Epidemic and pandemic viral infections: impact on tuberculosis and the lung: A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Mycobacterial Infections (ESGMYC)

Abstract

Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A (H1N1)pdm/09 and most recently COVID-19, affect the lung. Tuberculosis (TB) remains the top infectious disease killer, but apart from syndemic TB/HIV little is known regarding the interaction of viral epidemics and pandemics with TB. The aim of this consensus-based document is to describe the effects of viral infections resulting in epidemics and pandemics that affect the lung (MERS, SARS, HIV, influenza A (H1N1)pdm/09 and COVID-19) and their interactions with TB. A search of the scientific literature was performed. A writing committee of international experts including the European Centre for Disease Prevention and Control Public Health Emergency (ECDC PHE) team, the World Association for Infectious Diseases and Immunological Disorders (WAidid), the Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC) was established. Consensus was achieved after multiple rounds of revisions between the writing committee and a larger expert group. A Delphi process involving the core group of authors (excluding the ECDC PHE team) identified the areas requiring review/consensus, followed by a second round to refine the definitive consensus elements. The epidemiology and immunology of these viral infections and their interactions with TB are discussed with implications for diagnosis, treatment and prevention of airborne infections (infection control, viral containment and workplace safety). This consensus document represents a rapid and comprehensive summary on what is known on the topic.

FIGURE 1

The lungs and gut are exposed to environmental substances and pathogens. The early protection response to respiratory viruses includes mucus, surfactants and antiviral peptides that can prevent initial attachment and viral entry. Respiratory viruses enter via the respiratory epithelium. Epithelial cells have a key role in initiating the immune response by recognising viral components (pathogen-associated molecular patterns (PAMPs)) via Toll-like receptors (TLRs) and intracellular receptors. These cellular sensors trigger a signalling cascade resulting in the upregulation of type I and III interferon (IFN) and the inflammatory response. This leads to differentiation of dendritic cells that mediate the induction of the adaptive immunity and promote the recruitment of innate immunity cells, in particular neutrophils and natural killer (NK) cells. NK cells have the ability to kill virus-infected cells via perforin–granzyme-dependent mechanisms or by the Fas–Fas ligand pathway. Moreover, alveolar macrophages, recruited monocytes and macrophages as well as dendritic cells pick pathogen components and contribute to the immune response. All of these cells produce cytokines and chemokines that are important for the establishment of the adaptive responses and of the antiviral state. The adaptive response to respiratory viruses is mediated by both T- and B-cell compartments. T-cells contribute to the generation of the B-cell response. B-cells produce antibodies that may neutralise the respiratory viruses directly by binding to viral surface proteins that are essential for entry of the virus into host cells or through the ligation of Fc receptors to trigger the complement cascade and antibody-dependent cell-mediated cytotoxicity. Antibodies are in the form of IgA, mainly in the upper respiratory tract, or IgG, in the lower respiratory tract. Viral clearance is also mediated by CD8⁺-specific T-cells with cytolytic activity. The protective antiviral T-cell response is mainly mediated by IFN-γ production and is therefore biased toward a T-helper cell (Th) 1 response, whereas other T-cell subsets such as Th2 cells and Th17 cells play a minor role and they may be responsible for lung tissue damage. Moreover, regulatory mechanisms adopted by T-cells such as interleukin (IL)-10 secretion, or upregulation of inhibitory receptors such as programmed cell death protein 1 (PD-1) or expansion of the T-regulatory (Treg) cell subsets, work to balance tissue damage and viral clearance. TNF: tumour necrosis factor; CTL: cytotoxic T-lymphocyte; TFH: T-follicular helper; TGF: transforming growth factor.

FIGURE 2

Proposed mechanism of action of drugs used for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 can enter the cell through angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2). Camostat mesylate acts as an inhibitor of TMPRSS2 and umifenovir can inhibit the viral entry to the cell [180, 228, 229]. Chloroquine, hydroxychloroquine and baricitinib mechanisms of action are not fully understood; however, it is proposed that these drugs affect viral entry. Baricitinib also inhibits the AP-2-associated protein kinase [173, 180, 230]. Lopinavir/ritonavir and ASC-09/ritonavir as protease inhibitors inhibit the proteolysis. Lopinavir/ritonavir inhibits specifically the proteinase 3CLpro [231]. Ribavirin and favipiravir both have wide antiviral activity and have the potential to inhibit SARS-CoV-2 RNA replication [–234]. Azvudine, a nucleoside reverse transcriptase inhibitor, also inhibits RNA replication [235]. A probable mechanism of action for baloxavir marboxil is the inhibition of transcription through inhibiting cap-dependent endonuclease [236]. Favipiravir and remdesivir inhibit the RNA-dependent RNA polymerase (RdRp), which results in reduced RNA synthesis [180, 233, 234, 237]. Adapted from “Coronavirus Replication Cycle” (2020; https://app.biorender.com/biorender-templates).