SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset.

Rationale: In the upper respiratory tract, replicating (culturable) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recoverable for ∼4-8 days after symptom onset, but there is a paucity of data about the frequency and duration of replicating virus in the lower respiratory tract (i.e., the human lung).Objectives: We undertook lung tissue sampling (needle biopsy) shortly after death in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patients served as a control group.Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, and immunohistochemistry.Measurements and Main Results: Thirty-eight percent (16 of 42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 wk) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (P < 0.05). Nasopharyngeal culture was negative in 23.1% (6 of 26) of decedents despite lung culture positivity. This hitherto undescribed biophenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary proinflammatory response but with concurrent viral culture positivity.Conclusions: Concurrent rather than sequential active viral replication continues to drive a heightened proinflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe coronavirus disease (COVID-19).

Multidrug-resistant tuberculosis.

Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.

Diagnostic Performance of Unstimulated IFN-γ (IRISA-TB) for Pleural Tuberculosis: A Prospective Study in South Africa and India.

Background: Tuberculous pleural effusion (TPE) is the most common form of extrapulmonary tuberculosis in many settings. The diagnostic performance of the frontline polymerase chain reaction-based GeneXpert MTB/RIF Ultra (Xpert Ultra) remains suboptimal (sensitivity of ∼30%), but data are limited. Improved diagnostic approaches are urgently needed to detect extrapulmonary tuberculosis (EPTB) in tuberculosis (TB)-endemic settings. Methods: This multicenter, prospective cohort study evaluated the diagnostic performance of a rapid (same-day) interferon gamma rapid immunosuspension assay (IRISA-TB) in patients with presumed TPE from South Africa and India. Participants underwent pleural biopsy, and testing with other available same-day diagnostic assays (adenosine deaminase [ADA], Xpert Ultra, and IRISA-TB) was concurrently undertaken. The reference standard for TB was microbiological and/or histopathological confirmation using pleural fluid and/or pleural biopsy samples. Results: A total of 217 participants with presumed TPE were recruited (106 from South Africa, 111 from India). The sensitivity of IRISA-TB (cut-point 20.5 pg/mL) was significantly better than that of Xpert Ultra (81.8% [70.4-90.2] vs 32.9% [22.1-45.1]; P < .001) and ADA at the 40 IU/mL cut-point used in India (81.8% [70.4-90.2] vs 53.8% [41.0-66.3]; P  = .002). Compared with ADA at the 30 IU/mL cut-point used in South Africa, IRISA-TB had a higher specificity (96.6% [90.3-99.3] vs 87.1% [78.6-93.2]) and a higher positive predictive value (94.7% [85.5-97.3] vs 81.8% [72.4-88.5]). The negative predictive value (NPV; rule-out value) of IRISA-TB was significantly better than that of Xpert Ultra (87.5% [83.2-93.0] vs 64.9% [61.1-68.6]; P < .001) and ADA at the 40 IU/mL cut-point (87.5% [83.2-93.0] vs 74.1% [68.7-79.0]; P < .001). Conclusions: IRISA-TB demonstrated markedly better sensitivity and NPV than Xpert Ultra and excellent specificity for the diagnosis of TPE. These data have implications for clinical practice in TB-endemic settings.

Diagnostic Accuracy of Computer-Aided Detection During Active Case Finding for Pulmonary Tuberculosis in Africa: A Systematic Review and Meta-analysis.

Background: Computer-aided detection (CAD) may be a useful screening tool for tuberculosis (TB). However, there are limited data about its utility in active case finding (ACF) in a community-based setting, and particularly in an HIV-endemic setting where performance may be compromised. Methods: We performed a systematic review and evaluated articles published between January 2012 and February 2023 that included CAD as a screening tool to detect pulmonary TB against a microbiological reference standard (sputum culture and/or nucleic acid amplification test [NAAT]). We collected and summarized data on study characteristics and diagnostic accuracy measures. Two reviewers independently extracted data and assessed methodological quality against Quality Assessment of Diagnostic Accuracy Studies-2 criteria. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines were followed. Results: Of 1748 articles reviewed, 5 met with the eligibility criteria and were included in this review. A meta-analysis revealed pooled sensitivity of 0.87 (95% CI, 0.78-0.96) and specificity of 0.74 (95% CI, 0.55-0.93), just below the World Health Organization (WHO)-recommended target product profile (TPP) for a screening test (sensitivity ≥0.90 and specificity ≥0.70). We found a high risk of bias and applicability concerns across all studies. Subgroup analyses, including the impact of HIV and previous TB, were not possible due to the nature of the reporting within the included studies. Conclusions: This review provides evidence, specifically in the context of ACF, for CAD as a potentially useful and cost-effective screening tool for TB in a resource-poor HIV-endemic African setting. However, given methodological concerns, caution is required with regards to applicability and generalizability.

Integrating molecular and radiological screening tools during community-based active case-finding for tuberculosis and COVID-19 in southern Africa.

OBJECTIVES: To evaluate diagnostic yield and feasibility of integrating testing for TB and COVID-19 using molecular and radiological screening tools during community-based active case-finding (ACF). METHODS: Community-based participants with presumed TB and/or COVID-19 were recruited using a mobile clinic. Participants underwent simultaneous point-of-care (POC) testing for TB (sputum; Xpert Ultra) and COVID-19 (nasopharyngeal swabs; Xpert SARS-CoV-2). Sputum culture and SARS-CoV-2 RT-PCR served as reference standards. Participants underwent ultra-portable POC chest radiography with computer-aided detection (CAD). TB infectiousness was evaluated using smear microscopy, cough aerosol sampling studies (CASS), and chest radiographic cavity detection. Feasibility of POC testing was evaluated via user-appraisals. RESULTS: Six hundred and one participants were enrolled, with 144/601 (24.0%) reporting symptoms suggestive of TB and/or COVID-19. 16/144 (11.1%) participants tested positive for TB, while 10/144 (6.9%) tested positive for COVID-19 (2/144 [1.4%] had concurrent TB/COVID-19). Seven (7/16 [43.8%]) individuals with TB were probably infectious. Test-specific sensitivity and specificity (95% CI) were: Xpert Ultra 75.0% (42.8-94.5) and 96.9% (92.4-99.2); Xpert SARS-CoV-2 66.7% (22.3-95.7) and 97.1% (92.7-99.2). Area under the curve (AUC) for CAD4TB was 0.90 (0.82-0.97). User appraisals indicated POC Xpert to have 'good' user-friendliness. CONCLUSIONS: Integrating TB/COVID-19 screening during community-based ACF using POC molecular and radiological tools is feasible, has a high diagnostic yield, and can identity probably infectious persons.

The intersecting pandemics of tuberculosis and COVID-19: population-level and patient-level impact, clinical presentation, and corrective interventions.

The global tuberculosis burden remains substantial, with more than 10 million people newly ill per year. Nevertheless, tuberculosis incidence has slowly declined over the past decade, and mortality has decreased by almost a third in tandem. This positive trend was abruptly reversed by the COVID-19 pandemic, which in many parts of the world has resulted in a substantial reduction in tuberculosis testing and case notifications, with an associated increase in mortality, taking global tuberculosis control back by roughly 10 years. Here, we consider points of intersection between the tuberculosis and COVID-19 pandemics, identifying wide-ranging approaches that could be taken to reverse the devastating effects of COVID-19 on tuberculosis control. We review the impact of COVID-19 at the population level on tuberculosis case detection, morbidity and mortality, and the patient-level impact, including susceptibility to disease, clinical presentation, diagnosis, management, and prognosis. We propose strategies to reverse or mitigate the deleterious effects of COVID-19 and restore tuberculosis services. Finally, we highlight research priorities and major challenges and controversies that need to be addressed to restore and advance the global response to tuberculosis.