Changing patterns in leptospirosis : a threedecade study in Brazil

(1)

Changing

patterns

in

leptospirosis:

a

three-decade

study

in

Brazil

Elizabeth

De

Francesco

Daher

a,

*

,

Gabriela

Studart

Galdino

de

Carvalho

a

,

Douglas

de

Sousa

Soares

a

,

Matheus

Henrique

Mendes

a

,

Sérgio

Luiz

Arruda

Parente

Filho

a

,

Hermano

Alexandre

Lima

Rocha

b

,

Geraldo

Bezerra

da

Silva

Junior

c

a_Department_of_Internal_Medicine,_School_of_Medicine,_Walter_Cantídio_University_Hospital,_Federal_University_of_Ceará,_Fortaleza,_Ceará,_Brazil b_Department_of_Community_Health,_School_of_Medicine,_Federal_University_of_Ceará,_Fortaleza,_Ceará,_Brazil

c_School_of_Medicine,_Public_Health_Graduate_Program,_Health_Sciences_Center,_University_of_Fortaleza,_Fortaleza,_Ceará,_Brazil

ARTICLE INFO

Articlehistory:

Received7March2017

Receivedinrevisedform25April2017 Accepted28April2017

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark

Keywords:

Leptospirosis Changingpatterns Laboratoryﬁndings Acutekidneyinjury Mortality

SUMMARY

Background:Thisstudywasconductedtoinvestigatechangesintheclinicalpatternofleptospirosisover time,analyzingitsclinicalandlaboratorypresentationsinametropolitancityofBrazil.

Method:Thiswasaretrospectivestudyincludingallpatientswithleptospirosisadmittedtotertiarycare hospitalsinFortalezainthenortheastofBrazil,between1985and2015.Patientsweredividedintothree groupsaccordingtotheyearofhospitaladmission:groupIfortheyears1985–1995,groupIIfor1996– 2005,andgroupIIIfor2006–2015.Demographic,clinical,andlaboratorydatawerecomparedbetween thegroups.

Results:Atotalof507patientswereincluded.Theirmeanagewas37.315.9yearsand82.4%weremale. Themeantimebetweensymptomonsetandadmissionwas74days.Therewasalineardecreaseinthe levels of serumurea (190.192.7,13579.5, and 95.673.3mg/dl, respectively, p <0.0001) and

creatinine(5.82.9,3.82.6,and3.02.5mg/dl,respectively,p<0.0001)ineachdecade,whilelevels

of hemoglobin (10.311.9, 10.82.0, and 11.52.1g/dl, respectively, p <0.0001) and platelets

(57.90052.650, 80.13068.836, and 107.10199.699109_/l, _{respectively,} _p_<_0.0001) _increased. Therewasatendencytowardsalineardecreaseinmortality(22%,14%,and11.6%,respectively,p=0.060). Conclusions:Leptospirosisshowedsigniﬁcantchangesovertimeinthisregion.Themainchangespointto adecreaseindiseaseseverityandcomplications,suchasacutekidneyinjury.Mortalityhasdecreased, beingcloseto11%.

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Leptospirosisremainsthemostimportantzoonosisworldwide, with a higher frequency in low-income tropical countries (Victorianoetal.,2009;AdleranddelaPeñaMoctezuma,2010; HaakeandLevett,2015).Ithastraditionallybeenassociatedwith rural areas and people undertaking certain risk occupations, includingabattoirand sewageworkers,militarypersonnel, and individualsinvolved inwater sportsor recreation. However,its epidemiologicalpatternhaschangedoverthelastdecades,witha markedmovetourbanareas,especiallyduringnaturaldisasters (Sarkar et al., 2002). This disease is endemic in Brazil, with outbreaksduringtherainyseason,mostlyduetoprecariousliving

conditions (slums), a lack of basic sanitation, the presence of vectors, and frequentexposure toa contaminatedenvironment duringseasonalheavyrainfallandﬂooding(Sarkaretal.,2002;Ko etal.,1999;Costaetal.,2015).

Leptospirosis hasbeen recognizedas an important causeof undifferentiatedfeverandisusuallymisdiagnosedasmalariaor dengue,aswellasothercausesofacutefebrileillness,including recentlyemerging viraldiseases such asZika and chikungunya (Costaetal.,2015;Pattersonetal.,2016).Itsclinicalpresentation mayvaryfroma mild non-speciﬁcinﬂuenza-like infectiontoa severediseasewithlife-threateningcomplications,suchasacute kidney injury (AKI), jaundice, pulmonary hemorrhage (Weil’s disease),myocarditis,andliverfailure(Daheretal.,2010;Daher etal.,2011).

Unfortunately, mortality from severe leptospirosis remains unacceptablyhigh, rangingfrom5%to20%,evenwhenoptimal treatmentisprovided(Goswamietal.,2014).Duetothelackofan adequatediagnostictest,theunderreportingofcasesanddeathsis

*Correspondingauthorat:RuaVicenteLinhares,1198Fortaleza,CEP60270-135, CE,Brazil.Tel/Fax:(+5585)3224-9725/(+5585)3261-3777.

