Histopathologic Features of Drug Reaction With Eosinophilia and Systemic Symptoms.

IMPORTANCE: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous adverse reaction occurring 2 to 8 weeks after medication initiation. Diagnosis is clinical; RegiSCAR scoring includes biopsy "suggestive of DRESS," undefined in the literature. OBJECTIVE: This study correlates DRESS dermatopathology, culprit drugs, disease course, and outcome severity compared with maculopapular drug reactions (MDR). METHODS: Between 2014 and 2023, a retrospective cohort study at a tertiary care institute reviewed 55 patients with DRESS, assessing demographics, culprit drug, illness course, and histopathology. Biopsies of 15 patients with DRESS and 15 MDR patients were graded by a predefined histopathological scoring system. Statistical analysis (significant P -value<0.05) included the Fisher exact probability, ANOVA, and correlation tests. RESULTS: Among 55 patients with DRESS (mean age 50.13, 28 female/27 male), 15 (mean age 50.4, 7 female/8 male) had diagnostic biopsies. Compared with MDR patients, patients with DRESS exhibited significantly more interface dermatitis ( P = 0.04), lichenoid dermatitis ( P = 0.0007), pigment incontinence ( P = 0.04), and periadnexal interface dermatitis ( P = 0.002). MDR biopsies displayed perivascular inflammation and higher eosinophils than DRESS, trending toward significance. CONCLUSIONS: Key histopathologic features are interface dermatitis, periadnexal interface dermatitis, lichenoid dermatitis, pigment incontinence, and neutrophils dominance over eosinophils indicate DRESS clinically.

Azathioprine hypersensitivity syndrome: report of two cases with cutaneous manifestations.

Azathioprine is an immunosuppressant drug used in many dermatological and nondermatological pathologies. Azathioprine hypersensitivity syndrome (AHS) is a rare idiosyncratic reaction that is not related to dose or thiopurine methyltransferase activity. Up to half of cases of AHS can present with variable cutaneous manifestations besides fever, malaise and other systemic symptoms. It is important to be aware of AHS, as continuance or reintroduction of the drug can led to multiorgan failure and cardiovascular collapse.

Drug-induced hypersensitivity syndrome caused by minodronic acid hydrate.

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.

Current Perspective Regarding the Immunopathogenesis of Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (DIHS/DRESS).

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe type of adverse drug eruption associated with multiorgan involvement and the reactivation of human herpesvirus 6, which arises after prolonged exposure to certain drugs. Typically, two waves of disease activity occur during the course of DIHS/DRESS; however, some patients experience multiple waves of exacerbation and remission of the disease. Severe complications, some of which are related to cytomegalovirus reactivation, can be fatal. DIHS/DRESS is distinct from other drug reactions, as it involves herpes virus reactivation and can lead to the subsequent development of autoimmune diseases. The association between herpesviruses and DIHS/DRESS is now well established, and DIHS/DRESS is considered to arise as a result of complex interactions between several herpesviruses and comprehensive immune responses, including drug-specific immune responses and antiviral immune responses, each of which may be mediated by distinct types of immune cells. It appears that both CD4 and CD8 T cells are involved in the pathogenesis of DIHS/DRESS but play distinct roles. CD4 T cells mainly initiate drug allergies in response to drug antigens, and then herpesvirus-specific CD8 T cells that target virus-infected cells emerge, resulting in tissue damage. Regulatory T-cell dynamics are also suggested to contribute to the diverse symptoms of DIHS/DRESS. However, the pathomechanisms of this complex disease remain largely unknown. In particular, how viral infections contribute to the pathogenesis of DIHS/DRESS and why autoimmune sequelae arise in DIHS/DRESS are yet to be elucidated. This review describes the clinical features of DIHS/DRESS, including the associated complications and sequelae, and discusses recent advances in our understanding of the immunopathogenic mechanisms of DIHS/DRESS.

Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update.

Glucocorticoids are the final products of the neuroendocrine hypothalamic-pituitary-adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the human glucocorticoid receptor, which functions as a ligand-bound transcription factor inducing or repressing the expression of a large number of target genes. To achieve homeostasis, glucocorticoid signaling should have an optimal effect on all tissues. Indeed, any inappropriate glucocorticoid effect in terms of quantity or quality has been associated with pathologic conditions, which are characterized by short-term or long-lasting detrimental effects. Two such conditions, the primary generalized glucocorticoid resistance and hypersensitivity syndromes, are discussed in this review article. Undoubtedly, the tremendous progress of structural, molecular, and cellular biology, in association with the continued progress of biotechnology, has led to a better and more in-depth understanding of these rare endocrinologic conditions, as well as more effective therapeutic management.

