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[CATHOLIC CAUCUS] Fatima and the 2009 H1N1 Flu Pandemic
Faith, Reason and Health blog ^
| Brian Kopp
Posted on 07/14/2010 6:35:38 AM PDT by Brian Kopp DPM
Wednesday, July 14, 2010
Fatima and the 2009 H1N1 Flu Pandemic
In the fall of 1918, two young Portuguese shepherds contracted a virulent form of swine flu during a global pandemic that took the lives of 50 to 100 million. Francisco Marto barely survived the flu and died of complications, most likely a secondary bacterial infection, in April 1919. His sister Jacinta subsequently developed tuberculosis and died in February of 1920. With their cousin Lucia dos Santos, they are better known today for having witnessed the apparitions of Our Lady of Fatima.
Francisco and Jacinta likely would have survived the 1918 Spanish flu pandemic if modern antibiotics had been available. Science has subsequently assembled an impressive database for virology and immunology as well as more effective vaccines, antiviral medications and intensive care interventions for flu complications. Despite these advances there are increasing deaths, especially among pregnant women, the young and the healthy due to the current swine H1N1 pandemic, which has striking similarities to the Influenza A (H1N1) virus responsible for the 1918 pandemic. Both are noted for precipitating cytokine storm, an overreaction of the immune system that floods the lungs and can lead to multi-organ failure and death. Unlike 1918, the feared second wave during September of 2009 failed to produce a massive surge in fatalities. Complicating the debate, the scientific world is split on the implications of recent minor genetic changes in the virus and the best available options for prevention and treatment in the face of a possible third wave later this winter.
A good illustration of the dissension within the scientific community can be seen in the work of David Fedson, MD. Specializing in the epidemiology of influenza and vaccination, Fedson served as Director of Medical Affairs for Aventis Pasteur MSD and was a member of numerous US and World Health Organization (WHO) committees on influenza immunization. Having worked extensively within the field, he continues to believe that safe effective vaccines are the gold standard in preventing deaths from pandemic flu, but also grasps the inherent shortcomings of our reliance on flu vaccines and antiviral medications such as Tamiflu. A December study in the British Medical Journal has drawn into question the general effectiveness of Tamiflu, and due to a minor genetic mutation (known as H274Y) seasonal H1N1 flu is now 99% resistant to Tamiflu. There have been increasing reports of the H274Y mutation in 2009 swine H1N1 samples. Viral genetic drift, which helps a virus evade a hosts immune response, can also render pandemic vaccines ineffective, and global pandemic vaccine production capacity is only sufficient to immunize approximately a billion people, less than 1 in 7 of the worlds population. Fedson is an ardent promoter of adjuvants as an essential antigen sparing method to stretch limited supplies to vaccinate as many as four times as many individuals.
An interview with Fedson exploring these issues was published in July in L'Osservatore Romano as part of their coverage of the G8 Summit meeting. For over five years Fedson has been campaigning for research on the use of currently available generic medications to help control the cytokine storm precipitated by novel influenza strains. Targeted drugs include statins and fibrates (currently used for lowering cholesterol and triglycerides), glitizones (used in managing diabetes) and Resveratrol (a chemical in red wines and peanuts thought to be responsible for lowering rates of heart disease). Until recently, his pleas fell on deaf ears at the CDC, WHO, The Gates Foundation, and other major philanthropic organizations. Headlines this fall finally vindicated his efforts. Research funded by the CDC indicated that among people hospitalized with seasonal influenza, those taking statins were 50% less likely to die.
