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 such as:

• Allopurinol (see case report)
• Carbamazepine
• Phenytoin
• Barbiturates (Phenobarbital)
• Dapsone
• Sulfonamides
• Minocycline
• strontium ranelate (osteoporosis drug)
• vemurafenib/cobimetinib

Less commonly, the syndrome is associated with drugs such as: primidone, gold derivatives, cyclosporine, captopril, diltiazem, terbinafine, azathioprine and allopurinol (Kumari R et al 2011).

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

2-6 weeks after ingestion of triggering drugs (long latency period between drug ingestion and appearance of symptoms), appearance of a generalized, maculo-papular, lichenoid or multiforme, possibly also hemorrhagic (about 10%) exanthema, which may extend to erythroderma. Skin symptoms spread from the face to the entire body. The face is often reddened and swollen in areas, with accentuation of the periorbital region. The changes on the trunk and extremities are exceptionally polymorphic. Atypical cocardia are frequently encountered. Sterile follicular and non-follicular pustules and tension blisters are not uncommon.

Oral mucosal changes occur as planar redness of the cheeks and pharynx or as planar erosions.

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

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 before, a therapy with allopurinol 300 mg p.o./1x day had been started due to a first elevated uric acid value (!). 3 weeks after the beginning of the therapy the patient developed a severe generalized pruritus with otherwise undisturbed AZ, followed by a generalized exanthema appearing a few days later. The therapy with allopurinol was continued, at the same time an oral antihistamine in usual dosage was prescribed. One day later, when the intensity of the exanthema increased, a single intravenous application of 150 mg prednisolone was administered i.v. This did not improve the symptoms either. Thereupon stat. Admission.

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

Lab. Creatinine: 1.7 mg/dl (chronic renal insufficiency with serum creatinine values between 1.4 and 2.2 mg/dl, hypertensive cardiomyopathy and a metabolic syndrome: dyslipidaemia, 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%), markedly 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 level of 17 mmol/l. Liver enzymes were clearly 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 suspected drug-associated HSS, allopurinol therapy was stopped immediately. The patient received high doses of prednisolone (1.5 mg(kgKG i.v.). Due to anuric renal failure, he required repeated dialysis. Under this therapy, renal function returned to normal. The maculo-papular exanthema regressed markedly within 10 days on purely maintenance external therapy. The skin later desquamated exfoliatively with moderate pruritus.

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

Comment: DRESS (hypersensitivity syndrome) may occur in approximately 2% of all patients treated with allopurinol. About 1/5 may be life-threatening. Not infrequently, fever, eosinophilia, liver and kidney failure are observed in addition to exanthematous skin changes. The half-life of allopurinol and oxypurinol is markedly prolonged (>125 hours) in renal failure. This leads to increased (toxic) concentration of the drug or its metabolite in the kidney.

2) Reported case of a 58-year-old man who suffered from intolerable generalized pruritus one month after starting treatment with colchicine, amiodarone, perindopril, allopurinol, and spironolactone. From the beginning of treatment, he suffered from progressive patchy erythema, fever, anorexia, edema of the hands and face, abnormal blood eosinophilia (42%) at 5810 eosinophils / mm3), acute liver failure (including cholestatic icterus, coagulopathy and hypoproteinemia). Furthermore, exocrine pancreatic failure (with severe steatorrhea), renal failure, metabolic acidosis, exacerbation of pre-existing heart failure and lower extremity edema were diagnosed.

Therapy: All medications were discontinued.

Course: 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 response.

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.

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