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A 63-Year-Old Returned Traveller with Fever, Rash, Hepatitis and Eosinophilia

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A 63-Year-Old Returned Traveller with Fever, Rash, Hepatitis and Eosinophilia PRACTICE | WHAT IS YOUR CALL? CPD A 63-year-old returned traveller with fever, rash, hepatitis and eosinophilia Samira Jeimy MD PhD, Kathryn McRae MD, Reena Pattani MDCM MPH n Cite as: CMAJ 2018 July 9;190:E831-5. doi: 10.1503/cmaj.171134 63-year-old woman presented to the emergency Both (b) and (c) are correct. Fever has many possible causes, includ- department with a one-week history of headache, joint ing infectious and noninfectious etiologies. Given the patient’s pain, rash and fever. The rash had begun on her thighs recent travel and concomitant eosinophilia, we considered parasitic andA progressed to involve her whole body within 48 hours. She infection, because it can occur in the absence of a localizing symp- did not report gastrointestinal, genitourinary or respiratory tom like diarrhea. Of noninfectious etiologies, we considered inflam- symptoms, and there was no history of unintentional weight matory and neoplastic causes, as well as drug reactions. loss. She had returned three months previously from Mongolia, Eosinophilia is a hallmark of hypersensitivity reactions and Cambodia and Vietnam, and had received appropriate travel may be associated with systemic symptoms. Drug reactions that vaccinations. She did not smoke, drink alcohol or use any recre- should be considered medical emergencies in a setting of eosino- ational substances. philia, fever, rash and a recent change in medications include For the past one month, she had been treated with sulfasala- Stevens–Johnson syndrome and toxic epidermal necrolysis zine for seronegative rheumatoid arthritis, with bilateral erosive (which comprise a spectrum of the same disease), and drug reac- metacarpal involvement. Her family history included rheumatoid tion with eosinophilia and systemic symptoms, an important arthritis. She also had self-limited chronic urticaria with derma- consideration in our patient. tographism, ductal carcinoma in situ treated curatively with Primary hypereosinophilic syndrome (a) describes a group of lumpectomy, tubular adenomas on screening colonoscopy and clonal diseases characterized by an overproduction of eosino- presumed hepatitis in childhood. She was born in the Philippines phils (for which there is no identifiable underlying cause), with but had lived in Canada for several decades. Aside from occa- infiltration of target organs. The condition is marked by dysfunc- sional use of acetaminophen, our patient took no other over-the- tion of the affected organs. Investigations may include routine counter or naturopathic medications. blood tests to measure the extent of organ involvement and tests On examination, our patient was alert and in no apparent dis- to rule out secondary causes of eosinophil overproduction. In the tress, with a body temperature of 38.2°C. She had bilateral perior- absence of a secondary cause, a serum tryptase level may point bital edema. There was no lymphadenopathy. There was a non- towards a myeloproliferative disorder. At this stage, there were blanching, erythematous, morbilliform rash that spared the many potential secondary causes for eosinophil overproduction, palms and soles but no bullous lesions, skin scaling or mucosal and we felt it was too early to consider this diagnosis. lesions. She had deformities in her hands consistent with rheuma- Eosinophilic granulomatosis with polyangiitis (d) should also toid arthritis but no active joints and normal grip strength. Car- be considered when eosinophilia is associated with rheumato- diac and respiratory examinations were normal, and she did not logic symptoms such as rash and joint pain. However, our patient have hepatosplenomegaly or stigmata of cirrhosis. Her neurologic did not have atopic features, and her rash was atypical of eosino- examination was normal, with negative results for Brudzinski philic granulomatosis with polyangiitis, which tends to present sign, Kernig sign and jolt accentuation. as palpable purpura. Another inflammatory consideration, adult- onset Still disease (e), is characterized by daily fever, joint pain What diagnoses should be considered in this and typical evanescent salmon-coloured rash that primarily patient? affects the trunk. Based on our differential diagnosis (Box 1), we investigated a. Primary hypereosinophilic syndrome infectious, allergic and inflammatory causes. The patient’s ini- b. Parasitic infection tial laboratory investigations (Box 2) showed leukocytosis c. Drug reaction with eosinophilia and systemic symptoms (driven by atypical lymphocytosis and eosinophilia) and mixed- (DRESS) syndrome pattern hepatitis. Inflammatory markers, including C-reactive d. Eosinophilic granulomatosis with polyangiitis