Neighbourhood factors and tuberculosis incidence in Cape Town: A negative binomial regression and spatial analysis.

OBJECTIVES: Although the link between poverty and tuberculosis (TB) is widely recognised, limited studies have investigated the association between neighbourhood factors and TB incidence. Since the factors influencing different episodes of TB might be different, this study focused on the first episode of TB disease (first-episode TB). METHODS: All first episodes in previously linked and geocoded TB notification data from 2007 to 2015 in Cape Town, South Africa, were aggregated at the neighbourhood level and merged with the 2011 census data. We conducted an ecological study to assess the association between neighbourhood incidence of first-episode TB and neighbourhood factors (total TB burden [all episodes] in the previous year, socioeconomic index, mean household size, mean age, and percentage males) using a negative binomial regression. We also examined the presence of hotspots in neighbourhood TB incidence with the Global Moran's I statistic and assessed spatial dependency in the association between neighbourhood factors and TB incidence using a spatial lag model. RESULTS: The study included 684 neighbourhoods with a median first-episode TB incidence rate of 114 (IQR: 0-345) per 100,000 people. We found lower neighbourhood socioeconomic index (SEI), higher neighbourhood total TB burden, lower neighbourhood mean household size, and lower neighbourhood mean age were associated with increased neighbourhood first-episode TB incidence. Our findings revealed a hotspot of first-episode TB incidence in Cape Town and evidence of spatial dependency in the association between neighbourhood factors and TB incidence. CONCLUSION: Neighbourhood TB burden and SEI were associated with first-episode TB incidence, and there was spatial dependency in this association. Our findings can inform targeted interventions to reduce TB in high-risk neighbourhoods, thereby reducing health disparities and promoting health equity.

Sensitivity of C-Reactive Protein and Procalcitonin Measured by Point-of-Care Tests to Diagnose Urinary Tract Infections in Nursing Home Residents: A Cross-Sectional Study.

BACKGROUND: Diagnosing urinary tract infections (UTIs) in nursing home residents is complex, as specific urinary symptoms are often absent and asymptomatic bacteriuria (ASB) is prevalent. The aim of this study was to assess the sensitivity of blood C-reactive protein (CRP) and procalcitonin (PCT), measured by point-of-care tests (PoCTs), to diagnose UTIs in this setting. METHODS: Elderly residents (≥65 years old) with a suspected UTI were recruited from psychogeriatric, somatic, or rehabilitation wards across 13 participating nursing homes. CRP and PCT were tested simultaneously in the same study participants. To assess the tests' sensitivities, a stringent definition of "true" UTI was used that included the presence of symptoms, urinary leucocytes, a positive urine culture, and symptom resolution during antibiotic treatment covering isolated uropathogen(s). The original sample size was 440 suspected UTI episodes, in order to detect a clinically relevant sensitivity of at least 65% when calculated using the matched analysis approach to compare both PoCTs. RESULTS: After enrollment of 302 episodes (68.6% of the planned sample size), an unplanned and funder-mandated interim analysis was done, resulting in premature discontinuation of the study for futility. For 247 of 266 eligible episodes, all mandatory items required for the true UTI definition (92.9%) were available. In total, 49 episodes fulfilled our stringent UTI definition (19.8%). The sensitivities of CRP (cut-off, 6.5 mg/L) and PCT (cut-off, 0.025 ng/mL) were 52.3% (95% confidence interval [CI], 36.7-67.5%) and 37.0% (95% CI, 23.2-52.5%), respectively. CONCLUSIONS: Our results indicate that CRP and PCT are not suitable tests for distinguishing UTI and ASB in nursing home residents. CLINICAL TRIALS REGISTRATION: Netherlands Trial Registry NL6293.

"A false sense of confidence" The perceived role of inflammatory point-of-care testing in managing urinary tract infections in Dutch nursing homes: a qualitative study.

BACKGROUND: Diagnosing urinary tract infections (UTI) in nursing home residents is complex, due to frequent non-specific symptomatology and asymptomatic bacteriuria. The objective of this study was to explore health care professionals' perceptions of the proposed use of inflammatory marker Point-Of-Care Testing (POCT) in this respect. METHODS: We conducted a qualitative inquiry (2018-2019) alongside the multicenter PROGRESS study (NL6293), which assessed the sensitivity of C-reactive protein and procalcitonin POCT in UTI. We used semi-structured face-to-face interviews. The participants were physicians (n = 12) and nurses (n = 6) from 13 nursing homes in the Netherlands. Most respondents were not familiar with inflammatory marker POCT, while some used POCT for respiratory tract infections. Both the interview guide and the analysis of the interview transcripts were based on the Consolidated Framework for Implementation Research. RESULTS: All respondents acknowledged that sufficiently sensitive POCT could decrease diagnostic uncertainty to some extent in residents presenting with non-specific symptoms. They primarily thought that negative test results would rule out UTI and justify withholding antibiotic treatment. Secondly, they described how positive test results could rule in UTI and justify antimicrobial treatment. However, most respondents also expected new diagnostic uncertainties to arise. Firstly, in case of negative test results, they were not sure how to deal with residents' persisting non-specific symptoms. Secondly, in case of positive test results, they feared overlooking infections other than UTI. These new uncertainties could lead to inappropriate antibiotics use. Therefore, POCT was thought to create a false sense of confidence. CONCLUSIONS: Our study suggests that inflammatory marker POCT will only improve UTI management in nursing homes to some extent. To realize the expected added value, any implementation of POCT requires thorough guidance to ensure appropriate use. Developing UTI markers with high negative and positive predictive values may offer greater potential to improve UTI management in nursing homes.

