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Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1, c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC. [ABSTRACT FROM AUTHOR]

Abstract Giant cell myocarditis (GCM) is a rare but fatal disease that can lead to cardiac failure. Survival with a cardiac standstill requires mechanical circulatory support or a biventricular assist device (BiVAD) and prolonged survival is extremely rare. Drug‐induced hypersensitivity syndrome (DIHS) is a severe cutaneous adverse reaction. Some cases of DIHS are reportedly associated with the onset of GCM. We present a case of a 28‐year‐old woman who developed GCM during steroid tapering after DIHS. She went into continuous cardiac standstill but survived for 74 days under BiVAD support. Our case is noteworthy because the histopathologic specimens obtained on three occasions contributed to the diagnosis of this particular condition over time. We also reviewed previous literature on concomitant cases of GCM and DIHS. We found that two are potentially associated and most cases of GCM occur within 3 months of DIHS during steroid tapering.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Giant cell myocarditis (GCM) is a rare but fatal disease that can lead to cardiac failure. Survival with a cardiac standstill requires mechanical circulatory support or a biventricular assist device (BiVAD) and prolonged survival is extremely rare. Drug‐induced hypersensitivity syndrome (DIHS) is a severe cutaneous adverse reaction. Some cases of DIHS are reportedly associated with the onset of GCM. We present a case of a 28‐year‐old woman who developed GCM during steroid tapering after DIHS. She went into continuous cardiac standstill but survived for 74 days under BiVAD support. Our case is noteworthy because the histopathologic specimens obtained on three occasions contributed to the diagnosis of this particular condition over time. We also reviewed previous literature on concomitant cases of GCM and DIHS. We found that two are potentially associated and most cases of GCM occur within 3 months of DIHS during steroid tapering. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS), is a severe type of cutaneous adverse reaction. The gold standard therapy for DRESS involves the discontinuation of the culprit drug, supportive therapies, and administration of corticosteroids. However, in cases of primary treatment failure or suboptimal response, there arises an urgent need for alternative interventions. This review focuses on exploring alternative systemic therapies for patients with steroid-resistant DRESS, steroid-dependent DRESS, or refractory DRESS, encompassing immunosuppressive agents, intravenous immunoglobulin, plasmapheresis, biologics, and small molecule drugs, with an emphasis on their clinical efficacy and the underlying mechanisms in the treatment of DRESS. Furthermore, this review provides a summary of potential management strategies and laboratory workup during the treatment of DRESS.

Allergic reactions to drugs caused by piperacillin-tazobactam are common in clinical practice. However, we also found a few cases of drug-induced hypersensitivity syndrome (DiHS)/Drug reaction with eosinophilia and systemic symptoms (DRESS) caused by piperacillin-tazobactam in our clinical work. We report a case of a 60-year-old female patient who was treated with piperacillin-tazobactam anti-infective therapy after the diagnosis of hematogenous lung abscess, developed fever, rash, and blood abnormalities after 26 days of application, and was later diagnosed as DIHS, which was improved after the administration of glucocorticoid and anti-allergic drugs. In addition, we also retrospectively analyzed 17 cases of DiHS caused by piperacillin-tazobactam from the PubMed databases between March 1980 and September 2023. The majority of the patients had an incubation period of more than 14 days, and the common clinical features included elevated eosinophil count/percentage, fever, rash, liver damage, and lymph node enlargement. After treatment with topical or systemic glucocorticoids, 16 of the 17 patients improved and one died because of the underlying condition. The clinical features of DiHS were diverse and included a long incubation period, skin rash, elevated eosinophils, and impaired organ function. Since some patients have atypical clinical features, clinicians should raise awareness of the disease, recognize these features early, and treat them promptly.

Drug‐induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a type of drug eruption that causes multiorgan disorders after the administration of certain drugs such as anticonvulsants. Herein, we report the case of a 66‐year‐old man with DiHS/DRESS complicated by fulminant type 1 diabetes (FT1D), shock, and cardiac involvement who was treated conservatively without systemic corticosteroid administration. He had taken carbamazepine for trigeminal neuralgia for 7 weeks until he noticed eruptions on his trunk. Two days after admission, he developed diabetic ketoacidosis, resulting in hypovolemic shock. The patient was diagnosed with FT1D, and insulin was administered. Additionally, the patient had a fever over 38°C, elevated white blood cells (>20 000/μL), liver dysfunction, atypical lymphocytes, and lymphadenopathy, but no evidence of viral reactivation. The lymphocyte transformation test for carbamazepine was positive, and human leukocyte antigen typing revealed the A31:01 haplotype, a risk factor for carbamazepine‐induced cutaneous adverse drug reactions. Collectively, a diagnosis of atypical DiHS and a definitive case of DRESS was made. Moreover, myocardial dysfunction wall motion was observed. A close examination revealed mild coronary artery stenosis, leading to a diagnosis of type 2 myocardial infarction due to relative ischemia. The patient was carefully monitored without systemic corticosteroid administration because both clinical findings and laboratory data peaked on the same day. The patient's eruption and general condition improved, and he was discharged 4 weeks later. While most cases of DiHS/DRESS with cardiac involvement present with myocarditis, the possibility of ischemic heart disease should be considered in patients with cardiac involvement under shock. [ABSTRACT FROM AUTHOR]

