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INT J TUBERC LUNG DIS 19(5):596–602
Q
2015 The Union
http://dx.doi.org/10.5588/ijtld.14.0686
Childhood tuberculosis and exposure to indoor air pollution: a
systematic review and meta-analysis
N. Jafta,* P. M. Jeena,
†
L. Barregard,
‡
R. N. Naidoo*
*Discipline of Occupational and Environmental Health, School of Nursing and Public Health, and
†
Discipline of
Paediatrics and Child Health, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal,
Durban, South Africa;
‡
Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital
and University of Gothenburg, Gothenburg, Sweden
SUMMARY
BACKGROUND: Indoor air pollution (IAP) from envi-
ronmental tobacco smoke (ETS) and biomass fuel smoke
(BMS) poses respiratory health risks, with children and
women bearing the major burden.
OBJECTIVES: We used a systematic review and meta-
analysis to investigate the relation between childhood
tuberculosis (TB) and exposure to ETS and BMS.
METHODS: We searched three databases for epidemio-
logical studies that investigated the association of
childhood TB with exposure to ETS and BMS. We
calculated pooled estimates and heterogeneity for
studies eligible for inclusion in the meta-analysis and
stratified studies on ETS by outcome.
RESULTS: Five case-control and three cross-sectional
studies were eligible for inclusion in the meta-analysis
and quality assessment. Pooled effect estimates showed
that exposure to ETS is associated with tuberculous
infection and TB disease (OR 1.9, 95%CI 1.4–2.9)
among exposed compared to non-exposed children. TB
disease in ETS studies produced a pooled OR of 2.8
(95%CI 0.9–4.8), which was higher than the OR for
tuberculous infection (OR 1.9, 95%CI 0.9–2.9) for
children exposed to ETS compared to non-exposed
children. Studies on BMS exposure were too few and too
small to permit a conclusion.
CONCLUSION: Exposure to ETS increases the risk of
childhood TB disease or tuberculous infection.
KEY WORDS: pulmonary tuberculosis; cooking fuel;
passive smoke; risk factors; indoor air pollution
INDOOR AIR POLLUTION (IAP) has been identi-
fied as a public health problem in developing
countries, where the majority of people are still
dependent on biomass and fossil fuels for cooking,
heating and lighting; more than 10% of the global
respiratory di sease burden is attributable to this
exposure.
1,2
Exposure to biomass fuel smoke (BMS)
is not the only type of indoor exposure of concern.
Exposure to environmental tobacco smoke (ETS) is
recognised as a major risk factor for adverse
respiratory health outcomes.
3–13
The most vulnerable
groups in terms of exposure to ETS and BMS are
children, the elderly and the chronically ill, all of
whom spend a considerable amount of their time
indoors and are likely to be immunocompro-
mised.
1,14
In a recent systematic review and meta-analysis, Po
et al. reported that BMS exposure increased the risk
of respiratory diseases due to bacterial and viral
infections in both children and women.
15
Indoor
tobacco smoke also pos ed an increased risk for
tuberculosis (TB) disease.
5,7
Most studies investigat-
ing the relationship between exposure to IAP and TB
have either studied women alone or have combined
women, men and children as the population of
interest. These studies have shown an increased risk
of TB in children compared to adults. Children’s
studies of the natural history of TB disease (without
chemotherapy) have shown that the risk of develop-
ing extra-pulmonary TB (tuberculous meningitis and
miliary TB) is much higher in young children aged ,2
years than in older children or adults.
16
A systematic
review and meta-analysis on IAP and TB by Lin et al.
assessed exposure to ETS and risk of TB in fiv e studies
(two adult and three child participant trials), and
showed that ETS is a risk factor for childhood
tuberculous infection and TB disease.
5
Since the review by Lin et al.,
5
several studies on
IAP and childhood TB have been published.
4,8,10,13
Children aged 615 years are less likely to be
smokers, and therefore provide the best opportunity
to understand IAP-related respiratory effects. We
therefore conducted an updated systematic review to
establish the relation between exposure to ETS and
Correspondence to: Nkosana Jafta, Discipline of Occupational and Environmental Health, School of Nursing and Public
Health, University of KwaZulu-Natal, 321 George Campbell Building, Howard College Campus, Durban, 4041, South
Africa. Tel: (þ27) 31 269 4528. Fax: (þ27) 31 260 4663. e-mail: jaftan@ukzn.ac.za
Article submitted 9 September 2014. Final version accepted 6 January 2015.
BMS and tuberculous infection a nd T B disease
among children using both quantitative and qualita-
tive met hods.
METHODS
Data source and search strategy
We conducted a systemic search of the PubMed
(including Medline), Web of Science and CAB
abstracts online databases, with the aim of identifying
original research articles published between 1953 and
April 2014 coveri ng the association between expo-
sure to IAP and/or ETS and tuberculous infe ction
and/or TB disease. We also conducted a manual
search based on the reference lists of the review
articles and reports yielded by the electronic data-
bases. Our search strategy is described in the Table.
All results from the systematic search were entered
into EndNote X7 (Thomson Reuters Scientific Inc,
Carlsbad, CA, USA) and duplicates removed. NJ and
RN reviewed titles and abstracts with the aim of
removing publications that were unlikely to meet the
inclusion criteria. They then examined the full texts
of the remaining articles, and excluded any that did
not meet the inclusion criteria. Those publi cations
considered eligible were included in a systematic
review and meta-analysis. Figure 1 is a PRISMA
(Preferred Reporting Items for Systematic Reviews
and Meta-Analyses) flow chart of the selection
process for this study.
