Epidemiology of co-infections in tuberculosis patients in Tanzania : HIV, helminth infection and respiratory pathogens

Background: Tuberculosis (TB) caused by Mycobacterium tuberculosis complex is a global public health concern, causing significant morbidity and mortality. The resource limited settings are the worst hit, especially where there is also high burden of co-infections which increase the risk of developing TB and negatively affect TB treatment outcomes. HIV, helminth and respiratory pathogens are prevalent in Tanzania, a country that is in among the top 30 high burden countries as categorized by World Health Organization (WHO). There is epidemiological evidence of increased risk of developing TB with HIV, and little evidence on the association of TB and helminth infection and respiratory pathogens. It is therefore important to understand the epidemiology of TB and co-infections, so that we can design interventions that will address the burden of TB and relevant co-infections.
The objectives: The main objective of this PhD thesis was to determine the burden and the association of HIV, helminth and respiratory pathogens (viruses and bacteria) co-infections and TB at Temeke district, Dar es Salaam, Tanzania. The specific objectives were: i) to determine the treatment outcome of TB and HIV co-infected patients routinely diagnosed at Temeke district treated under home- and facility-based direct observed therapy (DOT), ii) to determine the prevalence of helminth infection and respiratory pathogens among smear positive TB cases and household contact controls without TB, iii) to investigate the risk factors for helminth infection and respiratory pathogens among smear-positive TB cases and household contact controls without TB, and iv) to determine the clinical effects of helminth infection and respiratory pathogens on clinical phenotypes and clinical outcomes among smear-positive TB patients.
Methods: This PhD is nested within a large TB cohort in Dar es Salaam region (TB-DAR): a prospective collection of clinical data and biological specimens to study the epidemiology of tuberculosis, including molecular epidemiology and the evaluation of new diagnostics and biomarkers). There are two distinctive methodological parts as described below:
Objective 1: We obtained anonymized electronic data from the TB district register of all adult TB patients (aged ≥15 years) who were notified between 2010 and 2013 in a single geographical area of two TB sub-districts (Wailes I and Wailes II) in the Temeke district, Dar es Salaam, Tanzania.
Objective 2-4: We consecutively enrolled ≥18 years TB patients and household contact controls between November 2013 until October 2015 to reach the required sample size. Any individual living in the same household as the index TB patients enrolled in the study is referred to as a household contact control. Controls at recruitment were free of symptoms and signs suggestive of TB, healthy on physical examination, and had a negative Xpert MTB/RIF result (Cepheid; California, USA). We collected sputum, nasopharyngeal swabs, stool and urine samples from TB patients and household controls at recruitment. Löwenstein-Jensen mycobacterial culture was used to confirm TB. Kato-katz and Bearman methods for detection of soil transmitted helminths infections from stool. Urine filtration and Circulating Cathodic Antigen (CCA) assay for detection of Schistosomiasis. Nasopharyngeal swabs samples were analyzed using Allplex™ Respiratory full panel assay and PCR Anyplex™II RV16 for detection of respiratory bacterial and viral pathogens respectively.
Principle findings: In a study to determine the treatment outcome of TB and HIV co-infected patients routinely diagnosed at Temeke district treated under home- and facility-based DOT: data of 4,835 adult TB patients were analyzed, with a median age of 35 years, 2,943 (60.9%) were men and TB/HIV co-infection prevalence of 39.9%. A total of 3,593 (74.3%) patients were treated under home-based DOT. Patients on home-based DOT were more likely to die compared to patients on facility-based DOT (RR 2.04, 95% Confidence Interval [95% CI]: 1.52-2.73), and more likely to complete TB treatment (RR 1.14, 95% CI: 1.06-1.23), but less likely to have a successful treatment outcome (RR 0.94, 95% CI: 0.92-0.97). Home-based DOT was preferred by women (adjusted Odds Ratio [aOR] 1.55, 95% CI: 1.34-1.80, p<0.001), older people (aOR 1.01 for each year increase, 95% CI: 1.00-1.02, p=0.001) and patients with extra-pulmonary TB (aOR 1.45, 95% CI: 1.16-1.81, p=0.001), but less frequently by patients on a retreatment regimen (aOR 0.12, 95% CI: 0.08-0.19, p<0.001).
In a study to assess the association of TB and helminth infection: a total of 597 TB patients and 375 household contact controls were included. The median age was 33 years and 60.2% (585/972) were men. The prevalence of any helminth infection among TB patients was 31.8% (190/597) and 25.9% (97/375) among controls. Strongyloides stercoralis was the predominant helminth species (16.6%, 161), followed by hookworm (9.0%, 87) and Schistosoma mansoni (5.7%, 55). An infection with any helminth was not associated with TB (aOR 1.26, 95% CI: 0.88-1.80, p=0.22), but S. mansoni infection was (aOR 2.15, 95% CI: 1.03-4.45, p=0.040). Moreover, S. mansoni infection was associated with lower sputum bacterial load (aOR 2.63, 95% CI: 1.38-5.26, p=0.004) and tended to have fewer lung cavitations (aOR 0.41, 95% CI: 0.12-1.16, p=0.088).
When assessing the interaction between TB and respiratory pathogens: we analyzed 794 study participants, of which 489 (61.6%) were TB patients and 305 (38.4%) were household contact controls. The median age of the study participants was 33 years; 61% (484/794) were men, and 21% (168/ 794) were HIV-positive. TB patients had a higher prevalence of HIV (28.6%; 140/489) than controls (9.2%; 28/305). Overall prevalence of respiratory viral pathogens was 20.4% (160/794; 95%CI 17.7-23.3%) and of bacterial pathogens 38.2% (303/794; 95%CI 34.9-41.6%). TB patients and controls did not differ in the prevalence of respiratory viruses (Odds Ratio [OR] 1.00, 95%CI 0.71-1.44), but respiratory bacteria were less frequently detected in TB patients (OR 0.70, 95%CI 0.53-0.94). TB patients with both respiratory viruses and respiratory bacteria were likely to have more severe disease (adjusted OR [aOR] 1.6, 95%CI 1.1-2.4; p=0.011). TB patients with respiratory viruses tended to have more frequent lung cavitations (aOR 1.6, 95%CI 0.93-2.7; p=0.089).
Conclusion: TB patients under home-based DOT had more risk factors for death such as older age, HIV infection and sputum smear-negative TB, and had higher TB mortality compared to patients under facility-based DOT. Assessment of TB mortality risk factors and offering additional clinical care could be beneficial in reducing TB mortality. Further operational research is warranted to monitor implementation of DOT and discern other risk factors for deaths. S. mansoni infection was an independent risk factor for active TB and altered the clinical presentation in TB patients. S. mansoni infection may play a role in TB pathogenesis in humans. Bidirectional screening of TB and helminth including treatment for both diseases should be considered in a clinical management of patients. Respiratory viruses are common for both TB patients and household controls. TB patients may present with more severe TB disease, particularly when they are co- infected with both bacteria and viruses.