Elsevier

Journal of Infection

Volume 67, Issue 3, September 2013, Pages 169-184
Journal of Infection

Review
Cigarette smoking and mechanisms of susceptibility to infections of the respiratory tract and other organ systems

https://doi.org/10.1016/j.jinf.2013.05.004Get rights and content

Summary

The predisposition of cigarette smokers for development of oral and respiratory infections caused by microbial pathogens is well recognised, with those infected with the human immunodeficiency virus (HIV) at particularly high risk. Smoking cigarettes has a suppressive effect on the protective functions of airway epithelium, alveolar macrophages, dendritic cells, natural killer (NK) cells and adaptive immune mechanisms, in the setting of chronic systemic activation of neutrophils. Cigarette smoke also has a direct effect on microbial pathogens to promote the likelihood of infective disease, specifically promotion of microbial virulence and antibiotic resistance. In addition to interactions between smoking and HIV infection, a number of specific infections/clinical syndromes have been associated epidemiologically with cigarette smoking, including those of the upper and lower respiratory tract, gastrointestinal tract, central nervous and other organ systems. Smoking cessation benefits patients in many ways, including reduction of the risk of infectious disease.

Introduction

In their landmark studies published in 1994, Sir Richard Doll, Sir Richard Peto and colleagues conclusively established the link between cigarette smoking and premature death.1, 2 Peto in his report on smoking and death stated that “smoking represents a great failure in public health; more than 40 years after the hazards were first established, cigarettes are still responsible for 30% of deaths in middle age in Britain and the United States, and worldwide sales are increasing.”1

These and other reports1, 2, 3 resulted in the vigorous implementation of anti-smoking strategies, most notably in developed countries. The most effective of these include embargoes on both advertising and smoking in public places, health awareness campaigns, prohibitive taxation on tobacco products, and development of smoking cessation aids, all of which have contributed to the progressive decline in smoking in many countries, including the UK and USA.4 Worryingly, however, these gains are being countered, not only by the indifference of individuals to the health risks of smoking, but more significantly, by changes in the patterns of global tobacco consumption.4, 5, 6 As recently reported by the Global Adult Tobacco Survey (GATS), the following are of particular concern: i) increasing rates of smoking in women in the UK and USA (20.6% and15.8% respectively), countries in which smoking amongst males has declined significantly; and ii) high tobacco use in those low-to-middle income countries with less stringent tobacco control policies where the average smoking rates are 48.6% and 11.3% for men and women respectively.4 These latter data support earlier projections made in 2004 by the Food and Agriculture Organization of the United Nations, which estimated that developing countries would account for 71% of global tobacco consumption by 2010, while the total number of smokers worldwide would increase from 1.1 to 1.3 billion between 1998 and 2010.7 All of this is largely in keeping with the “Tobacco Atlas 4th Edition” recently published by the American Cancer Society and World Lung Foundation, which reported 6 million deaths worldwide due to smoking in 2011.5

Clearly, the global public health response to the warnings issued by Doll, Peto and others 20 years ago1, 2, 3 has been disappointing. The tobacco industry continues to be resilient and cigarette smoking remains the most common and eminently avoidable cause of lifestyle-related premature death,4, 5 with those infected with human immunodeficiency virus (HIV) being particularly vulnerable.8, 9 Indeed, current statistics on smoking-related mortality, which are based primarily on the frequencies of various malignancies and degenerative disorders of the cardiovascular system and lungs, may even under-estimate the magnitude of the problem. This contention is based on increasing awareness of the association between smoking and predisposition to respiratory infections, which impacts not only on frequency and severity, but also restricts the efficacy of anti-infective therapy.10, 11, 12, 13, 14

The risk of infection, although greatest in active smokers of standard cigarettes, marijuana and other drugs, is also increased in those who are inadvertently exposed to sidestream smoke, with the overall risk being approximately double that of non-smokers.15, 16 Indeed, in 2004, it was estimated that passive smoking alone accounted for 165,000 deaths from lower respiratory infection in adults and children.17 The association of parental smoking with an increased frequency of respiratory infection in childhood is well-documented, causing between 200–500 and 1000–5000 excess hospitalisations and diagnoses respectively per 100,000 children.18

Although generally attributed to interference with oral and airway innate and adaptive host defences, recent research has also revealed significant pathogen-directed effects of cigarette smoking. Not only do these enhance microbial virulence, but may also lead to the emergence of antibiotic resistance, as well as to an altered composition of the airway microbiota. These interactive host- and pathogen-directed effects of cigarette smoking and associated infections represent the primary focus of the current review, which is preceded by a brief consideration of the most harmful constituents of cigarette smoke.

