Case
Report
A
case
of
giant
cell
arteritis
associated
with
culture-proven
Coxiella
burnetii
aortitis
S.
de
Worm
a,
J.B.
Giot
a,*,
C.
Courtoy
b,
E.
Gillet
c,
Sophie
Amrane
d,
P.
Huynen
e,
M.
Van
Esbroeck
f,
E.
Prudent
d,
H.
Lepidi
d,
Matthieu
Million
d,
M.
Moutschen
a,
Didier
Raoult
da
InternalGeneralMedicineandInfectiousDiseases,CHUdeLiège,4000Liège,Belgium
b
Rheumatology,CHRdeVerviers,4800Verviers,Belgium
c
GeneralPractitioner,4651Battice,Belgium
d
AixMarseilleUniversité,IRD,APHM,MEPHI,IHU-MéditerranéeInfection,Marseille,France
e
MedicalMicrobiology,CHUdeLiège,4000Liège,Belgium
f
BelgianNationalReferenceCentreforCoxiellaburnetii,InstituteofTropicalMedicine,2000Anvers,Belgium
ARTICLE INFO Articlehistory:
Received13November2017
Receivedinrevisedform24January2018 Accepted27January2018
CorrespondingEditor:EskildPetersen, Aar-hus,Denmark.
Keywords: Coxiellaburnetii Giantcellarteritis Aortitis Qfever Vascularinfection
ABSTRACT
AcaseofprovenCoxiellaburnetiiaortitis,possiblyassociatedwithgiantcellarteritis(GCA),isreported.A 72-year-oldman,whoisahunter,presentedwithweightloss,fever,jawclaudication,andhardened temporalarteriesassociatedwithapersistentinflammatorysyndromeandarteritisofthewholeaorta, includingthebrachiocephalicarteries,asseenon18F-fluorodeoxyglucosepositronemission tomogra-phy/computedtomography.ThediagnosisofGCAwasretained,andtreatmentwithprednisolonewas started. Given the aneurysm of the abdominal aorta, the patient underwent replacement of the abdominal aorta with an allograft. Histology showed intense chronic arteritis attributed to atherosclerosiswithdissection.However, Coxiellaburnetii infectionwasconfirmedbyserologyand thenbycultureandmolecularbiologyonthesurgicalspecimen.Acombinationofhydroxychloroquine anddoxycyclinewasaddedtotaperedprednisoloneandtheoutcomewasfavourable.
©2018TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.Introduction
Qfever is a zoonosis caused by an obligate intracellular bacterium, Coxiellaburnetii. The infectionusually followsthe inhalation of infectedparticlesfromcows,goats,sheep,cats,ordogs(Eldinetal., 2017).AcuteQfever(primaryinfection)isasymptomaticinabout 20–80%ofcases,orinducesfever,aflu-likesyndrome,pneumonia, orgranulomatoushepatitis(Eldinetal.,2017).
Persistent focalized infections (endocarditis, vascular infec-tions, pericarditis, osteoarticular infections, lymphadenitis, and genitalinfections)occurin1–5%ofpatients.InFrance,endocarditis withnegativebloodculturesisthemostfrequentmanifestation,
followedbyvascularprosthesisoraneurysminfections.However, in the Netherlands, vascular infections are diagnosed more frequently (Eldin et al., 2017).The diagnosis is difficult due to non-specificsymptomsandreliesonserology,PCR,andsometimes culture(Eldinetal.,2017).
Giantcellarteritis(GCA)isaninflammatoryvasculitisof large-and medium-sized vessels, typically including one or several branchesofthecarotid,especiallythetemporalarteries.GCAcan alsoinvolveotherlocalizationssuchastheaorta.Thissystemic disease, affecting people older than 50 years, is most often characterizedbyheadache,jawclaudication,fever,anaemia,and elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The aetiology remains unclear, but several infectious diseases have been suspected as triggers of this deleterious immune reaction (Nagel et al., 2013; Nagel and Gilden,2014).
*Correspondingauthorat:InternalGeneralMedicine&InfectiousDiseases.CHU ofLiège.Belgium.
E-mailaddress:jbgiot@chuliege.be(J.B. Giot).
https://doi.org/10.1016/j.ijid.2018.01.028
1201-9712/©2018TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
ContentslistsavailableatScienceDirect
International
Journal
of
Infectious
Diseases
Itappearsthatonlytwocasereportsshowinganassociation between GCA and Q fever have been published previously (Lefebvre et al., 2010; Odeh and Oliven, 1994). Another study reported a patientwho fulfilledthe criteria for GCA, but this case was considered as ‘Takayasu-like’ aortitis associated withC. burnetii (Baziaka etal., 2014).A newcase ispresented here.
