An Alternative Approach to Pandemic Influenza That Clinicians Everywhere Could Use
Guest Editorial by David S. Fedson, MD, July 23, 2010
The initial waves of the first influenza pandemic of the 21st Century have passed. Despite the best efforts of inﬂuenza scientists, health officials, and companies, more than 90% of the world’s people did not have timely access to affordable supplies of vaccines and antiviral agents. Instead, they had to rely on 19th Century public health “technologies.” They should have (and probably could have) had something better.1-5
The Central Importance of the Host Response
In the 1918 pandemic, young adults had high mortality rates, yet children were infected more frequently than young adults and they seldom died.5 This is best explained by the more benign host response of children, a feature shared with several other medical conditions. Few people who die of influenza do so during the first few days of illness when pro-inflammatory cytokine levels are high; instead, like patients with sepsis, they usually die in the second week, when anti-inflammatory cytokines and immunosuppression dominate. Influenza deaths at any age occur more frequently in persons with cardiopulmonary conditions, diabetes, renal disease, obesity, asthma and late pregnancy. All of these conditions share one characteristic in common: dysregulated innate immunity. Laboratory studies confirm the importance of the host response. For example, fatal acute lung injury can be induced in mice by inactivated H5N1 virus.4 In this model, antiviral agents would be useless; only the host response is responsible for disease. Could the host response be modified so patients would have a better chance of surviving?
Influenza, Acute Coronary Syndromes (ACS), Statins and Related Agents
Influenza is associated with ACS, and influenza vaccination and statins reduce its occurrence. These associations led to the suggestion in 2004 that statins might be used to treat pandemic influenza.1 Other agents that might also be effective include PPARα and PPARγ agonists (fibrates and glitazones, respectively) and AMPK agonists (metformin).3-5 These agents have been studied in laboratory models of sepsis, acute lung injury, ischemia/reperfusion injury, innate immunity, energy metabolism, mitochondrial function and programmed cell death. The results show that one or more of them:
down-regulate pro-inflammatory cytokines (e.g., NF-kappaB, TNFα, IL-1, IL-6);
upregulate anti-inflammatory cytokines (IL-10, TGFβ), pro-resolution factors (lipoxin A4, resolvin E1) and HO-1;
decrease TLR signaling by PAMPs and DAMPs;
restore iNOS/eNOS balance and stabilize cardiovascular function;
decrease reactive oxygen species and oxidative stress and restore mitochondrial biogenesis;
decrease tissue factor and its associated pro-thrombotic state;
stabilize the actin cytoskeleton in endothelial cells and shore up intracellular tight junctions, thereby increasing pulmonary barrier integrity and decreasing vascular leak;
modify macrophage function, caspase activation and apoptosis; and
increase the Bcl-2/Bax ratio in influenza virus-infected cells, thereby preventing the apoptosis necessary for virus replication.
The mechanisms demonstrated in these studies strongly suggest that these agents should benefit patients with severe influenza.
Evidence of Clinical Effectiveness
Outpatient statins decrease hospital admissions and mortality due to pneumonia.3-5 In mice infected with PR8 (H1N1), H2N2 and H5N1 viruses, fibrates and glitazones reduce mortality by 40-50%, often when treatment is started 2-4 days following infection.3-5 Remarkably, they do so without increasing virus replication. In influenza patients, these immunomodulatory agents should reduce pulmonary infiltrates, maintain oxygenation, stabilize and improve myocardial contractility and endothelial and epithelial cell function, reverse immunosuppression, restore mitochondrial biogenesis, prevent multi-organ failure and reduce mortality. There is already strong evidence that this can actually happen. In a soon-to-be published study of almost 4,000 patients hospitalized with laboratory-confirmed seasonal influenza, inpatient statin treatment reduced hospital mortality by 66%.6
Global Implications of Immunomodulatory Treatment
Simvastatin, pioglitazone, and metformin are produced as inexpensive generics in developing countries, and global supplies are huge. These agents would not be used to treat all influenza patients. Instead, only those at risk of multi-organ failure and death would need to be treated. The cost per patient would be less than $1.00 [DS Fedson, Unpublished observations]. Because these agents are available in all countries that have basic healthcare systems, they could be used on the first pandemic day.
Thus far, influenza scientists and the institutions that support their work (e.g., NIH, CDC, the Gates Foundation, the Wellcome Trust and the World Health Organization) have shown little interest in immunomodulatory treatment. Nonetheless, when vaccines and antiviral agents are not available, clinicians must have an alternative that will work. Consequently, they should demand that research be undertaken to determine whether generic immunomodulatory agents might be useful in managing seasonal influenza and the next pandemic.
Research on this approach must involve investigators in many fields outside influenza science. The laboratory studies needed to identify promising agents would probably cost less than $5-15 million [DS Fedson, Unpublished observation]. The results of these studies would inform clinical trials that intensive care physicians are already eager to undertake. Clinicians should easily understand that we simply cannot afford not to undertake this research.
Fedson DS. Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin Infect Dis 2006;43:199-205.
Fedson DS, Dunnill P. Commentary: From scarcity to abundance: pandemic vaccines and other agents for “have not” countries. J Public Health Policy 2007;28:322-40.
Fedson DS. Confronting the next influenza pandemic with inexpensive generic agents: can it be done? Lancet Infect Dis 2008;8:571-6.
Fedson DS. Meeting the challenge of influenza pandemic preparedness in developing countries. Emerg Infect Dis 2009;15:365-71.
Fedson DS. Confronting the next influenza pandemic with anti-inflammatory and immunomodulatory agents: why they are needed and how they might work. Influenza Other Respir Virus 2009;3:129-42.
Vandermeer M, Thomas A, Kamimoto L, Reingold A, Gershman K, Meek J et al. The role of statins in preventing death among patients hospitalized with lab-confirmed influenza infections (Abs. 706). Annual Meeting of the Infectious Diseases Society of America. October 30, 2009.
* Following a recent presentation by Dr. Fedson at the Center for Biosecurity, the CBN editors invited him to submit a guest editorial. Inquiries may be directed to him at email@example.com.