Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Cost and cost-effectiveness of tuberculosis treatment shortening: a model-based analysis.

BACKGROUND: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. METHODS: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. RESULTS: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. CONCLUSION: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.

The potential of a multiplex high-throughput molecular assay for early detection of first and second line tuberculosis drug resistance mutations to improve infection control and reduce costs: a decision analytical modeling study.

BACKGROUND: Molecular resistance detection (MRD) of resistance to second-line anti-tuberculous drugs provides faster results than phenotypic tests, may shorten treatment and allow earlier separation among patients with and without second-line drug resistance. METHODS: In a decision-analytical model we simulated a cohort of patients diagnosed with TB in a setting where drug resistant TB is highly prevalent and requires initial hospitalization, to explore the potential benefits of a high-throughput MRD-assay for reducing potential nosocomial transmission of highly resistant strains, and total costs for diagnosis of drug resistance, treatment and hospitalization. In the base case scenario first-line drug resistance was diagnosed with WHO-endorsed molecular tests, and second-line drug resistance with culture and phenotypic methods. Three alternative scenarios were explored, each deploying high-throughput MRD allowing either detection of second-line mutations in cultured isolates, directly on sputum, or MRD with optimized markers. RESULTS: Compared to a base case scenario, deployment of high-throughput MRD reduced total costs by 17-21 %. The period during which nosocomial transmission may take place increased by 15 % compared to the base case if MRD had currently reported suboptimal sensitivity and required cultured isolates; increased by 7 % if direct sputum analysis were possible including in patients with smear-negative TB, and reduced by 24 % if the assay had improved markers, but was still performed on cultured isolates. Improved clinical sensitivity of the assay (additional markers) by more than 35 % would be needed to avoid compromising infection control. CONCLUSIONS: Further development of rapid second-line resistance testing should prioritize investment in optimizing markers above investments in a platform for direct analysis of sputum.

Scale-up of TB and HIV programme collaborative activities in Zambia - a 10-year review.

OBJECTIVE: To review the activities, progress, achievements and challenges of the Zambia Ministry of Health tuberculosis (TB)/HIV collaborative activities over the past decade. METHODS: Analysis of Zambia Ministry of Health National TB and HIV programme documents and external independent programme review reports pertaining to 2000-2010. RESULTS: The number of people testing for HIV increased from 37 557 persons in 2003 to 1 327 995 persons in 2010 nationally. Those receiving anti-retroviral therapy (ART) increased from 143 in 2003 to 344 304 in 2010. The national HIV prevalence estimates declined from 14.3% in 2001 to 13.5% in 2009. The proportion of TB patients being tested for HIV increased from 22.6% in 2006 to 84% in 2010 and approximately 70% were HIV positive. The proportion of the HIV-infected TB patients who: (i) started on ART increased from 38% in 2006 to 50% in 2010; (ii) commenced co-trimoxazole preventive therapy (CPT) increased from 31% in 2006 to 70% in 2010; and (iii) were successfully treated increased to an average of 80% resulting in decline of deaths from 13% in 2006 to 9% in 2010. CONCLUSIONS: The scale-up of TB/HIV collaborative programme activities in Zambia has steadily increased over the past decade resulting in increased testing for TB and HIV, and anti-retroviral (ARV) rollout with improved treatment outcomes among TB patients co-infected with HIV. Getting service delivery points to adhere to WHO guidelines for collaborative TB/HIV activities remains problematic, especially those meant to reduce the burden of TB in people living with HIV/AIDS (PLWHA).

Does BCG vaccination protect against infection with M. tuberculosis?

BACKGROUND: Protection against infection by the bacille Calmette-Guérin vaccine against Mycobacterium tuberculosis remains a subject of controversy. We investigated the association between BCG vaccination at birth and infection by M. tuberculosis.MATERIAL and METHODS: This was a secondary analysis of data from tuberculin skin test (TST) surveys in Vietnamese schoolchildren between 1988 and 2001. We investigated whether a BCG scar was associated with a lower prevalence of TST positivity, adjusting for BCG-induced variation by varying cut-off values for a positive TST.RESULTS: We found a positive association between BCG scar and TST positivity. The strength of the association decreased with increasing TST cut-off values; however, it never inverted significantly, irrespective of geographic region and survey year.CONCLUSION: In Vietnam, BCG vaccination was not associated with reduced M. tuberculosis infection prevalence as measured using TST. This in contrary to a similar study conducted in Tanzania. These contradictory findings may be explained by geographical differences and the relatively high prevalence in Vietnam of the M. tuberculosis Beijing genotype, which is reported to be capable of circumventing BCG-induced immunity.

