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Home , Pinta (disease), Relapsing fever

PRACTICE | CASES CPD

Relapsing in a traveller returning from

Eric J. Eckbo MD, Marthe Charles MD MSc, Robert Wolber MD, Gannon Yu MD n Cite as: CMAJ 2021 February 22;193:E285-8. doi: 10.1503/cmaj.201644

24-year-old man presented to his family physician with a 1-day history of subjective fever, chills, , myal- KEY POINTS gia, arthralgia and mild diarrhea; he was advised to pro- • A broad differential should be maintained in the returning ceedA to the emergency department for further assessment. On traveller with fever, and a detailed travel, social and exposure arrival at our Vancouver-area emergency department, his tem- history elicited to help guide appropriate diagnostics. perature was 38.3°C (maximal documented temperature 38.4°C), • Spirochetes seen in routine peripheral blood or malaria smears blood pressure 117/67 mm Hg, heart rate 88 beats/min and res­ are pathognomonic for -borne or -borne relapsing piratory rate 16 breaths/min. He was diaphoretic but appeared fever caused by species. otherwise well. • In North America, tick-borne is endemic to British Columbia and the western United States, and is The patient had been travelling extensively and had returned transmitted by soft . home 9 days earlier. Eight months previously, he had embarked • Patients should be closely monitored for the Jarisch– on a solo trip that began in Europe before he continued on to Herxheimer reaction after initiation of effective therapy for all Morocco and finally spent several weeks in Senegal. He had not forms of relapsing fever. received any pretravel medical counselling or vaccinations and did not take malaria chemoprophylaxis. While in Senegal, he had stayed in a small village and was housed by locals. He ate malaria testing. At our regional facilities, malaria testing is per- local food and drank from the local water supply. Most of his formed using a rapid antigen test and preliminary screening of time was spent participating in cycling tours of the area. He had Giemsa-stained thin smears. If these initial tests are negative, no sexual contacts and was not in close proximity to anyone samples are forwarded to a centralized centre for polymerase who was sick. The patient noted that there were many dogs in chain reaction (PCR) testing and comprehensive review of thick the village, and many were visibly infested with ticks. Midway and thin blood smears. In the case of our patient, the rapid anti- through his stay, he experienced an “insect bite” to the leg, gen test was negative and no malaria parasites were seen on the which became pruritic and red. He then had 4 days of subjective thin smears; however, the emergency department physician fever, chills and headache. He sought medical attention at a later received a call from the laboratory, identifying spirochetes local health care facility, where a moist gauze that smelled of (Figure 1). gasoline was applied to the area of the lesion. A thick, white “worm” 2 cm in length was extracted and the patient’s systemic symptoms subsequently resolved without further treatment. A week later, he departed Senegal on a repatriation flight to Can- ada amid the coronavirus disease 2019 pandemic. The patient was noted to be febrile at the time of blood collec- tion. Complete blood count showed a normal leukocyte count (9.7 × 109/L), but low lymphocytes of 0.8 (normal 1.2–3.5) × 109/L; his thrombocyte count and hemoglobin were normal. The results of his electrolyte, liver function and transaminase tests were all within normal range. His C-reactive protein level was elevated at 116 (normal range < 3.1) mg/L. Given the patient’s travel history and recurrent fever, malaria was high on our dif- ferential diagnosis, as was infection with severe acute respira- tory syndrome coronavirus 2 (SARS-CoV-2). We obtained a naso- pharyngeal swab for SARS-CoV-2 testing and ordered urgent Figure 1: Peripheral blood smear showing single spirochete.

