r e v b r a s r e u m a t o l . 2014;54(5):397–399
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
ww w . r e u m a t o l o g i a . c o m . b r
Case
report
Legionella
pneumonia
after
infliximab
in
a
patient
with
Rheumatoid
Arthritis
Karina
de
Souza
Giassi
a,
Vilson
Furlanetto
Junior
a,
Sonia
Fialho
b,
Giovana
Gomes
Ribeiro
b,
Ivânio
Alves
Pereira
b,∗ aUniversidadeFederaldeSantaCatarina,Florianópolis,SC,BrazilbRheumatologyCenter,HospitalUniversitárioPolydoroErnanideSãoThiago,Florianópolis,SC,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received18June2012 Accepted15April2013 Availableonline20August2014
Keywords:
Legionellapneumophila
Tumournecrosisfactoralpha Rheumatoidarthritis Infliximab
a
b
s
t
r
a
c
t
Theantagonistsoftumournecrosisfactor(anti-TNF)havebeensuccessfullyusedin sev-eralchronicinflammatorydiseasessuchasRheumatoidArthritis(RA),butsomestudies haveobservedthedevelopmentofinfectionsbyintracellularpathogensinpatientsusing anti-TNF.WereportacaseofafemalepatientwithpreviousdiagnosisofRAfor16years thatusedseveraldisease-modifyinganti-rheumaticdrugs(DMARDs)thatresultedin treat-mentfailure,andthenwastreatedwithinfliximab.Afterfifteendaysoftheseconddose, thepatientdevelopedventilatory-dependentchestpain,drycoughanddyspnea.Shewas hospitalized,andthediagnosisofpneumoniabyLegionellapneumophilawasconfirmedby thepresenceofLegionellaantigeninanurinetest.TNFisaninflammatorycytokinethatalso actsinhibitingthebacterialgrowthofintracellularpathogens,anditsinhibitionseemsto increasesusceptibilitytotheseinfectionsinsomepatients.
©2014ElsevierEditoraLtda.Allrightsreserved.
Pneumonia
por
Legionella
após
uso
de
Infliximabe
em
paciente
com
Artrite
Reumatoide
Palavras-chave: Legionellapneumophila
Fatoralphadenecroseportumor Artritereumatoide
Infliximabe
r
e
s
u
m
o
Osantagonistasdofatordenecrosetumoral(anti-TNF)têmsidoutilizadoscomsucessoem váriasdoenc¸asinflamatóriascrônicas,comoartritereumatoide(AR),masalgunsestudos observaramaocorrênciadeinfecc¸õesporpatógenosintracelularesempacientesmedicados comanti-TNF.RelatamosumcasodepacientemulhercomdiagnósticopréviodeARdurante 16anosequeestavasendomedicadacomváriasdrogasantirreumáticasmodificadorasde doenc¸a(DARMDs),tendocomoresultadooinsucessoterapêutico,sendoemseguidatratada cominfliximab.Depoisdetranscorridos15diasdasegundadose,apacientefoiacometida
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.rbr.2013.04.008.
∗ Correspondingauthor.
E-mail:[email protected](I.A.Pereira).
http://dx.doi.org/10.1016/j.rbre.2013.04.006
398
r e v b r a s r e u m a t o l . 2 0 1 4;54(5):397–399pordortorácicaventilatório-dependente,tossesecaedispneia.Foihospitalizada,eo diag-nósticodepneumoniaporLegionellapneumophilafoiconfirmadopelapresenc¸adoantígeno de Legionellanaurina.TNFéumacitocinainflamatória quetambém promoveinibic¸ão docrescimentobacterianode patógenosintracelulares,esuainibic¸ãopareceaumentar asensibilidadeaessasinfecc¸õesemalgunspacientes.
©2014ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Antagonistsoftumornecrosisfactor(anti-TNF)haveshown significant changes in the course of a number of chronic inflammatorydiseases,suchasCrohn’sdisease,ankylosing spondylitisandRA.1
Thetumornecrosisfactor-␣(TNF-␣)isaproinflammatory
cytokine withmultiple targets and interactions, but it has a well-established role in the pathogenesis of rheumatoid inflammation.
Besidesthis proinflammatoryfunction inRA,TNF␣ also
actsasacellulardefencemechanismagainstinfections. Stud-ies haveobservedthatanti-TNF therapymay berelated to increasedriskofinfectionsbyintracellularpathogens, includ-ingMycobacterium tuberculosis, Legionellapneumophila, Listeria monocytogenes, Aspergillus fumigatus, Histoplasma capsulatum
andPneumocystisjiroveci.
Theevidence supporting this association between anti-TNFandincreasedriskofinfectionsincludecasereports, epi-demiologicalstudiesandexperimentswithanimalmodels.2
WereportacaseofLegionellapneumoniainapatientwith RAduringtheuseofanti-TNFanddiscussthemainfactors possiblyinvolvedinthegenesisofthistypeofinfection.
Case
report
Female patient, 50 years-old, with a history of erosive RA and rheumatoid factor-positivity for 16 years.The patient madeuseofseveraldisease-modifyingantirheumaticdrugs (DMARDs), including hydroxychloroquine, sulfasalazine, methotrexate(MTX),leflunomide,andcombinationtherapy withMTX and 25mg/weekSC,and leflunomide 20mg/day. After treatment failure and gastrointestinal intolerance to MTX,thepatientbegantreatmentwithinfliximab.