E-mailaddresses:ef.daher@uol.com.br,geraldobezerrajr@yahoo.com.br

(E.DeFrancescoDaher).

http://dx.doi.org/10.1016/j.ijid.2017.04.023

1201-9712/©2017TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

–

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

(2)

still common, leading to underestimations of morbidity and mortality(Costaetal.,2015).Ontheotherhand,somestudieshave shownthattheclinicalpatternofleptospirosishasbeenchanging. Anincreaseinthesevereformsofthediseasehasbeenreported,as wellasitsepidemiologicalspread,butmortalityhasdecreasedin recent decades,mainlydue to improvementsin treatment and medical educationprograms(Daheret al., 2011; Everard etal., 1995; Daheret al.,1999).Nevertheless,AKI remains oneof the most severe complications associated with increased mortality (SilvaJunioretal.,2011).

Therefore,theaimofthisstudywastoinvestigatechangesin theclinicalpatternsofleptospirosisovertime,analyzingitsclinical andlaboratorypresentationsinametropolitancityofBrazil.

Methods

Studypopulation

Thestudyincludedallpatientswithaconﬁrmeddiagnosisof leptospirosis admitted consecutively to the São José Infectious Diseases Hospital, Walter Cantídio University Hospital, and FortalezaGeneralHospital,inFortalezainthenortheastofBrazil, fromJanuary1985toDecember2015.

Studydesign

Thiswas aretrospectivecross-sectionalstudycoveringthree decades.Datawerecollectedfromthemedicalrecordsofpatients withleptospirosis admittedto thetertiary carehospitals men-tionedabove,whicharethethreereferencehospitalsinthisregion. Patientsweredividedintothreegroupsaccordingtotheperiodof hospitaladmission:groupIfortheyears1985–1995,groupIIfor 1996–2005,and groupIIIfor 2006–2015.Demographic,clinical, and laboratory data were compared between these groups to investigatedifferencesoverthisthree-decadeperiod.

Casedeﬁnition

Leptospirosiswasdeﬁnedasthepresenceofapositiveserology resultwithamicroscopicagglutinationtest(MAT)titerhigherthan 1:800, associated with an epidemiological and clinical history compatiblewithleptospirosis.

Parametersassessed

Demographiccharacteristics suchas age,sex, time between symptomonsetandhospitaladmission,andlengthofhospitalstay wererecorded.Theclinicalinvestigationincludedarecordofall clinicalsignsandsymptomspresentedbyeachpatientathospital admissionandduringtheirhospitalstay,vitalsigns(systolicand diastolic blood pressure, heart rate, and respiratory rate), developmentof AKI, and need for dialysis. Laboratory data on hospital admission included an assessment of serum urea, creatinine,sodium,potassium,directbilirubin,indirectbilirubin, aspartateaminotransferase(AST),alanineaminotransferase(ALT), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), hemoglobin,hematocrit,whiteblood cell(WBC) count,platelet count,andarterialbloodgasanalysis.

Deﬁnitions

AKIwas defined accordingtothe KidneyDisease Improving Global Outcomes (KDIGO) criteria; this is currently the most accepted definition and classification for AKI (Kidney Disease OutcomesQualityInitiative,2012).Thrombocytopeniawasdefined asaplateletcountlowerthan150109_/l,_anemia_as_hemoglobin

<12g/dl,andleukocytosisasaWBCcount>12109_/l. Hypoalbu-minemia was considered as serum albumin <3.5g/dl. The occurrenceofmetabolicacidosiswasconsideredinthepresence of a pH <7.35 and serum bicarbonate <20 mEq/l, and severe metabolic acidosis at a pH<7.10. Tachypneawas defined as a respiratoryratehigherthan25breathsperminute.Oliguriawas defined as urine output <400ml/day after 24h of effective hydration. Hypotension was defined as a mean arterial blood pressure(MAP)of<60mmHg,andtherapywithvasoactivedrugs wasinitiatedwhenMAPremainedlowerthan60mmHgdespite theuseofparenteralfluids.Hypertensionwasdefinedasasystolic pressure 140mmHg and/or diastolic pressure 90mmHg. Regarding dialysis therapy, hemodialysis was the method of choiceratherthanperitonealdialysis,and theintentionwas for thistobeinitiatedearlyafterintensivecareunitadmission(ICU) (< 24hafterAKIdiagnosis)andperformeddaily(untilasignificant improvementinrenalfunction).

Statisticalanalysis

Theresultsareshowninthetables;valueswererecordedasthe meanstandarddeviation(SD).AlldatawereanalyzedusingIBM SPSSStatisticsversion20.0software(IBMCorp.,Armonk,NY,USA). TheKolmogorov–Smirnovtestwasusedfornumericalvariables,to assess variable distribution. Analysis of variance (ANOVA) was used for comparisons of the data between the three groups studied.Thesigniﬁcancelevelwassetat5%(p< 0.05).

