ENTERIC FEVER AND ITS RARE COMPLICATIONS

ENTERICFEVERANDITSRARECOMPLICATIONS (MASSyndrome,liverabscessandentericencephalopathy) AUHTOR:DR.DEVESHCHATTERJEE,DR.SONALIBHATTACHARYA,DRRAGHAVI A.BEMBEY REVIEWEDBYDR.V.K.RASTOGI,DR.PARASPASSI ABSTRSACT:EntericfevercausedbySalmonellaTyphiandParatyphihavewideclinicalpresentationin humanbeingslikeincommonitmaypresentfromasimplegastroenteritis,bacteremia,entericfever. WhilemanagingIndoorpatientsinatertiarycareprivatehospitalofDelhiweobservedfew rare interestingcomplicationsofEntericfeverlikesecondaryhemophagocyticlymphohistiocytosis,liver abscessandencephalopathy.Itwasobservedthatwhilehandlingcertaincasesitisimportantto proceedoncorrectwaylike,approachtopatient,selectinggoodtoolsfordiagnosis,practicing advancetreatmentmodalitiesandfinallysavinglivesareofutmostimportance.Interestinglynoneof thesecasesareeasytorecognizeinearlydaysinfarflungremoteareaswerefacilitiesarelacking.In ourobservance01stcasewasof59yearmale,whopresentedwithacutefebrileillnessandfoundto havethrombocytopeniawithhepatosplenomegaly.Patientwashavingprogressivepancytopeniawith clinicaldetoriation.Afterrulingoutotherdifferentials,diagnosisandfurthermanagementdoneon linesofsecondaryhemophagocytosislymphohistiocytosis.02nd casewasof59yearsmalewho presentedasacutefebrileillnesswithacuteabdomen,workedupanddiagnosedaspyogenicliver abscesswhichwasdrainedunderulstrasonicguidanceandfinallydiagnosedasPyogenicliverabscess causedbysalmonellatyphiandtreatedaccordingly.03rd casewasof65yearoldfemalewho presented with acute febrile illnessassociated with neuropschychiatricand cerebellersigns, differentialsformeningo-encephalitis,strokeruledoutandfinallydiagnosedasentericencephalitis onthebasisofclinicpathologicalreportsandmanagedwithantibioticsalongwithcorticosteroids. LEARNINGOBJECTIVES 1. ENTERICFEVERRARECOMPLICATION 2. PRESENTSATIONOFDISEASES 3. APPROACHTOPATIENT 4. DISEASEPROGRESSION 5. DIAGNOSTICALGORITHEM 6. TREATMENTMODALITIES 7. RESPONSETOTREATMENT INTRODUCTION • Entericfeverisanendemicdiseaserecognizedassystemicdiseasecharacterizedbyfeverand abdominalpainandcausedbydisseminationofS.TyphiorS.Paratyphi. • Theetiologicagentsofentericfever—S.TyphiandS.ParatyphiserotypesA,B,andC. • Riskfactorsincludecontaminatedwaterandfood.SalmonellaismotileGram-negativebacillithatmay

infectorcolonizeawiderangeofmammalianhosts. • Mostcommonpresentingfeatures:- Gastroenteritis Entericfever Bacteremia butafterenteringthebloodstream,alltissuesandorgansaresusceptibleandmaymanifestina varietyofclinicalentitiesdependinguponthesiteoflocalization.[1] RARECOMPLICATION CASE1 Entericfeverandsecondaryhemophagocyticlymphohistiocytosis (MASsyndrome) • Patient59yrs/Male,presentedwithcomplaint highgradefever, severepainabdomen, recurrentstools, generalizedweakness×10daysbeforeadmission. • Onexamination:-consciousoriented PR:-130/minute, sPo2:-97%onroomair, BP:-100/80mmHg, RR:-28/minute Temperature:-102°F Signsofdehydration++ Pallor+ noicterus,lymphadenopathy,normalJVP • Systemicexamination P/A:-mildhepatosplenomegaly CVS:-S1S2+,Nomurmurs Chest:-bilaterallungfieldswereclear

CNS:-NoFND,noneckstiffness. APPROACH: • Consideringthedifferentialsforanacuteonsetfeverwiththrombocytopeniawith hepatosplenomegaly, dengue malaria leptospirosis scrubtyphuswasconsideredasthedifferentialdiagnosiswhich werenegative. • HewasstartedempiricallyonInjCeftriaxone2gmIVbidalongwithsupportivemeasuresincluding hydrationandantipyretics. • Inviewofthepresentationwithfever,splenomegalyandprogressivecytopeniawithrapidclinical deterioration,aworkupforIrondeficiency,vitB12deficiency,folicaciddeficiencyandsecondary hemophagocyticlymphohistiocytosiswasconsidered. • Ironstudy,vitaminsB12andfolatelevelswerewithinnormalrange • Bloodreportsrevealedprogressivecytopeniaandelevationofliverenzymes. • ACTscanoftheabdomenwasdoneinviewofpersistingabdominalsymptoms,showedileocecal thickeningwithhepatosplenomegaly. • WidaltestresultswereshowingOtiterof>1:320. • BloodcultureshowedSalmonellaTyphigrowth. • Theantibioticswerecontinuedandonthe7thdayofadmission,patientgotafebrile. • Patientneeded2-unitPRBCtransfusionand4unitsRDPprovidedwhichcytopeniapersisted. • Thereafter,patientwasstartedwithInjDexamethasoneatday5afterconsiderationwith hematologistinviewofHLHandpatient’sbloodcountsimprovedsubsequently. Day1 Day2 Day3 Day4 Day5 Day6 Day7 Day8 Day9 Hb 12.3 10.8 9.5 8.3 6.2 7.9 6.7 8.2 9.8 TLC(cells/cu.mm) 5300 4190 3200 2800 2000 2150 3300 4000 5680 Platelet 90000 52000 39000 22000 20000 16000 14500 32000 78000 SGOT(IU/L) 122 232 250 400 330 350 300 220 130 SGPT(IU/L) 178 250 245 340 440 450 400 320 300 S.Bilirubin(T)(mg/dl) 1.09 1.00 1.32 1.33 1.07 0.97 0.88 0.99 0.87

S.Creat(mg/dl) 0.93 - 0.88 - - 1.12 0.93 - - BUN(mg/dl) S.Na 14 - 13 S.K S.LDH 133 125 123 118 120 115 124 129 134 S.Ferritin(ng/ml) S.Triglycerides 4.1 4.5 4.2 - - - - - - (mg/dl) 728 1100 1120 2200 - 1870 - 1100 - - 1200 1840 2000 2200 2400 - 1800 1000 - 770 980 - - 960 - 600 230 DISCUSSION • Entericfeverisanonspecificfebrileillnesscausedbytyphoidalsalmonella(SalmonellaTyphiand SalmonellaParatyphiA,B,andC) • Characterizedby inflammationofpayer’spatches, intestinalulceration mesentericlymphadenitis. • Thediagnosisshouldbeconsideredinanypatientwithotherwiseunexplainedprolongedfever[2]. Otherclinicalfeaturesincludeheadache,chills,cough,myalgia,arthralgia,anorexia,abdominalpain, diarrhea,constipation,coatedtongue,hepatosplenomegalyandrarelyarash.

• Thesinisterpresentationinourcasemadeusworkupthecaseinlinesofsecondaryhemophagocytic lymphohistiocytosisinentericfever. • SimilarpresentationhasbeenmentionedbySoodetalinastudyinIndiain1997-6andacasereport byNonetalin2015wherethepatienthadrhabdomyolysis,sepsisandsecondaryHLHinasettingof entericfever[3]. • Ourpatienthadsevereanemiawhichrequiredbloodtransfusions,highLDH(lactatedehydrogenase), hightriglycerides,highferritin,highASTandALTlevelswhichallpointedouttothepossibilityof HLH[4]. CONCLUSSION • Entericfeverisacommonclinicalscenariointropicalcountries.However,itsclinicalmanifestations keepvaryingandapossibilityofsecondaryHLHshouldbeconsideredinthepresenceofamenacing presentationinentericfever.Carefulinvestigationsincaseofatypicalmanifestationsofacommon diseasewillanswermostoftheparadoxesinclinicalmedicine. CASE2 Pyogenicliverabscesscausedbysalmonellatyphi • Patient,59-year-oldmalewasadmittedwithcomplaintsof high-gradefeverwithchillsandrigors severeabdominalpainintheepigastricregion recurrentvomiting severenausea×1weekbeforeadmission. diarrheaandpainabdomen×1month. • Onexamination:-conscious,oriented temperature:-102°F PR:-160/min BP:-100/60mmHg • Icterus+ • Perabdomenexaminationelicitedthetendernessintherighthypochondriumandepigastricregion, andliverwaspalpableabout6cmbelowthecostalmargin. • Restofthesystemicexaminationwaswithinnormallimits. Day1 Day2 Day5 Day7

TLC(cells/cu.mm) 19000 23400 15000 11200 2.23 2.45 2.78 Platelet(lakh/cu.mm) 3.32 4.20 3.33 1.76 2.78 2.10 0.94 Serumbilirubin(T)(mg/dl) 3.45 500 430 123 670 400 110 Serumbilirubin(D)(mg/dl) 2.90 14 17 - 1.32 1.09 - SGOT(IU/L) 336 - - - SGPT(IU/L) 450 BUN(mg/dl) 18 S.Creat(mg/dl) 1.23 S.Procalcitonin 44.2 • SerologyforHIV,hepatitisBsurfaceantigenandanti-hepatitisCviruswerenonreactive. • WidaltestandIgMLeptospirawerenegative. • Ultrasonographyoftheabdomenshowedenlargementoftheliverwithfeaturessuggestiveof abscessmeasuring4cm×4cm×4.6cmandvolume180ccinvolvingsegmentVIandVIIalongwith mildascites. • ThepatientwasempiricallystartedonintravenousCeftriaxoneandMetronidazoleforliverabscess, butpatient’sconditiondeterioratedfurtherwithpersistenthighgradefeverandabdominalpain. • Contrastenhancedcomputedtomographyscanabdomenrevealedalargeliverabscessintheright lobeofsize5cm×4.9cm×4.6cm. • Ultrasoundguidedliveraspirationdone.About30mlofpuswasaspiratedandsentfor microbiologicalinvestigations. • PusculturerevealedgrowthofSalmonellatyphisubspeciesandIVAntibioticschangedaccordingly andIVMetronidazolestopped. • Bloodandurineculturesweresterile.Nopathogenicorganismwasgrowninstoolculture.Amoebic serologywasnegative. • Hepaticabscess,classifiedbyetiology,are pyogenic, amoebic, fungal[1]. • Themostcommonpathogensofthepyogenichepaticabscessesare Escherichiacoli,

Klebsiellapneumoniae, Bacteroides, Enterococci, Streptococci, Staphylococci. • PyogenicliverabscessduetoSalmonellaspeciesisnotthatcommonandlowincidenceofhepatic manifestationsmaybeexplainedbythephagocyticactivityofitswell-establishedreticulo- endothelialsystem. • Salmonellaliberabscesshavebeenreportedwithsomepreexistinghepatobiliarydiseaseslike cholelithiasis, amoebicabscess, echinococcalcysts, intrahepatichematoma, hepatocellularcarcinoma,etc. • Salmonellaliverabscessismostlyseenintheimmunocompromisedstate,whileourcasewasan immunocompetentadultmalewithnopreexistinghepatobiliarydisease. • Thebloodculturewassterileinthiscaseandlikelysourceoftheliverabscessinourpatientcouldbe secondarytotheseedingofinfectionfromthetransientportalbacteremiaorinfectionlocalizedin thegallbladdercouldhavetravelledtotheliverparenchyma. CASE3 AcaseofEntericencephalopathy • Patient,65yearoldfemalepresentedwithcomplaintsof -Onsetofhigh-gradecontinuousfeverwithsevereheadache -Unsteadinessofgaitsimultaneouslywhichbecamemoreunsteadyoverpast3daysbefore admission -Threetofourepisodesoftonic–clonicseizuresfollowedbyalteredmentation -Multipleepisodesofnon-projectilevomiting,non-biliousvomiting

