High Morbidity during Treatment and Residual Pulmonary Disability in Pulmonary Tuberculosis:...

High Morbidity during Treatment and Residual PulmonaryDisability in Pulmonary Tuberculosis Under-RecognisedPhenomenaAnna P Ralph12 Enny Kenangalem34 Govert Waramori5 Gysje J Pontororing3 Sandjaja6 EmilianaTjitra6 Graeme P Maguire78 Paul M Kelly910 Nicholas M Anstey12

1 Global and Tropical Health Division Menzies School of Health Research and Charles Darwin University Northern Territory Australia 2 Department ofInfectious Diseases Division of Medicine Royal Darwin Hospital Northern Territory Australia 3 Menzies School of Health Research-National Institute of HealthResearch and Development Research Program Timika Papua Province Indonesia 4 District Health Authority Timika Papua Province Indonesia 5 PublicHealth amp Malaria Control Department PT Freeport Indonesia Timika Papua Province Indonesia 6 National Institute of Health Research and DevelopmentJakarta Indonesia 7 Baker IDI Heart and Diabetes Institute Alice Springs Northern Territory Australia 8 School of Medicine and Dentistry James CookUniversity Cairns Queensland Australia 9 Population Health Division ACT Government Health Directorate Canberra Australian Capital Territory Australia10 Australian National University Medical School Canberra Australian Capital Territory Australia

Abstract

Background In pulmonary tuberculosis (PTB) morbidity during treatment and residual pulmonary disability can beunder-estimatedMethods Among adults with smear-positive PTB at an outpatient clinic in Papua Indonesia we assessed morbidityat baseline and during treatment and 6-month residual disability by measuring functional capacity (six-minute walktest [6MWT] and pulmonary function) quality of life (St Georgersquos Respiratory Questionnaire [SGRQ]) and AdverseEvents ([AE] new symptoms not present at outset) Results were compared with findings in locally-recruitedvolunteersResults 200 PTB patients and 40 volunteers were enrolled 6WMT was 497m (interquartile range 460-529) incontrols versus 408m (IQR 346-450) in PTB patients at baseline (plt00001) and 470m (IQR 418-515) in PTBpatients after 6 months (p=002 versus controls) SGRQ total score was 0 units (IQR 0-29) in controls versus 369(274-528) in PTB patients at baseline (plt00001) and 43 (17-88) by 6 months (plt00001) Mean percentage ofpredicted FEV1 was 92 (standard deviation 199) in controls versus 63 (194) in PTB patients at baseline(plt00001) and 71 (175) by 6 months (plt00001) After 6 months 27 of TB patients still had at least moderate-severe pulmonary function impairment and 57 still had respiratory symptoms despite most achieving lsquosuccessfulrsquotreatment outcomes and reporting good quality of life More-advanced disease at baseline (longer illness durationworse baseline X-ray) and HIV positivity predicted residual disability AE at any time during treatment were commonitch 59 arthralgia 58 headache 40 nausea 33 vomiting 16Conclusion We found high 6-month residual pulmonary disability and high AE rates Although PTB treatment ishighly successful the extent of morbidity during treatment and residual impairment could be overlooked if notspecifically sought Calculations of PTB-related burden of disease should acknowledge that TB-related morbiditydoes not stop at 6 months Early case detection and treatment are key in minimising residual impairment

Citation Ralph AP Kenangalem E Waramori G Pontororing GJ Sandjaja et al (2013) High Morbidity during Treatment and Residual PulmonaryDisability in Pulmonary Tuberculosis Under-Recognised Phenomena PLoS ONE 8(11) e80302 doi101371journalpone0080302

Editor Robert J Wilkinson Institute of Infectious Diseases and Molecular Medicine South Africa

Received August 21 2013 Accepted October 11 2013 Published November 29 2013

Copyright copy 2013 Ralph et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited

Funding The study received funding from the Australian Respiratory Council Royal Australasian College of Physicians (Covance Award to APR) NationalHealth and Medical Research Council (NHMRC) of Australia (Grants 605806 and 496600 a scholarship to APR and fellowships to APR TWY PMKNMA) Graeme Maguire is supported by an NHMRC Practitioner Fellowship and the Margaret Ross Chair in Indigenous Health Views expressed in thispublication are those of the authors and do not reflect the views of NHMRC The funders had no role in study design data collection and analysis decisionto publish or preparation of the manuscript

Competing interests The authors have declared that no competing interests exist

E-mail annaralphmenzieseduau

PLOS ONE | wwwplosoneorg 1 November 2013 | Volume 8 | Issue 11 | e80302

Introduction

The morbidity experienced by people with pulmonarytuberculosis (PTB) can be evaluated using measures such aspulmonary function testing quality of life questionnaires andassessment of treatment complications Quality-adjusted lifeyear calculations (QALY) which provide a measure of theburden of tuberculosis (TB)-related disease couldunderestimate true PTB morbidity if they assume a shortdisease duration [12] or do not incorporate long-termpulmonary disability resulting from permanent lung damage [3]Under-estimates in morbidity arising from TB disease or TBmedications may also occur in clinical or research settings inwhich passive reporting of symptoms is relied upon or in whichonly serious adverse effects (requiring medication cessation[4-6]) are captured The requirement for strict adverse eventreporting in clinical trials provides an important opportunity togather detailed information about symptoms experiencedduring TB treatment

TB is a well-recognised independent risk factor for chronicobstructive pulmonary disease (COPD) [7-11] Both earlyreversible lung impairment in pulmonary TB [812] and longer-term residual impairment after TB [810] are evaluable usingspirometric measures such as percentage of predicted forcedexpiratory volume in 1 second (FEV1) We have previouslyreported high rates of residual pulmonary disability in PTBpatients in eastern Indonesia [8] At treatment completion aquarter of successfully-treated patients still had significant lungfunction impairment (FEV1lt60 predicted using local healthyvolunteers as the reference population for calculation ofpercentage of predicted FEV1 [13]) Late residual pulmonarydisability has been reported by Pasipanodya et al showing thatpeople with previous active TB were 54 times more likely tohave abnormal pulmonary function than people withoutprevious active tuberculosis [10]

Quality of life questionnaires can also reveal a fuller scope ofPTB morbidity than is obtainable from standard severitymeasures such as sputum microscopy grade or radiologicaldisease extent The St Georgersquos Respiratory Questionnaire(SGRQ) has been shown to be an effective tool for measuringPTB morbidity [14] The SGRQ is a respiratory health-relatedquality of life (QoL) instrument formulated for use in COPD[1516] but validated in TB [814] and other respiratorydiseases It has been translated into many languages includingIndonesian [16] with minor modifications for local suitability