© 2021 Joule Inc. or its licensors CMAJ | FEBRUARY 22, 2021 | VOLUME 193 | ISSUE 8 E285 PRACTICE Relapsing fever should not be confused with other causes of system, liver,spleen,lung,gastrointestinal tractandeyes. tions arise from involvement of the heart, lung, central nervous rochete E286 fort. headache, myalgia,arthralgia, rigoursandabdominaldiscom- episodes offeverandnonspecificillness,whichmayinclude Relapsing fever is a distinct disease characterized by recurrent Relapsing fever Discussion with hissystemicsymptoms. probably beenaflylarva(myiasis),andwasnotlikelyassociated cluded thatthe“worm”removedfrompatient’sleghad Borrelia infection was confirmed by the laboratory, we con- panica (endemic to North Africa and the Mediterranean). Once closely relatedtoB.crocidurae(endemicinWestAfrica)orhis- Sequencing of 1d6S rRNA showed that the Borrelia was most relia PCRconfirmedthepresenceofBorreliaspeciesinblood. globulin G(1:256),andnonreactiveforimmunoglobulinM.Bor- immunofluorescenceassaywasreactiveforimmuno- B. hermsii but confirmatory testing using Western blot was negative. Control. firm thediagnosis,byBritishColumbiaCentreforDisease formed afterconsultationwiththeclinicalmicrobiologisttocon- to humans(Box1).Serology,PCRandsequencingwereper- coiling structure,containsmultiplegenerathatarepathogenic blood smearatthattimewasnegativeforspirochetes. the patientwasfeelinggreatlyimproved;repeatperipheral of therapy.Atthetimeinitialfollow-up,3daysintotreatment, switched todoxycyclinethefollowingday,complete10days wenotednoJarisch–Herxheimerreaction.Hewas 6 hours; We administeredadoseofceftriaxoneandmonitoredfor quately specific to begin directed treatment for relapsing fever. copy withthisclinicalpictureandexposurehistorywasade- access clinicforfurthermanagement.Spirochetesonmicros- Brachyspira Borrelia Genus Box 1:Medically important spirochetes The bacterialphylumSpirochaetes,sonamedfortheirunique The patientwasreferredtotheinfectiousdiseasesrapid 1,2 Itiscausedbyinfectionwith1 of severalspeciesthespi- Borrelia, whichistransmittedbyliceor ticks.Complica- enzyme immunoassay was positive, • • • • • • • • • • Intestinal spirochetosis Bejel (endemicsyphilis) (sexuallytransmitted) miyamotoi Hard tick–bornerelapsingfever(Borrelia Louse-borne relapsingfever Tick-borne relapsingfever Lyme borreliosis disease) Syndrome(s) CMAJ | FEBRUARY 22, 2021 1

| tem stimulation. leads totherepeatedcyclesofspirochetemiaandimmunesys- species arecapableofalteringtheirsurfaceantigens,which nent symptom.Afterestablishinginfectioninthehost,Borrelia tious diseasesthatmaypresentwithrecurrentfeverasapromi- recurrent febrileepisodes;Box2providesasummaryofinfec- may havelingeringsymptoms,suchasmalaise. Patients mayfeelcompletelywellbetweenfebrileepisodes,or most casesoccurredinsummermonths. tick-borne relapsingfeverwerereportedinthewesternUS,and Washington andColorado.Between19902011,483casesof found inthewesternstates,concentratedmostlyCalifornia, episodes withouttreatment. ted bysoftticks.Itmayresultinupwardof30recurrentfebrile 15 species of relapsing fever, tick-borne relapsing fever is caused by more than resolution ofthefirstepisodeandrelapsefeveris7–9days. when asampleisobtainedduringfebrileepisode. which limitsthesensitivityoftest.Thehighestyieldoccurs at least10 other spirochetes being detected in Giemsa smears. A density of suggestive ofrelapsingfever,althoughtherearerareinstances of Identification ofspirochetesinaperipheralbloodsmearishighly Diagnosis hermsii between2006and2015. relapsing fever;19patientsshowedevidenceofinfectionwithB. Columbia istheonlyregionofCanadawithendemictick-borne fever remainslessthan1%witheffectivetreatment. symptoms, lastingabout3–5days. followed by the first episode of fever and associated 2–14 d), ditions conducivetobodylouseinfestations. northern and easternAfrica,among populations living in con- with treatment.Itremainsapublichealthconcerninregionsof ing feverranges from 10%–40% when left untreated,and 2%–4% forms ofrelapsingfever.Thefatalityrateforlouse-bornerelaps- relapses, andtendstohaveamoreaggressivecoursethanother by thehumanbodylouse. single species, (Box 3).Louse-bornerelapsingfeverresultsfrominfectionwitha Borrelia moleculartesting and,asaresult,cliniciansshould not smears indiagnosingrelapsing feverislimitedcomparedwith immunofluorescent stainingor dark-fieldmicroscopy. light microscopy; visualization of these spirochetes requires a Wright-orGiemsa-stained blood smearexaminedbystandard sis andsyphilis, these organisms would not bereadilyvisible on chetal infectionscancauseacuteillness,suchasLymeborrelio - increase thesensitivityoftest. smears, suchasthoseorderedformalariadiagnosis,may with passivesurveillancethroughoutCanada. B. miyamotoi, hasbeenfoundinIxodes scapularis ticks,identified ted byhardticks;thecausativeagentofhard-tickrelapsingfever, patients withsuspectedorconfirmedLymedisease. logic evidenceofB.miyamotoiinfectionhasbeendocumentedin VOLUME 193 There are 3 forms of relapsing fever, each defined by its vector There are 3 formsof relapsing fever, each defined by itsvector It isimportanttorecognize that thesensitivityofblood 4 to10 Borrelia and refers to the disease when it is transmit- , and transmission is mediated , and transmission is mediated | ISSUE 8 1 5 Theinitialincubationperiodis7days(range spirochetespermillilitreofbloodisrequired, 3,4 5 Itischaracterizedby1ormore Mortality from tick-borne relapsing Mortalityfromtick-bornerelapsing 6 In the United States, this fever is IntheUnitedStates,thisfeveris 4 Althoughseveralotherspiro- 4 Theaveragetimebetween 7 Itcanalsobetransmit- 5 Unlike louse-borne Unlikelouse-borne 8 InManitoba,sero- 1 9 1 Thickblood 1 1,6 British 1

PRACTICE E287 Geographic distribution Geographic Northern hemisphere Worldwide (primarily Africa) eastern Worldwide Areas of endemicity of Areas In patients unable to tolerate oral In patients unable to tolerate oral 1,2 Tick-borne relapsing fever requires a 7- to7- a requires fever relapsing Tick-borne 1,2 North America Africa South America, America, Asia, South or Central South or southeast Africa Caribbean, Africa Widespread Widespread Widespread or subtropical especially in tropical Widespread, areas Asia America, North Predominantly Widespread Asia, southern or southeast south Predominantly Africa North America Widespread Asia Europe, North America, in sub-Saharan but predominantly Widespread, (“meningitis belt”) Africa Asia,Africa, South America Asia Europe, North America, Europe America, Asia,Africa, south or central (Mediterranean) Reservoir hosts Reservoir ISSUE 8 ISSUE | Humans Rodents 000 U) is effective. is 000 U) VOLUME 193 VOLUME Single-dose therapy with 100 mg of or 500 mg of louse-borne of treatment the for recommended is relapsing fever in nonpregnant adults. Alternatively, a single dose of erythromycin (500 mg) or intramuscular procaine G (600 Treatment medication or who have central nervous system involvement, involvement, system nervous central have who or medication 10-day course of doxycycline (100 mg twice a day) or erythromycin (500 mg 4 times a day). | Vector Pathogen Hard tick Hard spp.) ( Human humanus (Pediculus humanus) Soft tick spp.) (Ornithodoros Polymerase 1–3 1,6 FEBRUARY 22, 2021 FEBRUARY | CMAJ virus tick fever Colorado virus fever Yellow Dengue virus virus, Ebola virus, etc. Lassa virus, Marburg mammarenavirus choriomeningitis Lymphocytic A – E viruses Hepatitis species Brucella species Leptospira Spirillum minus moniliformis, Streptobacillus species Bartonella or Paratyphi Typhi serovar Salmonella enterica Ehrlichia species species Rickettsia tularensis Francisella Neisseria meningitidis Plasmodium species Babesia species species Leishmania Pathogen Borrelia Borrelia recurrentis Borrelia species > 15 Borrelia Hard tick–borne relapsing relapsing tick–borne Hard fever Louse-borne relapsing relapsing Louse-borne fever Tick-borne relapsing fever relapsing Tick-borne Syndrome Box 3: Comparison of relapsing fever syndromes fever relapsing of 3: Comparison Box Box 2: Differential diagnosis of relapsing relapsing of diagnosis 2: Differential Box Disease Viruses tick fever Colorado fever Yellow Dengue fever fevers hemorrhagic African choriomeningitis Lymphocytic hepatitis Viral Leptospirosis fever Rat-bite Bartonellosis fever Typhoid Rickettsiosis Meningococcemia Protozoa Malaria (kala-azar) leishmaniasis Visceral

rely on laboratories to routinely identify Borrelia in the absence of a request for serologic testing, as was the case here. Serologic testing can be performed with an immunofluorescence assay, with a titre of 1:256 or higher considered positive. chain reaction testing is currently offered by the British Columbia Centre for Disease Control. Genomic sequencing allows for species-level identification; this service is offered by the National Microbiology Laboratory (Winnipeg) or any laboratory providing 16S rRNA sequencing of clinical samples. PRACTICE E288 10. References tocol for malaria. As per the Canadian guidelines, incidentally byalaboratorytechnologist,afterdiagnosticpro- Borrelia, thecauseofourpatient’srelapsingfever,wasidentified Conclusion Uintravenouslyevery4hours)maybewarranted. (3 million parenteral therapywithceftriaxone(2gdaily)orpenicillinG

respiratory distress. include fever, rigours, tachycardia, diaphoresis, and spirochetes, whichactivatesacytokinestorm;symptomsmay reaction iscausedbythereleaseofendotoxinsfromrapidlydying molecular testingwhenrelevant. of suspicionforrelapsingfever,andorderspecificserologic to endemicareas;however,physiciansshouldalsokeepanindex should alwaysberuledoutinfebrilepatientswhohavetravelled typically occurswithinthefirst1–4hours. closely monitored for the Jarisch–Herxheimer reaction, which the firstdoseofanyeffectiveantibiotic,patientshouldbe 2. 7. 9. 6. 5. 4. 3. 1. 8.

