Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Part II diagnosis and management.

Drug-induced hypersensitivity syndrome, also known as drug reaction with eosinophilia and systemic symptoms, is a severe cutaneous adverse reaction characterized by an exanthem, fever, and hematologic and visceral organ involvement. The differential diagnosis includes other cutaneous adverse reactions, infections, inflammatory and autoimmune diseases, and neoplastic disorders. Three sets of diagnostic criteria have been proposed; however, consensus is lacking. The cornerstone of management is immediate discontinuation of the suspected drug culprit. Systemic corticosteroids remain first-line therapy, but the literature on steroid-sparing agents is expanding. Longitudinal evaluation for sequelae is recommended. Adjunctive tests for risk stratification and drug culprit identification remain under investigation. Part II of this continuing medical education activity begins by exploring the differential diagnosis and diagnosis of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms and concludes with an evidence-based overview of evaluation and treatment.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Part I. Epidemiology, pathogenesis, clinicopathological features, and prognosis.

Drug-induced hypersensitivity syndrome (DiHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is a severe cutaneous adverse reaction (SCAR) characterized by an exanthem, fever, and hematologic and visceral organ involvement. Anticonvulsants, antibiotics, and allopurinol are the most common triggers. The pathogenesis involves a complex interplay between drugs, viruses, and the immune system primarily mediated by T-cells. DiHS/DRESS typically presents with a morbilliform eruption 2-6 weeks after drug exposure, and is associated with significant morbidity, mortality, and risk of relapse. Long-term sequelae primarily relate to organ dysfunction and autoimmune diseases. Part I of this continuing medical education activity on DiHS/DRESS provides an update on epidemiology, novel insights into pathogenesis, and a description of clinicopathological features and prognosis.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53 years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

DRESS syndrome with multiorgan involvement and HHV-6 reactivation in the absence of a drug trigger.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction where patients present with fever, morbilliform rash and multiorgan manifestations, which may include acute renal failure, acute respiratory distress syndrome and eosinophilic myocarditis. We present a case of a 60-year-old woman with acute heart failure, DRESS syndrome features and human herpesvirus 6 reactivation in the absence of a drug trigger. She was diagnosed with eosinophilic myocarditis and successfully treated with corticosteroid therapy.

Leukemoid reaction in minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: A brief report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an idiosyncratic drug reaction hallmarked by cutaneous eruption, fever, lymphadenopathy, multiorgan involvement, and hematological abnormalities, most often eosinophilia and atypical lymphocytosis. Leukemoid reactions have rarely been described in DRESS syndrome and here we describe a 16-year-old male who was admitted to the hospital with DRESS syndrome due to minocycline, who had a severe leukocytosis up to 52.08 K/µL. He improved with cessation of minocycline and initiation of systemic steroids. We report this case to add to the literature on hematological abnormalities in pediatric DRESS syndrome.

Severe cutaneous adverse reactions associated with the immune checkpoint inhibitors: A case/non-case analysis using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND/OBJECTIVES: The immune checkpoint inhibitors (ICIs) have been increasingly associated with severe cutaneous adverse reactions (SCARs). These reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are uncommon but potentially lethal. Despite the severity of these reactions and growing association with the ICIs, their specific risk and mortality rates have been largely unexplored. METHODS: A case/non-case analysis was performed using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to examine the reporting odds ratios (RORs) for ICI-associated SCARs cases under two conditions: (1) ICIs compared with all drugs in FAERS and (2) ICIs compared with a reference group of pooled anticancer drugs to control for underlying malignancy. RESULTS: A statistically significant ROR for SJS (ROR: 5.44), TEN (ROR: 5.81) and DRESS (ROR: 1.38) were identified under Condition 1. Under Condition 2, this significance was maintained for SJS (ROR: 7.31), TEN (ROR: 7.40) and DRESS (ROR: 3.90), and mild significance was identified for AGEP (ROR: 1.89). Mortality rates for the ICIs were increased compared with the anticancer medications (28.5% vs. 24.5% for SJS, 55.3% vs. 46% for TEN, 3.0% vs. 2.1% for AGEP and 7.1% vs. 6.1% for DRESS). CONCLUSIONS: Our results suggest an association between SCARs and the ICIs independent of cancer status.

