key: cord-327324-4c4a4bfz
authors: Wilkinson, Robert J
title: Tuberculosis and type 2 Diabetes Mellitus: an inflammatory danger signal in the time of COVID-19
date: 2020-06-13
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa747
sha: 
doc_id: 327324
cord_uid: 4c4a4bfz

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However it is increasingly appreciated DM itself is an inflammatory disorder that may therefore interact with infection in more complex ways [10] .

Transcriptomic profiling of whole blood is a technique that has been widely applied and proven insightful in many infectious and inflammatory disorders [11] . Active tuberculosis has a transcriptomic signature dominated by a neutrophil-driven type 1 and 2 interferoninducible gene profile. The transcriptomic signature relates to disease extent and resolves during successful treatment [12] . The differentiation of active from latent tuberculosis and other conditions may be aided by transcriptomic profiling [13] . The exaggerated inflammation that characterizes HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is triggered by Toll-like receptor and inflammasome signalling [14] . Transcriptomic signatures may predict progression of, or detect, subclinical tuberculosis [15] [16] [17] .

In this issue of the journal Eckold and colleagues present an analysis of the effect of DM The study has the advantage of power and of validation across populations. Limitations are that HbA1 c is a relatively insensitive test for DM. It is known that tuberculosis itself associates with transiently impaired glucose tolerance which may even be in the frank diabetic range, yet which may resolve during tuberculosis treatment [7] , but the proportion of cases of IH falling into this category was not investigated longitudinally. Sex influences type 1 interferon and neutrophil transcript abundance and there were some very substantial gender differences between groups ranging from 18-90% males.

This publication coincides with the world grappling with the COVID-19 pandemic. Are there inferences that can be made from this very detailed study of susceptibility to tuberculosis conferred by diabetes? Male sex and diabetes have been identified in virtually every study as risk factors for severe COVID-19 infection, associated in the largest study to date with an adjusted hazard ratio for in-hospital death of 1.99 (male sex) and 1.50 for controlled (HbA1c < 58 mmol/mol) and 2.36 for uncontrolled DM [18] . The pulmonary innate immune response in COVID-19 patients with severe disease implicates a macrophage subpopulation with an interferon-associated hyperinflammatory response analogous to that observed in TB patients [19] . Type 1 and 2 interferon stimulation increases angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV2, expression on respiratory epithelial cells. In particular, lungs of patients with HIV-associated TB show A c c e p t e d M a n u s c r i p t 4 the highest expression of ACE2 in epithelial cells, compared to lungs of patients with TB only and healthy lungs [20] . HIV-1 infection, prior to antiretroviral therapy (ART) also induces a similar interferon signalling gene (ISG) profile to that of TB patients, a pattern also implicated in the context of HIV-TB co-infection, even prior to TB symptom onset [16] . Given these findings, it is plausible that individuals with HIV-1 and/or TB infection could be at increased risk of SARS-CoV2 infection not only via immunosuppression but also via increased ACE2 expression, predisposing to enhanced viral uptake. This theory is 

Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies

Effect of glycemic control and type of diabetes treatment on unsuccessful TB treatment outcomes among people with TB-Diabetes: A systematic review

The impact of diabetes on tuberculosis treatment outcomes: a systematic review

Diabetes is a strong predictor of mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients from Mwanza, Tanzania

Hyperglycemia during tuberculosis treatment increases morbidity and mortality in a contemporary cohort of HIV-infected patients in Rio de Janeiro, Brazil

Stress hyperglycaemia

Tuberculosis, HIV and the association with transient hyperglycaemia in peri-urban South Africa

Consultation meeting on tuberculosis and diabetes mellitus: meeting summary and recommendations

Infections in patients with diabetes mellitus: A review of pathogenesis

Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections

uninfected African adults using whole blood RNA expression signatures: a casecontrol study

HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling

Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography

Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis

A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is enriched in specific cell subsets across tissues

RJW is supported by the Francis Crick Institute which receives funding from Wellcome (FC0010218), UKRI (FC0010218) and CRUK (FC0010218). He also receives support from Wellcome (014803 and 203135), NIH (R01AI145436) and EDCTP (RIA2017T-2004) . The views in this article are the author's alone and do not reflect the views of these agencies.

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