-diagnosis.html (accessed2020Dec.8). canadian-recommendations-prevention-treatment-malaria/chapter-6-malaria​ 2020 Jan.16].Available:www.canada.ca/en/public-health/services/catmat/ and treatmentofmalaria.Ottawa:PublicHealthAgencyCanada;[updated Chapter 6-Malariadiagnosis:Canadianrecommendationsfortheprevention Open 2017;5:E690-3. miyamotoi Kadkhoda K,DumouchelC,BrancatoJ,etal.HumanseroprevalenceofBorrelia collected inCanada.ParasitVectors2014;7:183. infection, andco-infectionswithotherBorreliaspp.inIxodesscapularisticks Columbia: a10-yearreview(2006–2015).BCMedJ2017;59:412-7. Morshed MG,DrewsSJ,LeeM-K,etal.Tick-bornerelapsingfeverinBritish biol Infect2012;18:332-7. Badiaga S,BrouquiP.Humanlouse-transmittedinfectiousdiseases.ClinMicro- review. Medicine(Baltimore)1969;48:129-50. Southern PMJ,SanfordJP.Relapsingfever:aclinicalandmicrobiological 2017;376:1798. Thwaites GE,DayNPJ.Approachtofeverinthereturningtraveler.NEnglJMed Cutler SJ.RelapsingfeverBorreliae:aglobalreview.ClinLabMed2015;35:847-65. Dis ClinNorthAm2008;22:449-68. Dworkin MS,SchwanTG,AndersonDE,etal.Tick-bornerelapsingfever.Infect Dibernardo A, Cote T, Ogden NH, et al. The prevalence of (accessed 2020Dec.8) Prevention; 2015.Available:www.cdc.gov/relapsing-fever/distribution/index.html Tick-borne relapsingfever—distribution.Atlanta:CentersforDiseaseControland inManitoba,Canada,2011–2014:across-sectionalstudy.CMAJ 1,6 CMAJ 1,2 This life-threatening Thislife-threatening | FEBRUARY 22, 2021 Borrelia miyamotoi 10 malaria 2 After After

| VOLUME 193 Correspondence to:EricEckbo,[email protected] with spirocheteinfectionsandreviewingthemanuscript. forming extensive diagnostics for this case, offering their expertise trol for their assistance with acquiring and interpreting data, per and Min-Kuang Lee at the British Columbia Centre for Disease Con- Acknowledgements: TheauthorsthankDr.MuhammadMorshed licenses/by-nc-nd/4.0/ cations or adaptations are made. See: https://creativecommons.org/ use isnoncommercial(i.e.,researchoreducationaluse),andnomodifi- medium, provided that the original publication is properly cited, the ND 4.0) licence, which permits use, distribution and reproduction in any dance withthetermsofCreativeCommonsAttribution(CCBY-NC- Content licence: able forallaspectsofthework. approval oftheversiontobepublished,andagreedaccount- manuscript criticallyforimportantintellectualcontent,gavefinal Eric Eckbodraftedthemanuscript.Allofauthorsrevised design ofthework.EricEckboandRobertWolberacquireddata. Contributors: Lions GateHospital,Vancouver,BC oratory Medicine(Wolber)andDivisionofInfectiousDiseases(Yu), (Yu), UniversityofBritishColumbia;DepartmentPathology&Lab- ogy &LaboratoryMedicine(Eckbo,Charles,Wolber)andof (Eckbo, Charles),VancouverGeneralHospital;DepartmentofPathol- Affiliations: DivisionofMedicalMicrobiology&InfectionControl The authorshaveobtainedpatientconsent. This articlehasbeenpeerreviewed. Competing interests:Nonedeclared. necessity. Seeinformationforauthorsatwww.cmaj.ca. encouraged. Consentfrompatientsfor publication of their storyis a ferential diagnosis,clinicalfeaturesordiagnosticapproach)are lows (1000wordsmaximum).Visualelements(e.g.,tablesofthedif- words maximum), and a discussionoftheunderlying condition fol- common problems.Articlesstartwithacasepresentation(500 important rareconditions,andunusualpresentationsof practical lessons.Preferenceisgiventocommonpresentationsof The sectionCasespresentsbriefcasereportsthatconveyclear, All of the authors contributed to the conception and | ISSUE 8 This is an Open Access article distributed in accor - -