Febrile
rhabdomyolysis
of
unknown
origin
in
refugees
coming
from
West
Africa
through
the
Mediterranean
Silvia
Odolini
a,*
,
Federico
Gobbi
b,
Lorenzo
Zammarchi
c,d,
Simona
Migliore
e,
Paola
Mencarini
f,
Marco
Vecchia
g,
Nicoletta
di
Lauria
c,d,
Simona
Schivazappa
h,
Tony
Sabatini
i,
Leonardo
Chianura
j,
Elisa
Vanino
k,
Daniela
Piacentini
l,
Paola
Zanotti
a,
Anna
Bussi
m,
Alessandro
Bartoloni
c,d,
Zeno
Bisof
fi
b,
Francesco
Castelli
aa
UniversityDepartmentofInfectiousandTropicalDiseases,UniversityofBresciaandSpedaliCiviliGeneralHospital,Brescia,Italy
b
CentreforTropicalDiseases,SacroCuore-DonCalabriaHospital,Negrar,Verona,Italy
c
DipartimentodiMedicinaSperimentaleeClinica,UniversitàdiFirenze,Florence,Italy
d
SODMalattieInfettiveeTropicali,AziendaOspedalieroUniversitariaCareggi,Florence,Italy
e
RefugeeCentreofMineo,Catania,Italy
fIstitutoNazionaleperleMalattieInfettive“LazzaroSpallanzani”,IRCCS,Rome,Italy gClinicadiMalattieInfettive,FondazioneIRCCSPoliclinicoSanMatteo,Pavia,Italy h
InfectiousDiseases-IRCCSArcispedaleSantaMariaNuova,ReggioEmilia,Italy
i
DepartmentofInternalMedicine,GastroenterologyandDigestiveEndoscopy,PoliambulanzaHospitalClinicalInstitute,Brescia,Italy
j
DivisionofInfectiousDiseases,AONiguardaCa’GrandaHospital,Milan,Italy
k
InfectiousDiseasesUnit,DepartmentofMedicalandSurgicalSciences,AlmaMaterStudiorumUniversityofBologna,Bologna,Italy
l
InfectiousDiseasesUnit,G.B.RossiUniversityHospital,Verona,Italy
mClinicadiMedicinaInterna,AziendaSocioSanitariaTerritorialedelGarda,Manerbio(BS),Italy
ARTICLE INFO
Articlehistory: Received6June2017
Receivedinrevisedform17July2017 Accepted19July2017
CorrespondingEditor:EskildPetersen, Aar-hus,Denmark Keywords: Refugees WestAfrica Nigeria Rhabdomyolysis Fever Creatinekinase ABSTRACT
Objectives:CasesofundiagnosedseverefebrilerhabdomyolysisinrefugeescomingfromWestAfrica, mainlyfromNigeria,hasbeenobservedsinceMay2014.Theaimofthisstudywastodescribethis phenomenon.
Methods:Thiswasamulticentreretrospectiveobservationalstudyofcasesoffebrilerhabdomyolysis reportedfromMay2014toDecember2016in12Italiancentres.
Results:Atotalof48caseswereobserved,mainlyinyoungmales.Themeantimeintervalbetweenthe dayofdeparturefromLibyaandsymptomonsetwas26.2days.Anaverage8.3furtherdayselapsed beforemedicalcarewassought.Allpatientswerehospitalizedwithfeverandveryintensemuscleaches. Creatinephosphokinase,aspartateaminotransferase,andlactatedehydrogenasevalueswereabnormal inallcases.Therhabdomyolysiswasascribedtoaninfectiveagentin16(33.3%)cases.Intheremaining cases,theaetiologywasundefined.Fouroutofsevenpatientstestedhadsicklecelltrait.Noalcoholabuse ordrugintakewasreported,apartfromasinglereportedcaseofkhatingestion.
Conclusions: The longincubation period doesnot support amechanical cause of rhabdomyolysis. Furthermore,viralinfectionssuchasthosecausedbycoxsackievirusarerarelyassociatedwithsucha severeclinicalpresentation.Itishypothesizedthatotherpredisposingconditionslikegeneticfactors, unknowninfections,orunreportednon-conventionalremediesmaybeinvolved.Targetedsurveillanceof rhabdomyolysiscasesiswarranted.
©2017TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(
http://creativecommons.org/licenses/by-nc-nd/4.0/).
* Correspondingauthorat:UniversityDepartmentofInfectiousandTropicalDiseases,UniversityofBresciaandBresciaSpedaliCiviliGeneralHospital,PiazzaSpedaliCivili, 1,25123Brescia,Italy.Tel.:+390303995677;Fax:+390303996084.
E-mailaddress:silvia.odolini@gmail.com(S.Odolini).
http://dx.doi.org/10.1016/j.ijid.2017.07.018
1201-9712/©2017TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
InternationalJournalofInfectiousDiseases62(2017)77–80
ContentslistsavailableatScienceDirect
International
Journal
of
Infectious
Diseases
Introduction
Rhabdomyolysisisacomplexmedicalconditioninvolvingthe rapidbreakdownofdamagedskeletalmuscle.Theseverityofthe illness rangesfrom asymptomaticelevations of serum creatine phosphokinase(CPK)tolife-threateningdiseasessuchascardiac arrhythmia,acuterenalfailure,andevendeath.Thecharacteristic triadofcomplaints,i.e.musclepain,weakness,andpigmenturia,is seeninlessthan10%ofpatients(Zuttetal.,2014).
According to the International Organization for Migration, 153842peoplearriveddirectlyin Italyvia theseain 2015and 181 436 people in 2016, mainly coming from Nigeria, Eritrea, Guinea,IvoryCoast,Gambia,Senegal,Mali,and Sudan (Interna-tionalOrganizationforMigration,2017).Anincreasingnumberof cases of febrile rhabdomyolysis have been observed in these migrantssinceMay2014,andsofartherehasbeennospecific aetiologicaldiagnosis.The aimof this studywas toreport and describethisphenomenon.
Materialsandmethods
This was a multicentre retrospective observational study of cases of febrile rhabdomyolysis reported from May 2014 to December 2016 in 12 Italian centres: nine infectious diseases andtropicalmedicineunits,twointernalmedicineunits,andone refugeecentre(Figure1).
FebrilerhabdomyolysiswasdefinedasanincreaseinCPKlevels (1000IU/l)associatedwithmyalgiaandfever(>38C).Patient
demographic,clinical,andtravel-relateddatawerecollectedusing astandardizedanonymousquestionnaireandwereenteredintoa database.Datawerecollectedretrospectivelyandanalysedusing MicrosoftOfficeExcel2010(MicrosoftInc.,Redmond,WA,USA). Categoricalvariableswereexpressedasthenumberand propor-tion, and continuous variables were expressed as the mean standard deviation (SD). The study was conducted under the provisionsoftheDeclarationofHelsinkiandinaccordancewith the International Conference on Harmonization Consolidated Guideline on Good Clinical Practice. Since this study was retrospectiveandnon-pharmacological,writteninformedconsent wasnotprovided.InItaly,ethicalauthorizationforthesestudiesis not required (see Italian guidelines for the classification and conductofobservationalstudies,establishedbytheItalianDrug Agency,“AgenziaItalianadelFarmaco-AIFA”onMarch20,2008). Results
Atotalof48caseswereidentified;43weremale(89.6%),and theirmean agewas 22.45.8 years. They allcame from West Africa, mainly from Nigeria (58.3%) (Figure 2). Libya was the departureportinallcases.AftertheirarrivalinItaly,allpatients were hosted in specific shelter centres, according to Italian
immigrationpolicies. Themean time interval between theday ofdeparturefromLibyaandsymptomonsetwas26.239.5days (range2–252days),andanaveragefurther8.37.85dayselapsed beforemedicalcarewassought.Themeandurationofseatravel was1.71.26days.
