Development of a TB vaccine trial site in Africa and lessons from the Ebola experience.

Tuberculosis is the deadliest infection of our time. In contrast, about 11,000 people died of Ebola between 2014 and 2016. Despite this manifest difference in mortality, there is now a vaccine licensed in the United States and by the European Medicines Agency, with up to 100% efficacy against Ebola. The developments that led to the trialing of the Ebola vaccine were historic and unprecedented. The single licensed TB vaccine (BCG) has limited efficacy. There is a dire need for a more efficacious TB vaccine. To deploy such vaccines, trials are needed in sites that combine high disease incidence and research infrastructure. We describe our twelve-year experience building a TB vaccine trial site in contrast to the process in the recent Ebola outbreak. There are additional differences. Relative to the Ebola pipeline, TB vaccines have fewer trials and a paucity of government and industry led trials. While pathogens have varying levels of difficulty in the development of new vaccine candidates, there yet appears to be greater interest in funding and coordinating Ebola interventions. TB is a global threat that requires similar concerted effort for elimination.

Tuberculosis among HIV-infected population: incidence and risk factors in rural Tanzania.

BACKGROUND: The incidence of tuberculosis among HIV-infected populations with high CD4 count in high burden countries has not been well studied. OBJECTIVE: To assess the TB incidence in HIV-infected adults and its associated risk factors. METHOD: A cohort study with retrospective review of medical records and prospective follow-up of HIV-infected adult participants attending CTC who were 18-55 years old, had CD4 count more than 250 cells/mm3 in the period of 2008-2010 and were not on ART at enrolment. Cox proportional hazard regression was used to explore the predictors of incident TB. RESULTS: Overall 777 (24%) of 3,279 CTC enrolled HIV-infected adults fulfilled the inclusion criteria of the study. The incidence of TB in the study population ranged from 0.8/100 per person years (PY) at risk (95% CI 0.5-1.3) in the main analysis to 1.7/100 PY at risk (95% CI 1.0-2.6) in sensitivity analyses. Only prior history of TB disease was found to have a significant association with an increased risk of TB, hazard ratio 5.7 (95% CI 2.0-16.4, p value 0.001). CONCLUSION: Tuberculosis incidence among HIV-infected adults with medium/high CD4 count in Bagamoyo is lower than in other high TB burden countries. Previously TB treated patients have a much higher risk of getting TB again than those who never had TB before.

Added value of interferon-gamma release assays in screening for tuberculous infection in the Netherlands.

BACKGROUND: Interferon-gamma release assays (IGRAs) are reported to be more specific for the diagnosis of latent tuberculous infection (LTBI) than the tuberculin skin test (TST). The two-step procedure, TST followed by an IGRA, is reported to be cost-effective in high-income countries, but it requires more financial resources. OBJECTIVE: To assess the added value of IGRA compared to TST alone in the Netherlands. METHODS: Test results and background data on persons tested with an IGRA were recorded by the Public Municipal Health Services in a web-based database. The number of persons diagnosed with LTBI using different screening algorithms was calculated. RESULTS: In those tested with an IGRA, at least 60% of persons who would have been diagnosed with LTBI based on TST alone had a negative IGRA. Among those with a TST reaction below the cut-off for the diagnosis of LTBI, 13% had a positive IGRA. For 41% of persons tested with an IGRA after TST, the IGRA influenced whether or not an LTBI diagnosis would be made. CONCLUSION: With the IGRA as reference standard, a high proportion of persons in low-prevalence settings are treated unnecessarily for LTBI if tested with TST alone, while a small proportion eligible for preventive treatment are missed. Incremental costs of the two-step strategy seem to be balanced by the improved targeting of preventive treatment.

Willingness to participate in trials and to be vaccinated with new tuberculosis vaccines in HIV-infected adults.

