DRESS syndrome - the latest on diagnostics and therapy

DRESS syndrome should be considered as a suspected diagnosis, particularly in patients who have a new exanthema and fever >38°C within 2-6 weeks of starting drug therapy. The criteria of Shiohara and Bocquet offer a diagnostic aid. In severe cases, high doses of glucocorticoids are required for effective therapy. In steroid-refractory patients, alternative treatment options such as anti-IL-5 or anti-IL-5-R antibodies should be considered.

Drug hypersensitivity syndrome DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is rare but potentially life-threatening. The incidence is described in Deuel et al. 1:1000-10,000 drug exposures [1]. Pathophysiologically, the development and activation of drug-specific T cells and a dysregulation of regulatory T cells play an important role [2,3,21] In addition to DRESS syndrome, acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN) and Steven-Johnson syndrome (SJS) are also classified as severe cutaneous drug reactions [1]. What they all have in common is that they are based on an immunological reaction to the triggering drug, its metabolites or to a neoantigen resulting from interactions between the drug and the body’s own proteins.

What clinical signs are typical for DRESS?

Skin involvement is the most common finding in DRESS syndrome and occurs in 99-100% of patients regardless of age [2,3]. The rash typically presents as a disseminated maculopapular exanthema involving the trunk and extremities, often covering more than 50% of the body surface [1–3]. The exanthema usually manifests itself 2-6 weeks after ingestion, in rare cases it can occur after 8 weeks [4]. Pronounced facial edema occurs in about one third of cases, and the eponymous and usually marked eosinophilia (>1.5 G/l) is found in about 70-80% of cases [1,5]. If there is no skin involvement, this is referred to as DHS (drug hypersensitivity syndrome). In contrast to AGEP and SJS/TEN, DRESS syndrome usually also affects internal organs [1]. The exanthema manifests itself before the eosinophilia and other organ involvement. The progression of DRESS syndrome is often severe. Lymphadenopathy and hepatitis (elevated transaminases, hepatomegaly) are common, and nephritis, pneumonitis, carditis or thyroiditis are also prevalent. The mortality rate is stated in the specialist literature to be 10%, with causes of death including liver failure in the context of hepatitis, but also heart failure due to the cardiotoxic effect of pronounced eosinophilia [1].

Diagnostic work-up at a glance

The basis of every diagnosis is a careful medical history. Numerous medications can trigger DRESS syndrome, the most common being [1,5,6]:

Anticonvulsants (e.g. phenytoin, carbamazepine)
Allopurinol
Dapsone
Antibiotics (e.g. tetracyclines)

When taking a medication history, it is important to record all medications taken and to ask about the timing of the duration of therapy with the respective medications and the onset of the drug reaction [7]. Any previous allergic reactions to small-molecule substances, including possible contact allergens, should also be investigated. The inflammation values (CRP, BSR) should be determined in the laboratory and a differential blood count taken. A routine internal laboratory with liver values (transaminases, bilirubin, quick) and kidney function parameters (creatinine, urea with fractional excretion, electrolytes) is also part of the basic diagnostics [1]. An infectious or virological cause (e.g. HIV primoinfection, lues, mononucleosis or viral hepatitis) must be ruled out. This requires repeated blood cultures. HHV6/7 and other herpes viruses can be reactivated as part of DRESS syndrome [1]. Therefore, a positive PCR or serology for HHV6/7 increases the probability of diagnosis. The determination of ANA, ANCA and rheumatoid factor serves to rule out an autoimmune genesis. Last but not least, a rapid biopsy of the efflorescences is also part of the diagnosis, for example to rule out autoimmune and infectious dermatological differential diagnoses (especially bullous/pustular dermatoses) [1].

Slowly taper off systemic corticosteroids

The current recommendations on DRESS syndrome are based on case reports and expert opinions. The first step is to discontinue the triggering medication [5]. For further treatment, Brüggen et al. a severity-adapted approach [8–10]. In mild forms, the main focus is on supportive measures such as the use of topical steroids [9,10]. In more severe cases, systemic steroids are indicated, although high doses may be required for effective treatment, e.g. in the form of intravenous methylprednisolone doses over several days [1]. Due to the long persistence of symptoms, treatment often lasts for weeks. Slow tapering of systemic steroids is important, as rapid tapering is associated with relapse. The therapeutic rationale for the use of steroids is anti-inflammatory and immunosuppressive effects, which are achieved by inhibiting activated cytotoxic T cells and the production of inflammatory mediators [11,12].

Consider alternative therapies in steroid-refractory cases

In cases with severe corticosteroid-refractory DRESS syndrome, the use of intravenous immunoglobulins, ciclosporin or anti-IL-5 antibodies (Ak) or anti-IL-5-R-Ak may be considered, but should be indicated by an experienced team [1,9]. Recent studies show that blocking the IL-5/IL-5 receptor (R) axis is a promising targeted therapy with a good safety profile. Mepolizumab and reslizumab target the alpha chain of IL-5 and benralizumab targets the alpha subunit of IL-5R. In a case series published in 2024 (n=14), the use of mepolizumab, benralizumab or reslizumab achieved rapid clinical improvement and suppression of eosinophilia and a reduction in corticosteroids in 93% of cases [13]. Two or more doses were required in all but two cases with mepolizumab (dose: 100-600 mg) or reslizumab (dose according to body weight). In 4 out of 7 cases treated with benralizumab, a single dose of 30 mg proved sufficient.

Congress: Allergy & Immunology Update

Literature:

Deuel J, et al: Severe cutaneous drug reactions. Practice 2014, 103(21): 1231-1243.
Kardaun SH, et al: Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. BJD 2013; 169(5): 1071-1080.
Metterle L, Hatch L, Seminario-Vidal L: Pediatric drug reaction with eosinophilia and systemic symptoms: a systematic review of the literature. Pediatr Dermatol 2020; 37(1): 124-129.
Verstegen RHJ, Phillips EJ, Juurlink DN: First-line therapy in drug reaction with eosinophilia and systemic symptoms (DReSS): Thinking beyond corticosteroids. Front Med (Lausanne) 2023 Feb 8; 10: 1138464.
“Drug rash with eosinophilia”, Workshop, Allergy and Immunology Update, Grindelwald, 27.01.2024.
Cho YT, Yang CW, Chu CY: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System. Int J Mol Sci 2017; 18(6): 1243.
Merk HF: Allergic drug reactions of the skin: Current clinical, diagnostic and differential diagnosis. Act Dermatol 2014; 41: 407-417.
Schunkert EM, Divito SJ: Updates and Insights in the Diagnosis and Management of DRESS Syndrome. Curr Derm Rep 2021: 10: 192-204.
Brüggen MC, et al: DRESS Delphi consensus group; Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus. JAMA Dermatol 2024; 160(1): 37-44.
10 Brüggen MC, et al: Medical algorithm: Diagnosis and treatment of drug reaction with eosinophilia and systemic symptoms in adult patients. Allergy 2024, Apr 8. doi: 10.1111/all.16122.
Ramirez GA, et al: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Focus on the Pathophysiological and Diagnostic Role of Viruses. Microorganisms 2023; 11: 346. https://doi.org/10.3390/microorganisms11020346.
Yacoub MR, et al: Drug-induced exfoliative dermatitis: state of the art. Clin Mol Allergy 2016; Aug 22; 14(1): 9. doi: 10.1186/s12948-016-0045-0.
Gschwend A, et al: Treatment with IL5-/IL-5 receptor antagonists in drug reaction with eosinophilia and systemic symptoms (DRESS). Allergo J Int 2022 Aug 23: 1-8.
Xu J, et al: Apoptotic eosinophils in sputum from asthmatic patients correlate negatively with levels of IL-5 and eotaxin. Respir Med 2007; 101(7): 1447-1454.
Brusselle GG, Koppelman GH: Biologic therapies for severe asthma. NEJM 2022; 386(2): 157-171.
EGPA Mepolizumab Study Team. Wechsler ME, et al: Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. NEJM 2017; 376(20): 1921-1932.
Gevaert P, et al: The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 2022. doi: 10.1002/alr.22994.
HES Mepolizumab study group. Roufosse F, et al: Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. JACI 2020; 146(6): 1397-1405.
Straumann A, et al: Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomized, placebo-controlled, double-blind trial. Gut 2010; 59(1): 21-30.
Spergel JM, et al: Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. JACI 2012; 129(2): 456-463.e1-3.
Hama N, et al: Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): clinical features and pathogenesis. JACI Pract 2022; 10: 1155-1167.