The Impact of GeneXpert Cerebrospinal Fluid Testing on Tuberculous Meningitis Diagnosis in Routine Care in Botswana.

BACKGROUND: Tuberculous meningitis (TBM) disproportionately impacts high-HIV prevalence, resource-limited settings where diagnosis is challenging. The GeneXpert platform has utility in TBM diagnosis, but uptake remains limited. In Botswana, before the introduction of GeneXpert, tuberculosis (TB) testing was only available through mycobacterial culture at the National TB Reference Laboratory. Data describing routine use of Xpert MTB/RIF for cerebrospinal fluid (CSF) testing in resource-limited settings are scarce. METHODS: Electronic records for patients with CSF tested in government facilities in Botswana between 2016 and 2022 were obtained from a central online repository as part of ongoing national meningitis surveillance. Samples were excluded from 1 site where Xpert MTB/RIF is performed universally. The proportion receiving TB-specific investigation on CSF and the number positive for Mycobacterium tuberculosis following increased Xpert MTB/RIF capacity were determined. RESULTS: The proportion of CSF samples receiving TB-specific investigation increased from 4.5% (58/1288) in 2016 to 29.0% (201/693) in 2022, primarily due to increased analysis with Xpert MTB/RIF from 0.9% (11/1288) to 23.2% (161/693). There was an overall decline in the annual number of CSF samples analyzed, but the proportion with microbiologically confirmed TBM increased from 0.4% to 1.2%. The proportion of samples tested for TB that were collected from health care facilities >100 km from the National TB Reference Laboratory increased with Xpert MTB/RIF rollout from 65.9% (87/132) to 78.0% (494/633). CONCLUSIONS: In Botswana, access to TB culture is challenging in remote populations; more accessible near-patient testing using Xpert MTB/RIF increased the number of patients receiving TB-specific testing on CSF and the number of confirmed TBM cases

Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study.

BACKGROUND: CNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults. METHODS: In this prevalent cohort study, patient records from 2004-15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per μL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per μL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality. FINDINGS: We included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with culture-confirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per μL and 1209 with CSF WCC above 20 cells per μL). Median age was 37 years (IQR 31-46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per μL (IQR 63-271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0-20 cells per μL vs >20 cells per μL) was not predictive of mortality (average hazard ratio 0·93, 95% CI 0·80-1·09). INTERPRETATION: Mortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms. FUNDING: National Institutes of Health, President's Emergency Plan for AIDS Relief, National Institute for Health Research

Causes of Pediatric Meningitis in Botswana: Results From a 16-Year National Meningitis Audit.

BACKGROUND: Central nervous system infections are an important cause of childhood morbidity and mortality in high HIV-prevalence settings of Africa. We evaluated the epidemiology of pediatric meningitis in Botswana during the rollout of antiretroviral therapy, pneumococcal conjugate vaccine and Haemophilus influenzae type B (HiB) vaccine. METHODS: We performed a cross-sectional study of children (<15 years old) evaluated for meningitis by cerebrospinal fluid (CSF) examination from 2000 to 2015, with complete national records for 2013-2014. Clinical and laboratory characteristics of microbiologically confirmed and culture-negative meningitis were described and incidence of Streptococcus pneumoniae, H. influenzae and cryptococcal meningitis was estimated for 2013-2014. RESULTS: A total of 6796 unique cases were identified. Median age was 1 year [interquartile range 0-3]; 10.4% (435/4186) of children with available HIV-related records were known HIV-infected. Overall, 30.4% (2067/6796) had abnormal CSF findings (positive microbiologic testing or CSF pleocytosis). Ten percent (651/6796) had a confirmed microbiologic diagnosis; including 26.9% (175/651) Cryptococcus, 18.9% (123/651) S. pneumoniae, 20.3% (132/651) H. influenzae and 1.1% (7/651) Mycobacterium tuberculosis. During 2013-2014, national cryptococcal meningitis incidence was 1.3 cases per 100,000 person-years (95% confidence interval, 0.8-2.1) and pneumococcal meningitis incidence 0.7 per 100,000 person-years (95% confidence interval, 0.3-1.3), with no HiB meningitis diagnosed. CONCLUSIONS: Following HiB vaccination, a marked decline in microbiologically confirmed cases of H. influenzae meningitis occurred. Cryptococcal meningitis remains the most common confirmed etiology, demonstrating gaps in prevention-of-mother-to-child transmission and early HIV diagnosis. The high proportion of abnormal CSF samples with no microbiologic diagnosis highlights limitation in available diagnostics

