High Morbidity during Treatment and Residual Pulmonary

Disability in Pulmonary Tuberculosis: Under-Recognised

Phenomena
Anna P. Ralph1,2*, Enny Kenangalem3,4, Govert Waramori5, Gysje J. Pontororing3, Sandjaja6, Emiliana
Tjitra6, Graeme P. Maguire7,8, Paul M. Kelly9,10, Nicholas M. Anstey1,2
1 Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Northern Territory, Australia, 2 Department of
Infectious Diseases, Division of Medicine, Royal Darwin Hospital, Northern Territory, Australia, 3 Menzies School of Health Research-National Institute of Health
Research and Development Research Program, Timika, Papua Province, Indonesia, 4 District Health Authority, Timika, Papua Province, Indonesia, 5 Public
Health & Malaria Control Department, PT Freeport Indonesia, Timika, Papua Province, Indonesia, 6 National Institute of Health Research and Development,
Jakarta, Indonesia, 7 Baker IDI Heart and Diabetes Institute, Alice Springs, Northern Territory, Australia, 8 School of Medicine and Dentistry, James Cook
University, Cairns, Queensland, Australia, 9 Population Health Division, ACT Government Health Directorate, Canberra, Australian Capital Territory, Australia,
10 Australian National University Medical School, Canberra, Australian Capital Territory, Australia

Abstract
Background: In pulmonary tuberculosis (PTB), morbidity during treatment and residual pulmonary disability can be
under-estimated.
Methods: Among adults with smear-positive PTB at an outpatient clinic in Papua, Indonesia, we assessed morbidity
at baseline and during treatment, and 6-month residual disability, by measuring functional capacity (six-minute walk
test [6MWT] and pulmonary function), quality of life (St Georges Respiratory Questionnaire [SGRQ]) and Adverse
Events ([AE]: new symptoms not present at outset). Results were compared with findings in locally-recruited
volunteers.
Results: 200 PTB patients and 40 volunteers were enrolled. 6WMT was 497m (interquartile range 460-529) in
controls versus 408m (IQR 346-450) in PTB patients at baseline (p<0.0001) and 470m (IQR 418-515) in PTB
patients after 6 months (p=0.02 versus controls). SGRQ total score was 0 units (IQR 0-2.9) in controls, versus 36.9
(27.4-52.8) in PTB patients at baseline (p<0.0001) and 4.3 (1.7-8.8) by 6 months (p<0.0001). Mean percentage of
predicted FEV1 was 92% (standard deviation 19.9) in controls, versus 63% (19.4) in PTB patients at baseline
(p<0.0001) and 71% (17.5) by 6 months (p<0.0001). After 6 months, 27% of TB patients still had at least moderatesevere pulmonary function impairment, and 57% still had respiratory symptoms, despite most achieving successful
treatment outcomes, and reporting good quality of life. More-advanced disease at baseline (longer illness duration,
worse baseline X-ray) and HIV positivity predicted residual disability. AE at any time during treatment were common:
itch 59%, arthralgia 58%, headache 40%, nausea 33%, vomiting 16%.
Conclusion: We found high 6-month residual pulmonary disability and high AE rates. Although PTB treatment is
highly successful, the extent of morbidity during treatment and residual impairment could be overlooked if not
specifically sought. Calculations of PTB-related burden of disease should acknowledge that TB-related morbidity
does 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 Pulmonary
Disability in Pulmonary Tuberculosis: Under-Recognised Phenomena. PLoS ONE 8(11): e80302. doi:10.1371/journal.pone.0080302
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: 2013 Ralph et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted 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), National
Health and Medical Research Council (NHMRC) of Australia (Grants 605806 and 496600, a scholarship to APR, and fellowships to APR, TWY, PMK,
NMA). Graeme Maguire is supported by an NHMRC Practitioner Fellowship and the Margaret Ross Chair in Indigenous Health. Views expressed in this
publication 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, decision
to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: [email protected]

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November 2013 | Volume 8 | Issue 11 | e80302