Abstract Background Drug-induced hypersensitivity syndrome (DIHS), including Stevens-Johnson syndrome (SJS), is a severe rash that often develops 2–6 weeks after the intake of the causative drug; however, its diagnosis is sometimes difficult. This article describes a case in which a patient with DIHS-induced multiple organ failure was successfully treated with blood purification therapy. Case presentation A male patient in his 60s was admitted to our hospital with autoimmune encephalitis. The patient was treated with steroid pulse therapy, acyclovir, levetiracetam, and phenytoin. From the 25th day, he presented with fever (≥ 38 °C) as well as miliary-sized erythema on the extremities and trunk, followed by erosions. DIHS and SJS were suspected; accordingly, levetiracetam, phenytoin, and acyclovir were discontinued. On the 30th day, his condition further deteriorated, and he was admitted to the intensive care unit for ventilatory management. The next day, he developed multi-organ failure and was started on hemodiafiltration (HDF) for acute kidney injury. Although he presented with hepatic dysfunction and the appearance of atypical lymphocytes, he did not meet the diagnostic criteria for DIHS or SJS/toxic epidermal necrolysis. Therefore, he was diagnosed with multi-organ failure caused by severe drug eruption and underwent a 3-day treatment with plasma exchange (PE) in addition to HDF. Accordingly, the patient was diagnosed with atypical DIHS. After being started on blood purification therapy, the skin rash began to disappear; moreover, the organ damage improved, with a gradual increase in urine output. Eventually, the patient was weaned off the ventilator and transferred to the hospital on the 101st day. Conclusions HDF + PE could effectively treat multi-organ failure caused by atypical DIHS, which is difficult to diagnose.

Introduction: Human herpesvirus-6 (HHV-6) is a ubiquitous lymphotropic betaherpesvirus that can reactivate in drug rash with eosinophilia and systemic symptoms (DRESS). Despite recent publications advancing our understanding of HHV-6 in DRESS, the exact role of HHV-6 in disease pathogenesis remains unclear. Methods: A scoping review with the PubMed query "(HHV 6 AND (drug OR DRESS OR DIHS)) OR (HHV6 AND (drug OR DRESS OR DIHS))" was conducted in accordance with PRISMA guidelines. Articles containing original data on at least one DRESS patient with HHV-6 testing were included. Results: Our search returned a total of 373 publications, of which 89 met eligibility criteria. HHV-6 reactivation occurred in 63% of DRESS patients (n = 748), which was significantly more often than other herpesviruses. HHV-6 reactivation was associated with worse outcomes and greater severity in controlled studies. Case reports have demonstrated sometimes fatal HHV-6-related multi-organ involvement. Temporally, HHV-6 reactivation typically occurs 2 to 4 weeks after DRESS onset and has been linked to markers of immunologic signaling, such as OX40 (CD134), an HHV-6 entry receptor. Efficacy of antiviral or immunoglobulin treatment has only been demonstrated anecdotally, and steroid use may affect HHV-6 reactivation. Conclusion: HHV-6 is implicated in DRESS more than in any other dermatologic condition. It is still unclear whether HHV-6 reactivation is cause or consequence of DRESS dysregulation. Similar pathogenic mechanisms precipitated by HHV-6 in other contexts may be relevant in DRESS. Future randomized controlled studies to assess effects of viral suppression on clinical outcomes is needed. [ABSTRACT FROM AUTHOR]

Background: Drug-induced hypersensitivity syndrome (DIHS), including Stevens-Johnson syndrome (SJS), is a severe rash that often develops 2–6 weeks after the intake of the causative drug; however, its diagnosis is sometimes difficult. This article describes a case in which a patient with DIHS-induced multiple organ failure was successfully treated with blood purification therapy. Case presentation: A male patient in his 60s was admitted to our hospital with autoimmune encephalitis. The patient was treated with steroid pulse therapy, acyclovir, levetiracetam, and phenytoin. From the 25th day, he presented with fever (≥ 38 °C) as well as miliary-sized erythema on the extremities and trunk, followed by erosions. DIHS and SJS were suspected; accordingly, levetiracetam, phenytoin, and acyclovir were discontinued. On the 30th day, his condition further deteriorated, and he was admitted to the intensive care unit for ventilatory management. The next day, he developed multi-organ failure and was started on hemodiafiltration (HDF) for acute kidney injury. Although he presented with hepatic dysfunction and the appearance of atypical lymphocytes, he did not meet the diagnostic criteria for DIHS or SJS/toxic epidermal necrolysis. Therefore, he was diagnosed with multi-organ failure caused by severe drug eruption and underwent a 3-day treatment with plasma exchange (PE) in addition to HDF. Accordingly, the patient was diagnosed with atypical DIHS. After being started on blood purification therapy, the skin rash began to disappear; moreover, the organ damage improved, with a gradual increase in urine output. Eventually, the patient was weaned off the ventilator and transferred to the hospital on the 101st day. Conclusions: HDF + PE could effectively treat multi-organ failure caused by atypical DIHS, which is difficult to diagnose. [ABSTRACT FROM AUTHOR]