Ethics

ThestudyprotocolwasapprovedbytheEthicsCommitteeof SãoJoséInfectiousDiseasesHospital,WalterCantídioUniversity Hospital,andFortalezaGeneralHospital,Fortaleza,Ceará,Brazil. Patientidentitywasprotected,sincealldatawereanonymized.

Results

A total of 507 patients wereincluded. Their mean agewas 37.315.9yearsand82.4%weremale.Therewere86patientsin groupI,187ingroupII,and234in groupIII. Therewasa male predominanceinallgroups(76.7%,80.7%,and85.9%,respectively), andpatientsingroupIwereolder(43.217.8vs.34.413.7vs. 37.316.2years, respectively, p < 0.0001). The mean time between symptom onset and hospitalization was nearly 7days inallgroups,asshowninTable1.

Theanalysisof clinicalmanifestationsshowedaprogressive decreaseinthefrequencyofarrhythmias(20%vs.11.1%vs.0.06%, respectively, p< 0.0001), chills (67.1% vs. 56.3% vs. 25.3%, respectively, p< 0.0001), dehydration (60% vs. 57.4% vs. 18.2%, respectively,p< 0.0001),mentalconfusion(21.2%vs.9.5%vs.0%, respectively, p< 0.0001), jaundice (98.8% vs. 84.9% vs. 56%, respectively, p< 0.0001), and secondary infections (11.8% vs. 7.7%vs.4.0%,respectively,p=0.04).Diastolicbloodpressurelevels increasedlinearly(66.516.1vs.67.414.2vs.72.315.4mmHg, respectively,p< 0.002).Ofnote,initiallungmanifestations,which had decreased signiﬁcantly in the last decade, were more prevalentintheseconddecade,asshowninTable2.

Laboratory data on hospital admission showed a linear reduction in the levels of serum urea (190 92.7 vs. 13579.5 vs. 95.673.3mg/dl, respectively, p < 0.0001) and creatinine(5.82.9vs.3.82.6vs.3.02.5mg/dl,respectively,p < 0.0001), suggesting the occurrence of milder AKI in the last decade. The levels of direct bilirubin showed a consecutive reduction(15.110.1vs.11.78.4vs.5.56.3mg/dl,respectively, p < 0.0001), while hemoglobin (10.31.9 vs. 10.82.0 vs. 11.52.1g/dl, respectively, p< 0.0001) and platelet levels

(3)

(57.952.6 vs. 80.168.8 vs. 107.199.7109_/l, _{respectively,} p< 0.0001)werehigherineachdecade,asshowninTable3.

The percentage ofpatients withsevereAKI (KDIGOstage3) decreasedconsecutively (96.3%vs. 70.1%vs. 57.4%,respectively, p< 0.0001), as shown in Figure 1. Consequently, the need for dialysis also decreased (75.6%, 29.5%, and 31.6%, respectively, p< 0.0001).Theuseofantibioticsincreasedprogressively(43.8%, 93.8%, and 94.5%, respectively, p< 0.0001), while the use of vasoconstrictors, that could only be analyzed in the last two decades,was signiﬁcantly lowerin thethird decade (31.0% vs. 16.1%,p=0.05),asshowninTable4.Mortalityalsoshowedatrend towards a linear reduction (22% vs.14% vs.11.6%, respectively, p=0.060),asillustratedinFigure2.

Discussion

This is the ﬁrst study in the literature to assess data from leptospirosispatients overa three-decadeperiod.Differences in clinicalandlaboratorypatternswereevaluatedacrossthis three-decadeperiod,aswellaschangesintreatment.Thestudyperiod encompassesthetimefromtherecordingoftheﬁrstcasesinthe study region up to recent years, and important changes were observedthroughoutthesedecades,includingadecreaseinAKI severityandmortalityrates.

Leptospirosisisaseriouspublichealthproblemandaneglected disease,withahigherprevalenceintropicalareas,includingBrazil (Daheretal.,2010;Slack,2010).McBrideetal.(2005)recognized thatadvanceshavebeenmadeinunderstandingthepathogenesis ofleptospirosis,andfoundthattheeffectsofeducationalprograms inendemicareashadanimportantimpactindecreasingmortality (Daheretal.,2011).Therehasbeenaclearimprovementinthe disease diagnosis, mainly due to physician awareness of the differentialdiagnosisoffebrileillnessesintropicalcountries, as wellasmoreexperiencewithfebrilediseasesaffectingreturning travelersindevelopedcountries(McBrideetal.,2005;Ricaldiand Vinetz,2006;Waggoneretal.,2015).

Consistentwithpreviousstudies,mostpatientsinthepresent studyweremale.Themale sexhasbeenextensivelyassociated withtheriskofleptospirosisinfection,duetotheconnectionof leptospirosisinfectionwithoccupationstraditionallyattributedto men, such as abattoir and sewage workers, as well military personnel. Consequently, males are usually more exposed to Leptospiraspirochetes(Sarkaretal.,2002;Mikulskietal.,2015). Furthermore,patientsdiagnosedin thelast twodecadesofthis studyweresignificantlyyoungerthanthosein thefirstdecade. Thisfactmayhavestronglyinfluencedthereductioninmortality andpresenceoflesssevereformsofthediseaseinrecentyears, sinceolderpatientsusuallyhavemorecomorbiditiesandahigher

Table2

Comparisonofsigns,symptoms,andvitalsignsbetweengroupsI,II,andIII.a

GroupI,1985–1995 (n=86)

GroupII,1996–2005 (n=187)

GroupIII,2006–2015 (n=234)

p-Value

Signsandsymptoms

Arrhythmias(%) 17(20) 6(11) 1(0.6) <0.0001

Chills(%) 57(67) 90(56.3) 57(25.3) <0.0001

Headache(%) 56(65.9) 129(79.6) 132(58.7) <0.0001

Crackles(%) 12(14) 36(22.8) 20(8.9) 0.001

Dehydration(%) 51(60) 93(57.4) 41(18.2) <0.0001

Mentalconfusion(%) 18(21.2) 4(9.5) 0(0) <0.0001

Jaundice(%) 84(98.8) 141(84.9) 126(56) <0.0001

Secondaryinfections(%) 10(11.8) 12(7.7) 9(4) 0.041

Myalgia(%) 78(91.8) 157(94.6) 166(73.8) <0.0001

Petechiae(%) 11(12.9) 32(20.8) 8(3.6) <0.0001

Tachypnea(%) 17(20) 53(33.5) 20(8.9) <0.0001

Dyspnea(%) 1(1.2) 69(42.3) 71(31.6) <0.0001

Oligo/anuria(%) 20(23.5) 53(33.3) 57(25.3) 0.143

Fever(%) 84(98.8) 159(95.8) 205(91) 0.019

Calfpain(%) 70(82.4) 57(80.3) 109(52.4) <0.0001

Edema(%) 12(14.1) 24(45.3) 21(15.4) <0.0001

Vitalsigns

SBP(mmHg) 110.020.3 108.119.7 116.421.3 0.001

DBP(mmHg) 66.516.1 67.414.2 72.315.4 0.002

HR(/min) – 97.317.3 96.618.4 0.786

RR(/min) – 268 2610 0.716

SBP,systolicbloodpressure;DBP,diastolicbloodpressure;HR,heartrate;RR,respiratoryrate.

a_Analysis_of_variance_(ANOVA)._Values_are_expressed_as_the_mean_standard_deviation,_or_as_the_number_{(percentage).}_p_-Values_of_<_0.05_were_considered_{statistically}

signiﬁcant.

Table1

ComparisonofdemographicdatabetweengroupsI,II,andIII.a

GroupI,1985–1995 (n=86)

GroupII,1996–2005 (n=187)

GroupIII,2006–2015 (n=234)

p-Value

Age(years) 43.217.8 34.413.7 37.316.2 <0.0001

Sex

Male(%) 66(76.7) 151(80.7) 201(85.9) 0.121

Female(%) 20(23.3) 336(19.3) 33(14.1)

Hospitalstay(days) 13.28.7 8.15.0 11.18.2 <0.0001

Timebetweensymptomonsetand hospitalization(days)

72 73 75 0.822

Mortality(%) 22 14 11.6 0.060

a_Analysis_of_variance_(ANOVA)._Values_are_expressed_as_the_mean_standard_deviation,_or_as_the_number_{(percentage).}_p_-Values_of

<0.05wereconsideredstatistically

signiﬁcant.

(4)

riskofdeath.Olderageand thepresenceofcomorbiditieshave beenextensivelyassociatedwithdeathinleptospirosispatients (Koetal.,1999;Daheretal.,1999;Dupontetal.,1997).

In contrast to previousreports, the clinical presentation on admissionoftheleptospirosispatientsinthepresentstudyseems tohavebecomemilderoverthelastdecade.Aprogressivedecrease insomeofthelife-threateningmanifestations,suchas arrhyth-mias,chills,dehydration,mentalconfusion,jaundice,and second-ary infections, was noted, suggesting a decrease in severe leptospirosis,mostlyinthelastdecade.Itwasalsoobservedthat

the time between symptom onset and hospital admission remained nearly the same, while the length of hospital stay decreased.Thisprobablyreﬂectsamilderformofdisease,which maybeattributedtobettersanitaryconditionsinBrazilandearly diagnosis.Poorsanitationhasbeenstronglyassociatedwiththe developmentofleptospirosisinmanycountries(Mwachuietal., 2015).In addition,onlypeoplewithsevereformsofthedisease wouldhavebeendiagnosedandhospitalizedintheﬁrstdecadeof thisstudy.Thediagnosisandhospitalizationofmildercaseshave becomemorefrequentinrecentyears,probablyduetoeffective

Table3

ComparisonoflaboratorydatabetweenpatientsfromgroupsI,II,andIII.a

Parameters GroupI,1985–1995 (n=86)

GroupII,1996–2005 (n=187)

GroupIII,2006–2015 (n=234)

p-Value

Creatinine(mg/dl) 5.82.9 3.82.6 3.02.5 <0.0001

Urea(mg/dl) 190.192.7 135.379.5 95.673.3 <0.0001

Potassium(mEq/l) 4.01.0 3.61.1 3.91.9 0.019

Sodium(mEq/l) – 132.36.3 133.214.5 0.583

AST(UI/l) 75.554.5 141.1145.3 169.9259.2 0.006

ALT(UI/l) 51.933.5 102.4122.9 116.0196.0 0.019

LDH(UI/l) 595.7249.0 719.7482.4 890.7634.8 0.048

CPK(UI/l) 289.5395.6 1358.53550 17994163.7 0.164

Directbilirubin(mg/dl) 15.110.1 11.78.4 5.56.3 <0.0001 Indirectbilirubin(mg/dl) 5.64.4 5.35.2 2.564.0 <0.0001

Hematocrit(%) 32.35.9 32.06.2 34.221.8 0.376

Hemoglobin(g/dl) 10.31.9 10.82.0 11.52.1 <0.0001

WBC(109_/l) _16.34

10.84 12.966.4 13.614.2 0.110

Platelets(109_/l)

– 94.7582.73 123.048115.493 0.021

SerumpH 7.370.11 7.360.08 7.370.08 0.747

Bicarbonate(mEq/l) 18.86.6 18.84.4 18.34.7 0.668

SaO2(%) – 93.08.9 93.18.9 0.944

AST,aspartateaminotransferase;ALT,alanineaminotransferase;LDH,lactatedehydrogenase;CPK,creatinephosphokinase;WBC,whitebloodcellcount;SaO2,oxygen

saturation.

a_Analysis_of_variance_(ANOVA)._Values_are_expressed_as_the_mean_standard_deviation._p_-Values_of

<0.05wereconsideredstatisticallysigniﬁcant.

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

1985 - 1995 1996 - 2005 2006 - 2015

p <0.001

KDIGO 1

KDIGO 2

KDIGO 3

Figure1.AcutekidneyinjurystagesaccordingtotheKidneyDiseaseImprovingGlobalOutcomes(KDIGO)criteria,inpatientswithleptospirosisinthethreedifferent decades.

Table4

ComparisonoftreatmentinstitutedforpatientswithsevereleptospirosisbetweengroupsI,II,andIII.a

GroupI,1985–1995 (n=86)

GroupII,1996–2005 (n=187)

GroupIII,2006–2015 (n=234)

p-Value

Vasoconstrictors(%) – 9(31.0) 31(16.1) 0.05

Ceftriaxone(%) 9(64.3) 0(0) 125(67.9) 0.046

Penicillin(%) 7(22.6) 114(82.6) 64(28.4) <0.0001

Diuretics(%) 3(11.5) 10(34.5) 42(21.8) 0.118

Needfordialysis(%) 65(75.6 54(29.5) 74(31.6) <0.0001

Hemodialysis(%) 3(4.6) 53(98.1) 67(90.5) <0.0001

Peritonealdialysis(%) 62(95.4) 1(1.9) 7(9.5) <0.0001

a_Analysis_of_variance_(ANOVA)._Values_are_expressed_as_the_number_{(percentage).}_p_-Values_of_<_0.05_were_considered_{statistically}_signi_ﬁ_cant.

(5)

medical education programs (Daher et al., 2011). The early diagnosis of leptospirosis has been associated with fewer complications and a faster recovery from the infection (Daher etal.,2010;Dupontetal.,1997;Spichleretal.,2008).

Moreover,changesinthehemodynamicstatusandlaboratory parameters were observed, including a decrease in bilirubin levels and an increase in hemoglobin and platelet levels. The better hemodynamic status of the patients on admission, demonstrated by higher blood pressure levels, conﬁrms the presenceof themilderformsofthediseasein thelastdecade. Hyperbilirubinemia is extremely common in leptospirosis patients,more frequentlyin associationwith skin rash,which usuallyleadstothepresenceofa‘rubinicjaundice’pattern(Puca et al., 2016).Elevated bilirubin levels and jaundice have been associatedwithdeathandpooroutcomesinleptospirosis(Daher etal.,2016;Herrmann-Storcketal.,2010;Abgueguenetal.,2008), and their lower levels in the last decades among the study patients also reﬂect a reduction in disease severity in these patientsthroughthedecades.

Improvementsinhematologicalparameters,including hemo-globin and platelet levels, may be evidence of a less severe infectionandmayhavecontributedtothedecreaseinmortality.A decreaseinhemoglobinlevelsisacommonﬁndinginleptospirosis patients andhasbeen associatedwithseveredisease and poor outcomes(De Silva et al.,2014; Prabhu and Ramesh, 2016). In addition,thrombocytopenia isalsoextremelyfrequentin lepto-spirosispatients and it is usuallyassociated with hemorrhagic phenomena and complications. It hasbeen strongly associated with mortality and severity in leptospirosis and it has been includedinarecentdiagnosticscoringsystemforleptospirosisina resource-limited setting (Spichler etal., 2008;Rajapakse et al., 2016).InastudycarriedoutinPuertoRico,elevatedWBClevels wereassociatedwithfatal outcomes(Sharpetal.,2016).Inthe presentstudy,thiselevationmayhaveresultedfromamoresevere disease presentation on admission and a possible secondary infection.

