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A 63-year-old returned traveller with fever, rash, hepatitis and

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 , 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. 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 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 practice vided bytheRegiSCARproject(Box 3), helpful infollowingdiseaseactivityofrheumatoidarthritis. polyangiitis. Repeatingserologicaltesting(c)wouldnothavebeen palpable purpurathatsuggestedeosinophilicgranulomatosiswith imaging (e) because our patient didnot have a history of asthma or gations, andwedidnotundertakefurtherautoimmunework-upor peripheral blood and bone marrow analyses to this round of investi- E832 tions, withanincidenceofabout1in10 000drugexposures. drome isasubsetoftypeIVdrug-inducedhypersensitivityreac - Drug reactionwitheosinophiliaandsystemicsymptomssyn - Discussion c. b. a. How shouldthispatientbeevaluatedfurther? counts of1.5×10 greater incasesofmalignantdisease(inourexperience,eosinophil ments oncompletebloodcellcount.Inaddition,eosinophiliaisoften such aslymphadenopathy,splenomegalyormoreclassicderange- no clinicalfeaturesthatsuggestedahematologicmalignantdisease in myeloproliferativehypereosinophilicsyndromes.Ourpatienthad phil expansion.Similarly,FIP1L1– leukemia andotherhematologicneoplasmsinvolvingclonaleosino- tigating primaryhypereosinophilicsyndrome,chroniceosinophilic findings compatiblewithdrug-induceddermatitis(Figure 1). lymphocytic infiltrate, focal spongiosis and interface dermatitis, the underlying cause. Skin biopsy showed mild dermal perivascular reaction witheosinophiliaandsystemicsymptomssyndromeas tent rash,lymphocytosisandhepatitis,wenowconsidereddrug The answer is (b). Given the initial findings and the patient’s persis- e. d. toms (DRESS)syndromerelatedtosulfasalazinetherapy. diagnosis ofdrugreactionwitheosinophiliaandsystemicsymp- • • • *Based ontheauthors’ clinical experience. Box 1:Differential diagnosis considered ina returned traveller with fever, rash, hepatitis andeosinophilia*

Parasitic: helminthinfections Bacterial: malariaandenteric fever syndromes dengue fever, hemorrhagic hepatitis Dandhepatitis E, Viral: hepatitis A,hepatitis B, Matching our findings to thevalidated diagnostic criteria pro- Skin biopsyoftheeruption Bone marrowaspirationandbiopsy Bone marrowaspirationandbiopsy(a)areindicatedwheninves- Computed tomography(CT)ofthethorax,abdomenandpelvis peripheral bloodforFIP1L1–PDGFRAgenefusion Reverse transcriptase–polymerasechainreaction(RT–PCR)of factor andanti-cycliccitrullinatedpeptideantibodies Further autoimmunework-upincludingrepeatrheumatoid T ravel related 9 or more). Therefore, we did not add RT–PCR of /L ormore).Therefore,wedidnotaddRT–PCRof Infectious fusion genes (d) are present PDGFRA fusiongenes(d)arepresent • • Bacterial: syphilis cytomegalovirus, HIV Viral: Epstein–Barr virus, T ravel independent 1 wecametoaprobable CMAJ | JULY 9,2018 • • • 2 polyangiitis granulomatosis with eosinophilic atypical presentation of Vasculitis, including Adult-onset Still disease Autoimmune hepatitis It | Volume 190 Inflammatory tis isseenin5%–25%. Renal involvementisfoundin10%–30%ofcases,andpneumoni- DRESS syndromewerecausedbysulfonamides. of medications. Inoneretrospectivecaseseries,4of38 cases mon precipitantsincludeantiepilepticagentsandsulfonamide tated specificallybysulfasalazine. rospective reviewof172casesthesyndrome,10wereprecipi- patients withDRESSsyndrome,mortalityratesof5%–10%. eruption, whichmayprogresstoerythroderma. edema and pruritus herald the onset of diffuse, maculopapular drome isaclinical diagnosis. Fever, lymphadenopathy, facial Drug reactionwitheosinophiliaandsystemicsymptomssyn Clinical presentation megalovirus, Epstein–Barr virus and herpes virus within theHLAcomplex. stood. Markersforgeneticsusceptibilityhavebeenidentified The pathogenesis of DRESS syndrome is only partially under Pathogenesis longer durationofsymptomsandsystemicinvolvement. and isdistinctfrommorecommondrugrashesbecauseofthe afterthedrugisstarted characteristically occurstwotosix weeks after diagnosis. that requiresprotractedmonitoringoftestsforthyroidfunction (Box 3). not bepresentandisrequiredtomakethediagnosis definite diagnosis;itisimportanttonotethateosinophiliamay determine if the syndrome is an absent, possible, probable or based onsevenclinicalandlaboratoryparametersthathelp aly andjaundice. (involved in60%–80%ofcases),oftenpresentingashepatomeg- of organinvolvement.Theliverismostcommonlyaffected and encephalitisaspresentingfeaturesofthedisease. there arealsocasereportsofmyocarditis,colitis,pancreatitis includes hepatitis, pneumonitis and acute interstitial nephritis; cytes andeosinophilia.Systemicinvolvementmostcommonly laboratory investigationsincludeleukocytosis,atypicallympho- thematous andautoimmunehemolyticanemia. diabetesmellitus,systemiclupusery- literature includetype 1 The RegiSCARscoreisadiagnostictoolforDRESSsyndrome Prognosis depends on patient age, comorbidities and severity 1,2 | Issu e 27 3 Additionallatemanifestationsreportedinthe 2 neoplasm Myeloid orlymphoid Liverfailureistheleadingcauseofdeathin Neoplastic 2 Hypothyroidismisalatecomplication 7 Owingtohighco-incidencewithcyto- 4 sulfasalazine Adverse drugreaction to Drug reaction 2 5,6 Abnormalitiesin 3 Inanotherret- 6,7 reactivation, 1,2 2 Com- - - 2