Earlier initiation of antiretroviral therapy, increased tuberculosis case finding and reduced mortality in a setting of improved HIV care: a retrospective cohort study.

OBJECTIVES: High early mortality after antiretroviral therapy (ART) initiation in resource-limited settings is associated with low baseline CD4 cell counts and a high burden of opportunistic infections. Our large urban HIV clinic in Uganda has made concerted efforts to initiate ART at higher CD4 cell counts and to improve diagnosis and care of patients coinfected with tuberculosis (TB). We sought to determine associated treatment outcomes. METHODS: Routinely collected data for all patients who initiated ART from 2005 to 2009 were analysed. Median baseline CD4 cell counts by year of ART initiation were compared using the Cuzick test for trend. Mortality and TB incidence rates in the first year of ART were computed. Hazard ratios (HRs) were calculated using multivariable Cox proportional hazards models. RESULTS: First-line ART was initiated in 7659 patients; 64% were women, and the mean age was 37 years (standard deviation 9 years). Median baseline CD4 counts increased from 2005 to 2009 [82 cells/µL (interquartile range (IQR) 24, 153) to 148 cells/µL (IQR 61, 197), respectively; P<0.001]. The mortality rate fell from 6.5/100 person-years at risk (PYAR) [95% confidence interval (CI) 5.5-7.6 PYAR] to 3.6/100 PYAR (95% CI 2.2-5.8 PYAR). TB incidence rates increased from 8.2/100 PYAR (95% CI 7.1-9.5 PYAR) to 15.6/100 PYAR (95% CI 12.4-19.7 PYAR). A later year of ART initiation was independently associated with decreased mortality (HR 0.91; 95% CI 0.83-1.00; P=0.04). CONCLUSIONS: Baseline CD4 cell counts have increased over time and are associated with decreased mortality. Additional reductions in mortality might be a result of a better standard of care and increased TB case finding. Further efforts to initiate ART earlier should be prioritized even in a setting of capped or reduced funding for ART programmes.

Prevalence of smear-positive tuberculosis in persons aged ≥ 15 years in Bangladesh: results from a national survey, 2007-2009.

The aim of this study was to determine the nationwide prevalence of smear-positive tuberculosis (TB) in Bangladesh. A multi-stage cluster survey of a random sample of persons aged ≥ 15 years was included in 40 clusters (20 urban, 20 rural). Two sputum samples were collected from study participants and tested initially by fluorescence microscopy and confirmed by the Ziehl-Neelsen method. The crude and adjusted prevalence rates and 95% confidence intervals (CIs) were calculated using standard methods. A total of 33 new smear-positive TB cases were detected among 52 098 individuals who participated in the study. The average participation rate was over 80%. The overall crude prevalence of new smear-positive TB in persons aged ≥ 15 years was estimated as 63.3/100 000 (95% CI 43.6-88.9) and the adjusted prevalence was 79.4/100 000 (95% CI 47.1-133.8). TB prevalence was higher in males (n = 24) and in rural areas (n = 20). The prevalence was highest in the 55-64 years age group (201/100 000) and lowest in 15-24 years age group (43.0/100 000). The prevalence was higher in persons with no education (138.6/100 000, 95% CI 78.4-245.0). The overall prevalence of smear-positive TB was significantly lower than the prevalence estimate of the previous nationwide survey in Bangladesh in 1987-1988 (870/100 000).

Does distance to healthcare facility affect care-seeking for TB-related symptoms in Tanzania?