Updates on the immunopathology and genomics of severe cutaneous adverse drug reactions.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) cause significant morbidity and mortality and impede new drug development. HLA class I associations with SJS/TEN and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome have aided preventive efforts and provided insights into immunopathogenesis. In SJS/TEN, HLA class I-restricted oligoclonal CD8+ T-cell responses occur at the tissue level. However, specific HLA risk allele(s) and antigens driving this response have not been identified for most drugs. HLA risk alleles also have incomplete positive and negative predictive values, making truly comprehensive screening currently challenging. Although, there have been key paradigm shifts in knowledge regarding drug hypersensitivity, there are still many open and unanswered questions about SCAR immunopathogenesis, as well as genetic and environmental risk. In addition to understanding the cellular and molecular basis of SCAR at the single-cell level, identification of the MHC-restricted drug-reactive self- or viral peptides driving the hypersensitivity reaction will also be critical to advancing premarketing strategies to predict risk at an individual and drug level. This will also enable identification of biologic markers for earlier diagnosis and accurate prognosis, as well as drug causality and targeted therapeutics.

DRESS syndrome: More than just a rash.

ABSTRACT: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is rare but carries significant mortality and morbidity, making early identification and definitive management crucial. The diagnosis of DRESS is made clinically and involves consideration of a broad list of differential diagnoses. Given variable clinical presentations among patients with DRESS syndrome, clinicians should look for common findings and other hallmarks of the syndrome while monitoring for known complications. Additionally, clinicians should maintain a high index of suspicion to avoid missing more mild presentations, such as in this case patient with DRESS syndrome minor.

Association of antiviral drugs and their possible mechanisms with DRESS syndrome using data mining algorithms.

Antiviral drugs are not known for drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. The current study aims is to find out the association of antiviral drugs and their possible mechanism with DRESS. Data mining algorithms such as proportional reporting ratio that is, PRR (≥2) with associated χ2  value (>4), reporting odds ratio that is, ROR (≥2) with 95% confidence interval and case count (≥3) were calculated to identify a possible signal. Further, molecular docking studies were conducted to check the interaction of selected antiviral drugs with possible targets. The potential signal of DRESS was found to be associated with abacavir, acyclovir, ganciclovir, lamivudine, lopinavir, nevirapine, ribavirin, ritonavir, and zidovudine among all selected antiviral drugs. Further, subgroup analysis has also shown a potential signal in different age groups and gender. The sensitivity analysis results have shown a decrease in the strength of the signal, however, there was no significant impact on the outcome except for acyclovir. The docking results have indicated the possible involvement of human leukocyte antigen (HLA)*B1502 and HLA*B5801. The positive signal of DRESS was found with selected antiviral drugs except for acyclovir.

Viral infections and drug hypersensitivity.

Virus infections and T-cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like ß-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i): drugs tend to bind to proteins and may even bind to immune receptors. Without viral infections, this low affine binding may be insufficient to elicit T-cell activation. During a viral infection, immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p-i reactions and may even be sufficient for T-cell activation and symptoms. There is a situation where the virus-DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p-i mediated immune stimulation during acute DRESS, which coincidentally activates many herpes virus-specific T cells. Through p-i stimulation, they develop a cytotoxic activity by killing herpes peptide-expressing cells and releasing herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes-virus viraemia after DRESS.

Cefotaxime-induced drug reaction with eosinophilia and systemic symptom in a child with cross-reactivity to other cephalosporins and cosensitization to teicoplanin.

Drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction. Commonly related to anticonvulsant and allopurinol, DRESS can affect both adults and children. Cefotaxime is rarely associated with DRESS, especially with children. We report a cefotaxime-induced DRESS in a child and emphasize the role of allergological work-up to point out the culprit drug in exploring cross-reactivity and identifying a possible cosensitization. A 2-year-old boy was treated with cefotaxime, vancomycin and metronidazole for acute otomastoiditis. Metronidazole was withdrawn and vancomycin was changed by teicoplanin 10 and 15 days later, respectively. Nineteen days after ongoing cefotaxime and 4 days after teicoplanin intake, the patient developed hyperthermia, a widespread exanthema, facial oedema with neither mucosal involvement nor palpable lymphadenopathy. Biological tests revealed eosinophilia, atypical lymphocytes, mild cytolysis and a high lactate dehydrogenase level. Serological tests for viral and bacterial infections were negative. DRESS was suspected and the 2 antibiotics were withdrawn. Intradermal tests (IDT) were carried out 2 months later with cefotaxime and teicoplanin. They revealed a positive result at 48-hour reading. To assess cross-reactivity among ß-lactams, IDT to penicillins (benzylpenicillin, amoxicillin and oxacillin) was performed showing negative results at 48-hour reading. Nevertheless, IDT to cephalosporins (cefazolin, cefuroxime, ceftazidime and ceftriaxone) displayed positive results at 48-hour reading. As a result, IDT are of great interest and should be performed to confirm the role of cefotaxime and detect a potential cross-reactivity with chemically similar drugs and drugs taken before and during the episode of DRESS.

DRESS/DiHS syndrome induced by Propylthiouracil: a case report.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as Drug-induced hypersensitivity syndrome (DiHS), is a severe adverse drug reaction. Propylthiouracil, a member of thiouracils group, is widely used in medical treatment of hyperthyroidism. Propylthiouracil is associated with multiple adverse effects such as rash, agranulocytosis hepatitis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, but rarely triggers DRESS/DiHS syndrome. Here, we describe a severe case of propylthiouracil-induced DRESS/DiHS syndrome. CASE PRESENTATION: A 38-year-old female was treated with methimazole for hyperthyroidism at first. 4 weeks later, the patient developed elevated liver transaminase so methimazole was stopped. After liver function improved in 2 weeks, medication was switched to propylthiouracil therapy. The patient subsequently developed nausea and rash followed by a high fever, acute toxic hepatitis and multiple organ dysfunction (liver, lung and heart), which lasted for 1 month after propylthiouracil was started. According to the diagnostic criteria, the patient was diagnosed of DRESS/DiHS syndrome which was induced by propylthiouracil. As a result, propylthiouracil was immediately withdrawn. And patient was then treated with adalimumab, systematic corticosteroids and plasmapheresis in sequence. Symptoms were finally resolved 4 weeks later. CONCLUSIONS: Propylthiouracil is a rare cause of the DRESS/DiHS syndrome, which typically consists of severe dermatitis and various degrees of internal organ involvement. We want to emphasize through this severe case that DRESS/DiHS syndrome should be promptly recognized to hasten recovery.

Azathioprine hypersensitivity syndrome manifesting as subcutaneous Sweet syndrome and acute pancreatitis.

Azathioprine (AZA) is a commonly used immunosuppressive therapy that has been implicated in a number of cutaneous and systemic inflammatory reactions. Initiation of AZA has been associated with a hypersensitivity syndrome manifesting as acute pancreatitis and Sweet syndrome. Subcutaneous Sweet syndrome is a rare variant of Sweet syndrome where the dominant localization of inflammation is within the subcutaneous fat; it is commonly associated with underlying myeloproliferative disease. However, it has not been reported in the literature as a cutaneous manifestation of AZA hypersensitivity syndrome. We present a unique case of acute pancreatitis and biopsy-proven subcutaneous Sweet syndrome following the initiation of AZA with resolution upon discontinuation.

Gemcitabine-associated DRESS syndrome: A case report.