DRESS is a potentially life-threatening severe cutaneous adverse reaction (SCAR). Historically, it was most frequently linked with phenytoin and was initially described as phenytoin hypersensitivity syndrome; however, it was later found to be caused by various other medications, with the commonest been aromatic anticonvulsants, allopurinol and sulfonamides. The severity of this entity is related to systemic involvement, which can result in multiorgan failure and death. The diagnosis of DRESS, especially in the early stages, remains challenging and elusive due to its heterogeneous clinical presentation and the complex course of the disease with different patterns depending on the causal drug. The most important step in the management of DRESS is early diagnosis and immediate cessation of the suspected offending drug along with oral steroids or immunosuppressants to control the disease. We describe the varying presentation and management of six adults with DRESS from a tertiary care hospital, observed over a two-year period with a brief review of the literature. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) was initially described as a protein involved in bone metabolism, but the roles played by OPN in the immune system and allergic reactions have attracted increasing attention. Here, we clarify the OPN‐related dynamics of severe cutaneous adverse drug reactions, and assess whether the OPN level has utility for classifying such reactions and serving as a biomarker of severity. Serum OPN levels in patients with drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and erythema multiforme‐type drug reaction (EM‐DR) were quantified by ELISA. The OPN sources were analyzed by dual immunofluorescence assay of DIHS, SJS/TEN and EM‐DR biopsy specimens. The serum OPN levels of DIHS/DRESS patients (489.1 ± 37.0 ng/mL) and SJS/TEN patients (508.5 ± 47.8 ng/mL) were significantly higher compared with controls (314.4 ± 14.3 ng/mL; p < 0.001). After treatment, the serum OPN level of DIHS/DRESS patients decreased to that of controls. In addition, OPN levels in DIHS/DRESS patients and SJS/TEN patients were higher than in patients with EM‐DR (Mann–Whitney U test, p < 0.05). However, when the Kruskal–Wallis test was used to compare the OPN levels among the three groups of patients, the difference was not significant (p = 0.055). Dual immunofluorescence assay revealed that T lymphocytes and macrophages were the main OPN sources in DIHS, SJS/TEN and EM‐DR patients. These data suggest that the OPN level can be used to evaluate the severity of inflammation in patients experiencing drug reactions. [ABSTRACT FROM AUTHOR]

Abstract Background Drug-induced hypersensitivity syndrome (DIHS) is a rare, potentially life-threatening systemic drug reaction. Antithyroid drugs (ATDs) causing DIHS have seldom been reported before. Case presentation We present a case of propylthiouracil (PTU)-induced DIHS, which included fever, skin rash, lymphadenopathy, hepatosplenomegaly, serious liver and kidney dysfunction, peripheral blood eosinophilia, and atypical lymphocytosis. Following supportive therapy, intravenous immunoglobulin (IVIG), and systemic corticosteroid, the patient experienced a resolution of fever and rash combined with progressive normalization of hematological index and organ function. These clinical features, and the skin lesion biopsy confirmed DIHS diagnosis. Conclusions To our knowledge, this is the second reported case of PTU-induced DIHS worldwide and the first human leukocyte antigen (HLA) typing of PTU-induced DIHS. Clinicians should cautiously distinguish hyperthyroidism etiology and identify the indication of ATDs. Timely recognition and formal DIHS treatment are required in patients with ATDs.

Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a systemic inflammatory condition that is characterized by multisystemic involvement (liver, blood, and skin), heterogeneous manifestations (fever, rash, lymphadenopathy, and eosinophilia), and an unpredictable course; cases of DiHS/DRESS caused by sulfasalazine are rare in children compared to adults. We report a case of a 12-year-old girl with juvenile idiopathic arthritis (JIA) and sulfasalazine-related hypersensitivity who developed fever, rash, blood abnormalities, and hepatitis complicated with hypocoagulation. The treatment with intravenous and then oral glucocorticosteroids was effective. We also reviewed 15 cases (67% male patients) of childhood-onset sulfasalazine-related DiHS/DRESS from the MEDLINE/PubMed and Scopus online databases. All reviewed cases had a fever, lymphadenopathy, and liver involvement. Eosinophilia was reported in 60% of patients. All patients were treated with systemic corticosteroids, and one patient required emergency liver transplantation. Two patients (13%) died. A total of 40.0% of patients satisfied RegiSCAR definite criteria, 53.3% were probable, and 80.0% satisfied Bocquet's criteria. Only 13.3% satisfied typical and 20.0% atypical DIHS criteria from the Japanese group. Pediatric rheumatologists should be aware of DiHS/DRESS due to its similarities to other systemic inflammatory syndromes (especially systemic JIA, macrophage activation syndrome, and secondary hemophagocytic lymphohistiocytosis). Further studies of DiHS/DRESS syndrome in children are needed to improve its recognition and differential diagnostic and therapeutic options.