This study was performed within the context of a clinical trialof nutritional interventions where detailed information onsymptoms intercurrent illness and disease burden wascollected In order to gain an holistic understanding of thescope of morbidity during TB treatment in an outpatientresource-limited high TB-burden setting our objectives in thispaper were to investigate morbidity at baseline and duringfollow up (symptoms Adverse Events [AE] functional capacityand QoL) and residual disability at 6 months experienced byadults with PTB We furthermore sought to identify predictors ofresidual disability and compare functional and QoL measuresin PTB with reference ranges established from locally-recruitedhealthy controls

Methods

This study was performed within a clinical trial of adjunctivenutritional supplements (L-arginine and vitamin D) for PTB(clinicaltrialsgovNCT00677339) In this study theinterventions did not significantly affect outcome measuresincluding AE [17] Eligible sequential study participants withPTB who had no previous history of treatment were enrolled atthe tuberculosis clinic in Timika Indonesia Inclusion criteriaincluded age ge15 years sputum smear-positive for acid fastbacilli (AFB) and provision of written informed consent Thestandard 6-month tuberculosis treatment regimen [18] wasadministered in a directly observed fashion

Local healthy controls were eligible if they were aged ge18years gave written informed consent and had no co-morbidities Volunteers were approached via communitycontacts and social groups from among friends and relatives ofstaff members or patients (after undergoing TB contact tracingand if found not to have TB) Volunteers were eligible ashealthy controls if they passed a symptom screen andassessment of pulse and blood pressure They were ineligibleif they had lsquoany current sicknessrsquo cough angina fever or anyfebrile illness within the last week pulse gt120min systolicblood pressure gt180mmHg or diastolic blood pressure gt100mmHg The latter exclusions were to ensure safety for physicalexertion to perform 6MWT We did not ask minors aged lt18years to participate due to the requirement for them to attendthe clinic solely for research purposes and to undergo bloodtests and other procedures (in contrast to TB patients needingto attend the clinic anyway) especially given potentialdifficulties in locating a parentguardian to provide consent

Ethics statementThe study was approved by the Human Research Ethics

Committees of Menzies School of Health Research DarwinAustralia and the National Institute for Health Research andDevelopment Jakarta Indonesia Written informed consentwas obtained from the participant (and guardian if theparticipant was aged lt18 years) after discussion in Indonesianor a relevant Papuan language aided by pictorial and writteninformation

SettingTimika in southern Papua Province Indonesia population

~200000 comprises approximately half Indigenous Papuansand half Non-Papuan Indonesians Papua is relativelydisadvantaged within Indonesia having higher TB(311100000 [19]) and HIV rates [20] Population HIVseroprevalence among Papuans was estimated at 24 in2006 [21] Indonesian smoking rates have been estimated at67 of men and 45 of women [22] Traditional Papuans useindoor wood fires for cooking and heating however Papuansliving in the urban setting of Timika no longer tend to live intraditional huts with internal cooking fires In a previous study inTimika [8] exposure to indoor smoke was not found to beassociated with pulmonary function (unpublished data)

Morbidity and Residual Disability in Pulmonary TB


Definitions and ProceduresSymptoms were assessed at each visit using a

comprehensive checklist AE were defined in keeping withGood Clinical Practice (GCP) as any serious or non-seriousuntoward medical occurrence which had not been noted atbaseline regardless of perceived relatedness to medications orto TB [23] Such an occurrence reported at least once at anytime during TB treatment was documented as an AE Inkeeping with national practice liver function tests were notroutinely monitored [24] All participants were offered HIVtesting on venous blood using rapid point-of-care testsAnaemia was defined as gt135 gdL in males gt115 gdL infemales Where malaria co-infection was suspected diagnosiswas by blood film Sputum stained using the Ziehl-Neelsenmethod was examined for acid fast bacilli at the Timika fieldlaboratory weekly for 8 weeks then at weeks 20 and 24Treatment outcome was categorised as successful if thepatient successfully completed or was cured (smear-negativein the last month of treatment and on at least one previousoccasion) [25]

Postero-anterior chest radiographs were scored according toa previously-reported method the Timika TB x-ray score [26]The Indonesian Modified SGRQ was used to assess QoL thishas previously been tested in PTB patients in Timika [8] Ascore of 0 indicates no lung-related QoL impairment 100represents severe impairment A change of 4 units isconsidered clinically significant [27] Pulmonary function (forcedvital capacity [FVC] and forced expiratory volume in 1 second[FEV1]) was measured using a handheld spirometer(MicroLoopreg MicroMedical UK) with individual-use filteredone-way mouthpieces (Sure-Gardreg) The percentage ofpredicted FEV1 was calculated from previously-establishedlocal normal reference ranges [13] The 6-minute walk test(6MWT) was assessed on an outdoor track according toAmerican Thoracic Society guidelines [28] A lsquolearning effectrsquo of5-12 is recognised in serial 6MWT performed approximately20 minutes apart [2930] but such an effect is unlikely to beseen when tests were separated by at least 4 weeks as hereand if present would bias the interpretation of residualdisability results towards the null Lung function impairmentcategories were defined as normal ge80 predicted FEV1 mildlung function impairment 70-79 predicted moderate 60-69Moderate-severe 50-59 severe 35-49 very severe lt35[31] Pulmonary function 6MWT and the SGRQ wereundertaken at baseline then at 0 4 8 and 24 weeks and chestradiographs at 0 8 and 24 weeks Pulmonary function 6MWTand SGRQ scores at 6 months were used to assess of thepresence of residual disability

Statistical methodsAnalyses were undertaken using Stata 121 StataCorp

Texas USA To calculate adverse event rates participantswho attended less than half of the scheduled follow upappointments (lt6) were excluded Age was grouped as le35 orgt35 years where required since age gt35 is associated withhigher AE risks in active [4] or latent [3233] TB treatment Tocalculate percentage changes over time in serial measuresparticipants for whom results were unavailable at baseline or 6

months were excluded Proportions were compared using Chi-squared test or Fisherrsquos exact test where necessary Fortesting associations between continuous and categoricalvariables Studentrsquos 2-sample T test or Wilcoxon rank sum testwere used depending on the distribution For testingassociations between two continuous variables univariableand multivariable regression models were used if variableswere normally distributed or Spearmanrsquos Rho and correlationmatrices with Bonferroni correction for multiple comparisons ifnon-normally distributed and not amendable to transformationMultivariable models were constructed using a backwardsstepwise approach Variables included in the initial model werethose significantly associated in univariable analysis with theindependent variable or plausibly related to the independentvariable All tests were two-sided with a P value lt005considered to be statistically significant

