Figures
- FIGURE 1
A representative flow of immunological mechanisms for countering infection with Mycobacterium tuberculosis. Upon inhalation, M. tuberculosis enters the lungs, reaches the alveolar space and encounters macrophages (MΦ). Cross-priming of dendritic cells or direct presentation of antigen leads to the activation of antigen-specific CD4+ and CD8+ T-cells. CD8+ T-cells exert direct cytotoxic effects on infected cells and produce interferon-γ (IFN-γ) and tumour necrosis factor (TNF), which activate macrophages. CD4+ T-helper (Th) cells polarise into different subsets. Th1 cells produce interleukin (IL)-2 for T-cell activation, and IFN-γ or TNF for macrophage activation. Th17 cells activate polymorphonuclear granulocytes (PNGs) via IL-17 production, while Th2 cells activate B-cells via IL-4. Additionally, some CD4+ T-cells express class I-restricted T-cell associated molecule (CRTAM) and have the potential to differentiate into various cytotoxic CD4+ T-cell subsets based on environmental cytokines. Solid granulomas form to contain M. tuberculosis, but if the bacterial load exceeds containment, the granuloma will undergo caseous necrosis and fail to contain the infection. PRR: pattern recognition receptors; MHC: major histocompatibility complex; CD: cluster of differentiation; CTL: cytotoxic T-lymphocyte; IEL: intraepithelial lymphocyte.
- FIGURE 2
Countries in the three high-burden country lists for tuberculosis (TB), TB/HIV and multidrug-resistant TB (MDR-TB) identified by the World Health Organization (WHO) in 2016–2020, and their areas of overlap. Countries with a smoking prevalence >20% of all adult men as of 2018 are highlighted in bold. Data taken from the WHO Global TB Report 2020 [1] and the Global Health Observatory (GHO) data repository [3]. ¶: GHO data not available.
- FIGURE 3
The effects of cigarette smoke (CS) exposure on innate and adaptive immunity that may influence the control of Mycobacterium tuberculosis (Mtb) infection. IFN: interferon; NO: nitric oxide; Sp: surfactant protein; AM: alveolar macrophage; TNF: tumour necrosis factor; CD: cluster of differentiation; Th: T-helper cell; Ag: antigen; Treg: regulatory T-cell; IL: interleukin; MHC: major histocompatibility complex; CCL: C-C motif chemokine ligand; CXCL: C-X-C motif chemokine ligand; iNOS: inducible nitric oxide synthase; NET: neutrophil extracellular traps.
Tables
- TABLE 1
Summary of systematic reviews on the effects of smoking on TB
Systematic reviews on effects of smoking on TB Confounders Multivariate analysis Lin et al., 2007 [8]
Effect of smoking as a risk factor for TB infection, disease and mortality
Confounders:
TST cut-off for LTBI
Alcohol consumption
SESTST cut-off to diagnose LTBI Induration size of 5 mm Pooled OR 2.08
(95% CI 1.53–2.83)Induration size of 10 mm Pooled OR 1.83
(95% CI 1.49–2.23)Alcohol on risk of TB disease in current smokers Summary estimate 1.62
(95% CI 1.15–2.29)SES on risk of TB disease in current smokers Summary estimate 1.95
(95% CI 1.45–2.61)Alcohol on risk of TB disease in former smokers Summary estimate 1.58
(95% CI 1.24–2.02)SES on risk of TB disease in former smokers Summary estimate 1.54
(95% CI 1.18–2.01)Alcohol on risk of TB disease in ever-smokers Summary estimate 2.00
(95% CI 1.55–2.57)SES on risk of TB disease in ever-smokers Summary estimate 3.28
(95% CI 2.25–4.76)SES for risk of mortality from TB Summary estimate 2.55
(95% CI 1.82–3.56)Slama et al., 2007 [9]
Effect of smoking as a risk factor for TB infection, disease and mortality
Confounders:
Quality of study as rated by three independent reviewers for 25 indicators of quality regarding study population, assessment of exposure to tobacco smoke, assessment of passive smoking, assessment of TB outcome, study design, analysis and data presentationQuality of study on risk of being infected with TB High-quality studies only Pooled estimate 1.757 (95% CI 1.458–2.118) All studies Pooled estimate 1.762 (95% CI 1.467–2.116) Quality of study on risk of TB disease High-quality studies only Pooled estimate 2.641 (95% CI 2.066–3.378) All studies Pooled estimate 2.284 (95% CI 1.765–2.954) Quality of study on risk of TB mortality High-quality studies only Pooled estimate 1.347 (95% CI 1.107–1.638) All studies Pooled estimate 2.236 (95% CI 1.340–3.732) Wagnew et al., 2018 [10]
Effect of smoking on prevalence of TB
Confounder:
Diagnosis of diabetesSmoking on TB among diabetes patients OR 7.6 (95% CI 1.46–39.53) Bates et al., 2007 [11]
Effect of smoking on TB infection, disease and mortality
Confounders:
None reportedEffect of smoking on TB infection
(no adjustment for confounders reported)Summary relative risk 1.73 (95% CI 1.46–2.04) Effect of smoking on TB disease
(no adjustment for confounders reported)Summary relative risk 2.29 (95% CI 1.93–2.71) Effect of smoking on TB mortality
(no adjustment for confounders reported)Summary relative risk 1.60 (95% CI 1.31–1.95) Burusie et al., 2020 [12]