Section snippets

Harmful constituents of cigarette smoke

Cigarette smoke consists of more than 7300 chemical constituents distributed between the gas and tar (particulate) phases, many of which are potent carcinogens.19, 20 Notwithstanding various hydrocarbons, such as isoprene, benzene and benzo[a]pyrene, other major toxic constituents of cigarette smoke include nicotine, carbon monoxide, nitric oxide, hydrogen cyanide, tobacco-specific nitrosamines, and various pro-oxidative heavy metals (arsenic, cadmium, chromium, iron, lead, mercury, nickel,

Smoking and immune dysfunction

As mentioned below, smokers, as well as those exposed to sidestream smoke, are prone to viral infection of the upper (rhinovirus) and lower (influenza/varicella pneumonitis), respiratory tract, as well as to invasive disease caused by various bacterial pathogens, most notably Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus, Legionella pneumophila, and possibly Mycobacterium tuberculosis. Notwithstanding direct, smoke-mediated up-regulation of

Mucociliary escalator

The primary function of this system, which lines the airway luminal surface, is to entrap and expel pathogens from the lower airways. This involves interactions between pro-adhesive mucus secreted by goblet cells and submucosal glands operating in concert with ciliated respiratory epithelium. Pathogens adherent to the viscous, luminal gel phase of mucus are propelled upwards towards the larynx by the coordinated ciliary beating of epithelium immersed in the lower, less gelatinous, periciliary

Alveolar macrophages

Many studies, based mainly on murine models of smoke inhalation, have convincingly demonstrated the inhibitory effects of exposure to cigarette smoke on the phagocytic/pro-inflammatory activities of alveolar macrophages. Defective uptake of airway pathogens such as S. pneumoniae, non-typeable H. influenzae, and Pseudomonas aeruginosa has been described,36, 37, 38 while the pro-inflammatory responses of these cells following activation by soluble stimuli, including ligands of the pattern

Dendritic cells

Unlike epithelial cells, alveolar macrophages, and neutrophils, there are relatively few studies on the effects of cigarette smoking on other cell types involved in innate host defence, specifically dendritic cells and natural killer (NK) cells. In the case of dendritic cells (DCs), the available evidence is compatible with inhibitory effects of exposure to tobacco smoke on the protective functions of both myeloid and plasmacytoid DCs. Myeloid DCs represent a critical link between innate and

Natural killer (NK) cells

These are the large granular lymphocytes of the innate immune system which mediate the killing of virus-infected cells and tumour cells via the targeted release of granule cytotoxins and/or induction of apoptosis; they also orchestrate early host defences to intracellular microbial pathogens such as M. tuberculosis by producing the macrophage-activating cytokine, IFN-γ. In a model of experimental lung metastasis using immunosuppressed gene knockout mice, intravenous injection of melanoma cells

Neutrophils

In contrast to inhibitory effects on resident airway cells of the innate and adaptive immune systems, cigarette smoking causes a persistent, low grade leukocytosis, predominantly a neutrophilia, which is associated with a decrease in the post-mitotic mean transit time of these cells from the bone marrow.58 These immature neutrophils have a highly pro-inflammatory phenotype, characterised by increased expression of the adhesion molecule, L-selectin, and an elevated content of the pro-oxidative,

Adaptive immunity

As with innate immunity, cigarette smoking has been reported to compromise protective humoral and cell-mediated adaptive airway host defences, with some evidence of systemic immunosuppression following immunization with viral and microbial vaccines.

Humoral immunity

As documented in a 2008 review by Bagaitkar et al.,15 and confirmed in a very recent study,69 total circulating immunoglobulin (Ig) G concentrations are reduced in smokers, in the setting of increased concentrations of IgE.15, 70 With respect to immunization with hepatitis B vaccine, it was observed that a significantly higher proportion of smokers failed to seroconvert, irrespective of the schedule used, while in those who did, antibody levels were lower at 3 and 13 months post-immunization.71

Cell-mediated immunity

Exposure to cigarette smoke has been reported to inhibit the proliferative responses of T lymphocytes in vitro, as well as in murine models of experimental lung disease of both infective origin and non-infective origin.15, 76 In one such animal model, exposure to cigarette smoke was found to compromise pulmonary T cell responses following experimental infection with either M. tuberculosis,76, 77 or influenza virus,77 which was associated with an increased bacterial load and increased mortality

Pathogen-directed effects of cigarette smoking

Notwithstanding their presence in cured tobacco, there is increasing awareness that bacterial pathogens acquire a more virulent phenotype following exposure to cigarette smoke. Both events, particularly the latter, are likely to contribute to increased colonisation of the airways of smokers by bacterial pathogens with the accompanying risk of severe infection.