17
Selection criteria
We reviewed all potentially eligible studies written in
or translated into English and published in peer-
reviewed j ournals to ensure that the y me t the
inclusion and exclusion criteria. The inclusion criteria
were as follows: 1) the study population consisted of
children aged 615 years with either tuberculous
infection or TB disease and control groups at risk of
acquiring tuberculous infection or TB disease; 2)
tuberculous infection and/or TB disease diagnoses
were confirmed by laboratory diagnosis (acid-fast
bacilli [AFB], culture and/or molecular tests), clinical
diagnosis, radiograph, tuberculin skin test (TST) or a
combination of these; 3) the study was an epidemi-
ological study of primary or secondary data analysis
design; and 4) the study reported adjusted effect
estimates with 95% confidence intervals (95%CIs)
for the association between TB and IAP (i.e., fuel
smoke and/or ETS exposure). All studies of children
aged .15 years in whom the above criteria could not
be met were excluded.
Data extr action and analysis
Using a data extraction form, we extracted the
following data from publications that were eligible
for inclusion in the final meta-analysis: 1) study
authors, 2) year of publication, 3) setting (country),
4) associations studied, 5) participants, 6) study type,
7) sample size, 8) exposures studied, 9) outcome(s)
measured, 10) covariates adjusted for, 11) effect size
estimates and 12) 95%CIs of effect estimates (Appen-
dix Table A.1).* The effect estimates reported by
Jubulis et al. were for different definitions of TB
disease, namely probable TB only, confirmed TB only,
and both probable TB and confirmed TB, according to
the broader definition of TB.
13
For this meta-analysis,
we extracted data using the definition for confirmed
TB. Although Jubulis et al. define IAP as a combina-
tion of ETS and BMS and report combined adjusted
effect estimates,
13
we used only the disaggregated
reported estimates on ETS and BMS in the analysis.
After extracting the relevant data on all studies
judged eligible for the meta-analysis, we assessed the
association between exposure and outcome using a
forest plot of the adjusted odds ratio (OR) for TB
(tuberculous infection and TB disease) for each study
and exposure effect estimate. We pooled all studies on
ETS exposure (Figure 2), and then stratified them by
health outcome (latent tuberculous infection [LTBI]
and TB disease) (Figure 3) and obtained pooled overall
random effect estimates (ORs and 95%CIs) for the
different strata
21,22
using the DerSimonian-Laird
method.
21,22
We did not pool estimates of association
between BMS and TB, as there were only two studies;
however, we reported their individual estimates and
analysed them for quality. We assessed heterogeneity
between the studies on ETS by calculating the I
2
statistic for each of the strata and for all the studies on
ETS. The area of the square of each study plot reflects
the Mantel-Haenszel weight that the study contributed
to the final pooled effect estimate.
We also performed a qualitative analysis of the risk
of bias on all eight studies included us ing a
Table Search strategy and terms used to identify studies on
biomass fuel smoke (BMS), fossil fuel smoke, and environmental
tobacco smoke (ETS) exposures
Medical subject headings (MeSH) term search:
1 ‘tuberculosis’
2 ‘tobacco smoke pollution’
3 ‘biomass’
4 ‘fossil fuels’
5 ‘fuel oils’
6 ‘air pollution, indoor’
7 ‘(1) AND (2)’ OR ‘(1) AND (3)’ OR ‘(1) AND (4)’ OR ‘(1) AND
(5)’ OR ‘(1) AND (6)’
Direct keyword search:
8 ‘childhood tuberculosis’
9 ‘passive smoke’
10 ‘environmental tobacco smoke’
11 ‘secondhand smoke’
12 ‘cooking fuels’
13 ‘predictors’
14 ‘risk factors’
15 ‘(8) AND (9)’ OR ‘(8) AND (10)’ OR ‘(8) AND (11)’OR ‘(8)
AND (12)’ OR ‘(8) AND (13)’ OR ‘(8) AND (14)’
16 ‘(7) OR (15)’
* The appendix i s available in the online ver sion of this article, at
http://www.ingentaconnect.com/content/iuatld/ijtld/2015/
00000019/00000005/art 00018
Childhood TB and indoor air pollution 597
combination of elements of the Critical Appraisal
Skills Programme (CASP, Oxford, UK, 2014; http://
www.caspinternational.org/?o¼1012) for case con-
trol studies and a method used by Ijaz et al.
23
The six
elements included were 1) a definition of outcome
and its assessment or measure, 2) the definition for
exposure used, 3) the source and method for
measuring the exposure, 4) reliability, 5) controlling
for confounding covariates in the analys is, and 6) the
analysis performed in the study (Appendix Table
A.2).
We tested for bias on studies on ETS and study
design strata using a method described by Egger et
al.
24
to identify asymmetry in a funnel plot. All
statistical analyses were performed using Stata IC 13
(StataCorp, College Station, TX, USA).
RESULTS
Search and selection of studies
Figure 1 summari ses the process used to identify the
studies eligible for the systematic review and meta-
analysis according to the PRISMA reporting pro-
cess.
