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.

Delayed hypersensitivity reaction following lip fillers, not one but four times in the same patient.

This case report describes a healthy 25-year-old woman who underwent lip filler augmentation and developed a delayed hypersensitivity reaction not once but four times. A Caucasian female with no medical history presented to the authors in March 2022 with diffuse painful swelling on the left upper lip. Upon examination, the affected area was soft and tender on palpation, with no palpable nodules or lumps. Five days later,the patient reported waking up with tenderness and swelling on her right upper lip this time. Two months after this incident the patient reported that she had experienced two similar incidents at the beginning of May. She again reported waking up with the same symptoms on her right upper lip, which spontaneously resolved within 48 h; and then four days later, she exhibited the same symptoms on her left upper lip. When questioned, she did not recall any flu-like symptoms or signs of COVID-19. She had been vaccinated against COVID-19, but this was long before she had lip fillers injected, namely, in 2020 (two years before the events described here). In this case, no obvious triggering factor was identified, apart from the fact that the patient had been stressed due to upcoming examination. Stress is known to cause flares of autoimmune or infectious diseases, such as herpes simplex virus, through complicated processes that influence immune function. Therefore, stress could have been the triggering factor in the current case.

A Rare Case of Delayed Hypersensitivity Following COVID-19 Booster Necessitating Treatment With Dupilumab.

Following vaccination, patients can develop symptoms of eczema flare, which could range from mild skin irritation and urticaria to diffuse skin involvement. Delayed immunologic reactions have been described in association with the novel mRNA COVID-19 vaccines and boosters. We report the case of an 83-year-old female who presented with widespread pruritic urticarial indurated papules on the arms, legs, and palms, sparing the face six months following the booster vaccine. She denied constitutional symptoms, new medications, recent illnesses, or new personal care products. Punch biopsy demonstrated acanthosis, spongiosis, and superficial and mild dermal perivascular lymphocytic infiltration with occasional eosinophils compatible with a dermal hypersensitivity reaction. The patient was admitted to the hospital due to the need for systemic steroids as well as IV antibiotics secondary to a superimposed bacterial skin infection in the setting of severe itching and skin injury; she was discharged on oral steroids with follow-up to dermatology and rheumatology. Delayed hypersensitivity reactions typically peak within four days following vaccination and may be observed with COVID-19 vaccines or boosters. However, reports remain limited, and people's history of eczema should not preclude them from receiving a COVID-19 vaccine that is both safe and effective.

[Multiform exudative erythema caused by hydroxychloroquine, diagnosed by epicutaneous tests: A case report]. / Eritema exudativo multiforme provocado por hidroxicloroquina, diagnosticado mediante pruebas epicutáneas: reporte de un caso.

INTRODUCTION: Multiform exudative erythema is a rare delayed hypersensitivity reaction associated with medications. The manifestations caused by hydroxychloroquine are exceptional; however, due to the increase in its prescription due to the recent SARS-CoV-2 pandemic, adverse reactions have been exacerbated. CASE REPORT: A 60-year-old female patient, who attended the Emergency Department for a picture of erythematous rash of one week of evolution, with involvement of the trunk, face and palms of the hands. Laboratory studies reported: leukocytosis with neutrophilia and lymphopenia, without eosinophilia or abnormal liver enzymes. The lesions continued to descend towards her extremities, with subsequent desquamation. She was prescribed prednisone 15 mg/24 h for three days, tapering to 10 mg/24 h, until her new assessment, in addition to antihistamines. Two days later, new macular lesions appeared in the presternal area and on the oral mucosa. Control laboratory studies did not show alterations. Skin biopsy reported: vacuolar interface dermatitis with spongiosis and parakeratosis, compatible with erythema multiforme. Epicutaneous tests were carried out with meloxicam and 30% hydroxychloroquine in water and vaseline, occluded for two days and interpreted at 48 and 96 hours, with a positive result for the latter. The diagnosis of multiform exudative erythema due to hydroxychloroquine was established. CONCLUSIONS: This study confirms the efficacy of patch tests in patients with delayed hypersensitivity reactions to hydroxychloroquine.

INTRODUCCIÓN: El eritema exudativo multiforme es una reacción de hipersensibilidad retardada poco frecuente asociada con medicamentos. Las manifestaciones provocadas por hidroxicloroquina son excepcionales; sin embargo, debido al incremento de su prescripción, por la reciente pandemia de SARS-CoV-2, las reacciones adversas se han exacerbado. REPORTE DE CASO: Paciente femenina de 60 años, que acudió al servicio de Urgencias por un cuadro de exantema eritematoso de una semana de evolución, con afectación hacia el tronco, la cara y las palmas de las manos. Los estudios de laboratorio informaron: leucocitosis con neutrofilia y linfopenia, sin eosinofilia ni alteración de las enzimas hepáticas. Las lesiones continuaron descendiendo hacia las extremidades, con posterior descamación. Se le indicó prednisona 15 mg/24 h durante tres días, con disminución a 10 mg/24 h, hasta su nueva valoración, además de antihistamínicos. Dos días posteriores aparecieron nuevas lesiones maculares en la zona preesternal y en la mucosa oral. Los estudios de laboratorio de control no mostraron alteraciones. La biopsia cutánea informó: dermatitis de interfase vacuolar con espongiosis y paraqueratosis, compatible con eritema multiforme. Se llevaron a cabo pruebas epicutáneas con meloxicam e hidroxicloroquina al 30% en agua y vaselina, ocluidos dos días e interpretados a las 48 y 96 horas, con resultado positivo para esta última. Se estableció el diagnóstico de eritema exudativo multiforme por hidroxicloroquina. CONCLUSIONES: Este estudio confirma la eficacia de las pruebas epicutáneas en pacientes con reacciones de hipersensibilidad retardada a hidroxicloroquina.

Tools to improve the diagnosis and management of T-cell mediated adverse drug reactions.

Delayed drug T-cell immune-mediated hypersensitivity reactions have a large clinical heterogeneity varying from mild maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and severe skin necrosis and blistering as seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Given the knowledge gaps related to the immunopathogenesis of these conditions, the absence of validated diagnostic tools and the significant associated morbidity and mortality, patients with SCARs often have limited drug choices. We performed a comprehensive review aiming to evaluate in vivo diagnostic tools such as delayed intradermal skin and patch testing and ex vivo/in vitro research assays such as the lymphocyte transformation test (LTT) and the enzyme-linked ImmunoSpot (ELISpot) assay. We searched through PubMed using the terms "drug allergy," "in vivo" and "ex vivo" for original papers in the last 10 years. A detailed meticulous approach adapted to the various clinical phenotypes is recommended for the diagnostic and management of delayed drug hypersensitivity reactions. This review highlights the current diagnostic tools for the delayed drug hypersensitivity phenotypes.

Low Prevalence of Amalgam-Associated Lichenoid Lesions in the Oral Cavity: A Prospective Study.

INTRODUCTION: Amalgam has been the restoration of choice for years, but its popularity has declined due to concerns about aesthetics, mercury toxicity and lichenoid lesions associated with it. Lichenoid reaction is considered to be a delayed hypersensitivity type of reaction and it has been associated with dental materials in general and amalgam in particular. MATERIALS AND METHODOLOGY: Two thousand patients having at least one amalgam restoration were examined for signs of lichenoid lesions when visiting the OPD of Conservative Dentistry and Endodontics at the Nair Hospital Dental College in Mumbai, India. Indirect spatial correlation to the amalgam restoration and the same were recorded. Descriptive analysis was used. RESULTS: Three (0.15%) out of 2000 patients with amalgam-associated lichenoid lesions showed complete resolution of lesions after the replacement of the restorations. CONCLUSION: Amalgam associated lichenoid lesions have a low prevalence and should not be a contraindication to its use in routine restorative dental practice. Patch tests and biopsies have questionable diagnostic and prognostic value. Identification of the lesions should be made after the elimination of all other causative factors for the presenting symptoms. A close spatial association of the lesion to amalgam and the regression of symptoms after its removal should be considered as confirming the diagnosis.

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

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

Cutaneous Complications of mRNA and AZD1222 COVID-19 Vaccines: A Worldwide Review.

