Applications of machine learning tools for ultra-sensitive detection of lipoarabinomannan with plasmonic grating biosensors in clinical samples of tuberculosis.

BACKGROUND: Tuberculosis is one of the top ten causes of death globally and the leading cause of death from a single infectious agent. Eradicating the Tuberculosis epidemic by 2030 is one of the top United Nations Sustainable Development Goals. Early diagnosis is essential to achieving this goal because it improves individual prognosis and reduces transmission rates of asymptomatic infected. We aim to support this goal by developing rapid and sensitive diagnostics using machine learning algorithms to minimize the need for expert intervention. METHODS AND FINDINGS: A single molecule fluorescence immunosorbent assay was used to detect Tuberculosis biomarker lipoarabinomannan from a set of twenty clinical patient samples and a control set of spiked human urine. Tuberculosis status was separately confirmed by GeneXpert MTB/RIF and cell culture. Two machine learning algorithms, an automatic and a semiautomatic model, were developed and trained by the calibrated lipoarabinomannan titration assay data and then tested against the ground truth patient data. The semiautomatic model differed from the automatic model by an expert review step in the former, which calibrated the lower threshold to determine single molecules from background noise. The semiautomatic model was found to provide 88.89% clinical sensitivity, while the automatic model resulted in 77.78% clinical sensitivity. CONCLUSIONS: The semiautomatic model outperformed the automatic model in clinical sensitivity as a result of the expert intervention applied during calibration and both models vastly outperformed manual expert counting in terms of time-to-detection and completion of analysis. Meanwhile, the clinical sensitivity of the automatic model could be improved significantly with a larger training dataset. In short, semiautomatic, and automatic Gaussian Mixture Models have a place in supporting rapid detection of Tuberculosis in resource-limited settings without sacrificing clinical sensitivity.

Trends in pediatric tuberculosis diagnosis utilizing xpert Mycobacterium tuberculosis/Rifampicin in a poor-resource, high-burden region: A retrospective, multicenter study.

Background: The burden of tuberculosis (TB) in Nigeria remains high, and diagnosis in children, a challenge. We aimed to document yield from Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) as a mode of diagnosis for children and the variables associated with a positive result. Methods: This was a retrospective review of TB treatment cards of children aged 0-15 years managed from January 2017 to December 2021 across six public tertiary institutions in Nigeria. The data obtained were analyzed using the descriptive and inferential statistics. Statistical significance was set at P < 0.05. Results: Of 1489 children commenced on TB treatment, 1463 (97.9%) had sufficient data for analysis the median age of study participants was 60 months (interquartile range [IQR]: 24, 120), and 814 (55.6%) were males. Xpert MTB/RIF test was performed in 862 (59%) participants and MTB was detected in 171 (19.8%) participants, of which 6.4% (11/171) had RIF resistance reported. The use of Xpert MTB/RIF rose from 56.5% in 2017 to 64% in 2020 but fell to 60.9% in 2021. We found that older age (> 10 years), the presence of pulmonary TB (PTB), and a negative human immunodeficiency virus (HIV) status were associated with positive Xpert MTB/RIF tests (P = 0.002, 0.001, and 0.012, respectively). Conclusion: The utilization of Xpert MTB/RIF in children increased in the years before the COVID-19 pandemic. Factors associated with MTB detection by Xpert MTB/RIF include older age, the presence of PTB, and a negative HIV status. Clinical and radiological evaluation continues to play vital roles in the diagnosis of childhood TB in Nigeria.

Progress on diagnosis and treatment of drug-resistant tuberculosis in line with World Health Organization recommendations in six priority countries in the Western Pacific Region.

Background: Diagnosis and treatment of drug-resistant tuberculosis (DR-TB) have radically changed in accordance with recommendations from the World Health Organization (WHO) in the past decade, allowing rapid and simple diagnosis and shorter treatment duration with new and repurposed drugs. Methods: A descriptive analysis of the status and progress of DR-TB diagnosis and treatment in six priority countries in the Western Pacific Region was conducted using information from interviews with countries and the WHO TB database. Results: Over the past decade, the use of Xpert MTB/RIF has increased in the six priority countries, in parallel with implementation of national policies and algorithms to use Xpert MTB/RIF as an initial diagnostic test for TB and detection of rifampicin resistance. This has resulted in increases in the number of people diagnosed with multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB). Shorter treatment regimens with new and repurposed drugs have also been adopted for MDR/RR-TB cases, alongside a decentralized model of care, leading to improved treatment outcomes. Discussion: The Western Pacific Region has achieved considerable progress in the diagnosis and treatment of DR-TB, in line with the evolving WHO recommendations in the past decade. The continued commitment of Member States is needed to address remaining challenges, such as the impact of the coronavirus disease pandemic, suboptimal management and health system issues.