17
Of the 1088 publications identified from
electronic databases and manual search, 224 were
excluded because they were duplicates, not related to
ETS an d/or BMS exposure and TB, or were non-
human studies, while a further 633 were not related
to IAP and TB, leaving 125 publications eligible and
relevant for detailed review. Following this full-text
review, we excluded 114 of these, as children were
not the population of interest, the analysis did not
include a stratum for children (aged 615 years) or
the exposure variable was personal smoking rather
than ETS. We excluded a further three studies because
they did not adjust for covariates and reported only
crude ORs and 95%CIs. The remaini ng eight
publications, all of which were either case-control
or cross-sectional studies, were eligible for further
detailed review and meta-analysis. Appendix Table
A.1 lists the studies that were included in the final
analysis, along with the main variables that were
considered in the assessment and extraction of data.
Exposure measures
All eight studies reported an association between ETS
exposure and TB. Five reported ETS expo sure
only;
4,8,18–20
the remaining three reported an associ -
ation between both ETS and BMS exposure with TB
in children. Of these three studies reporting BMS
exposure, two reported adjusted r isk estimates
separately for both ETS and BMS,
9,13
and the other
reported adjusted risk estimates for ETS and only
crude estimates for BMS.
10
Outcome measures
Five studies
9,10,13,19,20
looked at TB disease as an
outcome based on clinical diagnosis, with two of
these studies
13,19
also adding laboratory identifica-
tion (smear and/or culture) of Mycobacterium tuber-
culosis in the diagnostic method. Three studies
included children with both pulmonary and extra-
pulmonary disease,
9,10,20
whereas the other two
included children with only pulmonary TB.
13,19
All
three studies that had infection as an outcome
variable used the TST diameter as indicator; Du Preez
et al. used three cut-off points, with 10 mm as the
primary measure and 5 mm and 15 mm as secondary
measures or cut-offs for infection,
8
whereas Singh et
al.
18
and Den Boon et al.
4
used only the 10 mm cut-
off. For this review, the 10 mm TST cut-off risk
estimate was used in the analysis. The study by Altet
et al., which used TB disease as outcome variable, also
used TST as part of the definition of disease, with a 5
mm diameter as the cut-off for diagnosing active
pulmonary TB in children.
19
None of the studies
indicated whether a positive TST was the result of
bacille Calmette-Gu
´
erin (BCG) vaccination.
Association of exposure to environmental tobacco
smoke and biomass fuel smoke with tuberculosis in
children
Six of the eight studies showed a statistically
significantly increased risk of tuberculous infection
or TB disease when children were exposed to ETS,
with adjusted ORs ranging from 1.8 (95%CI 1.2–2.7)
Figure 1 Flow chart of the literature search for studies
investigating IAP and TB in children. IAP ¼ indoor air pollution;
TB ¼ tuberculosis; ETS ¼ environmental tobacco smoke; HAP ¼
hazardous air pollutant; BMS ¼ biomass fuel smoke.
598 The International Journal of Tuberculosis and Lung Disease
to 9.3 (95%CI 3.1–27.6), compared to non-exposed
children (Figure 2). Two studies foun d no statistically
significant association between ETS exposure and TB
disease and tuberculous infection (OR 1.4, 95%CI
0.9–2.1, and OR 2.9, 95%CI 0.7–12.4, respective-
ly).
4,13
The studies by Ramachandran et al.
9
and
Jubulis et al.,
13
which reported an association of BMS
exposure and TB, had significant estimates (ORs) of
6.9 (95%CI 2.5–18.9) and 7.2 (95%CI 1.4–44.5),
respectively.
9,13
We estimated random effects by pooling the effect
estimates of the eight studies 1) for all the studies on
ETS (Figure 2), and 2) for each stratum of outcome
for the ETS exposure studies (tuberculous infection or
TB disease; Figure 3). Two studies, by Den Boon et
al.
4
and Patra et al.,
10
had risk estimates that were not
statistically significant and that weighted .70% to
the pooled estimate.
The pooled forest plot of effect estim ates (ORs) of
the eight studies reporting an association between
tuberculous infection and TB disease in children and
exposure to ETS was 1.9 (95%CI 1.3–2.5) (Figure 2).
Studies with TB disease as an outcome (defined as
clinical symptoms and radiological abnormality
consistent with TB, plus a TST induration above the
cut-off diameter) showed a slightly stronger associa-
tion (OR 2.8, 95%CI 0.86–4.78) than those with
tuberculous infection as an endpoint (OR 1.9, 95%CI
0.9–2.9) when exposed to ETS (Figure 3).
The degree o f heterogeneity between all ETS
studies (I
2
¼ 20.6%, P ¼ 0.266) showed that although
the studies made different contributions to the final,
pooled estimate, the differences between the strata
were not significant when random effect estimates
were computed (Figures 2 and 3).
Although the method employed by Egger et al. to
assess publication bias is not sensitive when the
number of studies is small,
24
we nevertheless comput-
ed a funnel plot of logOR estimates of the eight studies
on ETS against their standard errors (selogOR). The
asymmetric results, with three of the studies falling
outside the funnel plot, suggest that there may have
been a reporting bias or chance variation in the studies
selected for this review (Figure 4).