Because of the increasing emergence of cutaneous reactions from COVID-19 vaccines worldwide, we investigated the published reports of these complications. We searched the PubMed, Google Scholar, and Scopus databases and the preprint server bioRxiv for articles on cutaneous complications linked to mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and AZD1222 (AstraZeneca-Oxford University) vaccines published until 30 September 2021. Eighty studies describing a total of 1415 reactions were included. Cutaneous reactions were more prevalent in females (81.6%). Delayed large local reactions were the most common complication (40.4%), followed by local injection site reactions (16.5%), zoster (9.5%), and urticarial eruptions (9.0%). Injection site and delayed large local reactions were predominantly caused by the mRNA-1273 vaccine (79.5% and 72.0%, respectively). BNT162b2 vaccination was more closely linked to distant reactions (50.1%) than mRNA-1273 (30.0%). Zoster was the most common distant reaction. Of reactions with adequate information for both vaccine doses, 58.3% occurred after the first dose only, 26.9% after the second dose only, and 14.8% after both doses. Overall, a large spectrum of cutaneous reaction patterns occurred following the COVID-19 vaccination. Most were mild and without long-term health implications. Therefore, the occurrence of such dermatologic complications does not contraindicate subsequent vaccination.

Delayed-onset Nodules (DONs) and Considering their Treatment following use of Hyaluronic Acid (HA) Fillers.

Delayed-onset nodules (DONs) represent a poorly understood and generally neglected group of complications. It is not a diagnosis. The underlying pathologies and their incidences are largely unknown due to the lack of specificity in clinical signs and the challenges in accessing diagnostic tests, cost implications, or reluctance from patients to undergo them. A lack of presumptive clinical diagnosis, coupled with management ranging from "scatter-gun" polypharmacy to clinical inertia, is believed to result in chronicity and increased morbidity. This paper provides guidance on the identification and understanding of the underlying pathologies and encourages the increased utilization of a medical model of care. The more routine adoption of histopathology, inflammatory markers, and ultrasound will permit a more targeted management and a greater understanding of the incidences and evolution of the pathologies.

Corrigendum: Dose Dependent Antimicrobial Cellular Cytotoxicity-Implications for ex vivo Diagnostics.

[This corrects the article DOI: 10.3389/fphar.2021.640012.].

High occurrence of simultaneous multiple-drug hypersensitivity syndrome induced by first-line anti-tuberculosis drugs.

BACKGROUND: Multiple drug hypersensitivity syndrome (MDHS) results in treatment delay or failure and often results in severe drug hypersensitivity reactions. There are few reports of MDHS in response to anti-tuberculosis drugs; however, clinical information is scarce. Understanding the frequency and clinical characteristics of simultaneous MDHS against first-line anti-tuberculosis drugs in patients with non-severe drug hypersensitivity reactions is necessary. METHODS: We reviewed 27 patients with drug fever or maculopapular exanthem in response to first-line anti-tuberculosis drugs between January 2010 and June 2019. Drug fever or maculopapular exanthem occurred when isoniazid, rifampin, ethambutol, and pyrazinamide were administered simultaneously. Drug provocation tests for the 4 drugs were performed to identify the culprit drugs. RESULTS: All patients showed positive reactions to 1 or more drugs. MDHS was diagnosed in 13 (48%) patients, of whom 11 and 2 patients reacted to 2 and 3 drugs, respectively. In comparison to the patients with single-drug hypersensitivity, the patients with MDHS did not exhibit any differences in characteristics. Ethambutol and rifampin were the common drugs that induced a reaction, and the combination of these 2 drugs induced MDHS most frequently. Among the patients with MDHS, there were no differences between the drugs that caused drug fever and maculopapular exanthem. All patients with MDHS were successfully treated with alternative drugs. CONCLUSIONS: Simultaneous MDHS may occur frequently in patients with drug fever or maculopapular exanthem caused by first-line anti-tuberculosis drugs, indicating the need to evaluate the allergy responses for all 4 drugs, even in patients without severe drug hypersensitivity. The combination of ethambutol and rifampin was the most common trigger that induced MDHS.

Non-IgE-Mediated Drug Hypersensitivity Reactions.

PURPOSE OF REVIEW: Non-IgE-mediated drug reactions have traditionally been poorly defined and studied, though they are the most common form of hypersensitivity. Their presentations are highly variable and can range in severity from mild, cutaneous-only reactions to severe systemic disease. RECENT FINDINGS: The most notable advance in non-IgE-mediated hypersensitivity reactions is in diagnostics. HLA alleles have traditionally been used for identifying certain patients at risk for abacavir hypersensitivity syndrome, but more recent studies have shown several other HLA alleles associated with severe cutaneous adverse reactions with various medications. This article also highlights the use of delayed intradermal testing for radiocontrast media and patch testing for delayed antibiotic reactions. Drug reactions remain a major cause of morbidity and reason for treatment changes. Non-IgE-mediated reactions have had an increase in research interest over the past decade with an increased emphasis on better understanding the clinical presentation and underlying pathophysiology.

Dose Dependent Antimicrobial Cellular Cytotoxicity-Implications for ex vivo Diagnostics.

Introduction: Ex vivo and in vitro diagnostics, such as interferon-γ (IFN-γ) release enzyme linked ImmunoSpot (ELISpot) and flow cytometry, are increasingly employed in the research and diagnostic setting for severe T-cell mediated hypersensitivity. Despite an increasing use of IFN-γ release ELISpot for drug causality assessment and utilization of a range of antimicrobial concentrations ex vivo, data regarding antimicrobial-associated cellular cytotoxicity and implications for assay performance remain scarcely described in the literature. Using the measurement of lactate dehydrogenase (LDH) and the 7-AAD cell viability staining, we aimed via an exploratory study, to determine the maximal antimicrobial concentrations required to preserve cell viability for commonly implicated antimicrobials in severe T-cell mediated hypersensitivity. Method: After an 18-h incubation of patient peripheral blood monocytes (PBMCs) and antimicrobials at varying drug concentrations, the cell cytotoxicity was measured in two ways. A colorimetric based assay that detects LDH activity and by flow cytometry using the 7-AAD cell viability staining. We used the PBMCs collected from three healthy control participants with no known history of adverse drug reaction and two patients with a rifampicin-associated drug reaction with eosinophilia and systemic symptoms (DRESS), confirmed on IFN-γ ELISpot assay. The PBMCs were stimulated for the investigated drugs at the previously published drug maximum concentration (Cmax), and concentrations 10- and 100-fold above. Results: In a human immunodeficiency virus (HIV) negative and a positive rifampicin-associated DRESS with positive ex vivo IFN-γ ELISpot assay, use of 10- and 100-fold Cmax drug concentrations decreased spot forming units/million cells by 32-100%, and this corresponded to cell cytotoxicity of more than 40 and 20% using an LDH assay and 7-AAD cell viability staining, respectively. The other antimicrobials (ceftriaxone, flucloxacillin, piperacillin/tazobactam, and isoniazid) tested in healthy controls showed similar dose-dependent increased cytotoxicity using the LDH assay, but cytotoxicity remained lower than 40% for all Cmax and 10-fold Cmax drug concentrations except flucloxacillin. All 100-fold Cmax concentrations resulted in cell death >40% (median 57%), except for isoniazid. 7-AAD cell viability staining also confirmed an increase in lymphocyte death in PBMCs incubated with 10-fold and 100-fold above Cmax for ceftriaxone, and flucloxacillin; however, piperacillin/tazobactam and isoniazid indicated no differences in percentages of viable lymphocytes across concentrations tested. Conclusion: The LDH cytotoxicity and 7-AAD cell viability staining techniques both demonstrate increased cell death corresponding to a loss in ELISpot sensitivity, with use of higher antimicrobial drug concentrations for ex vivo diagnostic IFN-γ ELISpot assays. For all the antimicrobials evaluated, the use of Cmax and 10-fold Cmax concentrations impacts cell viability and potentially affects ELISpot performance. These findings inform future approaches for ex vivo diagnostics such as IFN-γ release ELISpot.