Results

Study participants and healthy volunteers were enrolled fromJune 2008 to February 2010 as described elsewhere[173435] Data from all 200 participants included in theoverall trial are included here [36] Compared with TB patientsvolunteers were adequately matched according to sex ageethnicity and height but had higher body weight as expected(Table 1)

Symptoms functional capacity and quality of lifeamong TB patients

PTB patients were most symptomatic and had greatestfunctional and QoL impairment at baseline as expected allmeasures significantly improved with TB treatment (Figures 1and 2) Almost 80 of people had a successful treatmentoutcome (Table 1) However no measures other than sputummicrobiology showed complete normalisation by 6 monthsDespite rapid resolution of fever lethargy headache anddizziness other symptoms while mostly decreasing over timeremained well-represented with over half the participants still

Table 1 Participant characteristics

TB patient Healthy volunteerP valuen 200 40

Age in years median (IQR) 28 (23-365) 265 (235-33) 07

Female number () 69 (345) 9 (225) 01

Papuan number () 89 (445) 20 (500) 05Female number () 29 (326) 6 (300) 10

Current or ex-smoker number () 109 (55) 19 (48) 04

Height in metres mean (SE) 161 (001) 158 (001) 008

Weight in kg mean (SE) 625 (163) 485 (054) lt00001

Successful TB treatment outcome(curedcompleted)

146186 (79) - -

Multidrug-resistant TB 2149 (13) - - Outcome category and culture and susceptibility results were unavailable in someparticipantsdoi 101371journalpone0080302t001



having respiratory symptoms at treatment completion (Figure1) Musculoskeletal symptoms (chiefly arthralgia) easedinitially then increased up until week 8 before decreasingagain this was frequently attributed by clinical staff topyrazinamide Baseline symptoms were un-associated withage sex ethnicity or HIV status (data not shown)

Functional capacity (6MWT percent predicted FEV1) QoL(SGRQ) and chest X-ray results are shown in Figure 2 Thosewho were most unwell walked very short distances creating askewed distribution in 6MWT data (Figure 2A) All participantsincluded in this study were ambulant as they were allmanageable in an outpatient setting (needing to be able to walkinto the clinic) but the most unwell had very limited exercisetolerance being only able to walk minimal distances Fourpeople walked for only 55 metres or less stopping well before6 minutes and another 9 people could only walk for 200m orless 6MWT predicted FEV1 and SGRQ were each stillsignificantly worse among PTB patients at treatmentcompletion than in the healthy controls Only small percentageimprovements were achieved in predicted FEV1 and 6MWT(148 and 147 respectively) by TB patients over the 6months by 6 months 27 of TB patients still had at leastmoderate-severe pulmonary function impairment (Figure 2B)More substantial improvements occurred in serial SGRQ andTimika TB x-ray scores (Figures 2C and D) The medianFEV1FVC ratio was gt070 (not suggestive of an obstructivepattern [37]) and did not differ between TB patients at baseline(087 range 051-100) and controls (086 range 069-099)Nine TB patients (45) and 1 control (45) had FEV1FVCratio lt070

Predictors of residual disabilityIn univariable analyses HIV+ status was significantly

associated with worse QoL (SGRQ) and shorter 6MWT at 6months the length of patient-reported diagnostic delay prior totreatment commencement (lsquoillness durationrsquo) was significantlyassociated with residual lung function impairment x-ray scoreand weight at 6 months baseline Timika TB x-ray score wassignificantly associated with final x-ray score and lung functionimpairment at 6 months (Table 2) No other significantassociations between baseline demographicclinical variablesand 6-month outcomes were identified In multivariable modelsHIV status was no longer associated with 6WMT and theassociations between illness duration and 6-month outcomeswere attenuated (Table 2)

Establishment of local normal reference rangesThe healthy volunteers had a mean 6MWT distance of

497plusmn63m (range 360-640m) Males walked further thanfemales no significant difference in distance was observedbetween ethnic groups (Table 3 Figure 3A) Modified SGRQscores (total and individual domains) were obtained in 35volunteers the median total score being 0 (range 0-923)(Table 3 Figure 3B) with no differences between sex or ethnicgroups in total or domain scores

Intercurrent illnessAmong the 200 study participants with PTB there were 2237

clinical reviews (on average 11 appointments per participant)Nineteen participants (13) were HIV positive (also reported in[20]) One hundred thirty three (55) had anaemia at baselinewhich had decreased to 26 of people by week 24 [35]Twenty two episodes of malaria were recorded in this region ofunstable malaria transmission [38] 8 Plasmodium falciparum 8Plasmodium vivax 6 unspecified These included threePapuan individuals (2 males 1 female) who each had 2discreet episodes of fever with different malarial speciesreported on blood films (P falciparum then Pvivax or viceversa) at intervals of 4 8 and 13 weeks respectively Anadditional 11 people had symptoms consistent with malaria butnegative blood films

Adverse EventsTwo participants had TB medications withheld or ceased due

to AE 1 due to rash (attributed to both pyrazinamide andethambutol) the other due to vomiting (attributed to rifampicin)Excluding participants who attended lt6 follow upappointments the proportions who experienced AE duringfollow up are shown in Table 4 and Figure 4 Participants whoattended lt6 follow up appointments did not differdemographically or clinically from those who attended ge6appointments (data not shown) Commonest AE were itch andarthrlagia Few predictors of AE were identified itch was morecommon in people aged gt35 than those le35 years nauseawas more common but diarrhoea less common in people ofNon-Papuan than Papuan ethnicity vomiting was morecommon in females than males

Discussion

We have shown high morbidity and residual disabilityamongst ambulatory outpatient PTB patients in whomtreatment outcomes were mostly considered successful and

Figure 1 Proportion of participants reporting symptomsat enrolment and during each week of follow up doi 101371journalpone0080302g001



Figure 2 Functional radiological and quality of life measures Data shown only for participants who had measures performedboth at enrolment of 6 months (numbers shown in brackets)A 6 minute walk test (n=107)B Percentage of predicted forced expiratory volume in 1 second (n=112)C St Georgersquos respiratory questionnaire total score (n=76)D X-ray score (n=73)doi 101371journalpone0080302g002



drug-resistant TB rates were low (Table 1) After 6 months oftreatment the majority of participants had impaired functionalor QoL scores compared to the average healthy control aquarter had at least moderate-to-severe pulmonary functionimpairment (Figure 2B) and 57 of study participants still hadrespiratory symptoms (Figure 1) Thus 6-month residualdisability especially that assessed using objective functionalmeasures (6MWT and pulmonary function) is very prevalent inthis setting after the standard duration of treatment for PTBPeople with advanced disease at baseline (prolongeddiagnostic delay or advanced x-ray changes) and those withHIV were most likely to suffer residual disability (Table 2)emphasising the critical importance of early diagnosis andtreatment initiation and optimised management of HIV co-infection [20] Our findings are supported by previousinvestigations calling for recognition in the calculation of TB-related QALYs that TB-related morbidity does not stop after 6months [38]

Table 2 Associations between baseline measures andresidual disability at 6 months

Baseline variable Six-month outcome p value

HIV status Six-month St Georgersquos RespiratoryQuestionnaire total score median (IQR)

HIV- 325 units (172-718) 002 HIV+ 158 units (701-292)

Six-month Six-minute walk test median(IQR)

HIV- 480m (425-520) 06 HIV+ 440m (420-475)

Illness duration(diagnostic delay) priorto commencingtreatmentdagger

Six-month Weight mean (SD)

Illness duration le3 monthsDagger 545kg (84) 004 Illness duration gt3 months 511kg (73) Six-month X-ray score median (IQR) Illness duration le3 months 6 units (2-14) 005 Illness duration gt3 months 19 units (6-65) Six-month Predicted FEV1 mean (SD) Illness duration le3 months 754 (158) 006 Illness duration gt3 months 629 (183)

X-ray score at treatmentcommencementdagger

Six-month X-ray score median (IQR)

X-ray score le70Dagger 5 units (1-11) lt00001 X-ray score gt70 105 units (2-19) Six-month Predicted FEV1 mean (SD) X-ray score le70 782 (133) lt00001 X-ray score gt70 642 (191) p values calculated using multivariable logistic regressiondagger p values calculated using pairwise correlation between continuous variables withBonferroni correction for multiple comparisonsDagger continuous explanatory variables have been dichotomised to illustratedifferencesdoi 101371journalpone0080302t002

It is possible that at least some pulmonary impairmentamong TB patients was pre-existing and that pulmonarydisability at 6 months reflected their pre-TB level of functionespecially given that smoking and COPD are risk factors forTB However based on our findings here and previous studies[310] it is very plausible that the added burden of pulmonaryimpairment attributable to TB which was at least partlyreversible contributed to the large disparity between TBpatients at treatment completion and controls Also the factremains that at TB treatment completion patients still haveimportant ongoing health care requirements related to lungdisease be they pre-existing or resulting from the PTB We didnot collect data on exposure to indoor air pollution from cookingfires however this would have affected Papuansdisproportionally compared with Non-Papuans who do nottraditionally use indoor fires whereas we found no difference inlung function impairment in the ethnic groups

Adverse event rates in this study are much higher thanreported elsewhere although medication cessation due to AEwas uncommon AE rates vary widely among different studies(Table 4) potentially attributable to differing study designs AEdocumentation method average participant age andthresholds among staff and patients to tolerate adverse effectsbefore reporting them or withholding medications Muchliterature only reports TB drug side-effects serious enough torequire drug cessation [4-639] Our high rates of non-seriousAE might relate to the particular GCP definition used (seeMethods) [23] that participants were actively questioned aboutsymptoms at each visit cultural factors among staff and

Table 3 Normal reference ranges for 6 minute walk testand modified (Indonesian) St Georgersquos RespiratoryQuestionnaire in Timika Papua Indonesia

All Male Female PapuanNon-Papuan

St GeorgersquosRespiratoryQuestionnaire(Units) median(range)

Symptom score 0 (0-2151) 0 (0-2151) 0 (0-1239)0 (0-2151)

0 (0-1307)

Activity score 0 (0-1278) 0 (0-1274) 0 (0-1278)0 (0-1278)

0 (0-0)

Impact score 0 (0-151) 0 (0-151) 0 (0-373)0 (0-887)

0 (0-151)

Total score 0 (0-923)086(0-923)

0 (0-797)188 (0-797)

0 (0-923)

6-minute walktest (m) mean(SD)dagger

497 (63) 511 (60) 477 (46) 503 (58) 490 (69)

6MWD and total SGRQ score summary statistics in these healthy controlswithout sex or ethnic group breakdown have been previously cited [34]dagger 6-minute walk test male vs female p=0006 No other significant differences inSGRQ or 6MWT between sex or ethnic groupsdoi 101371journalpone0080302t003



patients regarding symptom documentation and intercurrentillness Other researchers use tighter definitions of AE (egevents lsquopossibly or probably related to treatmentrsquo [40])Regardless of the aetiology of documented AE in this studythese data offer a real-world perspective on the high burden ofillness suffered during a 6-month period by people undergoingTB treatment in a low-resource setting This is likely to begeneralisable to other TB-endemic settings but may passunrecognised if only sputum microscopy chest x-ray andweight are tracked or if only severe symptoms or thosedetected passively are reported Awareness of non-serious AEis important regarding their potential impact on adherenceeven in directly-observed treatment (DOT) programs sincelsquoDOTrsquo may comprise weekly or in the continuation phasemonthly clinic supervision with opportunities for incompleteadherence between appointments if AE are present

Increasing age is recognised to be a major risk factor forserious TB medication side effects (chiefly isoniazid-relatedhepatotoxicity)[4323339] and female sex is also identified asan occasional predictor of serious adverse event risk [439]We did not find consistent associations between these or otherfactors and the occurrence of non-serious AE (Figure 4)

We established normal reference ranges for 6MWT andSGRQ in this population for the first time The healthy Timikavolunteers walked a substantially shorter mean distance(497m) than healthy people elsewhere (571-659m [294142])Factors other than sex and anthropometric differences arebelieved to influence 6MWT results including cultural normsregarding usual walking pace mood the motivation of the

subject andor technician and characteristics of the providedwalking track [41] Short stature and the ambient heat andhumidity may also have contributed to the low 6MWTs hereThe SGRQ results were lower (better) among volunteers in thisstudy (median 0 units Table 3 Figure 1) compared with otherhealthy populations in whom overall mean scores of 12 [43]and 967 [44] have been reported The younger ages ofcontrols in this study may explain the difference but localexpectations regarding personal health and wellbeing may alsobe important Thus the establishment of locally-relevantreference ranges is especially important for both 6MWT andSGRQ for men and women of both ethnic groups