Twenty-twopatients(45.8%)hadtravelledbetweenSeptember and April and 20 had travelled betweenMay and August (this informationwasnotavailableforsixpatients).Allpatientshada feverandveryintensemuscleaches,andwereunabletostandor walk.CPK,aspartateaminotransferase,andlactatedehydrogenase valueswereabnormalin allcases(Table1).Seventeenpatients (35.4%) reported having a forced position during travel. No seawateringestionwasreportedandnocaseofhypernatraemia was identified: the mean serum sodium value was 1371.26 mmol/l.
Therhabdomyolysiswasascribedbythetreatingphysiciansto aninfectiveagentin16(33.3%)cases.Indetail,Epstein–Barrvirus (EBV)DNAwas detectedin eightof 32 patientstested, IgMfor coxsackieviruswasdetectedinfiveof27casestested,andIgMfor cytomegaloviruswasidentifiedinthreeof29casestested(Table2). The aetiologywas undefined in theremaining cases.The most frequentinfectiouscausesofrhabdomyolysiswereexcluded.Four outofsevenpatientswhoweretestedforabnormalhaemoglobin hadsicklecelltrait(SCT)andonepatienthadhaemophiliaA.
Allpatientswereaskedaboutdrugandalcoholabuse,butnone reportedeither,withtheexceptionofonepatientwhodeclared Catha edulis (khat) consumption during his stay in Libya, 2–3 weeksbeforesymptomonset.
Onlyonepatientwas treatedwithrifampicin, isoniazid,and pyridoxine before symptom occurrence. Following supportive treatmentwithhydration,almostallpatientsrecovered complete-lyinabout aweek.However,theywereoftensymptomaticfor months.Twowerehospitalizedintheintensivecareunitandone patienthadacutekidneyinjury.
Discussion
Thisstudydescribes48cases of rhabdomyolysisinrefugees comingfromWestAfrica. Thephenomenon caughttheauthors’ attentionbecauseoftheseverityofthesymptoms,theinabilityto obtainadefinitivediagnosis,andtheconsistentnumberofcases. CaseswereobservedincentresdistributedthroughoutItaly,from thenorthtothesouth. Upto20%of individuals inthegeneral populationhaveanasymptomaticincreaseinserumCPK,andthis particularlyaffectstheblackrace(Gabowetal.,1982). Neverthe-less,thepresenceofseveresymptomsandfever,aswellasthe youngage of thepresent studycases, promptedfurther inves-tigationstodetermineanaetiologicalcause.
Many causes of rhabdomyolysis have been identified and reported in the literature, and these can be categorized into acquiredandinheritedcauses(Gabowetal.,1982;Huerta-Alardin
Figure1.NumberofcasesreportedfromeachItalianCentre. 78 S.Odolinietal./InternationalJournalofInfectiousDiseases62(2017)77–80
etal.,2005;Mellietal.,2005;Zuttetal.,2014).Withregardtoa possibleinfectious aetiology, EBV hasbeenassociated withthe developmentofrhabdomyolysis,butonlyrarely(Roychowdhury,
2007), and a wide spectrum of muscle disorders caused by
coxsackievirus B, ranging from acute non-specific myalgia to rhabdomyolysis, has been described (Fodili and van Bommel, 2003;Gómezetal.,2008;Marinella,1998;Wangetal.,2006).
Amechanicalcauseofrhabdomyolysisshouldalsobe consid-ered.However,thelongincubationperiodisnotconsistentwith thishypothesis.ItisknownthatCPKincreasesapproximately2– 12haftertheonsetofmuscleinjury,reachingapeakconcentration after24–72h(Zuttetal.,2014).Inthecasesinthisstudy,themean time interval between travel and symptom occurrence was 26.239.5days.Inmoredetail,thesymptomsoccurredabout2 months after arrival in three cases, and in one case 252days elapsedbetweenarrivalandtheclinicvisitdate.
Itcouldbe hypothesizedthat a commonviralinfection,like coxsackievirusB,couldhavetriggeredtherhabdomyolysisbecause ofunderlyingmuscledamageduetothepatient’sforcedposition during travel. Otherwise viral infections caused by EBV and coxsackievirusareonlyrarelyassociatedwithsuchasevereclinical presentation.Furthermore,intheauthors’experience,serological testswerepositiveonlyinaminorityofcases(25%and18.5%of cases,respectively).Theingestionofseawaterhasrecentlybeen reported as a cause of hypernatremia and rhabdomyolysis in AfricanmigrantsarrivinginLampedusathroughtheStraitofSicily
(PastaandMesaSuero,2012).Nevertheless,nocasesofseawater ingestion were reported in the study population and their electrolytebalancewasalwaysnormal.
Allpatientswereaskedaboutdrugoralcoholabuse,butnone reported this except for one patientwho declared Catha edulis (khat) consumptionduring hisstay in Libya,2–3 weeksbefore symptom onset.KhatisafloweringplantnativetotheHornof AfricaandtheArabianPeninsula,classifiedbytheWorldHealth Organizationasadrugofabuse.Itisusedasastimulantforits amphetamine-likeeffect,causingexcitement,lossofappetite,and euphoria. This risk factor must be further addressed in a prospective mannerin thefuture,as patientsmaybereluctant todisclosetheintakeorabuseofillicitherbsordrugs.
Different genetic defectscausingvariousneuromuscular and metabolicdisordersareknowntobeassociatedwith rhabdomy-olysis. In some instances, rhabdomyolysis may be due to a combination ofenvironmental triggeringcauses combinedwith predisposing genetic factors that may well be overlooked. Therefore,theriskofrecurrenceishighifthegeneticdiagnosis isnotconsidered(Scalcoetal.,2015).
The common geographic area of origin suggests a genetic predisposition to rhabdomyolysis. Many genetic variants have been described associated with rhabdomyolysis secondary to trauma, strenuous exercise, specific drugs, and myopathies. Of note, several case reports publishedsincethe early1970s have describedsignificantmorbidityandmortalityofacuteexertional rhabdomyolysisinpatientswithSCT.Acaseofsevereexertional rhabdomyolysisaftera1.5milerunwasreportedina27-year-old medicaldoctorwhohadapastmedicalhistorysignificantonlyfor SCT(Makaryusetal.,2007).Inthepresentstudysample,fouroutof sevenpatientsscreenedforSCTwerepositive.Despitethesmall sample,itmaybeworthlookingforthisandpossiblyothergenetic predisposingfactorsthatmaybecommontorefugeescomingfrom WestAfrica.
Otherhaematologicaldisordersandhaemoglobinopathieshave been recognized as associated with rhabdomyolysis, such as glucose-6-phosphatedehydrogenase(G6PDH)deficiency(Mangat et al., 2014) and thalassemia (Niwa et al.,1979), especially in situationsofstress,afterexposuretoastrongoxidant,fooditems, ormedicines,ordrugintake.
Another recent report observed a significant difference in coenzymeQ10 (CoQ10)betweenhealthyAfricanAmericansand whites,indicatingthathighercreatinephosphokinase(CPK)and lowerCoQ10areassociatedwithsevereexertionalrhabdomyolysis onlyin AfricanAmericans. TheCKtoCoQ10ratioiseven more
Table1
Laboratory tests at presentation (meanstandard deviation values). WBC(109 /l)(n=48/48) 5.873.1 RBC(109 /l)(n=48/48) 4.785.59 Hb(g/dl)(n=48/48) 13.21.61 PLT(109 /l)(n=46/48) 15646.4 AST(U/l)(n=47/48) 355.8240.1 ALT(U/l)(n=48/48) 142.2158.2 GGT(U/l)(n=37/48) 50.947.6 CPK(U/l)(n=48/48) 8422.26630.8 Creatinine(mg/dl)(n=35/48) 0.980.41 LDH(U/l)(n=32/48) 722.8399.04 Myoglobin(ng/ml)(n=14/48) 2088.91299.0 CRP(mg/l)(n=14/48) 33.938.2 ALT,alanineaminotransferase;AST,aspartateaminotransferase; CPK,creatinephosphokinase;CRP,C-reactiveprotein;GGT, gamma-glutamyltransferase;Hb,haemoglobin;LDH,lactate dehydroge-nase;PLT,plateletcount;RBC,redbloodcellcount;WBC,white bloodcellcount.