CD134/OX40, a member of the tumor necrosis factor receptor superfamily, is a cell‐specific receptor for human herpesvirus 6 (HHV‐6) variant B. Patients with drug‐induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) present a significant increase in CD134 expression in peripheral blood CD4+ T cells. We aimed to investigate the frequency of CD134+ CD4 T cells infiltrating skin lesions in patients with DIHS/DRESS and its association with disease severity. We retrospectively included 21 patients with DIHS/DRESS and 11 patients with erythema multiforme (EM). By immunohistochemistry, the frequency of CD134+ CD4 T cells in DIHS was significantly higher than that in EM (p = 0.0083). The DIHS/DRESS severity score was significantly correlated with the frequency of CD134+ CD4 T cells (p = 0.0272); moreover, there was a significant difference between severe and mild/moderate cases. Double immunofluorescence staining revealed that numerous cells presented CD134/CD4 and CD134/Foxp3 overlap in patients with DIHS/DRESS. These data suggest increased susceptibility to HHV‐6 infection at localized skin sites. HHV‐6 may be involved in the mechanism underlying the progression and pathophysiology of DIHS/DRESS. [ABSTRACT FROM AUTHOR]

Background: In high HIV prevalence settings, first-line antituberculosis drug (FLTD)-associated drug reaction with eosinophilia and systemic symptoms (DRESS) poses therapeutic challenges. A sequential and additive drug challenge (SADC) of FLTDs best identifies offending drug(s), avoids unnecessary exclusions, and optimizes reinitiation of nonoffending drugs. However, SADC-associated reaction complexities limit its utility., Objective: We aimed to describe the characteristics of patients with FLTD-associated DRESS, their treatment-limiting SADC reactions, and related outcomes., Methods: Patients hospitalized with FLTD-associated DRESS from 2013 to 2023 in a South African tertiary hospital and enrolled (retrospectively or prospectively) in an existing registry were eligible., Results: SADC was undertaken in 41 patients. Overall, 47 classifiable reactions occurred. 34/47 (72%) reactions in 29/41 (71%) patients were treatment-limiting and 12 of 41(29%) patients reinitiated FLTDs uneventfully. Fifteen single and 8 multiple drug reactors were identified. Rifampicin in 13 of 23(57%) reactors was the most common individual offender. Ethambutol was most frequently involved in multiple drug reactors. The median (interquartile range) time to a detectable reaction was 24(12-120) hours, 6 of 34(18%) being immediate (<6 hours). Itch (65%), eosinophilia (56%), fever (41%), atypical lymphocytosis (41%), rash (38%), transaminitis (32%), and facial edema (18%) singly or in combination were the most common features. Three reactions, 1 epidermal necrolysis and 2 liver derangements, were Common Terminology Criteria for Adverse Events grade 4 (life-threatening) events. No predictors of multiple drug reactivity were identified, but multiple reactors were hospitalized significantly longer, 125(100-134) days versus 60(45-80) days., Conclusions: SADC optimizes FLTD reinitiation. However, timing, clinical presentation, and severity of SADC-associated reactions after FLTD-associated DRESS are markedly heterogeneous. Additionally, multiple drug reactors are a complex group that require longer hospitalization. There are no routine biomarkers available to distinguish true multiple drug hypersensitivity from nonspecific flare-ups and to guide long-term drug avoidance strategies., (Copyright © 2024. Published by Elsevier Inc.)

Abstract Although the development of autoimmune disorders is recognized in drug‐induced hypersensitivity syndrome (DIHS), the serial change of B‐cell activity has not been well‐addressed. Herein, the serum levels of IL‐6, IL‐10, B‐cell activating factor of the tumor necrosis factor family (BAFF), and a proliferation‐inducing ligand (APRIL) in three DIHS patients were tracked over time. While IL‐6 and IL‐10 tended to be elevated according to the disease activity, BAFF and APRIL increased during the improved phase. Our results imply that the continuous activation of B cells may be involved in the prolonged disease activity of DIHS and the development of autoimmune disorders.

Abstract Background Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an important adverse reaction caused by a few drugs. Reactivation of human herpesvirus 6 (HHV-6) is known to be associated with its pathogenesis. DIHS occasionally manifests as pulmonary lesions with a variety of imaging findings. Case presentation An 83-year-old woman started taking minodronic acid hydrate 5 years before admission. She noticed a generalized skin rash 44 days before admission and started oral betamethasone-d-chlorpheniramine maleate combination tablets for allergic dermatitis. She developed a fever and cough in addition to the rash, and was referred to our hospital. Laboratory data showed a high level of eosinophils and liver and biliary enzymes. Computed tomography (CT) studies revealed bilateral diffuse ground-glass opacities with ill-defined centrilobular nodules from the central to peripheral regions of the lungs. Transbronchial lung cryobiopsy specimens showed that lymphocyte infiltration was observed in the alveolar walls and fibrinous exudates and floating macrophages in the alveolar lumina. Immunohistochemistry of biopsy specimens showed more CD4+ lymphocytes than CD8+ lymphocytes, while few Foxp3+ lymphocytes were recognized. The serum anti-HHV-6 immunoglobulin G titer increased at 3 weeks after the first test. Based on these findings, we diagnosed her with DIHS. We continued care without using corticosteroids since there was no worsening of breathing or skin condition. Eventually, her clinical symptoms chest CT had improved. Minodronic acid hydrate was identified as the culprit drug based on the positive results of the patch test and drug-induced lymphocyte stimulation test. Conclusions We described the first case of DIHS caused by minodronic acid hydrate. Lung lesions in DIHS can present with bilateral diffuse ground-glass opacities and ill-defined centrilobular nodules on a CT scan during the recovery phase. Clinicians should be aware of DIHS, even if patients are not involved with typical DIHS/DRESS-causing drugs.