Compared with controls exercise capacity was poor in TBpatients including at treatment completion Improvement overtime was only 147 the same improvement as observed inpredicted FEV1 This simple and inexpensive test offunctional capacity has been previously tested in TB [845] butwithout comparison with controls High SGRQ among TBpatients indicated substantially impaired QoL at baseline butmajor improvement occurred over time As in the controlsSGRQ scores in TB patients in this study (total score median369 units) are similar to or better than previously reported inTB We previously reported a mean total SGRQ score of 454in Timika PTB patients at diagnosis [8] A mean score of 235was reported in a study of post-TB QoL in the USA [14]whereas our study participants had a median score of 41 attreatment completion (Figure 4B) Our TB participantsexperienced an overall decrement of gt30 points a major (87)improvement Thus despite their limitations in 6MWT and FEV1

Figure 3 References ranges in healthy volunteers A Six minute walk testB St Georgersquos Respiratory Questionnairedoi 101371journalpone0080302g003



and persisting symptoms and despite the SGRQ result still notrecovering to that seen in their healthy counterparts PTBpatients in this study nevertheless perceived their QoL to berelatively good by 6 months This could be a reason for treating

Table 4 Adverse event rates in a range of study types andlocations

AdverseEvent Proportion Rate

Studyparticipantmean ormedian age(years) Study type Reference

Arthralgia

Non-severe 71123 58 28Prospectiveobservational

This studyIndonesia2013

44165dagger 27 31Randomisedtrial

Burman et alAfrica andNorthAmerica2006 [47]

SevereDagger 13519 2 44Retrospectiveobservational

Schaberg etal Germany1996 [5]

Nausea


This study

15165 9 31Randomisedtrial

[47]

124 4 33Randomisedtrial in multi-drugresistant TB

Diacon et alSouth Africa2009 [48]

Severe 5519 09 44Retrospectiveobservational

[5]

Rash


This study


[5]

18430 4 40Retrospectiveobservational

Yee et alCanada 2003[4]

Vomiting


This study


[47]


[48]

Diarrhoea


This study


[47]


[48]

clinicians to under-appreciate the extent of objective residualdisability if they use subjective assessments (asking patients ifthey feel better) In an environment such as Papua whereburden of disease is high [46] reported wellness may be higherin the setting of low-grade symptoms or functional limitationscompared with people in more affluent settings with differentexpectations about their health

We did not find an association between smoking andincreased risk of post-TB residual disability for which therecould be several explanations Smoking cessation may bemore common in those susceptible to the adverse effects ofsmoking including those with more advanced PTB andsmoking may be more available to those of higher economicstatus Indeed a lsquohealthy smokerrsquo effect has been noted in thisenvironment before [8] The young age of the majority ofpatients may mean low opportunity for established smoking-related lung damage to have developed supported by thefinding that airways obstruction (FEV1FVC ratio lt07) wasuncommon The fact that smoking rates were high (76 ofmales were current or ex-smokers) meant that the sample sizeof non-smokers for comparison was small

A possible limitation of the study is recall bias which couldaffect recollection of illness duration prior to TB treatment orsymptoms which occurred since the last appointment Howeverthe prospective nature of the study minimises recall bias for

Table 4 (continued)



Temporaryorpermanentcessation ofTBmedicationdue toadverseevent

2200 1 28Prospectiveobservational

This study


[47]


[48]


[5]


Gulbay et alTurkey 2006[6]

For the current study denominators are the subset of the 200 patients who hadge6 follow up visits and did not have that symptom at baselinedagger For randomised trials adverse event rates are given for the standard-treatmentarm where a novel comparison arm was usedDagger Severe = requiring drug cessationdoi 101371journalpone0080302t004



Figure 4 Adverse event rates during TB treatment doi 101371journalpone0080302g004



most measures Not all participants attended all appointmentsbut we restricted serial analyses to those for whom serialresults were available Hepatoxicity was not assessed due toliver function not being routinely tested in this setting multipleother studies have previously examined rates of and riskfactors for hepatotoxicity and our intention was to focus onneglected and non-severe events in particular symptomswhich can be assessed inexpensively The modest number ofcontrol subjects means that the healthy reference ranges maynot be completely representative of the larger population butreassuringly our controls showed similar pulmonary function to107 previously-studied people in Timika from whom predictedFEV1 data were obtained [13] however 6MWT and SGRQwere not tested in the previous study

We have shown that standard PTB treatment is highlysuccessful in reducing symptoms improving functionalcapacity and enhancing quality of life as expected Howeverour study reveals the extent of the morbidity which persists attreatment completion which would be overlooked if onlyroutine tests (sputum and chest x-rays) were performedAssigning a lsquosuccessfulrsquo treatment outcome to a patient whohas been microbiologically cured ignores their functional stateMorbidity is likely to be underestimated both by treatingclinicians and by patients if objective functional measures arenot performed Patients here reported major improvements inwell-being by 6 months compared to how sick they had been atdiagnosis but may have persisting impairment lifelong[37-1114] At a global level calculations of PTB-relatedburden of disease should take this into account At theindividual level people who are lsquocuredrsquo of pulmonary TB may

still have important health care requirements relating toresidual lung disease understanding residual disability couldassist in planning ongoing patient care including anti-smokingvaccination (pneumococcal and influenza) and pulmonaryrehabilitation advice where this exists Our findings emphasisethe key importance of early case detection and treatment toreduce the likelihood of residual impairment

Acknowledgements

We greatly thank the Timika District Health Authority forsupporting the study DB Lolong and the National Institute ofHealth Research and Development Jakarta P Penttinen MBangs and M Stone Public Health amp Malaria Control (PHMC)and International SOS Bapak Istanto and PHMC laboratorystaff J Lempoy and Timika TB clinic staff P Sugiarto EMalonda and Mimika Community Hospital (RSMM) DLampah Prayogo Ferryanto Chalfein ND Haryanti SHasmunik S Rahayu G Bellatrix and clinical and laboratorystaff Timika Research Facility R Soemanto and Y Rukminiati(University of Indonesiarsquos Faculty of Microbiology) membersand K Piera and E Curry (MSHR) We thank P Glaziou forhelpful discussions about burden of disease calculations