Susan Chu, MD was a cosigner of Fedsons seminal 2006 letter to The Times (UK) urging research on this issue. An editor of the popular newfluwiki2.com website, Chu parts company with Fedson when it comes to the use of adjuvants in flu vaccines. Chu has posted a series of essays at newfluwiki2.com about the possibility of adjuvants causing autoimmune disease and spontaneous miscarriages. The medical literature and vaccine manufacturers simply have not provided adequate documentation to allay Chus concerns, though Fedson maintains that, with 40 million adjuvanted vaccines administered so far in Europe, such complications would already have been widely reported. Adjuvant promoters also point to a possible additional benefit, the potential of cross protection via broader immunity to pandemic viruses that displays genetic drift away from the original vaccine target. Recent minor genetic mutations (known as D225G) that have been noted in samples from the Ukraine and Norway were also seen in the 1918 and H5N1 influenza strains. These mutations are associated with infections that strike deeper in the lungs, causing widespread damage to alveolar cells and triggering cytokine storm, increasing virulence and death rates. One Ukraine specimen with this minor genetic mutation was characterized as a low reactor, indicating that current vaccines might not be as effective against strains with this mutation.
An additional concern is an immunological concept called, ironically, Original Antigenic Sin (OAS). According to the OAS theory the immune system will create a robust immune response to a novel virus, but if the individual is subsequently infected with a strain of virus closely related to the first strain, the body reacts as if it were being reinfected with the original strain, failing to confront the mutated virus. This could have implications for the minor genetic variations noted between waves of any given pandemic flu. Individuals infected with the spring 1918 pandemic wave had at least partial immunity to the fall 1918 wave, but little or none to the Winter 1918/1919 wave. Fortunately, the 2009 H1N1 Live Attenuated Influenza Vaccine (LAIV) nasal spray appears to have included the D225G variant. The injectable inactivated vaccines do not, and no one in the medical community can foretell the significance of this at present.
The evolutionary explanations for these mutations are being hotly debated among the scientific community and point to one of the greatest controversies among virologists. The current genetic theories of random mutation and viral reassortment, representing the reigning orthodoxy at the CDC and WHO, simply cannot explain the appearance of some of these mutations among widespread samples and differing genetic backgrounds. Henry Niman, PhD, is the leading proponent of a relatively new theory of homologous recombination to explain and predict such mutations, and his company, Recombinomics, hopes to cash in on the ability to predict such changes to better guide vaccine production. By shear tenacity he has managed to drive the online flu community towards his point of view, and in the process has precipitated wider access to genetic sequence data online. His signature comments, Release of sequences would be useful and [the genetic mutation du jour] is cause for concern have become both a thorn in the side of mainstream science as well as a rallying cry among the online flu community seeking transparency from government labs and influenza researchers.
The scientific establishment points to a lack of peer reviewed publications supporting Nimans theory of recombination, but the recent ClimateGate controversy has illustrated the tyranny and political correctness of the peer review process. As in the global warming debate, the mainstream position isnt holding up to scrutiny. Tamiflu resistance is becoming too widespread to continue to claim it is randomly popping up in multiple patients simultaneously, or that resistance to Tamilflu makes the virus less able to spread. In France, one fatal case contained both D225G and Tamiflu resistance mutations. According to Niman, low reactors to current vaccines due to the virulent D225G mutation along with increasing prevalence of Tamiflu resistance could create the perfect storm for a deadly third or fourth pandemic wave later in 2010.
Fortunately, some common concerns expressed since early in the pandemic cycle have been settled. Current pandemic vaccines do not utilize any technologies that are intrinsically objectionable from a pro-life perspective, and there never was any validity to claims that current pandemic vaccines might be used for population control purposes. Brian Clowes, PhD, is director of research at Human Life International, and exposed the use of abortifacient hCG hormone-linked Tetanus vaccines in third world countries in the early 1990's. When asked if current pandemic vaccines might be used for population control purposes, he stated that although sterilization vaccines are still being researched, they are only used by western nations against the third world countries targeted in the 1974 National Security Study Memorandum 200.
By mid December, at least 200 million doses of pandemic flu vaccine had been administered globally, and the complications that were feared, based on the infamous 1976 Swine Flu vaccine campaign, have simply failed to materialize. Though GuillainBarré syndrome has not become an issue in the current vaccine campaign, there have been some credible reports of increased allergic reactions and anecdotal reports of miscarriages associated with adjuvanted vaccines. The non-adjuvanted pandemic vaccines have displayed a safety level similar to seasonal flu vaccines, but it is still too early to tell whether current vaccines will actually prevent deadly infections during subsequent waves of influenza.
Most of the hysterical claims regarding the current pandemic have originated among promoters of alternative medicine, who insist that herbs, vitamins and other natural remedies can prevent and cure influenza. While proclaiming that the pandemic declaration itself is a hoax or conspiracy, theyll be happy to sell supplements to the credulous, and adjust their flow of energy for optimum immune response. A central theme of the new age Gnostic alternative health field is the notion that the human body should be symptom and disease free, simply as a result of living a "healthy" lifestyle, and therefore able to overcome any illness. Unfortunately, this concept implicitly denies that disease entered human history as a result of Original Sin and continues due to personal sin. Gluttony and sloth arent bad lifestyle choices because they disturb karma or displease Gaia, they are cardinal sins that have temporal consequences. Obesity, diabetes and heart disease are the highest risk factors in the current pandemic.
Mainstream medicine has been neutered in its ability to address modern lifestyle choices, be they nutritional, behavioral, or sexual, because the scientism that animates modern medicine is non-judgmental. This scientism promised a utopia of health, happiness, and freedom from disease, and eventually the answers to all human questions and problems, but also forbids the intrusion of traditional morality into modern mainstream medicine.
Decembers headlines, H1N1 Pandemic a Dud, may be true. Or the mounting viral mutations could cause a brutal third wave later this winter. Regardless, it is apparent that scientism has failed to deliver on its grand promises, at least in this current pandemic. The new age Gnosticism inherent in the alternative medicine industry is blind to the reality that human suffering comes from The Fall, the answers to which can be found only in the Cross. Disease will not be eliminated by science or by a healthy lifestyle. It will only end in that place where all tears are wiped away.
There are messages for us in the midst of this pandemic, in the message of Our Lady of Fatima. Blessed Francisco and Jacinta, please pray for us, and help us discern.
TOPICS: Catholic; Current Events; Religion & Culture; Religion & Science
Monday, October 12, 2009
The unforgiving arithmetic of pandemic
15 July 2009
Dr David Fedson on aiding developing countries in the treatment of pandemic diseases
"The world situation, as the news in recent months amply demonstrates, continues to present serious problems and the "scandal' of glaring inequalities which have endured despite past efforts". These were the words of Pope Benedict XVI during the General Audience Catechesis outlining the fundamental messages of his recently released Encyclical Letter, Caritas in Veritate (see p. 11).
When viewing the current world situation from a Catholic perspective, the pursuit of social justice within all sectors is essential, as the Holy Father clearly expresses in his social Encyclical. This constitutes the task of securing both the physical and spiritual well-being of every human being.
For this to happen the support of the governmental, medical and philanthropic communities of first world nations is urgently needed. Thus a broader vision concerning the challenges facing the world's less developed areas is crucial. This view was also expressed at the recent G8 Summit.
In the spirit of this same kind of solidarity, Brian J. Kopp, DPM, spoke with David Fedson, MD, on 3 July about the current H1N1 swine flu pandemic and the prospects for equitable treatment alternatives in developing countries. Indeed, a testament to the importance of this particular issue was President Obama's participation from Italy via telephone link in the Influenza Preparedness Summit held at the National Institutes of Health on 9 July.
Dr. Fedson is a retired American physician living in France. He has long worked on the epidemiology of influenza and influenza vaccination, first as a Professor of Medicine at the University of Virginia and later as Director of Medical Affairs for Aventis Pasteur MSD. He has served on several American and World Health Organization (WHO) committees on influenza immunization, and was instrumental in establishing the Influenza Vaccine Supply (IVS) International Task Force and the Macroepidemiology of Influenza Vaccination (MIV) Study Group. He clearly knows the influenza vaccine industry from the inside. He also knows that the arithmetic for a pandemic is simple: you can only treat the victims of a pandemic if effective vaccines and medications are widely available. For 90% of the world's population, this won't be the case.