Drug-induced hypersensitivity syndrome (DiHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug-induced reaction characterized by various symptoms: skin rash, fever, lymph node enlargement and internal organ involvement, which starts within 2 weeks to 3 months after drug initiation. It is challenging to diagnose this syndrome due to the variety of cutaneous and visceral symptoms. Different mechanisms have been implicated in its development, including genetic susceptibility associated with human leucocyte antigen (HLA) loci, detoxification defects leading to reactive metabolite formation and subsequent immunological reactions, slow acetylation, and reactivation of human herpes, including Epstein-Barr virus and human herpes virus (HHV)-6 and HHV-7. The most frequently reported causes of DiHS/DRESS are antiepileptic agents, allopurinol and sulfonamides. We report a case of DiHS/DRESS induced by second-line treatment for tuberculosis, prothionamide and para-aminosalicylic acid, and Epstein-Barr virus re-infection. Patch testing, which was performed in this case, is not fully standardized, but it can be helpful and a safe way to evaluate and diagnose DiHS/DRESS.

What is Known and Objective: Allopurinol‐induced drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but serious and potentially life‐threatening drug hypersensitivity syndrome. In this study, we aimed to investigate the clinical features, treatment outcomes, and prognostic factors of allopurinol‐induced DRESS. Methods: Case reports of allopurinol‐induced DRESS published by China from January 2000 to August 2021 were retrieved from CNKI, Wan Fang, VIP, and PubMed databases for analysis. Results and Discussion: This study included 52 patients, consisting of 41 (78.8%) males and 11 (21.2%) females (M:F = 3.7:1). The mean of age was 56.1 ± 17.1 years (range: 18–86 years). The mean of latency periods was 24.6 ± 15.0 days (range:1‐63 days). Most patients presented with fever, cutaneous eruption, eosinophilia, lymphadenopathy, and facial edema. 36/52 (69.2%) patients showed two or more internal organs involved. Liver and kidney injuries were the most common visceral manifestation. Pulmonary involvement (34.6%), cardiac involvement (25.0%) and gastrointestinal involvement (21.2%) were relatively less known but severe complications. 2/52 (3.8%) patients showed nervous system involved, presenting as leukoencephalopathy or peripheral neuropathy. 2/52 (3.8%) patients presented with secondary hemophagocytic lymphohistiocytosis.1/52 (1.9%) patient developed pure red cell aplasia and 1/52 (1.9%) patient developed painless thyroiditis. HLA*B 58:01 allele was tested in 18/52 (34.6%) patients. 16/18 (88.9%) cases were positive. 48/52 (92.3%) patients were treated with systemic corticosteroids. 16/52 (30.8%) patients were cured, 23/52 (44.2%) patients received partial recovery, and 13/52 (25.0%) patients were died. Septic shock, gastrointestinal bleeding and multiple organ failure were the leading causes of death. Advanced age, underlying cardiovascular disease, chronic kidney disease and high dose of allopurinol, infection and internal organ involvement (including kidney, heart, lung and gastrointestinal tract) were risk factors for death. What is New and Conclusion: We explored clinical features, treatment outcomes and prognostic factors of 52 allopurinol‐induced DRESS cases in China. Ethnicity, especially Han Chinese, and positive HLA‐B*58:01 allele are the clearest risk factors so far. Advanced age, underlying cardiovascular disease, chronic kidney disease and high dose of allopurinol, infection and internal organ involvement (including kidney, heart, lung and gastrointestinal tract) were associated with poorer outcomes. Early identification and discontinuation of the causative drug are crucial to the management of DRESS. For patients with severe disease, corticosteroids are recommended as the first‐line therapy. However, further studies are needed to address diagnostic criteria of DRESS for early diagnosis, as well as to develop standardized corticosteroid treatment regimens. [ABSTRACT FROM AUTHOR]