Country differences and determinants of yield in programmatic migrant TB screening in four European countries.

INTRODUCTION The WHO End TB Strategy emphasises early diagnosis and screening of TB in high-risk groups, including migrants. We analysed TB yield data from four large migrant TB screening programmes to inform TB policy.METHODS We pooled routinely collected individual TB screening episode data from Italy, the Netherlands, Sweden and the United Kingdom under the European Union Commission E-DETECT.TB grant, described characteristics of the screened population, and analysed TB case yield.RESULTS We collected data on 2,302,260 screening episodes among 2,107,016 migrants, mostly young adults aged 18-44 years (77.8%) from Asia (78%) and Africa (18%). There were 1,658 TB cases detected through screening, with substantial yield variation (per 100,000): 201.1 for Sweden (95% confidence intervals CI 111.4-362.7), 68.9 (95% CI 65.4-72.7) for the United Kingdom, 83.2 (95% CI 73.3-94.4) for the Netherlands and 653.6 (95% CI 445.4-958.2) in Italy. Most TB cases were notified among migrants from Asia (n = 1,206, 75/100,000) or Africa (n = 370, 76.4/100,000), and among asylum seekers (n = 174, 131.5/100,000), migrants to the Netherlands (n = 101, 61.9/100,000) and settlement visa migrants to the United Kingdom (n = 590, 120.3/100,000).CONCLUSIONS We found considerable variations in yield across programmes, types of migrants and country of origin. These variations may be partly explained by differences in migration patterns and programmatic characteristics.

Health-seeking behaviour among adults with prolonged cough in Vietnam.

OBJECTIVE: To assess health-seeking behaviour among adults with prolonged cough in a population-based, nationally representative sample in Vietnam. METHODS: Cross-sectional survey conducted from September 2006 to July 2007. All inhabitants aged ≥15 years were invited for screening for cough, history of tuberculosis (TB) treatment and chest X-ray (CXR) examination. TB suspects, defined as any survey participant with CXR abnormalities consistent with TB, or productive cough for more than 2 weeks or TB treatment either currently or in the preceding 2 years submitted sputum specimens for smear examination and culture and provided information on health-seeking behaviour in an in-depth interview. RESULTS: Of 94 179 persons participating in the survey, 4.6% had prolonged productive cough. Forty-four percentage of those had sought health care and reported pharmacies (35%), commune health posts (29%), public hospitals (24%) and private physicians (10%) as first point of contact. Only 7% had undergone sputum smear examination. Of TB suspects with prolonged productive cough, 2.9% were diagnosed with TB; 10.2% of these reported smear and 21.9% reported X-ray examination when visiting a health care facility. The average patient delay was 4.1 weeks (95% CI: 3.9-4.4) among cough suspects and 4.0 weeks (95% CI: 3.1-4.9) among TB cases. CONCLUSIONS: In this Vietnamese survey, nearly half of persons with cough for more than 2 weeks had visited a health care provider. The commonest first health facility contacted was the pharmacy. Sputum smears were rarely examined, except in the provincial TB hospital. Our findings highlight the need to improve diagnostic practices by retraining health staff on the performance of sputum examination for TB suspects.

Monocyte-to-lymphocyte ratio as a predictor of TB among people living with HIV.

BACKGROUND: Diagnostic tools to identify incipient or subclinical TB stages will be helpful for preventive intervention. A simple biomarker to predict TB may be the monocytes to lymphocytes ratio (ML ratio) in peripheral blood.METHODS: We assessed the relationship between multiple time-updated ML ratio measurements and incidence of TB in people living with HIV (PLWH) after antiretroviral therapy (ART) was initiated. The ML ratio was updated at least every 6 months. TB incidence with corresponding 95% confidence intervals stratified according to time-updated ML ratio was calculated using ML ratio in quartiles.RESULTS: A total of 1305 PLWH were included in the analyses: 46 had incident TB and 1259 remained TB-free. The TB incidence rate was 10.3 (95% CI 7.1-14.9) cases/1000 patient-years (PYR) among participants with ML ratio ≥0.25 compared with 1.1/1000 PYR (95% CI 0.4-2.9) among those with ML ratio <0.15. At cut-point 0.23, the ML ratio provided a diagnostic area under the receiver operating characteristics curve (AROC) of 0.849 (95% CI 0.784-0.914) and a sensitivity of 85% and specificity of 71%.CONCLUSION: Increased ML ratio was predictive of incident TB among PLWH on or after ART. The ML ratio can be a simple tool to stratify the risk of TB in PLWH.

