Environment International 124 (2019) 161–16

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Environment International
journal homepage: www.elsevier.com/locate/envin

Ambient air pollution exposures and risk of drug-resistant tuberculosis ..

a,1 b,c,1 a a a a,⁎ a,⁎
Liu Yao , Cui LiangLiang , Liu JinYue , Song WanMei , Su Lili , Li YiFan , Li HuaiChen
a
Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China b
Department of Biostatistics, School of Public Health, Shandong University, Jinan, Shandong, China c Jinan Municipal Center for
Disease Control and Prevention, Jinan, Shandong, China

1. Introduction
Despite the persistent international efforts to combat
tuberculosis (TB), TB continues to be a global health emergency
especially in developing countries and is particularly compounded
by high burdens of drug-resistant tuberculosis (DR-TB). According
to World Health Organization (WHO) reports, emergence of DR-
TB is recognized as a substantial threat to the efforts to reach the
goal of a 95% reduction of TB incidence by 2035 (WHO, 2016;
WHO, 2011). Multidrug-resistant tuberculosis (MDR-TB), refer to
resistance to both isoniazid and rifampin, has been increased from
2009 to 2015 for > 20% annually (Odone et al., 2016; Iseman,
1993; Caminero, 2010; Monedero and Caminero, 2010). As a
result, DR-TB has become a major focus for TB research in recent
years. The major challenge is how to prevent acquired DR-TB,
ensure early detection, and prevent transmission of DRTB
(Monedero and Caminero, 2010; Perri et al., 2011). The secular
trends and unique characteristics of DR-TB in China can give a
better understanding of current status of DR-TB epidemic.
Understanding environmental determinants of the disease is
urgently required to guide effective DR-TB infection control
measures (Smith et al., 2014a, 2014b; Gao et al., 2016; Mathuria et
al., 2013).
Air pollution, undoubtedly, is an alarming concern in China
today. Its short- and long-term adverse effects have been seen to be
a great threat to public health (Chen et al., 2012; Guo et al., 2013).
Recent reports suggest that ambient air pollution exposure might
increase the risk of pulmonary TB. Previous evidence showed
positive associations
between major ambient air pollutants, including particulate
populations (Jassal et al., 2013; Hwang et al., 2014; Chen et al.,
2016; Smith et al., 2014a, 2014b; Smith et al., 2016; Zhu et al.,
2018). However, little is known about the impact of air pollution
on the risk of DR-TB development. Several reviews combined the
epidemiological findings and demonstrate strong association
between air movements, ventilation and DR-TB transmission (Li et
al., 2007). Further studies demonstrated that effective
environmental control measures could reduce the concentration of
airborne infectious nuclei and prevent airborne TB transmission
(Escombe et al., 2009). Whereas, the high levels of PM pollutants
display complex compositions including bacteria and pathogens
which provide an important route for bacteria transmission (Yan et
al., 2018; Sun et al., 2018). Moreover, it is well known ambient air
pollution exposure has direct detrimental effects on respiratory
symptom (Peng et al., 2017). Therefore, investigations of the
association between air pollution and DR-TB may improve the
understanding of the pollutant effects on DR-TB risk and further
help to elucidate the mechanisms involved in DR-TB development
and transmission.
Publishing results linked that an increased risk of pulmonary
TB development was related to different long-term exposure
windows. A case-control study in a cohort of California
populations explored the associations of pulmonary TB and annual
average of individual air pollution exposure to 24 months window
(Smith et al., 2016). A retrospective study showed the associations
of smear-positive TB to annual mean values of individual pollutant
exposure to ambient pollutants with a 2-year interval (Jassal et al.,
2013). A following retrospective case-control study also examines
the association between sputum culture conversion TB risk and
individual average exposure to 365 days air pollutants (Chen et al.,