Effect of smoking on TB treatment outcomes
Confounders:
Income category of the study country's economy (not individuals’ SES)Lower-middle income economy on effect of smoking on TB treatment outcomes OR 1.74 (95% CI 1.31–2.30) Upper-middle income economy on effect of smoking on TB treatment outcomes OR 1.52 (95% CI 1.16–1.96) High-income economy on effect of smoking on TB treatment outcomes OR 1.34 (95% CI 1.03–1.74) Samuels et al., 2018 [13]
Effect of smoking on treatment outcomes in MDR-TB
Confounders:
None reportedEffect of smoking on unsuccessful treatment outcomes for MDR-TB (no adjustment for confounders reported) Pooled relative risk 0.94 (95% CI 0.75–1.19) Chaves Torres et al., 2019 [14]
Effect of smoking on TB treatment outcomes
Confounders:
None reportedEffect of not smoking on favourable TB treatment outcomes (no adjustment for confounders reported) OR 1.5 (95% CI 1.3–1.7) Patra et al., 2015 [15]
Effect of exposure to second-hand smoke on LTBI and active TB
Confounders:
Age
Biomass fuel use
SES
Presence of TB patient in householdAge on effect of exposure to second-hand smoke on LTBI Children Summary relative risk 1.64 (95% CI 1.00–2.83) Adults Summary relative risk 1.78 (95% CI 1.19–2.68) Age on effect of exposure to second-hand smoke on active TB disease Children Summary relative risk 3.41 (95% CI 1.81–6.45) Adults Summary relative risk 1.32 (95% CI 1.04–1.68) Biomass fuel use on effect of exposure to second-hand smoke on LTBI Summary relative risk 2.66 (95% CI 1.31–5.39) Biomass fuel use on effect of exposure to second-hand smoke on active TB disease Summary relative risk 2.03 (95% CI 1.13–3.63) Presence of a TB patient in the household on effect of exposure to second-hand smoke on LTBI Summary relative risk 2.03 (95% CI 1.25–3.28) Presence of a TB patient in the household on effect of exposure to second-hand smoke on active TB disease Summary relative risk 1.87 (95% CI 1.30–2.69) Combined SES and age on effect of exposure to second-hand smoke on LTBI Summary relative risk 1.11 (95% CI 0.54–2.31) Combined SES and age on effect of exposure to second-hand smoke on active TB disease Summary relative risk 2.13 (95% CI 1.18–3.83) Obore et al., 2020 [16]
Effect of smoking and exposure to second-hand smoke on contracting TB
Confounders:
None reportedEffect of second-hand smoke exposure on risk of contracting TB (no adjustment for confounders reported) Relative risk 2.15 (95% CI 1.419–3.242) Effect of smoking on risk of contracting TB (no adjustment for confounders reported) Relative risk 2.67 (95% CI 2.017–3.527) TB: tuberculosis; TST: tuberculin skin test; LTBI: latent tuberculosis infection; SES: socioeconomic status; OR: odds ratio; MDR: multidrug resistant.
- TABLE 2
Comparison of combined CS exposure and M. tuberculosis infection experiments in vivo
CS exposure TB infection Key findings Reference Female C57BL/6
Whole body exposure
Teague Enterprises, Davis, CA, USA
1× 1R4F cigarette
2 h exposure twice per day
5 days per week for 6 weeks10–25 CFU Mtb Erdman via aerosol
No CS exposure post-infection
Harvest 28 days post-infectionCS exposure results in: ↓ frequency of IFN-γ+ T-cells in lungs and spleens ↓ c-Jun, ATF2 and CREB expression in lungs ↑ Mtb burden in lungs ↓ Mtb antigen-specific T-cell responses post-vaccination [139] Female C57BL/6 mice
Whole body exposure
Teague Enterprises, Davis, CA, USA
170–180× 3R4F cigarettes
5 h exposure twice per day
5 days per week for 14 weeks10–25 CFU Mtb Erdman via aerosol
No CS exposure post-infection
Harvest 1, 7, 14 and 30 days post-infectionCS exposure results in: ↓ number of lung macrophages and DCs producing TNF and IL-12 ↑ number of lung macrophages and DCs producing IL-10 ↓ number of CD4+ T-cells producing IFN-γ and TNF in lungs and spleens ↑ Mtb burden in lungs and spleen from day 14 post-infection ↑ Mtb lung lesion area in lungs [118] Female C57BL/6 mice
Whole body exposure
SIU-48, Promech Lab AB, Vintrie, Sweden
12× 2R4F cigarettes
50 min exposure twice per day
5 days per week for 6 weeks104 CFU Mtb H37Rv intranasally
No CS exposure post-infection
Harvest 28 and 42 days post-infection
OR
0.5×106 CFU BCG intratracheally
CS exposure post-infection
Harvest 28 days post-infectionCS exposure results in: ↓ number of CD4+IFN-γ+ T-cells in lungs ↑ frequency of CD4+IL-4+ T-cells in lungs ↓ RANTES concentration in BALF ↓ TNF, IL-12, IFN-γ and NO production by lung mononuclear cells ↑ Mtb burden in lungs and spleens ↓ Mtb granuloma size, number and cellular infiltration [149] CS: cigarette smoke; TB: tuberculosis; CFU: colony-forming units; IFN: interferon; ATF2: activating transcription factor 2; CREB: cAMP response element-binding protein; Mtb: Mycobacterium tuberculosis; DC: dendritic cells; TNF: tumour necrosis factor; IL interleukin; CD: cluster of differentiation; BCG: bacille Calmette–Guérin; BALF: bronchoalveolar lavage fluid; NO: nitric oxide.