The presence of arrhythmiasis alsoa predictorof death in leptospirosis.Arrhythmiasarethemostcommoncardiac manifes-tationofleptospirosisandoftenderivefromelectrolytedisorders, such as hypokalemia and hypocalcemia, which are usually secondarytoAKI(Sacramentoetal.,2002;NavinanandRajapakse, 2012;Soaresetal.,2017).Electrocardiographicabnormalitieshave

beendescribedasriskfactorsfordeathinleptospirosispatients (Daheretal.,1999;Dupontetal.,1997).

Interestingly,therewasasignificantlinearreductioninserum ureaandcreatinineinthepatientsincludedinthepresentstudy.A progressivereductionofsevereAKIcases(KDIGOstage3)ineach decadewasalsoshown,suggestingearlydiagnosisandtreatment. Consequently,lessrenalreplacementtherapywasneededoverthe lastdecades,arelevantfactorthathascontributedtothedecrease inmortality,sinceAKIisstronglyassociatedwithahigherriskof deathinleptospirosis(SilvaJunioretal.,2011;Daheretal.,2008; Telesetal.,2016).LeptospirosisisasignificantcauseofAKIin low-and middle-income tropical countries (Bouchard and Mehta, 2016).AKIisalsoanimportantcomponentofthesevereformof leptospirosis(Weil’ssyndrome),leadingtoseveralcomplications. Referraltospecializedcare,includinganephrologistconsultation, aswellasearlyimplementationofdialysis,seemstobeessential forslowingtheprogressionofAKItomoresevereformsandfor decreasing mortality (Andrade et al., 2007). Regarding the treatmentofAKI, intermittent peritonealdialysis(IPD)was the predominantmethodin theperiodfrom 1985to1996,usedin 95.4%ofpatientswhoneededdialysis;dailyhemodialysis(DHD) wasthemethodmostoftenusedintheperiodfrom1997to2015. Theinstitutionofearlyhemodialysis(<24hafterAKIdiagnosis) insteadofIPDwasessentialforthebetterprognosisofpatientsin thesecondandthirddecadesofthestudy,withprovenbenefitsin leptospirosis patients (Andrade et al., 2007). Furthermore,it is hypothesized that the reduction in AKI development and AKI severity,aswellastheestablishmentofearlyandeffectiverenal replacementtherapywerekeypointsinthereductionofmortality inthesepatientsinrecentyears.

Acleardecreasingtrendinmortalitywasseenoverthesethree decades(decreasingfrom22%to14%,andthento11.6%inthelast decade),whichprobablyreflectstheearlydiagnosisof complica-tionsandtheprovisionofadequatetreatment.Althoughprevious studieshaveshownevidencethatmortalitydoesnotseemtobe significantlyinfluencedbyantibioticuse(Daheretal.,2012;Costa etal.,2003),arecentstudybythepresentinvestigatorgroupfound that ceftriaxone was a protective factor for ICU admission in leptospirosispatients(Daheretal.,2016).Thereisalsoevidence thattheuseofpenicillinisassociatedwithareductioninhospital lengthofstayandfewercomplications,includingAKI(Daheretal., 2012).Itwasalsodemonstratedinthepresentstudythattheuseof

Figure2. Decreaseinmortalityofleptospirosiscasesoverthethree-decadeperiodp=0.06.

(6)

antibioticsincreasedprogressivelythroughoutthedecadesinthis cohort(43.8%,93.8%,and94.5%,respectively,p< 0.0001),although itwasnotdirectlyassociatedwithadeclineinmortalityaccording tothemultivariateanalysis.Theuseofantibioticsinleptospirosisis now a consensus in the literature and it is believed that the increase in use has probably contributed to a reduction in mortality,sincetheuseofantibioticshasbeenassociatedwitha shorterlengthofhospitalstay,milderAKI,andlessneedfordialysis (Daheretal.,2012),aswellasalowerfrequencyofICUadmission (Daheretal.,2016).

In summary, leptospirosis is a life-threatening neglected tropicaldiseaseanditspresentationhaschangedsigniﬁcantlyin thestudyregionovertime.Themainchangespointtoareduction inseverityandcomplications,suchasAKI.Mortalityhasshowna cleardecreasingtrendinrecentdecades.

Studylimitations

Themainlimitationsofthisstudyderivefromitsretrospective design.Admissiondatawerenotavailableinsomepatientrecords. ThestudywasperformedinonlyoneregionofBrazil,sodisease patternsmaydifferinotherregionsofBrazilandworldwide.

