Dress T88.7

Merritt et al. 1938; Bocquet et al. 1996;

DRESS is the acronym for "Drug reaction (rash) with eosinophilia and systemic symptoms". Clinically, it is a rare, potentially life-threatening, febrile drug reaction (hypersensitivity syndrome) with exanthema and variable blood eosinophilia and elevation of liver enzymes. In addition to the triggering drug (frequently carbamazepine and phenytoin - former name: carbamazepine-phenytoin hypersensitivity syndrome), a reactivation of viral infections (especially HHV-6) plays a pathogenetic role.

Drugs described as triggers include:

• Allopurinol (see case report)
• carbamazepine
• phenytoin
• Barbiturates (phenobarbital)
• dapsone
• sulfonamides
• Minocycline
• Strontium ranelate (osteoporosis medication)
• Vemurafenib/cobimetinib
• celecoxib

The syndrome is less frequently associated with drugs such as primidone, gold derivatives, cyclosporine, captopril, diltiazem, terbinafine, azathioprine and allopurinol (Kumari R et al. 2011).

Remark: Apparently there are also correlations between the reactivation of HHV-6 and the clinical severity of the reaction.

2-6 weeks after taking the triggering medication (long latency period between taking the medication and the onset of symptoms), occurrence of a generalized, maculo-papular, lichenoid or multiforme, possibly also haemorrhagic (about 10%) exanthema, which can develop into erythroderma. The skin symptoms spread from the face to the whole body. The face is often reddened and swollen over a large area, with the periorbital region being emphasized. The changes on the trunk and extremities are extremely polymorphic. Atypical cockades are frequently encountered. Sterile follicular and non-follicular pustules and tension blisters are not uncommon.

Changes in the oral mucosa occur as extensive reddening of the cheeks and throat or as extensive erosions.

The exanthema is usually combined with a considerable reduction in AZ, high (>38.5°C) fever (>80%), hepatopathy (>70%), nephropathy (50%), pulmonary involvement (31%- acute respiratory distress syndrome, dyspnea, interstitial pneumonitis, dry cough, pathologic lung function), arthralgias, myositis, lymphadenopathies of several (>2) stations, CNS involvement (aspetic meningitis, encephalitis, coma, seizures, speech disorders). Gastrointestinal involvement is rather rare. Recurrent flare-ups over weeks are not uncommon (Mockenhaupt M 2017). See also validation score to confirm the diagnosis.

Dress has also been observed in association with COVID vaccination (Korekawa A et al. 2022).

Non obligatory (60-70% of patients) eosinophilia > 1500/ul; occurrence of atypical lymphocytes. Other path. laboratory parameters depending on organ involvement (see also case report) e.g. path. kidney and liver values.

Mostly superficial perivascular and interstitial edematous dermatitis with lymphocytes and a variable proportion of eosinophilic granulocytes. Edema in the str. papillare; focal epitheliotropy with vacuolization of basal epithelia. Eczematous changes with spongiosis also detectable.

A band-shaped epidermotropic infiltrate of atypical lymphocytes is also suggestive of cutaneous T-cell lymphoma (see also figure: DRESS in angioimmunoblastic T-cell lymphoma).

Clinical:

• maculo-papular drug exanthema: generally lacks the highly acute, potentially life-threatening hazard scenario of DRESS.
• viral exanthema of different genesis (varicella, hand-foot-mouth disease - positive serology!)
• Erythema multiforme: exanthem with typical cocard efflorescences; systemic involvement of DRESS is absent
• Staphylococcal Scalded Skin Syndrome (SSSS): Markedly reduced general condition with fever, skin tension, and possibly purulent rhinitis or conjunctivitis. Initially, there is a large, indistinct, bruised, scarlatiniform exanthema. Positive Nikolski sign.
• Stevens-Johnson syndrome: exanthema with typical cocardial lesions and blistering, positive Nikolski's sign, involvement of the mucous membranes close to the skin.
• Toxic epidermal necrolysis: exanthema of extensive blistering, skin can be pushed off towel-like. Involvement of the mucous membranes close to the skin

Histologic:

• Viral exanthema: difficult differentiation (laboratory diagnosis).
• Exanthema of the erythema multiforme group: always varying intensity of keratinocyte necrosis which is rare in DRESS.

1) A 73-year-old patient in a severely reduced AZ and a hemodynamically unstable condition with anuric renal failure was referred for intensive medical therapy. 5 weeks previously, a therapy with allopurinol 300 mg p.o./1x day had been started with a first elevated uric acid value (!). 3 weeks after the start of therapy, the patient developed severe generalized pruritus with otherwise undisturbed AZ, followed a few days later by a generalized exanthema. Treatment with allopurinol was continued and an oral antihistamine was prescribed in the usual dosage. As the exanthema became more severe, a single intravenous application of 150 mg prednisolone was administered 1 day later. Thereupon stat. Admission.

Findings: Subfebrile, somewhat somnolent, hemodynamically unstable patient with a generalized, maculo-papular, in places multiforme and hemorrhagic exanthema.

Lab.: Creatinine: 1.7 mg/dl (further known was chronic renal insufficiency with serum creatinine values between 1.4 and 2.2 mg/dl, hypertensive cardiomyopathy and metabolic syndrome: dyslipidemia, obesity grade II, diabetes mellitus type 2, arterial hypertension). Furthermore: normochromic, normocytic anemia, mild thrombocytopenia (145 G/l), normal total leukocyte count with evidence of eosinophilia (12%), highly elevated renal retention parameters (creatinine 7.2 mg/dl, urea 163 mg/dl, CRP 115 mg/l (norm < 5 mg/l), hyperkalemia (6.4 mmol/l - norm 3.5-5.5 mmol/l) and metabolic acidosis with a pH of 7.1 and a bicarbonate value of 17 mmol/l. Liver values significantly elevated; rheumatoid factor, ANA, ENA, ANCA, and HIV, hepatitis B and C serology were negative.

Chest x-ray: bilateral pleural effusions, no infiltrate; cardiomegaly.

Sonography: Hepatomegaly, splenomegaly (12 cm).

Therapy and course: In case of a drug-associated HSS, allopurinol therapy was stopped immediately. The patient received high doses of prednisolone (1.5 mg(kgKG i.v.). He had to be dialyzed repeatedly due to anuric renal failure. Under this therapy, the kidney function normalized to the original level. The maculo-papular exanthema regressed significantly within 10 days with external therapy. The skin later flaked off exfoliatively with moderate itching.

Dg.: Allopurinol hypersensitivity syndrome with acute anuric renal failure.

Comment: DRESS (hypersensitivity syndrome) may occur in about 2% of all patients treated with allopurinol. About 1/5 may be life-threatening. In addition to exanthematic skin changes, fever, eosinophilia, liver and kidney failure are often observed. The half-life of allopurinol and oxypurinol is significantly prolonged in renal insufficiency (>125 hours). This leads to an increased (toxic) concentration of the drug or its metabolite in the kidney.

2) The case of a 58-year-old man who suffered from unbearable, generalized pruritus one month after starting treatment with colchicine, amiodarone, perindopril, allopurinol and spironolactone is reported. From the start of treatment, he suffered from progressive, extensive erythema, fever, anorexia, edema of the hands and face, conspicuous blood eosinophilia (42%) at 5810 ^{eosinophils/mm3}), acute liver failure (including cholestatic jaundice, coagulation disorders and hypoproteinemia). Furthermore, exocrine pancreatic failure (with severe steatorrhea), renal failure, metabolic acidosis, exacerbation of pre-existing heart failure and edema of the lower extremities were diagnosed.

Therapy: All medication was discontinued.

Progression: The condition gradually improved until complete remission was achieved 4 months later.

Diagnosis: Patch tests with the drugs in question were negative except for spironolactone. Spironolactone showed a strong positive reaction. 10 controls in healthy volunteers were negative.

Diagnosis: Spironolactone induced DRESS with blood eosinophilia, acute liver failure, exocrine pancreatic failure, renal failure, metabolic acidosis, and exacerbation of pre-existing heart failure.

3) A 68-year-old man became acutely ill with fever, erythroderma, vomiting and loss of appetite. He started taking carbamazepine 49 days prior to admission due to a diagnosis of trigeminal neuralgia. He received the first dose of COVID-19 vaccine (Pfizer-BioNTech) 22 days prior to admission. Sixteen days prior to admission, he developed a low-grade fever with generalized fatigue and extensive skin rashes on his trunk and extremities. Despite persistent symptoms, he received the second dose of COVID-19 vaccine three days prior to admission. Erythroderma developed rapidly with facial swelling, high fever, vomiting and loss of appetite. There was a history of hypertension, diabetes mellitus and myocardial infarction.

Physical examination revealed diffuse redness of the entire body with numerous scratch marks and swelling of the face and lower legs. Enanthema was seen on the hard palate, which was tender on palpation. Lymphadenopathies were present in the neck, axillary and inguinal areas. The patient had a high fever (39.2 °C).

Histopathologic findings: Infiltration of lymphocytes around the vessels in the dermis and slight vacuolar changes in the epidermis. No atypia of the infiltrating cells (hematoxylin-eosin, original magnification × 200).

The blood test on the first day of hospital admission showed an increased leukocyte count (20,100/μl), eosinophil count (2,312/μl), atypical lymphocyte sequestration (0.5%) and values for creatinine (1.69 mg/dl), aspartate aminotransferase (AST; 35 U/l) aspartate aminotransferase (ALT; 94 U/L) and C-reactive protein (CRP; 8.37 mg/dl). On the 10th day of hospitalization, reactivation of HHV-6 was detected. The serum level of thymus and activation-regulated chemokine (TARC) was 73 200 pg/ml on the second day of hospitalization. Computed tomography showed no evidence of an infectious lesion. Blood cultures showed no bacteria or fungi.

Diagnosis: carbamazepine-induced DRESS.

Oral prednisolone (1 mg/kg/day) was administered. The rash, high fever and laboratory abnormalities gradually resolved over a period of 5 weeks. The steroid dose continues to be gradually reduced.

1. EMEA:European public assessment report (EPAR) Protelos (2007) www.emea.europa.eu/htms/human/epar/p.htm
2. Ghislain PD et al. (2004) Drug-induced eosinophilia and multisystemic failure with positive patch-test reaction to spironolactone: DRESS syndrome. Acta Derm Venereol 84: 65-68

3. Korekawa A et al. (2022) Three cases of drug-induced hypersensitivity syndrome associated with mRNA-based coronavirus disease 2019 vaccines. J Dermatol 49:652-655):

4. Kumari R et al (2011) Drug hypersensitivity syndrome. Indian J Dermatol Venereol Leprol 77:7-15.
5. Lin IC et al. (2015) Liver injury in patients with DRESS: A clinical study of 72 cases. J Am Acad Dermatol 72:984-991.
6. Mangana Jet al. (2017) Angioimmunoblastic T-Cell Lymphoma Mimicking Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome). Case Rep Dermatol 9:74-79.
7. Marrakchi C et al (2004) Allopurinol induced DRESS syndrome. Rev Med Internal 25: 252-254
8. Mockenhaupt M (2017) Severe cutaneous drug reactions in childhood. Dermatologist 68: 803-814
9. Müller PA et al.(2012) Maculopapular exanthema with acute renal insufficiency. Dermatologist 63: 223-225
10. Passeron T et al. (2004) Drug rash with eosinophilia and systemic symptoms (DRESS) due to streptomycin. Acta Derm Venereol 84: 92-93
11. Paulmann M, Mockenhaupt M (2015) Severe drug-induced skin reactions: clinic, diagnosis, etiology and therapy. JDDG 13: 625-643
12. Pickert J et al. (2017) DRESS under combination therapy with vemurafinib and cobimetinib. Allergo J Int 26: 85
13. Schmitt J et al. (2011) Dapsone hypersensitivity syndrome: a systematic review on prevalence, course and risk factors for fatal outcome. Abstract CD 46th DDG Conference: P09
14. Valencak J et al. (2004) Carbamazepine-induced DRESS syndrome with recurrent fever and exanthema. Int J Dermatol 43: 51-54