Effect of pulmonary hypertension on outcome of pulmonary tuberculosis

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braz j infect dis.2014;18(5):487–490

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Original

article

Effect

of

pulmonary

hypertension

on

outcome

of

pulmonary

tuberculosis

Majid

Marjani

a

_,

_Parvaneh

_Baghaei

a,∗

_,

_Majid

_{Malekmohammad}

b

_,

_Payam

_Tabarsi

c

_,

Babak

Sharif-Kashani

d

_,

_Neda

_Behzadnia

e

_,

_Davood

_Mansouri

a

_,

Mohammad

Reza

Masjedi

f

_,

_Ali

_Akbar

_Velayati

a

a_Clinical_Tuberculosis_and_Epidemiology_Research_Center,_National_Research_Institute_of_Tuberculosis_and_Lung_Diseases_(NRITLD), ShahidBeheshtiUniversityofMedicalSciences,Tehran,Iran

b_Chronic_Respiratory_Diseases_Research_Center,_National_Research_Institute_of_Tuberculosis_and_Lung_Diseases_(NRITLD),_Shahid BeheshtiUniversityofMedicalSciences,Tehran,Iran

c_{Mycobacteriology}_Research_Center,_National_Research_Institute_of_Tuberculosis_and_Lung_Diseases_(NRITLD),_Shahid_Beheshti_University ofMedicalSciences,Tehran,Iran

d_Tobacco_Prevention_and_Control_Research_Center,_National_Research_Institute_of_Tuberculosis_and_Lung_Diseases_(NRITLD),_Shahid BeheshtiUniversityofMedicalSciences,Tehran,Iran

e_Lung_{Transplantation}_Research_Center,_National_Research_Institute_of_Tuberculosis_and_Lung_Diseases_(NRITLD),_Shahid_Beheshti UniversityofMedicalSciences,Tehran,Iran

f_Telemedicine_Research_Center,_National_Research_Institute_of_Tuberculosis_and_Lung_Diseases_(NRITLD),_Shahid_Beheshti_University_of MedicalSciences,Tehran,Iran

a

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Articlehistory:

Received28October2013

Accepted12February2014

Availableonline27April2014

Keywords: Tuberculosis Pulmonaryhypertension Echocardiography Survival

a

b

s

t

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c

t

Background:ThisstudyperformedattheNationalResearchInstituteofTuberculosisand

LungDisease,Tehran,Iran,aimedtoevaluatetheeffectofconcomitantpulmonary

hyper-tensionontheoutcomeofpulmonarytuberculosis.

Methods:Newcasesofpulmonarytuberculosis wererecruitedforthestudy.Pulmonary

hypertensionwasdeﬁnedassystolicpulmonaryarterialpressure≥35mmHgestimatedby

transthoracicDopplerechocardiography.Weassessedtherelationshipbetweenpulmonary

hypertensionandmortalityduringthesix-monthtreatmentoftuberculosis.

Results:Of777newcasesofpulmonarytuberculosis,74(9.5%)hadsystolicpulmonary

arte-rialpressure≥35mmHg.Tenofthem(13.5%)diedduringtreatmentcomparedto5%ofcases

withpulmonaryarterialpressurelessthan35mmHg(p=0.007).Logisticregressionanalysis

showedthatpulmonaryhypertensionanddrugabuseremainedindependentlyassociated

withmortality(OR=3.1;95%CI:1.44–6.75andOR=4.4;95%CI:2.35–8.17,respectively).

Conclusion: Asigniﬁcant associationwasfoundbetweenmortality andpresence of

pul-monaryhypertensionanddrugabuseamongnewcasesofpulmonarytuberculosis.

∗ _{Corresponding}_author.

E-mailaddress:[email protected](P.Baghaei).

http://dx.doi.org/10.1016/j.bjid.2014.02.006

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braz j infect dis.2014;18(5):487–490

Introduction

Pulmonary tuberculosis (TB) continues to be a major

healthproblemworldwide.Inspiteofeffective

chemother-apy, excess morbidity and mortality are attributed to TB.

Because treatment success in pulmonary TB has been

deﬁnedasmycobacteriologicalresponse,littleattentionhas

been paid to the related chronic disabilities inthose who

survived the disease.1 _Despite _successful_treatment, _a

sig-niﬁcant permanent damage of lung function has been

reported in more than 50% of pulmonary TB patients.

They may be obstructive or restrictive2 _and _lead _to _gas

exchange abnormalities and development of pulmonary

hypertension.3

Pulmonary hypertension(PH) isa serious disorder with

poorprognosis. Itisdeﬁnedasa mean pulmonaryarterial

pressure(PAP)ofmorethan25mmHgatrest.4_Recently,_new

therapeuticoptionshavebeendevelopedfortreatingPHthat

improvequalityoflifeandprognosisofthedisease.5

Symp-tomsofPHconsistingofdyspnea,palpitations,fatigue,and

syncopearevaguethatpostponedetectionofit.4_As_a_result,

anappropriateplanforscreeningPHisnecessaryamonghigh

riskgroupsofpatients.

FewstudiesdescribedPHintreatedTBpatientsbutmost

ofthemwereconductedduringpre-chemotherapyera.6

Stud-ies about PHduring activepulmonaryTBare very scarce.7

Moreover,accordingtodifferentdeﬁnitionsofthediseaseand

variousscreeningmethodsandpopulationgroups,theresults

arewidelydifferent.

ThisstudywasaimedtoevaluatetheeffectsofPHinthe

outcomeofactivepulmonaryTB.Duetothegrowingrangeof

therapeuticoptions,earlydiagnosisofpulmonary

hyperten-sionmaychangepatientsurvival.

Materials

and

methods

Thisretrospectivecohortstudywasconductedoninpatient

newcases of pulmonarytuberculosis that were diagnosed

intheNational ResearchInstituteofTuberculosisandLung

Diseases(NRITLD), Tehran,Iran between 2005and 2009. A

diagnosisofTBwasmadebypositivesmearandcultureresults

for Mycobacterium tuberculosis or histopathological ﬁndings.

New cases ofTB were deﬁned asthose who had received

eithernoanti-TBdrugsorlessthanonemonthoftreatment

inthepast. TBtreatmenthasbeen initiatedatthe timeof

diagnosis,asrecommendedbytheWorldHealthOrganization

(WHO)guidelines,8_consisting_of_isoniazid,_rifampin,

ethamb-utolandpyrazinamidefortwomonthsasinitialphaseand

isoniazid and rifampin forthe next four monthsas

main-tenancephase.All the patientswere referredtoperipheral

healthcentersforcontinuingmedicationunderthedirectly

observed treatment (DOT) strategy inaccordance with our

NationalTuberculosisProgram(NTP).Theoutcomeof

treat-mentwasdeﬁnedaccordingtoWHOguidelines.Deathdueto

anyreasonduringthecourseoftuberculosistreatmentwas

considered.8

For calculation ofpulmonary artery pressure ﬁrstly

tri-cuspidvalveregurgitant jetwasidentiﬁedbycolor Doppler

echocardiography(Vivid7dimension;Mannhealthcare,GE).

Then the trans-tricuspid pressure gradient was calculated

using modiﬁed Bernoulli equation and right atrium

pres-surewasaddedtoobtainedpeakpulmonaryarterypressure.

For this study we considered pulmonary hypertension as

peaksystolicpulmonaryarterialpressureequalormorethan

35mmHgestimatedbyrestingtransthoracic

echocardiogra-phy.

Recordeddataofallnewcasesofpulmonarytuberculosis

fromourhospitalregistrywerepresetforrecentstudy.

Demo-graphic,characteristics andother variableswereenteredin

SPSS(version11.5)software.

The relationship between pulmonary hypertension and

the outcome ofTBtreatment was assessed controllingfor

confounding factors (age, sex,smoking,drug abuse,

symp-toms and adverse effects of anti TB drugs) by regression

analysis.The2 _test_was_used_for_categorical_variables,_and

whenevernecessary,theFisherexacttestwasutilized.

Con-tinuousvariableswithnormaldistributionwereanalyzedby

t-Student test, andMann–Whitney Utestincaseof

abnor-maldistribution.Ap-value<0.05wasconsideredstatistically

signiﬁcant.

The scientiﬁc and ethics committee of the NRITLD

approvedthestudyprotocol.

Results

A total of 777 new cases of pulmonary tuberculosis were

diagnosed in the study period. Systolic pulmonaryarterial

pressure morethan35mmHgwasdetectedin74(9.5%)by

Doppler echocardiography. Right heart catheterization was

notperformed.