Morbidity and Residual Disability in Pulmonary TB

Introduction

Methods

The morbidity experienced by people with pulmonary

tuberculosis (PTB) can be evaluated using measures such as
pulmonary function testing, quality of life questionnaires and
assessment of treatment complications. Quality-adjusted life
year calculations (QALY), which provide a measure of the
burden of tuberculosis (TB)-related disease, could
underestimate true PTB morbidity if they assume a short
disease duration [1,2], or do not incorporate long-term
pulmonary disability resulting from permanent lung damage [3].
Under-estimates in morbidity arising from TB disease or TB
medications may also occur in clinical or research settings in
which passive reporting of symptoms is relied upon, or in which
only serious adverse effects (requiring medication cessation
[4-6]) are captured. The requirement for strict adverse event
reporting in clinical trials provides an important opportunity to
gather detailed information about symptoms experienced
during TB treatment.
TB is a well-recognised independent risk factor for chronic
obstructive pulmonary disease (COPD) [7-11]. Both early,
reversible lung impairment in pulmonary TB [8,12] and longerterm residual impairment after TB [8,10] are evaluable using
spirometric measures such as percentage of predicted forced
expiratory volume in 1 second (FEV1). We have previously
reported high rates of residual pulmonary disability in PTB
patients in eastern Indonesia [8]. At treatment completion, a
quarter of successfully-treated patients still had significant lung
function impairment (FEV1<60% predicted, using local healthy
volunteers as the reference population for calculation of
percentage of predicted FEV1 [13]). Late residual pulmonary
disability has been reported by Pasipanodya et al, showing that
people with previous active TB were 5.4 times more likely to
have abnormal pulmonary function than people without
previous active tuberculosis [10].
Quality of life questionnaires can also reveal a fuller scope of
PTB morbidity than is obtainable from standard severity
measures such as sputum microscopy grade or radiological
disease extent. The St Georges Respiratory Questionnaire
(SGRQ) has been shown to be an effective tool for measuring
PTB morbidity [14]. The SGRQ is a respiratory health-related
quality of life (QoL) instrument formulated for use in COPD
[15,16], but validated in TB [8,14] and other respiratory
diseases. It has been translated into many languages including
Indonesian [16], with minor modifications for local suitability.
This study was performed within the context of a clinical trial
of nutritional interventions, where detailed information on
symptoms, intercurrent illness and disease burden was
collected. In order to gain an holistic understanding of the
scope of morbidity during TB treatment in an outpatient,
resource-limited, high TB-burden setting, our objectives in this
paper were to investigate morbidity at baseline and during
follow up (symptoms, Adverse Events [AE], functional capacity
and QoL), and residual disability at 6 months, experienced by
adults with PTB. We furthermore sought to identify predictors of
residual disability, and compare functional and QoL measures
in PTB with reference ranges established from locally-recruited
healthy controls.

This study was performed within a clinical trial of adjunctive

nutritional supplements (L-arginine and vitamin D) for PTB
(clinicaltrials.gov/NCT00677339).
In
this
study,
the
interventions did not significantly affect outcome measures
including AE [17]. Eligible sequential study participants with
PTB who had no previous history of treatment were enrolled at
the tuberculosis clinic in Timika, Indonesia. Inclusion criteria
included age 15 years, sputum smear-positive for acid fast
bacilli (AFB), and provision of written informed consent. The
standard 6-month tuberculosis treatment regimen [18] was
administered in a directly observed fashion.
Local healthy controls were eligible if they were aged 18
years, gave written informed consent, and had no comorbidities. Volunteers were approached via community
contacts and social groups from among friends and relatives of
staff members or patients (after undergoing TB contact tracing
and if found not to have TB). Volunteers were eligible as
healthy controls if they passed a symptom screen and
assessment of pulse and blood pressure. They were ineligible
if they had any current sickness, cough, angina, fever or any
febrile illness within the last week, pulse >120/min, systolic
blood pressure >180mmHg or diastolic blood pressure >100
mmHg. The latter exclusions were to ensure safety for physical
exertion to perform 6MWT. We did not ask minors aged <18
years to participate, due to the requirement for them to attend
the clinic solely for research purposes and to undergo blood
tests and other procedures (in contrast to TB patients needing
to attend the clinic anyway), especially given potential
difficulties in locating a parent/guardian to provide consent.

PLOS ONE | www.plosone.org

Ethics statement
The study was approved by the Human Research Ethics
Committees of Menzies School of Health Research, Darwin,
Australia and the National Institute for Health Research and
Development, Jakarta, Indonesia. Written informed consent
was obtained from the participant (and guardian if the
participant was aged <18 years) after discussion in Indonesian
or a relevant Papuan language aided by pictorial and written
information.

Setting
Timika, in southern Papua Province, Indonesia, population
~200,000, comprises approximately half Indigenous Papuans
and half Non-Papuan Indonesians. Papua is relatively
disadvantaged within Indonesia, having higher TB
(311/100,000 [19]) and HIV rates [20]. Population HIV
seroprevalence among Papuans was estimated at 2.4% in
2006 [21]. Indonesian smoking rates have been estimated at
67% of men and 4.5% of women [22]. Traditional Papuans use
indoor wood fires for cooking and heating; however, Papuans
living in the urban setting of Timika no longer tend to live in
traditional huts with internal cooking fires. In a previous study in
Timika [8], exposure to indoor smoke was not found to be
associated with pulmonary function (unpublished data).

November 2013 | Volume 8 | Issue 11 | e80302

Morbidity and Residual Disability in Pulmonary TB

Introduction

Methods

The morbidity experienced by people with pulmonary

tuberculosis (PTB) can be evaluated using measures such as
pulmonary function testing, quality of life questionnaires and
assessment of treatment complications. Quality-adjusted life
year calculations (QALY), which provide a measure of the
burden of tuberculosis (TB)-related disease, could
underestimate true PTB morbidity if they assume a short
disease duration [1,2], or do not incorporate long-term
pulmonary disability resulting from permanent lung damage [3].
Under-estimates in morbidity arising from TB disease or TB
medications may also occur in clinical or research settings in
which passive reporting of symptoms is relied upon, or in which
only serious adverse effects (requiring medication cessation
[4-6]) are captured. The requirement for strict adverse event
reporting in clinical trials provides an important opportunity to
gather detailed information about symptoms experienced
during TB treatment.
TB is a well-recognised independent risk factor for chronic
obstructive pulmonary disease (COPD) [7-11]. Both early,
reversible lung impairment in pulmonary TB [8,12] and longerterm residual impairment after TB [8,10] are evaluable using
spirometric measures such as percentage of predicted forced
expiratory volume in 1 second (FEV1). We have previously
reported high rates of residual pulmonary disability in PTB
patients in eastern Indonesia [8]. At treatment completion, a
quarter of successfully-treated patients still had significant lung
function impairment (FEV1<60% predicted, using local healthy
volunteers as the reference population for calculation of
percentage of predicted FEV1 [13]). Late residual pulmonary
disability has been reported by Pasipanodya et al, showing that
people with previous active TB were 5.4 times more likely to
have abnormal pulmonary function than people without
previous active tuberculosis [10].
Quality of life questionnaires can also reveal a fuller scope of
PTB morbidity than is obtainable from standard severity
measures such as sputum microscopy grade or radiological
disease extent. The St Georges Respiratory Questionnaire
(SGRQ) has been shown to be an effective tool for measuring
PTB morbidity [14]. The SGRQ is a respiratory health-related
quality of life (QoL) instrument formulated for use in COPD
[15,16], but validated in TB [8,14] and other respiratory
diseases. It has been translated into many languages including
Indonesian [16], with minor modifications for local suitability.
This study was performed within the context of a clinical trial
of nutritional interventions, where detailed information on
symptoms, intercurrent illness and disease burden was
collected. In order to gain an holistic understanding of the
scope of morbidity during TB treatment in an outpatient,
resource-limited, high TB-burden setting, our objectives in this
paper were to investigate morbidity at baseline and during
follow up (symptoms, Adverse Events [AE], functional capacity
and QoL), and residual disability at 6 months, experienced by
adults with PTB. We furthermore sought to identify predictors of
residual disability, and compare functional and QoL measures
in PTB with reference ranges established from locally-recruited
healthy controls.

This study was performed within a clinical trial of adjunctive

nutritional supplements (L-arginine and vitamin D) for PTB
(clinicaltrials.gov/NCT00677339).
In
this
study,
the
interventions did not significantly affect outcome measures
including AE [17]. Eligible sequential study participants with
PTB who had no previous history of treatment were enrolled at
the tuberculosis clinic in Timika, Indonesia. Inclusion criteria
included age 15 years, sputum smear-positive for acid fast
bacilli (AFB), and provision of written informed consent. The
standard 6-month tuberculosis treatment regimen [18] was
administered in a directly observed fashion.
Local healthy controls were eligible if they were aged 18
years, gave written informed consent, and had no comorbidities. Volunteers were approached via community
contacts and social groups from among friends and relatives of
staff members or patients (after undergoing TB contact tracing
and if found not to have TB). Volunteers were eligible as
healthy controls if they passed a symptom screen and
assessment of pulse and blood pressure. They were ineligible
if they had any current sickness, cough, angina, fever or any
febrile illness within the last week, pulse >120/min, systolic
blood pressure >180mmHg or diastolic blood pressure >100
mmHg. The latter exclusions were to ensure safety for physical
exertion to perform 6MWT. We did not ask minors aged <18
years to participate, due to the requirement for them to attend
the clinic solely for research purposes and to undergo blood
tests and other procedures (in contrast to TB patients needing
to attend the clinic anyway), especially given potential
difficulties in locating a parent/guardian to provide consent.

PLOS ONE | www.plosone.org

Ethics statement
The study was approved by the Human Research Ethics
Committees of Menzies School of Health Research, Darwin,
Australia and the National Institute for Health Research and
Development, Jakarta, Indonesia. Written informed consent
was obtained from the participant (and guardian if the
participant was aged <18 years) after discussion in Indonesian
or a relevant Papuan language aided by pictorial and written
information.

Setting
Timika, in southern Papua Province, Indonesia, population
~200,000, comprises approximately half Indigenous Papuans
and half Non-Papuan Indonesians. Papua is relatively
disadvantaged within Indonesia, having higher TB
(311/100,000 [19]) and HIV rates [20]. Population HIV
seroprevalence among Papuans was estimated at 2.4% in
2006 [21]. Indonesian smoking rates have been estimated at
67% of men and 4.5% of women [22]. Traditional Papuans use
indoor wood fires for cooking and heating; however, Papuans
living in the urban setting of Timika no longer tend to live in
traditional huts with internal cooking fires. In a previous study in
Timika [8], exposure to indoor smoke was not found to be
associated with pulmonary function (unpublished data).

November 2013 | Volume 8 | Issue 11 | e80302

Morbidity and Residual Disability in Pulmonary TB

Definitions and Procedures

Table 1. Participant characteristics.

Symptoms were assessed at each visit using a

comprehensive checklist. AE were defined, in keeping with
Good Clinical Practice (GCP), as any serious or non-serious
untoward medical occurrence which had not been noted at
baseline, regardless of perceived relatedness to medications or
to TB [23]. Such an occurrence reported at least once at any
time during TB treatment was documented as an AE. In
keeping with national practice, liver function tests were not
routinely monitored [24]. All participants were offered HIV
testing on venous blood using rapid point-of-care tests.
Anaemia was defined as >13.5 g/dL in males, >11.5 g/dL in
females. Where malaria co-infection was suspected, diagnosis
was by blood film. Sputum stained using the Ziehl-Neelsen
method was examined for acid fast bacilli at the Timika field
laboratory weekly for 8 weeks then at weeks 20 and 24.
Treatment outcome was categorised as successful if the
patient successfully completed or was cured (smear-negative
in the last month of treatment and on at least one previous
occasion) [25].
Postero-anterior chest radiographs were scored according to
a previously-reported method, the Timika TB x-ray score [26].
The Indonesian Modified SGRQ was used to assess QoL; this
has previously been tested in PTB patients in Timika [8]. A
score of 0 indicates no lung-related QoL impairment; 100
represents severe impairment. A change of 4 units is
considered clinically significant [27]. Pulmonary function (forced
vital capacity [FVC] and forced expiratory volume in 1 second
[FEV1]) was measured using a handheld spirometer
(MicroLoop, MicroMedical, UK), with individual-use filtered
one-way mouthpieces (Sure-Gard). The percentage of
predicted FEV1 was calculated from previously-established
local normal reference ranges [13]. The 6-minute walk test
(6MWT) was assessed on an outdoor track according to
American Thoracic Society guidelines [28]. A learning effect of
5-12% is recognised in serial 6MWT performed approximately
20 minutes apart [29,30], but such an effect is unlikely to be
seen when tests were separated by at least 4 weeks, as here,
and if present, would bias the interpretation of residual
disability results towards the null. Lung function impairment
categories were defined as: normal 80% predicted FEV1; mild
lung function impairment 70-79% predicted, moderate 60-69%,
Moderate-severe 50-59%, severe 35-49%, very severe <35%
[31]. Pulmonary function, 6MWT and the SGRQ were
undertaken at baseline then at 0, 4, 8 and 24 weeks and chest
radiographs at 0, 8 and 24 weeks. Pulmonary function, 6MWT
and SGRQ scores at 6 months were used to assess of the
presence of residual disability.

Healthy volunteerP value

200

40

Age in years: median (IQR)

28 (23-36.5)

26.5 (23.5-33)

0.7

Female: number (%)

69 (34.5)

9 (22.5)

0.1

Papuan: number (%)

89 (44.5)

20 (50.0)

0.5

Female: number (%)

29 (32.6)

6 (30.0)

1.0

19 (48%)

0.4

Current or ex-smoker: number (%) 109 (55%)

Height in metres: mean (SE)

1.61 (0.01)

1.58 (0.01)

0.08

Weight in kg: mean (SE)

62.5 (1.63)

48.5 (0.54)

<0.0001

Successful TB treatment outcome

(cured/completed)*
Multidrug-resistant TB*

146/186 (79%) -

2/149 (1.3)

* Outcome category and culture and susceptibility results were unavailable in some

participants
doi: 10.1371/journal.pone.0080302.t001

months were excluded. Proportions were compared using Chisquared test, or Fishers exact test where necessary. For
testing associations between continuous and categorical
variables, Students 2-sample T test or Wilcoxon rank sum test
were used depending on the distribution. For testing
associations between two continuous variables, univariable
and multivariable regression models were used if variables
were normally distributed, or Spearmans Rho and correlation
matrices, with Bonferroni correction for multiple comparisons, if
non-normally distributed and not amendable to transformation.
Multivariable models were constructed using a backwards
stepwise approach. Variables included in the initial model were
those significantly associated in univariable analysis with the
independent variable, or plausibly related to the independent
variable. All tests were two-sided with a P value <0.05
considered to be statistically significant.

Results
Study participants and healthy volunteers were enrolled from
June 2008 to February 2010, as described elsewhere
[17,34,35].. Data from all 200 participants included in the
overall trial are included here [36]. Compared with TB patients,
volunteers were adequately matched according to sex, age,
ethnicity and height, but had higher body weight, as expected
(Table 1).

