Guidance on How to Diagnose and Treat the Psychotropic Drug Reaction Known as DRESS

 

The Case

You receive a telephone call from an outpatient -- a 45-year-old attorney under treatment for major depressive disorder --  concerned about a new skin rash on her back that appears to be spreading. The patient was prescribed aripiprazole three weeks earlier as an adjunct to duloxetine for persistent depression. She takes no other medications. On further questioning, the patient reports a flu-like illness with fever, muscle aches, and diarrhea one week before, with resolution of those symptoms. Among the differential diagnoses is DRESS syndrome.

 

The DRESS syndrome – Drug Reaction with Eosinophilia and Systemic Symptoms – is a delayed onset drug reaction characterized by a severe drug rash associated with fever, lymphadenopathy, internal organ involvement, and hematologic abnormalities. Internal organs affected include the liver, kidneys, lungs, heart, and pancreas, and brain involvement takes the form of encephalitis and/or meningitis. The syndrome has a 10% or greater mortality rate, even with early recognition and treatment. DRESS has generally been under-recognized in psychiatry, even though many of the implicated drugs are psychotropics. The pathogenesis of DRESS is thought to involve an interaction of specific HLA haplotypes, viral infection or reactivation (HHV-6 herpesvirus, Epstein-Barr virus, cytomegalovirus), and medication.

 

The presentation of DRESS is variable, with a range of signs and symptoms that may present sequentially rather than simultaneously such that many cases may go undetected. Key criteria are listed in Box 1.

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The DRESS rash typically appears 2-8 weeks after the drug is initiated, with earlier presentations seen with drug re-challenge. The rash is classically described as morbilliform, as shown in Figure 1, but many other presentations are seen, including urticarial, targetoid (erythema multiforme-like), and pustular. The rash spreads rapidly to involve more than 50% of the body. In about one-third of cases, gross facial edema accompanies the rash, and this is consistent with more serious disease. Lymphadenopathy typically involves more than one node, with enlargement often ≥ 1 cm. 

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The internal organ most affected in DRESS is the liver, with presenting features of hepatitis, jaundice, or asymptomatic transaminitis. The pattern of injury can be hepatocellular, cholestatic, or mixed. Kidney involvement takes the form of acute interstitial nephritis with proteinuria, hematuria, and sterile pyuria. Pulmonary manifestations include pneumonia, effusions, nodules, and acute respiratory distress. Myocarditis associated with DRESS may develop in association with the rash or as a late manifestation, up to 4 months after first symptoms. Pancreatic involvement can be acute or late-appearing, and may involve endocrine more than exocrine functions. Hematologic signs include eosinophilia, thrombocytopenia, leukocytosis, lymphocytopenia, and atypical lymphocytes. Several autoimmune conditions may be late-appearing sequelae of DRESS. The most common is autoimmune thyroiditis, which may manifest at any time from several weeks to three years after initial symptoms. Other syndromes include systemic lupus erythematosus, diabetes mellitus type 1, and autoimmune hemolytic anemia.

When DRESS is suspected, a formal diagnosis can be made using an algorithm such as that developed by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR). Scoring yields a diagnosis of possible, probable, or definite DRESS. Formes frustes presentations are possible. The RegiSCAR with scoring is reproduced in the paper by *Cho, et al. cited in the reference list and available through PubMed.

Signs and symptoms of DRESS may persist for weeks to months after the offending drug is withdrawn. The syndrome can recur, and recurrence is associated with a higher mortality rate than the initial episode.

Drugs implicated in DRESS include a range of antibiotics, antivirals, anticonvulsants, analgesics, and psychotropics. Individual drugs such as allopurinol are often cited. Table 1 lists psychotropic medications reported with DRESS. Among psychotropics, anticonvulsants are most involved, with carbamazepine, lamotrigine, and valproate implicated most often, although this could reflect more frequent use of these drugs.

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Laboratory testing for patients presenting with DRESS symptoms includes the following:

• CBC with differential and platelets (including search for atypical lymphocytes)

• C-reactive protein

• Liver function tests

• Creatinine, glucose, calcium

• Urinalysis for protein, cells

• Creatine kinase, troponin

• ECG

Other tests are recommended by specialists to evaluate specific internal organ involvement. In addition, PCR testing for herpesvirus 6 and other viruses may be suggested. For more complex cases, patch tests and lymphocytic transformation tests can be used to identify specific drugs implicated.

 

When DRESS is diagnosed, the offending drug must be discontinued and not restarted. Supportive care should be initiated, and this may require admission to a specialized ICU or burn unit in cases where erythroderma or extensive exfoliative dermatitis are present. Systemic glucocorticoids are a mainstay of treatment in all but the mildest cases, which can be treated with high-potency topical glucocorticoids. Detection and monitoring of visceral organ involvement is critical and should involve appropriate medical specialists. 

 

 

 

References

Bommersbach TJ, Lapid MI, Leung JG, et al: Management of Psychotropic Drug-Induced DRESS Syndrome: A Systematic Review. Mayo Clin Proc 91(6):787-801, 2016 

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Cardones AR: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Clin Dermatol 38(6):702-711, 2020

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*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 18(6):1243, 2017

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Clark A, St Clair B. Severe Cutaneous Adverse Reactions Associated With High-Dose Lamotrigine for Mood Disorders: A Case Series. Innov Pharm. 2022;13(2):10.24926/iip.v13i2.4541. Published 2022 Dec 12. doi:10.24926/iip.v13i2.4541

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de Filippis R, Soldevila-Matías P, De Fazio P, et al: Clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a systematic review. Expert Rev Clin Pharmacol13(8):875-883, 2020

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de Filippis R, Soldevila-Matías P, Guinart D, et al: Unravelling cases of clozapine-related Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in patients reported otherwise: A systematic review. J Psychopharmacol 35(9):1062-1073, 2021

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­­ Isaacs M, Cardones AR, Rahnama-Moghadam S: DRESS syndrome: clinical myths and pearls. Cutis102(5):322-326, 2018

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Jevtic D, Dumic I, Nordin T, et al: Less Known Gastrointestinal Manifestations of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome: A Systematic Review of the Literature. J Clin Med 10(18):4287, 2021

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Li JC. Reactivation of Human Herpesvirus (HHV) 6 as Etiology of Acute Liver Injury in Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome: A Case Report. Cureus. 2022;14(9):e29697. Published 2022 Sep 28. doi:10.7759/cureus.29697

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Onuora, S. DRESS linked to HLA alleles. Nat Rev Rheumatol 18, 62 (2022). https://doi.org/10.1038/s41584-021-00744-6

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Schunkert EM, Divito SJ. Updates and Insights in the Diagnosis and Management of DRESS Syndrome. Curr Dermatol Rep. 2021;10(4):192-204. doi: 10.1007/s13671-021-00348-z. Epub 2021 Nov 9. PMID: 34777921; PMCID: PMC8577395.

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Taleb S, Zgueb Y, Ouali U, et al: Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome Related to Aripiprazole Therapy. J Clin Psychopharmacol 39(6):691-693, 2019

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Thaiwat S, Rojanapanthu P. Cutaneous adverse drug eruption: the role of drug patch testing. Int J Dermatol. 2023;62(1):108-114. doi:10.1111/ijd.16398