Characteristics of patients and clinical factors for both

groupsareshowedinTable1.

Malescomprised357(45.9%).Mean(±SD)ageofpatients

was 54.51±21.73; 84%were ofIranian nationality. HIVtest

was performed in 309 patients with 36 (4.7% of all cases)

positivecases.AllTBpatientswithPAP≥35mmwereHIV

neg-ative.

Therewasnosigniﬁcantdifferencebetweenpatientswith

PAPaboveandbelow35mmHgconcerninggender,smoking

status,opiumaddiction,andhistoryofhemoptysis.

Cases with pulmonary hypertension were older and

presentdyspneaandchestpainmoreoften.

Adverse effects of anti-TB medications occurred in 26

(35%)patientswithPAP≥35mmHg andin38%patientsof

the control (p=0.68). The major adverse effect was

drug-induced hepatitis, which was not different between two

groups(p=0.18).

TheoutcomeofTBtreatmentwasknownfor700patients.

TenpatientswithPAP≥35mmHg(13.5%)diedduring

treat-ment in comparison to 5% of cases without PH (p=0.007)

(Fig.1).

To determine the independent association of risk

fac-tors (gender, age>65, nationality, smoking status, and

PAP≥35mmHg)withmortality,alogisticregressionwas

per-formed.DrugabuseandPAP≥35mmHgwerethefactorsthat

remainedindependentlyassociatedwithmortalityintheﬁnal

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brazj infect dis.2014;18(5):487–490

489

Table1–CharacteristicsofTBpatientswithandwithoutpulmonaryhypertension.

Variables PAP≥35mmHg n(%) PAP<35mmHg n(%) p-value Gender Male 34(45.9) 323(45.9) NS Female 40(54.1) 380(54.1) Age(mean±SD) 68.50±15.56 52.99±21.78 <0.001 Smoker 23(31.1) 183(26) NS Opiumaddiction 14(18.9) 131(18.6) NS Hemoptysis 8(10.8) 127(18.1) NS Chestpain 42(56.8) 311(44.3) 0.049 Dyspnea 66(89.2) 470(66.9) <0.001 Total 74 703

PAP,pulmonaryarterypressure;NS,notsigniﬁcant.

Table2–RelationshipbetweenindependentriskfactorsanddeathinTBpatients.

Variables p-value OR (95%CI)

Gender 0.41 – – Nationality 0.76 – – Smoking 0.14 – – Age>65 0.64 – – PAP≥35mmHg 0.004 3.12 (1.44–6.75) Drugabuse 0.001 4.38 (2.35–8.17)

PAP,pulmonaryarterypressure;OR,oddsratio;CI,conﬁdenceinterval.

Discussion

Overall,wefounda9.7%prevalenceofpulmonaryartery pres-sureequalormorethan35mmHgamongpatientswithactive pulmonarytuberculosis.PatientswithhigherPAPwereolder and present with dyspnea more often. Mortality rate was higheramongcaseswithPAPequalormorethan35mmHg.

Sincethe19thcenturymyocardialdamagehasbeenfound on autopsy studies in pulmonary tuberculosis patients.9

Accentuated 2nd heart sound over the pulmonary area

of chronic TB patients is associated with an unfavorable

outcome.10

Associationofactivetuberculosisand pulmonary

hyper-tensionhasbeenassessedinfewpreviousstudies,inwhich

700 600 500 400 300 200 100 0 PAP≥35 mmHg PAP<35 mmHg Alive Death

Fig.1–DistributionofdeathsintwogroupsofTBpatients. Datawasavailablefor700patients.PAP,pulmonaryartery pressure.