⁎
Corresponding authors at: Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, No. 324 Jingwuweiqi Road, Jinan 250021,
Shandong, China.
E-mail addresses: 1035312289@qq.com (L. YiFan), lihuaichen@163.com (L. HuaiChen).
1
first authors.
These authors contributed equally to this work and should be considered as co-

https://doi.org/10.1016/j.envint.2019.01.013
Received 5 August 2018; Received in revised form 3 January 2019; Accepted 5 January 2019
Available online 12 January 2019
0160-4120/ © 2019 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
matter≤ 2016). Considering the priority of air pollutant exposure windows
2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide to pulmonary TB risk, it is necessary to further examine different
(SO2), and carbon monoxide (CO), and TB development in general air pollution exposure windows. Therefore, our study honored this
L. Yao et al.
opportunity to investigate: (1) the associations of active pulmonary
DR-TB risk with the ambient air pollutants, including PM 2.5, PM10,
SO2, NO2, O3, and CO, in a severe polluted large city in China; (2)
the priority of ambient air pollutants in 5 different exposure
windows, vary from 90 days to 720 days.
2. Materials and methods
Environment International 124 (2019) 161–169
2.5. Definition
Mono-drug resistant TB refers to TB resistant to any one of the
first-line drugs isoniazid, rifampin, streptomycin, and ethambutol.
Poly-drug resistant TB refers to TB resistant to more than one
firstline anti-TB drug, other than both isoniazid, rifampin.
MDR-TB refers to TB resistant to at least isoniazid and rifampin.

2.1. Ethics 2.6. Exposure assessment

Ethics approval was obtained from the Ethics Committee of Individual exposures estimates were determined using average
Shandong Provincial Hospital, affiliated with Shandong University, ambient concentrations of PM 2.5, PM10, SO2, NO2, O3, and CO from
Shandong, China. Before analysis, patient records were all relevant monitors in Jinan city. Daily mean hourly air pollutant
anonymized and deidentified. concentration data (inhalable PM2.5, PM10, SO2, NO2, and CO) and
daily maximum of 8-hourly running mean of O3 were obtained
2.2. Setting from 14 fixed monitoring stations sourced by Environmental
Monitoring Center of Jinan from January 1, 2012 to December 31,
This study was carried out in Jinan (Fig. 1), the capital of 2015. The pollutant monitoring stations including 12 sites located
Shandong province, a large urban city in eastern China, with a
in the urban and 2 sites located in a suburban county. In order to
resident population of about 700,000 inhabitants. It is located at obtain individual air pollution exposure concentration, the
36.40°N latitude and 110.00°E longitude, and with an area of 8227
geocoded patient's addresses were assigned the pollutant level of
km2. It is a warm temperate continental monsoon climate with clear the closest monitor stations. For each study participant, the
seasons, hot summers and temperate winters. Jinan has rapidly
aggregate air pollution concentration during the different five
industrialized in the past few decades, and the urban center
exposure windows, including 90 days, 180 days, 360 days, 540
characterized by increasing population density and heavy traffic
days, and 720 days before diagnosis were estimated separately.
congestion. It featured the special “small basin” terrain that makes
Individual-level effect measure modifiers and potential
the poor air fluidity and the dust is easily accumulated in the sky of confounders were considered, including information on socio-
the city. demographic information (age, sex, alcohol use, and smoking
status). Weather confounding for the same period to air pollution
2.3. Study population and data collection
was also considered (Oguntoke et al., 2012; Luo et al., 2013).
Daily weather data of average temperature, average relative
This retrospective study enrolled consecutive new diagnosed
humidity, air pressure, and sunshine was collected from the China
and culture-confirmed TB cases reported in TB prevention and
Meteorological Science Data Sharing Service Network
control institutions of Jinan from January 1, 2014 to December 31,
(http://cdc.cma.gov.cn/home.do).
2015. Trained research clinicians collected and recorded the
patients' information confirmed within their jurisdiction using a 2.7. Statistical analysis
standard case report form and reported them to the provincial
health department –Katharine Hsu International Research Center of
Human Infectious Diseases (KICID), which was set up by
Prevention Center of Shandong province in 2004, and responsible
for the TB surveillance and laboratory quality assurance in
Shandong. Socio-demographic information, clinical data including
treatment history, prior TB contact, chest radiology, and medical
conditions were available.

