Case series: Drug reaction with eosinophilia and systemic symptoms (DRESS)

Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially fatal drug-induced hypersensitivity reaction. Historically named ‘Phenytoin Hypersensitivity Syndrome’, being first described with the use of the latter, it has undergone frequent changes in its nomenclature over the years owing to associations with multiple drugs noted. ¹ Anticonvulsants and sulphonamides are the most common offending drugs. ²

DRESS is believed to occur in approximately 1 in 1000 to 10,000 patients, though this estimate may indeed be higher, as it is seldom diagnosed. ¹ The treatment of DRESS typically involves discontinuing the causative drug and initiating therapy with agents such as steroids. Other immunosuppressants, such as cyclosporine, may also be required. Visceral involvement (hepatitis, pneumonitis, myocarditis, pericarditis, nephritis, and colitis) is the major cause of morbidity. ³ Mortality due to DRESS is estimated to be 10% in adults and 5.4% in children. ⁴

Case 1: Allopurinol-induced DRESS in a patient with rheumatoid arthritis (RA)

A 39-year old female presented with intermittent high-grade fever for ten days and generalised rash for seven days. The rash initially began over the trunk and then extended peripherally and was associated with itching. She had been evaluated at a local hospital and started on intravenous antibiotics (ceftriaxone), but was referred to our tertiary care owing to persisting symptoms.

She had a past history of hyperthyroidism treated by carbimazole 10 mg od for the previous four months, and rheumatoid arthritis treated by hydroxychloroquine 100 mg od, Allopurinol 100 mg od, Leflunomide 5 mg od and Prednisolone 5 mg od for the previous month.

At presentation, she was febrile (38.0 °C). A purpuric, non-blanching, maculopapular rash was present all over her body. Facial puffiness and oedema of the neck and fingers were noted. Oral ulcers were seen over the soft palate. Systemic examination was otherwise unremarkable.

Laboratory investigations showed a leucocytosis (11 × 10⁹/L) and eosinophilia with raised erythrocyte sedimentation (64/min) and raised C-reactive protein (22 mg/L). Rheumatoid factor and anti-cyclic citrullinated peptide were positive. Antinuclear antibody (ANA) profile was found to be positive for Smith protein (though clinical history and profile did not confirm lupus) and ribonucleoprotein. Initial presentation photographs are shown in Figure 1.

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Figure 1.

Initial presentation of the patient before treatment: (a) facial oedema, (b) rashes on the lower limb, and (c) rashes and dryness on the back.

Microscopy showed a mild acanthotic spongiotic epidermis, and the upper dermis had occasional vessels showing fibrinoid necrosis, perivascular lymphohistiocytic infiltrate, admixed with few neutrophils, nuclear dust and a few eosinophils (Fig. 2).

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Figure 2.

Microscopy and histopathological findings showing fibrinoid necrosis and perivascular lymphohistiocytic infiltrate: (a) high magnification and (b) low magnification.

The allopurinol that had been commenced for elevated uric acid levels prior to the development of her widespread purpuric and pruritic rash was discontinued on clinical suspicion of DRESS syndrome, upon which our patient's symptoms resolved promptly with no recurrence. The temporal relationship and resolution of symptoms upon withdrawal strongly implicate Allopurinol rather than Leflunomide as the causative agent of DRESS in this case.

Further treatment with Hydrocortisone initially and intravenous antibiotics (IV Ceftriaxone in view of DRESS) were given. Topical calamine lotion to relieve itching was also given. Significant improvement was seen, allowing discharge after 10 days.

Case report 2: Leflunomide-induced DRESS in a patient also with rheumatoid arthritis

A 37-year old female patient presented with a pruritic reddish rash over her arms, trunk, and face, which was present for ∼5 weeks. She complained of having oral ulcers for one month and a fever for 10 days. She also gave a history of joint pains of three months’ duration, for which she was prescribed Leflunomide.

After this, the pruritus and skin lesions over her arms and face began. She was then prescribed Wysolone and cyclosporine, but started vomiting and developed a fever, nodular skin lesions, erythema, and crusting of the lips. She had also been prescribed other oral and topical immunosuppressants (hydrochloroquine, methylprednisolone, non-steroidal anti-inflammatory drugs, prednisolone, and clobetasol), as well as antibiotics and antifungals multiple times for the skin rash and for joint aches.

Laboratory tests showed a leucocytosis (10.8 × 10⁹/L) with mild eosinophilia, raised alanine aminotransaminase levels (0.750 µkat/L) and aspartate aminotransferase levels (0.8667 µkat/L), increased erythrocyte sedimentation rate (25/min) and increased CRP (20 mg/L).

Blood cultures, malarial parasites, Dengue IgM, Weil-Felix, severe-acute respiratory syndrome-coronavirus-2, HIV, ANA, complement component 3 (C3), human herpes virus and rheumatoid factor were all negative.

Abdominal ultrasonography was suggestive of liver parenchymal changes with mild ascites. Transthoracic echocardiography was normal. Ultrasonography of the neck was suggestive of multiple bilateral reactive lymph nodes. Fine needle aspiration cytology showed reactive lymphadenitis only.

Immunofluorescence of skin, performed to rule out Lupus, was negative. A skin biopsy showed parakeratosis and mild acanthosis, but was negative for pustular psoriasis.

DRESS syndrome was diagnosed, and treatment with prednisolone and immunoglobulin therapy (IVIG 100 g over two days) commenced. Significant improvement was shown immediately and complete recovery after two weeks.

Discussion

DRESS has a delayed onset and longer duration compared to other drug reactions, with the latent period range being around 2–8 weeks. The reaction may also be associated with sequential reactivation of Herpes virus infections; hence, there is sometimes a paradoxical worsening of symptoms after withdrawal of the offending drug. ⁵ The pathogenesis of the reaction is not completely understood, but is considered to have two or more of the following:

A genetic insufficiency of enzymes needed to detoxify metabolites, which leads to an accumulation that causes cell death.

Usually, patients will not have any recurrence, but very rarely, a relapse unrelated to the original offending drug may present. Its severity may be driven by a persistent immune activation, with inflammatory cytokine production and expansion of cytotoxic T-cells. ⁷

According to the European Registry of Severe Adverse Cutaneous Reactions to Drugs and Collection of Biological Samples (RegiSCAR), the inclusion criteria for a diagnosis of DRESS must include at least three of the following:

a. Hospitalisation.

Cutaneous reactions are most obvious, together with hepatic and haematologic abnormalities; kidneys and lungs may also be affected.^8,9 Cutaneous changes may range from a mild exanthema to widespread blistering and skin loss, but it is usually a pruritic, macular erythema with papules, pustules, and/or vesicles. ⁹ Sometimes, facial oedema is also reported.

Haematological changes are usually seen two weeks after onset, presenting with leucocytosis and a high number of abnormal lymphocytes. Eosinophilia is usual, and occasionally there is also thrombocytopenia and anaemia.

Treatment must first remove the offending drug and then manage the symptoms. All patients should receive supportive therapy to stabilise their haemodynamic status and reduce fever, best by corticosteroids, which should be slowly tapered over a period of 6–8 weeks. In some cases, when patients are not responding to steroids, IVIG may be used.^8–10