Author Contributions

Conceived and designed the experiments PMK NMA GPMAPR EK S ET Performed the experiments APR GW GJP EKAnalyzed the data APR Wrote the manuscript APR GPMPMK NMA Facilitated the study EK S ET

References

1 Sassi F (2006) Calculating QALYs comparing QALY and DALYcalculations Health Policy Plan 21 402-408 doi101093heapolczl018 PubMed 16877455

2 World Health Organisation (2011) Methods used to estimate the burdenof disease caused by TB Annex 1 global TUBERCULOSIS Report2012

3 Pasipanodya JG McNabb SJ Hilsenrath P Bae S Lykens K et al(2010) Pulmonary impairment after tuberculosis and its contribution toTB burden BMC Public Health 10 259 doi1011861471-2458-10-259 PubMed 20482835

4 Yee D Valiquette C Pelletier M Parisien I Rocher I et al (2003)Incidence of serious side effects from first-line antituberculosis drugsamong patients treated for active tuberculosis Am J Respir Crit CareMed 167 1472-1477 doi101164rccm200206-626OC PubMed12569078

5 Schaberg T Rebhan K Lode H (1996) Risk factors for side-effects ofisoniazid rifampin and pyrazinamide in patients hospitalized forpulmonary tuberculosis Eur Respir J 9 2026-2030 doi101183090319369609102026 PubMed 8902462

6 Guumllbay BE Guumlrkan OU Yildiz OA Onen ZP Erkekol FO et al (2006)Side effects due to primary antituberculosis drugs during the initialphase of therapy in 1149 hospitalized patients for tuberculosis RespirMed 100 1834-1842 doi101016jrmed200601014 PubMed16517138

7 Hnizdo E Singh T Churchyard G (2000) Chronic pulmonary functionimpairment caused by initial and recurrent pulmonary tuberculosisfollowing treatment Thorax 55 32-38 doi101136thorax55132PubMed 10607799

8 Maguire GP Anstey NM Ardian M Waramori G Tjitra E et al (2009)Pulmonary tuberculosis impaired lung function disability and quality oflife in a high-burden setting Int J Tuberc Lung Dis 13 1500-1506PubMed 19919767

9 Menezes AM Hallal PC Perez-Padilla R Jardim JR Muintildeo A et al(2007) Tuberculosis and airflow obstruction evidence from the

PLATINO study in Latin America Eur Respir J 30 1180-1185 doi1011830903193600083507 PubMed 17804445

10 Pasipanodya JG Miller TL Vecino M Munguia G Garmon R et al(2007) Pulmonary impairment after tuberculosis Chest 1311817-1824 doi101378chest06-2949 PubMed 17400690

11 Salvi SS Barnes PJ (2009) Chronic obstructive pulmonary disease innon-smokers Lancet 374 733-743 doi101016S0140-6736(09)61303-9 PubMed 19716966

12 Plit ML Anderson R Van Rensburg CE Page-Shipp L Blott JA et al(1998) Influence of antimicrobial chemotherapy on spirometricparameters and pro-inflammatory indices in severe pulmonarytuberculosis Eur Respir J 12 351-356 doi101183090319369812020351 PubMed 9727784

13 Handojo T Anstey N Kelly P Pain M Kenangalem E et al (2006)Normal spirometry gas transfer and lung volume values in PapuaIndonesia - Southeast Asian J Trop Med Public Health 37 571-577

14 Pasipanodya JG Miller TL Vecino M Munguia G Bae S et al (2007)Using the St George respiratory questionnaire to ascertain healthquality in persons with treated pulmonary tuberculosis Chest 1321591-1598 doi101378chest07-0755 PubMed 17890471

15 Jones PW Quirk FH Baveystock CM Littlejohns P (1992) A self-complete measure of health status for chronic airflow limitation The StGeorges Respiratory Questionnaire Am Rev Respir Dis 1451321-1327 doi101164ajrccm14561321 PubMed 1595997

16 American Thoracic Society (2013) St Georges RespiratoryQuestionnaire (SGRQ) Available httpwwwthoracicorgassembliessrnquestionairessgrqphp Accessed 5 August 2013

17 Ralph AP Waramori G Pontororing GJ Kenangalem E Wiguna A etal (2013) L-arginine and Vitamin D adjunctive therapies in pulmonarytuberculosis a randomised double-blind placebo-controlled trialPLOS ONE 8 e70032 doi101371journalpone0070032 PubMed23967066



18 World Health Organisation (2002) Operational guide for the for nationaltuberculosis programs on the introduction and use of fixed-dosecombination drugs WHOCDSTB2002308

19 Ardian M Meokbun E Siburian L Malonda E Waramori G et al (2007)A public-private partnership for TB control in Timika Papua ProvinceIndonesia - Int J Tuberc Lung Dis 11 1101-1107

20 Pontororing GJ Kenangalem E Lolong DB Waramori G Sandjaja etal (2010) The burden and treatment of HIV in tuberculosis patients inPapua Province Indonesia a prospective observational study BMCInfect Dis 10 362 doi1011861471-2334-10-362 PubMed 21605474

21 Statistics Indonesia and the Ministry of Health (2006) Risk Behaviourand HIV Prevalence in Tanah Papua 2006 Results of the IBBS 2006 inTanah Papua Available httpsiteresourcesworldbankorgINTINDONESIAResourcesPublicationPapuaHIV_enpdf AccessedFebruary 2009

22 Campaign for Tobacco-Free Kids Indonesia (2010) Available httpglobaltobaccofreekidsorgenglobal_epidemicindonesia Accessed 20August 2013

23 Therapeutic Goods Administration (2000) Note for guidance on GoodClinical Practice (CPMPICH13595) annotated with TGA commentsCommonwealth Department of Health and Aged Care Available httpwwwtgagovauDOCSpdfeuguideichich13595pdf Accessed 1 May2013

24 Kesehatan Departemen Republik Indonesia (2007) Nasional PedomanPendenggulangan Tuberkulosis Edisi 2 Cetakan pertama JakartaIndonesia

25 World Health Organization International Union Against Tuberculosisand Lung Disease Royal Netherlands Tuberculosis Association (2001)(2001) Revised international definitions in tuberculosis control Int JTuberc Lung Dis 5 213-215 PubMed 11326818