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.

Seasonal drivers of tuberculosis: evidence from over 100 years of notifications in Cape Town.

BACKGROUND: Tuberculosis incidence varies seasonally in many settings. However, the role of seasonal variation in reactivation vs. transmission is unclear.METHODS: We reviewed data on TB notifications in Cape Town, South Africa, from 1903 to 2017 (exclusive of 1995-2002, which were unavailable). Data from 2003 onward were stratified by HIV status, age and notification status (new vs. retreatment). We performed seasonal decomposition and time-dependent spectral analysis using wavelets to assess periodicity over time. We estimated monthly peak-to-peak seasonal amplitude of notifications as a percentage of the annual notification rate.RESULTS: A seasonal trend was intermittently detected between 1904 and 1994, particularly during periods of high notification rates, but was consistently and strongly evident between 2003 and 2017, with peaks in September through November, following winter. Among young children, a second, higher seasonal peak was observed in March. Seasonal variation was greater in children (<5 years, 54%, 95% CI 47-61; 5-14 years, 63%, 95% CI 58-69) than in adults (36%, 95% CI 33-39).CONCLUSIONS: Stronger seasonal effects were seen in children, in whom progression following recent infection is known to be the predominant driver of disease. These findings may support increased transmission in the winter as an important driver of TB in Cape Town.

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement.

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

Protecting patients' rights, ensuring safety and quality assurance in tuberculosis prevalence surveys.

The conduct of biomedical studies is guided by statements of internationally recognised principles of human rights. The first principle of the Nuremberg Code was the centrality of voluntary participation of subjects with informed consent. All prevalence surveys should be reviewed by the appropriate ethics review committees. Each potential survey participant should be adequately informed of the aims, methods and sources of funding of the survey, any possible conflicts of interest, the institutional affiliations of the researchers, the anticipated benefits and potential risks of the study, and any discomfort it may entail. Attention should be paid to safety in each component of the survey. Test procedures that require particular attention are chest radiography (CXR) and bacteriological examination. Quality assurance should be applied to all aspects of research and, in particular, to any measurements undertaken, including CXR assessments, laboratory examinations and questionnaire and data management. Furthermore, to ensure comparability of data from different surveys, it is important to apply the same survey design and methodology and to use the same reporting format.

Inclusion of information on risk factors, socio-economic status and health seeking in a tuberculosis prevalence survey.

Data on socio-economic status, exposure to risk factors for tuberculosis (TB) and previous health-seeking for TB may be included in a TB prevalence survey to gain better knowledge about the distribution of TB in the population as well as a better understanding of what factors are driving the TB epidemic in a given setting. This article provides an overview of how such additional information may be collected. The article highlights the need to carefully consider the risk of jeopardising the quality of the overall survey by overburdening it with additional data collection, and concludes that additional time and resources for planning, training, logistics and supervision are required to safeguard quality. The article also discusses special considerations regarding sampling, sample size and data interpretation when including such information in a TB prevalence survey.

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.

Evaluation of a large-scale tuberculosis contact investigation in the Netherlands.

The aim of the present study was to evaluate yield and effectiveness of a large-scale contact investigation around a supermarket employee with infectious tuberculosis. Supermarket customers were screened by tuberculin skin test (TST) and/or radiography, depending on individual characteristics. The number of recent infections was estimated based on historical reference data after correction for false-positive TST results. TST screening of 15,518 subjects yielded 12 cases of tuberculosis disease as a direct result of the investigation (1,293 screenings per case identified). Radiographical screening of 5,945 subjects yielded no cases. There were 359 (2.6%) positive TSTs; 117 (34%) were estimated to be due to recent exposure. The number of customers screened in order to find one case of recent infection was 114, varying from 43 for customers who visited the supermarket twice per week or more, to 4,148 for customers who visited less than once per month. In conclusion, although this patient probably transmitted Mycobacterium tuberculosis to at least 117 customers, the contact investigation was inefficient, as large numbers of customers had to be screened and the majority of identified tuberculosis infections were probably not related to the index case. The efficiency could have been improved by omitting radiographical screening and limiting tuberculin skin test screening to customers who reported frequent supermarket visits.

