Understanding the epidemiology and transmission of tuberculosis among adults in rural and urban Tanzania

Background: Tuberculosis (TB) is the leading cause of death in the world from a single infectious disease and resulted in about 1.5 million deaths in 2018. Globally, close to one third of the population is latently infected with Mycobacterium tuberculosis (Mtb), of which about 5-10% during their lifetime, will develop active TB depending on the age of infection. TB is an airborne disease transmitted by airways from one person to the next when an uninfected individual breathes in air containing Mtb expired from an infected person. One way to estimate the risk of TB transmission begins with measuring environmental levels of carbon dioxide (CO2) levels exhaled by humans. CO2 levels combined with social contact data allow calculation of the volumes of rebreathed air in order to estimate the potential for airborne disease transmission by considering time at risk, quanta of contagion and the number of people occupying the confined space etc.
Unfortunately, most TB patients are diagnosed at later stages of the disease, due to poor health-seeking behavior, inappropriate diagnostic investigations requested by health care providers, and limited access to better TB diagnostics which forces patients to seek relief by using self-prescribed medication. Delaying diagnosis and treatment of TB has important consequences for disease control at both the individual (poor treatment outcome) as well as the community level (continued transmission). Within the country, the prevalence of TB varies considerably across regions, and is higher among males, older persons, and those with lower socioeconomic status. Lastly, patients with TB often have additional comorbidities such as anemia, helminthiasis etc., which can result in poor treatment outcomes. Anemia of chronic disease is primarily found in patients with chronic disease status such as those with chronic immune activation such as TB and HIV-positive patients.
Objectives: The overall goal of this PhD project was to understand the epidemiology and transmission of tuberculosis in Tanzania by studying the infrastructure-related risk of TB transmission through measuring environmental CO2 levels at locations of public importance; determining the TB diagnostic delay and its associated factors among TB patients; understanding differences in the epidemiology of TB and comorbidities among TB patients from rural and urban Tanzania; and investigating the association of hepcidin levels with coinfections, TB disease severity and progression from TB infection to disease among adults in Tanzania.
Methods: This PhD project was embedded in the ongoing hospital-based cohort of adult TB cases and controls in Temeke, Dar es Salaam and Ifakara, Morogoro, Tanzania. The field work for this PhD study was carried out between September 2016 and April 2018. The project had two designs; infrastructure-related and patient-related design. For objective 1, an observational study was carried out which employed exposure assessment methods where we collected environmental data (CO2, geo-coordinates etc.,) from locations of public importance. We used the modified Wells-Riley equation to estimate the annual risk of TB transmission which was calculated as a function of time spent per year at a given location. For objectives 2-3, we analysed data from the ongoing cohort of adult TB patients and their household contacts (TB DAR). Briefly, recruitment of study participants began in 2013 at Temeke Regional Referral Hospital (Temeke district) and 2014 at the St. Francis Referral Hospital (Kilombero district). Participants collected baseline information and provided specimen for further analysis. Multivariate logistic regression models were used to find associations and presented as crude and adjusted odds ratio. Lastly, for objective 4, we designed a nested case-control study matched by age and sex. Descriptive statistics were used to summarize participants characteristics. We compared cases and controls using conditional logistic regression model to determine associations between outcomes of interest and various predictors.
Results: We found that the annual risks of TB transmission were highest among prison inmates (41.6%) and drivers (20.3%) in public transport. Lower transmission risks were found in central markets (4.8% for traders, but 0.5% for their customers), passengers on public transport (2.4%), public schools (4.0%), nightclubs (1.7%), religious (0.13%), and social halls (0.12%).
Diagnostic delay was positively associated with absence of chest pain (aOR = 7.97, 95% confidence intervals [CI] = 3.15 – 20.19), and presence of hemoptysis (aOR = 25.37, 95% CI = 11.15 – 57.74) and negatively associated with use of medication prior to TB diagnosis (aOR = 0.31, 95% CI = 0.14 – 0.71). Patients living far from pharmacies were less likely to visit a health care facility (incremental increase of distance versus visit to any facility: OR = 0.51, 95% CI = 0.28 – 0.96). Patients from the rural setting were older (median age 37 years vs. 34 years, p=0.003), had a lower median body mass index (17.5 kg/m2 vs. 18.5 kg/m2, p<0.001), a higher proportion of recurrent TB cases (9% vs. 1%, p<0.001) compared to those from urban Tanzania. The overall prevalence of helminth co-infections was 22.9% with differences in the etiology of helminthiasis. The higher prevalence of helminthiasis in the urban setting (25.7% vs. 17.3%, p=0.018) was predominantly driven by Strongyloides stercoralis (17.0% vs. 4.8%, p<0.001) while Schistosoma mansoni infection (4.1% vs. 16.4%, p<0.001) dominated in the rural setting. Recurrent TB was associated with living in a rural setting (adjusted odds ratio [aOR] 3.97, 95% CI 1.16-13.67) and increasing age (aOR 1.06, 95% CI 1.02-1.10). Anemia of chronic disease (ACD) was more frequent among cases than controls (59.8% vs. 26.1%), but iron-deficiency anemia more frequent in controls (10% vs. 1%). The median hepcidin level was higher in cases than controls (63.7 vs. 14.2 ng/mL), but coinfections with HIV, helminths, and respiratory pathogens did not show cumulative effects. Hepcidin was associated with more severe TB symptom scoring (coefficient 0.8, 95% confidence interval [CI] 0.5-1.2) and higher mycobacterial load (0.7, 95% CI 0.4-1.0). Hepcidin was higher in TB cases and controls who developed TB compared to controls without TB (p<0.001), even when restricting to HIV-negative study participants.
Conclusions: From this PhD project, we have demonstrated that environmental CO2 from locations of public importance, could identify locations with higher risk of TB transmission. This novel approach can be used by National TB Programs (NTP) to guide targeted infection control interventions for TB control in sub-Saharan Africa to reduce TB transmission. Adults from urban Tanzania, are still faced with significant TB diagnosis delay and that the use of medication prior to TB diagnosis was common. This provides a unique opportunity for inclusion of pharmacies in the formal referral systems from communities to TB diagnostic facilities. We found TB patients from rural Tanzania were likely to be older, with recurrent TB, with features of advanced TB disease due to a longer TB diagnosis delay and seek more frequently care from traditional healers. The overall prevalence of helminth co-infections among TB patients was higher in urban Tanzania, predominantly driven by Strongyloides stercoralis infection, but the prevalence of Schistosoma mansoni was higher in the rural Tanzania. NTPs should strive to understand fundamental differences in the TB epidemiology in different settings and translate that into specific interventions based on such differences. For example, the NTLP should build the capacity of traditional healers in rural Tanzania, for improving early detection of TB cases and referral for TB treatment. Lastly, we found hepcidin to be marginally upregulated by coinfections other than Mtb, and thus this could be used as a marker for identifying patient with severe TB disease and high-risk persons exposed to TB.