Background: Drug-induced hypersensitivity syndrome (DIHS) is a rare, potentially life-threatening systemic drug reaction. Antithyroid drugs (ATDs) causing DIHS have seldom been reported before. Case presentation: We present a case of propylthiouracil (PTU)-induced DIHS, which included fever, skin rash, lymphadenopathy, hepatosplenomegaly, serious liver and kidney dysfunction, peripheral blood eosinophilia, and atypical lymphocytosis. Following supportive therapy, intravenous immunoglobulin (IVIG), and systemic corticosteroid, the patient experienced a resolution of fever and rash combined with progressive normalization of hematological index and organ function. These clinical features, and the skin lesion biopsy confirmed DIHS diagnosis. Conclusions: To our knowledge, this is the second reported case of PTU-induced DIHS worldwide and the first human leukocyte antigen (HLA) typing of PTU-induced DIHS. Clinicians should cautiously distinguish hyperthyroidism etiology and identify the indication of ATDs. Timely recognition and formal DIHS treatment are required in patients with ATDs. [ABSTRACT FROM AUTHOR]

Drug‐induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug adverse reaction with skin eruption and visceral organ involvement. The characteristic clinical features of DIHS/DRESS are reactivation of human herpesviruses (HHV) and the development of autoimmune diseases, but their pathogenesis and associations are not yet understood. Here, we report a 66‐year‐old man who presented with fever, generalized erythema, diffuse lymphadenopathy, and diarrhea after 3 weeks of treatment with zonisamide. Reactivation of HHV‐6 and cytomegalovirus (CMV) was detected during the clinical course. The patient was diagnosed with DIHS/DRESS and treated with systemic prednisolone, i.v. immunoglobulin therapy, and ganciclovir. However, severe enterocolitis persisted for 6 months. A series of examinations revealed features of both CMV enterocolitis, as indicated by identification of a few CMV‐positive cells on immunohistochemical analysis, and graft‐versus‐host disease (GVHD)‐like enterocolitis indicated by orange‐peel appearance on endoscopic examination and histopathological loss of goblet cells. Intractable enterocolitis continued and the patient finally died of pneumonia. An autoimmune predisposition in DIHS/DRESS patients in combination with CMV reactivation was considered to trigger the severe enterocolitis of this case that showed GVHD‐like features of the gastrointestinal tract. GVHD‐like organ damage is a pathological condition rarely observed in DIHS/DRESS but should be recognized as one of the most severe complications of the disease. [ABSTRACT FROM AUTHOR]

The literature on positive patch test results in drug reaction with eosinophilia and systemic symptoms (DRESS) is reviewed. One hundred and five drugs were identified that have together caused 536 positive patch tests in 437 DRESS patients. By far, the most reactions (n = 145) were caused by carbamazepine, followed by amoxicillin, isoniazid, phenytoin, ethambutol, fluindione, phenobarbital, rifampicin, and ceftriaxone; 43 drugs each caused a single case only. The drug classes causing the highest number of reactions were anticonvulsants (39%), beta-lactam antibiotics (20%), antituberculosis agents (11%), non-beta-lactam antibiotics (6%), and iodinated contrast media (5%). The sensitivity of patch testing (percentage of positive reactions) is high for anticonvulsants (notably carbamazepine), beta-lactam antibiotics (notably amoxicillin), and, possibly, iodinated contrast media. Allopurinol and sulfasalazine frequently cause DRESS but never give positive patch tests. Patch testing in DRESS appears to be safe, although mild recurrence of DRESS symptoms, mostly skin reactions, may not be rare. Multiple drug hypersensitivity was found to occur in 16% of all patients, but it is argued that the true frequency is higher. Clinical aspects of DRESS, including diagnosing the disease and identifying culprit drugs (patch tests, intradermal tests, in vitro tests, challenge tests) are also provided, emphasizing the role of patch testing. [ABSTRACT FROM AUTHOR]

Drug‐induced hypersensitivity syndrome (DiHS) is a severe drug eruption that can induce reactivation of herpesviruses such as human herpesvirus 6, resulting in symptom flare‐up and organ damage. DiHS is known as drug reaction with eosinophilia and systemic symptoms (DRESS) in Europe. We report three cases of DiHS that could have been triggered by mRNA‐based coronavirus disease 2019 (COVID‐19) vaccines. In these three patients, symptoms of DiHS developed 2–6 days after the first dose of an mRNA‐based COVID‐19 vaccine. Although there have been no reports of DiHS/DRESS induced by mRNA‐based COVID‐19 vaccines in domestic and international journals despite the progress in vaccination worldwide, we speculate that mRNA‐based COVID‐19 vaccines might have triggered the development of DiHS/DRESS in our patients. In the current coronavirus epidemic, it might be important to assess mRNA‐based COVID‐19 vaccination status and date of vaccination when evaluating a patient with DiHS/DRESS. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DReSS), also known as drug-induced hypersensitivity syndrome (DiHS), is a severe, systemic, T cell mediated drug reaction with combinations of cutaneous, hematologic, and internal organ involvement. Pathogenesis of DReSS is multi-factorial, involving drug-exposure, genetic predisposition through specific human leukocyte antigen (HLA) alleles and metabolism defects, viral reactivation, and immune dysregulation. Clinical features of this condition are delayed, stepwise, and heterogenous, making this syndrome challenging to recognize and diagnose. Two sets of validated diagnostic criteria exist that can be employed to diagnose DReSS/DiHS. Methods to improve early recognition of DReSS and predict disease severity has been a recent area of research focus. In vitro and in vivo tests can be employed to confirm the diagnosis and help identify culprit drugs. The mainstay treatment of DReSS is prompt withdrawal of the culprit drug, supportive treatment, and immunosuppression depending on the severity of disease. We present a comprehensive review on the most recent research and literature on DReSS, with emphasis on pathogenesis, clinical features, diagnosis, confirmatory testing modalities, and treatment. Additionally, this summary aims to highlight the differing viewpoints on this severe disease and broaden our perspective on the condition known as DReSS. [ABSTRACT FROM AUTHOR]