Figure2.Countryofresidenceofrefugees.
specific.However,possibleadditionalexertionalrhabdomyolysis risk factors and multiple required deficiencies in the same individualmustbeconsidered(Princeetal.,2015).
An outbreak of Haff diseasehas been described recently in Salvador,Brazil, startingearlyDecember2016,andseveralcases haveoccurredinrecentyearsinEasternEurope,Sweden,China, Japan,andtheUSA(Bandeiraetal.,2017;Diaz,2015).Haffdisease isasyndromeofmyalgiaandrhabdomyolysisthatoccurswithin 24hafterconsumingcooked seafood;itis caused byanasyet unidentifiedheat-stabletoxin.Nodataabouttheingestionoffish werecollectedfromthepresentstudypatients,butHaffdisease wasexcludedfromthephysicians’workingdiagnosisduetothe presenceoffever(whichhasnotbeendescribedinHaffdisease), the heterogeneous incubation period, and the distribution throughoutthecountry.Furthermore,nocaseshavebeenreported intheliteratureinItalianpeople,andthisallowedthepossibilityof adiseaserelatedtotheconsumptionofItalianfishbeingruledout. This study has several limitations. Data were not collected systematicallyinallinfectious diseasesunits ofthecountry, so theymaynotberepresentativeofallmigrantswith rhabdomyoly-sis.Thiswasnotapopulation-basedstudy,soratesandriskscould notbedetermined.Thedatacollectionsystemchangedwithtime. Theprogressiveincreaseinthenumberofcasesobservedmayhave beendue in parttoa raisedawareness.Moreover, themedical recordswerenotalwayshomogeneous.Despitetheselimitations, this study provides the best current estimates available on rhabdomyolysisinrefugees.
In conclusion,rhabdomyolysisisapotentiallyseriousclinical illness.Theconsistentnumberofcasesobservedservedasa wake-upcallandpromptedtheauthorstowonderwhethersomething unusual and unexpected was occurring. Genetic predisposing factorsmust beconsidered and studied,and a full analysis for haemoglobinopathiesandG6PDHdeficiencyshouldbeperformed. A detailed history of drug/herbal intake is also essential. Additionally,amoreuniformandorganizeddatacollectionsystem forthesepatientsisnecessaryinordertobetterunderstandthe phenomenon. Targeted surveillance of rhabdomyolysiscases is warranted.
Fundingsource
Nofundingsourceswereneededfortheperformance ofthis researchorthepreparationofthearticle.
Conflictofinterest
Allauthorsdeclarenoconflictsofinterest. References
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Diagnostictests.
Pathogen Laboratoryevidenceofrecentorchronicactiveinfectiona
,n/N(%) Laboratoryevidenceofnon-immunity,n/N(%)whereappropriate
Adenovirus 0/15(0) 10/15(66.6) CMV 3a /29(10.3) 3/29(10.3) Coxsackievirus 5a /27(18.5) 0/27(0) EBV 8b /32(25) 21/32(65.6) Plasmodiumfalciparum 1c /44(2.27) – Dengue 0/17(0) 13/17(76.4) Schistosoma 3d/10(30) – Chikungunya 2e /10(20) – HCV 0/35(0) – HBV 3/38(7.9) – HIV 2/39(5.1) –
n,numberofpatientstested;N,numberofpatientswithavailabledata;CMV,cytomegalovirus;EBV,Epstein–Barrvirus;HBV,hepatitisBvirus;HCV,hepatitisCvirus.
aIgGandIgMpositiveordocumentedseroconversion(fromnegativetopositiveIgG). b EightpatientswithpositiveEBVDNA.
c
Thinandthickbloodsmearpositive.
d
ThreepatientswithSchistosomaIgGpositive(probablechronicinfection).
e
TwopatientspositiveforbothchikungunyaIgGandIgM.