PHorcorpulmonalewasdiagnosedeitherby

electrocardiogra-phyorpost-mortem.6_Cor_pulmonale_was_the_cause_of_death

atnecropsyin23%ofTBpatientsinonestudywithover50%of

thesepatientswithahistoryofclinicalsignsrelatedtocardiac

failurebeforedeath.10

InacrosssectionalstudyAhmedandcolleaguesdescribed

14 patients who presented with shortness of breath after

successfultreatmentofpulmonarytuberculosis.PHwas

con-sidered as pulmonary artery systolic pressure ≥40mm Hg

estimated byDopplerechocardiography.Most ofthem had

ﬁbrocavitaryorﬁbroticchangesinthechestX-ray.Theirwork

isdifferentfromoursasnoneoftheircaseshadactiveTBand

themeanintervalsinceTBdiagnosiswas9.4years.6

Inastudy with52 newcasesofpulmonarytuberculosis

44.2%hadsystolicpulmonaryarterypressureabove25mmHg

byechocardiography.Allthepatientswereyoungandmajority

ofthemhad disseminateddiseaseor involvementof

intra-thoraciclymphatics.7

Inourstudy,deathwassigniﬁcantlyhigheramongpatients

whohadPAP≥35mmHg.Thisﬁndingisnotinlinewiththe

resultsobtainedbyTomonoshowingnoassociationbetween

PHandlatesequelaofTB.Comparisonoftheseresultstothe

presentstudymaybeproblematicasweinvestigatedactive

TBcasesandshort-termoutcomeasopposedtooldTBcases

andlong-termoutcomesoftheJapanesestudy.11

Pathogenesisofpulmonaryarterialhypertensionamong

TB patients is not clear. In the past some suggested that

repeated secondary infections inresidual cavities and scar

lesions ofhealed TBmight have a role.Exudative

secreti-ons cause respiratorypassageblockage, impairmentingas

exchangeandultimatelyrisingcardiacoutput.9_Nonetheless,

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arterialpressureofactiveandnewcasesofTB.Active

tuber-culosisbyunknownmechanismsmaybedirectlyresponsible

forrisingPAP.Moreover,PHmayberelatedtoparenchymal

destructionand hypoxiainthecourseofthedisease

espe-ciallyincaseofdelayed diagnosisand initiationofanti-TB

treatment.ConcomitantlungdiseasessuchasCOPDaswell

asmyocardialinvolvementcouldbethecauseofPH.

Theoverall ﬁndingsofourstudy corroboratethe results

of previous studies concerning the relevance of PH in TB

patients,butourstudywasconductedinactiveTBcasesand

evaluatedshort-termoutcomes.Althoughthecurrentstudy

hassomestrongpointssuchaslargenumberofcases,there

aresomeimportantlimitations.First,echocardiographyhad

notbeenperformedinallcases, whichmayhave

underes-timated diagnosis of PH. Second, other causes of PH such

asconcomitantpulmonarydiseasehavenotbeenruledout.

Finally,diagnosisofPHhadnotbeenconﬁrmedbyrightheart

catheterization (RHC). Although RHC is the gold-standard

procedureandnecessaryforPHconﬁrmation,12_it_is_an

inva-siveandexpensiveprocedure,unsuitableasascreeningtool.

TransthoracicDopplerechocardiographyhasbeenshownto

beasafe,sensitiveandspeciﬁcmethodforscreeningPHin

patientswithsystemicdiseases likesystemic sclerosisand

lupuserythematosus.13,14 _Measurement _of_PAP_by

echocar-diographyinpatientswithseveretricuspidregurgitationmay

leadtounderestimation. Alsooverestimationiscommon.15

Soechocardiographymaybenotasuitablescreeningtoolfor

asymptomaticpatientswithmildPH.12_Several_cut-off_points

of PAP were used by investigators when screening for PH

withDopplerechocardiography,suchas30mmHg,13₄₀_mm

Hg,6 _and ₅₀_mm _Hg.14 _The _European_Society _of _Cardiology

andtheEuropeanRespiratorySocietysuggestarbitrary

crite-riafordiagnosingPHbasedonDopplercalculationandother

echocardiographicﬁndings.12

AlthoughourstudyshowstherelevanceofPHinactive

pul-monarytuberculosis,thereremainsmanyunresolvedissues:

whataretheriskfactorsofPHamongTBpatients?Isscreening

ofPHindicatedforthecasesofpulmonaryTB,minimallyfor

thosewhoarehighriskforPH?Whatistheoptimaltoolfor

suchscreening?AfterdetectionofPH,isthereany

interven-tionthatcouldimproveoutcomeofTBpatients?Prospective

well-designedstudiesarenecessarytorespondthese

ques-tions.

Conclusion

Pulmonaryhypertensioniscommonamongactivepulmonary

tuberculosis patients and needs more attention. Higher

pulmonary artery pressure in Dopplerechocardiography is

signiﬁcantlyassociatedtomortalityamongnewcasesof

pul-monarytuberculosis.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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