2.Casereport
A72-year-oldmanwashospitalizedattheUniversityHospital ofLiègeinBelgiumfortheinvestigationofanorexia,weightlossof 13kg, dyspnoea on exertion, asthenia, transit disorder, and possiblejawclaudicationwithadurationofseveralmonths.Only oneepisodeoffever(38C)wasobservedduringthe hospitaliza-tion.Withtheexceptionofbilaterallyhardenedtemporalarteries, his physical examination was unremarkable. Chronic kidney disease,gout,one episodeof urolithiasis,agallbladder lithiasis, a phlebitis of the lower limbs complicated by pulmonary embolism,avitreoushaemorrhage,andidiopathicbilateraluveitis werenotedinthepatient's medicalhistory.Hewas retired.He practicedhuntingasahobbyandregularlyconsumedthefleshof gameafterhavingpreparedithimself.
Onadmission,hishaemoglobinwas10.9g/dl,leukocytecount was12.78109/lwith77.8%polymorphonuclearneutrophils,and
ESRwas75mm/h.TheCRPlevelrangedbetween59.6mg/land 105mg/l during his stay. He was negative for anti-neutrophil cytoplasmic antibodies (ANCA). Serology for hepatitis A and C viruses,HIV,Brucella,Bartonella,Treponemapallidum,Francisella tularensis, and Echinococcus were all negative, as were a QuantiFERONtestandbloodculturesforbacteria.Anultrasound ofthetemporalarteriesperformedbeforeadmissionwasnormal. Fundoscopywasnormalandtheventilation–perfusion(V/Q)scan didnot show any abnormality. Transthoracicechocardiography (TTE)revealedaslightlyloweredleftventricularejectionfraction (50%)andthickeningofthefreeedgeofthenon-coronarycusp without dysfunction of the aortic or mitral leaflets. Trans-oesophageal echocardiography (TOE) showed aortic sclerosis without vegetation onthe aortic or mitral leaflets. Abdominal
computed tomography (CT) revealed a thickening of the abdominal infrarenal aorta wall taking the contrast, with a fusiform aneurysm located on the posterior wall (Figure 1).
18F-fluorodeoxyglucosepositronemissiontomography/computed
tomography(18F-FDGPET/CT)demonstratedintenseanddiffuse
hyperactivity of the thoraco-abdominal aorta, subclavian arteries, and internal and external carotids bilaterally (Figure
Figure1.AbdominalCTshowingthickeningoftheabdominalaortawallsandananeurysmlocatedontheposteriorwalloftheinfrarenalaorta(redarrows).Thecystic structureontherightkidneyisabenignnon-infectiouscyst.
Figure2. Sagittalsectionsof18
F-FDGPET/CTcentredontheabdominalaorta.Left: diffusehyperactivityofthewallsofthethoraco-abdominalaorta,subclavianand axillaryarteries,andcarotids.Theaneurysmlocatedontheposteriorwallofthe infrarenal aortapresentsmore intensehyperactivity. Right:follow-upafter4 monthsofantibioticsandcorticosteroids,showingalmostcompleteresolutionof theaortawallhyperactivity.Moderatehyperactivity ofthesubclavianarteries persists.
2). The diagnosis of GCA was retained without performing a temporalarterybiopsy.Prednisolonewasstartedat64mgoncea day.
Giventhecoveredrupture ofthepseudo-aneurysm,theaorta was replacedwithanallograft3weekslater(August4,2016).Anallograft waspreferredtoendovasculartreatmentusingastentgraftbecause infectiousaortitiscouldnotbeexcluded.Histologyofthesurgical specimenrevealedintenseaortitiswithasignificantinflammatory infiltrate(mainlylymphocytesandplasmocytes),rarefociofgiant cellgranulomawithout necrosis,calcifications,andfootprints of cholesterolcrystals(Figure3).Thesefeaturessuggestedaortitisdue toatherosclerosisandadissectionoftheaorta.
