The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli.
In addition to providing effective treatment and reducing mortality, a primary aim of tuberculosis (TB) control programs in countries of high TB incidence is to reduce the transmission from infectious TB cases. The development of TB in an exposed individual is a two-stage process following infection. In most infected persons, infection is contained by the immune system and bacteria become walled off in caseous granulomas or tubercles. In about 5% of infected cases, rapid progression to tuberculosis will occur within the first two years after infection [
The risk of progression to infection and disease is two different aspects and proper understanding of these factors is essential for planning TB control strategies [
The search strategy for this paper included searching PubMed, Medline, and EMBASE databases for known risk factors. Only English language papers were included in the search, and the searches were limited to studies of risk factors influencing TB infection and disease. Factors related to TB treatment outcomes such as mortality and default were not included. Broad search terms included the following: Tuberculosis, transmission, contacts as a MeSH or heading term as well as “tuberculosis,” “risk factors,” and “transmission,” as text words AND infectious diseases, Tuberculosis and risk factors as MeSH or subject terms and keywords. More focused searches were undertaken within specific Tuberculosis journals such as the International Journal of Tuberculosis and Lung Disease, the Indian Journal of Tuberculosis, the Bulletin of the World Health Organization, and the Indian Journal of Medical Research. Only major risk factors related to TB infection and disease were identified, relevant literature was reviewed, and factors influencing TB treatment outcomes were not included.
Figure
Risk factors for Tuberculosis infection and disease.
Epidemiological studies conducted during mid-20th century have shown that smear positive cases are more infectious than the others [
The concentration of bacilli in the sputum from a TB case is positively correlated with the infectivity of the TB patient. Espinal and colleagues, in their prospective study of 803 household contacts of 174 index TB patients in the Dominican Republic, administered 5 TU Tubersol PPD to contacts at baseline and followed them up at 2, 8, and 14 months to study the effect of HIV on the infectiousness of
Smear negative patients are expected to have reduced number of bacilli than smear positive patients but can also transmit infection [
Behr et al. in their molecular study in San Francisco identified 71 clusters of patients infected with identical strains, and, out of 183 secondary cases in those clusters, 17% [
Close contacts of infectious TB cases including household contacts and care givers/health care workers [
The risk of TB disease among individuals with LTBI (diagnosed as TST positive) relative to a person with no risk factors varies by several orders of magnitude. Several studies have asserted this finding. In two controlled clinical trials by Ferebee [
Contact tracing efforts have therefore been targeted towards household members of TB cases based on the “stone in the pond” principle, with the probability of infection increasing with the proximity [
The importance of casual contacts was noted in early epidemiological studies which showed that majority of older children with a positive TST reported no household contact with a source case and were therefore likely to have been infected in the community [
Molecular studies that identify the strain of the TB organisms have also confirmed the importance of casual transmission in both low- and high-incidence settings. In USA, Bishai and colleagues were able to show that there is an extensive transmission of TB occurring in the community. Of the 182 patients who had isolates available, 84 (46%) showed molecular clustering with 58 (32%) defined as being recently transmitted. Only 20 (24%) of 84 cases with clustered DNA fingerprints had epidemiologic evidence of recent contact. The remaining 64 (76%) cases without epidemiological links shared socioenvironmental risk factors for casual exposure to infectious TB cases (young age, homeless, alcohol, and drug use) and demographic features such as geographic aggregation in an area with inadequate housing [
These studies show that TB can be transmitted within a short period of contact [
HIV coinfection is the most potent immunosuppressive risk factor for developing active TB disease [
HIV coinfection exacerbates the severity of TB disease while additionally TB coinfection accelerates HIV replication in affected organs including lungs and pleura [