26 Ralph AP Ardian M Wiguna A Maguire GP Becker NG et al (2010) Asimple valid numerical score for grading chest x-ray severity in adultsmear-positive pulmonary tuberculosis Thorax 65 863-869 doi101136thx2010136242 PubMed 20861290

27 Jones PW (2002) Interpreting thresholds for a clinically significantchange in health status in asthma and COPD Eur Respir J 19398-404 doi101183090319360200063702 PubMed 11936514

28 American Thoracic Society (2002) ATS statement guidelines for thesix-minute walk test Am J Respir Crit Care Med 166 111-117Available online at doi101164ajrccm1661at1102 PubMed12091180

29 Camarri B Eastwood PR Cecins NM Thompson PJ Jenkins S (2006)Six minute walk distance in healthy subjects aged 55-75 years RespirMed 100 658-665 doi101016jrmed200508003 PubMed16229997

30 Stevens D Elpern E Sharma K Szidon P Ankin M et al (1999)Comparison of hallway and treadmill six-minute walk tests Am J RespirCrit Care Med 160 1540-1543 doi101164ajrccm16059808139PubMed 10556117

31 Pellegrino R Viegi G Brusasco V Crapo RO Burgos F et al (2005)Interpretative strategies for lung function tests Eur Respir J 26948-968 doi101183090319360500035205 PubMed 16264058

32 Nolan CM Goldberg SV Buskin SE (1999) Hepatotoxicity associatedwith isoniazid preventive therapy a 7-year survey from a public healthtuberculosis clinic JAMA 281 1014-1018 doi101001jama281111014 PubMed 10086436

33 Kunst H Khan KS (2010) Age-related risk of hepatotoxicity in thetreatment of latent tuberculosis infection a systematic review Int JTuberc Lung Dis 14 1374-1381 PubMed 20937175

34 Ralph AP Yeo TW Salome CM Waramori G Pontororing GJ et al(2013) Impaired pulmonary nitric oxide bioavailability in pulmonarytuberculosis association with disease severity and delayed

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35 Kenangalem E Waramori G Pontororing GJ Sandjaja S Tjitra E et al(2013) Tuberculosis outcomes in Papua Indonesia the relationshipwith different body mass index characteristics between Papuan andnon-Papuan ethnic groups PLOS ONE 8 e76077 doi101371journalpone0076077 PubMed 24086690

36 Ralph AP Waramori G Pontororing GJ Kenangalem E Wiguna A etal (2013) L-arginine and Vitamin D Adjunctive Therapies in PulmonaryTuberculosis A Randomised Double-Blind Placebo-Controlled TrialPLOS ONE 8 e70032 doi101371journalpone0070032 PubMed23967066

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39 Ormerod LP Horsfield N (1996) Frequency and type of reactions toantituberculosis drugs observations in routine treatment Tuber LungDis 77 37-42 doi101016S0962-8479(96)90073-8 PubMed8733412

40 Ruslami R Nijland HM Alisjahbana B Parwati I van Crevel R et al(2007) Pharmacokinetics and tolerability of a higher rifampin doseversus the standard dose in pulmonary tuberculosis patientsAntimicrob Agents Chemother 51 2546-2551 doi101128AAC01550-06 PubMed 17452486

41 Casanova C Celli BR Barria P Casas A Cote C et al (2011) The 6-min walk distance in healthy subjects reference standards from sevencountries Eur Respir J 37 150-156 doi1011830903193600194909PubMed 20525717

42 Miyamoto S Nagaya N Satoh T Kyotani S Sakamaki F et al (2000)Clinical correlates and prognostic significance of six-minute walk test inpatients with primary pulmonary hypertension Comparison withcardiopulmonary exercise testing Am J Respir Crit Care Med 161487-492 doi101164ajrccm16129906015 PubMed 10673190

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Introduction

The morbidity experienced by people with pulmonarytuberculosis (PTB) can be evaluated using measures such aspulmonary function testing quality of life questionnaires andassessment of treatment complications Quality-adjusted lifeyear calculations (QALY) which provide a measure of theburden of tuberculosis (TB)-related disease couldunderestimate true PTB morbidity if they assume a shortdisease duration [12] or do not incorporate long-termpulmonary disability resulting from permanent lung damage [3]Under-estimates in morbidity arising from TB disease or TBmedications may also occur in clinical or research settings inwhich passive reporting of symptoms is relied upon or in whichonly serious adverse effects (requiring medication cessation[4-6]) are captured The requirement for strict adverse eventreporting in clinical trials provides an important opportunity togather detailed information about symptoms experiencedduring TB treatment

TB is a well-recognised independent risk factor for chronicobstructive pulmonary disease (COPD) [7-11] Both earlyreversible lung impairment in pulmonary TB [812] and longer-term residual impairment after TB [810] are evaluable usingspirometric measures such as percentage of predicted forcedexpiratory volume in 1 second (FEV1) We have previouslyreported high rates of residual pulmonary disability in PTBpatients in eastern Indonesia [8] At treatment completion aquarter of successfully-treated patients still had significant lungfunction impairment (FEV1lt60 predicted using local healthyvolunteers as the reference population for calculation ofpercentage of predicted FEV1 [13]) Late residual pulmonarydisability has been reported by Pasipanodya et al showing thatpeople with previous active TB were 54 times more likely tohave abnormal pulmonary function than people withoutprevious active tuberculosis [10]

Quality of life questionnaires can also reveal a fuller scope ofPTB morbidity than is obtainable from standard severitymeasures such as sputum microscopy grade or radiologicaldisease extent The St Georgersquos Respiratory Questionnaire(SGRQ) has been shown to be an effective tool for measuringPTB morbidity [14] The SGRQ is a respiratory health-relatedquality of life (QoL) instrument formulated for use in COPD[1516] but validated in TB [814] and other respiratorydiseases It has been translated into many languages includingIndonesian [16] with minor modifications for local suitability

This study was performed within the context of a clinical trialof nutritional interventions where detailed information onsymptoms intercurrent illness and disease burden wascollected In order to gain an holistic understanding of thescope of morbidity during TB treatment in an outpatientresource-limited high TB-burden setting our objectives in thispaper were to investigate morbidity at baseline and duringfollow up (symptoms Adverse Events [AE] functional capacityand QoL) and residual disability at 6 months experienced byadults with PTB We furthermore sought to identify predictors ofresidual disability and compare functional and QoL measuresin PTB with reference ranges established from locally-recruitedhealthy controls

