alcohol dosage increases, with evidence of a threshold effect (∼40–60 g per day) [95, 98, 99]. Alcohol affects the innate and acquired immune system, thereby increasing susceptibility to progression to TB [100]. Alcohol-use disorders or heavy alcohol consumption can also lead to altered pharmacokinetics, thus affecting TB treatment [96]. There are behavioural pathways linking alcohol to an increased risk of TB and treatment failure through social marginalisation and drift, resulting in social exclusion, financial deterioration and increased likelihood of treatment interruption [96]. Solid organ transplantation and the use of TNF-α inhibitors Organ transplantation can pose a TB risk in two ways: 1) activation of incipient or subclinical TB in the recipient (and in rare cases, the donor tissue), due to the use of immunosuppressive drugs, and 2) de novo infection with M. tuberculosis [101]. A systematic review of 60 studies on TB post-transplantation found a pooled prevalence of TB of 3% [102]. The relative risk of TB infection for solid organ transplantation patients ranged 11.3–26.6 compared with the general population, usually measured over the first 2 years following immunosuppression (table 3). Immunosuppression therapy is used to prevent recipients from rejecting their donor organ. However, this also impairs the body’s ability to control TB infection [101]. TNF-α inhibitors are often used to treat immune or inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease. TNF-α antagonists have been shown to increase TB risk by up to 25 times (table 3). This elevated risk is true for both high- and low-endemic regions. TNF-α is an important immune mediator that helps the host control M. tuberculosis infection by inducing bactericidal activity of macrophages through production of reactive nitrogen and oxygen intermediates, along with the upregulation of chemokine secretion [112]. The use of TNF-α blockers can therefore have an adverse effect on these immune responses and increase the risk of progression to TB [113]. This is most commonly associated with monoclonal antibody TNF-α inhibitors such as infliximab and adalimumab. Other risk factors Additional risk factors for TB infection include occupational exposure to TB among healthcare workers [114]. Other conditions increase the risk of progression from infection to disease. These include silicosis (RR 4–30) [115, 116], kidney failure (RR 10–25) [117, 118], rheumatoid arthritis (RR 2–16) [111] and cancer (RR 2–40) [119–121]. In each of the conditions, the immune system is affected by the required treatment, making the patient less capable of self containing M. tuberculosis infection. Finally, previous TB is a risk factor for TB disease [122]. Recurrent TB episodes, which are the result of exogenous TB infection or relapse after cure, are not uncommon. A recent cohort study in South Africa showed TB recurrence rates of 1.64 per 100 person-years and increases in risk with each recurrent episode [123]. TABLE 3 Relative risk of TB per risk factor Risk factor Relative risk [Refs] HIV infection 8.3–18 [46, 103] Diabetes 1.5–3.1 [103, 104, 105] Undernourishment 3.2–4.0 [46, 103] Smoking 1.6–2.6 [92, 103] Alcohol 2.9–4.9 [96, 103] Solid organ transplantation 11.3–26.6 [106, 107] Use of anti-TNF drugs 1.6–25.1 [108–111] 28 https://doi.org/10.1183/2312508X.10023922 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY