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No smoke without fire: the impact of cigarette smoking on the immune control of tuberculosis

Diana H. Quan, Alexander J. Kwong, Philip M. Hansbro, Warwick J. Britton
European Respiratory Review 2022 31: 210252; DOI: 10.1183/16000617.0252-2021
Diana H. Quan
1Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Sydney, Australia
5D.H. Quan and W.J. Britton contributed equally to this article as lead authors and supervised the work
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  • For correspondence: d.quan@centenary.org.au
Alexander J. Kwong
2NSW Dept of Education and Training, Parramatta, Australia
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Philip M. Hansbro
3Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, Australia
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Warwick J. Britton
1Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Sydney, Australia
4Dept of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia
5D.H. Quan and W.J. Britton contributed equally to this article as lead authors and supervised the work
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  • FIGURE 1
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    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
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    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
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    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

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  • TABLE 1

    Summary of systematic reviews on the effects of smoking on TB

    Systematic reviews on effects of smoking on TBConfoundersMultivariate 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
      SES
    TST cut-off to diagnose LTBI
     Induration size of 5 mmPooled OR 2.08
    (95% CI 1.53–2.83)
     Induration size of 10 mmPooled OR 1.83
    (95% CI 1.49–2.23)
    Alcohol on risk of TB disease in current smokersSummary estimate 1.62
    (95% CI 1.15–2.29)
    SES on risk of TB disease in current smokersSummary estimate 1.95
    (95% CI 1.45–2.61)
    Alcohol on risk of TB disease in former smokersSummary estimate 1.58
    (95% CI 1.24–2.02)
    SES on risk of TB disease in former smokersSummary estimate 1.54
    (95% CI 1.18–2.01)
    Alcohol on risk of TB disease in ever-smokersSummary estimate 2.00
    (95% CI 1.55–2.57)
    SES on risk of TB disease in ever-smokersSummary estimate 3.28
    (95% CI 2.25–4.76)
    SES for risk of mortality from TBSummary 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 presentation
    Quality of study on risk of being infected with TB
     High-quality studies onlyPooled estimate 1.757 (95% CI 1.458–2.118)
     All studiesPooled estimate 1.762 (95% CI 1.467–2.116)
    Quality of study on risk of TB disease
     High-quality studies onlyPooled estimate 2.641 (95% CI 2.066–3.378)
     All studiesPooled estimate 2.284 (95% CI 1.765–2.954)
    Quality of study on risk of TB mortality
     High-quality studies onlyPooled estimate 1.347 (95% CI 1.107–1.638)
     All studiesPooled estimate 2.236 (95% CI 1.340–3.732)
    Wagnew et al., 2018 [10]
     Effect of smoking on prevalence of TB
     Confounder:
      Diagnosis of diabetes
    Smoking on TB among diabetes patientsOR 7.6 (95% CI 1.46–39.53)
    Bates et al., 2007 [11]
     Effect of smoking on TB infection, disease and mortality
     Confounders:
      None reported
    Effect 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 outcomesOR 1.74 (95% CI 1.31–2.30)
    Upper-middle income economy on effect of smoking on TB treatment outcomesOR 1.52 (95% CI 1.16–1.96)
    High-income economy on effect of smoking on TB treatment outcomesOR 1.34 (95% CI 1.03–1.74)
    Samuels et al., 2018 [13]
     Effect of smoking on treatment outcomes in MDR-TB
     Confounders:
      None reported
    Effect 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 reported
    Effect 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 household
    Age on effect of exposure to second-hand smoke on LTBI
     ChildrenSummary relative risk 1.64 (95% CI 1.00–2.83)
     AdultsSummary relative risk 1.78 (95% CI 1.19–2.68)
    Age on effect of exposure to second-hand smoke on active TB disease
     ChildrenSummary relative risk 3.41 (95% CI 1.81–6.45)
     AdultsSummary relative risk 1.32 (95% CI 1.04–1.68)
    Biomass fuel use on effect of exposure to second-hand smoke on LTBISummary relative risk 2.66 (95% CI 1.31–5.39)
    Biomass fuel use on effect of exposure to second-hand smoke on active TB diseaseSummary 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 LTBISummary 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 diseaseSummary relative risk 1.87 (95% CI 1.30–2.69)
    Combined SES and age on effect of exposure to second-hand smoke on LTBISummary 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 diseaseSummary 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 reported
    Effect 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 exposureTB infectionKey findingsReference
      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 weeks
      10–25 CFU Mtb Erdman via aerosol
      No CS exposure post-infection
      Harvest 28 days post-infection
      CS 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 weeks
      10–25 CFU Mtb Erdman via aerosol
      No CS exposure post-infection
      Harvest 1, 7, 14 and 30 days post-infection
      CS 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 weeks
      104 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-infection
      CS 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.

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      No smoke without fire: the impact of cigarette smoking on the immune control of tuberculosis
      Diana H. Quan, Alexander J. Kwong, Philip M. Hansbro, Warwick J. Britton
      European Respiratory Review Jun 2022, 31 (164) 210252; DOI: 10.1183/16000617.0252-2021

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      No smoke without fire: the impact of cigarette smoking on the immune control of tuberculosis
      Diana H. Quan, Alexander J. Kwong, Philip M. Hansbro, Warwick J. Britton
      European Respiratory Review Jun 2022, 31 (164) 210252; DOI: 10.1183/16000617.0252-2021
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