BACKGROUND: In high TB burden countries, delayed diagnosis remains a big challenge in TB control. The objective of this study is to assess the role of distance between residence and healthcare facility (HCF) on care-seeking among individuals with symptoms associated with pulmonary TB in Tanzania.METHODS: In this cross-sectional study, using data from a national TB survey, coordinates of 300 (residential) sites within 62 clusters were obtained through Google searches and average distances to HCF were calculated per cluster. Univariable and multivariable logistic regression analyses were conducted, with care-seeking behaviour being the primary outcome variable.RESULTS: Distance from residence to HCF had no effect on care-seeking behaviour of individuals with TB-related symptoms in this study (OR 1.00, 95% CI 1.00-1.00). Over 85% of HCFs where care has been sought lack TB diagnostic capacity, mostly comprising dispensaries with staff less educated in TB-related symptoms.CONCLUSION: Care-seeking behaviour among individuals with TB-related symptoms in Tanzania was not found to be associated with distance to HCF. First-line diagnostics should be improved 1) by equipping local dispensaries with basic TB diagnostic capacity, and 2) by educating staff of local dispensaries more thoroughly about basic TB symptoms and the importance of swift referrals.

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.

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.

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.

Management of patients with multidrug-resistant tuberculosis.

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

Measuring tuberculosis burden, trends, and the impact of control programmes.

The targets for tuberculosis control, framed within the United Nations' Millennium Development Goals, are to ensure that the incidence per head of tuberculosis is falling by 2015, and that the 1990 prevalence and mortality per head are halved by 2015. In monitoring progress in tuberculosis control, the ultimate aim for all countries is to count tuberculosis cases (incidence) accurately through routine surveillance. Disease prevalence surveys are costly and laborious, but give unbiased measures of tuberculosis burden and trends, and are justified in high-burden countries where many cases and deaths are missed by surveillance systems. Most countries in which tuberculosis is highly endemic do not yet have reliable death registration systems. Verbal autopsy, used in cause-of-death surveys, is an alternative, interim method of assessing tuberculosis mortality, but needs further validation. Although several new assays for Mycobacterium tuberculosis infection have recently been devised, the tuberculin skin test remains the only practical method of measuring infection in populations. However, this test typically has low specificity and is therefore best used comparatively to assess geographical and temporal variation in risk of infection. By 2015, every country should be able to assess progress in tuberculosis control by estimating the time trend in incidence, and the magnitude of reductions in either prevalence or deaths.

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.

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.

[Estimation of the incidence of tuberculosis in The Netherlands in 2030]. / Projectie van het aantal tuberculosepatiënten in Nederland in 2030.

OBJECTIVE: To estimate the number of cases of tuberculosis (TB) in 2030 for the purpose of planning future TB control. DESIGN: Statistical modelling in 5-year intervals until 2030. METHOD: The number of Dutch TB cases infected by a Dutch source was estimated using a survival model. The number ofnon-Dutch patients was estimated by calculating the proportion of culture-positive TB patients among first-generation immigrants in 2005 and applying this proportion to the projected size of the non-Dutch population. It was assumed that each non-Dutch TB patient infected by a non-Dutch source would cause one infection in the population in The Netherlands. RESULTS: The estimated number of TB cases is expected to decrease to 877 in 2010. Only a limited decrease in the number of TB patients is expected after 2010 as the number of non-Dutch TB cases increases due to increased immigration. This increase negates the expected decrease in Dutch TB patients infected by a Dutch source. In 2030, non-Dutch TB cases will account for 85% of all TB cases. The proportion of non-Dutch TB cases is greater in the 4 largest cities, i.e. Amsterdam, Rotterdam, The Hague and Utrecht (89%) than in the rest of The Netherlands (76%). CONCLUSION: The decrease in TB incidence observed over the past several years may cease by 2010 due to an increase in non-Dutch TB patients as a result of increased immigration. However, the confidence intervals associated with these estimates were large. Future TB control efforts must be organised in a flexible way so that they can be adapted to changing epidemiological situations.

Treatment responses in multidrug-resistant tuberculosis in Germany.

BACKGROUND: Excellent treatment outcomes have recently been reported for patients with multi/extensively drug-resistant tuberculosis (M/XDR-TB) in settings where optimal resources for individualised therapy are available. OBJECTIVE: To ascertain whether differences remain in treatment responses between patients with M/XDR-TB and those with non-M/XDR-TB. METHOD: Patients with TB were prospectively enrolled between March 2013 and March 2016 at five hospitals in Germany. Treatment was conducted following current guidelines and individualised on the basis of drug susceptibility testing. Two-month and 6-month sputum smear and sputum culture conversion rates were assessed. A clinical and radiological score were used to assess response to anti-tuberculosis treatment. RESULTS: Non-M/XDR-TB (n = 29) and M/XDR-TB (n = 46) patients showed similar rates of microbiological conversion: 2-month smear conversion rate, 90% vs. 78%; culture conversion rate, 67% vs. 61%; time to smear conversion, 19 days (IQR 10-32) vs. 31 days (IQR 14-56) (P = 0.066); time to culture conversion, 39 days (IQR 17-67) vs. 39 days (IQR 6-85) (P = 0.191). Both clinical and radiological scores decreased after the introduction of anti-tuberculosis treatment. CONCLUSION: There were no significant differences in scores between the two groups until 6 months of treatment. Under optimal clinical conditions, with the availability of novel diagnostics and a wide range of therapeutic options for individualised treatment, patients with M/XDR-TB achieved 6-month culture conversion rates that were compatible with those in patients with non-M/XDR-TB.

Tuberculosis resistance-conferring mutations with fitness cost among HIV-positive individuals in Uganda.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is considered to be less transmissible due to the fitness cost associated with drug resistance-conferring mutations in essential genes. OBJECTIVE: To test the hypothesis that TB drug resistance-conferring mutations with fitness cost are more frequent among human immunodeficiency virus (HIV) positive than among HIV-negative patients. DESIGN: We analysed all strains from the two TB drug resistance surveys conducted in Uganda between 2008 and 2011. Strains phenotypically susceptible to rifampicin and/or isoniazid were assumed to be wild-type; in all other cases, we performed whole-genome sequencing. Mutations at the rpoB531 and katG315 codons were considered without fitness loss, whereas other rpoB codons and non-katG were considered with fitness loss. RESULTS: Of the 897 TB patients, 286 (32.1%) were HIV-positive. Mutations with fitness loss in HIV-positive and HIV-negative patients were respectively as follows: non-531 rpoB: 1.03% (n = 3), 0.71% (n = 4) (OR 1.46, 95%CI 0.58-3.68); non-katG: 0.40% (n = 1), 1.0% (n = 6) (OR 0.40, 95%CI 0.07-2.20); rpoB531: 1.49% (n = 4), 0.69% (n = 4) (OR 2.29, 95%CI 0.83-5.77); katG315: 3.86% (n = 11), 2.55% (n = 15) (OR 1.54, 95%CI 0.81-2.90). The odds of mutations with and without fitness cost were higher for patients with a history of previous anti-tuberculosis treatment. CONCLUSIONS: Our data do not support the hypothesis that resistance-conferring mutations with fitness cost are likely to be often present in HIV-positive individuals.

[The use of the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz in the treatment of patients with a chronic HIV-I infection]. / Het gebruik van de niet-nucleoside-'reverse'-transcriptaseremmers nevirapine en efavirenz in de behandeling van patiënten met een chronische hiv I-infectie.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important group ofantiretroviral drugs in the treatment of a chronic HIV-I infection. The risk of viral resistance to NNRTIs is strongly diminished when they are used as part of a highly active antiretroviral combination therapy (HAART). Randomised trials have shown that nevirapine and efavirenz have a comparable antiretroviral efficacy. While rash and hepatotoxicity are associated with the use of nevirapine, the use of efavirenz is associated with neuropsychiatric abnormalities. The increase in HDL-cholesterol, which may be associated with a lower risk of cardiovascular disease, is greater with nevirapine than with efavirenz. The choice between the two drugs can be tailored to the needs of the patient. The rapid selection ofNNRTI-resistant HIV-I strains during the sub-optimal use of nevirapine and efavirenz demands the development of new NNRTIs.

Prevalence of pulmonary tuberculosis in adult population of Tanzania: a national survey, 2012.

SETTING: Tanzania is classified as one of the 22 high tuberculosis (TB) burden countries; however, the true burden of TB disease in the country remains unknown. OBJECTIVE: To assess the prevalence of bacteriologically confirmed pulmonary TB (PTB) in the adult population. DESIGN: This was a community-based cluster randomised survey with proportional-to-population-size selection of primary sampling units (districts). Participants were screened for TB using a symptom questionnaire and chest X-ray (CXR). Those with abnormal CXR and/or at least one symptom suggestive of TB were classified as individuals with presumptive TB, and asked to submit three sputum specimens for smear microscopy and culture. RESULTS: The weighted prevalence for sputum smear-positive TB cases was 249 per 100 000 adult population (95%CI 192-305) and that for bacteriologically confirmed TB cases was 293/100 000 (95%CI 228-358). Individuals aged ⩾45 years comprised 55% (71/129) of the identified smear-positive cases, but just 28% (6793/24 648) of the notified TB cases. CXR screening identified more TB cases than symptom screening. When weighted for human immunodeficiency virus prevalence among notified new smear-positive cases, the overall case detection of incident TB cases in 2012 was between 37% and 48%. CONCLUSIONS: The prevalence of sputum smear-positive PTB and bacteriologically confirmed PTB in the adult population was higher than previous World Health Organization estimates. There is a potential underestimation of the number of bacteriologically confirmed PTB cases in the adult population. The age distribution of prevalent cases suggests an epidemiological shift towards the older generations, which has been a sign of successful TB control activities in the past. However, the survey shows that many infectious TB cases are currently missed by the National Tuberculosis Programme.