Interface dermatitis as an indicator of hepatic involvement in drug reaction with eosinophilia and systemic symptoms (DRESS).

BACKGROUND: There are conflicting reports on the association between interface dermatitis and hepatic involvement in DRESS. METHODS: A cross-sectional analysis of the clinical and the histopathologic features of DRESS was performed to study the association between the histopathology of the skin rash and hepatic involvement. RESULTS: The clinical and the histopathologic findings were evaluated in 40 cases of DRESS. Thirty patients (75%) had a hepatic involvement. Thirty (75%) biopsy specimens showed a combination of different inflammatory patterns. The interface dermatitis was noted in 24 specimens (60%). Twenty-one patients with the interface dermatitis had a hepatic involvement (P = .04). CONCLUSIONS: The skin rash of DRESS often shows the coexistence of different inflammatory patterns. The interface dermatitis showed a statistically significant association with the hepatic involvement in DRESS.

A case of vancomycin-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome with failure to respond to cyclosporine treatment.

Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare delayed drug reaction that often occurs 2-6 weeks after initiation of therapy and may develop into a life-threatening systemic reaction. Besides immediate discontinuation of the suspected inciting drug, initiation of high dose systemic corticosteroids has long been the mainstay of treatment for severe cases. Nevertheless, significant drawbacks associated with systemic corticosteroid therapy, such as the requirement of a long tapering period post resolution and extensive adverse side effects profile, have motivated clinicians to seek alternative treatment options. Over the past decade, an undisputed increasing number of favorable case reports has highlighted cyclosporine as an emerging, safe, and effective alternative despite inconsistent dosing regimens reported. Herein, we report a severe case of vancomycin-induced DRESS syndrome in which the patient failed initial intervention with cyclosporine and needed rescue with methylprednisolone. To the best of our knowledge, this constitutes the first unsuccessful report of cyclosporine treatment for DRESS syndrome.

Facial pustules due to drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report.

Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.

Ethosuximide-induced drug reaction with eosinophilia and systemic symptoms with mediastinal lymphadenopathy.

Lymphadenopathy is a common sign for drug reaction and eosinophilia with systemic symptoms (DRESS) syndrome, but hilar and mediastinal lymphadenopathy may be underreported. We describe a 7-year-old boy who started taking ethosuximide for absence seizures and presented with diffuse rash, fever, elevated transaminases, facial swelling, and hilar and mediastinal lymphadenopathy. His mediastinal lymphadenopathy was concerning for lymphoma, which led to more invasive testing to rule out malignancy. This report highlights an unusual and likely underreported presenting sign of DRESS syndrome in children.

Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy.

Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways.

Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): An update in 2019.

The aim of this review was to provide an updated overview of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS). Several new insights have been made, particularly with regards to the diagnosis, pathogenesis and care of some important complications and sequelae. The indication of herpesvirus reactivations in diagnosis in the assessment of disease severity is now better specified. Nevertheless, because fatal complications and autoimmune sequelae have been under-recognized, there is a clear need to identify effective parameters for assessing disease severity and predicting prognosis of the disease in the early phase. In this regard, we have established a scoring system that can be used to monitor severity, predict prognosis and stratify the risk of developing severe complications including fatal cytomegalovirus (CMV) disease. Regulatory T cells are likely to be central to the mechanism and would represent potential targets for therapeutic approaches that can ameliorate inflammatory responses occurring at the acute phase while preventing the subsequent development of harmful outcomes, such as CMV disease and autoimmune diseases.

[Histopathology of cutaneous drug reactions]. / Histopathologie des réactions cutanées médicamenteuses.

There are many different types of cutaneous adverse reactions. The most classical reactions are driven by T lymphocytes that specifically react towards a drug, with an individual genetic susceptibility linked to certain type I major histocompatibility complex alleles. These reactions are characterized by a wide variety of clinical and histopathological presentations, and a wide range of severity. The most frequent entity is the maculopapular rash, while the most aggressive forms are the Steven-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). The histopathological alterations associated to each of these syndromes have been better described in the literature during the past 10 years, encompassing non-specific lesions, as in most drug induced maculopapular rashes, to more specific inflammatory patterns. The finding of confluent apoptotic keratinocytes with epidermal detachment is the prototypical aspect of SJS-TEN. There are however numerous pitfalls, and a similar aspect to those observed in each cutaneous drug reactions entities can be found in other diseases. DRESS syndrome can indeed present with dense and epidermotropic T-cell infiltrate, sometimes with nuclear atypias, and thus can be difficult to distinguish from a primary or secondary cutaneous T-cell lymphoma. The diagnosis of cutaneous adverse reactions relies on a clinical-pathological confrontation and requires an accurate evaluation of drug imputability.

DRESS syndrome and acute generalized exanthematous pustulosis induced by antituberculosis medications and moxifloxacin: case report
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OBJECTIVE: To report a rare case of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome caused by antituberculosis (TB) drugs, which progressed to acute generalized exanthematous pustulosis (AGEP) after moxifloxacin treatment. CASE SUMMARY: A 25-year-old female was hospitalized for dyspnea and dizziness. She had a history of TB and experienced rifampin-induced skin rash. She was treated for TB with moxifloxacin, isoniazid, ethambutol, and pyrazinamide. Upon admission, she had a fever of 39.2 °C, and aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, and eosinophil count increased during the first 10 days after admission. The patient had a rash all over the body with itching, pain, and a burning sensation. Diagnosis of DRESS syndrome was made. Immunoglobulin and prednisolone administration improved the DRESS symptoms. After the first DRESS syndrome diagnosis, anti-TB medications were changed to isoniazid, ethambutol, pyrazinamide, cycloserine, and streptomycin, which also caused a skin rash, itching, and elevated AST/ALT levels, and eosinophil count. Then, the anti-TB treatment was changed to cycloserine, streptomycin, ethionamide, and para-aminosalicylic acid. The rash and itching persisted and eosinophil count increased further. All TB medications were discontinued except streptomycin. Due to the flushing and a burning sensation by streptomycin at the injection site, it was replaced with moxifloxacin. The patient experienced erythematous pustules and patches on skin with desquamation, fissures, and swelling. Therefore, a diagnosis of moxifloxacin-induced AGEP was made. CONCLUSION: DRESS syndrome induced by anti-TB drugs developed in a 25-year-old woman with moxifloxacin-related subsequent AGEP.
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Histopathology of the Exanthema in DRESS Is Not Specific but May Indicate Severity of Systemic Involvement.

OBJECTIVE: Exanthema in drug reaction with eosinophilia and systemic symptoms (DRESS) has no specific clinical diagnostic hallmark and there are few histopathologic studies. The aim of this study was to describe dermal-epidermal histopathologic features in DRESS and correlate them with the culprit drug, viral reactivation, or systemic organ involvement. METHODS: Skin biopsies were independently evaluated by 2 dermatopathologists who characterized the main histological patterns and scored dermal and epidermal changes, which were further correlated with clinical and laboratorial data. RESULTS: In 15 DRESS patients (9 male/6 female patients, mean age 53.3 years), the main observation was lymphocyte exocytosis (1.87 ± 1.25), spongiosis (0.93 ± 0.94), scattered keratinocyte necrosis (1.70 ± 1.44), basal cell vacuolization (2.13 ± 1.42), lymphocyte infiltration around dermal vessels (2.93 ± 0.92) or at the dermal-epidermal junction (2.07 ± 1.12), often with eosinophils and extravasated erythrocytes, swollen endothelial cells, and intravascular neutrophils but no vasculitis. Histopathologic patterns were classified mainly as spongiotic (5), erythema multiforme-like (3), or lichenoid (2). There was a significant positive correlation between the intensity of lymphocyte infiltration and the severity of hepatic cytolysis (r = 0.51; P < 0.05) and eosinophilia (r = 0.51; P < 0.05). No correlation was observed between the intensity and type of dermal inflammation and the degree of epidermal damage or the culprit drug. Human herpes virus type 6-positive patients had a pseudolymphomatous reaction or a perifollicular localization of the infiltrate. CONCLUSIONS: Histopathology in DRESS is variable with no specific diagnostic aspect, but there is a possible correlation between the intensity of the lymphocyte infiltrate and DRESS severity, namely, liver cytolysis.