Non-technicalsummary

Leptospirosis is a bacterialdisease transmitted byrat urine, whichisverycommonintropicalcountries.Thecharacteristicsof patientswithleptospirosisinalargecityinBrazilwereassessed, overaperiodofthreedecades.Thereisevidencethatthedisease hasbecomemilder,includingmilderformsofrenalfailure,oneof themostseverediseasecomplications.Adecreaseinmortalitywas alsofound. These ﬁndings could bedue tomore frequent and earlieridentiﬁcationofthediseasebyclinicians,andconsequently tobetterhealthcareprovision.

Financialsupport

E.F.DaherandG.B.SilvaJuniorarerecipientsofagrantfromthe Conselho NacionaldeDesenvolvimentoCientíﬁcoeTecnológico (CNPq).Thefundershadnoroleinthestudydesign,datacollection andanalysis,decisiontopublish,orpreparationofthemanuscript.

Conﬂictofinterest

The authors declare no conﬂicts of interest regarding this manuscript.

Acknowledgements

Weareverygratefultotheteamofclinicians,medicalresidents, medical students, and nurses fromSão José InfectiousDiseases Hospital,WalterCantídioUniversityHospital,andFortalezaGeneral Hospital fortheassistance providedto thepatientsand for the technicalsupportprovidedforthedevelopmentofthisresearch.

References

AbgueguenP,DelbosV,BlanvillainJ,ChennebaultJM,CottinJ,FanelloS,etal. Clinicalaspects and prognosticfactors of leptospirosis in adults.J Infect 2008;57:171–8.

AdlerB, delaPeñaMoctezumaA.Leptospiraandleptospirosis.VetMicrobiol 2010;140:287–96.

AndradeL,CletoS,SeguroAC.Door-to-DialysisTimeandDailyHemodialysisin Patientswith Leptospirosis:Impact onMortality. Clin J Am SocNephrol 2007;2:739–44.

BouchardJ,MehtaRL.AcuteKidneyInjuryinWesternCountries.KidneyDis(Basel) 2016;2:103–10.

CostaE,LopesAA,SacramentoE,CostaYA,MatosED,LopesMB,etal.Penicillinat thelatestageofleptospirosis:arandomizedcontrolledtrial.RevInstMedTrop SaoPaulo2003;45:141–5.

CostaF,HaganJE,CalcagnoJ,KaneM,TorgersonP,Martinez-SilveiraMS,etal.Global MorbidityandMortalityofLeptospirosis:ASystematicReview.PLoSNeglTrop Dis2015;9:e0003898.

DaherE,ZanettaDM,CavalcanteMB,AbdulkaderRC.Riskfactorsfordeathand changingpatternsinleptospirosisacuterenalfailure.AmJTropMedHyg 1999;61:630–4.

DaherEF,MarquesCN,LimaRSA,SilvaJúniorGB,BarbosaAS,BarbosaES,etal.Acute kidneyinjuryinaninfectiousdiseaseintensivecareunit-anassessmentof prognosticfactors.SwissMedWkly2008;138:128–33.

DaherEDF,deAbreuKLS,daSilvaJuniorGB.Leptospirosis-associatedacutekidney injury.JBrasNefrol2010;32:400–7.

DaherEF,SilvaGB,LimaRSA,MotaRMS,RochaHAL,deAbreuKLS,etal.Different PatternsinaCohortofPatientswithSevereLeptospirosis(WeilSyndrome): EffectsofanEducationalPrograminanEndemicArea.AmJTropMedHyg 2011;85:479–84.

Daher EF, Silva GB, de AbreuKLS, MotaRMS, Batista DV, RochaNA, et al. Leptospirosis-associatedacutekidneyinjury:penicillinatthelatestageis still controversial: Penicillinin leptospirosis. J Clin Pharm Ther 2012;37: 420–5.

DaherEF,SoaresDS,deMenezesFernandesATB,GirãoMMV,SidrimPR,Pereira EDB,etal.Riskfactorsforintensivecareunitadmissioninpatientswithsevere leptospirosis:acomparativestudyaccordingtopatients’severity.BMCInfect Dis2016;16:40.

DeSilvaNL,NiloofaMJR,FernandoN,KarunanayakeL,RodrigoC,DeSilvaHJ,etal. Changesinfullbloodcountparametersinleptospirosis:aprospectivestudy.Int ArchMed2014;7:31.

DupontH,Dupont-PerdrizetD,PerieJL,Zehner-HansenS,JarrigeB,DaijardinJB. Leptospirosis:prognosticfactors associatedwith mortality.Clin InfectDis 1997;25:720–4.

Everard CO, Edwards CN, EverardJD, CarringtonDG. A twelve-yearstudy of leptospirosisonBarbados.EurJEpidemiol1995;11:311–20.

GoswamiRP,GoswamiRP,BasuA,TripathiSK,ChakrabartiS,ChattopadhyayI. Predictors of mortalityin leptospirosis:an observational study from two hospitals in Kolkata,easternIndia.TransR SocTrop Med Hyg2014;108: 791–6.

Haake DA, Levett PN. Leptospirosis in humans. Curr TopMicrobiol Immunol 2015;387:65–97.