Pathogens in tobacco

During the manufacturing process, intact tobacco flakes apparently translocate from the tip of the cigarette to the filter where they are released into mainstream smoke and inhaled during smoking.79 Cured tobacco from a variety of different brands of cigarettes have been reported to contain a broad range of potential microbial pathogens, including, Acinetobacter, Bacillus, Burkholderia, Clostridium, Serratia, and Pseudomonas, and Staphylococcus species, as well as Mycobacterium avium

Microbiota of the upper and lower respiratory tract in smokers

The composition of the nasopharyngeal flora of smokers has been reported to differ from that of non-smokers. Notable differences include: i) fewer competitive aerobic and anaerobic commensal organisms; and ii) an increased frequency of pathogens, specifically S. pneumoniae, non-typeable H. influenzae, Moraxella catarrhalis, and Streptococcus pyogenes.82 Colonisation of the upper respiratory tract is a probable consequence of the interactive effects of cigarette smoke on host defences and

Smoking and microbial virulence

Adherence to the nasooropharynx is a prerequisite for colonisation of the airways by microbial pathogens and is a risk factor for development of pneumonia. Colonisation precedes, and promotes, the formation of biofilm by the pneumococcus,85 and presumably other respiratory bacterial pathogens, favouring both persistence and resistance to antibiotics.86

Adherence to respiratory epithelium

Notwithstanding smoke-mediated damage to respiratory epithelium, as well as up-regulation of receptors for microbial adhesins such as the PAF receptor in the case of the pneumococcus,35 smoke affects pathogens directly, promoting epithelial adhesion. Examples of the latter include: i) increased production of histolytic enzymes and adherence to dental surfaces following exposure of Candida albicans to CSE in vitro, possibly favouring oral yeast carriage87; ii) increased adherence of S. aureus to

Biofilm formation

Biofilm, which has been implicated in 60–80% of all microbial infections, is a self-generated, hydrated and well-ordered extracellular matrix of polymeric substances, predominantly polysaccharides, proteins and nucleic acids which insulate potential pathogens against both host defences and antibiotics.86 Encased and protected in biofilm, the pathogens can re-emerge when the microenvironment is less hostile.

Exposure to cigarette smoke has been reported to induce the formation of biofilm by

Smoking and antibiotic resistance

Although unproven, the efficacy of antimicrobial therapy in smokers13, 86 may be limited by the following mechanisms:

  • Smoking-induced formation of biofilm, which not only restricts access of antibiotics to pathogens, but also negates cooperative interactions between already compromised host defences and antibiotics, as well as creating an environment conducive to the horizontal transfer of resistance genes, especially in polymicrobial biofilms.86

  • The potential of mutagens present in cigarette

Community-acquired pneumonia

Smoking increases the risk for development of community-acquired pneumonia (CAP) approximately twofold, with a clear relationship between smoking history and an increased frequency of invasive disease.95, 96, 97 With respect to susceptibility for infection caused by specific respiratory pathogens, Nuorti et al., in their landmark study, convincingly documented cigarette smoking as being the strongest independent risk factor for invasive pneumococcal disease (IPD), even in immunocompetent,

Bacteraemia

Studies have documented the association of both active and passive smoking with diverse bacteraemic infections.14, 167, 168, 169 In one study of community-acquired Acinetobacter infections, including bacteraemic infections, in countries with a tropical or subtropical climate, patients were mainly those with underlying comorbidities, heavy smokers, or drinkers.14 In another study of S. aureus, S. pneumoniae, β-haemolytic streptococci and Escherichia coli bacteraemias, smoking, among other

Acknowledgements

Professor Charles Feldman is supported by the National Research Foundation (SA).

References (211)

  • K.M. Horvath et al.

    Live attenuated influenza virus (LAIV) induces different mucosal T cell function in nonsmokers and smokers

    Clin Immunol

    (2012)
  • T. Terashima et al.

    Release of polymorphonuclear leukocytes from the bone marrow by interleukin-8

    Blood

    (1998)
  • P.C. Stone et al.

    Neutrophil capture by selectins on endothelial cells exposed to cigarette smoke

    Biochem Biophys Res Commun

    (2002)
  • A.P. Winter et al.

    Influence of smoking on immunological responses to hepatitis B vaccine

    Vaccine

    (1994)
  • M.J. Miguez-Burbano et al.

    Non-tuberculous mycobacteria in HIV-infected patients: geographic, behavioural and immunological factors

    Lancet Infect Dis

    (2005)
  • I. Brook et al.

    Recovery of potential pathogens and interfering bacteria in the nasopharynx of smokers and nonsmokers

    Chest

    (2005)
  • H.B. Fung et al.

    Community-acquired pneumonia in the elderly

    Am J Geriatr Pharmacother

    (2010)
  • R. Doll et al.