With the current swine H1N1 pandemic influenza virus, as with the H5N1 avian flu and 1918 pandemic viruses, deaths have been prominent among the 15- to 45-year old adults. These deaths have been associated with a severe immune reaction, often called a "cytokine storm." For more than five years, Fedson has been calling for urgent and sharply focused research to determine whether drugs that reduce inflammation or modify the host response the way that the body responds to infection or injury could be used to manage the pandemic. Focusing on inexpensive generic drugs that are readily available, even in developing countries, could address the inequity already being seen, and could save millions of lives in the current and in future pandemics.
Roche announced on 2 July that they would now sell their Tamiflu to third world nations at a reduced price. Is Tamiflu still a reliable treatment option?
Tamiflu resistant swine flu viruses have already been isolated in Denmark, Japan, and Hong Kong, and the virus that was isolated in Hong Kong came from a woman who had not taken Tamiflu. Knowing that seasonal H1N1 viruses are now almost completely resistant to Tamiflu, we should expect Tamiflu-resistant swine flu viruses to appear sooner or later. It's just a matter of time, and we're seeing it already. Yet if we're fortunate and this doesn't happen, we will still have problems. Current government stockpiles of Tamiflu in "have not' countries (countries that don't produce influenza vaccines) would be sufficient to treat only 1% of the people who live in these countries. Roche has said publicly that its capacity for producing courses of Tamiflu treatment is 400 million doses per year. That's it; they can't go beyond that.
Has vaccine production capacity improved in the last few years?
No, the situation has not changed a great deal. I keep going back to the arithmetic. Two years ago it was estimated that within 9 months of the emergence of the pandemic virus, all of the world's influenza vaccine companies could produce enough doses of a new pandemic vaccine to vaccinate with two doses approximately 750 million people. More recently, a report sponsored by the WHO estimated that 6 months after the emergence of a new pandemic virus, the companies could produce 860 million doses of vaccine. These numbers are similar to the number of people living in the nine countries that produce almost all of the world's seasonal influenza vaccines.
If you're talking only about the US and want to vaccinate everyone, you will need 300 million doses. If you need two doses per person, you'll need 600 million doses and you're not going to get 600 million doses right away unless you have an antigen sparing formulation. This requires adding an adjuvant, a chemical that boosts the immune response and allows companies to decrease the amount of virus in each dose. However, US regulatory authorities are concerned about the safety of adjuvanted vaccines. As long as the virus doesn't get more virulent and the case fatality rate among non vaccinated individuals remains very low, the social and political impact of the pandemic will be tolerable; although a huge number of infections will occur, 99.5% of those infected will survive. The choice between an adjuvanted or non adjuvanted vaccine will determine whether companies produce more or fewer doses of vaccine. Erring on the side of caution will mean that developing countries will have even less chance of obtaining supplies of pandemic vaccines.
Are there any plans to provide vaccines to developing countries?
Currently, there is no logistical plan for distributing supplies of pandemic vaccines to the "have not' countries that will not be able to produce them. These countries are home to approximately 88% of the world's population.
Whether the political leaders of the nine countries that produce almost all of the world's influenza vaccines will take an active role in the allocation of H1N1 vaccines supplies is an important question, at least in my view. Given the desire of political leaders never to make decisions unless they are absolutely unavoidable, they may view the H1N1 pandemic as being no more severe in its consequences for individuals than a seasonal H1N1 outbreak. Therefore, they may decide they don't need to take an active role in deciding where doses of vaccine will be distributed, at least after they have satisfied their domestic needs. Yet we must keep in mind that whatever WHO, companies and governments do for a mild H1N1 pandemic will establish the precedents for managing vaccine production, licensing and distribution for a more severe H5N1 pandemic. For me, this is the most fascinating aspect of what we are currently seeing. It is also the most unpredictable and consequently the most worrisome.
If there will be inadequate supplies of vaccines and Tamiflu, what other options are being pursued?
Since 2004 I have tried to persuade government agencies and foundations in the US and Europe as well as the WHO to convene one or more workshops that would bring together 25-30 scientists who work with animal models of influenza, sepsis and multi-organ failure. They would be asked to review the scientific rationale for using agents that modify the host response. The agents they should consider most strongly are those that are now produced as inexpensive generics and that are widely available in developing countries. Statins, fibrates and glitazones are, in my view, prime candidates. No one has been interested in this proposal.
The generic agents I talk about affect the host response, and this is something that, with the exception of the immune response, influenza virologists know little about. We must enlist the support of scientists in other fields sepsis, critical care, cardiovascular and pulmonary diseases, metabolic disorders and mitochondrial function. They must tell influenza scientists what they know about the host response to infection, and how it might be useful to them in their research.
I'm worried that the H1N1 virus could get worse, that it could develop the virulence of the 1918 pandemic virus, or possibly combine with an H5N1 avian flu virus to give us a monster virus. Each of these developments is possible. Now if they're possible, we could spend perhaps 10 to 20 million dollars and get 90% of the answers we need to determine whether these generic agents could save lives. Is it worth organizing the research in such a way that we could quickly get the answers needed to manage a global pandemic? That's the big question. Why don't we do it?
Where, then, would efforts ideally be focused in the fight against this pandemic?
The focus of all of our efforts right now must be on ways to manage the pandemic throughout the world in ways that will save lives in this and any future pandemic. This will require a focus on the host response.
Several studies have suggested that prescriptions for statins are associated with a 50% reduction in pneumonia hospitalizations and deaths. If statins prove to be effective against pneumonia, they might be similarly effective against pandemic influenza. Experimental studies in mice show that gemfibrozil and pioglitazone dramatically reduce influenza-related mortality. A 2005 study of resveratrol showed a 54% decrease in mortality in a mouse model of influenza.
The practical implications of these findings for an influenza pandemic are enormous. For example, in 2008, 29 billion doses of statins were produced worldwide, 16 billion of them as generics. If only 5% of this output had been set aside, it would have been sufficient to provide five days of treatment for 160 million people. Since treatment would probably be necessary only for those patients at risk of serious complications, multi-organ failure and death, supplies sufficient to over 2-10% of an infected population would probably be sufficient (perhaps H5N1 excepted). Gemfibrozil and pioglitazone are also produced as generics, and many of the companies that produce them are located in developing countries. As generics, these agents would be far less expensive than vaccines and antiviral agents; according to 2008 prices, five days of treatment would cost less than $1.00. Thus, stockpiles would be affordable and distribution channels could be set up in advance of a pandemic.
We don't know how any of these drugs are handled in people who are already sick. That's key. However, we have a wonderful research opportunity right now to develop multi-center trials of single dose treatment in patients with severe H1N1 influenza. We could measure drug levels and cytokine changes following treatment at different times during the course of illness. It would not be difficult to recruit several hundred people for studies like this, but no one is organized to do them. We can't afford not to do this work.
The message that needs to go out to the world is that health officials everywhere have a responsibility to find ways to manage a pandemic in all countries. This means that they don't have to explain the molecular biology of everything that's going on. Instead, they must find agents that can be used to save lives. We have enough evidence from experimental work and enough suggestions from clinical observations to suggest that we could do this by modifying the host response using inexpensive generic agents that are already being produced in developing countries. Making effective therapies widely available is the key to a global response to a pandemic, whether it is caused by the current swine H1N1 virus, an H5N1 virus or something in between.
