infection [54]. Poverty and hunger increase susceptibility to both infection and progression to disease, along with the severity of TB [46]. There is a strong relationship between TB incidence and per capita gross domestic product [1]. Although TB can affect anyone, it is a prime example of a poverty-related disease. Being poor increases the risk and severity of TB, and suffering from TB increases the likelihood of impoverishment [55]. It is only by tackling the foundation causes of poor health, including poverty and the lack of social protection, that we can begin to accelerate the progress made towards ending TB [56, 57]. HIV, diabetes and undernourishment Undernourishment is the primary population-level risk factor for TB globally (figure 4) [58], with an estimated population-attributable fraction of 2.2 million (20.8%) cases in 2021 [1]. The effect of undernutrition is acutely important in countries with high TB burden. For instance, in India (with 2.9 million new cases in 2021), undernourishment accounts for a quarter of TB cases (738 000 cases) [45]. Undernutrition, which is a physiological condition based on individual nutrition status (most commonly approximated as a body mass index of 18.5 kg·m−2), is increasingly being used as a measure of TB risk instead of undernourishment, which is an indicator of chronic hunger at a national level [59]. Along with an increased risk of progression to TB, undernutrition (deficiency of both macro- and micronutrients) has been associated with higher disease severity, risk of treatment failure, relapse and even TB mortality [58, 60]. Poor treatment outcomes are hypothesised to be caused by changes in pharmacokinetics and pharmacodynamics of anti-TB drugs, along with a delayed and unregulated immune response, caused by impacted T-helper cell type 1 (Th) responses and reduced T-cell signalling [58, 61–63]. Reductions in treatment efficacy are likely to be a result of decreased absorption of some drugs (rifampin and isoniazid) and increased toxicity of others (such as aminoglycosides) [64–66]. Worryingly, food insecurity increased in 2020 due to the effects of the COVID-19 pandemic, with an estimated increase of 3.8%, which is almost equal to the previous 5 years combined (from 22.6% in 2014 to 26.6% in 2019) [67]. The impact of hunger is only expected to grow as climate change, global conflict and economic slowdown continue to affect the food security of vulnerable populations [67, 68]. a) b) 10% 10–14% 15–19% ≥20% No data Not applicable 1% 1–4% 5–9% 10% No data Not applicable FIGURE 4 Percentage TB cases attributable to two risk factors in 2021: a) undernourishment and b) HIV infection. Reproduced and modified from [44] with permission. 26 https://doi.org/10.1183/2312508X.10023922 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY