Fitzpatrickʼs Dermatology in General Medicine

Severe cutaneous adverse reactions to drugs.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered a delayed-type hypersensitivity reaction to drugs. They represent true medical emergencies and an early recognition and appropriate management is decisive for the survival. SJS/TEN manifest with an “influenza-like” prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. The difference between SJS, SJS/TEN overlap, and TEN is defined by the degree of skin detachment: SJS is defined as skin involvement of  30%, and SJS/TEN overlap as 10–30% skin involvement. The diagnosis of different degrees of epidermal necrolysis is based on the clinical assessment in conjunction with the corresponding histopathology. The mortality rates for SJS and TEN have decreased in the last decades. Today, the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is available for SJS/TEN severity assessment. Drugs with a high risk of causing SJS/TEN are anti-infective sulfonamides, anti-epileptic drugs, non-steroidal anti-inflammatory drugs of the oxicam type, allopurinol, nevirapine, and chlormezanone. Besides conventional drugs, herbal remedies and new biologicals should be considered as causative agents. The increased risk of hypersensitivity reactions to certain drugs may be linked to specific HLA antigens. Our understanding of the pathogenesis of SJS/TEN has improved: drug-specific T cell-mediated cytotoxicity, genetic linkage with HLA- and non-HLA-genes, TCR restriction, and cytotoxicity mechanisms were clarified. However, many factors contributing to epidermal necrolysis still have to be identified, especially in virus-induced and autoimmune forms of epidermal necrolysis not related to drugs. In SJS/TEN, the most common complications are ocular, cutaneous, or renal. Nasopharyngeal, esophageal, and genital mucosal involvement with blisters, erosions as well as secondary development of strictures also play a role. However, in the acute phase, septicemia is a leading cause of morbidity and fatality. Pulmonary and hepatic involvement is frequent. The acute management of SJS/TEN requires a multidisciplinary approach. Immediate withdrawal of potentially causative drugs is mandatory. Prompt referral to an appropriate medical center for specific supportive treatment is of utmost importance. The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A.

Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/all.12886

In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments.

https://www.mdpi.com/1422-0067/18/6/1243/pdf

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System.

Background The development of autoimmune sequelae is one of the characteristic features of drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome; however, the incidence of sequelae and prognosis of patients with DRESS are unknown. Objective We sought to investigate the incidence of sequelae, including less well-known sequelae, and long-term prognosis in patients with DRESS/drug-induced hypersensitivity syndrome. Methods A retrospective cohort study was conducted at a medical center in northern Taiwan using a DRESS/drug-induced hypersensitivity syndrome database. Patients who were followed up for at least 1 year were included in the study. Results Nine patients died before interview, whereas 43 patients completed a specially designed questionnaire. The overall cumulative incidence of long-term sequelae was 11.5% (6 of 52 patients). Four patients developed autoimmune diseases, specifically Graves disease (n = 2), type 1 diabetes mellitus (n = 1), and autoimmune hemolytic anemia (n = 1). Alopecia areata was also noted in 1 of the 2 patients with Graves disease. The other 2 patients developed renal failure after visceral involvement and required lifetime hemodialysis. Limitations Our study included a small number of patients. Further, viral studies were not performed. Conclusion The sequelae of DRESS can be divided into 2 major types that appear to occur in different age groups: young patients tend to develop autoimmune diseases, whereas elderly patients are more vulnerable to end-organ failure.

https://www.jaad.org/article/S0190-9622(12)00862-6/pdf

Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: A retrospective cohort study from Taiwan

Background Generalized bullous fixed drug eruption (GBFDE), a particular form of fixed drug eruption (FDE), is characterized by widespread blisters and erosions and can be confused with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Objective We sought to analyze specific features of GBFDE and differentiate it from SJS/TEN. Methods We retrospectively studied patients with GBFDE and SJS/TEN during a period of 10 years. GBFDE was defined as typical FDE lesions with blisters involving at least 10% body surface area on at least 3 of 6 different anatomic sites. Clinical presentations; histopathological features; immunohistochemical patterns of cluster-of-differentiation (CD)3, CD4, CD8, CD56, Fas, Fas ligand, granzyme B, perforin, granulysin, and forkhead box P3 (Foxp3); and serum granulysin levels were compared. Results Twenty-three cases of GBFDE were collected. Patients with GBFDE had shorter latent periods, less mucosal involvement, more eosinophil infiltration, and dermal melanophages. Lesional infiltrates in GBFDE had more dermal CD4 + cells including Foxp3 + regulatory T cells, fewer intraepidermal CD56 + cells, and fewer intraepidermal granulysin + cells. The serum level of granulysin in GBFDE was also significantly lower than in SJS/TEN. Limitations The number of cases in this study is small. Conclusion GBFDE is a distinct disease distinguishable from SJS/TEN by particular features such as granulysin, CD56, and Foxp3 expressions.

Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features.

Drug reaction with eosinophilia and systemic symptoms: A drug-induced hypersensitivity syndrome with variable clinical features

Background

Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV-6, HHV-7, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined.



Methods

A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum-specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples.



Results

Among the various cADRs, HHV-6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)-1β, IL-2, IL-6, interferon-γ, tumor necrosis factor-α, were significantly lower in DRESS patients with HHV-6 reactivation when compared to those without HHV-6 reactivation. In addition, these mediators were significantly lower before and during HHV-6 reactivation, compared to cytokine levels after HHV-6 reactivation in the same patient.



Conclusion

HHV-6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV-6 reactivation.

Chia-Ying Chang

Papers

Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: A retrospective cohort study from Taiwan

Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features.

Drug reaction with eosinophilia and systemic symptoms: A drug-induced hypersensitivity syndrome with variable clinical features

Human herpes virus reactivations and dynamic cytokine profiles in patients with cutaneous adverse drug reactions --a prospective comparative study.

Fixed-drug eruption: A retrospective study in a single referral center in northern Taiwan