Tracking cryptococcal meningitis to monitor HIV program success during the Treat-All era: an analysis of national data in Botswana.

BACKGROUND: Cryptococcal meningitis causes substantial mortality in high-HIV prevalence African countries despite advances in disease management and increasing antiretroviral therapy coverage. Reliable diagnosis of cryptococcal meningitis is cheap and more accessible than other indicators of AHD burden such as CD4 testing or investigation for disseminated tuberculosis; therefore, monitoring cryptococcal meningitis incidence has the potential to serve as a valuable metric of HIV programmatic success. METHODS: Botswana national meningitis surveillance data from 2015 to 2022 were obtained from electronic health records. All electronic laboratory records from cerebrospinal fluid samples analysed within government healthcare facilities in Botswana were extracted from a central online repository. Adjustments for missing data were made through triangulation with prospective cohort study datasets. Cryptococcal meningitis case frequency was enumerated using a case definition and incidence calculated using national census data. RESULTS: A total of 1,744 episodes of cryptococcal meningitis were identified; incidence declined from 15.0 (95% CI 13.4-16.7) cases/100,000 person-years in 2015 to 7.4 (95% CI 6.4-8.6) cases/100,000 person-years in 2022. However, the rate of decline slowed following the introduction of universal treatment in 2016. The highest incidence was observed in men and individuals aged 40-44. The proportion of cases diagnosed through cryptococcal antigen testing increased from 35.5% to 86.3%. CONCLUSION: Cryptococcal meningitis incidence has decreased in Botswana following expansion of ART coverage but persists at a stubbornly high incidence. Most cases are now diagnosed through the cheap and easy-to-use cryptococcal antigen test highlighting the potential of using cryptococcal meningitis as key metric of programme success in the Treat All era

Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: Results from the Botswana national meningitis survey.

OBJECTIVES: Data on meningitis epidemiology in high HIV-prevalence African settings following antiretroviral therapy scale-up are lacking. We described epidemiology of adult meningitis in Botswana over a 16-year period. METHODS: Laboratory records for adults undergoing lumbar puncture (LP) 2000-2015 were collected, with complete national data 2013-2014. Cerebrospinal fluid (CSF) findings and linked HIV-data were described, and national incidence figures estimated for 2013-2014. Temporal trends in meningitis were evaluated. RESULTS: Of 21,560 adults evaluated, 41% (8759/21,560) had abnormal CSF findings with positive microbiological testing and/or pleocytosis; 43% (3755/8759) of these had no confirmed microbiological diagnosis. Of the 5004 microbiologically-confirmed meningitis cases, 89% (4432/5004) were cryptococcal (CM) and 8% (382/5004) pneumococcal (PM). Seventy-three percent (9525/13,033) of individuals undergoing LP with identifiers for HIV registry linkage had documented HIV-infection. Incidence of LP for meningitis evaluation in Botswana 2013-2014 was 142.6/100,000 person-years (95%CI:138.3-147.1); incidence of CM was 25.0/100,000 (95%CI:23.2-26.9), and incidence of PM was 2.7/100,000 (95%CI:2.4-3.1). In contrast to previously reported declines in CM incidence with ART roll-out, no significant temporal decline in pneumococcal or culture-negative meningitis was observed. CONCLUSIONS: CM remained the predominant identified aetiology of meningitis despite ART scale-up. A high proportion of cases had abnormal CSF with negative microbiological evaluation

Impact of Health System Inputs on Health Outcome: A Multilevel Longitudinal Analysis of Botswana National Antiretroviral Program (2002-2013).

To measure the association between the number of doctors, nurses and hospital beds per 10,000 people and individual HIV-infected patient outcomes in Botswana.Analysis of routinely collected longitudinal data from 97,627 patients who received ART through the Botswana National HIV/AIDS Treatment Program across all 24 health districts from 2002 to 2013. Doctors, nurses, and hospital bed density data at district-level were collected from various sources.A multilevel, longitudinal analysis method was used to analyze the data at both patient- and district-level simultaneously to measure the impact of the health system input at district-level on probability of death or loss-to-follow-up (LTFU) at the individual level. A marginal structural model was used to account for LTFU over time.Increasing doctor density from one doctor to two doctors per 10,000 population decreased the predicted probability of death for each patient by 27%. Nurse density changes from 20 nurses to 25 nurses decreased the predicted probability of death by 28%. Nine percent decrease was noted in predicted mortality of an individual in the Masa program for every five hospital bed density increase.Considerable variation was observed in doctors, nurses, and hospital bed density across health districts. Predictive margins of mortality and LTFU were inversely correlated with doctor, nurse and hospital bed density. The doctor density had much greater impact than nurse or bed density on mortality or LTFU of individual patients. While long-term investment in training more healthcare professionals should be made, redistribution of available doctors and nurses can be a feasible solution in the short term

High incidence of tuberculosis in the first year of antiretroviral therapy in the Botswana National antiretroviral therapy programme between 2011 and 2015.

OBJECTIVE:Tuberculosis (TB) remains one of the leading causes of mortality and morbidity among people living with HIV. We sought to estimate the incidence of TB in a national database of HIV-infected patients receiving antiretroviral therapy (ART) in Botswana. DESIGN:A retrospective analysis of HIV-infected adult patients (≥18years) who initiated ART between 2011 and 2015 in the Botswana ART program. METHODS:Multivariable analysis using Cox regression included sex, age, viral load and CD4 counts. RESULTS:Of 45,729 patients, with a median follow-up of 1·7 years Q1, Q3: 0·5,3·1), 1,791 patients developed TB over a median of 1·5 years (Q1, Q3: 0·3,3·1) of follow-up (IR 1·9 per 100 py; 95% CI 1·8-2·0). At baseline, the median CD4+ T-cell count was 272 cells/μl (Q1:Q3 146, 403). The risk of TB was greatest within the first year of ART (IR 2·9 per 100 py; 95% CI 2·7-3·1) and in patients with CD4 counts below 50 cells/μl (IR 8·3/100 py; 95% CI 7·1-9·7). Patients with viral loads above 10,000 copies/ml at 3 months post ART initiation had two-times higher risk of TB, HR 2.5 (95% CI 1·8-2·3). CONCLUSIONS:We report a high incidence of TB within the first year of ART and in patients with advanced immunodeficiency. Improved screening strategies and virologic monitoring during this early period on ART, coupled with TB preventative treatment, will reduce the burden of TB

Physician, Nurse, and Hospital Bed Density per 10,000 Population in Botswana Health Districts (2002–2013).

<p>Physician, Nurse, and Hospital Bed Density per 10,000 Population in Botswana Health Districts (2002–2013).</p

Multilevel Analysis of Variables Predictive of Overall Survival and LTFU among Adult Patients in Masa Program.

<p>Multilevel Analysis of Variables Predictive of Overall Survival and LTFU among Adult Patients in Masa Program.</p

Baseline Patient Characteristics for Patients^† Initiating Antiretroviral Treatment in the Botswana National HIV/AIDS Treatment Program, 2002–2013.

<p>Baseline Patient Characteristics for Patients^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160206#t001fn001" target="_blank">†</a>} Initiating Antiretroviral Treatment in the Botswana National HIV/AIDS Treatment Program, 2002–2013.</p