BACKGROUND: New tuberculosis (TB) vaccines are required to meet global targets for TB control. OBJECTIVES: To determine willingness to participate (WTP) in new TB vaccine trials, willingness to be vaccinated with a newly licensed TB vaccine and associated factors among human immunodeficiency virus (HIV) infected persons. SETTING: Two primary care clinics in South Africa. DESIGN: Cross-sectional study design. Participants were asked about WTP and willingness to be vaccinated. Demographic, clinical, knowledge of TB and perception of risk information were collected. Log binomial regression was used to determine associated factors. RESULTS: A total of 827 participants were included in the analysis: 80.4% female, 72.2% on antiretroviral therapy, median age 35 years (interquartile range [IQR] 29-42 years), CD4 count 523 cells/µl (IQR 427-659 cells/µl). WTP and willingness to be vaccinated were high, at 84.5% and 92.6%, respectively. WTP was associated with knowledge about TB (prevalence ratio [PR] 1.10, 95% confidence interval [CI] 1.03-1.17) and perception of risk (PR 1.07, 95%CI 1.01-1.13). Willingness to be vaccinated was associated with employment (PR 1.04, 95%CI 1.01-1.08) and perception of risk (PR 1.05, 95%CI 1.01-1.09). CONCLUSIONS: There was high WTP in TB vaccine trials and willingness to be vaccinated among HIV-infected patients with good TB knowledge and high perceived risk of contracting TB.

Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial.

SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guérin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations. RESULTS: A total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs. CONCLUSION: Home visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups.

Tuberculin skin test and QuantiFERON® assay in young children investigated for tuberculosis in South Africa.

SETTING: Although the literature on interferon-gamma release assays on tuberculosis (TB) in children has increased, data pertaining to young children remain relatively limited. OBJECTIVE: To compare results from the tuberculin skin test (TST) and the QuantiFERON®-TB Gold In-Tube assay (QFT) in children aged <3 years investigated for TB disease. DESIGN: TB suspects were evaluated by medical history and examination, TST, QFT, chest radiography, induced sputum and gastric washings for smear and culture for Mycobacterium tuberculosis. RESULTS: A total of 400 children were enrolled. Among 397 children with both test results, 68 (17%) were QFT-positive and 72 (18%) were TST-positive (≥10 mm). Agreement between the tests was excellent (94%, κ = 0.79, 95%CI 0.69-0.89). TB disease was diagnosed in 52/397 (13%) participants: 3 definite, 35 probable and 14 possible TB. QFT sensitivity and specificity for TB disease were respectively 38% and 81%. TST sensitivity and specificity were respectively 35% and 84%. CONCLUSION: While TST and QFT had excellent concordance in this population, both tests had much lower sensitivity for TB disease than has been reported for other age groups. Our results suggested equivalent performance of QFT and TST in the diagnosis of TB disease in young children in a high-burden setting.

Capture-recapture to estimate completeness of tuberculosis surveillance in two communities in South Africa.

BACKGROUND: Reliable surveillance is essential for any tuberculosis (TB) control programme; however, under-registration of TB cases due to under-notification of patients on treatment or failure to initiate treatment has been well-documented internationally. OBJECTIVE: To determine the contribution of capture-recapture methods in estimating the completeness of bacteriologically confirmed pulmonary TB registration in two high-incident communities in South Africa. METHODS: Record linkage between the TB treatment register and two laboratory sputum TB result registers and three-source log-linear capture-recapture analysis. RESULTS: The number of bacteriologically confirmed pulmonary TB cases in the TB treatment register was 243, with an additional 63 cases identified in the two laboratory databases, resulting in 306 TB cases. The observed completeness of the TB treatment register was 79%. The log-linear model estimated 326 (95%CI 314-355) TB cases, resulting in an estimated completeness of registration of 75% (95%CI 68-77). CONCLUSION: Capture-recapture can be useful in evaluating the completeness of TB control surveillance and registration, including in resource-limited settings; however, methodology and results should be carefully assessed. Interventions are needed to increase the completeness of registration and to reduce the number of initial defaulters.

Risk of travelling to the country of origin for tuberculosis among immigrants living in a low-incidence country.

SETTING: Two thirds of tuberculosis (TB) patients in the Netherlands are foreign-born. OBJECTIVE: To determine if travelling to the country of origin is a risk factor for TB among two different immigrant groups that have lived in the Netherlands for at least 2 years. DESIGN: In this unmatched case-control study, the frequency and duration of travel to the country of origin in the preceding 12 months were compared between adult Moroccan and Turkish TB patients and community controls. RESULTS: Moroccan patients had travelled more often (26/32 = 81%) in the preceding year than Moroccan controls (472/816 = 58%). The travel-associated odds ratio (OR) for TB among Moroccans was 3.2 (95%CI 1.3-7.7), and increased to 17.2 (95%CI 3.7-79) when the cumulative duration of travel exceeded 3 months. The corresponding population fraction of Moroccan TB cases attributable to recent travel was 56% (95%CI 19-71). Among Turkish immigrants TB was not associated with travel (OR 0.9, 95%CI 0.3-2.4). CONCLUSION: Travel to the country of origin was a risk factor for TB among Moroccans, but not among Turkish people living in the Netherlands. The difference in travel-associated OR between these two immigrant groups is probably related to differences in TB incidence in these countries.

Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa.

SETTING: A high tuberculosis (TB) burden area in South Africa (notification rate for all TB cases 1400 per 100 000 population). OBJECTIVE: To determine the prevalence of and predictive factors associated with latent TB infection in adolescents. DESIGN: Adolescents aged 12-18 years were recruited from high schools, clinical and demographic data were collected, and a tuberculin skin test (TST) and a QuantiFERON®-TB Gold In-Tube (QFT) assay performed. RESULTS: A total of 6363 (58.2%) of 10 942 adolescents at the schools were enrolled. After exclusions, of 5244 participants, 55.2% (95%CI 53.8-56.5) had TST ≥ 5 mm, while 50.9% (49.5-52.2) were QFT-positive. On multivariate analysis, Black/mixed race racial groups, male sex, older age, household TB contact, low income and low education level were predictive factors for both TST- and QFT-positive results. CONCLUSION: About half of the adolescents were found to be latently infected with TB in a high TB burden area with demographic and poverty-related socio-economic factors predicting the risk of TB infection. Adolescents from deprived communities should be considered an important target group for educational interventions by TB control programmes in high-burden settings.

Accuracy and completeness of recording of confirmed tuberculosis in two South African communities.

BACKGROUND: Although tuberculosis (TB) treatment registers and laboratory records are essential tools for recording and reporting in TB control programmes, the accuracy and completeness of routinely collected data are seldom monitored. OBJECTIVE: To assess the accuracy and completeness of TB treatment register data in two South African urban communities using record linkage. METHODS: All cases of bacteriologically confirmed TB, defined as two smear-positive results and/or at least one culture-positive result, were included. Record linkage was performed between three data sources: 1) TB treatment registers, 2) the nearest central laboratory, and 3) the referral hospital laboratory. RESULTS: The TB treatment registers had 435 TB cases recorded, of which 204 (47%) were bacteriologically confirmed. An additional 39 cases recorded as non-bacteriological cases in the TB treatment registers were reclassified as bacteriologically confirmed, and 63 bacteriologically confirmed cases were identified from the laboratory databases that were not recorded in the TB treatment registers. The final number of bacteriologically confirmed TB cases was 306, giving an increase of 50%. CONCLUSIONS: The accuracy and completeness of the TB treatment register and central laboratory data were inadequate. A high percentage of bacteriologically confirmed cases from both laboratories were not recorded in the TB treatment registers. We are developing an electronic result management system to improve the management of laboratory results.

The tuberculin skin test: a comparison of ruler and calliper readings.

BACKGROUND: The Mantoux tuberculin skin test (TST) is widely used to diagnose latent infection with Mycobacterium tuberculosis. TST skin induration may be measured either by a transparent ruler or by a pair of callipers. We hypothesised that the type of instrument used may affect the reading. OBJECTIVE: To determine whether variability in Mantoux TST measurement is affected by the type of reading instrument. METHOD: A TST (Mantoux method) was performed among healthy adolescents. The indurations were read with among ruler and calliper by two independent readers. Limits of agreement and Kappa (κ) scores at TST positivity cut-off points were calculated. A Bland-Altman graph was constructed. RESULTS: The 95% limits of agreement between instruments ranged from -5 mm to 3 mm. The limits of agreement between readers ranged from -5 mm to 4 mm. κ scores between instruments were respectively 0.7 and 0.8 at 15 mm and 10 mm cut-offs. CONCLUSION: The variability between readers of TST indurations is not influenced by changing the reading instrument.

Use of simulated sputum specimens to estimate the specificity of laboratory-diagnosed tuberculosis.

SETTING: Cross-contamination is not uncommon in mycobacteriology laboratories of high-income countries, as documented by bacterial genotyping. The extent of this problem in low-income countries is largely unknown, where this method is impractical. OBJECTIVE: To estimate the rate of cross-contamination in a high-volume tuberculosis (TB) laboratory in South Africa. DESIGN: Simulated sputum specimens labelled with false names were sent from a TB clinic, interspersed with patient samples, and processed for culture and microscopy. Results were interpreted in the context of the observed proportion of samples with positive microscopy and culture results. RESULTS: With microscopy, 6/190 (3.2%) simulated specimens were positive (estimated specificity = 96.8%). Considering the 881 positive microscopy results in 6093 clinical samples, we extrapolate that 19.3% (95%CI 7.0-42.8) of positive smears were false-positives. On culture, 2/190 (1.1%) of the simulated specimens were positive for Mycobacterium tuberculosis (estimated specificity = 98.9%). Considering the 1862 positive cultures from 6093 clinical samples, we estimate that 2.4% (95%CI 0.3-8.8) of positive cultures were false-positives. CONCLUSION: Simulated specimens offer a simple means of estimating the proportion of false-positive results, providing information on all sources of potential error from the clinic, through the laboratory and to reporting of results.

Age-related tuberculosis incidence and severity in children under 5 years of age in Cape Town, South Africa.

SETTING: Limited data are available on the characteristics of tuberculosis (TB) disease in young children, especially in high-burden countries. OBJECTIVE: To assess the incidence and severity of TB in children aged <5 years. METHODS: TB records and chest radiographs of children born in Cape Town in 1999 and diagnosed with TB between 1999 and 2004 were reviewed retrospectively. RESULTS: A total of 1607 cases were registered. The cumulative incidence of definite (bacteriologically confirmed) and probable (radiological evidence and > or =1 TB clinical feature) TB in children aged <5 years was 2.9% and was highest between the ages of 12 and 23 months. Of 1233 children with definite or probable TB, 506 (41%) had severe disease (dissemination, cavities or >1 lobe involved). The under 5 years incidence of disseminated TB was 0.33%. Of 239 (15%) cases that were bacteriologically confirmed, clinical features typical of TB disease were individually present in <60%. The most common combined symptoms were cough for >2 weeks and weight loss, occurring in 43/239 (18%). CONCLUSION: TB incidence was high, and peaked in children aged 12-23 months. Many children experienced severe disease. A fifth of children with microbiologically confirmed disease presented with only one feature typically associated with TB.

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-gamma release assays (IGRAs), QuantiFERON-TB Gold In-tube (QFT-GIT) and T-SPOT.TB, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged > or =16 yrs and their TST result was > or =5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST > or =5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3-5.0%) for TST > or =10 mm, 7/184 = 3.8% (95% CI 1.7-5.9%) for TST > or =15 mm, 5/178 = 2.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3-5.3%) for T-SPOT.TB. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT.TB and TST for progression to TB disease among immigrant close contacts were comparable.

Migrant tuberculosis screening in the EU/EEA: yield, coverage and limitations.

A systematic literature review was performed with the objective of assessing the effectiveness of tuberculosis (TB) screening methods and strategies in migrants in European Union/European Economic Area (including Switzerland) countries. Extracted data on yield and coverage were used as indicators of effectiveness. Reported yields varied considerably between studies and countries. Considering only the 14 studies representative of national screening programmes, a median yield of TB disease of 0.18% (interquartile range 0.10-0.35%) was reported. The data did not indicate differences in effectiveness between the three main strategies: 1) screening at port of entry; 2) screening just after arrival in reception/holding centres; and 3) screening in the community following arrival in European Union countries. The variation seen probably reflects variation in risk factors for TB, in particular the composition of the migrants entering the country. Recommendations include the need for improved data for guiding the optimal frequency and duration of screening; assessment and improvement of cost-effectiveness; access to healthcare for migrants, including illegal migrants; ensuring a continuum of care for those screened; and consideration of screening for latent TB infection with caution. Finally, screening should be a component of a wider approach, rather than a stand-alone intervention.

Interferon-gamma release assays in immigrant contacts and effect of remote exposure to Mycobacterium tuberculosis.

OBJECTIVE: To assess the association between remote exposure to tuberculosis (TB) and results of the tuberculin skin test (TST), and two interferon-gamma release assays (IGRAs)-QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB-in immigrant contacts of sputum smear-positive TB patients. METHODS: Immigrants aged >or=16 years in close contact with smear-positive TB patients were included. QFT-GIT and T-SPOT.TB were performed if the TST induration size was >or=5 mm. Associations between test results and origin from an endemic country were assessed. RESULTS: Of 433 close contacts, 322 (74%) had TST >or=5 mm, of whom, 282 (88%) had valid test results for all assays. Positive QFT-GIT results were obtained for 152/282 (54%) and positive T-SPOT.TB for 168/282 (60%). After adjustment for age, sex and recent contact, positive IGRA results and TST results >/=10 mm were found to be more frequent among immigrants who originated from Africa, in particular sub-Saharan Africa. CONCLUSION: When IGRAs are used to determine latent TB infection in foreign-born individuals, positive findings not only relate to recent TB infection, but also reflect prior TB exposure in the country of origin. This late reactivity will limit their usefulness in contact investigations among immigrants originating from endemic areas.

Annual meeting of the Tuberculosis Surveillance and Research Unit, 2008.

The Tuberculosis Surveillance and Research Unit (TSRU) held its last annual meeting in Helsinki, Finland, from 1 to 4 April 2008. Several topics of current interest for tuberculosis (TB) research and new research projects were presented and discussed in depth by 60 delegates from Europe, Africa and Asia. This paper summarises some of the highlights of the meeting which may be of interest to epidemiologists and managers active in the field of TB.

From suspect to patient: tuberculosis diagnosis and treatment initiation in health facilities in South Africa.

SETTING: Thirteen primary health care (PHC) facilities in the Stellenbosch District, South Africa. OBJECTIVE: To assess the use of a sputum register to evaluate the tuberculosis (TB) diagnostic process and the initiation of TB treatment in selected PHC facilities in a country with a centralised laboratory system. DESIGN: This prospective study was conducted between April 2004 and March 2005. The names of all individuals submitting sputum samples for TB testing were noted in a newly introduced sputum register. We classified all TB suspects with two positive smears as TB cases and consulted TB treatment registers until 3 months after sputum submission to determine how many had started treatment. RESULTS: A total of 4062 persons aged > or =15 years submitted sputum samples, of whom 2484 were TB suspects. There were 2037 suspects with at least two results, 367 (18%) had at least two positive smears and 64 (17%) of these did not start treatment (initial defaulters). Over the entire diagnostic process, up to 5% of TB cases were missed, and up to 26% did not start treatment and were not reported. CONCLUSION: By correcting diagnostic weaknesses identified in the sputum register, PHC facilities will be able to detect, treat and cure a higher percentage of TB patients.

Tuberculosis culture testing at a tertiary care hospital: options for improved management and use for treatment decisions.

SETTING: Chris Hani Baragwanath Hospital, a tertiary care hospital in Johannesburg, South Africa. OBJECTIVES: To determine the proportion of patients with positive Mycobacterium tuberculosis cultures and whether those who were positive were on treatment. DESIGN: Tuberculosis (TB) culture results were obtained from the laboratory for a 3-month period. Positive results were checked against registrations at the hospital TB Care Centre (TBCC). The treatment status of non-registered patients was obtained from various records at the hospital, district clinics and from home visits. RESULTS: Overall, 3909 patients had 5404 samples sent for culture. Of these, 708 patients (18%) had at least one positive culture. The positive yield from 2749 adult sputum samples was 33% and ranged from 6% to 40% for different extra-pulmonary specimens. Among 1160 children, the yield varied from 0% to 12%, with 12% in sputum and gastric washing specimens. Of the 708 culture-positive patients, 429 (61%) patients were registered at the TBCC and were known to have started TB treatment. Of the 279 subjects not registered (39% overall), 100 (36%) died. Only 67 of the 179 survivors were confirmed on treatment, 40 were not on treatment and 72 could not be traced. CONCLUSIONS: Large numbers of TB culture tests were performed, some inappropriately. Study findings highlight inadequacies in the management of culture-confirmed TB at this hospital.