Abstract A sulfasalazine‐induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's‐like colitis. We demonstrated HHV‐6 reactivation with presence of HHV‐6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV‐6 reactivation in DRESS manifestations and the importance of looking for HHV‐6 reactivation in DRESS.

Purpose: Cutaneous reactions to BRAF inhibitors are common, but severe reactions resembling or consistent with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are relatively rare. Several reports suggest that cutaneous reactions including DRESS/DIHS to BRAF inhibitors are more frequent and severe in the setting of previous immune checkpoint inhibition (ICI). Methods: To characterize existing literature on these reports, we queried the PubMed/MEDLINE database for cases of DIHS/DRESS to BRAF inhibitors. Results: We identified 23 cases of DIHS to BRAF inhibitors following checkpoint inhibition and 14 cases without prior checkpoint inhibitor therapy. In both cohorts, DIHS occurred relatively early, with median time to onset from drug exposure of 8–10 days. Patients who received prior ICI were less likely to have peripheral eosinophilia (26% vs 71%), atypical lymphocytes (9% vs 50%), renal involvement (61% vs 79%), hepatic involvement (52% vs 86%), and lymphadenopathy (9% vs 43%) compared to patients who did not receive prior ICI. Thrombocytopenia was more common with prior ICI (17% vs 7%). Only patients who received prior ICI experienced hypotension (26%) during the course of their DIHS. All cases of BRAF-induced DIHS generally improved on systemic steroids/supportive care, and no cases of death were identified. Conclusion: Dermatologists should consider a diagnosis of DIHS following BRAF inhibitor initiation, particularly in the setting of past checkpoint inhibition, with atypical features including relatively rapid onset and steroid responsiveness, lack of peripheral eosinophilia, lymphocytosis, or lymphadenopathy, and increased risk of thrombocytopenia and hypotension. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS), is a severe type of cutaneous adverse reaction. The gold standard therapy for DRESS involves the discontinuation of the culprit drug, supportive therapies, and administration of corticosteroids. However, in cases of primary treatment failure or suboptimal response, there arises an urgent need for alternative interventions. This review focuses on exploring alternative systemic therapies for patients with steroid-resistant DRESS, steroid-dependent DRESS, or refractory DRESS, encompassing immunosuppressive agents, intravenous immunoglobulin, plasmapheresis, biologics, and small molecule drugs, with an emphasis on their clinical efficacy and the underlying mechanisms in the treatment of DRESS. Furthermore, this review provides a summary of potential management strategies and laboratory workup during the treatment of DRESS., Competing Interests: The authors declare no conflicts of interest in relation to this work., (© 2024 The Authors.)

Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1 , c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC., Competing Interests: MK received contracts and honoraria from Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd., Daiichi Sankyo Co., Ltd., and UCB Japan Co., Ltd. MK is an associate editor for BMC Neurology. The remaining authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Tsuburaya-Suzuki, Ohori, Hamanaka, Fujita, Matsumoto and Kinoshita.)

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. [ABSTRACT FROM AUTHOR]

Although the development of autoimmune disorders is recognized in drug‐induced hypersensitivity syndrome (DIHS), the serial change of B‐cell activity has not been well‐addressed. Herein, the serum levels of IL‐6, IL‐10, B‐cell activating factor of the tumor necrosis factor family (BAFF), and a proliferation‐inducing ligand (APRIL) in three DIHS patients were tracked over time. While IL‐6 and IL‐10 tended to be elevated according to the disease activity, BAFF and APRIL increased during the improved phase. Our results imply that the continuous activation of B cells may be involved in the prolonged disease activity of DIHS and the development of autoimmune disorders. [ABSTRACT FROM AUTHOR]

Background: Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an important adverse reaction caused by a few drugs. Reactivation of human herpesvirus 6 (HHV-6) is known to be associated with its pathogenesis. DIHS occasionally manifests as pulmonary lesions with a variety of imaging findings.Case Presentation: An 83-year-old woman started taking minodronic acid hydrate 5 years before admission. She noticed a generalized skin rash 44 days before admission and started oral betamethasone-d-chlorpheniramine maleate combination tablets for allergic dermatitis. She developed a fever and cough in addition to the rash, and was referred to our hospital. Laboratory data showed a high level of eosinophils and liver and biliary enzymes. Computed tomography (CT) studies revealed bilateral diffuse ground-glass opacities with ill-defined centrilobular nodules from the central to peripheral regions of the lungs. Transbronchial lung cryobiopsy specimens showed that lymphocyte infiltration was observed in the alveolar walls and fibrinous exudates and floating macrophages in the alveolar lumina. Immunohistochemistry of biopsy specimens showed more CD4+ lymphocytes than CD8+ lymphocytes, while few Foxp3+ lymphocytes were recognized. The serum anti-HHV-6 immunoglobulin G titer increased at 3 weeks after the first test. Based on these findings, we diagnosed her with DIHS. We continued care without using corticosteroids since there was no worsening of breathing or skin condition. Eventually, her clinical symptoms chest CT had improved. Minodronic acid hydrate was identified as the culprit drug based on the positive results of the patch test and drug-induced lymphocyte stimulation test.Conclusions: We described the first case of DIHS caused by minodronic acid hydrate. Lung lesions in DIHS can present with bilateral diffuse ground-glass opacities and ill-defined centrilobular nodules on a CT scan during the recovery phase. Clinicians should be aware of DIHS, even if patients are not involved with typical DIHS/DRESS-causing drugs. [ABSTRACT FROM AUTHOR]

Drug-induced hypersensitivity syndrome (DiHs) or drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug-induced reaction characterized by various symptoms: skin rash, fever, lymph node enlargement and internal organ involvement, which starts within 2 weeks to 3 months after drug initiation. It is challenging to diagnose this syndrome due to the variety of cutaneous and visceral symptoms. Different mechanisms have been implicated in its development, including genetic susceptibility associated with human leucocyte antigen (HLA) loci, detoxification defects leading to reactive metabolite formation and subsequent immunological reactions, slow acetylation, and reactivation of human herpes, including epstein-Barr virus and human herpes virus (HHV)-6 and HHV-7. the most frequently reported causes of DiHS/DRESS are antiepileptic agents, allopurinol and sulfonamides. We report a case of DiHS/DRESS induced by second-line treatment for tuberculosis, prothionamide and para-aminosalicylic acid, and epstein-Barr virus re-infection. Patch testing, which was performed in this case, is not fully standardized, but it can be helpful and a safe way to evaluate and diagnose DiHs/Dress. [ABSTRACT FROM AUTHOR]

Keywords: atopic dermatitis; generalized anhidrosis; drug-induced hypersensitivity syndrome EN atopic dermatitis generalized anhidrosis drug-induced hypersensitivity syndrome 7563 7563 3 08/02/22 20220715 NES 220715 Recent dermatological research has progressed, particularly novel technologies and analytical methodologies, providing great advances in the exploration of previously poorly understood interactions between the skin - the outermost surface of humans - and the external environment. Gallegos-Alcala et al. explained the close relationship between the skin barrier and immune responses in the pathogenesis of AD. In the last cornification phase, these cells die and form a physiological barrier with filaggrin in granular cells, which is genetically involved in the pathogenesis of atopic dermatitis (AD). [Extracted from the article]

We experienced a rare case of drug-induced hypersensitivity syndrome (DIHS) in which salazosulfapyridine (SASP) reactivated human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), which resulted in a relapse of skin symptoms after changing to mizoribine. At the time of recurrence of skin erythema after the initiation of mizoribine, the serum DNA titers of not HHV-6 but CMV were elevated. A drug-induced lymphocyte stimulation test was negative for mizoribine but positive for SASP. In this case, DIHS developed with SASP in association with HHV-6 and CMV reactivation. The immunocompromised state induced by herpes virus reactivation and mizoribine might have caused the relapse of skin erythema.

Currently, only a few reports exist on the cytokine release syndrome (CRS) as one of the severe immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Notably, it is very rare that grade 4 CRS related to ICI therapy overlaps with the drug-induced hypersensitivity syndrome (DiHS). A 46-year old woman with metastatic kidney cancer had grade 3 interstitial pneumonitis induced by four cycles of combination therapy of anti-programmed death-1 and anti-cytotoxic T lymphocyte-4 antibodies after right cytoreductive nephrectomy. Prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) was started concomitantly with prednisolone therapy to treat the interstitial pneumonitis. She developed hypotensive shock when reducing the dosage of prednisolone, and required intubation and ventilation using vasopressors at the intensive care unit. She subsequently exhibited prominent leukocytosis and an increased level of C-reactive protein, suggesting markedly increased cytokine levels. Interestingly, facial edema and erythema increased in association with pyrexia, leukocytosis, liver dysfunction, and renal failure, suggesting that she developed DiHS. She received hemodialysis three times, a plasma exchange, and anti-interleukin-6 therapy to treat severe renal dysfunction, a thrombotic thrombocytopenic purpura-suspected condition, and possible grade 4 CRS, respectively. Although these therapies did not elicit sufficient effects, high-dose administration of intravenous immunoglobulin was successful. With steroid mini-pulse therapy and the subsequent administration of prednisolone, she recovered successfully. To the best of our knowledge, this is the first report that ICIs and TMP/SMX can induce hypotensive shock accompanied with CRS and DiHS during immunosuppressive therapy for an irAE. Importantly, the prophylactic administration of TMP/SMX should be performed cautiously to avoid severe drug reactions such as CRS or DiHS.