The eight studies showed varying results when
assessed for quality using CASP in combination with
Figure 2 Forest plot showing studies on ETS exposure and childhood TB, with pooled ORs. ETS ¼ environmental tobacco smoke; OR
¼ odds ratio; CI ¼ confidence interval; TB ¼ tuberculosis.
Figure 3 Forest plot showing studies on ETS and childhood TB, stratified by outcome variable and the calculated pooled effect
estimate. ETS ¼ environmental tobacco smoke; OR ¼ odds ratio; CI ¼ confidence interval; TB ¼ tuberculosis; LTBI ¼ latent tuberculous
infection.
Childhood TB and indoor air pollution 599
the qualitati ve m ethod employed by Ijaz et al .
(Appendix Table A.2).
23
Five of the eight studies
had low risk rating in at least four of the six elements
of bias assessed, and only one of the eight studies had
a high risk of bias rating for one of the elements
assessed. Most of the elements were rated ‘unclear’
because insufficient detail was provided in the
publications.
DISCUSSION
The pooled effect estimates of this meta-analysis
showed that children exposed to ETS had a two-fold
increased risk of acquiring tuberculous infection and
TB disease compared to non-exposed children. This
was higher than the estimates reported in adult
studies or in studies that included all age
groups.
5,11,19,25
Stratification of ETS exposure by
outcome showed that the OR for TB disease was
higher (OR 2.8) than that for tuberculous infection
(OR 1.9) in children exposed to ETS than in non-
exposed children (Figure 3). However, as all of the
studies with tuberculous infection as an outcome had
a cross-sectional design (Appendix Table A.1), the
influence of study design on the effect estimate could
not be disentangled from the effect of how outcome
was defined (disease or infection).
Theliteratureprovidesevidenceofbiological
mechanisms of exposure to air pollution and respira-
tory illnes ses, with indoor air constituents such as
nicotine, particulate matter (PM
2.5
), nitrogen dioxide
and carbon monoxide implicated.
26,27
The biological
mechanisms involved in the relationship between IAP
exposure and tuberculous infecti on and TB disease
can be extrapolated from the work that has investi-
gated the mechanism(s) involved in IAP constituents
and other respiratory infections.
26–30
A failure of the
involved immune system components, such as cell-
mediated immuni ty t o acti vate response that is
optimal for M. tuberculosis clearance, can lead to
the pa thogen causing tuberculous infection or TB
disease. The four major immunological systems that
may be implicated are 1) particle or bacterial
clearance,
28,29
2) recognition and immune signalling
to the pathogen,
31
3) intra cellul ar a ntibact erial
response,
30
and 4) recruitment of adaptive immune
components in elimination and containment of the
M. tuberculosis pathogen.
32
Two studies, by Den Boon et al.
4
and Patra et al.,
10
contributed .70% to the weighting of the pooled
overall OR for the eight studies, and neither was
statistically significant. Furthermore, when both
studies were assessed for confounding or adjustment
for covariates, they were rated respectively as high risk
and unclear for bias, as they were either vague in their
description or had excluded important covariates.
The results from the pooling of studies on ETS
which used tuberculous infection as outcome or as a
measure contributing to the outcome definition of
disease should be interpreted with caution, as the
standard induration of the TST weal for positive
infection is not the same across different populations.
In populations with a high prevalence of BCG
immunisation against TB and high human immuno-
deficiency virus (HIV) prevalence in children, the
diagnosis of tuberculous infection using the TST
diameter is variable. The choice of a 10-mm cut-off
for three of the four studies
4,8,19,20
that used TST
could be due to the high BCG vaccination coverage or
TB prevalence in the two populations studied, namely
India and South Africa. On the other hand, in the
study by Altet et al.,
19
the use of a 5-mm cut-off could
be related to the low BCG vaccination coverage and
low TB prevalence in the Spanish population at the
time of the study.
In all the studies included in this review, exposure to
IAP was assessed by asking the participating care
givers about energy use and/or presence of smokers in
their homes. This measure of pollutant exposure
could have varied from study to study, depending on
the details of the assessment. Most of these studies had
exposure time as a factor in their assessment,
Figure 4 Funnel plot with pseudo 95% CIs assessing publication bias of the eight studies on
environmental tobacco smoke included in the meta-analysis. CI ¼ confidence interval; SE logOR ¼
standard errors logOR; logOR ¼ log odds ratio.
600 The International Journal of Tuberculosis and Lung Disease
especially for ETS. In some of the studies, children
living in the same house as a smoker for at least 6 or
12 months were considered to be exposed to
ETS,
8,10,19
but the time the child spent each day in
that environment was not taken into account. On the
other hand, behaviours that could influence exposure
of young children to BMS, such as the child being
carried on the back of a woman during cooking, were
usually not adequately assessed or described in most
studies. Air pollution emissions from indoor cooking
are affected not only by the number of hours, but also
by the quality of the fuel and the technique used in
burning fuel. Moreover, exposure to IAP (ETS or
BMS) depends not only on the emissions, but also on
the ventilation in the house (chimney, open doors and
windows) and on the climate. Objective methods of
exposure assessment are therefore necessary, such as
measurements of air pollution in the homes. Expo-
sures reported by care givers represent a relatively
crude measure of IAP, and are usually not compara-
ble. ETS and BMS exposures are a result of different
indoor pollution sources, and a detailed assessment is
needed to characterise them, especially for children, as
these exposures could result in effects that are additive
or synergistic. The age and sex of the children
33
are
also determinants for IAP exposure. In the studies
included in our meta-analysis, this was addressed
either by matching or by adjustment in the analysis.