Symptoms, functional capacity and quality of life

among TB patients

Statistical methods

PTB patients were most symptomatic and had greatest

functional and QoL impairment at baseline, as expected; all
measures significantly improved with TB treatment (Figures 1
and 2). Almost 80% of people had a successful treatment
outcome (Table 1). However, no measures other than sputum
microbiology showed complete normalisation by 6 months.
Despite rapid resolution of fever, lethargy, headache and
dizziness, other symptoms, while mostly decreasing over time,
remained well-represented, with over half the participants still

Analyses were undertaken using Stata 12.1, StataCorp,

Texas, USA. To calculate adverse event rates, participants
who attended less than half of the scheduled follow up
appointments (<6) were excluded. Age was grouped as 35 or
>35 years where required, since age >35 is associated with
higher AE risks in active [4] or latent [32,33] TB treatment. To
calculate percentage changes over time in serial measures,
participants for whom results were unavailable at baseline or 6

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TB patient
n

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Morbidity and Residual Disability in Pulmonary TB

having respiratory symptoms at treatment completion (Figure

1). Musculoskeletal symptoms (chiefly arthralgia) eased
initially, then increased up until week 8 before decreasing
again; this was frequently attributed by clinical staff to
pyrazinamide. Baseline symptoms were un-associated with
age, 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. Those
who were most unwell walked very short distances, creating a
skewed distribution in 6MWT data (Figure 2A). All participants
included in this study were ambulant as they were all
manageable in an outpatient setting (needing to be able to walk
into the clinic), but the most unwell had very limited exercise
tolerance, being only able to walk minimal distances. Four
people walked for only 55 metres or less, stopping well before
6 minutes, and another 9 people could only walk for 200m or
less. 6MWT, %predicted FEV1 and SGRQ were each still
significantly worse among PTB patients at treatment
completion than in the healthy controls. Only small percentage
improvements were achieved in %predicted FEV1 and 6MWT
(14.8% and 14.7% respectively) by TB patients over the 6
months; by 6 months, 27% of TB patients still had at least
moderate-severe pulmonary function impairment (Figure 2B).
More substantial improvements occurred in serial SGRQ and
Timika TB x-ray scores (Figures 2C and D). The median
FEV1/FVC ratio was >0.70 (not suggestive of an obstructive
pattern [37]) and did not differ between TB patients at baseline
(0.87, range 0.51-1.00) and controls (0.86, range 0.69-0.99).
Nine TB patients (4.5%) and 1 control (4.5%) had FEV1/FVC
ratio <0.70.

Figure 1. Proportion of participants reporting symptoms

at enrolment and during each week of follow up.
doi: 10.1371/journal.pone.0080302.g001

Intercurrent illness
Among 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 baseline,
which had decreased to 26% of people by week 24 [35].
Twenty two episodes of malaria were recorded in this region of
unstable malaria transmission [38]: 8 Plasmodium falciparum, 8
Plasmodium vivax, 6 unspecified. These included three
Papuan individuals (2 males, 1 female) who each had 2
discreet episodes of fever, with different malarial species
reported on blood films (P. falciparum then P.vivax or vice
versa), at intervals of 4, 8 and 13 weeks respectively. An
additional 11 people had symptoms consistent with malaria, but
negative blood films.

Predictors of residual disability

In univariable analyses, HIV+ status was significantly
associated with worse QoL (SGRQ) and shorter 6MWT at 6
months; the length of patient-reported diagnostic delay prior to
treatment commencement (illness duration) was significantly
associated with residual lung function impairment, x-ray score
and weight at 6 months; baseline Timika TB x-ray score was
significantly associated with final x-ray score and lung function
impairment at 6 months (Table 2). No other significant
associations between baseline demographic/clinical variables
and 6-month outcomes were identified. In multivariable models,
HIV status was no longer associated with 6WMT, and the
associations between illness duration and 6-month outcomes
were attenuated (Table 2).

Adverse Events
Two participants had TB medications withheld or ceased due
to AE; 1 due to rash (attributed to both pyrazinamide and
ethambutol), the other due to vomiting (attributed to rifampicin).
Excluding participants who attended <6 follow up
appointments, the proportions who experienced AE during
follow up are shown in Table 4 and Figure 4. Participants who
attended <6 follow up appointments did not differ
demographically or clinically from those who attended 6
appointments (data not shown). Commonest AE were itch and
arthrlagia. Few predictors of AE were identified: itch was more
common in people aged >35 than those 35 years; nausea
was more common but diarrhoea less common in people of
Non-Papuan than Papuan ethnicity; vomiting was more
common in females than males.

Establishment of local normal reference ranges

The healthy volunteers had a mean 6MWT distance of
49763m (range 360-640m). Males walked further than
females; no significant difference in distance was observed
between ethnic groups (Table 3, Figure 3A). Modified SGRQ
scores (total and individual domains) were obtained in 35
volunteers, the median total score being 0 (range 0-9.23),
(Table 3, Figure 3B) with no differences between sex or ethnic
groups in total or domain scores.

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Discussion
We have shown high morbidity and residual disability
amongst ambulatory outpatient PTB patients, in whom
treatment outcomes were mostly considered successful, and

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Morbidity and Residual Disability in Pulmonary TB

Figure 2. Functional, radiological and quality of life measures. *Data shown only for participants who had measures performed
both 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 Georges respiratory questionnaire total score (n=76)
D X-ray score (n=73)
doi: 10.1371/journal.pone.0080302.g002

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November 2013 | Volume 8 | Issue 11 | e80302

Morbidity and Residual Disability in Pulmonary TB

Table 3. Normal reference ranges for 6 minute walk test

and modified (Indonesian) St Georges Respiratory
Questionnaire in Timika, Papua, Indonesia*.