INTRODUCTION: Gemcitabine is a well-tolerated pyrimidine antimetabolite chemotherapeutic that is increasingly utilized to treat non-small cell lung carcinoma, breast, pancreatic, and urogenital cancers. Myelosuppression is a common side effect and skin rashes can be observed. We discuss a case of the exceedingly rare DRESS syndrome, which appeared following Gemcitabine treatment. CASE REPORT: A 60-year-old patient with pancreatic cancer and liver metastases received therapy with Gemcitabine as a single agent. Fever, itching, and redness started to be reported on the third day of receiving Gemcitabine treatment. The patient's diffuse maculopapular rash steadily got worse, leading to hospitalization. MANAGEMENT AND OUTCOME: In the patient's physical examination, a high fever, hepatomegaly, and a diffuse macular papular rash were detected, an increase in eosinophils in the complete blood count and peripheral blood. A skin biopsy was performed. It was determined that the patient had Gemcitabine-associated DRESS syndrome. Antihistamines and local steroids were administered. On the fifth day following treatment, skin lesions and eosinophilia decreased. DISCUSSION: The most common cause of DRESS syndrome, a disorder marked by extensive skin eruption, fever, eosinophilia, and systemic symptoms, is medication use. Infections including HHV-6, EBV, and CMV can occasionally be the reason. Gemcitabine is one of the medications that is frequently used in cancer, and a case was provided because the literature review did not mention Gemcitabine-related DRESS syndrome.

Management and treatment outcome of DRESS patients in Europe: An international multicentre retrospective study of 141 cases.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. OBJECTIVE: To explore treatment approaches across Europe and their impact on the disease course, as well as prognostic factors and culprit drugs. METHODS: In this retrospective European multicentric study, we included patients with probable or certain DRESS (RegiSCAR score ≥ 4) between January 2016 and December 2020. Independent associations between clinical parameters and the risk of intensive care unit admission and mortality at three months were assessed using a multivariable-adjusted logistic regression model. RESULTS: A total of 141 patients from 8 tertiary centres were included. Morbilliform exanthem was the most frequent cutaneous manifestation (78.0%). The mean affected body surface area (BSA) was 67%, 42% of the patients presented with erythroderma, and 24.8% had mucosal involvement. Based on systemic involvement, 31.9% of the patients had a severe DRESS. Anticonvulsants (24.1%) and sulphonamides (22.0%) were the most frequent causative agents. In all, 73% of the patients were treated with systemic glucocorticoids, and 25.5% received topical corticosteroids as monotherapy. Few patients received antiviral drugs or anti-IL5. No patients received intravenous immunoglobulins. The overall mortality was 7.1%. Independent predictors of mortality were older age (≥57.0 years; fully adjusted OR, 9.80; 95% CI, 1.20-79.93; p = 0.033), kidney involvement (fully adjusted OR, 4.70; 95% CI, 1.00-24.12; p = 0.049), and admission in intensive care unit (fully adjusted OR, 8.12; 95% CI, 1.90-34.67; p = 0.005). Relapse of DRESS and delayed autoimmune sequelae occurred in 8.5% and 12.1% of patients, respectively. CONCLUSIONS: This study underlines the need for diagnostic and prognostic scores/markers as well as for prospective clinical trials of drugs with the potential to reduce mortality and complications of DRESS.

Multiple Drug Hypersensitivity in a Small Child with DRESS Syndrome - A Case Report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) belongs to the group of severe cutaneous adverse reactions. Here we report a case of drug hypersensitivity against multiple antibiotics with DRESS in a young child with necrotizing pneumonia.

Drug reaction with eosinophilia and systemic symptoms in a paediatric population: Interest of skin tests.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction. It is uncommon in the paediatric population and can be difficult to diagnose as its initial symptoms may mimic a viral infection. OBJECTIVE: To analyse the features of paediatric DRESS and to evaluate the interest of skin tests in identifying the causative drugs. METHODS: It is a retrospective analysis (2004-2021) of DRESS cases diagnosed in paediatric patients. The DRESS diagnosis was defined using the RegiSCAR scoring. The skin tests were performed according to the ENDA recommendations. RESULTS: We included 19 cases of DRESS occurred in 18 patients. Common clinical symptoms were exanthema and fever in 94.7% of cases each. The most commonly affected organ was the liver (84.2%). Among the implicated drugs, 16 were tested and skin tests were positive in 75%. To assess cross-reactivity and co-sensitization, skin tests with related and/or co-administered drugs were performed in eight patients. Among them, only one child had positive results. CONCLUSION: Early diagnosis of DRESS and discontinuation of the incriminated drug might reduce the incidence of mortality in the paediatric population. Skin tests could be a safe and useful tool to identify the causative drug and assess cross-reactivity.

Comparison of cyclosporine and systemic corticosteroid for treating drug reaction with eosinophilia and systemic symptoms syndrome: A retrospective 20-year single-centre study in South Korea.

BACKGROUND/OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening hypersensitive disorder. Cyclosporine has been indicated for adverse cutaneous drug eruptions. However, studies evaluating its clinical effectiveness in DRESS syndrome have been rare. This study aimed to evaluate the clinical efficacy of cyclosporine in DRESS syndrome compared to that of systemic corticosteroids. METHODS: In the cyclosporine group, oral cyclosporine was administered twice a day for a total of 2-3 mg/kg/day for 1 week, and subsequently reduced to 1-1.5 mg/kg/day for extended treatment. In the corticosteroid group, intravenous or oral methylprednisolone was administered at 1-1.5 mg/kg/day for 1 week, with variable tapering plans. Laboratory changes before and after treatment, hospitalized days, treatment periods, and time to normalization from clinical manifestations in each group were statistically evaluated. Adverse effects of these regimens were observed during the entire treatment period. RESULTS: Eighty patients were enrolled in this retrospective study. The cyclosporine and corticosteroid group had 27 and 53 patients, respectively. Total leucocyte and eosinophil counts, liver enzymes, and C-reactive proteins were significantly decreased after treatment in both groups. There were no statistically significant differences observed in hospitalized days, treatment period, and time to normalization from clinical manifestations between the two groups. The corticosteroid group experienced relatively more adverse effects than the cyclosporine group. CONCLUSIONS: Cyclosporine was discovered to be clinically effective in DRESS syndrome and this study suggests that cyclosporine could be a feasible primary therapeutic option for DRESS syndrome.

Immune Reactions in Major Types of Oncological Treatment.

In recent years, there has been a noticeable development in oncological treatment, including chemotherapy and biological treatment. Despite their significant effectiveness, they are not free from side effects, such as allergic and dermatological reactions. These reactions can vary in severity and outcome, including potential death. Examples, among others, are type I-IV hypersensitivity reactions of various origins and skin reactions including rashes, itching and redness, but also severe cutaneous syndromes. Due to the therapy used, these may include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis. In some cases, it is necessary to interrupt therapy, which may result in a poorer outcome and shorten the patient's survival. This paper reviews various types of research documents published since 2016. It aims to systematize the latest knowledge and highlight the need for further research into ways to avoid adverse reactions.

Malondialdehyde as a Potential Oxidative Stress Marker for Allergy-Oriented Diseases: An Update.

Malondialdehyde (MDA) is a compound that is derived from the peroxidation of polyunsaturated fatty acids. It has been used as a biomarker to measure oxidative stress in various biological samples in patients who are affected by a wide range of diseases. The aim of our work is to provide an updated overview of the role of MDA as a marker of oxidative stress in allergy-related diseases. We considered studies involving both paediatric and adult patients affected by rhinitis, asthma, urticaria and atopic dermatitis. The measurement of MDA was performed on different types of samples. The reported data highlight the role of serum MDA in inflammatory airway diseases. According to the literature review, the oxidative stress status in asthmatic patients, assessed via MDA determination, appears to worsen in the presence of other allergic airway diseases and in relation to the disease severity. This suggests that MDA can be a suitable marker for monitoring the disease status. However, there are several limitations in the considered studies due to the different samples used and the lack of phenotyping and description of the clinical period of patients examined. In cutaneous allergic diseases, the role of MDA is controversial because of the smallness of the studies and the heterogeneity of the samples and patients.