The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has attracted interest because of its global rapid spread, clinical severity, high mortality rate and capacity to overwhelm healthcare systems [1, 2]. SARS-CoV-2 transmission occurs mainly through droplets, although surface contamination contributes and debate continues on aerosol transmission [3-5]. The disease is usually characterised by initial signs and symptoms [4-9] similar to those of related viral infections (e.g. influenza, SARS, Middle East respiratory syndrome) and tuberculosis (TB), although prognosis and complications sometimes differ. Experience with concomitant TB and COVID-19 is extremely limited. One case-control study of COVID-19 patients with interferon-γ release assay-confirmed TB infection [10] and a single case of TB with COVID-19 have been submitted to, but not yet published in, peer-reviewed journals [11]. In a recent analysis of 1217 consecutive respiratory specimens collected from COVID-19 patients (Mycobacterium tuberculosis was not tested), the authors concluded that higher rates of co-infection between SARS-CoV-2 and other respiratory pathogens can be expected [12]. The present study describes the first-ever global cohort of current or former TB patients (post-TB treatment sequelae) with COVID-19, recruited by the Global Tuberculosis Network (GTN) in eight countries and three continents. No analysis for determinants of outcome was attempted. The study is nested within the GTN project monitoring adverse drug reactions [13, 14] for which the coordinating centre has an ethics committee approval, alongside ethics clearance from participating centres according to respective national regulation [13, 14]. A specific nested database was created in collaboration with the eight countries reporting patients with TB and COVID-19; the remaining countries had not yet observed COVID-19 in their patients at the time this manuscript was written. Continuous variables, if not otherwise specified, are presented as medians with interquartile ranges. Overall, 49 consecutive patients with current or former TB and COVID-19 from 26 centres in Belgium (n=1), Brazil (Porto Alegre, Rio Grande do Sul State; n=1), France (n=12), Italy (n=17), Russia (Moscow Region; n=6), Singapore (n=1), Spain (n=10) and Switzerland (Vaud Canton; n=1) were recruited (dataset updated as of

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8 + T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb-specific CD8 + T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb-specific CD8 + T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb-specific CD8 + T cells in LTBI subjects were mostly T EMRA cells (CD45RA + CCR7 − ), coexpressing 2B4 and CD160, and in TB patients were mostly T EM cells (CD45RA − CCR7 − ), expressing 2B4 but lacking PD-1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb-specific CD8 + T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro-expanded Mtb-specific CD8 + T cells expressed perforin and granulysin. Finally, Mtb-specific CD8 + T-cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb-specific CD8 + T-cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb-specific CD8 + T-cell responses. These results provide new insights in the interaction between Mtb and the host immune response.Keywords: Active TB disease r Cytotoxicity r Functional profile r Latent Mtb infection r Mtb-specific CD8 + T cells Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2013Immunol. . 43: 1568Immunol. -1577 Immunity to infection 1569 IntroductionOne-third of the world's population is believed to be latently infected with Mycobacterium tuberculosis (Mtb) and two million people die of tuberculosis (TB) every year [1], thus underscoring the tremendous need for protective vaccines, new diagnostic tools, and medications. T lymphocytes are thought to play an important role in the control of TB and Mtb may reactivate under certain conditions of immunodeficiency such as in elderly or secondary to coinfection with HIV or to immunosuppressive therapy [2,3]. Several studies have underscored the essential role of CD4 + T cells in protection against Mtb, since CD4 + T-cell depletion is also associated with Mtb reactivation in HIV-infected individuals [4] and uncontrolled bacilli growth [5,6]. The protective Mtb-specific CD4 + T-cell response is considered to be a typical T H 1 response with CD4 + T cells producing cytokines such as IFN-γ or TNF-α that contribute to the recruitment of monocytes and granulocytes and activate the antimicrobial activity of macrophages [7,8]. Of interest, we recently demonstrated that Mtb-specific CD4 + T-cell responses were functionally different in patients with active TB disease as compared with those in subjects with latent Mtb infection (LTBI) [9]. Several studies also suggested a role of T H 17 cells in the con...