Strategy to Survive H5N1 Avian Influenza

1.      Introduction: The Challenge of H5N1 Avian Influenza 

            H5N1 highly pathogenic avian influenza (HPAI) may soon gain the ability to transmit human-to-human. It has not achieved that yet but appears to inch closer each month. It could happen soon – or not so soon. H5N1 already has infected and killed tens of thousands of dairy cattle in 15 states (Gutierrez). Over 108 million chickens have died or had to be culled nationwide (Abbott) since the virus arrived in the U.S. from Northern Europe in 2021. (Peacock) Most wild bird species that crisscross American skies carry H5N1 and have infected both domestic fowl and 200 mammal species in America since it first appeared. It has killed half the American bald eagles in some states. (M. Johnson) 

       Cows (Kristensen), pigs (Saey 4/24), minks (Tufekci ‘23), ferrets (Belser) and cats (Chothe) all carry both human (a-2,6) and avian (a-2,3) receptors for influenza viruses. That makes them perfect mixing vessels for viral reassortment that could create a viral strain that would take H5N1 a giant step toward becoming transmissible between people. (Cushman) The National Institutes of Health (NIH) reports that a H5N1viral sample they recently tested “infected and replicated efficiently in cultured human lung cells.” It “caused lethal infection in all infected mice and ferrets” and the virus “was found not just in the respiratory tract, but in many tissues throughout the body including blood, spleen and liver.” “The [NIH] findings support those of the earlier study suggesting that HPAI H5N1 viruses from cows could potentially transmit via respiratory droplets to infect humans.” (NIH 11/05/24) The virus found in the teenager in British Columbia who recently was in critical conditions contains several mutations that would make it more likely to spread between people. (Branswell 11/24)   

            Since it first appeared in 1996 among geese in Southern China, the H5N1 virus has repeatedly mutated and reassorted growing into “a huge family tree of bird flu viruses” that according to Mia Torchetti, Director of the USDA Diagnostic Virology Laboratory “undergoes reassortment far more often than earlier relatives.” (Saey) The current viral clade 2.3.4.4b originated from a reassortment event in the Netherlands in October 2020.(Cui) That H5N1 clade and others continue to mutate and reassort, exchanging genetic material both in the United States and in other countries including the Netherlands, Egypt and South-East Asia where H5N1 is endemic (CIDRAP). At the end of 2023 there was a sudden increase in human H5N1 infections and deaths of people in Cambodia who became infected from poultry with a new variant that included the PB2 E627K mutation “that has been linked to adaption to mammals and airborne transmission.” (CIDRAP 11/24) According to scientists at the Center for Scientific Excellence for Influenza Viruses, National Research Center in Cairo, Egypt; in March 2023, 4.6% of adult workers in live bird markets in Cairo already carried post infection antibodies for H5N1. (Gomaa) They explained that “the true burden of H5 infection in humans has been underestimated as global surveillance systems tend to detect only severe cases that require hospitalization and miss asymptomatic, mild or moderate cases.” (Gomaa) That also suggests that the high mortality rate for H5N1 in humans that currently stands at 48% (Branswell 12/24) could be grossly overstated. Still, there is no denying the many reports that H5N1 mortality rates among some mammal species often approach 100%. However, mortality rates could change drastically once a resorted H5N1 variant gains the ability to transmit person-to-person.

            Indeed, every human case of H5N1 presents the potential for coinfection and reassortment with a more contagious strain of seasonal influenza that could lead to a rapid worldwide pandemic expansion of the disease. In a test in August of this year in American dairy workers in Colorado and Michigan who had worked with infected cattle, 7% tested positive for antibodies (CDC 11/07/24) of this highly pathogenic flu strain that has not yet learned how to infect human respiratory epithelial cells and become contagious. Because humans lack historic natural antibody-based immunity to this flu strain, once it does become contagious, a pandemic will soon follow. Immediate pandemic preparedness planning is urgently required, but the World Health Organization’s (WHO) and the U.S. National Institutes of Health’s (NIH) and Center for Disease Control’s (CDC) conceptualization of HPAI H5N1 therapeutic defense is copy-paper thin and not fit for purpose. The two currently recommended classes of flu antivirals that include Tamiflu (OTV) and Zofluza (BXM), together are still wholly inadequate. They are both subject to the rapid development of resistance by the virus, and therapy is usually started after the first two days of symptoms when they would have been most effective. A more robust, multidimensional therapeutic combination is required if health officials are serious about saving potentially millions of lives.      

 In 2022 there was only one confirmed human case of H5N1 influenza in the U.S. - in Colorado (CDC ‘23). There were no cases reported in 2023. (Johnson) However, between April 1 and November 15, 2024, there were 52 confirmed human cases of H5N1 in the U.S., primarily among dairy workers (Abbott) with most of the remanding cases in poultry workers who contracted it while culling chickens. There have been two idiosyncratic HPAI flu cases in two housemates in Missouri who apparently became infected from an undetermined source at the same time. Both exhibited gastrointestinal symptoms but reported no previous contact with farm animals. (Shutt, Narappil) These 52 confirmed infections obviously represent only the tip of the iceberg with numerous, less severe cases going undetected and unreported. (Len) Yet every human infection with highly pathogenic H5N1 presents the potential for coinfection with a seasonal flu strain that might result in an exchange of genetic material between the two viruses - genetic reassortment. That opens the possibility of developing a novel viral strain exhibiting altered characteristics for severity and transmissibility that could potentially ignite a deadly pandemic. Having more people infected with H5N1 increases the chance this may occur, especially during flu season when seasonal flu is circulating.   

Since 1997 when H5N1 first infected a few people who had direct contact with chickens in China, the historic human mortality rate for those confirmed and treated for H5N1 avian influenza has averaged 52%. (A. Johnson, WHO) More recently the virus has killed close to 100% of some mammal groups it has infected including sea lions in Argentina (Plaza) and mice and ferrets purposefully infected in lab experiments (Eisfeld, Gu). Thus, it is impossible to predict what level the human mortality rate will be once the eventual pandemic triggering variant finally reassorts and jumps the species barrier to cause human-to-human transmission as most scientists predict it eventually will. Indeed, this virus has genetically reassorted dozens of times since 1997 and the variant currently circulating in the U.S. is designated HPAI H5N1 clade 2.3.4.4b genotype B3.13. Like SARS-CoV-2 (SARS-2) during the Covid-19 pandemic, B3.13 will continue to mutate and reassort, perhaps becoming less or more deadly each time it does. Like a Rubric’s cube, each time the virus changes, it stands to resolve itself to become one of the worst pandemic catastrophes in human history. What is so frightening is that H5N1 does not just infect the human respiratory system. Like SARS-2 it infects the body systemically, affecting all organ systems, but the highest viral replication rates are in respiratory tissue. (Schnirring) Worse, as a neurotropic virus it infects the central nervous system and the brain resulting in encephalitis as a major cause of death among the mammals it infects. (Mirolo, Sillman) Influenza-related, often deadly encephalitis can develop quite quickly, within one day of symptoms appearing. (Morishima, Kawada) It behooves national and international health officials to take this pandemic threat more seriously than they did Covid-19. They should not ignore the last three decades of research on how to treat respiratory viruses with broad-spectrum antivirals, and how to suppress the intense immune reactions viruses engender, as they did during the Covid pandemic.  Medical journal articles referenced here detail how simple existing medications can be highly effective against these killer diseases. H5N1 HPAI has the potential to be an order of magnitude more deadly than Covid-19. Developing and testing a truly effective first-line combination therapeutic strategy that can be used from day one of infection is an immediate imperative.      

            The California Department of Food and Agriculture confirmed its first case of H5N1 avian influenza in three dairy herds in the Central Valley on August 29^th, 2024. (Molteni) They confirmed the first infected dairy worker there five weeks later, on October 3^rd (Bluth). Since it was first detected in a Texas dairy herd in March 2024, as of the end of October the epidemic has spread to over 387 dairy farms in fourteen states and over 1,195 commercial poultry farms in 48 states. (Wen) Within one month, confirmed human cases in dairy workers in California rose from one to 36. With 1.7 million dairy cows in California and 17,500 low paid dairy workers, (Gutierrez) these mostly undocumented immigrants (Rust) have little incentive to test for a virus that might cause them to miss valuable days from work. Given the relatively mild symptoms many infected dairy workers have experienced, primarily conjunctivitis, (CDC 10/18/24) most have failed to report their symptoms, in part to avoid contact with state or national authorities that may complicate their employment or residency situation. This creates a dangerous situation when workers fail to get vaccinated against seasonal flu. That increases the chance a worker might become co-infected with both avian and seasonal flu and genetic reassortment would occur with two flu strains exchanging genetic material. When H5N1finally does become easily transmissible, it will cause a flu pandemic that will spread worldwide as fast as Covid-19 did in 2020. In a recent report from virologists at the University of Wisconsin, H5N1 already has mutated to be able to spread among mammals more easily. In an experiment with ferrets that provides a close model of the human respiratory system, the virus transmitted through the air between ferrets held in close but separated cages. (Cushman, CDC 10/28/24)  

            Meanwhile, dairy cows are dying by the thousands in California. Despite earlier news articles that failed to report the extent of death among dairy herds, the CEO of the Western United Dairies trade association, Anja Raudabaugh admitted that up to fifteen per cent of cows had died on many infected farms. (Gutierrez) Raudabaugh explained that on some farms “animals are dying in droves.” (Rust) One dairy lost almost half its cows. Surprisingly, “the mortality rate among H5N1 dairy cows has been much higher than anticipated” and “most of the animals that are succumbing are young”. (Rust) Cows that do survive infection produce milk at much reduced quantities. (Burrough) That damage to the dairy industry had been incurred in only eight weeks since H5N1 was first detected in California. It will surely affect the price of milk, just as it has already affected egg prices over the past two years. No one can guarantee that the unmedicated, unvaccinated, eventual human mortality rate will be any lower than those in other mammal species. That alarming fact demands that responsible government agencies should plan for the worst now – and especially educate themselves about safe, affordable, effective therapies that can be used from day one to save lives.     

            One recent discovery about the current H5N1 2.3.4.4b B3.13 variant is that it seems to have “an affinity for mammary tissue.” (Rust) Researcher Yoshihiro Kawaoka of the University of Wisconsin reports that this H5N1 clade is found in the mammary glands of mice even when they are not lactating, and it can be passed on to suckling mice pups. (Mandavilli 5/24/24) Recently it was discovered that cow udders have receptors for both human and avian influenza. (Kristensen) The NIH states “This suggests that the virus could infect cells in the human upper respiratory tract.” (NIH 07/23/24)    