practice E833 — 28 59 35 55 36 4.5 115 132 245 524 615 309 94.8 8.60 those cases that those cases that 1426 1.376 2.924 Not tested Not Not tested Not Not tested Not or biliary disease On day 5 of admission On day 5 of Periportal inflammation Periportal without hepatosplenomegaly without hepatosplenomegaly Positive for hepatitis A IgG only hepatitis for Positive 26 55 42 15 23 4.1 747 130 137 213 138 418 402 95.0 7.36 11.7 1.01 0.514 1.174 C3 1.25 C4 0.37 IgA 1.38 IgM 0.77 Negative Negative Negative Negative IgG 11.90 Not tested Not AMA negative ue 27 Iss On day of admission On day of Atypical lymphocytes Atypical | ANA 0.3, ASMA negative, ANA 0.3, ASMA negative, Treatment - syndrome are lack for treatment of DRESS guidelines Currently, sup- and agent offending the of withdrawal is mainstay the ing; of 38 cases A retrospective review portive care. of the syndrome cortico­ benefit with topical that patients received suggested scores were no severity in mild cases; however, steroid creams early identification of provided to help with e 190 lum Vo | 0–7 7–40 0–23 0–20 0–5.0 22–30 10–45 35–50 3.5–5.0 42–102 1.0–3.2 35–125 12 –192 135–145 115–155 140–400 0.04–0.4 0.9–1.20 ANA ≤ 1.0 82.0–97.0 4.00–11.00 C3 0.79–1.52 C4 0.16–0.38 IgA 0.82–4.52 IgM 0.46–3.04 eference range eference IgG 7.51–15.60 R JULY 9, 2018 JULY | The theory that drug The theory 8 CMAJ /L 7 /L /L 9 /L /L /L 9 9 /L 9 esults for laboratory investigations laboratory for esults ymphocytes, × 10 ymphocytes, Ferritin, µg/Ferritin, L Autoimmune hepatitis serology hepatitis Autoimmune of abdomen Ultrasonography Mean corpuscular volume, fL volume, corpuscular Mean × 10 count, Platelet Blood film (including thin and thick smears) Sodium, mmol/L L mmol/ Potassium, mmol/L Bicarbonate, µmol/L Creatinine, Note: AMA = antimitochondrial antibody, ANA = antinuclear antibody, ASMA = anti-smooth muscle antibody, C3 = complement component 3, C4 = complement component 4, IgA = component 3, C4 = complement component C3 = complement muscle antibody, ASMA = anti-smooth antibody, ANA = antinuclear antibody, AMA = antimitochondrial Note: test. laboratory research disease immunoglobulin A, IgG = immunoglobulin G, IgM = immunoglobulin M, VDRL = venereal Hemoglobin, g/L Laboratory test Laboratory Box 2: R Box Eosinophils, × 10 Eosinophils, White blood cell count, × 10 count, blood cell White Aspartate aminotransferase, IU aminotransferase, Aspartate IU Alanine aminotransferase, IU phosphatase, Alkaline Albumin, g/L µmol/L Bilirubin, total; Antineutrophil cytoplasmic antibody cytoplasmic Antineutrophil Blood cultures cultures Stool in stool and parasites Ova B, A, hepatitis Serology: hepatitis virus, Epstein−Barr HIV, hepatitis C, VDRL cytomegalovirus, g/Immunoglobulin (Ig) quantification, L L Erythrocyte sedimentation rate, mm/h rate, Erythrocyte sedimentation Bilirubin, direct; µmol/L Bilirubin, direct; Complement, g/L International normalized ratio normalized International mg/ protein, L C-reactive hypersensitivity is the cause of drug reaction with DRESS syn- drug reaction with is the cause of hypersensitivity symptoms in onset of by the accelerated drome is supported cases with drug rechallenge. it is thought that the syndrome may mediate its effects in part in part its effects mediate may the syndrome that it is thought anti- cross-reactivity between mimicry with through molecular and stimulates T-cell production and viruses; this gens on drugs response. host inflammatory an aggressive practice E834 drome. Hematoxylinandeosinstain.Originalmagnification× 400. text ofdrugreactionwitheosinophiliaandsystemicsymptomssyn- epidermal junction.Thelatterfindinghasoftenbeenreportedinthecon- interface dermatitis,withlymphocytesaggregatedaroundthedermal– bracketed region),perivascularlymphocyteinfiltration(arrows)andfocal focal epidermalspongiosis(orintercellularedema,highlightedinthe Figure 1:Histologicexaminationofskinbiopsytheeruption would benefitfromtopicalversussystemictherapy. immunosuppression using agents such as cyclosporine, cyclo courses. Inrefractorycases,treatmentmayrequiremorepotent after stoppingthedrug,necessitatingprolongedcorticosteroid kg/d) are often used. Symptoms may persist or increase even ence oforgandysfunction,systemiccorticosteroids(0.5–1 mg/ Adapted from Kardaun andcolleagues. Note: DRESS =drugreaction witheosinophiliaandsystemic symptoms. Probability ofadiagnosisDRESS: <2,unlikely; –3,possible;4–5,probable; >5,definite. Enlarged lymphnodes(two sites ormore, >1 cm) Fever (≥ 38.5°C) Feature symptoms syndrome Box 3:TheR > 1.5×10 Distribution over more than50%ofbodysurface area Skin rash Atypical lymphocytes At least two ofedema,infiltration, purpura orscale 0.7to 1.5×10 Eosinophilia Biopsysuggesting DRESS Resolution inmore than15days Two ormore One Internal organ involved alternative diagnoses At least three negative results from biologicinvestigations into 9 /L or≥20%ofwhite bloodcell count egiSCAR project diagnostic score for aprobable diagnosis of drugreaction witheosinophilia andsystemic 9 /L or10%–19%ofwhite bloodcell count 1 CMAJ | JULY 9,2018 3 Inthepres- showing - | Volume 190 steroids (regardlessofdurationtherapy). pressed, includingthosewhoreceivedtreatmentwithcortico­ tion ismostcommonlyseeninpatientswhoareimmunosup- and 84%–92%,respectively. require serology,whichhassensitivityandspecificityof82%–95% can precipitatestrongyloideshyperinfectionsyndrome. with corticosteroids,inthepresenceofS.stercoraliscolonization, However, sensitivityofstoolstudiesisonly50%. stool samplesat24-hourintervalstoidentifyovaandparasites. asymptomatic patientsinvolvescollectionofthreeconsecutive bowel, filariform larvae precipitate leakage of gut flora from damaged syndrome, whichcarriesamortalityrateashigh87%,invasive ginated fromcountrieswhereS.stercoralisisendemic. Asia, SoutheastandCentralSouthAmerica. Strongyloides stercoralis nematode,whichisendemicinAfrica, mindful ofthepotentialforlatentstrongyloidiasiscausedby considered treatment with systemic corticosteroids, but we were patients withDRESSsyndromewhopresenthepatitis,we in totalanddirectbilirubin.Giventhehighmortalityrate mine treatment.Herhepatitisdeteriorated,however,witharise hospital, herskineruptionslowlyresolvedwithoralantihista- sented to the emergency department, and, during her stay in ies andisbasedoncaseseriesexpertopiniononly. However, useoftheseagentsisnotvalidatedbycontrolledstud- some cases,intravenousimmunoglobulinorplasmapheresis. phosphamide, mycophonelate mofetil and rituximab, and, in Between 1991and2001,77.5%ofimmigrantstoCanadaori­ Our patienthadstoppedtakingsulfasalazinebeforeshepre- 9 No –1 –1 –1 –1 disseminatingbacterialandfungalinfections.Hyperinfec- 0 0 0 0 | Issu e 27 9 Imaging modalities, including CT of Imagingmodalities,includingCTof Yes 0 1 2 1 1 1 1 0 2 1 0 1 9 High-risk patients High-riskpatients Unknown 10 Diagnosisin –1 –1 0 0 0 0 0 0 9 Treatment Treatment 10 Inthis practice

E835 BMJ Case Rep approval of the version to be published and and approval of the version to be published agreed to be accountable for all aspects of the work. Correspondence to: Samira Jeimy, jeimysb@ gmail.com , Musette P, et al. Twelve-year analysis of severe cases of drugof cases severe of analysis Twelve-year al. et P, Musette L, ue 27 Iss | Eshki M, Allanore M, Eshki and systemic symptoms: a cause of unpredictable reaction with eosinophilia 2009;145:67-72. multiorgan failure. Arch Dermatol JD. Drug reaction with eosinophilia and systemic Matta JM, Flores SM, Cherit relation with autoimmunity in a reference center in symptoms (DRESS) and its Mexico. An Bras Dermatol 2017;92:30-3. in drug allergy. Allergol Int 2006;55:27-33. Roujeau JC. Immune mechanisms Mouyis M, et al. Rash and fever after sulfasalazine Raithatha N, Mehrtens S, use. BMJ 2014;349:g5655. and management. CMAJ 2004;171:479-84. Canadians: risk factors, diagnosis hyperinfection syndromeMyint A, Chapman C, Almira-Suarez I, et al. Strongyloides death. and bandemia in resulting host immunocompetent an in 2017;Mar 22;2017. pii: bcr2016217911. Hoetzenecker W, Nägeli M, Mehra ET, et al. Adverse cutaneous drug eruptions: drug eruptions: cutaneous ET, et al. Adverse M, Mehra W, Nägeli Hoetzenecker 2016;38:75-86. Semin Immunopathol current understanding. of S, et al. Therapeutic management E, Duong TA, Bouvresse Funck-Brentano J Am Acad Dermatol 2015;72:246-52. study of 38 cases. DRESS: a retrospective a literature al. The DRESS syndrome: P, Descamps V, et Cacoub P, Musette 2011;124:588-97. review. Am J Med

