Table 2.

Studies of the effects of statins on influenza.

	Study design	Key findings
a) Animal studies
Liu et al., 2009	BALB/c mice infected with A(H5N1), A(H3N2), or A(H1N1) influenza virus	Combination of 50 μg statin +200 μg caffeine ameliorated lung damage and inhibited viral replication, and appeared to be at least as effective as oseltamivir and ribavirin. However, the statin/caffeine combination seemed to be more effective when administered preventatively, rather than as treatment.
Radigan et al., 2012	A murine model of influenza A virus infection,	Administration of rosuvastatin had no effect on viral clearance after infection or on mortality.
Belser et al., 2013	Mice infected with A(H1N1) or A(H5N1) viruses.	Simvastatin did not reduce morbidity, mortality, or viral load. A combination of simvastatin and oseltamivir did not improve the effectiveness of oseltamivir alone following highly pathogenic avian influenza A(H5N1) virus infection in mice despite modest reductions in lung cytokine production.
Gluck et al., 2013	This study evaluated the efficacy of simvastatin against influenza A/PR/ 8/34 (H1N1) virus infection in BALB/c-mice. In the first study, simvastatin was administered orally. To achieve high plasma levels, intraperitoneal application was used in a second study.	Treatment with simvastatin resulted in lower survival rates and in more distinct body mass loss in comparison to virus-infected control mice. Furthermore, the viral load in lungs and tracheas as well as histopathological lesions were not reduced by simvastatin.
b) Human epidemiology studies
Kwong et al., 2009	A population-based cohort study over 10 influenza seasons (1996–2006) in Ontario, Canada with propensity-based matching.	Chronic use of statins showed small protective effects against pneumonia hospitalization ([OR] 0.92; 95% CI 0.89–0.95), 30-day pneumonia mortality (0.84; 95% CI 0.77–0.91), and all-cause mortality (0.87; 95% CI 0.84–0.89). However, these positive effects were reduced substantially following multivariate adjustment for confounding factors.
Brett et al., 2011	A retrospective case-control study of the UK Influenza Clinical Information Network database of 1520 patients hospitalized with A(H1N1)pdm09 influenza from April 2009 to January 2010.	No statistically significant association between pre-admission statin use and the severity of outcome in patients aged ≥35 years [adjusted OR: 0.81 (95% CI: 0.46–1.38); n = 571]. Following adjustment for age, sex, obesity and indication for statins, there was no statistically significant association between pre-admission statin use and the severity of outcome.
Vandermeer et al., 2012	A study of hospitalized adults in 10 states in the USA during the 2007-08 influenza season, which was analyzed to evaluate the association between receiving statins and influenza-related death.	Statins treatment before or during hospitalization was associated with a protective adjusted odds-of-death of 0.59 (95%CI 0.38–0.92), following adjustment for age, race, comorbid diseases, influenza vaccination and antiviral administration.
Laidler, et al. 2015	A study using population-based, influenza hospitalization surveillance data, propensity score-matched analysis, and Cox regression to determine if there was an association between mortality (within 30 days of a positive influenza test) and statin treatment among hospitalized cohorts from 2 influenza seasons (October 1, 2007 to April 30, 2008 and September 1, 2009 to April 31, 2010).	Hazard ratios for death within the 30-day follow-up period were 0.41 (95%CI, 0.25–0.68) for a matched sample from the 2007–2008 season and 0.77 (95% CI, 0.43–1.36) for a matched sample from the 2009 pandemic. The data suggest a protective effect of statins against death from influenza among patients hospitalized in 2007–2008 but not during the pandemic.
Lee et al., 2015	A retrospective study of factors influencing outcomes of adults hospitalized for seasonal and A(H1N1)pdm09 influenza in 2008–2011 in 3 cities (Hong Kong, Singapore and Beijing; N = 2649).	Chronic statin use decreased death risks (adjusted HR 0.44, 95% CI 0.23–0.84)
Brassard et al., 2017	A study of the UK Clinical Practice Research Datalink to identify all patients aged ≥30 years diagnosed with influenza-like illness during 1997–2010. The study cohort included 5181 statin users matched to 5181 non-users.	The 30-day incidence of hospitalization or death was 3.5% in statin users vs 5.2% in non-users, resulting in a 27% lower incidence with statin use (cumulative incidence ratio: 0.73, 95%CI: 0.59–0.89). However, the protective effect of statins was less pronounced among new users and those with concomitant chronic illness predisposing to influenza complications such as respiratory and cardiac disease.