Herrmann-StorckC,Saint-LouisM,FoucandT,LamauryI,DeloumeauxJ,BarantonG, etal.Severeleptospirosisinhospitalizedpatients,Guadeloupe.EmergInfect Dis2010;16:331–4.

KidneyDiseaseOutcomesQualityInitiative.KDIGOclinicalpracticeguidelinesfor acutekidneyinjury–Summaryofrecommendationstatements.KidneyInt Suppl2012;2:1–138.

KoAI,GalvãoReisM,RibeiroDouradoCM,JohnsonWD,RileyLW.Urbanepidemicof severe leptospirosis in Brazil. Salvador Leptospirosis Study Group. Lancet 1999;354:820–5.

McBrideAJ,AthanazioDA,ReisMG,KoAI.Leptospirosis.CurrOpinInfectDis 2005;18:376–86.

MikulskiM,BoisierP,LacassinF,Soupé-GilbertMRE,MauronC,Bruyere-OstellsL, etal.SeverityMarkersinsevereleptospirosis.EurJClinMicrobiolInfectDis 2015;34:687–95.

MwachuiMA,CrumpL,HartskeerlR,ZinsstagJ,HattendorfJ.Environmentaland behaviouraldeterminantsofleptospirosistransmission:asystematicreview. PLoSNeglTropDis2015;9:e0003843.

NavinanMR,RajapakseS.Cardiacinvolvementinleptospirosis.TransRSocTrop MedHyg2012;106:515–20.

Patterson J, Sammon M, Garg M.Dengue, Zika and Chikungunya:emerging arbovirusesinthenewworld.WestJEmergMed2016;17:671–9.

PrabhuMV,RameshV.Fever,thrombocytopenia,andAKI-Aproﬁleofmalaria, dengue,andleptospirosiswithrenalfailureinaSouthIndiantertiary-care hospital.ClinNephrol2016;86:128–30.

PucaE,PilacaA,KaloT,PiperoP,BinoS,HysenajZ,etal.Ocularandcutaneous manifestationofleptospirosisacquiredinAlbania:aretrospectiveanalysiswith implicationsfortravelmedicine.TravelMedInfectDis2016;14:143–7.

RajapakseS,WeeratungaP,NiloofaR,FernandoN,deSilvaNL,RodrigoC,etal.A DiagnosticScoringModelforLeptospirosisinResourceLimitedSettings.PLoS NeglTropDis2016;10:e000451.

RicaldiJN,VinetzJM.Leptospirosisinthetropicsandintravelers.CurrInfectDisRep 2006;8:51–8.

Sacramento E,LopesAA, CostaE, PassosOL,Costa YA,MatosED. Electrocar-diographic alterations in patients hospitalized with leptospirosis in the BraziliancityofSalvador.ArqBrasCardiol2002;78:267–70.

Sarkar U, Nascimento SF, Barbosa R, MartinsR, Nuevo H, Kalofonos I, etal. Population-basedcase-controlinvestigationofriskfactorsforleptospirosis duringanurbanepidemic.AmJTropMedHyg2002;66:605–10.

SharpTM,GarcíaBR,Pérez-PadillaJ,GallowayRL,GuerrAM,RyffKR,etal.Early IndicatorsofFatalLeptospirosisduringthe2010EpidemicinPuertoRico.PLoS NeglTropDis2016;10:e0004482.

SilvaJuniorGB,AbreuKL,MotaRM,BarretoAG,AraújoSM,RochaHA,etal.RIFLE and Acute Kidney Injury Network classiﬁcations predict mortality in leptospirosis-associated acutekidney injury.Nephrology (Carlton)2011;16: 269–76.

(7)

SlackA.Leptospirosis.AustFamPhysician2010;39:495–8.

SoaresDS,GaldinoGS,RodriguesBC,SilvaJuniorGB,DaherEF.Arrhythmiasin leptospirosis-associatedacutekidneyinjury:acaseseries.BrazJInfectDisin press2017;inpress.

SpichlerAS,VilaçaPJ,AthanazioDA,AlbuquerqueJO,BuzzarM,CastroB,etal. PredictorsoflethalityinsevereleptospirosisinurbanBrazil.AmJTropMedHyg 2008;79:911–4.

TelesF,deMendonçaUchôaJV,MendonçaDMB,CostaAFP.Acutekidneyinjuryin leptospirosis:theKidneyDiseaseImprovingGlobalOutcomes(KDIGO)criteria andmortality.ClinNephrol2016;86:303–9.

VictorianoAFB,SmytheLD,Gloriani-BarzagaN,CavintaLL,KasaiT, Limpakarnja-naratK,etal.LeptospirosisintheAsiaPaciﬁcregion.BMCInfectDis2009;9:1.

WaggonerJJ, SodaEA, Seibert R, GrantP, Pinsky BA.Molecular detection of Leptospiraintworeturnedtravelers:higherbacterialloadincerebrospinalﬂuid versusserumorplasma.AmJTropMedHyg2015;93:238–40.