All of the studies included in this meta-analysis
have been adjusted for one or more of the important
covariates implicated in tuberculous infection or TB
disease: household TB contact, socio-economic status
(SES), malnutrition, age, HIV status, vaccination
status, and crowding. Although HIV status of
children is known to be the major driver of
acquisition (tuberculous infection) and progression
(TB disease),
34
none of the studies quantified the
effect of HIV when modelling the association
between TB and IAP exposure. Six of the studies
included in this meta-analysis were from high HIV
burden countries, India and South Africa, where
.20% of TB patients are HIV-positive.
12
The
covariates adjusted for across the studies were not
consistent, and this could have caused some of the
heterogeneity observed between them.
Some covariates, such as BCG vaccination status
and HIV status, are particularly important when
studying TB in certain populations. This can be
observed in the differences between the two studies
from similar communities in South Africa published 4
years apart.
4,8
In South Africa, antiretroviral treat-
ment had been rolled out publicly only to a limited
extent during the earlier study period (2003–2007),
4
whereas it was widely available when the later study
was conducted (from 2009 onwards).
8
Neither study
assessed the HIV status of the participants. The study
by Den Boon et al. was conducted in populations with
higher HIV prevalence,
4
and may have underestimat-
ed the occurrence of tuberculous infection, as these
authors used an induration of 10 mm as cut-off, and
there was no stratification or control for HIV in the
analysis.
4,16
Studies investigating the relation between IAP
exposure and childhood TB have used proxy mea-
sures for estimating exposure, such as reported
exposures obtained from care giver interviews and
medical records. In this review, sources of bias for
four of the eight studies were classified as ‘unclear’ or
‘high risk’ due to the definition of exposure, and for
two of these studies also due to the measurement of
exposure. A standardised methodology using a
questionnaire or walkthrough instrument for assess-
ing exposure to IAP needs to be developed for future
studies. Studies that objectively quantify exposure are
needed for estimating the dose-response relation of
exposure to disease outcome.
The limitations of this review include reporting
bias that could result from a higher likelihood of
studies with positive and significant findings being
published than studies with negative or non-signifi-
cant findings. In this systematic review, we excluded
three studies because they did not report adjusted
effect estimates and documented only positive signif-
icant results regarding associations between IAP and
childhood TB. Furthermore, only two of the three
studies separately reported the adjusted effect esti-
mate for exp osure to BMS. These studies on BMS
exposure had very wide CIs, which could be the result
of the small number of observations.
CONCLUSIONS
Despite the limitations, pooled effect estimate indi-
cates an increased risk of childhood TB in children
exposed to ETS compared to those not exposed. The
limited number of studies on the association of BMS
exposure and childhood TB and the small sizes of the
studies do not permit any conclusions to be drawn on
causality. Although some of the reviewed studies may
suffer from bias, programmes addressing IAP should
be considered in the comprehensive management of
the TB epidemic because of the known high incidence
and severity of TB disease in children. Future studies
should consider BCG and HIV status, molecular TB
tests and/or isolation for better clinical definition of
tuberculous infection or TB disease and more accurate
evaluation of IAP exposure to confirm these findings.
Acknowledgements
NJ is a recipient of the National Institutes for Health-Fogarty
International (Bethesda, MD, USA) and South African TB/AIDS
Research Training (SATBAT, Johannesburg, South Africa) Grant:
5U2RTW00773 and 5U2RTW007373.
Conflicts of interest: none declared.
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602 The International Journal of Tuberculosis and Lung Disease
RESUME
CONTEXTE : La pollution de l’air int´erieur par la fum´ee
de tabac dans l’environnement (ETS) et la fum´ee
´emanant de la combustion de biomasse (BMS)
constitue un risque sanitaire respiratoire qui affecte
surtout les femmes et les enfants.
OBJECTIF : R´ealiser une revue syst´ematique et une
m´eta-analyse afin de d´eterminer la relation entre la
tuberculose (TB) de l’enfant et l’exposition `a l’ETS et `a
la BMS.
ME
´
THODES : Nous avons recherch´e dans trois bases de
donn´ees des ´etudes ´epid ´emiologiques consacr´ees `a
l’association de la TB de l’enfant avec l’exposition `a
l’ETS et `a la BMS. Nous avons calcul´e les estimations
regroup´ees et l’h´et´erog´en´eit´e des ´etudes ´eligibles pour
l’inclusion dans la m´eta-analyse, et les ´etudes ont ´et´e
stratifi´ees sur l’ETS par r´esultat.
RE
´
SULTATS : Cinq ´etudes cas t´emoins et trois ´etudes
transversales ont ´et´e´eligibles pour inclusion dans la
m´eta-analyse et l’´evaluation de qualit´e. Les estimations
de l’effet pool´e ont montr´e que l’exposition `a l’ETS ´etait
associ´ee `a l’infection et `a la maladie tuberculeuse (OR
1,9 ; IC95% 1,4–2,9) par comparaison aux enfants non-
expos´es. Les ´etudes de l’ETS ont mis en ´evidence un OR
regroup´e de la maladie tuberculeuse de 2,8 (IC95% 0,9–
4,8), plus ´elev´e que l’OR de l’infection tuberculeuse
(1,9 ; IC95% 0,9–2,9) pour les enfants expos´es `a l’ETS
compar´es aux enfants non-expos´es. Les ´etudes
consacr´ees `a l’exposition `a la BMS ´etaient trop peu
nombreuses et trop limit´ees pour permettre une
conclusion.
CONCLUSIONS : L’exposition `a l’ETS augmente le
risque d’infection ou de maladie tuberculeuse de
l’enfance.
RESUMEN
MARCO DE REFERENCIA: La contaminaci ´on del aire en
locales cerrados por el humo de tabaco ambiental (ETS)
y de los combustibles de biomasa (BMS) genera riesgos
sanitarios respiratorios, cuyas repercusiones son
mayores en los ni
˜
nos y las mujeres.
OBJETIVOS: Se llev ´o a cabo una investigaci ´on
bibliogra´fica exhaustiva y un metana´lisis con el
prop ´osito de examinar la relaci ´on entre la tuberculosis
(TB) de la infancia y la exposici´on al ETS y BMS.
ME
´
TODOS: Se investigaron tres bases de datos en busca
de estudios epidemiol ´ogicos sobre la asociaci ´on de la TB
de la infancia y la exposici ´on al ETS y los BMS. Se
obtuvieron estimaciones por combinaci ´on de datos y se
evalu ´o la heterogeneidad de los estudios que cumpl´ıan
con los requisitos de inclusi ´on en el metana´lisis; los
estudios sobre la exposici ´on al ETS se estratificaron en
funci ´on del desenlace cl´ınico.
RESULTADOS: Se incluyeron en el metana´lisis y la
evaluaci ´on de la calidad cinco estudios de casos y
testigos y tres estudios transversales. Las estimaciones
del efecto obtenidas por combinaci ´on de datos puso en
evidencia que la exposici ´on al ETS se asociaba con la
infecci ´on tuberculosa y la enfermedad activa, en
comparaci ´on con una poblaci ´on de ni
˜
nos no expuestos
(OR 1,9; IC95% 1,4–2,9). La enfermedad tuberculosa
en los estudios sobre el ETS gener ´o un OR acumulado de
2,8 (IC95% 0,9–4,8); esta cifra es superior al OR
obtenido para la infecci ´on tuberculosa (1,9; IC95% 0,9–
2,9) en los ni
˜
nos expuestos al ETS comparados con los
ni
˜
nos no expuestos. El escaso n ´umero de estudios sobre
la exposici´on al BMS y su tama
˜
no muestral reducido no
permite sacar conclusiones a este respecto.
CONCLUSIO
´
N: La exposici ´on al ETS aumenta el riesgo
de contraer la infecci ´on tuberculosa y la enfermedad
activa durante la infancia.
Childhood TB and indoor air pollution i
Table A.1 Studies included in the meta-analysis of exposure to household air pollution and childhood TB
Outcome studied
Author, year,
country, refer-
ence Study design
Participants/setting
(age) Exposure definition Outcome definition
Variables adjust-
ed for in the
analysis Findings
Adjusted OR
(95%CI)
Tuberculous infection Singh, 2005,
India
18
Cross-sectional 95 TST-positive and
186 TST-negative
children in contact
with adult TB
patients (,5 years)
Definition of ETS not
stated; ETS
exposure was
assessed by history
taking during
clinical assessment
Tuberculous infection
diagnosed by TST 7
10 mm, and PTB and
EPTB disease
diagnosed by clinical
examination and
smear positivity
Age, adult TB
contact,
malnutrition,
and BCG scar/
vaccination
Risk of tuberculous
infection in
children increases
with exposure to
ETS
2.68 (1.52–4.71)
Den Boon, 2007,
South Africa
4
Cross-sectional 1344 children from
664 households in
two communities
(,15 years)
ETS was defined as
at least one
smoker living in
the children’s
household for 1
year
Tuberculous infection
diagnosed by TST 7
10 mm
Family income,
age, crowding,
and household
TB contact
ETS exposure
increases the risk
of acquiring TB in
children living in
households with
and without an
adult TB contact
1.35 (0.86–2.12)
Du Preez, 2011,
South Africa
8
Cross-sectional 196 children in
contact with
household adult
TB cases (3
months–15 years)
ETS exposure was
defined as at least
one smoker living
in the household
for 6 months
Tuberculous infection
diagnosed by TST 7
10 mm (5 mm and 15
mm TST used as
secondary cut-off
points)
Age, ethnicity,
household TB
contact, and
previous anti-
tuberculosis
treatment
Increased risk of
tuberculous
infection in
children with more
than two
household
members smoking
2.66 (1.28–5.25)
TB disease Altet, 1996,
Spain
19
Case control 93 active TB cases
and 95 controls
with no evidence
of TB but TST-
positive (,15
years)
ETS exposure was
defined as
exposure to
tobacco
combustion
products from
others for at least
6 months prior to
study period
Active pulmonary TB
diagnosed by M.
tuberculosis isolation,
clinical history, chest
X-ray, physical
examination and TST
75mm
Age and number
of cigarettes
smoked per
household
Children in contact
with smear-
positive adults had
increased risk of
active TB when
exposed to ETS
5.39 (2.44–
11.91)
Tipayamongkholgul,
2005, Thailand
20
Case control 130 TB cases
being, or
having been,
treated in
hospital and
130 matched
controls
identified from
the same
hospital (,15
years)
ETS exposure was
assessed using a
questionnaire – no
further definition
given
Clinical diagnosis
of PTB and
EPTB
ii The International Journal of Tuberculosis and Lung Disease
Table A.1 (continued)
Outcome studied
Author, year,
country, refer-
ence Study design
Participants/setting
(age) Exposure definition Outcome definition
Variables adjust-
ed for in the
analysis Findings
Adjusted OR
(95%CI)
Age, crowding,
frequency of illness,
SES, etc.
Risk of TB
increased with
close exposure
to ETS in
children in
contact with
TB patients
9.31 (3.14–27.58)
Ramachandran,
2011, India
9
Case control 41 TB cases and 82
neighbourhood
controls (0–14
years)
ETS exposure was
defined as
inhalation of
tobacco smoke
from another
individual; BMS
exposure was not
defined
PTB and EPTB diagnosed
by clinical examination
Birth weight,
malnutrition
Increased risk of TB
in children
exposed to BMS
and ETS
6.29 (1.32–
17.05)
6.91 (2.53–
18.91)*
Patra, 2012,
India
10
Case control 200 cases diagnosed
as having TB and
200 hospital
controls with no
TB (1–14 years)
ETS exposure was
defined as regular
exposure of
children to
tobacco smoke.
Both ETS and BMS
were assessed by
questionnaire
Clinical diagnosis of PTB
and EPTB
TB contact,
parental
education
Increased risk of
developing TB
observed in
children exposed
to ETS
1.75 (1.15–2.66)
Jubulis, 2014,
India
13
Case control 60 TB clinical disease
cases and 118
hospital controls
(25 cases
confirmed TB
cases) (0–5 years)
IAP (ETS and BMS)
was assessed by
questionnaire,
with questions
about tobacco
smokers in the
home and about
primary cooking
fuel used
Two definitions used: 1)
PTB disease diagnosed
using guidelines—
clinical examination
and radiography and/
or 2) confirmed by
positive culture
Age, school
attendance,
exposure to TB
contact,
household
food insecurity,
vitamin D
deficiency
Significantly
increased risk of
TB disease in
children exposed
to IAP (ETS and
BMS) observed
2.88 (0.67–
12.39)
7.16 (1.39–
44.54)*
* Reported adjusted risk estimate for BMS exposure.
TB ¼ tuberculosis; OR ¼ odds ratio; CI ¼ confidence interval; TST ¼ tuberculin skin test; ETS ¼ environmental tobacco smoke; PTB ¼ pulmonary TB; EPTB ¼ extra-pulmonary TB; BCG ¼ bacille Calmette-Gu
´
erin; SES ¼ socio-economic status;
BMS ¼ biomass fuel smoke; IAP ¼ indoor air pollution.
Childhood TB and indoor air pollution iii
Table A.2 Bias risk assessment of the eight studies included for final review and meta-analysis, using a combination of the Critical
Appraisal Skills Programme methodology and the method used by Ijaz et al.
24
Study identification, rating and justification of the qualitative rating
Category Qualitative rating used Altet et al.
19
Singh et al.
21
Tipayamongkholgul et al.
20
Definition and
assessment of
study outcome
High risk
Only clinical methods for TB diagnosis; no
reported standardised guidelines used
Low risk
Active TB
diagnosed using a
combination of
clinical and
radiological
diagnoses, and
TST results
Low risk
Combination
of clinical and
radiological
examinations
and TST used
to diagnose
active TB
Low risk
Guidelines used for TB
disease diagnosis
Low risk
Standardised objective diagnosis or clinical
methods for infection and disease used
Unclear
Active TB and tuberculous infection
diagnosis not reported or clearly defined
Definition of
study exposure
High risk
Exposure to ETS and/or BMS (intensity of
exposure as a function of duration and/or
proximity to source and/or amount of
tobacco used) not defined in detail
Low risk
Exposure to ETS
defined as
presence of a
household smoker
for at least 6
months before the
study
Unclear
No details of
definition of
exposure to
ETS given;
study refers to
collecting
detailed history
of exposure to
ETS
Unclear
Intensity of ETS exposure
defined as closeness of
cases to smoker, but
duration not defined
Low risk
Exposure to ETS and/or BMS (intensity of
exposure as a function of duration and/or
proximity to source and/or amount of
tobacco used) defined in detail
Unclear
Exposure not defined
Source of, and
measurement
method for,
exposure
High risk
Reported exposure to BMS and/or ETS (i.e.,
proximity of the child to the source and/or
the intensity of the source) not assessed in
detail
Low risk
Questionnaire
used to assess
exposure of the
child to ETS
during, and prior
to, study
Unclear
Exposure to
ETS assessed
by
questionnaire;
no details of
the included
questions
given
Low risk
Questionnaire containing
questions about presence
and proximity of the
source to the child used
Low risk
Investigators assessed household use of
BMS and detailed the questionnaire used to
assess ETS
Unclear
Method of assessing exposure to ETS and/or
BMS not reported in detail
Reliability — for
case control
and cross-
sectional
studies
High risk
Authors report using different methods for
cases and controls/comparison group to
measure TB outcome
Low risk
Clinical,
radiological, and
TST assessments
used for both
groups, i.e., cases
and controls
Low risk
All children
participating in
the study
underwent
clinical,
radiological
and TST
assessment for
TB diagnosis
Unclear
Authors do not specify if
similar or different
methods were used to
assess TB disease status in
controls
Low risk
Authors used the same methods for cases
and controls/comparison group to measure
TB outcome
Unclear
Authors do not state if the same methods
were used to measure TB outcome in cases
and controls/comparison group
Confounding/
controlling for
covariates
High risk
Major confounding factors/effect modifiers
(age, SES, TB contact, HIV status, BCG,
crowding, malnutrition) not assessed
Low risk
Two of the seven
covariates, SES
and crowding, not
assessed, but the
study controlled
for other
important
covariates
Low risk
Complete
assessment of
the seven
variables
categorised as
major
confounding
factors
Unclear
Two of the seven variables
that could be classified as
major, i.e., HIV status and
BCG vaccination in
children, assessed
Low risk
Major confounding factors/effect modifiers
(age, SES, TB contact, HIV status, BCG,
crowding) assessed in full
Unclear
No, or incomplete, reports given on at least
four major confounding factors/effect
modifiers
Analysis of the
study methods
to reduce bias
Low risk
Authors report use of one or more methods
to reduce bias (standardisation, matching,
adjustment in the multivariate model,
stratification, propensity scoring)
Low risk
Multiple logistic
regression used to
estimate risk of TB
disease due to ETS
exposure
Low risk
Multiple
logistic
regression used
in assessing the
association
between
exposure to
ETS and TB
disease
Low risk
Authors factored in other
covariates in multiple
regression modelling
when testing for
association between TB
outcome and other
environmental factors,
including ETS
High risk
No methods to reduce bias used/reported
TB¼ tuberculosis; TST ¼ tuberculin skin test; ETS ¼ environmental tobacco smoke; HAP ¼ household air pollution; BMS ¼ biomass fuel smoke; SES ¼ socio-economic
status; HIV ¼ human immunodeficiency virus; BCG ¼ bacille Calmette-Gu
´
erin.
iv The International Jour nal of Tuberculosis and Lung Disease
Table A.2 (continued)
Study identification, rating and justification of the qualitative rating
Den Boon et al.
4
Patra et al.
10
Du Preez et al.
8
Ramachandran et al.
9
Jubulis et al.
13
Low risk
Tuberculous infection
diagnosed using TST
induration
Low risk
TB disease diagnosis
not defined, but
reference guidelines
used
Low risk
TB diagnosed using a
standardised method,
i.e., TST induration
Low risk
TB disease diagnosis
defined using clinical
methods
Low risk
TB diagnosed using
standard clinical and
laboratory methods
Unclear
Exposure to ETS is not
defined in detail.
Low risk
Frequency and
duration as a
definition of exposure
are mentioned
Low risk
Child exposure to ETS
defined as presence of
a household smoker
for at least 12 months
Unclear
No details given on
how exposure to HAP
was defined
Low risk
Definition of exposure
to ETS and BMS given
Low risk
Exposure to ETS
assessed with a
questionnaire about
smoking behaviours in
the children’s homes
Low risk
Detailed questionnaire
assessing frequent ETS
exposure of the child
in the household used
Low risk
Questionnaire with
detailed questions on
ETS and BMS
exposure of child used
Low risk
Study indicates how
exposure to ETS was
measured using a
questionnaire, but no
details given of how
exposure to BMS was
measured
Low risk
Questionnaire used
with questions on
primary fuel used and
presence of smokers
in children’s homes
Low risk
TST used for assessing
tuberculous infection
in all participants, i.e.,
exposed and non-
exposed
Unclear
History and clinical
assessment methods
used to assess
controls, but no
specific details of the
criteria used to
diagnose cases
reported
Low risk
TST used for diagnosis
of tuberculous
infection in all
participants, exposed
and non-exposed.
Unclear
Clinical assessment
used to screen
controls, but no
specific details given
on the criteria used to
diagnose cases
Low risk
Both probable and
confirmed TB
explained for cases;
definition for controls
consistent with that
for the cases
High risk
HIV and BCG
vaccination status of
the children, crowding
and nutritional status
not assessed
Unclear
Major variables
assessed except for
HIV and malnutrition
status, important
determinants of TB
disease
Low risk
Two of the seven
major variables, SES
and crowding, not
assessed, but the
control group was
from the same
population
Unclear
Major variables
assessed except for
HIV status, an
important
determinant of TB
disease
Unclear
Variables that would
be considered
important for TB risk
not included in the
multivariate model
Low risk
Logistic regression
model used to
establish associations,
stratification and
adjustment for
different covariates
Low risk
Cases and controls
matched for sex and
age; multiple logistic
regression used to test
association between
exposure and
outcome
Low risk
Multiple logistic
modelling used to
assess relationship
between TB disease
and exposure to ETS
Low risk
Multivariate analysis
used to assess he
association of
exposure with TB
outcome
High risk
Multivariate model
used to estimate risk,
but some important
variables associated
with TB risk not
included and only 25
TB cases classified as
confirmed
Childhood TB and indoor air pollution v