Basedonthat,weoptedtointroduceinfliximabassociated withleflunomide.Onthatoccasion,thechestX-raywas nor-mal,andPPD=10mm;isoniazid300mg/daywasintroduced aspreventionagainstreactivationoflatenttuberculosis.
Fifteendaysaftertheseconddoseofinfliximab,thepatient developedfever,drycough,ventilatory-dependentchestpain, and dyspnea. Shewas admittedatthe hospitalpresenting hypoxemiaandalveolarconsolidationsintheleft hemitho-rax(Fig.1A).Thebronchoalveolarlavagefluidwasnegative foracid-fast bacilliandfungi,aswell asforHIV.A diagno-sisoflegionellosiswasconfirmedbyapositivesearchforL. pneumophilaantigeninurine.
Thepatient experienced improvement after four weeks ofcombined use ofa macrolide and aquinolone (Fig. 1B), remaining persistent activity (DAS28>5.1) despite the
combination of methotrexate and leflunomide used as therapeutic option. One year after the resolution of the infection,thepatientrestartedinfliximab,andsincethen,has maintainedclinicalremission(DAS-28<2.6)withoutfurther infectiouscomplications.
Discussion
Anti-TNF drugsact,ingeneral,byblockingTNF-␣. Theuse
ofthesedrugshasprovidedexcellentresults.Itseffectsrange fromsymptomaticimprovementinpatientsresistantto treat-mentwithDMARDstotheinterruptionofprogressionofjoint damageinRA.3
TNFisacytokinewithanimportantroleinthedefence againstintracellularmicroorganisms.Itisproducedby mono-cytes and macrophages, stimulates nitric oxideproduction and induces differentiation of macrophages in epithelioid macrophages,whicharenecessaryfortheformationof gran-ulomas.Macrophagesand monocytesarealsousefulinthe recognitionanddestructionofanymacrophages,and mono-cytesarealsousefulintherecognitionanddestructionofany intracellularpathogenableorunableofforminggranulomas. Inaddition,TNFisessentialformaintainingtheintegrityof thegranuloma.4Granulomaformationisessentialtocounter
infections and,thus,topreventtheirspread.Thisbecomes particularlyimportantininfectionswithMycobacterium tuber-culosis.
L.pneumophilaisafacultativeintracellularbacteriumthat preferablyinvadesandinfectsmacrophagesandmonocytes. Studies inanimal modelshaveshown thattheinfectionof macrophages by L. pneumophila induces the production of proinflammatorycytokines,suchasTNFandIL-1,andthatthe additionofrecombinantTNFtomacrophagesinfectedwithL. pneumophilaresultsinasignificantresistanceofthesecellsto bacterialgrowth.5ThemechanismbywhichTNFreducesthe
bacterialreplicationhasnotbeenfullyclarified;somesuggest thatthecytokineactssynergisticallywithinterferon-gamma synthesized byTlymphocytes inthe inhibitionofbacterial growth,aidedbyincreasedconcentrationsofnitricoxideand bythedepletionofintracellularironinducedbyTNFactivity.6
Inadditiontotheseaforementionedmechanisms,TNFalso appearstoactmediatingtheinductionofglutathione,a pow-erfulantioxidant.Inthisway,TNFwouldminimizetheeffects ofL.pneumophila-andhyperoxia-inducedlunginjury.7
r e v b r a s r e u m a t o l . 2 0 1 4;54(5):397–399
399
Figure1–A.Chestradiographshowingextensiveconsolidationintothelefthemithorax.B.Chestradiographafter treatmentwithamacrolideandaquinolone(azithromycinandlevofloxacin).
thesecultures.In addition, animalmodelsinfected withL. pneumophilatreatedwithanti-TNFexhibitedpersistent pneu-monia,withgreater numbersofinfectedmacrophagesand bacteriaversuscontrolsuntreatedwithanti-TNF.8
Epidemiological studies suggesting an increased risk of opportunisticinfections ingeneralinpatientstreated with anti-TNFwerepublished.9,10 Casereportsandcaseseriesin
theliteraturecalledtheattentionofphysicianstothe devel-opmentofL.pneumophila infectioninpatientstreated with anti-TNF.Tubachetal.estimatedthattherelativeriskof infec-tion byL. pneumophila inpatients treated with anti-TNF is about 16.5times greater than inthe generalpopulation in France.11
MostreportsofL.pneumophilainfectionareassociatedwith infliximab.ThesamepatternisconfirmedwhenwerefertoM. tuberculosisinfection.DatafromtheFoodandDrug Adminis-tration(FDA)showthattheincidenceofthisinfectionmaybe 8to9timesgreaterinpatientstreatedwithinfliximabversus
etanercept.
Theanti-TNFdrugsmentionedhavedifferentmechanisms of action, which may partly explain the difference in the incidence ofinfections. Infliximab, bybeing a monoclonal antibody,formsmorestableandirreversiblebondswiththe TNFboundtocellmembrane.Etanercept,whichbehaveslike asolubleTNFreceptor,formscomplexeslesscytokine-avid.12
Therefore,physiciansshouldbealerttothe diagnosisof thisdiseaseinpatientstreatedwithanti-TNF.Despitethewell establishedeffectivenessandsafetyofthesedrugs,potentially serioussideeffectsshouldbemonitored.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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