Here's a recent research initiative written up in the Lancet that was based on Dr. Fedson's work:
InFACT: a global critical care research response to H1N1
The H1N1 pandemic presents acute care researchers with an extraordinary challenge and an unprecedented opportunity. By early October, 2009, there had been more than 340 000 reported cases of H1N1 infection in 191 countries, with more than 4100 deaths.1 WHO initially projected that up to 2 billion people could become infected with the virus over the next 2 years.2 Although vaccination programmes and other factors should reduce this number, plausible estimates of the number of infected individuals who might benefi t from admission to intensive care range from 200 000 to 10 million. Infl uenza killed at least 50 million people during the 1918 pandemic.3 Today, with antibiotics and antiviral agents, mechanical ventilation, and the supportive measures available in intensive care, most of those deaths could have been prevented. The mortality for H1N1-infected patients admitted to intensive care ranges from 10 to 40% over the fi rst month,4–8 and survivors spend a median of 2 weeks in the intensive care unit. To reduce this toll requires a better understanding of the epidemiology and clinical biology of the disease, and the identifi cation of effective management strategies. New knowledge must be gathered with unprecedented speed and effi ciency. Beyond antiviral agents, anecdotal reports and data from animal studies suggest that illness severity can be attenuated by readily available agents, such as corticosteroids and statins, that can modulate the host’s infl ammatory response.9 None of these drugs has been adequately studied for effi cacy. It is within the intensive care unit that the most severely aff ected patients will be treated. As international leaders of investigator-led clinical research consortia, and as clinicians dedicated to the care of critically ill patients, we have joined together as the International Forum for Acute Care Trialists (InFACT)10 to promote a scientifi cally rigorous, geopolitically inclusive, and academically collegial research response to this challenge (panel). We call on those who share this goal to join us. The InFACT H1N1 research programme incorporates four core initiatives. We have harmonised fi ve regional databases to create a common global registry of critically ill patients with H1N1 infection.6–8 We urge clinicians and researchers to contribute cases. The database will enable real-time study of the epidemiology, natural history, and treatment of severe H1N1 disease. In parallel, we will develop a biobank to facilitate studies of genetic susceptibility and clinical biology. We are starting a programme of collaborative, investigator-led randomised trials of treatment strategies that target both the virus and the host response. Our initial three studies will evaluate inexpensive interventions that are available in both the developed and the developing world: corticosteroids and statins. They use adaptive designs to ensure that results can be quickly incorporated into practice, and that ineff ective treatments are dropped. As measures of effi cacy, they will measure survival of individual patients and the rapidity with which patients can be liberated from limited intensive-care resources. We seek to reduce the consequences of severe H1N1 infection in the developed world, where available research infrastructure is most robust, and in the developing world, where the human toll is likely to be the greatest. To this end, we will catalogue international critical care capacity, and promote, mentor, and support clinical research activities in resource-poor areas. Research during a pandemic poses unique ethical and logistical challenges. Our position paper seeks toreconcile the potentially competing imperatives of a deliberate and conservative approach to the protection of the rights of the individual patient with the societal need to minimise the burden of illness and rapidly determine optimum approaches to prevention and treatment. The H1N1 pandemic transcends geographic, economic, and political boundaries—our response must be similarly inclusive. We have committed ourselves, and the scientifi c constituencies we represent, to a methodologically rigorous and intellectually open collaboration to learn as much as we can and as quickly as we can to reduce the burden of illness of severe H1N1 infection. We call on clinicians, regulatory agencies, governmental authorities, research ethics boards, and funding bodies to support this unparalleled response to an extraordinary global challenge. The InFACT Global H1N1 Collaboration* St Michael’s Hospital, Toronto, ONT, Canada M5B 1W8 marshallj@smh.toronto.on.ca
Guest Editorial*
An Alternative Approach to Pandemic Influenza
That Clinicians Everywhere Could Use
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:
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.
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