Based on 7996 newly diagnosed tuberculosis cases in Shandong, China, we sought to investigate the independent and joint effect of alcohol drinking and tobacco smoking on TB drug-resistance respectively. In short, smoker+drinker(G3) had a higher risk of MDR1(INH+RFP), but had a lower risk of DR-TB, RFP-related resistance, SM-related resistance, EMB-related resistance, MDR3(INH+RFP+SM), and any INH+SM resistance. However, there were no significant impact of alcohol drinking only or tobacco smoking only on various drug-resistant sub-types (P>0.05). Compared with the control(G0), whether TB cases belonged to smoker only(G1), drinker only(G2), or G3, they all had more males, comorbidities (total), and diabetes. Furthermore, males and cavitary diseases were more likely to be DR-TB among non-smoker+non-drinker group(G0).
According to our study, compared with G0, TB cases with both drinking and smoking habits had a different drug-resistant profiles such as an increased risk of MDR1(INH+RFP) but lower risk of DR-TB. Our findings were not identical to a previous meta-analysis which showed that smoking habits was associated with an increased risk of DR-TB (OR=1.57, 95% CI 1.33–1.86), MDR-TB (OR=1.49, 95% CI 1.19–1.86). Another study found that alcohol abuse (OR=1.3; 95% CI: 1.0-1.8) was risk factor identified for MDR-TB. However, the absence of an correlation between alcohol drinking only, tobacco smoking only with TB resistance in our research was inconsistent with the findings of most previous studies[16, 17].
As we all know, many factors such as incomplete and inadequate treatment, complications of diabetes, direct transmission of drug-resistant strains contribute to the development of DR-TB[4, 17, 18]. Therefore, alcohol drinking and tobacco smoking may also affect the resistance of TB through the above pathways. There may be some explanations for the joint impact of both drinking and smoking habits on TB resistance: 1) Tobacco smoking and TB resistance: It has been found that tobacco smoking was associated with the evaluated risk of TB infection, the increased TB-related mortality, and the lower treatment compliance[7, 8]. The roles of tobacco smoking in the pathogenesis of TB were that cigarette smoke decreased the mucociliary clearance, reduced the immune response of alveolar macrophage, lead to a lower production of TNF-αand interleukin-12 (IL-12), and impeded granuloma formation, thus creating conditions for the infection and development of TB[8, 19]. Previous studies suggested that mutations associated with TB resistance usually lead to an impaired bacterial growth rate and a decreased virulence which was also known as “fitness cost”, presumably, reduced immune function in human body caused by tobacco smoking may contribute to the infection of some drug-resistant TB strains such as MDR1. In addition, TB cases with tobacco smoking had a lower compliance and were less likely to complete anti-TB therapy, which may result in acquired resistance[16, 21]. 2) Alcohol drinking and TB resistance: Similar to smokers, TB cases with alcohol drinking habits also had poorer treatment outcomes including loss to follow-up, death, treatment failure among both sensitive TB (OR=1.99, 95% CI 1.57–2.51) and MDR-TB (OR=2.00, 95% CI 1.73–2.32), while treatment failure were independent a risk factor for acquired resistance[22, 23]. Alcohol use could also lead to weakened immunity, liver damage and nutritional deficiency, which may contribute to both sensitive and resistant TB infection. Interestingly, we found a protective effects of alcohol drinking and tobacco smoking on some resistance, it may also be caused by the altered susceptibility to different TB strains, but more potential mechanisms remained to explored. Finally, our study indicated that the combined effects alcohol drinking and tobacco smoking may be stronger than alone, which may explained the results without statistical significance among drinker-only group and smoker-only group.
People with both smoking and drinking habits were more likely to be males (accounted for 99.7%) and aged between 45-64 (accounted for 47.56%). They also had a higher rate of comorbidities (16.87%) and diabetes (10.03%). The gender difference of smoking and drinking habits is huge, for example, a population-based study in china found that 45% men and 3% women were cigarette smokers, 34% male and 4% female were alcohol drinkers. TB cases also have more males, it was reported that about 6 million adult men and 3.2 million adult women fell ill with TB in 2017. Smoking and drinking had many adverse effects on human health, they could increase the risk of cardiovascular disease, stroke, infection, diabetes and so on[9, 21, 27].
Among TB cases with drinking and smoking habits, those who with cavity had a higher risk of DR-TB, while among TB cases without these habits, both males and cavitary disease were risk factors for DR-TB. So far, studies on the association of gender and TB resistance were still not consistent, some found females were more likely to have MDR-TB than males (aOR=1.315 95% CI: 1.117-1.548, p=0.001), but another found that either sex were at higher risk of MDR/RR-TB[28, 29]. Different gender often means differences in living habits such as smoking and drinking, social pressures, access to health-care services, and exposure to other risk factors[29, 30]. Both males and TB diseases with cavity should be recognized as a vulnerable population to DR-TB, and improve their access to DST and directly-observed treatment strategy (DOTS) may help to reduce the burden of TB in China more effectively, which may also lead to a gender equity in TB therapy and care.
Our study has several strengths. Firstly, although the joint effects of smoking and drinking on TB resistance including many sub-types were rarely discussed in former publications, our study not only explored the combined impact but also investigated the independent effects. Secondly, our study had a great scale and time span, and we collected all newly diagnosed TB cases with DST results, smoking and drinking status in Shandong, China, from 2004 to 2020. Thirdly, our study was conducted among new TB cases after excluding all retreated cases, and which would help to reduce more confounding factors. A disadvantage of our study was that it had not divided smoking and drinking status into more subgroups, and we had to only use the information available because it was a retrospective study. Another limitation was that DST of second-line anti-TB drugs were not routinely conducted in China unless the patient asks for it.