2.4. Laboratory methods

Sputum samples from presumptive patients with TB were sent

to local hospital laboratories and processed for smear and culture.
Only the samples from newly diagnosed cases were included, and
the samples from recurrent TB patients and patients who have been
treated with anti-TB drugs were excluded. Drug resistance
prevalence was determined using drug-susceptibility testing (DST)
among culture-confirmed tuberculosis cases. The hospital
laboratories performed DST for first-line anti-TB drugs (isoniazid,
rifampin, streptomycin, and ethambutol) on all Mycobacterium
tuberculosis samples. For second-line drugs such as
fluoroquinolones (ofloxacin, moxifloxacin, and ciprofloxacin) and
injectables (amikacin, capreomycin, and kanamycin), DST was
also performed on rifampin-resistant isolates. External quality
assessment (EQA) for smear, culture and DST was performed by
the prefectural and provincial hospital laboratories. The
Supranational Tuberculosis Reference Laboratory (STRL)
conducted EQA based on the WHO guideline (WHO, 2016).

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We summary the condition of ambient air pollution and 86 μg/m3, 154 μg/m3, 78 μg/m3, 43 μg/m3, 92 μg/m3, and 1228

Fig. 1. Map of Jinan.

weather from 2012 to 2015 in Jinan, and then described the μg/m3, respectively.
characteristic of active pulmonary TB cases including drug-
resistant TB and drug-sensitive TB cases. Among the DR-TB 3.2. Characters of active pulmonary TB cases
cases, we calculated the proportion of drug resistance. In order to
have a quick overview of the relationship between air pollution Initially, a total of 809 newly diagnosed pulmonary TB patients
and active pulmonary DR-TB risk, the comparison on the air Table 1
pollution level was conducted between Mono-drug resistant TB Descriptive characteristic of 752 active pulmonary TB cases in Jinan, 2014–
and Mono-drug sensitive TB cases, between Poly-drug resistant 2015.
TB and Poly-drug sensitive TB cases, and between MDR-TB and Item All patients (%) Drug- resistant Drugsensitive p
TB (%) TB
Multi-drug sensitive TB cases, respectively. (%)
We used a logistic regression model, which adjusted for
confounding factors of socio-demographic (age, sex, alcohol use, N 752 141 (18.8) 611 (81.3)
smoking status, and so on) and weather conditions to evaluate the
Age,years
odds ratios (ORs) and 95% confidence intervals (CIs) for the
Mean SD 43.7 ± 19.0 43.02 ± 18.3 43.9 ± 19.1 0.622
correlation between active pulmonary DR-TB and air pollutant Gender 0.486
concentration (PM2.5, PM10, SO2, NO2, O3, and CO), further varying
5 different exposure windows (90, 180, 360, 540, and 720 days) Male 504 (67.0) 90 (64.3) 414 (67.6)
prior to diagnosis date.
Sensitive analysis of the multi-pollutant Female 248 (33.0) 50 (35.7) 198 (32.4)
model
(PM2.5 + PM10 + SO2 + NO2 + O3 + CO) for each pollutant and active Smoking 0.748

pulmonary DR-TB was conducted. All statistical analyses for this

Smoker 193 (25.7) 34 (24.3) 159 (26.0)
study were performed using R software (version 3.3.2).
Significance was defined as two-sided P < 0.05 for all analyses. Nonsmoker 559(74.3) 106(75.7) 453(74.0)

3. Results Drinking 0.359

3.1. Characters of ambient air pollution and weather Yes 111 (14.8) 17 (12.1) 94 (15.4)

The daily air pollution concentrations and meteorological No 641 (85.2) 123 (87.9) 518 (84.6)
conditions from 2012 to 2015 in Jinan are shown in Table 1. The
Medical conditions
median concentrations of PM2.5, PM10, SO2, NO2, O3, and CO was
Respiratory disease 29 (3.9) 10 (7.1) 19 (3.1) 0.047

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Cardiovascular 59 (7.8) 18 (12.8) 41 (6.7) Poly-drug resistance 92 12.3
disease INH + SM 29 3.9
Diabetes 69 (9.2) 8 (5.7) 61 (10.1) RFP +SM 63 8.4
Hepatopathy 8 (1.1) 2 (1.2) 6 (1.0) Multi-drug resistance (MDR) 25 3.3
Cerebrovascular 12 (1.6) 6 (4.3) 6 (1.0) MDR1: INH + RFP 25 3.3
disease MDR2: INH + RFP + EMB 21 2.8
Gastrointestinal 14 (1.9) 1 (0.7) 13 (2.1) MDR3: INH + RFP + SM 13 1.7
disease MDR4: INH + RFP + EMB + SM 13 1.7
Cancer 10 (1.3) 3 (2.1) 7 (1.1) Mono resistance: Resistance to one first-line anti-TB drug only. Polydrug
Connective tissue 4 (0.5) 0 (0.0) 4 (0.7) resistance: Resistance to more than one first-line anti-TB drug, other than
diseases both isoniazid and rifampicin.
Hormonotherapy 6 (0.8) 0 (0.0) 6 (1.0) Multidrug resistance (MDR): Resistance to at least both isoniazid and
rifampicin.
were notified in Jinan during the 2-year study period with DST
First-line anti-TB drug: INH, isoniazid; RFP, rifampin; SM, streptomycin;
results for anti-TB drugs were available. We excluded 57 cases EMB, ethambutol.
with definite TB contact history. After these exclusions, we had a Second-line anti-TB drug: FQ, fluoroquinolines (specifically ciprofloxacin
total of 752 TB cases and levofloxacin); AMK, amikacin; CPM,capreomycin; PAS;para-
Table 2 aminosalicylic acid; KM, kanamycin.
Summary of ambient air pollution concentrations and weather condition (7.9%), capreomycin (4.4%), kanamycin (3.3%), and amikacin
from 2012 to 2015, Jinan city. (3.1%).
Item Mean (SD) Min Median
A total of 92 (12.3%) cases were resistant to > 1 drug but were
Air pollutants(ug/m )3 not MDR (poly-drug resistant), and 25 cases (3.3%) were MDR-
PM2.5 96 (31) 57 86 TB (Table 3). For poly-drug resistant TB patients, 63 cases (8.4%)
PM10 173 (46) 30 154 were resistant to rifampin and streptomycin, and 29 cases (3.9%)
SO2 70 (37) 21 78 were resistant to isoniazid and streptomycin. For MDR-TB
NO2 56 (14) 25 43 patients, 25 cases (3.3%) were resistant to isoniazid and rifampin,
O3 120 (49) 20 92 21 cases (2.8%) were resistant to isoniazid, rifampin and
CO 1427 (410) 643 1228 ethambutol, and 13 cases (1.7%) were resistant to isoniazid,
Meteorology
rifampin and streptomycin.
Average temperature (°C) 14.9 (10.7) −9.4 16.5
Relative humidity (%) 54 (19) 13 55
3.4. Comparison of air pollution level between TB cases with and
during 2014–2015. without drug resistance
Baseline characteristics of the study population are shown in
Table 2. Among enrolled participants, 504 patients were male Table S1 showed the mean and differences of air pollutants
(67%), the mean age was 43.7 ± 19.0 years old, TB cases were concentration between mono-drug resistant TB cases and mono-
more likely to be never smokers and have lower alcohol intake. drug sensitive TB cases. Higher air pollution exposure
Among the 752 TB cases with culture positive for M. tuberculosis concentration was observed for mono-drug resistance TB cases
complex, 141 cases (18.8%) were first-line DR-TB resistant cases. compared with mono-drug sensitive TB cases for PM 2.5, PM10, SO2,
Age, gender, smoking history and drinking history were similar for O3, and CO at different exposure windows, but the NO2 showed the
TB cases with and without first-line drug resistant (P > 0.05), opposite difference. For PM10 and CO, statistically significant
whereas, DR-TB cases were more likely to be complicated with difference was found between the mono-drug resistance TB cases
respiratory disease (P = 0.047), cardiovascular disease (P = 0.039), and sensitive TB cases at more than two exposure windows. The
and cerebrovascular disease (P = 0.013). same trend was observed for poly-drug resistant TB cases (Table
S2) and MDR-TB cases (Table S3). Overall, the dominant
3.3. Proportion of drug resistance statistically significant associations for air pollutants and drug
resistance TB were observed at 540 days exposure.
Among the 141 TB cases with first-line anti-TB drug
resistance, streptomycin was associated with the highest rate of 3.5. Regression results
resistance (15.3%), followed by rifampin (10.8%), isoniazid
(5.2%), and ethambutol (1.9%) (Table 3). The overall second-line 3.5.1. Mono-drug resistance and air pollution
anti-TB drug resistance rate was 13.0% (98/752). Fluoroquinolones The ORs and 95% CIs in the single- and multi-pollutant models
were associated with the highest rate of resistance (11.3%), for the associations between first-line anti-TB drug mono-
followed by paraaminosalicylic acid resistance and air pollution were presented in Fig. 2.