Sadly, the arithmetic for pandemic vaccines and antivirals is unforgiving. WHO is focused on vaccines and antivirals that will only be available to people who can afford them, and that's ten percent of the world's population. Consequently, it doesn't matter that arguments for their use are scientifically well grounded; in practical terms they are pointless, in the same way that it is pointless to tell a starving man he should eat if there's no food in the kitchen. For pandemic vaccines and antiviral agents, the kitchen is empty. We should stop talking about things that people in developing countries will never have, and start talking about things they've already got.
To: Judith Anne; mlizzy; NYer; Salvation; narses; Mad Dawg; JSteff; wagglebee; johngrace; ...
This is an article I wrote for a Catholic periodical in late November, but H1N1 fell off the radar screen before it would have been published, so it was not used.
I'm just pinging a couple Catholics off the top of my head here, but I'm also starting a CATHOLIC CAUCUS ping list. Please send me a PM if you would like to be added to or removed from the list.
To: Dr. Brian Kopp
Thanks for posting! I did not realize you had such a background in the flus.
posted on 07/14/2010 7:02:09 AM PDT
by Judith Anne
(Holy Mary, Mother of God, please pray for us sinners now and at the hour of our death.)
To: Judith Anne
Just a personal interest. Its a long way from my specialty ;-)
To: Dr. Brian Kopp
bookmarking to read later
posted on 07/14/2010 7:11:09 AM PDT
To: Judith Anne
By the way, it was because of the Fatima link that I followed H1N1 so intently. Honestly, now that H5N1 and H1N1 are co circulating in many third world regions, Im more concerned than ever.
When I wrote the article for LOsservatore Romano on H1N1 in the summer of 2009, that was the greatest fear of the doctor I interviewed. It wasn’t H1N1 that he feared, but “the next one.”
To: Dr. Brian Kopp
As far as I understand, the H5N1 virus is not as deadly as it might be, if it could survive the temperatures in the human respiratory system.
It likely wouldn’t take much change to be a bit more dangerous...
posted on 07/14/2010 7:22:14 AM PDT
by Judith Anne
(Holy Mary, Mother of God, please pray for us sinners now and at the hour of our death.)
To: Judith Anne
To: Dr. Brian Kopp
I wasn’t aware of any of this. Thank you.
posted on 07/14/2010 8:39:49 AM PDT
("With God all things are possible." Matthew 19:26)
To: Dr. Brian Kopp
I wish priests would emphasize Confession, daily Mass, and the Recitation of the Rosary to their parishioners. Because although we all have to die somehow and someday, we can acquire a better standing with Christ (and get ourselves eventually into heaven), if we take part in the Sacraments and use the sacramentals frequently. Should an epidemic hit, hopefully one’s scapular and miraculous medal will be in firm place. (Purchase today, and beat the rush!!)
posted on 07/14/2010 11:05:48 AM PDT
(Hail Mary, full of grace, the Lord is with thee ...)
Should an epidemic hit, hopefully ones scapular and miraculous medal will be in firm place.
Always. Right next to my Crucifix of St. Benedict.
To: Dr. Brian Kopp
So, I have a question: if statins are effective in the H1N1 treatment, would niacin be as well as it is more effective than statins in some circumstances?
At this point, I'm just glad I've already had it (H1N1). For me it came with a nasty sinus infection that I killed with a neti-pot. I guess I'm too old for the worst of it.
posted on 07/14/2010 6:26:15 PM PDT
(VIVA ESPANA! No relation: http://www.youtube.com/watch?v=yg3cshE_HbU)
I don't think Niacin has the same anti-inflammatory properties as statins.
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,48 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 hosts 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.68 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 boundariesour 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 Michaels Hospital, Toronto, ONT, Canada M5B 1W8 email@example.com
To: Dr. Brian Kopp
UPMC Center For Biosecurity
Clinicians Biosecurity Network
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 worlds 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.
* 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 firstname.lastname@example.org.
- 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.
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