protein level, erythrocyte sedimentation rate and ferritin level, e. Adult-onset Still disease were elevated. © 2018 Joule Inc. or its licensors CMAJ | JULY 9, 2018 | VOlumE 190 | ISSUE 27 E831 How should this patient be evaluated further? characteristically occurs two to six weeks after the drug is started and is distinct from more common drug rashes because of the a. Bone marrow aspiration and biopsy longer duration of symptoms and systemic involvement.2 Com- b. Skin biopsy of the eruption mon precipitants include antiepileptic agents and sulfonamide c. Further autoimmune work-up including repeat rheumatoid medications. In one retrospective case series, 4 of 38 cases of factor and anti-cyclic citrullinated peptide antibodies DRESS syndrome were caused by sulfonamides.3 In another ret- d. Reverse transcriptase–polymerase chain reaction (RT–PCR) of rospective review of 172 cases of the syndrome, 10 were precipi- PRACTICE peripheral blood for FIP1L1–PDGFRA gene fusion tated specifically by sulfasalazine.4 e. Computed tomography (CT) of the thorax, abdomen and pelvis Clinical presentation The answer is (b). Given the initial findings and the patient’s persis- Drug reaction with eosinophilia and systemic symptoms syn- tent rash, lymphocytosis and hepatitis, we now considered drug drome is a clinical diagnosis. Fever, lymphadenopathy, facial reaction with eosinophilia and systemic symptoms syndrome as edema and pruritus herald the onset of diffuse, maculopapular the underlying cause. Skin biopsy showed mild dermal perivascular eruption, which may progress to erythroderma.2 Abnormalities in lymphocytic infiltrate, focal spongiosis and interface dermatitis, laboratory investigations include leukocytosis, atypical lympho- findings compatible with drug-induced dermatitis (Figure 1). cytes and eosinophilia. Systemic involvement most commonly Bone marrow aspiration and biopsy (a) are indicated when inves- includes hepatitis, pneumonitis and acute interstitial nephritis; tigating primary hypereosinophilic syndrome, chronic eosinophilic there are also case reports of myocarditis, colitis, pancreatitis leukemia and other hematologic neoplasms involving clonal eosino- and encephalitis as presenting features of the disease.1,2 phil expansion. Similarly, FIP1L1–PDGFRA fusion genes (d) are present The RegiSCAR score is a diagnostic tool for DRESS syndrome in myeloproliferative hypereosinophilic syndromes. Our patient had based on seven clinical and laboratory parameters that help no clinical features that suggested a hematologic malignant disease determine if the syndrome is an absent, possible, probable or such as lymphadenopathy, splenomegaly or more classic derange- definite diagnosis; it is important to note that eosinophilia may ments on complete blood cell count. In addition, eosinophilia is often not be present and is not required to make the diagnosis greater in cases of malignant disease (in our experience, eosinophil (Box 3).1,2 counts of 1.5 × 109/L or more). Therefore, we did not add RT–PCR of Prognosis depends on patient age, comorbidities and severity peripheral blood and bone marrow analyses to this round of investi- of organ involvement. The liver is most commonly affected gations, and we did not undertake further autoimmune work-up or (involved in 60%–80% of cases), often presenting as hepatomeg- imaging (e) because our patient did not have a history of asthma or aly and jaundice.2 Liver failure is the leading cause of death in palpable purpura that suggested eosinophilic granulomatosis with patients with DRESS syndrome, with mortality rates of 5%–10%.2 polyangiitis. Repeating serological testing (c) would not have been Renal involvement is found in 10%–30% of cases, and pneumoni- helpful in following disease activity of rheumatoid arthritis. tis is seen in 5%–25%.2 Hypothyroidism is a late complication Matching our findings to the validated diagnostic criteria pro- that requires protracted monitoring of tests for thyroid function vided by the RegiSCAR project (Box 3),1 we came to a probable after diagnosis.3 Additional late manifestations reported in the diagnosis of drug reaction with eosinophilia and systemic symp- literature include type 1 diabetes mellitus, systemic lupus ery- toms (DRESS) syndrome related to sulfasalazine therapy. thematous and autoimmune hemolytic anemia.5,6 Discussion Pathogenesis The pathogenesis of DRESS syndrome is only partially under- Drug reaction with eosinophilia and systemic symptoms syn- stood. Markers for genetic susceptibility have been identified drome is a subset of type IV drug-induced hypersensitivity reac- within the HLA complex.7 Owing to high co-incidence with cyto- tions, with an incidence of about 1 in 10 000 drug exposures.2 It megalovirus, Epstein–Barr virus and herpes virus6,7 reactivation, Box 1: Differential diagnosis considered in a returned traveller with fever,
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