Table 3 3.5.1.1. Isoniazid resistance. In the single-pollutant model, high

Drug resistance of 752 active pulmonary TB cases in Jinan, 2014–2015. exposure to PM2.5 (OR = 1.016, 95%CI: 1.006–1.026), PM10 (OR =
Item n 1.021, 95%CI: 1.013–1.029), SO2 (OR = 1.011, 95%CI: 1.001–
1.021), and CO (OR = 1.004, 95%CI: 1.003–1.006) were all
First-line drug 140
significantly associated with increased risk of resistance to
INH 39
RFP 81 isoniazid at 540 days. PM10 and CO were also significantly
SM 115 associated with increased risk of isoniazid resistance at 90, 180,
EMB 14 and 360 days, and a significant effect was observed for O3 at 180
Second-line drug resistance 98
days. In the multi-pollutant models, when adjusted for the other
FQ 85
AMK 23 pollutants, exposure to PM2.5 (540 days), PM10 (90, 180, 360, 540,
CPM 33 and 720 days), and CO (90 and 540 days) was still significantly
PAS 59 associated with elevated risk of resistance to isoniazid (P < 0.05)
KM 25
(Table S4).
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L. Yao et al.
3.5.1.2. Rifampin resistance. In the single-pollutant model, we
observed a statistically significant effect on rifampin resistance for
exposure to PM2.5 (OR = 1.014, 95%CI: 1.007–1.022), SO2 (OR =
1.008, 95% CI: 1.001–1.016) and O3 (OR = 1.017, 95%CI: 1.007–
1.027) at 540 days. Both PM10 and CO were significantly associated
with increased risk of rifampin resistance at all exposure period,
and the strongest risk estimate for PM 10 (OR = 1.039, 95%CI:
1.031–1.046) was observed at 360 days exposure, and for CO was
observed at 540 days (OR = 1.005, 95%CI: 1.004–1.006). In the
multi-pollutant models, exposure to PM 2.5 (540 days), PM10 (90,
Environment International 124 (2019) 161–169
180, 360, 540, and 720 days), and CO (90, 180, and 540 days) was
still significantly associated with elevated risk of resistance to
rifampin (P < 0.05) (Table S4).
3.5.1.3. Streptomycin resistance. In the single-pollutant models,
PM2.5 (540 days), O3 (540 days), PM10 (90, 180, 360, 540, and
720 days), and CO (90, 180, 360, 540, and 720 days) were found to
be significantly associated with elevated risk of streptomycin
resistance. Most of the significant effects detected in the single-
regression models remained statistically significant in multi-
regression models (Table S4).
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Fig.2. ORs and95%con fi denceinterval(95% CI ofMono-drugresistanceTBandairpollutionindi ff erentexposurewindows.

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3.5.1.4. Ethambutol resistance. In the single-pollutant models, PM10 (180, 360, and 540 days), and CO (180, 360, and 540 days) were
found to be significantly associated with elevated risk of
ethambutol resistance. PM2.5 (90 days), PM10 (180, and 360 days),
and CO (180, and 540 days) was significantly associated with
elevated risk of ethambutol resistance in multi-pollutant models
(Table S4).

3.5.2. Poly-drug resistance and air pollution

3.5.2.1. Isoniazid and streptomycin resistance. Statistically
significant effects were observed for exposure to PM 2.5 (540
days), PM10 (180, 360, 540 days), O3 (180 days), and CO (90,
360, 540 days) in the singlepollutant models, and most of the effects
remain robust in the multipollutant models except for O3 (Fig. 3)
(Table S5).
ff erentexposurewindows.
3.5.2.2. Rifampin and streptomycin resistance. Exposure to PM2.5
(540 days), PM10 (90, 180, 360, 540, and 720 days), SO2 (540 and 720
days), O3 (540 days), and CO (180, 360, and 540 days) were
significantly associated with elevated risk of rifampin and
streptomycin resistance in the single-pollutant models. Most of
the positive effects were stable in the multi-pollutant models, only
the effect of SO2 was substantially diminished (Fig. 3) (Table S5).

3.5.3. Multi-drug resistance and air pollution

High exposure to PM2.5, PM10, and CO was significantly
CI ofPoly-drugresistanceTBandairpollutionindi

associated with increased risk of MDR both in the single- and

multi-pollutant models (Fig. 4) (Table S6).

4. Discussion

The present study of the Chinese TB patient cohort in Jinan, a

severely polluted large city was the first attempt to show
associations between ambient air pollution and increased risk of
DR- TB. Specifically, we observed significantly positive correlation
between ambient PM2.5, PM10, O3, and CO exposures and the
incidence of DR-TB, including firstline mono drug resistance,
poly drug resistance as well as MDR in both single- and multi-
regression models. The positive effects of PM10, and CO were
observed from 90 to 540 days exposure before the onset of
fi denceinterval(95%

DRTB, whereas the dominant significant effects of PM2.5 and O3

were observed at 540 and 180 days exposure respectively.
Additionally, a negative association between ambient NO 2
exposure and the risk of DRTB was observed, and the stronger
protective health effect of NO2 was found at 540 days exposure
)

window.
ORs and95%con

Our analysis is a pioneering study to explore the effect of air

pollutants exposure on the incidence of DR-TB. Although no
previous research has this specific purpose, a number of relevant
studies have showed significant associations between ambient air
pollutant exposure and the risk of TB development. For example,
Fig.3.

a nested case-control study reported NO2 and CO were

significantly associated with increased incidence of pulmonary
TB among residents in Northern California, but no positive
correlation between PM 2.5 or O3 and TB were observed (Smith et
al., 2016). Another U.S.-based analysis suggested a significant
association between smear-positive TB cases and PM 2.5 exposure
(Sm ith et al., 2014a, 2014b). A South Korea study showed SO2
increased the risk of TB in males, but not O 3, CO, and NO2
(Hw ang et al., 2014). The inconsistent results suggest that further
epidemiological research is needed to provide evidence on the
association between air pollution exposure and the risk of TB.
Moreover, a recent retrospective Chinese study suggests long-
term exposure to PM2.5 may increase the mortality from TB and other

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diseases among TB patients (Peng et al., 2017). The above evidence provided a link exist between ambient air pollution exposure and
increased morbidity and mortality of TB.
The underlying mechanisms for increase in DR-TB risk with ambient air pollution exposure
might be multifactorial. Firstly, it has been well recognized that ambient air pollution
exposure has direct detrimental effects on respiratory and cardiovascular system. Short-term
exposure to PM is associated with increases in cardiopulmonary morbidity and mortality (Brook et
al., 2010; Newell et al., 2017). The possible mechanism for adverse health effects of pollutants on
respiratory symptoms through promoting oxidative stress and inflammation (Brook et al.,
2010; Kelly and Fussell, 2015; Ling and van Eeden, 2009; Li et al., 1996). The oxidative stress
caused by particles or other pollutants can directly damage the epithelium of the airways and
reduce the immune response (Cao et al., 2011). Moreover, particles can penetrate through the
vessel and create vascular dysfunction with potential systemic inflammation reaction [33].
Inflammation induction and particle deposits in the damaged lungs may further reduction
pulmonary function and promote disease progression especially for TB patients
complicated with other pulmonary disease (Atkinson et al., 2010). Previous epidemic study
ff erentexposurewindows.

indicated that acquired resistance was more likely in TB patients complicated with other
pulmonary disease such as COPD and asthma (Schikowski et al., 2014a; Schikowski et al., 2014b).
Indeed, TB patients complicated with other cardiopulmonary disease should be more vulnerable to
ambient air pollution than healthier people. In the present study, DR-TB cases were more
likely to be complicated with respiratory and cardiovascular disease. As a result, air
pollution may exacerbate the underlying cardiopulmonary diseases and increase the
occurrence of complications, so as to prolong treatment duration and increase treatment
failure rate. Ineffective treatment, could contributed to acquired drug resistance and further
contributed to the DR strains transmission (WHO, 2016).
Additionally, air pollution might increase the risk of direct infection with a resistant TB
CI ofMulti-drugresistanceTBandairpollutionindi

strain. Previous evidence revealed DR-TB is predominantly caused by transmission rather than
acquisition in most regions of the world (WHO, 2016). The high polluted air condition might be
contributed to increased resistant tuberculosis strains transmission. Starting from early January
2011, northern China was hit by multiple prolonged and severe air pollution and “Chinese
haze” was created to describe the air quality problem. The Chinese haze was characterized by
extremely high- level concentrations of ambient gaseous and PM (e.g., PM 2.5 and PM10)
pollutants (Chen et al., 2012). Previous evidence suggests PM pollutants display complex
compositions including microorganisms, and most of the microorganisms adhere to the
particles because the microbes could not use air components directly for growth and reproduction
(Zhang et al., 2013; Zhang et al., 2014). Moreover, a number of studies revealed that the PM
fractions significantly affected the airborne bacterial composition, and the abundances of
several bacteria greatly increased in heavy-haze days. As a result, the high levels of PM
pollutants provide an important route for the transmission of bacteria and pathogens (Brook et al.,
2010; Atkinson et al., 2015) and thus can be potentially route for DR-TB strains transmission.
fi denceinterval(95%

Further investigations aiming to examine how particles and gaseous pollutants affect
DR-TB strains transmission are required.
Moreover, air pollution might have contributed to DR-TB transmission in congregate settings.
TB outbreaks often occurred in congregate settings such as hospital, homeless shelters, and other
health care settings (Mohle-Boetani et al., 2002; Alland et al., 1994). Occupational TB and
nosocomial TB transmission are common in congregate settings where TB is prevalent.
)
ORs and95%con

Guidelines for preventing DR-TB transmission advocate effect environmental control actions
to reduce the airborne infectious droplet nuclei in hospitals and other health care settings
(WHO, 1999; Jensen et al., 2005). Previous research provided substantial evidence to
demonstrate the correlation between air movements, ventilation in buildings and the
transmission infectious diseases including pulmonary TB. Natural ventilation is important
environmental control measure which provides greater protection and with little cost (Escombe
Fig.4.

et al., 2007), but is climate dependent. In the polluted air conditions, the increase of the air-
tightness measures would be used to prevent the ingress of outdoor pollution. As a result,
ventilation in congregate settings might be greatly hampered and airborne DR-TB strain
transmission in high-risk settings may increase. Further research aiming to specify the
association between air pollution and DR-TB strains transmission are needed.
We find a dominant detrimental effect of PM2.5 to DR-TB was observed at
positive correlation 540 days exposure, whereas both the short- and long-term (from 90
between exposures to to 720 days) exposure to PM 10 was significantly associated with
ambient PM (PM2.5 and increased incidence of DR-TB. These effects remained significant
PM10) and after adjustment for other air pollutants. The results support the
increased incidence of hypothesis that PM might be a potential vector for DR-TB strain
mono-, poly- and transmission and PM also play direct detrimental health effect to
multiDR TB. The TB patients. We also found positive associations between

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increased incidence of DRTB and exposure to O 3 and CO,
however, most of the significant effects of O3 were not present in
the multi-pollutant models. The effects of CO were sensitive to the
addition of other pollutants and the highest effect estimates were
observed at 540 days exposure. Previous studies suggested the
impact of indoor air pollution such as CO on TB disease should
transpose into a specific mechanism in vivo. A closer look at the
physiological effects of CO and the biology of TB suggests coal
fumes shut down the immune response of the host. Whether
outdoor CO contributes to DR-TB transmission might via similar
mechanisms warrant future examination.
Interestingly, we showed a negative correlation between
ambient NO2 and the risk of DR-TB which effects were enhanced
after adjustment of other pollutants, and negative association was
also observed for SO2 exposure in the multi-pollutant model.
Similarly, in a recent study conducted in Chengdu, China, ambient
SO2 exposure was shown to be associated with decreased risk of
TB outpatient visits. Possible mechanism is that the
mycobacterium TB have unique cell surface with rich complex
lipids, such as wax-D, cord factor, and mycolic acids. However,
exogenous admission of SO2 may lead to oxidative injury to
proteins, lipids, and DNA (Rencuzogullari et al., 2001), thus
inhibiting/ killing mycobacterium TB (Malwal et al., 2012).
Further studies are advocated to elucidate correlations between
NO2, SO2 and DR-TB and may provide some insights into possible
biological mechanisms.
The present study has several limitations. Firstly, a large
proportion of TB cases were diagnosed on the basis of clinical and
radiologic evidence. This is prone to some diagnosis
misclassification. Secondly, measurement of long-term air
pollution exposure might lead to misclassification. In this analysis,
the air pollution concentration at the patient's dwelling place was
used to characterize exposure. We do not have precise data about
multiple modifiers of air pollution exposure and subsequent
respiratory uptake of air pollutants that are consequences of the
behavior and overall activity levels (sport, physical labor), type of
work, and time spent indoors and outdoors of the study subjects
that all could impact on the strength of the exposures. Thirdly,
previous evidence suggested indoor air pollution was a risk factor
for TB. We have not assessed the indoor pollutants level, which
might lead to an overestimate of the pollutants effect if there is
higher indoor exposure.
In summary, our analysis provide novel findings that long-term
exposures to four key air pollutants (PM2.5, PM10, O3 and CO) are
associated with significantly increased risk of first line DR-TB. To
our knowledge this is the first large scale epidemiologic study with
individual estimates of air pollution levels aiming to investigate the
correlation between air pollution and DR-TB. These findings
warrant further investigation and suggest that ambient air pollution
control might help decrease the incidence of DR-TB.

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