    Mortality in relation to smoking: 40years' observations on male British doctors

    Br Med J

    (1994)
  • R. Peto

    Smoking and death. Smoking and death: the past 40 years and the next 40

    Br Med J

    (1994)
  • A report of the Surgeon general: preventing tobacco use among young people

    (1994)
  • M. Eriksen et al.

    The tobacco World Atlas

    (2012)
  • NHS National Statistics

    Statistics on smoking

    (2011)
  • Food and Agriculture Organization of the United Nations: Higher world tobacco use expected by 2010–growth rate slowing...
  • K. Crothers et al.

    The impact of cigarette smoking on mortality, quality of life, and comorbid illness among HIV-positive veterans

    J Gen Intern Med

    (2005)
  • M. Helleberg et al.

    Mortality attributable to smoking among HIV-infected individuals: a nationwide, population-based cohort study

    Clin Infect Dis

    (2013)
  • J.P. Nuorti et al.

    Cigarette smoking and invasive pneumococcal disease. Active bacterial core surveillance team

    N Engl J Med

    (2000)
  • L. Brunet et al.

    High prevalence of smoking among patients with suspected tuberculosis in South Africa

    Eur Respir J

    (2011)
  • R.N. van Zyl Smit et al.

    Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD

    Eur Respir J

    (2010)
  • N. Tachfouti et al.

    Association between smoking status, other factors and tuberculosis treatment failure in Morocco

    Int J Tuberc Lung Dis

    (2011)
  • R. Huttunen et al.

    Obesity and smoking are factors associated with poor prognosis in patients with bacteraemia

    BMC Infect Dis

    (2007)
  • J. Bagaitkar et al.

    Tobacco use increases susceptibility to bacterial infection

    Tob Induc Dis

    (2008)
  • A. Rodgman et al.

    The chemical components of tobacco and tobacco smoke

    (2009)
  • a report of the Surgeon general

    (2013)
  • A.J. Theron et al.

    Harmful interactions of non-essential heavy metals with cells of the innate immune system

    J Clin Toxicol

    (2012)
  • A.J. Ghio et al.

    Particulate matter in cigarette smoke alters iron homeostasis to produce a biological effect

    Am J Respir Crit Care Med

    (2008)
  • W.A. Pryor

    Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity

    Environ Health Perspect

    (1997)
  • W.A. Pryor et al.

    Fractionation of aqueous cigarette tar extracts: fractions that contain the tar radical cause DNA damage

    Chem Res Toxicol

    (1998)
  • D.R. Curran et al.

    Advances in mucus cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease

    Am J Respir Cell Mol Biol

    (2010)
  • H. Mehta et al.

    Cigarette smoking and innate immunity

    Inflamm Res

    (2008)
  • H. Maunders et al.

    Human bronchial epithelial cell transcriptome: gene expression changes following acute exposure to whole cigarette smoke in vitro

    Am J Physiol Lung Cell Mol Physiol

    (2007)
  • R. Mahanonda et al.

    Cigarette smoke extract modulates human beta-defensin-2 and interleukin-8 expression in human gingival epithelial cells

    J Periodontal Res

    (2009)
  • C. Herr et al.

    Suppression of pulmonary innate host defence in smokers

    Thorax

    (2009)
  • M.H. Hudy et al.

    Cigarette smoke modulates rhinovirus-induced airway epithelial cell chemokine production

    Eur Respir J

    (2010)
  • M.A. Modestou et al.

    Inhibition of IFN-γ-dependent antiviral airway epithelial defense by cigarette smoke

    Respir Res

    (2010)
  • J. Eddleston et al.

    Cigarette smoke decreases innate responses of epithelial cells to rhinovirus infection

    Am J Respir Cell Mol Biol

    (2011)
  • W. Wu et al.

    Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the lung

    Am J Physiol Lung Cell Mol Physiol

    (2011)
  • I. Jaspers et al.

    Reduced expression of IRF7 in nasal epithelial cells from smokers after infection with influenza

    Am J Respir Cell Mol Biol

    (2010)
  • J. Grigg et al.

    Cigarette smoke and platelet-activating factor receptor dependent adhesion of Streptococcus pneumoniae to lower airway cells

    Thorax

    (2012)
  • J.C. Phipps et al.

    Cigarette smoke exposure impairs pulmonary bacterial clearance and alveolar macrophage complement-mediated phagocytosis of Streptococcous pneumoniae

    Infect Immun

    (2010)
  • P. Marti-Lliteras et al.

    Nontypeable Haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke

    Infect Immun

    (2009)
  • Cited by (158)

    • Cigarette Smoking and Asthma

      2022, Journal of Allergy and Clinical Immunology: In Practice
    View all citing articles on Scopus
    View full text