Methods

This study was performed within a clinical trial of adjunctivenutritional supplements (L-arginine and vitamin D) for PTB(clinicaltrialsgovNCT00677339) In this study theinterventions did not significantly affect outcome measuresincluding AE [17] Eligible sequential study participants withPTB who had no previous history of treatment were enrolled atthe tuberculosis clinic in Timika Indonesia Inclusion criteriaincluded age ge15 years sputum smear-positive for acid fastbacilli (AFB) and provision of written informed consent Thestandard 6-month tuberculosis treatment regimen [18] wasadministered in a directly observed fashion

Local healthy controls were eligible if they were aged ge18years gave written informed consent and had no co-morbidities Volunteers were approached via communitycontacts and social groups from among friends and relatives ofstaff members or patients (after undergoing TB contact tracingand if found not to have TB) Volunteers were eligible ashealthy controls if they passed a symptom screen andassessment of pulse and blood pressure They were ineligibleif they had lsquoany current sicknessrsquo cough angina fever or anyfebrile illness within the last week pulse gt120min systolicblood pressure gt180mmHg or diastolic blood pressure gt100mmHg The latter exclusions were to ensure safety for physicalexertion to perform 6MWT We did not ask minors aged lt18years to participate due to the requirement for them to attendthe clinic solely for research purposes and to undergo bloodtests and other procedures (in contrast to TB patients needingto attend the clinic anyway) especially given potentialdifficulties in locating a parentguardian to provide consent

Ethics statementThe study was approved by the Human Research Ethics

Committees of Menzies School of Health Research DarwinAustralia and the National Institute for Health Research andDevelopment Jakarta Indonesia Written informed consentwas obtained from the participant (and guardian if theparticipant was aged lt18 years) after discussion in Indonesianor a relevant Papuan language aided by pictorial and writteninformation

SettingTimika in southern Papua Province Indonesia population

~200000 comprises approximately half Indigenous Papuansand half Non-Papuan Indonesians Papua is relativelydisadvantaged within Indonesia having higher TB(311100000 [19]) and HIV rates [20] Population HIVseroprevalence among Papuans was estimated at 24 in2006 [21] Indonesian smoking rates have been estimated at67 of men and 45 of women [22] Traditional Papuans useindoor wood fires for cooking and heating however Papuansliving in the urban setting of Timika no longer tend to live intraditional huts with internal cooking fires In a previous study inTimika [8] exposure to indoor smoke was not found to beassociated with pulmonary function (unpublished data)









Results







Female number () 69 (345) 9 (225) 01






146186 (79) - -














Discussion














HIV- 480m (425-520) 06 HIV+ 440m (420-475)












Symptom score 0 (0-2151) 0 (0-2151) 0 (0-1239)0 (0-2151)

0 (0-1307)

Activity score 0 (0-1278) 0 (0-1274) 0 (0-1278)0 (0-1278)

0 (0-0)

Impact score 0 (0-151) 0 (0-151) 0 (0-373)0 (0-887)

0 (0-151)

Total score 0 (0-923)086(0-923)

0 (0-797)188 (0-797)

0 (0-923)


497 (63) 511 (60) 477 (46) 503 (58) 490 (69)
















Arthralgia







Nausea


This study


[47]




[5]

Rash


This study


[5]



Vomiting


This study


[47]


[48]

Diarrhoea


This study


[47]


[48]




Table 4 (continued)





This study


[47]


[48]


[5]












Acknowledgements




References





























































Results







Female number () 69 (345) 9 (225) 01






146186 (79) - -














Discussion














HIV- 480m (425-520) 06 HIV+ 440m (420-475)












Symptom score 0 (0-2151) 0 (0-2151) 0 (0-1239)0 (0-2151)

0 (0-1307)

Activity score 0 (0-1278) 0 (0-1274) 0 (0-1278)0 (0-1278)

0 (0-0)

Impact score 0 (0-151) 0 (0-151) 0 (0-373)0 (0-887)

0 (0-151)

Total score 0 (0-923)086(0-923)

0 (0-797)188 (0-797)

0 (0-923)


497 (63) 511 (60) 477 (46) 503 (58) 490 (69)
















Arthralgia







Nausea


This study


[47]




[5]

Rash


This study


[5]



Vomiting


This study


[47]


[48]

Diarrhoea


This study


[47]


[48]




Table 4 (continued)





This study


[47]


[48]


[5]












Acknowledgements




References

































































Discussion














HIV- 480m (425-520) 06 HIV+ 440m (420-475)












Symptom score 0 (0-2151) 0 (0-2151) 0 (0-1239)0 (0-2151)

0 (0-1307)

Activity score 0 (0-1278) 0 (0-1274) 0 (0-1278)0 (0-1278)

0 (0-0)

Impact score 0 (0-151) 0 (0-151) 0 (0-373)0 (0-887)

0 (0-151)

Total score 0 (0-923)086(0-923)

0 (0-797)188 (0-797)

0 (0-923)


497 (63) 511 (60) 477 (46) 503 (58) 490 (69)
















Arthralgia







Nausea


This study


[47]




[5]

Rash


This study


[5]



Vomiting


This study


[47]


[48]

Diarrhoea


This study


[47]


[48]




Table 4 (continued)





This study


[47]


[48]


[5]












Acknowledgements




References
































































HIV- 480m (425-520) 06 HIV+ 440m (420-475)












Symptom score 0 (0-2151) 0 (0-2151) 0 (0-1239)0 (0-2151)

0 (0-1307)

Activity score 0 (0-1278) 0 (0-1274) 0 (0-1278)0 (0-1278)

0 (0-0)

Impact score 0 (0-151) 0 (0-151) 0 (0-373)0 (0-887)

0 (0-151)

Total score 0 (0-923)086(0-923)

0 (0-797)188 (0-797)

0 (0-923)


497 (63) 511 (60) 477 (46) 503 (58) 490 (69)
















Arthralgia







Nausea


This study


[47]




[5]

Rash


This study


[5]



Vomiting


This study


[47]


[48]

Diarrhoea


This study


[47]


[48]




Table 4 (continued)





This study


[47]


[48]


[5]












Acknowledgements




References



































































Arthralgia







Nausea


This study


[47]




[5]

Rash


This study


[5]



Vomiting


This study


[47]


[48]

Diarrhoea


This study


[47]


[48]




Table 4 (continued)





This study


[47]


[48]


[5]












Acknowledgements




References





























































Acknowledgements




References























































High Morbidity during Treatment and Residual Pulmonary Disability in Pulmonary Tuberculosis:...

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