests, urea/creatinine and troponin elevation were present in 74, 32 and 42%, respectively. The median time to develop the skin rash after the drug exposure was 3.7 weeks (interquartile range 2.4-4.2 wk). Eosinophilia (≥0.7 × 109 /L) was present in 95% of the patients and peaked around 10 days after the skin manifestations. Leucocytosis and reactive lymphocytes were reported in 84% and 26% of all patients respectively. Treatment with systemic steroids was reported in 16 patients. The mean recovery time was 2 weeks (interquartile range 2-3.5 wk) and mortality was 5%. DRESS is a serious condition with significant morbidity and mortality, which requires more research for a better understanding.

Drug-Induced Severe Cutaneous Adverse Reactions: Insights Into Clinical Presentation, Immunopathogenesis, Diagnostic Methods, Treatment, and Pharmacogenomics.

SCARs are rare and life-threatening hypersensitivity reactions. In general, the increased duration of hospital stays and the associated cost burden are common issues, and in the worst-case scenario, they can result in mortality. SCARs are delayed T cell-mediated hypersensitivity reactions. Recovery can take from 2 weeks to many months after dechallenging the culprit drugs. Genetic polymorphism of the HLA genes may change the selection and presentation of antigens, allowing toxic drug metabolites to initiate immunological reactions. However, each SCARs has a different onset latency period, clinical features, or morphological pattern. This explains that, other than HLA mutations, other immuno-pathogenesis may be involved in drug-induced severe cutaneous reactions. This review will discuss the clinical morphology of various SCARs, various immune pathogenesis models, diagnostic criteria, treatments, the association of various drug-induced reactions and susceptible alleles in different populations, and the successful implementation of pharmacogenomics in Thailand for the prevention of SCARs.

Clinical aspects and therapeutic approach of drug-induced adverse skin reactions in a quaternary hospital: a retrospective study with 219 cases

BackgroundAdverse drug reactions are frequent, with cutaneous manifestations being the most common. In the hospital environment, the incidence of cutaneous drug reactions varies from 2% to 3%. ObjectiveTo analyze the profile of cutaneous drug reactions, relating clinical forms, suspected medications, histopathological alterations, systemic repercussions, treatment and course. MethodsClinical, retrospective and observational study of patients seen by the Dermatology Interconsultation team from January 2013 to December 2016. ResultsThe frequency of cutaneous drug reactions among the evaluated patients was 13.6%, with 219 cases diagnosed. In 65.7%, the reaction was considered mild, of which the most common was exanthema, while in 34.2%, the reaction was considered severe, with DRESS being the main form of reaction(18.2%). Antibiotics (36.5%) and anticonvulsants (10%) were the most involved drugs. In addition to drug discontinuation, systemic corticosteroids were prescribed in 47% of cases and intravenous immunoglobulin (IVIg) in 4.5%. Of the mild forms, in 62%, expectant management and/or exclusive use of symptomatic treatment was used. Study limitationsRetrospective study, with limitations inherent to this type of investigation; lack of some information in medical records; long evaluation period, with a possible change in external validity. ConclusionThe most frequently identified clinical form was exanthema, and antibiotics and anticonvulsants were the most frequently involved drug classes. About one-third of the patients had severe cutaneous drug reactions, with DRESS being the main one. Cutaneous drug reactions are frequent in clinical practice, and the dermatologist should be called in as soon as possible to assist in the diagnosis and management of these cases.

Blister fluid as a cellular input for exvivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.

Drug-induced severe cutaneous adverse reactions (SCARs) are presumed T-cell-mediated hypersensitivities associated with significant morbidity and mortality. Traditional invivo testing methods, such as patch or intradermal testing, are limited by a lack of standardization and poor sensitivity. Modern approaches to testing include measurement of IFN-γ release from patient PBMCs stimulated with the suspected causative drug. We sought to improve exvivo diagnostics for drug-induced SCARs by comparing enzyme-linked immunospot (ELISpot) sensitivities and flow cytometry-based intracellular cytokine staining and determination of the cellular composition of separate samples (PBMCs or blister fluid cells [BFCs]) from the same donor. ELISpot and flow cytometry analyses of IFN-γ release were performed on donor-matched PBMC and BFC samples from 4 patients with SCARs with distinct drug hypersensitivity. Immune responses to suspected drugs were detected in both the PBMC and BFC samples of 2 donors (donor patient 1 in response to ceftriaxone and case patient 4 in response to oxypurinol), with BFCs eliciting stronger responses. For the other 2 donors, only BFC samples showed a response to meloxicam (case patient 2) or sulfamethoxazole and its 4-nitro metabolite (case patient 3). Consistently, flow cytometry revealed a greater proportion of IFN-γ-secreting cells in the BFCs than in the PBMCs. The BFCs from case patient 3 were also enriched for memory, activation, and/or tissue recruitment markers over the PBMCs. Analysis of BFC samples for drug hypersensitivity diagnostics offers a higher sensitivity for detecting positive responses than does analysis of PBMC samples. This is consistent with recruitment (and enrichment) of cytokine-secreting cells with a memory/activated phenotype into blisters.

Association of HLA Alleles with Antiepileptic Drug-Induced Mild Cutaneous Reactions: A Case-Control Study of a Northeast Han Chinese Population.

Human leukocyte antigen (HLA) is associated with drug-induced cutaneous adverse reactions, including antiepileptic drugs (AEDs). HLA gene polymorphism has a regional discrepancy, and it is therefore important to study it in different populations. To investigate the role of HLA in AED-induced mild cutaneous adverse drug reactions (cADRs) in a Northeast Han Chinese population. A case-control study was performed in the First Hospital of Jilin University between August 2016 and March 2017. In total, 26 patients with mild cADRs induced by AEDs and 23 AED-tolerant control patients were included. Sequence-based typing (SBT) was used to detect HLA-A and HLA-B genotypes. Differences in genotype frequencies between groups were assessed using Fisher's exact test. In the mild cADRs group, 22 patients (84.6%) presented with maculopapular exanthema (MPE) and four patients (15.4%) presented with an isolated itch. The median duration between the AED exposure and cADRs was 7.5 days (IQR, 3 - 14 days). We failed to find statistically significant differences in HLA alleles between the cADRs group and the control group when considering all the drugs included in our study together or when considering oxcarbazepine (OXC), carbamazepine (CBZ), and levetiracetam (LEV) alone (P > 0.05). Our findings indicated that there was no correlation between HLA alleles and AED-induced mild cADRs in the Northeast Han Chinese population.

Diagnostic Challenges of Old Diseases in the COVID-19 Era: A Report of Two Cases of Carbamazepine-Induced DRESS Syndrome

A new MIS-C that develops after the acute stage of COVID-19 infection has recently been reported worldwide. Drug reaction with eosinophilia and systemic symptoms syndrome is a rare but potentially severe adverse drug-induced reaction most commonly associated with anticonvulsants. Due to variability in clinical presentation involving cutaneous and multiorgan systems, broad differential diagnosis, and lack of definitive diagnostic tests, diagnosis may be delayed. The authors report 2 cases of pediatric patients who presented with fever, diffuse rash, and exposure to COVID-19 infection with suspected MIS-C. Both patients' medical histories revealed carbamazepine treatment for approximately 2 months. The diagnosis of DRESS syndrome was associated with the use of carbamazepine. Distinguishing between MIS-C and DRESS syndrome may be difficult due to similar clinical and laboratory features and the lack of definitive diagnostic tests for either condition. When encountering cases like the current report, it is important to consider DRESS syndrome for early diagnosis and medical intervention.

26546 Allopurinol induced Stevens–Johnson syndrome/DRESS overlap: A rare manifestation

Drug-induced severe cutaneous adverse reactions (SCARs) encompass a group of conditions often associated to various degrees of morbidity and mortality. Although clinical and histopathologic characteristics differ among SCARs, cutaneous manifestations can occasionally be nonspecific, representing a diagnostic challenge. Although infrequently reported, overlapping syndromes can be considered in cases fulfilling diagnostic criteria for at least 2 of these entities using the RegiSCAR validations scores. Only 5 cases of overlapping SCARs have been reported in the literature, It is still unclear if SJS/DRESS overlap is a distinct clinical entity, or a subtype of DRESS. We report the case of a 40-year-old Hispanic man with allopurinol-induced SCAR which fulfilled diagnostic criteria for both SJS and DRESS. To the best of our knowledge, only 1 case of allopurinol-induced SJS/DRESS overlap has been reported in the literature. This case highlights the importance of using RegiSCAR validation scores in the diagnosis of SCARs. Given the differences in prognosis, management, clinical course, associated morbidities and mortality that exist among SCARs, an accurate initial diagnosis is essential.

Genotyping HLA alleles to predict the development of Severe cutaneous adverse drug reactions (SCARs): state-of-the-art

ABSTRACT Introduction: Pharmacogenomics has great potential in reducing drug-induced severe cutaneous adverse drug reactions (SCARs). Pharmacogenomic studies have revealed an association between HLA genes and SCARs including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Areas covered: Pharmacogenomics-guided therapy could prevent severe drug hypersensitivity reactions. The US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG) provided guidelines in the translation of clinically relevant and evidence-based SCARs pharmacogenomics research into clinical practice. In this review, we intended to summarize the significant HLA alleles associated with SCARs induced by different drugs in different populations. We also summarize the SCARs associated with genetic and non-genetic factors and the cost-effectiveness of screening tests. Expert opinion: The effectiveness of HLA screening on a wider scale in clinical practice requires significant resources, including state-of-the-art laboratory; multidisciplinary team approach and health care provider education and engagement; clinical decision support alert system via electronic medical record (EMR); laboratory standards and quality assurance; evidence of cost-effectiveness; and cost of pharmacogenomics tests and reimbursement.