Therapeutic Targeting of Inflammation and Virus Simultaneously Ameliorates Influenza Pneumonia and Protects from Morbidity and Mortality.

Influenza pneumonia is a severe complication caused by inflammation of the lungs following infection with seasonal and pandemic strains of influenza A virus (IAV), that can result in lung pathology, respiratory failure, and death. There is currently no treatment for severe disease and pneumonia caused by IAV. Antivirals are available but are only effective if treatment is initiated within 48 h of onset of symptoms. Influenza complications and mortality are often associated with high viral load and an excessive lung inflammatory cytokine response. Therefore, we simultaneously targeted the virus and inflammation. We used the antiviral oseltamivir and the anti-inflammatory drug etanercept to dampen TNF signaling after the onset of clinical signs to treat pneumonia in a mouse model of respiratory IAV infection. The combined treatment down-regulated the inflammatory cytokines TNF, IL-1ß, IL-6, and IL-12p40, and the chemokines CCL2, CCL5, and CXCL10. Consequently, combined treatment with oseltamivir and a signal transducer and activator of transcription 3 (STAT3) inhibitor effectively reduced clinical disease and lung pathology. Combined treatment using etanercept or STAT3 inhibitor and oseltamivir dampened an overlapping set of cytokines. Thus, combined therapy targeting a specific cytokine or cytokine signaling pathway and an antiviral drug provide an effective treatment strategy for ameliorating IAV pneumonia. This approach might apply to treating pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Simultaneous therapeutic targeting of inflammation and virus ameliorates influenza pneumonia and protects from morbidity and mortality (preprint)

Pneumonia is a severe complication caused by inflammation of the lungs following infection with seasonal and pandemic strains of influenza A virus (IAV) that can result in lung pathology, respiratory failure and death. There is currently no treatment available for severe disease and pneumonia caused by IAV. Antivirals are available, but they are far from satisfactory if treatment is not initiated within 48 hours of symptoms onset. Influenza complications and mortality are often associated with high viral load and excessive lung inflammatory cytokine response. Therefore, we simultaneously targeted IAV with the antiviral drug oseltamivir and inflammation with the anti-inflammatory drug etanercept, targeting TNF after the onset of clinical signs to treat IAV pneumonia effectively. The combined treatment effectively reduced lung viral load, lung pathology, morbidity and mortality during respiratory IAV infection in mice, contemporaneous with significant downregulation of the inflammatory cytokines TNF, IL-1β, IL-6, IL-12p40, chemokines CCL2, CCL5 and CXCL10 and dampened STAT3 activation. Consequently, combined therapy with oseltamivir and a STAT3 inhibitor also effectively reduced clinical disease and lung pathology. Combined treatment using either of the anti-inflammatory drugs and oseltamivir dampened an overlapping set of cytokines. Thus, combined therapy targeting a specific cytokine or cytokine signaling pathway plus an antiviral drug provides an effective treatment strategy for ameliorating IAV pneumonia. Effective treatment of IAV pneumonia required multiple doses of etanercept and a high dose of oseltamivir. This approach might apply to the treatment of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Significance Statement Antivirals against influenza A virus (IAV) are ineffective in treating pneumonia if administered 48 h after onset of disease symptoms. The host inflammatory response and tissue damage caused by IAV are responsible for lung pathology. We reasoned that targeting both virus and inflammation would be more effective in reducing lung pathology and pneumonia, morbidity and mortality. The simultaneous treatment with an anti-inflammatory drug targeting TNF or STAT3, combined with the anti-IAV antiviral drug, oseltamivir, significantly improved clinical disease, reduced lung viral load and pathology, and protected mice from severe pneumonia. The combined treatment suppressed multiple pro-inflammatory cytokines and cytokine signaling pathways. Thus, after the onset of disease symptoms, both virus and inflammation must be targeted to treat IAV pneumonia effectively.

Smoking and COVID-19: What we know so far.

The ongoing COVID-19 pandemic has placed a spotlight on infectious diseases and their associations with host factors and underlying conditions. New data on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus are entering the public domain at a rapid rate such that their distillation often lags behind. To minimise weak associations becoming perceived as established paradigms, it is imperative that methodologies and outputs from different studies are appropriately critiqued and compared. In this review, we examine recent data on a potential relationship between smoking and COVID-19. While the causal role of smoking has been firmly demonstrated in regard to lung cancer and chronic obstructive pulmonary disease, such associations have the benefit of decades' worth of multi-centre epidemiological and mechanistic data. From our analysis of the available studies to date, it appears that a relationship is emerging in regard to patients with a smoking history having a higher likelihood of developing more severe symptoms of COVID-19 disease than non-smokers. Data on whether COVID-19 has a greater incidence in smokers than non-smokers is thus far, contradictory and inconclusive. There is therefore a need for some caution to be exercised until further research has been conducted in a wider range of geographical settings with sufficient numbers of patients that have been carefully phenotyped in respect of smoking status and adequate statistical control for confounding factors.