Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

BACKGROUND: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population. METHODS: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895. FINDINGS: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively. INTERPRETATION: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications. FUNDING: World Health Organization.

Patient-Pathway Analysis of Tuberculosis Services in Cameroon.

In Cameroon, in 2019, tuberculosis (TB) treatment coverage was estimated at 53%, indicating that almost half of all people sick with TB were not diagnosed or linked to care. To inform strategies to improve access to TB services, we conducted an evaluation of the alignment between patient-initiated care-seeking behavior and spatial and institutional allocation of TB services. Data sources included the Cameroon Demographic and Health Survey (2018), the Health Facility List (2017), and routinely collected TB surveillance data. Data visualization was performed in Tableau and QGIS. The pathway analysis showed that only an estimated 9% of people attended a health facility providing TB services at initial care-seeking, with access varying from <3% to 16% across the ten regions of the country. While 72% of government and 56% of private hospitals (Level 2 facilities) provide TB services, most Cameroonians (87%) initially chose primary care (Level 1) or informal private sector sites (Level 0) without TB services. The gaps were greatest in regions with the highest prevalence of poverty, a significant determinant for TB. These results indicate that access may be improved by expanding TB services at both public and private facilities across the country, prioritizing regions with the greatest gaps.

Transmission patterns of rifampicin resistant Mycobacterium tuberculosis complex strains in Cameroon: a genomic epidemiological study.

BACKGROUND: Determining factors affecting the transmission of rifampicin (RR) and multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains under standardized tuberculosis (TB) treatment is key to control TB and prevent the evolution of drug resistance. METHODS: We combined bacterial whole genome sequencing (WGS) and epidemiological investigations for 37% (n = 195) of all RR/MDR-TB patients in Cameroon (2012-2015) to identify factors associated with recent transmission. RESULTS: Patients infected with a strain resistant to high-dose isoniazid, and ethambutol had 7.4 (95% CI 2.6-21.4), and 2.4 (95% CI 1.2-4.8) times increased odds of being in a WGS-cluster, a surrogate for recent transmission. Furthermore, age between 30 and 50 was positively correlated with recent transmission (adjusted OR 3.8, 95% CI 1.3-11.4). We found high drug-resistance proportions against three drugs used in the short standardized MDR-TB regimen in Cameroon, i.e. high-dose isoniazid (77.4%), ethambutol (56.9%), and pyrazinamide (43.1%). Virtually all strains were susceptible to fluoroquinolones, kanamycin, and clofazimine, and treatment outcomes were mostly favourable (87.5%). CONCLUSION: Pre-existing resistance to high-dose isoniazid, and ethambutol is associated with recent transmission of RR/MDR strains in our study. A possible contributing factor for this observation is the absence of universal drug susceptibility testing in Cameroon, likely resulting in prolonged exposure of new RR/MDR-TB patients to sub-optimal or failing first-line drug regimens.

Systematic screening for tuberculosis among hospital outpatients in Cameroon: The role of screening and testing algorithms to improve case detection.

BACKGROUND: Better screening and testing approaches are needed to improve TB case finding, particularly in health facilities where many people with TB seek care but are not diagnosed using the existing approaches. OBJECTIVE: We aimed to evaluate the performance of various TB screening and testing approaches among hospital outpatients in a setting with a high prevalence of HIV/TB. METHODS: We screened outpatients at a large hospital in Cameroon using both chest X-ray and a symptom questionnaire including current cough, fever, night sweats and/or weight loss. Participants with a positive screen were tested for TB using smear microscopy, the Xpert MTB/RIF assay, and culture. RESULTS: Among 2051 people screened, 1137 (55%) reported one or more TB symptom and 389 (19%) had an abnormal chest X-ray. In total, 1255 people (61%) had a positive screen and 31 of those screened (1.5%) had bacteriologically confirmed TB. To detect TB, screening with cough >2 weeks had a sensitivity of 61% (95% CI, 44-78%). Screening for a combination of cough >2 -weeks and/or abnormal chest X-ray had a sensitivity of 81% (95% CI, 67-95%) and specificity of 71% (95% CI, 69-73%), while screening for a combination of cough >2 weeks or any of 2 or more symptoms had a similar performance. Smear microscopy and Xpert MTB/RIF detected 32% (10/31) and 55% (17/31), respectively, of people who had bacteriologically-confirmed TB. CONCLUSIONS: Screening hospital outpatients for cough >2 weeks or for at least 2 of current cough, fever, night sweats or weight loss is a feasible strategy that had a high relative yield to detect bacteriologically-confirmed TB in this population. Clinical diagnosis of TB is still an important need, even where Xpert MTB/RIF testing is available.

Using artificial intelligence to read chest radiographs for tuberculosis detection: A multi-site evaluation of the diagnostic accuracy of three deep learning systems.

Deep learning (DL) neural networks have only recently been employed to interpret chest radiography (CXR) to screen and triage people for pulmonary tuberculosis (TB). No published studies have compared multiple DL systems and populations. We conducted a retrospective evaluation of three DL systems (CAD4TB, Lunit INSIGHT, and qXR) for detecting TB-associated abnormalities in chest radiographs from outpatients in Nepal and Cameroon. All 1196 individuals received a Xpert MTB/RIF assay and a CXR read by two groups of radiologists and the DL systems. Xpert was used as the reference standard. The area under the curve of the three systems was similar: Lunit (0.94, 95% CI: 0.93-0.96), qXR (0.94, 95% CI: 0.92-0.97) and CAD4TB (0.92, 95% CI: 0.90-0.95). When matching the sensitivity of the radiologists, the specificities of the DL systems were significantly higher except for one. Using DL systems to read CXRs could reduce the number of Xpert MTB/RIF tests needed by 66% while maintaining sensitivity at 95% or better. Using a universal cutoff score resulted different performance in each site, highlighting the need to select scores based on the population screened. These DL systems should be considered by TB programs where human resources are constrained, and automated technology is available.

Tuberculosis in people newly diagnosed with HIV at a large HIV care and treatment center in Northwest Cameroon: Burden, comparative screening and diagnostic yields, and patient outcomes.

BACKGROUND: Diagnosis of tuberculosis in people living with HIV is challenging due to non-specific clinical presentations and inadequately sensitive diagnostic tests. The WHO recommends screening using a clinical algorithm followed by rapid diagnosis using the Xpert MTB/RIF assay, and more information is needed to evaluate these recommendations in different settings. METHODS: From August 2012 to September 2013, consecutive adults newly diagnosed with HIV in Bamenda, Cameroon, were screened for TB regardless of symptoms by smear microscopy and culture; the Xpert MTB/RIF assay was performed retrospectively. Time to treatment and patient outcomes were obtained from routine registers. RESULTS: Among 1,149 people enrolled, 940 (82%) produced sputum for lab testing; of these, 68% were women, the median age was 35 years (IQR, 28-42 years), the median CD4 count was 291cells/µL (IQR, 116-496 cells/µL), and 86% had one or more of current cough, fever, night sweats, or weight loss. In total, 131 people (14%, 95% CI, 12-16%) had sputum culture-positive TB. The WHO symptom screening algorithm had a sensitivity of 92% (95%CI, 86-96%) and specificity of 15% (95%CI, 12-17%) in this population. Compared to TB culture, the sensitivity of direct smear microscopy was 25% (95% CI, 18-34%), and the sensitivity of Xpert was 68% (95% CI, 58-76); the sensitivity of both was higher for people reporting more symptoms. Only one of 69 people with smear-negative/culture-positive TB was started on TB treatment prior to culture positivity. Of 71 people with bacteriologically-confirmed TB and known outcome after 6 months, 13 (17%) had died, including 11 people with smear-negative TB and 6 people with both smear and Xpert-negative TB. CONCLUSIONS: Use of the most sensitive rapid diagnostic test available is critical in people newly diagnosed with HIV in this setting to maximize the detection of bacteriologically-confirmed TB. However, this intervention is not sufficient alone and should be combined with more comprehensive clinical diagnosis of TB to improve outcomes.

Template-assisted patterning of nanoscale self-assembled monolayer arrays on surfaces.

We report a general, simple, and inexpensive approach to pattern features of self-assembled monolayers (SAMs) on silicon and gold surfaces using porous anodic alumina films as templates. The SAM patterns, with feature sizes down to 30 nm and densities higher than 10(10)/cm(2), can be prepared over large areas (>5 cm(2)). The feature dimensions can be tuned by controlling the alumina template structure. These SAM patterns have been successfully used as resists for fabricating gold and silicon nanoparticle arrays on substrates by wet-chemical etching. In addition, we show that arrays of gold features can be patterned with 10-nm gaps between the dots.

High-density arrays of InGaN nanorings, nanodots, and nanoarrows fabricated by a template-assisted approach.

Dense, crystalline arrays of InGaN nanorings, nanodots, and nanoarrows have been fabricated on GaN substrates by template-assisted nano-area selective growth. To create the nanostructures, we have used nanoporous anodic alumina films as templates to pattern nanopores in an SiO2 transfer layer, and then used this patterned SiO2 layer as a template for nitride growth by metalorganic chemical vapor deposition. We have varied the diameter of the deposited nitride nanostructures from 35 to 250 nm by changing the initial anodic alumina template structure. In addition, by controlling the nitride growth time we have created various types of nanostructures, from nanorings to nanoarrows. This structural evolution begins with the nucleation and formation of a nanoring structure, followed by coalescence and growth to form faceted nanodots, and finally lateral overgrowth to form faceted nanoarrows.

Aligned arrays of nanotubes and segmented nanotubes on substrates fabricated by electrodeposition onto nanorods.

We describe an electrochemical-based approach to create vertically aligned nanotube arrays on substrates. Initially, nanoporous anodic alumina films are used as templates to electrodeposit nanorods, and then the alumina templates are removed and nanotube arrays are electrodeposited using the nanorod arrays as templates. We have used this approach to fabricate gold nanotube arrays using nickel nanorods as templates. By anodizing the ends of the nickel nanorods before gold electrodeposition, no deposition occurs at the ends of the rods, resulting in open-ended nanotubes. In addition, we have used layered nickel-gold nanorods as templates to create gold nanostructure arrays with alternating segments of filled and empty nanotubes. This approach is versatile and may be used to electrodeposit a wide range of nanotube materials with good control over the nanotube dimensions.