6. 7. 8. 9. Complicated and fatal Strongyloides infection in lim S, Katz K, Krajden S, et al. 2. 3. 4. 5. 10.

e 190 lum Vo | JULY 9, 2018 JULY | (McRae, Pattani), University of Toronto; Divi- sion of General Internal Medicine (Pattani), St. Michael’s Hospital, Toronto, Ont. Contributors: Samira Jeimy drafted the manu­ script. All of the authors provided patient care in this case, revised the manuscript critically for important intellectual content, gave final CMAJ ondon, Ont.; Department of Medicine Medicine of Department Ont.; ondon, Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia drug reaction. adverse and systemic symptoms (DRESS): an original multisystem 2013;169:1071-80. Results from the prospective RegiSCAR study. Br J Dermatol In our patient, results from stool studies were negative for Stron- studies were negative results from stool In our patient, Competing interests: None declared. This article has been peer reviewed. The authors have obtained patient consent. Affiliations: Department of Clinical Immu- nology and Allergy (Jeimy), Western Univer- L sity, 1.

References Case revisited led to rapid resolution of our Treatment with corticosteroids and biochemical derangements, and patient’s clinical symptoms from hospital with scheduled outpatient we discharged her of prednisone. Ultimately, results from ­follow-up and tapering were negative. serology testing for Strongyloides the thorax, abdomen and pelvis, are not recommended for latent for not recommended pelvis, are and abdomen the thorax, Strongyloides . infection caused by screening for - delay in obtaining serol anticipated a two-week gyloides, and, as we infec- empirically for Strongyloides we decided to treat ogy results, (200 µg/kg/dtion with ivermectin two days) for before administering for the treatment of DRESS syndrome. prednisone (1 mg/kg/d)