-Decreasedoralintake. Thepatientprimarilyreceivedantibioticsfromlocalpractitionerbutdidnotimprovedandthusgot admittedforfurthermanagement. • Onexamination:-conscious,confused,agitated,toxic -Temperature:-102°F -BP:-120/70mmHg -PR:-99/min • Onneurologicalexamination, -horizontalnystagmus+, -ataxia+ -hyporeflexiainallthefourlimbs; -Babinski’ssignwasbilaterallypositive -NeckstiffnesswasnegativeandKernig’ssignwasnegative. • CSFreportshowedcolorless,transparentfluid -Totalleukocytecount:-7/hpf(alllymphocytes) -CSFprotein131mg/dl -CSFsugar65mg/dl -NoorganismswereseeninCSFoncultureorZNstain. • Brainmagneticresonanceimaging(MRI)wasdonewhichshowedasmallinfarctontheleftsideof cerebellum,restwithinnormallimits. • Widaltest:-SalmonellatyphiO:-1:640; S.typhiH:-1:320 SalmonellaParatyphiAandBnegative. • BloodculturewhichgrewStyphi. • ShewastreatedwithI.VCeftriaxone2gmIVBiDfor14daysalongwithI.V.Levetiracetam500mgBID forconvulsionsandsupportivecare. • NormalMRIexcludedacutedemyelinatingencephalomyelitis(ADEM)andCSFcultureexcluded bacterialmeningo-encephalitis.Consideringthehypothesisofatoxicreaction,treatmentwith corticosteroids(Prednisone1mg/kg/day)[14,18] • Shebecameafebrilewithin2daysofstartingthetreatmentandgradually,herneurologicaldisorders alsostartedreducinginintensity. • After14daysoftreatmentwithCeftriaxone,sheimprovedgraduallybecameafebrile,conscious, orientedandwasdischargedlateroninahemodynamicallystablecondition.

DISCUSSION • Neurologicalmanifestationsoftyphoidfeverareveryuncommonandhardtoidentifyinregular practice.Wehavetothinkofpossibilitiesofencephalopathyinthesetypesofcases,consideringthe symptomsandhistoryoffeverassociatedwithheadache,non-projectilevomiting,seizureswith alteredmentation;withsupportingdiagnosticresultfavoringsystemicTyphoidalinfectionwith negativeCSFandneuro-imagingmodalitiesinoldpersonswithpostantibiotictoxemia.[15,16] • Stupor,deliriumandcomaareassociatedwithapoorprognosisandamortalityrateabove40%inthe tropics. • Neuroimagingfindingsoftyphoid-associatedencephalopathyaresparse,withdiffuseedema, symmetricalhypodensity,multifocalcerebellarhyperdensityandgeneralizedcerebralatrophy reported[19]. • Inthepresentcase,neurologicalcomplicationswithin1weekofstartingantibiotictreatment,raising thepossibleroleoftyphoidendotoxemia. • Inaddition,theneurologicalstatusofthepatientonlyimprovedaftercorticosteroidtreatmenthad beeninstituted.Suchreactionsareconsideredasaresultofadversereactiontotoxinsreleasedby Salmonella(whicheverserotypeisTyphiorParatyphi)duringbacteriallysiswithtyphoidtoxinshaving animportantaffinityforthecentralnervoussystem. • IthasbeensuggestedthatendotoxinsreleasedbyS.Typhicouldstimulatemacrophagestoproduce cytokines,arachidonicacidanditsmetabolitesthatcouldberesponsibleforthetoxiceffects, particularlythoseseeninentericfever’sencephalopathy[20]. CONCLUSSION • Inconclusion,neuropsychiatriccomplicationscanbeseenseveraldaysaftertheinitiationof appropriateantibiotictreatment.Endotoxinreleaseinducedbythebacteriallysisisthemostlikely mechanismofthesetoxicreactions,andcorticosteroidisthemostefficienttreatment. • Earlyrecognitionandappropriatemanagementofsuchcomplicationsshouldreducemorbidity, mortalityandpromisesfastrecovery. References:- 1. MahajanRK,SharmaS,MadanP,DuggalN.PyogenicliverabscesscausedbySalmonellaEnteritidis:A rarecasereport.IndianJPatholMicrobiol[serialonline]2014[cited2020Mar21];57:632-634, http://www.ijpmonline.org/text.asp?2014/57/4/632/142715 2. Mandell,Douglas,andBennett'sPrinciplesandPracticeofInfectiousDiseases:2-VolumeSet Volume2ofMandell,Douglas,andBennett'sPrinciplesandPracticeofInfectiousDiseases, John EugeneBennett PrinciplesandPracticeofInfectiousDiseases ScienceDirecte-books