Atthesametime,apositiveresultfortheC.burnetiiserology was received, compatible with a persistent focalized infection (Table 1). PCR and culturewere thus performed onperi-aortic tissuesampledduringthesurgery.PCRwaspositivefortwogenes (IS1111andIS30a)specifictoC.burnetiiandculturewaspositive1 monthlater(Figure4).PCRonbloodwasnegative. Immunohis-tochemistry(IHC)and fluorescencein situ hybridization(FISH), performedasreportedpreviously(Melenotteet al.,2016),were negative.Acombinationofhydroxychloroquine600mgonceaday and doxycycline 100mg twice a day was added to the slowly tapered prednisolone upon receipt of the serology result. The antibiotic therapy was recommended by the French National ReferralCentreforQFeverforadurationof24months.
At14monthsoffollow-up,thepatientwasdoingwell,except formildphotosensitivityreactionsonthesun-exposedareadue todoxycycline.AcontrolPETscan4monthsafterthebeginning ofantibiotictherapyshowedalmostcompletedisappearanceof the aortic wall hyperactivity (Figure 2). The follow-up of antibodiesshoweda favourableprogression (Table1). Concen-trations in the serum of 5–10
m
g/ml for doxycycline and 10.2m
g/ml for hydroxychloroquine are recommended (Eldin etal.,2017).Drugmonitoringafter3monthsoftherapyshowed levelsof8.95m
g/mlfordoxycyclineand1.75m
g/mlfor hydroxy-chloroquine. Thushydroxychloroquine wasreduced to 200mg twicedaily,andsubsequentlevelswerewithintherecommended range.3.Discussion
AnewcaseofvascularinfectionduetoC.burnetiiinvolvingthe abdominalaortaisdescribed,althoughthepatientalsofulfilledthe criteriaforGCA.
Figure3.Focus(magnification20)onagranulomawithraregiantcells(arrows). Thewhitecentralstructurescorrespondtocrystalsofcholesterol.
Table1
AntibodytitresagainstCoxiellaburnetii(indirectfluorescencetechnique) Date PhaseIantigens PhaseIIantigens
IgA IgM IgG IgA IgM IgG 11/07/2016a ND 512 4096 ND <32 2048 04/08/2016 Aorticsurgery 10/08/2016a ND 512 512 ND <32 256 15/08/2016b 0 0 400 0 0 400 23/11/2016a ND <32 256 ND <32 64 22/02/2017a ND <32 128 ND <32 <64 26/05/2017a ND <32 128 ND <32 <64 ND,notdone. a
DoneattheInstituteofTropicalMedicineinBelgium.
b DoneattheFrenchNationalReferralCentreforQFever.Thetwolaboratories
useddifferentassays.
Atleast230casesofC.burnetiivascularinfection(aneurysmsor vasculargrafts)havebeenreported,mostlyaffectingthe abdomi-nalaorta(Botelho-Neversetal.,2007;Edouardetal.,2013;Eldin etal.,2016;Wegdam-Blansetal.,2011),andsimilartoC.burnetii endocarditis,theywereclassicallyconsideredaschronicdiseases. These infections are highly chronic. However, a diagnosis of chronic Q fever should not be retained on the sole basis of biological criteria (serology or molecular biology) without clinically evident infection. Hence, the vague term ‘chronic Q fever’shouldbereplaced byanatomicallywell-defineddiseases (endocarditis,vascularorboneandjointinfections)(Millionand Raoult,2015;MillionandRaoult,2017).
TheelevatedlevelsofantibodiesagainstphaseIantigensledto thesuspicionofacardiovascularinfection,butsuchinfectionsare alsoreportedinpatientswithlowtitresofphaseIIgG(Edouard etal.,2013).Notably,follow-upantibodydetection(performedin two laboratories) (Table 1) showed concordant rapid and pronounceddecreasesinthelevelsofantibodiesagainstphaseI antigensafterthesurgery(August4,2016),asalreadyobservedin othercases (Eldin et al., 2016).A definite diagnosis of Qfever vascularinfectioncouldberetainedhere(positivecultureandPCR oftheaortaissufficientforthispurpose,butonemajorandthree minorcriteriawerealsofound;A1B2C3)(Raoult,2012).Negative IHCandFISH resultsdo notexclude thediagnosis,becausethe sensitivitiesofthesemethodsarenotperfect.Endocarditiscannot be ruled out since valvular involvement can be as minimal as thickening or sclerosis without vegetation and the saccular aneurysm can be an embolic consequence of endocarditis, so thevascularinfectioncouldhavebeenassociatedwithapossible endocarditis(Raoult,2012).
ThediagnosisofGCAassociatedwithCoxiellainfectionversus infectiousaortitisonlyisthesubjectofdiscussion.Giantcellsare rareandsurroundcrystalsofcholesterol.However,thecasepatient fulfilledfourofthecriteriaoftheAmericanCollegeof Rheumatol-ogy(ACR)classificationofvasculitis(age>50years,tendernessof the temporal arteries, ESR >50mm/h, and granuloma with multinucleatedgiantcells)(Hunderetal.,1990).Thehyperactivity oftheentireaortaon18F-FDGPET/CTmaybeanotherargumentfor
GCA,sinceitappearsthatnocaseofCoxiellainfectionaffectingthe wholeaortahasbeenreportedpreviously.Baziakaetal.described acaseofglobalaortitisfollowingacuteQfever,buttheyconcluded thatthepatienthadaninflammatorydisease,whichwastreated withmethylprednisoloneandmethotrexate,althoughthepatient alsoreceiveddoxycyclineandhydroxychloroquineformorethan1 year(Baziakaetal.,2014).Ofnote,thepatientdescribedbyBaziaka etal.fulfilledtheACRcriteriaforGCA,althoughitwasreportedasa ‘Takayasu-like’aortitis.Finally,thefavourableclinicaland biologi-caloutcomesinthecase presentedhere,whowas treatedwith prednisolone alone before surgery and antibiotics (CRP had normalizedatthesecondhospitaladmission forsurgery)arein favourofGCA.
PositiveIgManticardiolipinandanti
b
2GP1antibodieswere found in the patient reported by Baziaka et al., but IgG anticardiolipin(otherantiphospholipidtestswerenotperformed) was normal in thepatient case presentedherein; however the patientofBaziakaetal.presentedanacuteQfeverwithaheart valvevegetation,recentlyreportedasanewclinicalentity(Million etal.,2016).Severeatherosclerosis(obviousontheabdominalCT) unde-niablyfavouredCoxiellaaortitis,whichcouldhavebeeninturna triggerforGCA.Theinvolvementofinfectiousagentsinatleast some cases of GCA is probable, and varicella zoster virus has recently been suspected as a causal agent (Nagel et al., 2013; NagelandGilden,2014).IncludingthecaseofBaziakaetal.,the associationofGCAandQfeverappearstohavebeendescribed onlythreetimes in theliterature from1994 to2014(Lefebvre
et al., 2010; Odeh and Oliven, 1994; Baziaka et al., 2014). Fortuitousassociations couldbesuspected,but a pathophysio-logical link between the two conditions is likely. Vascular C. burnetiiinfectionsareprobablyunder-diagnosed,ascouldbethe involvementofC.burnetiiinGCA,andcorticosteroidtherapycan maskinfectiousaortitis,atleasttransiently.Cliniciansshouldbe awareofthisagentwhenexploringaortitisand/orpersistentfever inpatientswithriskfactorsfor previousexposure (e.g.,leisure, hunting).
PET/CTisusefultoidentifycardiac,vascular,andosteoarticular Q fever in patients with unexplained increases in C. burnetii antibodies(Eldinetal.,2016;Eldinetal.,2017;MillionandRaoult, 2015).
TheFrenchNationalReferralCentreforQFeverrecommends testing surgicalaorticspecimensfor Coxiella(PCRand culture), especially for non-degenerative diseases, and to screen for abdominal aneurysmin patientswithacute Qfeverolder than 65yearsorwithafamilyhistoryofaneurysm.Aprophylactic 12-month treatment with hydroxychloroquine and doxycycline should beproposed for patientswith acuteQ fever and aortic aneurysm or prosthesis (Eldin et al., 2016; Million and Raoult, 2015).AsforC.burnetiiendocarditis,thisstrategyaimstodecrease the occurrence of vascular C. burnetii infections, which are currently associated with a mortality rate of 18–25% (Eldin etal.,2016).
Overall, this report highlights the importance of C. burnetii vascularinfections,whichcurrentlyrepresentthemostsevererisk among non-pregnant adults, asmortalityrates for endocarditis have dropped below 10% since the optimizationof therapeutic protocolswithdoxycyclineandhydroxychloroquine(Millionetal., 2010).Futurestudiesshouldfurtherclarifythedirect(infectious) orindirect(non-infectiousauto-immuneorinflammatory) mech-anisms that make C. burnetii a potentially lethal pathogen for humansthroughvascularlesions,aspreviouslydemonstratedfor endocarditis(Eldinetal.,2016).
Funding:None.
Ethical approval: Written patient consent was obtained for publication.
Conflictofinterest:Noconflictofinteresttodeclare.
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