Associations Between Exposures To Ambient Air Pollutants And Outcomes Related To The Tuberculosis Process

Tuberculosis（TB）is an ancient airborne infectious disease caused by Mycobacterium tuberculosis（M.tuberculosis）,and currently remains one of the world’s important health issues.Active tuberculosis patients discharge droplet nuclei containing M.tuberculosis into the air by coughing,shouting,sneezing,etc,and healthy people may become infected with M.tuberculosis after inhaling them.Major risk factors of tuberculosis include the pandemic of human immunodeficiency virus,lack of health care services accompanied by low socioeconomic conditions,overcrowding,smoking,alcoholism,malnutrition,etc.In addition,ambient air pollutants in environmental factors may also be risk factors in the occurrence and development of tuberculosis.Although until now there have been only a couple of studies on the relationship between exposures to ambient air pollutants and outcomes related to tuberculosis,the possible associations between the two have been indicated.On one hand,recent epidemiological studies have shown associations of exposures to ambient air pollutants with increased risks of tuberculosis incidence and outpatient visits and mortality of tuberculosis patients.On the other hand,some studies have indicated possible biological mechanisms for exposures to ambient air pollutants on the occurrence and development of tuberculosis from aspects of the source of infection,route of transmission,and susceptible population of tuberculosis.Especially a series of toxicological experimental evidences have shown that exposures to ambient air pollutants can alter the immune functions of host local parts and the whole system,reduce host resistance to M.tuberculosis infection,and promote M.tuberculosis growth.Nevertheless,current researches on the associations between exposures to ambient air pollutants and outcomes related to the tuberculosis process are still in their infancy,especially lacking researches on the exposure-response relationships between fluctuations of atmospheric pollutant concentrations in a short period of time and the outcomes,as well as their lag effects.Based on the disease progression of tuberculosis and taking tuberculosis patients’initial outpatient visits,notifications,and death as the main line,this study was performed to explore the associations between air pollutant concentrations routinely monitored and three outcomes in the tuberculosis process from the following three aspects:（1）The associations between exposures to ambient air pollutants and the number of initial outpatient visits for tuberculosis using weekly time series data;（2）The associations between long-term exposures to ambient air pollutants and the number of tuberculosis notifications using monthly time series data;（3）The associations between individual-level short-term exposures to ambient air pollutants and all-cause mortality of tuberculosis patients during treatments using a case-crossover design.Part One:The associations between exposures to ambient air pollutants and the number of initial outpatient visits for tuberculosisObjectives:To investigate the weekly associations between exposures to ambient air pollutants and the number of initial outpatient visits for tuberculosis.Methods:A time-series study was conducted using a Poisson regression model combined with a distributed lag non-linear model（DLNM）with weekly ambient air pollutant data(including PM₁₀,PM_2.5,SO₂,NO₂,CO,and O₃)and the number of initial outpatient visits for tuberculosis during 2014-2017 in Wuhan.Stratified analyses were then performed by patients’age and gender,as well as the season of tuberculosis incidence（peak and trough）.Results:A 10μg/m³increase in NO₂ was associated with a 11.74%（95%confidence interval,CI:0.70%,23.98%;lag 0-1 weeks）,21.45%（95%CI:1.44%,45.41%;lag 0-2）,and 12.80%（95%CI:0.97%,26.02%;lag 0-1）increase in the cumulative number of initial outpatient visits among the total tuberculosis patients,old patients（≥60 years old）,and male ones,respectively.A 0.1 mg/m³increase in CO was associated with a 42.32%（95%CI:1.16%,100.22%;lag 0-16）increase in the cumulative number of initial outpatient visits among the old patients,and with a 201.9%（95%CI:29.42%,604.28%;lag 0-16）increase in the cumulative number of initial outpatient visits among the total tuberculosis patients from each September to the next February（the trough of tuberculosis incidence）.A 10μg/m³increase in PM_2.5 was associated with a 17.38%（95%CI:0.28%,37.38%;lag 0-16）increase in the cumulative number of initial outpatient visits among the old patients,and with a 4.64%（95%CI:0.22%,9.26%;lag 0）increase in the cumulative number of initial outpatient visits in the total tuberculosis patients from each September to the next February.In addition,each 10μg/m³increase in O₃,a 9.78%（95%CI:1.30%,18.98%）increase in the cumulative number of initial outpatients visits in male tuberculosis patients at the same week and a 18.92%（95%CI:0.93%,33.64%;lag 0-6）decrease in the cumulative number of initial visits in elderly patients were observed.Each10μg/m³increase in SO₂ was associated with a 22.23%（95%CI:0.49%,39.23%;lag 0-16）,28.65%（95%CI:8.58%,44.3%;lag 0-16）,23.85%（95%CI:0.37%,41.79%;lag 0-8）,and 23.82%（95%CI:1.11%,41.31%;lag 0-16）decline in the cumulative number of initial outpatient visits among the total,young（aged 15-59 years old）,old,and male patients,respectively.In addition,no significant associations were found between PM₁₀and the number of initial visits for tuberculosis.Conclusion:This study found lagged associations between weekly concentrations of ambient air pollutants(including PM_2.5,SO₂,NO₂,CO and O₃)and the number of initial outpatient visits for tuberculosis among the particular group in Wuhan.Part Two:The associations of long-term exposures to ambient air pollutants and the number of tuberculosis notificationsObjects:To preliminarily analyze the associations of long-term exposures to ambient air pollutants with the number of tuberculosis notifications.Methods:Using monthly ambient air pollutant concentrations(including PM₁₀,PM_2.5,SO₂,NO₂,NO_X,and CO)and the number of tuberculosis notifications in Hong Kong from 1999 to 2018,a Poisson regression model combined with a DLNM were conducted to assess the associations and attributable risks（attributable fractions）of long-term exposures to ambient air pollutants with the number of tuberculosis notifications.Results:Nonlinear relationships between long-term exposures to PM₁₀,PM_2.5,and NO_X and risks of tuberculosis cases notified were identified.The concentrations of PM₁₀,PM_2.5,and NO_X corresponding to the minimum numbers of tuberculosis notifications（the minimum tuberculosis notification concentrations,MTNCs）were 63.2μg/m³,41.7μg/m³,and 167.3μg/m³,respectively.Compared with the MTNCs,the number of tuberculosis notifications increased by 78.90%（95%CI:17.03%,173.50%）,79.54%（95%CI:25.43%,156.99%）,and 99.10%（95%CI:4.87%,278.00%）for the 95th percentiles of PM₁₀,PM_2.5,and NO_X.The tuberculosis notifications rates attributed to concentration ranges above the MTNCs of PM₁₀,PM_2.5,and NO_X were 9.26%（95%empirical confidence intervals,e CI:3.17%,15.19%）,8.70%（95%e CI:3.27%,13.34%）,and 7.94%（95%e CI:0.68%,13.79%）.Tuberculosis notifications rates attributed to concentration ranges above their 95th percentiles were 5.26%,5.96%,and 4.84%,respectively.In addition,no significant associations of SO₂,NO₂,and CO with the number of tuberculosis notifications were found.Conclusion:Long-term exposures to high concentrations（ranges above the 95th percentiles）of ambient air pollutants(including PM₁₀,PM_2.5,and NO_X)in Hong Kong may be associated with increases in the number of tuberculosis notifications in this area.Part Three:The associations between short-term exposures to ambient air pollutants and all-cause mortality during treatmentsObjectives:To assess the associations between short-term exposures to ambient air pollutants and all-cause mortality during treatments.Methods:551 tuberculosis patients who lived in Wuhan,China and died during treatments in 2013 and 2019 were investigated.The individual-level exposures to air pollutants(including PM₁₀,PM_2.5,SO₂,NO₂,CO and O₃)were estimated using the monitored data from the nearest air quality monitoring stations of home addresses of each tuberculosis patient.Associations between short-term exposures to ambient air pollutants and all-cause mortality during treatments were analyzed using a case-crossover design and conditional logistic regression models.In addition,stratified analyses by patients’age,gender,treatment types（initial treatment and retreatment）,and diagnostic results（smear negative and positive tuberculosis）were further conducted.Results:Short-term exposures to PM_2.5（lag 0 day）,NO₂（lag 1,lag 6,and lag 01-lag 07）,and O₃（lag 4）were significantly associated with all-cause mortality during treatments in Wuhan.Each 10μg/m³increase in PM_2.5（lag 0）,NO₂（lag 07）,and O₃（lag4）during treatments were significantly associated with all-cause mortality in tuberculosis patients,with odds ratios of 0.962（95%CI:0.930,0.995）,1.144（95%CI:1.040,1.260）,and 0.926（95%CI:0.862,0.995）,respectively.No significant associations were found between short-term exposures to PM₁₀,CO,and SO₂ and all-cause mortality during treatments.In addition,the treatment type had an effect modification on the associations between O₃ and all-cause mortality in tuberculosis patients.Conclusion:The associations between short-term exposures to ambient air pollutants(including PM_2.5,NO₂,and O₃)and all-cause mortality during treatments were found among tuberculosis patients in Wuhan,providing relevant evidence for acute health effects of short-term exposures to ambient air pollutants on death.