Organisation of a tuberculosis prevalence survey.

Measuring tuberculosis (TB) prevalence trends provides information on progress towards the Millennium Development Goals. The World Health Organization recently published guidelines on assessing TB prevalence through population-based surveys. The current manuscript describes in detail the organisation of the field activities in such a survey. These activities need to be embedded in a strong organisational framework where the steering committee has the overall responsibility and the survey coordinator the day-to-day supervision. Field activities need to be tailored to the community, with respect to both time and place and direct involvement of community members. Frequent and well-described monitoring procedures need to be in place to be able to identify systematic and non-systematic errors at the earliest opportunity.

High tuberculosis prevalence in a psychiatric hospital in Vietnam.

Little is known about tuberculosis (TB) prevalence in psychiatric hospitals in Vietnam, but prevalence may be higher than in the general population. We assessed the TB prevalence among in-patients of a psychiatric hospital in 2005 in Danang City, Vietnam. Of 300 in-patients, 70 had an abnormal X-ray or prolonged cough, and underwent sputum smear examinations. The prevalence of smear-positive TB was 0.33% (1/300, 95%CI 0.008-1.9). Twenty-three (7.7%) patients had X-ray lesions suggesting active TB and 22 (7.3%) had a history of TB treatment. TB prevalence was high in this psychiatric hospital, and TB infection control needs strengthening.

Tuberculosis prevalence surveys: rationale and cost.

This article is the first of the educational series 'Assessing tuberculosis (TB) prevalence through population-based surveys'. The series will give overall guidance in conducting cross-sectional surveys of pulmonary TB (PTB) disease. TB prevalence surveys are most valuable in areas where notification data obtained through routine surveillance are of unproven accuracy or incomplete, and in areas with an estimated prevalence of bacteriologically confirmed TB of more than 100 per 100,000 population. To embark on a TB prevalence survey requires commitment from the national TB programme, compliance in the study population, plus availability of trained staff and financial resources. The primary objective of TB prevalence surveys is to determine the prevalence of PTB in the general population aged >or=15 years. Limitations of TB prevalence surveys are their inability to assess regional or geographic differences in prevalence of TB, estimate the burden of childhood TB or estimate the prevalence of extra-pulmonary TB. The cost of a prevalence survey is typically US$ 4-15 per person surveyed, and up to US$ 25 per person with radiographic screening. A survey of 50,000 people, of limited precision, would typically cost US$ 200,000-1,250,000.

Steep increases in tuberculosis notification among young men in the industrialised districts of Danang, Vietnam.

BACKGROUND: Tuberculosis (TB) notification is increasing among young adults in urban provinces in Vietnam, despite having achieved World Health Organization targets for treatment success and case detection. OBJECTIVES: To identify causes for non-declining TB case rates in an urban area of Vietnam, and to describe trends in new smear-positive pulmonary TB notification by age, sex and district in the period 1999-2004 in Danang City, Vietnam. RESULTS: Age and sex-standardised notification rates declined by 1.3% (95%CI -2.3-0.3%) annually. Notification rates among men aged 15-44 in Danang City increased significantly (5%, 95%CI 2.4-7.7 annually), most notably in industrialised districts (>or=12% annually). CONCLUSION: TB notification rates among young men in an urban setting in Vietnam increased most notably in industrialised districts. We hypothesise that this is due to poor living and working conditions and internal migration rather than to an emerging human immunodeficiency virus epidemic.

HIV-related mortality among tuberculosis patients in The Netherlands, 1993-2001.

Human immunodeficiency virus (HIV) infection in tuberculosis (TB) patients in The Netherlands during the period 1993-2001 was associated with an increased risk of death (adjusted odds ratio 4.71, P < 0.002). Age and sex-standardised mortality rates among HIV-infected TB patients decreased significantly over time, from 22.9% in 1993-1995 to 11.8% in 1999-2001 (P < 0.001). No such change was observed for HIV-negative patients. The decrease in mortality is likely due to the more widespread use of highly active antiretroviral therapy (HAART).