Table 2. Associations between baseline measures and

residual disability at 6 months.

Baseline variable
HIV status*

Six-month outcome

p value
Non-

Six-month St Georges Respiratory

All

Questionnaire total score: median (IQR)

HIV- : 3.25 units (1.72-7.18)

0.02

Respiratory

Six-month Six-minute walk test: median

Questionnaire
0.6

Illness duration
Six-month Weight: mean (SD)

treatment
Illness duration 3 months: 54.5kg (8.4)

0.04

Illness duration >3 months: 51.1kg (7.3)

Six-month X-ray score: median (IQR)
Illness duration 3 months: 6 units (2-14)

0.05

commencement

0 (0-21.51) 0 (0-21.51) 0 (0-12.39)

Activity score

0 (0-12.78) 0 (0-12.74) 0 (0-12.78)

Impact score

0 (0-15.1)

Total score

0 (0-9.23)

test (m): mean

Six-month %Predicted FEV1: mean (SD)

(SD)

0.86
(0-9.23)

0 (0-3.73)
0 (0-7.97)

21.51)
0 (012.78)
0 (08.87)
1.88 (07.97)

0 (0-13.07)
0 (0-0)
0 (0-15.1)
0 (0-9.23)

497 (63)

511 (60)

477 (46)

503 (58)

490 (69)

* 6MWD and total SGRQ score summary statistics in these healthy controls,

0.06

without sex or ethnic group breakdown, have been previously cited [34]
6-minute walk test male vs female p=0.006. No other significant differences in

Six-month X-ray score: median (IQR)

X-ray score 70: 5 units (1-11)

0 (0-15.1)

0 (0-

6-minute walk

Illness duration >3 months: 62.9% (18.3)

X-ray score at treatment

Symptom score

Illness duration >3 months: 19 units (6-65)

Illness duration 3 months: 75.4% (15.8)

Papuan

(range)

HIV+ : 440m (420-475)

to commencing

Papuan

(Units): median

(IQR)

(diagnostic delay) prior

Female

St Georges

HIV+ : 15.8 units (7.01-29.2)

HIV- : 480m (425-520)

Male

SGRQ or 6MWT between sex or ethnic groups.

<0.0001

doi: 10.1371/journal.pone.0080302.t003

X-ray score >70: 10.5 units (2-19)

Six-month %Predicted FEV1: mean (SD)
X-ray score 70: 78.2% (13.3)

It is possible that at least some pulmonary impairment

among TB patients was pre-existing, and that pulmonary
disability at 6 months reflected their pre-TB level of function,
especially given that smoking and COPD are risk factors for
TB. However, based on our findings here, and previous studies
[3,10], it is very plausible that the added burden of pulmonary
impairment attributable to TB, which was at least partly
reversible, contributed to the large disparity between TB
patients at treatment completion and controls. Also, the fact
remains that at TB treatment completion, patients still have
important ongoing health care requirements related to lung
disease, be they pre-existing or resulting from the PTB. We did
not collect data on exposure to indoor air pollution from cooking
fires; however, this would have affected Papuans
disproportionally compared with Non-Papuans who do not
traditionally use indoor fires, whereas we found no difference in
lung function impairment in the ethnic groups.
Adverse event rates in this study are much higher than
reported elsewhere, although medication cessation due to AE
was uncommon. AE rates vary widely among different studies
(Table 4), potentially attributable to differing study designs, AE
documentation method, average participant age, and
thresholds among staff and patients to tolerate adverse effects
before reporting them or withholding medications. Much
literature only reports TB drug side-effects serious enough to
require drug cessation [4-6,39]. Our high rates of non-serious
AE might relate to the particular GCP definition used (see
Methods) [23]; that participants were actively questioned about
symptoms at each visit; cultural factors among staff and

<0.0001

X-ray score >70: 64.2% (19.1)

* p values calculated using multivariable logistic regression
p values calculated using pairwise correlation between continuous variables with

Bonferroni correction for multiple comparisons

continuous explanatory variables have been dichotomised to illustrate

differences.
doi: 10.1371/journal.pone.0080302.t002

drug-resistant TB rates were low (Table 1). After 6 months of

treatment, the majority of participants had impaired functional
or QoL scores compared to the average healthy control, a
quarter had at least moderate-to-severe pulmonary function
impairment (Figure 2B), and 57% of study participants still had
respiratory symptoms (Figure 1). Thus 6-month residual
disability, especially that assessed using objective functional
measures (6MWT and pulmonary function), is very prevalent in
this setting after the standard duration of treatment for PTB.
People with advanced disease at baseline (prolonged
diagnostic delay or advanced x-ray changes), and those with
HIV, were most likely to suffer residual disability (Table 2),
emphasising the critical importance of early diagnosis and
treatment initiation, and optimised management of HIV coinfection [20]. Our findings are supported by previous
investigations calling for recognition in the calculation of TBrelated QALYs that TB-related morbidity does not stop after 6
months [3,8].

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Morbidity and Residual Disability in Pulmonary TB

Figure 3. References ranges in healthy volunteers. A Six minute walk test.

B St Georges Respiratory Questionnaire.
doi: 10.1371/journal.pone.0080302.g003

patients regarding symptom documentation; and intercurrent

illness. Other researchers use tighter definitions of AE (e.g.
events possibly or probably related to treatment [40]).
Regardless of the aetiology of documented AE in this study,
these data offer a real-world perspective on the high burden of
illness suffered during a 6-month period by people undergoing
TB treatment in a low-resource setting. This is likely to be
generalisable to other TB-endemic settings, but may pass
unrecognised if only sputum microscopy, chest x-ray and
weight are tracked, or if only severe symptoms, or those
detected passively, are reported. Awareness of non-serious AE
is important regarding their potential impact on adherence,
even in directly-observed treatment (DOT) programs, since
DOT may comprise weekly or, in the continuation phase,
monthly, clinic supervision, with opportunities for incomplete
adherence between appointments if AE are present.
Increasing age is recognised to be a major risk factor for
serious TB medication side effects (chiefly isoniazid-related
hepatotoxicity)[4,32,33,39], and female sex is also identified as
an occasional predictor of serious adverse event risk [4,39].
We did not find consistent associations between these or other
factors and the occurrence of non-serious AE (Figure 4).
We established normal reference ranges for 6MWT and
SGRQ in this population for the first time. The healthy Timika
volunteers walked a substantially shorter mean distance
(497m) than healthy people elsewhere (571-659m [29,41,42]).
Factors other than sex and anthropometric differences are
believed to influence 6MWT results, including cultural norms
regarding usual walking pace, mood, the motivation of the

PLOS ONE | www.plosone.org

subject and/or technician, and characteristics of the provided

walking track [41]. Short stature and the ambient heat and
humidity may also have contributed to the low 6MWTs here.
The SGRQ results were lower (better) among volunteers in this
study (median 0 units, Table 3, Figure 1), compared with other
healthy populations, in whom overall mean scores of 12 [43]
and 9.67 [44] have been reported. The younger ages of
controls in this study may explain the difference, but local
expectations regarding personal health and wellbeing may also
be important. Thus the establishment of locally-relevant
reference ranges is especially important for both 6MWT and
SGRQ, for men and women of both ethnic groups.
Compared with controls, exercise capacity was poor in TB
patients, including at treatment completion. Improvement over
time was only 14.7%, the same improvement as observed in
%predicted FEV1. This simple and inexpensive test of
functional capacity has been previously tested in TB [8,45], but
without comparison with controls. High SGRQ among TB
patients indicated substantially impaired QoL at baseline, but
major improvement occurred over time. As in the controls,
SGRQ scores in TB patients in this study (total score median
36.9 units) are similar to or better than previously reported in
TB. We previously reported a mean total SGRQ score of 45.4
in Timika PTB patients at diagnosis [8]. A mean score of 23.5
was reported in a study of post-TB QoL in the USA [14],
whereas our study participants had a median score of 4.1 at
treatment completion (Figure 4B). Our TB participants
experienced an overall decrement of >30 points; a major (87%)
improvement. Thus despite their limitations in 6MWT and FEV1,

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Morbidity and Residual Disability in Pulmonary TB

Table 4 (continued).

Table 4. Adverse event rates in a range of study types and

locations.

Study
participant

Study

mean or

participant
Adverse
Event

Proportion Rate

mean or

Adverse

median age

Event

(years)

Study type

Reference

71/123*

58%

27%

28

31

Prospective
observational

Randomised
trial

This study,

permanent

Indonesia,

cessation of

2013

TB

Burman et al,

medication

Africa and

due to

North

adverse

America,

event

2006 [47]
13/519

2%

44

Retrospective
observational

Schaberg et
al, Germany,
1996 [5]

Nausea
Non-severe

42/129
15/165

33%
9%

28
31

Prospective
observational
Randomised
trial
Randomised

1/24

4%

33

5/519

0.9% 44

[47]

Severe

Retrospective

11%

31

0/47

0%

33

121/519

23%

44

51/1149

4%

36

observational

observational

Randomised
trial
Randomised
trial
Retrospective
observational
Retrospective
observational

This study

[47]
[48]
[5]
Gulbay et al,
Turkey, 2006
[6]

For randomised trials, adverse event rates are given for the standard-treatment

arm where a novel comparison arm was used

[5]

Severe = requiring drug cessation

doi: 10.1371/journal.pone.0080302.t004

47/171

27%

28

33/519

6%

44

18/430

4%

40

Prospective
observational
Retrospective
observational
Retrospective
observational