3. ACatastrophicPresentationofEntericFeverwithSecondaryHemophagocyticLymphohistiocytosis NettoGeorge1,PrayasSethi2,NeerajNischal2,ArvindKumar2,GovindaSiripurapu1,NaveetWig3, SurabhiVyas4 4. Typhoid Fever Complicated by Hemophagocytic Lymphohistiocytosis and Rhabdomyolysis, Article in The American journal of tropical medicine and hygiene 93(5) · August 2015, DOI: 10.4269/ajtmh.15-0385 ·Source: PubMed 5. DanielTLeungetalstudyon:FactorsassociatedwithEncephalopathyinpatientswithSalmonella enterica,Feb2009-June2011,doi:10.4269/ajtmh.2012.11-0750 6. Harrison’s–Textbookofinternalmedicine 7. HuangDB,DuPontHL.Problempathogens:extra-intestinalcomplicationsofSalmonella entericaserotypeTyphiinfection,PMID:15919620DOI:10.1016/S1473-3099(05)70138-9, LancetInfectDis.2005Jun;5(6):341-8. 8. PuneetChopra,RupinderSBhatia,andRahulChopra,MildEncephalopathy/Encephalitiswith ReversibleSplenialLesioninaPatientwithSalmonellatyphiInfection:AnUnusualPresentationwith ExcellentPrognosis,PMID:31988550,doi:10.5005/jp-journals-10071-23300 9. RouphaelNG,TalatiNJ,VaughanC,CunninghamK,MoreiraR,GouldC.,Infectionsassociatedwith haemophagocyticsyndrome,LancetInfectDis.2007Dec;7(12):814-22.,PMID:18045564DOI: 10.1016/S1473-3099(07)70290-6 10.JuanitaUribe-Londono,LinaMariaCastano-Jaramillo,LauraPenagos-Tascon,AndreaRestrepo-Gouzy, andAndres-FelipeEscobar-Gonzalez,HemophagocyticLymphohistiocytosisAssociatedwith SalmonellatyphiInfectioninaChild:ACaseReportwithReviewofLiterature,PMID:30595935,doi: 10.1155/2018/6236270 11.DanielT.Leung,JoriBogetz,MegumiItoh,LakshmiGanapathi,MarkA.C.Pietroni,EdwardT.Ryan, andMohammodJobayerChisti,FactorsAssociatedwithEncephalopathyinPatientswith SalmonellaentericaSerotypeTyphiBacteremiaPresentingtoaDiarrhealHospitalinDhaka, Bangladesh,PMID:22492156,doi:10.4269/ajtmh.2012.11-0750 12.GuillaumeMellon,MD,MPH ,Anne-LineEme,MD,BenjaminRohaut,MD,PhD,FlorenceBrossier, PharmD,LoïcEpelboin,MD,MPH,EricCaumes,MD,Encephalitisinatravellerwithtyphoidfever: efficacyofcorticosteroids,JournalofTravelMedicine,Volume24,Issue6,November-December2017, tax063,https://doi.org/10.1093/jtm/tax063 13.JannainaF.Jorge,AndressaB.V.Costa,JorgeL.N.Rodrigues,EvelyneS.Girão,RobertaS.S. Luiz,AnastácioQ.Sousa,SeanR.Moore,DalgimarB.Menezes,andTerezinhaM.J.S.Leitão, SalmonellatyphiLiverAbscessOverlyingaMetastaticMelanoma,PMID:24591434,doi: 10.4269/ajtmh.13-0573. 14GuillaumeMellon,MD,MPH,Anne-LineEme,MD,BenjaminRohaut,MD,PhD,Florence Brossier,PharmD,LoïcEpelboin,MD,MPH,EricCaumes,MD,Encephalitisinatraveller withtyphoidfever:efficacyofcorticosteroids, JournalofTravelMedicine,Volume24, Issue6,November-December2017,tax063, https://doi.org/10.1093/jtm/tax063

15Azmel,A.,Azmel,A.,&Shunmugarajoo,A.(2018).Typhoidassociatedencephalopathy-Acasereportand ReviewofLiterature. AsianJournalofMedicineandBiomedicine,1.Retrievedfrom https://journal.unisza.edu.my/ajmb/index.php/ajmb/article/view/50 16Grimm,M.,Lübbert,C.,Mössner,J. etal. Ayoungtravellerpresentingwithtyphoidfever afteroralvaccination:acasereport. JMedCaseReports 7, 237(2013). https://doi.org/10.1186/1752-1947-7-237 17.A.Venkatesan,A.R.Tunkel,K.C.Bloch,A.S.Lauring,J.Sejvar,A.Bitnun,J-P.Stahl, A.Mailles,M.Drebot,C.E.Rupprecht,J.Yoder,J.R.Cope,M.R.Wilson,R.J.Whitley,J. Sullivan,J.Granerod,C.Jones,K.Eastwood,K.N.Ward,D.N.Durrheim,M.V.Solbrig,L. Guo-Dong,C.A.Glaser,onbehalfoftheInternationalEncephalitisConsortium,Heather Sheriff,DavidBrown,EileenFarnon,SharonMessenger,BeverleyPaterson,Ariane Soldatos,SharonRoy,GovindaVisvesvara,MichaelBeach,RogerNasci,CarolPertowski, ScottSchmid,LisaRascoe,JoelMontgomery,SuxiangTong,RobertBreiman,Richard Franka,MattKeuhnert,FredAngulo,JamesCherry,CaseDefinitions,Diagnostic Algorithms,andPrioritiesinEncephalitis:ConsensusStatementoftheInternational EncephalitisConsortium, ClinicalInfectiousDiseases,Volume57,Issue8,15October 2013,Pages1114–1128, https://doi.org/10.1093/cid/cit458 18.N.I.Girgis,Z.Farid,Y.Sultan,R.G.Hibbs,Useofdexamethasoneintreatmentof entericfevercomplicatedbycerebellarinvolvement, TransactionsofTheRoyalSociety ofTropicalMedicineandHygiene,Volume87,Issue6,November-December1993, Pages690–691, https://doi.org/10.1016/0035-9203(93)90297-4 Ali,G.,Rashid,S.,Kamli,M.A.,Shah,P.A.andAllaqaband,G.Q.(1997),Spectrum of neuropsychiatriccomplicationsin791casesoftyphoidfever.TropicalMedicine&International Health,2:314-318.doi:10.1111/j.1365-3156.1997.tb00145.x                                                                 19.SejvarJ,LutterlohE,NaieneJ,etal.Neurologicmanifestationsassociatedwithanoutbreakof typhoidfever,Malawi--Mozambique,2009:anepidemiologicinvestigation. PLoSOne. 2012;7(12):e46099.doi:10.1371/journal.pone.0046099 20.Sejvar,James&Lutterloh,Emily&Naiene,Jeremias&Likaka,Andrew&Manda,Robert&Nygren, Benjamin&Monroe,Steve&Khaila,Tadala&Lowther,Sara&Capewell,Linda&Date,Kashmira&Townes, David&Redwood,Yanique&Schier,Josh&TippettBarr,Beth&Demby,Austin&Mallewa,Mac& Kampondeni,Sam&Blount,Ben&Mintz,Eric.(2012).NeurologicManifestationsAssociatedwithanOutbreak ofTyphoidFever,Malawi-Mozambique,2009:AnEpidemiologicInvestigation.PloSone.7.e46099. 10.1371/journal.pone.0046099.