The Great Masquerader: Tuberculosis Presenting as Community-Acquired Pneumonia.

According to World Health Organization estimates, tuberculosis (TB) and lower respiratory tract infections (LRTIs) are both among the top 10 global causes of death. TB and community-acquired pneumonia (CAP), if mortality estimates are combined, would rank as the third most common cause of death globally. It is estimated that each year there are approximately 10 million new cases of TB that are associated with approximately 1.2 million deaths, and almost 450 million new episodes of LRTI (synonymous with CAP) with approximately 4 million associated deaths. Globally, Streptococcus pneumoniae remains the most common cause of CAP. However, although well documented, it is not widely appreciated that in several parts of the world, including sub-Saharan Africa, Asia, and South America, Mycobacterium tuberculosis is an important cause of CAP, if not the most common organism isolated in such settings. Thus, CAP due to M. tuberculosis is not uncommon in some parts of the world with up to a third of cases being attributable to M. tuberculosis. Consequently, TB remains an important clinical entity in the intensive care unit in these settings. Despite its frequency and importance, there are very limited data about TB CAP. In this review we discussed the epidemiology, immunopathogenesis, clinical presentation, diagnosis, management, prognosis, and prevention of TB CAP. The utility of newer diagnostic approaches is highlighted

IL-4 subverts mycobacterial containment in Mycobacterium tuberculosis-infected human macrophages.

Protective immunity against Mycobacterium tuberculosis is poorly understood. The role of interleukin (IL)-4, the archetypal T-helper type 2 (Th2) cytokine, in the immunopathogenesis of human tuberculosis remains unclear.Blood and/or bronchoalveolar lavage fluid (BAL) were obtained from participants with pulmonary tuberculosis (TB) (n=23) and presumed latent TB infection (LTBI) (n=22). Messenger RNA expression levels of interferon (IFN)-γ, IL-4 and its splice variant IL-4δ2 were determined by real-time PCR. The effect of human recombinant (hr)IL-4 on mycobacterial survival/containment (CFU·mL-1) was evaluated in M. tuberculosis-infected macrophages co-cultured with mycobacterial antigen-primed effector T-cells. Regulatory T-cell (Treg) and Th1 cytokine levels were evaluated using flow cytometry.In blood, but not BAL, IL-4 mRNA levels (p=0.02) and the IL-4/IFN-γ ratio (p=0.01) was higher in TB versus LTBI. hrIL-4 reduced mycobacterial containment in infected macrophages (p<0.008) in a dose-dependent manner and was associated with an increase in Tregs (p<0.001), but decreased CD4+Th1 cytokine levels (CD4+IFN-γ+ p<0.001; CD4+TNFα+ p=0.01). Blocking IL-4 significantly neutralised mycobacterial containment (p=0.03), CD4+IFNγ+ levels (p=0.03) and Treg expression (p=0.03).IL-4 can subvert mycobacterial containment in human macrophages, probably via perturbations in Treg and Th1-linked pathways. These data may have implications for the design of effective TB vaccines and host-directed therapies

A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis.

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable.We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline-delamanid combination regimen (n=40).There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline-delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment multidrug-resistant TB therapy failure; p60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients.A bedaquiline-delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings