Advancing the chemotherapy of tuberculous meningitis: a consensus view.

Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus an aminoglycoside + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial-an update to the published protocol.

This article reports an update to the protocol of the IMASOY trial, which was prospectively registered on clinicaltrials.gov (NCT04110340) in October 2019.

An independent, multi-country head-to-head accuracy comparison of automated chest x-ray algorithms for the triage of pulmonary tuberculosis.

Background: Computer-aided detection (CAD) algorithms for automated chest X-ray (CXR) reading have been endorsed by the World Health Organization for tuberculosis (TB) triage, but independent, multi-country assessment and comparison of current products are needed to guide implementation. Methods: We conducted a head-to-head evaluation of five CAD algorithms for TB triage across seven countries. We included CXRs from adults who presented to outpatient facilities with at least two weeks of cough in India, Madagascar, the Philippines, South Africa, Tanzania, Uganda, and Vietnam. The participants completed a standard evaluation for pulmonary TB, including sputum collection for Xpert MTB/RIF Ultra and culture. Against a microbiological reference standard, we calculated and compared the accuracy overall, by country and key groups for five CAD algorithms: CAD4TB (Delft Imaging), INSIGHT CXR (Lunit), DrAid (Vinbrain), Genki (Deeptek), and qXR (qure.AI). We determined the area under the ROC curve (AUC) and if any CAD product could achieve the minimum target accuracy for a TB triage test (≥90% sensitivity and ≥70% specificity). We then applied country- and population-specific thresholds and recalculated accuracy to assess any improvement in performance. Results: Of 3,927 individuals included, the median age was 41 years (IQR 29-54), 12.9% were people living with HIV (PLWH), 8.2% living with diabetes, and 21.2% had a prior history of TB. The overall AUC ranged from 0.774-0.819, and specificity ranged from 64.8-73.8% at 90% sensitivity. CAD4TB had the highest overall accuracy (73.8% specific, 95% CI 72.2-75.4, at 90% sensitivity), although qXR and INSIGHT CXR also achieved the target 70% specificity. There was heterogeneity in accuracy by country, and females and PLWH had lower sensitivity while males and people with a history of TB had lower specificity. The performance remained stable regardless of diabetes status. When country- and population-specific thresholds were applied, at least one CAD product could achieve or approach the target accuracy for each country and sub-group, except for PLWH and those with a history of TB. Conclusions: Multiple CAD algorithms can achieve or exceed the minimum target accuracy for a TB triage test, with improvement when using setting- or population-specific thresholds. Further efforts are needed to integrate CAD into routine TB case detection programs in high-burden communities.

Solicited Cough Sound Analysis for Tuberculosis Triage Testing: The CODA TB DREAM Challenge Dataset.

Cough is a common and commonly ignored symptom of lung disease. Cough is often perceived as difficult to quantify, frequently self-limiting, and non-specific. However, cough has a central role in the clinical detection of many lung diseases including tuberculosis (TB), which remains the leading infectious disease killer worldwide. TB screening currently relies on self-reported cough which fails to meet the World Health Organization (WHO) accuracy targets for a TB triage test. Artificial intelligence (AI) models based on cough sound have been developed for several respiratory conditions, with limited work being done in TB. To support the development of an accurate, point-of-care cough-based triage tool for TB, we have compiled a large multi-country database of cough sounds from individuals being evaluated for TB. The dataset includes more than 700,000 cough sounds from 2,143 individuals with detailed demographic, clinical and microbiologic diagnostic information. We aim to empower researchers in the development of cough sound analysis models to improve TB diagnosis, where innovative approaches are critically needed to end this long-standing pandemic.

Prevalence of pulmonary tuberculosis and HIV infections and risk factors associated to tuberculosis in detained persons in Antananarivo, Madagascar.

The incidence rate of tuberculosis in prisons is estimated to be 8 times greater than that in the general population in Madagascar. Our objectives were to estimate the prevalence of pulmonary tuberculosis and HIV infection among prisoners and to identify risk factors associated with tuberculosis. We conducted a cross-sectional study at the central prison of Antananarivo from March to July 2021. Individual male and female inmates aged ≥ 13 years who had lived in the prison for at least three months prior to the study period were included as participants. Acid-fast bacilli detection by microscopy and/or culture, an intradermal tuberculin test, a chest X-ray, and a rapid diagnostic orientation test for HIV were performed. Among 748 participants, 4 (0.5%) were confirmed to have pulmonary tuberculosis. Overall, 14 (1.9%) patients had "confirmed" or "probable" tuberculosis [0.90-2.84, 95% CI]. The proportion of participants with latent tuberculosis infection was 69.6% (517/743) based on a positive tuberculin test without clinical symptoms or radiography images indicating tuberculosis. Out of 745 HIV screening tests, three showed reactive results (0.4%). Age (OR = 4.4, 95% CI [1.4-14.0]) and prior tuberculosis treatment (or episodes) were found to be associated with confirmed and probable tuberculosis.

Implementation of an antibiotic resistance surveillance tool in Madagascar, the TSARA project: a prospective, observational, multicentre, hospital-based study protocol.

INTRODUCTION: Antimicrobial resistance (AMR) has become a significant public health threat. Without any interventions, it has been modelled that AMR will account for an estimated 10 million deaths annually by 2050, this mainly affects low/middle-income countries. AMR has a systemic negative perspective affecting the overall healthcare system down to the patient's personal outcome. In response to this issue, the WHO urged countries to provide antimicrobial stewardship programmes (ASPs). ASPs in hospitals are a vital component of national action plans for AMR, and have been shown to significantly reduce AMR, in particular in low-income countries such as Madagascar.As part of an ASP, AMR surveillance provides essential information needed to guide medical practice. We developed an AMR surveillance tool-Technique de Surveillance Actualisée de la Résistance aux Antimicrobiens (TSARA)-with the support of the Mérieux Foundation. TSARA combines bacteriological and clinical information to provide a better understanding of the scope and the effects of AMR in Madagascar, where no such surveillance tool exists. METHODS AND ANALYSIS: A prospective, observational, hospital-based study was carried out for data collection using a standardised data collection tool, called TSARA deployed in 2023 in 10 hospitals in Madagascar participating in the national Malagasy laboratory network (Réseau des Laboratoires à Madagascar (RESAMAD)). Any hospitalised patient where the clinician decided to take a bacterial sample is included. As a prospective study, individual isolate-level data and antimicrobial susceptibility information on pathogens were collected routinely from the bacteriology laboratory and compiled with clinical information retrieved from face-to-face interviews with the patient and completed using medical records where necessary. Analysis of the local ecology, resistance rates and antibiotic prescription patterns were collected. ETHICS AND DISSEMINATION: This protocol obtained ethical approval from the Malagasy Ethical Committee n°07-MSANP/SG/AGMED/CNPV/CERBM on 24 January 2023. Findings generated were shared with national health stakeholders, microbiologists, members of the RESAMAD network and the Malagasy academic society of infectious diseases.

High Seroprevalence of IgG Antibodies to Multiple Arboviruses in People Living with HIV (PLWHIV) in Madagascar.

To estimate the prevalence of IgG antibodies against six arboviruses in people living with HIV-1 (PLWHIV) in Madagascar, we tested samples collected between January 2018 and June 2021. We used a Luminex-based serological assay to detect IgG antibodies against antigens from Dengue virus serotypes 1-4 (DENV1-4), Zika virus (ZIKV), West Nile virus (WNV), Usutu virus (USUV), Chikungunya virus (CHIKV), and O'nyong nyong virus (ONNV). Of the 1036 samples tested, IgG antibody prevalence was highest for ONNV (28.4%), CHIKV (26.7%), WNV-NS1 (27.1%), DENV1 (12.4%), USUV (9.9%), and DENV3 (8.9%). ZIKV (4.9%), DENV2 (4.6%), WNV-D3 (5.1%), and DENV4 (1.4%) were lower. These rates varied by province of origin, with the highest rates observed in Toamasina, on the eastern coast (50.5% and 56.8%, for CHIKV and ONNV, respectively). The seroprevalence increased with age for DENV1 and 3 (p = 0.006 and 0.038, respectively) and WNV DIII (p = 0.041). The prevalence of IgG antibodies against any given arborvirus varied over the year and significantly correlated with rainfalls in the different areas (r = 0.61, p = 0.036). Finally, we found a significant correlation between the seroprevalence of antibodies against CHIKV and ONNV and the HIV-1 RNA plasma viral load. Thus, PLWHIV in Madagascar are highly exposed to various arboviruses. Further studies are needed to explain some of our findings.

An extensive arterial thrombosis with lower limb ischemia in a COVID-19 patient: A case report.

The coronavirus disease 2019 (COVID-19) pandemic is responsible for huge morbidity and mortality throughout the world. Several serious complications of this disease have been reported. It can cause hypercoagulability, which may lead to venous and arterial thromboembolic diseases. This hypercoagulability state is also associated with high morbidity and mortality. Arterial thrombosis in COVID-19 is poorly described compared to venous thrombosis and pulmonary embolism. We report a case of an extensive arterial thrombosis leading to a limb ischemia with extremely high D-dimer in a COVID-19 patient. A 69-year-old man was hospitalized for febrile dyspnea. He is a hypertensive and diabetic patient. On admission, pulse oxygen saturation was 72% on room air. He had cyanosis of the left foot up to the mid-thigh. The left pedal, posterior tibial, popliteal and femoral pulses were abolished. Chest CT scan was in favor of COVID-19. He has a high D-dimer level of 257,344 ng/mL. Arterial Echo-Doppler found an extensive intraluminal thrombus along the arterial axes of the left lower limb, completely obstructing them, starting from the primitive iliac artery just after its bifurcation with the aorta, and extending distally (external iliac; common femoral; superficial femoral; popliteal; anterior tibial; posterior tibial; fibular and pedal). The patient was diagnosed with COVID-19 critical form, associated with ischemia of the left lower limb secondary to an extensive arterial thrombosis. He was receiving anticoagulation, and underwent surgical amputation of the ischemic limb. The patient survived the event; however, he was on long-term oxygen therapy at home. Arterial thrombosis may occur during COVID-19 and may be responsible for peripheral or central ischemia aggravating morbidity and mortality. The occurrence of these events is related to the D-dimer value. Anticoagulation is an important part of the management of COVID-19, especially in severe forms in order to limit the occurrence of these thromboembolic diseases.

A retrospective cohort analysis of people living with HIV/AIDS enrolled in HIV care at a reference center in Antananarivo, Madagascar.

Background: The impact of the "Treat all" policy on the individual and in terms of public health is closely related to early diagnosis and retention in care. Patient-level data are scarce in Madagascar. In this study, we aimed to describe the profile of a cohort of newly diagnosed people living with HIV/AIDS (PLHIV), identify their outcomes, and assess factors associated with attrition from care and advanced HIV disease (AHD) at presentation. Methods: We conducted a retrospective cohort study of PLHIV aged ≥15 years newly diagnosed at the University Hospital Joseph Raseta Befelatanana Antananarivo from 1 January 2010 to 31 December 2016. Results: A total of 490 PLHIV were included in the cohort analysis. In total, 67.1% were male. The median age (interquartile range) at enrollment in care was 29 years (24-38). Overall, 36.1% of PLHIV were diagnosed with AHD at baseline. The proportion of patients with WHO stage IV at baseline increased significantly from 3.3% in 2010 to 31% in 2016 (p = 0.001 for trend). The probability of retention in care after the diagnosis at 12 months, 24 months, and 36 months was 71.8%, 65.5%, and 61.3%, respectively. Age ≥ 40 years (aHR: 1.55; 95% CI: 1.05-2.29; p = 0.026), low level of education (aHR:1.62; 95% CI: 1.11-2.36; p = 0,013), unspecified level of education (aHR:2.18; 95% CI: 1.37-3.47; p = 0.001) and unemployment (aHR:1.52; 95% CI: 1.07-2.16; p = 0.019) were independently associated with attrition from care. Factors associated with AHD at baseline were age ≥ 40 (aOR: 2.77; 95% CI: 1.38-5.57, p = 0.004), unspecified level of education (aOR: 3.80; 95% CI: 1.58-9.16, p = 0.003) and presence of clinical symptoms at baseline (aOR: 23.81; 95% CI: 10.7-52.98; p < 0.001). Sex workers were independently less likely to have an AHD at presentation (aOR: 0.23; 95% CI: 0.05-0.96, p = 0.044). Conclusion: Sociodemographic determinants influenced retention in care more than clinical factors. The presence of clinical symptoms and sociodemographic determinants were the main factors associated with AHD at baseline.