Diagnostic biomarkers for active tuberculosis: progress and challenges.

Tuberculosis (TB) is a leading cause of morbidity and mortality from a single infectious agent, despite being preventable and curable. Early and accurate diagnosis of active TB is critical to both enhance patient care, improve patient outcomes, and break Mycobacterium tuberculosis (Mtb) transmission cycles. In 2020 an estimated 9.9 million people fell ill from Mtb, but only a little over half (5.8 million) received an active TB diagnosis and treatment. The World Health Organization has proposed target product profiles for biomarker- or biosignature-based diagnostics using point-of-care tests from easily accessible specimens such as urine or blood. Here we review and summarize progress made in the development of pathogen- and host-based biomarkers for active TB diagnosis. We describe several unique patient populations that have posed challenges to development of a universal diagnostic TB biomarker, such as people living with HIV, extrapulmonary TB, and children. We also review additional limitations to widespread validation and utilization of published biomarkers. We conclude with proposed solutions to enhance TB diagnostic biomarker validation and uptake.

Evaluating the Effectiveness of a Novel Systematic Screening Approach for Tuberculosis among Individuals Suspected or Recovered from COVID-19: Experiences from Niger and Guinea.

Evidence suggests that the COVID-19 pandemic negatively impacts tuberculosis (TB) activities. As TB and COVID-19 have similar symptoms, we assessed the effectiveness of integrated TB/COVID-19 screening in Guinea and Niger. From May to December 2020, TB screening was offered to symptomatic patients after a negative COVID-19 PCR test or after recovery from COVID-19 in Guinea. From December 2020 to March 2021, all presumptive COVID-19 patients with respiratory symptoms were tested simultaneously for COVID-19 and TB in Niger. We assessed the TB detection yield and used micro-costing to estimate the costs associated with both screening algorithms. A total of 863 individuals (758 in Guinea, and 105 in Niger), who were mostly male (60%) and with a median age of 34 (IQR: 26-45), were screened for TB. Reported symptoms were cough ≥2 weeks (49%), fever (45%), and weight loss (30%). Overall, 61 patients (7%) tested positive for COVID-19 (13 in Guinea, 48 in Niger) and 43 (4.9%) were diagnosed with TB disease (35 or 4.6% in Guinea, and 8 or 7.6% in Niger). The cost per person initiating TB treatment was USD $367 in Guinea and $566 in Niger. Overall, the yield of both approaches was high, and the cost was modest. Optimizing integrated COVID-19/TB screening may support maintaining TB detection during the ongoing pandemic.

Tuberculosis Phenotypic and Genotypic Drug Susceptibility Testing and Immunodiagnostics: A Review.

Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.

TB and COVID-19: An Exploration of the Characteristics and Resulting Complications of Co-infection.

Tuberculosis (TB) and Coronavirus Disease-19 (COVID-19) infection are two respiratory diseases that are of particular concern epidemiologically. Tuberculosis is one of the oldest diseases recorded in the history of mankind dating back thousands of years. It is estimated that approximately one quarter of the world's population is infected with latent Mycobacterium tuberculosis (LTBI). This contrasts with COVID-19, which emerged in late 2019. Data continues to accumulate and become available on this pathogen, but the long-term side effect of fibrotic damage in COVID-19 patients evokes parallels between this novel coronavirus and its ancient bacterial affiliate. This similarity as well as several others may incite inquiries on whether coinfection of individuals with latent TB and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lead to excessive fibrosis in the lungs and thus the emergence of an active TB infection. While it is well understood how TB leads to structural and immunological lung complications including granuloma formation, fibrosis, and T cell exhaustion, less is known about the disease course when coinfection with SARS-CoV-2 is present. Past and present research demonstrate that IL-10, TNF-α, IFN class I-III, TGF-ß, IL-35, and Regulatory T cells (T-regs) are all important contributors of the characteristics of host response to mycobacterium tuberculosis. It has also been noted with current research that IL-10, TNF-α, IFN class I, II, and III, TGF-ß, ACE-2, and T-regs are also important contributors to the host response to the SARS-CoV-2 virus in different ways than they are to the TB pathogen. Both pathogens may lead to an unbalanced inflammatory immune response, and together a shared dysregulation of immune response suggests an increased risk of severity and progression of both diseases. We have reviewed 72 different manuscripts between the years 1992 and 2021. The manuscripts pertaining to the SARS-COV-2 virus specifically are from the years 2020 and 2021. Our literature review aims to explore the biomolecular effects of these contributors to pathogenicity of both diseases along with current publications on TB/COVID-19 coinfection, focusing on the pathogenicity of SARS-CoV-2 infection with both latent and active TB, as well as the challenges in treating TB during the COVID-19 pandemic. The compiled material will then aid the latticework foundation of knowledge for future research leading to a hopeful improved system of therapeutic strategies for coinfection.

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects.

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.