Individuals with immune-mediated inflammatory disorders (IMID) are also known to be at increased risk of developing active TB, particularly after the use of tumour necrosis factor (TNF)—alpha inhibitors to treat a variety of autoimmune disease [
Studies have shown that malnutrition (both micro- and macro-deficiency) increases the risk of TB because of an impaired immune response [
Children are at higher risk of contracting TB infection and disease. Studies have shown that 60–80% exposed to a sputum smear-positive case became infected compared to only 30–40% who are exposed to a sputum smear-negative source case [
Diabetes has been shown to increase the risk of active TB disease [
Biological evidence supports the theory that diabetes directly impairs the innate and adaptive immune responses, thereby accelerating the proliferation of TB. Animal studies showed a higher bacterial load among diabetic mice experimentally infected with
Healthcare workers (HCWs) are at increased risk of exposure to TB. A review by Seidler et al. showed that, among HCWs in high-income countries, the overall incidence of TB disease in the general population and native born HCWs was less than 10 and 25 per 100 000 per year [
Rapid urbanization [
The association between smoking and TB has been studied in several systematic reviews [
Biological explanations including impaired clearance of mucosal secretion [
Alcohol has been recognized as a strong risk factor for TB disease [
In developing countries, the percentage usage of solid fuels for cooking is more than 80% [
Studies from Canada and Australia have shown that indigenous or aborigines are at a higher risk of TB than the nonaborigines [
Evidences from China have demonstrated gains through strengthening health systems (by improving notification through web-based reporting), by which hospital referrals improved from 59% to 87% and the contribution of sputum positive pulmonary TB cases from hospitals doubled from 16% to 33% [
Table
Relative risk, prevalence and population attributable risk of selected risk factors for TB.
Risk factor (reference) | Relative risk for active TB disease (range)a | Weighted prevalence, total population, 22 TB high burden countriesb | Population attributable fraction (range)c |
---|---|---|---|
HIV infection | 8.3 (6.1–10.8) | 1.1% | 7.3% (5.2–6.9) |
Malnutrition | 4.0 (2.0–6.0) | 17.2% | 34.1% (14.7–46.3) |
Diabetes | 3.0 (1.5–7.8) | 3.4% | 6.3% (1.6–18.6) |
Alcohol use > 40 g/day | 2.9 (1.9–4.6) | 7.9% | 13.1% (6.7–22.2) |
Active smoking | 2.6 (1.6–4.3) | 18.2% | 22.7% (9.9–37.4) |
Indoor pollution | 1.5 (1.2–3.2) | 71.1% | 26.2% (12.4–61.0) |
aRange is equal to 95% confidence interval, except for malnutrition and diabetes.
b22 countries that together have 80% of the estimated global TB burden.
cPopulation attributable fraction = (prevalence × (relative risk − 1))/(prevalence × (relative risk + 1)).
Source: adapted from Lönnroth and Raviglione [
Screening for TB (to diagnose latent TB infection) and prophylactic therapy remain the most important tools to reduce the risk of progression to TB disease among high risk individuals (close contacts, HIV infected individuals, health care workers, etc.) and be considered in endemic countries to reduce the progression from infection to disease. Screening for latent TB also warrants highly sensitive and specific tools. The existing array (the newly available IGRAs) of diagnostic tests detect latent TB infection are highly specific but has reduced sensitivity [
HIV coinfection is the most important and potent risk factor for TB infection and disease. Interventions such as early HIV counselling and screening for TB patients and early diagnosis and initiation of antiretroviral therapy (ART) to coinfected individuals have all been shown to be effective in preventing TB disease [
In endemic countries, diagnosis and treatment (through DOTS) of smear-positive cases remains the key to TB control by reducing transmission from infectious cases. In addition to passive case-finding practices, early diagnosis of smear-positive cases can be improved through untargeted case-finding strategies in endemic countries [
The growing population (especially in countries like China and India) is likely to inflate the number of TB cases in future. Smoking rates are high among men in these endemic countries [
Malnutrition and indoor air pollution are recognized risk factors which are confounded with the socioeconomic status of a setting. Rapid urbanization is shown to offset these components to an extent (by decreasing malnutrition rates and increased usage of clean fuels) [
The authors declared that there is no conflict of interests.