High dose rifampin for 2 months vs standard dose rifampin for 4 months, to treat TB infection: Protocol of a 3-arm randomized trial (2R2).

INTRODUCTION: Tuberculosis preventive treatment (TPT) is an essential component for TB elimination. In order to be successfully implemented on a large scale, TPT needs to be safe, affordable and widely available in all settings. Short TPT regimens, that are less burdensome than longer regimens, to patients and health systems, are needed. Doses of rifampin higher than the standard 10mg/kg/day were tolerated in studies to reduce duration of treatment for tuberculosis disease (TBD). The objective of this trial is to test the safety of high dose rifampin monotherapy to shorten the duration of the currently recommended TPT of 4 months rifampin. METHODS AND ANALYSIS: This is a phase 2b, randomised, controlled, parallel group, superiority, partially-blind trial. Primary outcomes are completion of treatment (as a proxy measure of tolerability) and safety. The two experimental arms comprise 60 days of (i) 20mg/kg/day or (ii) 30mg/kg/day rifampin; the control arm comprises 120 days of 10mg/kg/day rifampin as TPT. Participants are adults and children 10 years or older, eligible for TPT. Completion is the primary outcome, measured by pill count and is defined as taking minimum of 80% of treatment in 120% of allowed time; it will be tested for superiority by logistic regression. Safety outcome comprises proportion of grade 3-5 adverse events and grade 1-2 rash, adjudicated related to study drug, and resulting in permanent drug discontinuation; compared for non-inferiority between each of the two high dose arms and the standard arm, using Poisson regression. A sample size of 1,359 participants will give 80% power to detect a 10% difference in completion rates and a 1% difference in the safety outcome. The study is conducted in Canada, Indonesia and Vietnam. Enrolment is ongoing at all sites. ETHICS AND DISSEMINATION: Approvals from a local research ethics board (REB) have been obtained at all participating sites and by the trial coordinating centre. Approval has been given by drug regulatory agencies in Canada and Indonesia and by Ministry of Health in Vietnam; participants give written informed consent before participation. All data collected are non-nominal. Primary results will be submitted for publication in a peer-reviewed journal when all participants have completed treatment; results of secondary outcomes will be submitted for publication at the end of study; all sites will receive the final data of participants from their sites. TRIAL REGISTRATION: Trial registered in ClinicalTrials.gov (Identifier: NCT03988933). Coordinating center is the study team working at McGill University Health Center-Research Institute (MUHC-RI); sponsor is the MUHC-RI; funding has been granted by Canadian Institute of Health Research (FDN-143350).

Detection of Mycobacterium tuberculosis Complex Using the Xpert MTB/RIF Ultra Assay on the Stool of Pediatric Patients in Dushanbe, Tajikistan.

We report the findings of a prospective laboratory diagnostic accuracy study to evaluate the sensitivity, specificity, and predictive values of the Xpert MTB/RIF Ultra assay for Mycobacterium tuberculosis detection in fresh stool specimens from children under 15 years of age with confirmed tuberculosis (TB) disease from Dushanbe, Tajikistan. Six hundred eighty-eight (688) participants were enrolled from April 2019 to October 2021. We identified 16 participants (2.3%) with confirmed TB disease, defined as ≥1 TB sign/symptom plus microbiologic confirmation. With the Xpert MTB/RIF Ultra assay for stool, we found a sensitivity of 68.8% (95% CI, 46.0 to 91.5) and a specificity of 98.7% (95% CI, 97.8 to 99.5) in confirmed TB disease. Our results are comparable to other published studies; however, our cohort was larger and our confirmed TB disease rate lower than most. We also demonstrated that this assay was feasible to implement in a centralized hospital laboratory in a low-middle-income Central Asian country. However, we encountered obstacles such as lack of staffing, material ruptures, outdated government protocols, and decreased case presentation due to COVID-19. We found eight patients whose only positive test was an Xpert Ultra stool assay. None needed treatment during the study; however, three were treated later, suggesting such cases require close observation. Our report is the first from Central Asia and one of a few from a low-middle-income country. We believe our study demonstrates the generalizability of the Xpert MTB/RIF Ultra assay on fresh stool specimens from children and provides further evidence supporting WHO's approval of this diagnostic strategy. IMPORTANCE The importance of this report is that it provides further support for WHO's recent recommendation that fresh stool is an acceptable sample for GeneXpert TB testing in children, especially small children who often cannot produce an adequate sputum sample. Diagnosing TB in this age group is difficult, and many cases are missed, leading to unacceptable rates of TB illness and death. In our large cohort of children from Dushanbe, Tajikistan, the GeneXpert stool test was positive in 69% of proven cases of TB, and there were very few false-positive tests. We also showed that this diagnostic strategy was feasible to implement in a low-middle-income country with an inefficient health care delivery system. We hope that many more programs will adopt this form of diagnosing TB in children.

Treatment and management of hypersensitivity reactions developed against anti-tuberculosis drug.

Background: The World Health Organization Global Tuberculosis Report 2021 defines tuberculosis as the second infectious disease that causes sickness and death after COVID 19 and ranks it as the 13^th among the global causes of death. However, the prevalence of the patients developing a hypersensitivity reaction against antituberculosis treatment is yet unknown. This study aimed to investigate the prevalence of drug allergy against antituberculosis treatment and the management of such a problem. Methods: This is a case--control study. All patients hospitalized in the tuberculosis inpatient service between February 01, 2015 and May 01, 2021 due to hypersensitivity reaction or who developed hypersensitivity during hospitalization were included in the case group. Patients who received inpatient treatment between the same dates and did not develop any drug allergy were included in the control group. The demographic characteristics of the patients, the tuberculosis diagnostic indicator, the type of hypersensitivity reaction that developed, the duration of the manifestation of the reaction and its treatment were evaluated for the purpose of the study. Results: A total of 2677 patients were hospitalized in the tuberculosis inpatient service between the specified dates. Two hundred and ten patients were consulted for drug hypersensitivity reactions in the Allergy Clinic. The prevalence of drug allergy in inpatients was calculated as 7.8%. One hundred and forty-eight patients examined by the authors were included in the study. Seventy-nine of the 148 patients (53.4%) who developed a hypersensitivity reaction were male, the mean age of these patients was 47.20 ± 18.95 years, 89.2% (n = 132) were citizens of the Republic of Turkey, 7.4% (n = 11) of the patients had received tuberculosis treatment before, 16.9% (25) had developed antituberculosis drug resistance and the bacteriological diagnosis was present in 79.7% (118) of the patients. Chi-square test results applied in the allergy group revealed that the risk of developing a hypersensitivity reaction is statistically significantly higher in female patients (P < 0.001), Turkish citizen patients (P = 0.004), in new cases (P = 0.017), in the group not diagnosed bacteriologically (histopathologically, clinically, and radiologically) (P = 0.006). The results of the logistic regression analysis performed also revealed that the risk of developing a hypersensitivity reaction is statistically significantly higher in female patients (P = 0.006), Turkish citizen patients (P = 0.023), in new cases (P = 0.017) and in the group not diagnosed bacteriologically (histopathologically, clinically, and radiologically) (P = 0.006). The success of the treatment was higher in the group that developed a hypersensitivity reaction compared to the control group. About 63.5% (94) of the patients examined developed Type I hypersensitivity reactions, whereas 36.7% (53) of the patients examined developed Type IV hypersensitivity reactions. Type I and Type IV reactions were observed simultaneously in a single patient. Considering the prevalence of developing a hypersensitivity reaction, pyrazinamide was determined as the drug inducing the hypersensitivity reaction in 25 (48.1%) patients. This figure was 15 patients (28.2%) for rifampicin, nine patients (17.3%) for isoniazid, and five patients (9.6%) for ethambutol. As a result, even patients who developed Type I or Type IV reactions were able to complete their antituberculous drug regimens with successful desensitization. Conclusion: The risk of developing an allergic reaction in patients who are administered on antituberculosis treatment is common, particularly in the first 2 months of treatment. However, we believe that the compliance of the patients to the antituberculosis treatment has been improved at the end of appropriate management of hypersensitivity reactions and the treatment results in success.

Chronic purulent pericarditis: case report.

Purulent pericarditis is an infection of the pericardial space that produces pus that is found on gross examination of the pericardial sac or on the tissue microscopy. In this case report, we will discuss a 31-year-old male who presented with a chief complaint of low-grade fevers, dry cough and difficulty breathing for about two weeks which preceded after removing of dental also two weeks prior. He was admitted and treated as COVID-19 in the isolation ward, he later developed cardiac tamponade and during pericardiocentesis thick pus was discharged. Pus culture and Gene Xpert tests were all negative. After his condition improved, the patient was transferred to the general ward with the pericardial window still discharging pus. Pericardiectomy was chosen as definitive management. The key takeaway in this report is that Empirical treatment with RHZE (rifampin, isoniazid, pyrazinamide, and ethambutol) in resource-limited settings is recommended due to difficulty in identifying the exact cause at a required moment.

Evaluating the effect of short-course rifapentine-based regimens with or without enhanced behaviour-targeted treatment support on adherence and completion of treatment for latent tuberculosis infection among adults in the UK (RID-TB: Treat): protocol for an open-label, multicentre, randomised controlled trial.

INTRODUCTION: The successful scale-up of a latent tuberculosis (TB) infection testing and treatment programme is essential to achieve TB elimination. However, poor adherence compromises its therapeutic effectiveness. Novel rifapentine-based regimens and treatment support based on behavioural science theory may improve treatment adherence and completion. METHODS AND ANALYSIS: A pragmatic multicentre, open-label, randomised controlled trial assessing the effect of novel short-course rifapentine-based regimens for TB prevention and additional theory-based treatment support on treatment adherence against standard-of-care. Participants aged between 16 and 65 who are eligible to start TB preventive therapy will be recruited in England. 920 participants will be randomised to one of six arms with allocation ratio of 5:5:6:6:6:6: daily isoniazid +rifampicin for 3 months (3HR), routine treatment support (control); 3HR, additional treatment support; weekly isoniazid +rifapentine for 3 months (3HP), routine treatment support; weekly 3HP, additional treatment support ; daily isoniazid +rifapentine for 1 month (1HP), routine treatment support; daily 1HP, additional treatment support. Additional treatment support comprises reminders using an electronic pillbox, a short animation, and leaflets based on the perceptions and practicalities approach. The primary outcome is adequate treatment adherence, defined as taking ≥90% of allocated doses within the pre-specified treatment period, measured by electronic pillboxes. Secondary outcomes include safety and TB incidence within 12 months. We will conduct process evaluation of the trial interventions and assess intervention acceptability and fidelity and mechanisms for effect and estimate the cost-effectiveness of novel regimens. The protocol was developed with patient and public involvement, which will continue throughout the trial. ETHICS AND DISSEMINATION: Ethics approval has been obtained from The National Health Service Health Research Authority (20/LO/1097). All participants will be required to provide written informed consent. We will share the results in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT 2020-004444-29.

TB-PRACTECAL: study protocol for a randomised, controlled, open-label, phase II-III trial to evaluate the safety and efficacy of regimens containing bedaquiline and pretomanid for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis.

BACKGROUND: Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis. METHODS: TB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24-week regimens containing bedaquiline and pretomanid to treat rifampicin-resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin-resistant pulmonary tuberculosis and requiring a new course of therapy were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site. DISCUSSION: TB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment. TRIAL REGISTRATION: Clinicaltrials.gov NCT02589782. Registered on 28 October 2015.

Tuberculosis/COVID-19 co-infection detected in a single sputum sample using a rapid molecular test.

Tuberculosis (TB) and COVID-19 affect the lungs and are transmitted mainly by aerosols or particles of saliva from infected persons. Clinical similarities between diseases can affect correct diagnosis. Individuals belonging to the population deprived of liberty (PDL) are at increased risk of contagion due to precarious sanitary conditions and overcrowded environments. A variety of specimens may be suitable for the diagnosis of COVID-19, using molecular diagnostic techniques; however, there is little data on the analysis of sputum samples with the Xpert Xpress SARS-CoV-2® for the diagnosis of COVID-19, especially in this population group. The present study reports a case of TB and COVID-19 co-infection detected in sputum from an individual belonging to the PDL. For the detection, it used the GeneXpert platform (Cepheid, USA). Mycobacterium tuberculosis complex (MTC) was detected using the Xpert MTB/RIF Ultra® cartridge and SARS-CoV-2 was detected using the Xpert Xpress SARS-CoV-2® cartridge. The genes IS6110 and IS1081 were detected within 80 min indicating the presence of MTC, with no mutations related to resistance to rifampicin. The SARS-CoV-2 E and N2 genes were detected within 45 min. The result was confirmed by RT-qPCR with detection of E, N, and RdRP/S genes in the sputum and nasopharyngeal (NP) specimens. Rapid diagnoses that allow the identification and differentiation of such diseases are important for adequate epidemiological surveillance, isolation of infected individuals, and interruption of the transmission chain. Using the GeneXpert platform, specimens can be tested as soon as they are received, without the need for prior preparation. The US Food and Drug Administration has issued emergency authorization for the use of the Cepheid Xpert Xpress SARS-CoV-2 for the rapid detection of SARS-CoV-2 using specimens from a NP or nasal wash/aspirate. The case presented here gains an innovation with the use of the sputum to COVID-19 diagnosis.

Severe Bartonella henselae bone infection in a kidney transplanted young man.

We present a case of a young kidney transplanted man. He was admitted with lymphadenopathy, fluctuating fever and night sweats 2 months after a cat bite. After admission, he developed severe pain around his right hip. An 18F-fluorodeoxyglucose (FDG)-positron emission tomography/CT revealed intense FDG-uptake in lymph nodes, spleen and bone, suggestive of lymphoma. An extracted lymph node showed confluent granulomas, microabscesses with neutrophils and scattered multinucleated giant cells histologically. The patient had history of latent tuberculosis and proteinase 3 -anti-neutrophil cytoplasmic antibodies associated (PR3-ANCA) vasculitis, making differential diagnostic considerations complicated. Bartonella henselae antibodies was detected in blood and B. henselae DNA in a lymph node. He was started on doxycycline and rifampicin. Due to severe drug interactions with both tacrolimus and increasing morphine doses, rifampicin was changed to azithromycin. He received 12 days of relevant antibiotic treatment and responded well. He was discharged after 16 days with close follow-up and was still in habitual condition 12 months later.

Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study.

BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19). METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR. INTERPRETATION: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. FUNDING: National Institute for Communicable Diseases of South Africa.

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.

How to Effectively Identify Patients With Rifampin-Resistant Tuberculosis in China: Perspectives of Stakeholders Among Service Providers.

To evaluate China's current rifampin-resistant tuberculosis (RR-TB) screening strategy from stakeholders' perspectives, the perceptions, attitudes, and interests of 245 stakeholders from three eastern, central, and western China provinces on RR-TB screening strategies, were investigated through stakeholder survey and interview. The attitudes toward three RR-TB screening strategies were statistically different: inclination to choose who to screen (Z = 98.477; P < 0.001), funding for rapid diagnostic technology screening either by reimbursed health insurance or directly subsidized financial assistance (Z = 4.142, P < 0.001), and respondents' attitude during RR-TB screening implementation levels (Z = 2.380, P = 0.017). In conclusion, RR-TB screening scope could be expanded by applying rapid diagnostic technologies. Provinces with different economic status could adjust their screening policies accordingly.

Tuberculosis Co-Infection Is Common in Patients Requiring Hospitalization for COVID-19 in Belarus: Mixed-Methods Study.

A significant drop in tuberculosis (TB) case-finding has been widely reported during the period of the COVID-19 pandemic. To address a decrease in TB notification, Belarus introduced laboratory TB testing in patients with the laboratory-confirmed coronavirus disease 2019 (COVID-19). We conducted a secondary analysis of health records among 844 patients with laboratory-confirmed COVID-19 diagnosis who were admitted to repurposed departments at TB hospitals and who were tested by Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) in five Belarus regions between April and October 2021. Quantitative analysis followed by 13 individual interviews with health managers, physicians, and nurses participating in the intervention. Most patients were male (64%) and mean age was 43.5 ± 16 years. One in twenty (n = 47, 5.6%) patients were co-infected with active pulmonary TB, and over one-third of them (n = 18) had rifampicin resistance. In-hospital mortality was comparable in patients with and without TB co-infection (2.1% and 2.3% respectively, p > 0.99). Laboratory TB testing among patients with COVID-19 at repurposed departments of TB hospitals is feasible in Belarus and may improve TB case-finding.

MDR Tuberculosis Treatment.

Multidrug-resistant (MDR) tuberculosis (TB), resistant to isoniazid and rifampicin, continues to be one of the most important threats to controlling the TB epidemic. Over the last few years, there have been promising pharmacological advances in the paradigm of MDR TB treatment: new and repurposed drugs have shown excellent bactericidal and sterilizing activity against Mycobacterium tuberculosis and several all-oral short regimens to treat MDR TB have shown promising results. The purpose of this comprehensive review is to summarize the most important drugs currently used to treat MDR TB, the recommended regimens to treat MDR TB, and we also summarize new insights into the treatment of patients with MDR TB.

Pooled testing of sputum with Xpert MTB/RIF and Xpert Ultra during tuberculosis active case finding campaigns in Lao People's Democratic Republic.

INTRODUCTION: Active case finding (ACF) of individuals with tuberculosis (TB) is a key intervention to find the 30% of people missed every year. However, ACF requires screening large numbers of individuals who have a low probability of positive results, typically <5%, which makes using the recommended molecular tests expensive. METHODS: We conducted two ACF surveys (in 2020 and 2021) in high TB burden areas of Lao PDR. Participants were screened for TB symptoms and received a chest X-ray. Sputum samples of four consecutive individuals were pooled and tested with Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) (Xpert-MTB/RIF) (2020) or Xpert-Ultra (2021). The agreement of the individual and pooled samples was compared and the reasons for discrepant results and potential cartridge savings were assessed. RESULTS: Each survey included 436 participants, which were tested in 109 pools. In the Xpert-MTB/RIF survey, 25 (sensitivity 89%, 95% CI 72.8% to 96.3%) of 28 pools containing MTB-positive samples tested positive and 81 pools containing only MTB-negative samples tested negative (specificity 100%, 95% CI 95.5% to 100%). In the Xpert-Ultra survey, all 32 (sensitivity 100%, 95% CI 89.3% to 100%) pools containing MTB-positive samples tested positive and all 77 (specificity 100%, 95% CI 95.3% to 100%) containing only MTB-negative samples tested negative. Pooling with Xpert-MTB/RIF and Xpert-Ultra saved 52% and 46% (227/436 and 199/436, respectively) of cartridge costs alone. CONCLUSION: Testing single and pooled specimens had a high level of agreement, with complete concordance when using Xpert-Ultra. Pooling samples could generate significant cartridge savings during ACF campaigns.

Diagnosis of tuberculosis among COVID-19 suspected cases in Ghana.

BACKGROUND: Tuberculosis (TB) and COVID-19 pandemics are both diseases of public health threat globally. Both diseases are caused by pathogens that infect mainly the respiratory system, and are involved in airborne transmission; they also share some clinical signs and symptoms. We, therefore, took advantage of collected sputum samples at the early stage of COVID-19 outbreak in Ghana to conduct differential diagnoses of long-standing endemic respiratory illness, particularly tuberculosis. METHODOLOGY: Sputum samples collected through the enhanced national surveys from suspected COVID-19 patients and contact tracing cases were analyzed for TB. The sputum samples were processed using Cepheid's GeneXpert MTB/RIF assay in pools of 4 samples to determine the presence of Mycobacterium tuberculosis complex. Positive pools were then decoupled and analyzed individually. Details of positive TB samples were forwarded to the NTP for appropriate case management. RESULTS: Seven-hundred and seventy-four sputum samples were analyzed for Mycobacterium tuberculosis in both suspected COVID-19 cases (679/774, 87.7%) and their contacts (95/774, 12.3%). A total of 111 (14.3%) were diagnosed with SARS CoV-2 infection and six (0.8%) out of the 774 individuals tested positive for pulmonary tuberculosis: five (83.3%) males and one female (16.7%). Drug susceptibility analysis identified 1 (16.7%) rifampicin-resistant tuberculosis case. Out of the six TB positive cases, 2 (33.3%) tested positive for COVID-19 indicating a coinfection. Stratifying by demography, three out of the six (50%) were from the Ayawaso West District. All positive cases received appropriate treatment at the respective sub-district according to the national guidelines. CONCLUSION: Our findings highlight the need for differential diagnosis among COVID-19 suspected cases and regular active TB surveillance in TB endemic settings.