This study

clinicians to under-appreciate the extent of objective residual

disability if they use subjective assessments (asking patients if
they feel better). In an environment such as Papua where
burden of disease is high [46], reported wellness may be higher
in the setting of low-grade symptoms or functional limitations,
compared with people in more affluent settings with different
expectations about their health.
We did not find an association between smoking and
increased risk of post-TB residual disability, for which there
could be several explanations. Smoking cessation may be
more common in those susceptible to the adverse effects of
smoking, including those with more advanced PTB, and
smoking may be more available to those of higher economic
status. Indeed, a healthy smoker effect has been noted in this
environment before [8]. The young age of the majority of
patients may mean low opportunity for established smokingrelated lung damage to have developed, supported by the
finding that airways obstruction (FEV1/FVC ratio <0.7) was
uncommon. The fact that smoking rates were high (76% of
males were current or ex-smokers) meant that the sample size
of non-smokers for comparison was small.
A possible limitation of the study is recall bias, which could
affect recollection of illness duration prior to TB treatment, or
symptoms which occurred since the last appointment. However
the prospective nature of the study minimises recall bias for

[5]
Yee et al,
Canada, 2003
[4]

23/142

16%

28

15/165

9%

31

2/24

8%

33

14/153

9%

28

6/165

4%

31

1/24

4%

33

Prospective
observational
Randomised
trial
Randomised
trial

This study
[47]
[48]

Diarrhoea
Non-severe

35/332

Prospective

6 follow up visits, and did not have that symptom at baseline

2009 [48]

Vomiting
Non-severe

28

Reference

* For the current study, denominators are the subset of the 200 patients who had

Diacon et al,

Rash
Non-severe

1%

This study

trial in multi-drug South Africa,

resistant TB

Severe

2/200

Study type

or

44/165

Severe

(years)

Temporary

Arthralgia
Non-severe

median age
Proportion Rate

Prospective
observational
Randomised
trial
Randomised
trial

This study
[47]
[48]

and persisting symptoms, and despite the SGRQ result still not
recovering to that seen in their healthy counterparts, PTB
patients in this study nevertheless perceived their QoL to be
relatively good by 6 months. This could be a reason for treating

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November 2013 | Volume 8 | Issue 11 | e80302

Morbidity and Residual Disability in Pulmonary TB

Figure 4. Adverse event rates during TB treatment.

doi: 10.1371/journal.pone.0080302.g004

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November 2013 | Volume 8 | Issue 11 | e80302

Morbidity and Residual Disability in Pulmonary TB

still have important health care requirements relating to

residual lung disease; understanding residual disability could
assist in planning ongoing patient care including anti-smoking,
vaccination (pneumococcal and influenza) and pulmonary
rehabilitation advice, where this exists. Our findings emphasise
the key importance of early case detection and treatment to
reduce the likelihood of residual impairment.

most measures. Not all participants attended all appointments,

but we restricted serial analyses to those for whom serial
results were available. Hepatoxicity was not assessed due to
liver function not being routinely tested in this setting; multiple
other studies have previously examined rates of and risk
factors for hepatotoxicity, and our intention was to focus on
neglected and non-severe events, in particular, symptoms
which can be assessed inexpensively. The modest number of
control subjects means that the healthy reference ranges may
not be completely representative of the larger population, but
reassuringly, our controls showed similar pulmonary function to
107 previously-studied people in Timika, from whom predicted
FEV1 data were obtained [13]; however, 6MWT and SGRQ
were not tested in the previous study.
We have shown that standard PTB treatment is highly
successful in reducing symptoms, improving functional
capacity, and enhancing quality of life, as expected. However,
our study reveals the extent of the morbidity which persists at
treatment completion, which would be overlooked if only
routine tests (sputum and chest x-rays) were performed.
Assigning a successful treatment outcome to a patient who
has been microbiologically cured ignores their functional state.
Morbidity is likely to be underestimated both by treating
clinicians and by patients, if objective functional measures are
not performed. Patients here reported major improvements in
well-being by 6 months compared to how sick they had been at
diagnosis, but may have persisting impairment lifelong
[3,7-11,14]. At a global level, calculations of PTB-related
burden of disease should take this into account. At the
individual level, people who are cured of pulmonary TB may

Acknowledgements
We greatly thank the Timika District Health Authority for
supporting the study; D.B. Lolong and the National Institute of
Health Research and Development, Jakarta; P. Penttinen, M.
Bangs and M. Stone, Public Health & Malaria Control (PHMC)
and International SOS; Bapak Istanto and PHMC laboratory
staff; J. Lempoy and Timika TB clinic staff; P. Sugiarto, E.
Malonda and Mimika Community Hospital (RSMM); D.
Lampah, Prayogo, Ferryanto Chalfein, N.D. Haryanti, S.
Hasmunik, S. Rahayu, G Bellatrix and clinical and laboratory
staff, Timika Research Facility; R. Soemanto and Y. Rukminiati
(University of Indonesias Faculty of Microbiology); members,
and K. Piera and E. Curry (MSHR). We thank P. Glaziou for
helpful discussions about burden of disease calculations.

Author Contributions
Conceived and designed the experiments: PMK NMA GPM
APR EK S ET. Performed the experiments: APR GW GJP EK.
Analyzed the data: APR. Wrote the manuscript: APR GPM
PMK NMA. Facilitated the study: EK S ET.

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