Even more troubling than the report from Missouri concerning the two housemates who were infected from an unknown source, after more than a quarter century of advanced warnings that a deadly H5N1 pandemic was looming on the horizon, the officially approved approach to therapeutic intervention for saving lives of people who become infected is no more scientifically enlightened than it was when the SARS-2 pandemic suddenly emerged in late 2019, or even when the 1957 or 1918 flu pandemics struck. The frequently resuscitated official mantra “There is no treatment. There is no cure.” is no longer a good enough excuse for the inaction of health officials and their failure to acknowledge effective early therapeutic strategies. The nation faces a probable pandemic that some scientists project could kill hundreds of millions worldwide, with a proportionate death toll of many millions in the U.S. H5N1 HPAI threatens to be the gravest human plague in 650 years, since the Black Death or at least since the Spanish flu of 1918 killed 675,000 Americans (Johnson) and an estimated 50 to 100 million worldwide (Johnson). It will be the worst unless it mutates to be less lethal. That is a possibility. Of course, after that, it also could reassort again to be highly lethal again. However, even tamer influenza strains like H1N1 or H3N2 quickly become resistant to the grossly inadequate antiviral therapies the CDC claims is all they offer to protect the public’s health. The drugs Tamiflu (Jarhult) and Zofluza (Jones) directly target the virus itself, but they rapidly become completely ineffective if people delay more than a few days seeing a physician to get a prescription and begin treatment. The current, anti-flu, viral-targeted medical paradigm reflects the monumental failure of health officials to consider how H5N1 HPAI kills. They ignore what the broader scientific community suggests in numerous medical journal articles as a more effective treatment strategy against influenza. The current, status quo anti-influenza medical armamentarium offered by health officials represents a pyrrhic victory of myopic virologists over visionary immunologists who recognize it is the dysregulated, out-of-control immune system, not the virus itself that kills. (    ) What has been predicted to be perhaps the greatest pandemic challenge of all time may end up being the greatest medical trainwreck ever witnessed unless current approaches to influenza therapeutics are radically reconceptualized and the existing threadbare medical paradigm jettisoned. The therapeutic defense strategy against influenza needs to be rationally redirected to treat the disease itself, especially preventing and treating the cytokine storm, instead of merely trying to treat the initial cause of the disease – the virus. In most cases, viral replication that peaks between 48 and 72 hours after infection (Pulit-Penaloza) is beginning to decline by the time antiviral drugs are applied. By then the viral horse is already out of the barn after already igniting a cytokine storm that began brewing the first day of infection. Unlike in most strains of flu, the immune system based hypercytokineamia storm in H5N1 affects all bodily systems. That is what kills. Suppressing and containing that deadly explosion of immune system factors from day one is how to save lives from highly pathogenic avian influenza and other respiratory disease such as those caused by SARS-1 and SARS-2.        

If the coming H5N1 pandemic turns out to be even nearly as lethal as H5N1 has proved to be in the past, killing over half the people it infects, tens of millions of American lives are endangered. The current NIH/CDC defense plan consisting of Tamiflu (oseltamivir, or OTV) plus Zofluza (Baloxavir marboxil, or BXM) is a one-and-a-half-dimensional therapeutic strategy designed to fight a five-dimensional respiratory disease. The NIH/CDC therapeutic plan would never pass muster at the U.S. Department of Defense. It is comparable to trying to fight a world war with only one type of weapon – and a rusty one at that. The NIH and CDC ignore the last three decades of immunological research that has gradually discovered broad-spectrum anti-viral drugs, many of them repurposed from their original use. They also ignore an anti-viral drug that is significantly superior to either OTV or BXM in treating both influenza A and B. Unlike those two currently recommended specifically targeted anti-flu drugs, the broad-spectrum antiviral non-steroidal anti-inflammatory drug (NSAID) naproxen does not cause the virus to develop resistance. That is because unlike OTV or BXM, naproxen targets a part of the virus that does not change. The current, officially announced defensive strategy against influenza ignores addressing what really kills a person - the immune system generated cytokine storm that induces sepsis and multiorgan failure - not the virus. The official anti-flu play-plan is a medical paradigm built of straw, ill-designed to protect the American population against what may prove to be the most lethal version of the disease that medical historians say has caused more pandemics than any other in human history – influenza. Although useful as a component of a more multifaceted combination therapy approach, alone OTV/BXM is an outmoded, resistance generating, flimsy defense against a virus that may turn out to be ten to fifty times as lethal as SARS-CoV-2 (SARS-2). The NIH/CDC recommended antiviral dual therapy is roughly equivalent to the effectiveness of HIV antiviral combination therapies in 1990, prior to the introduction of life-saving protease inhibitors. That current, scientifically threadbare strategy is a sorry excuse for what once was known as American know how. It is like a house constructed with only one wall - potentially endangering the life of every American. Thus, it is past time for a serious, scientifically based reappraisal and upgrade to the national health strategic defense plan against H5N1 highly pathogenic avian influenza. Part 1 of this essay proposes a significantly improved therapeutic response to initial infection. It is a defensive strategy composed of five components, not just the weakest two as currently presented by health officials.           

This essay proposes a significantly stronger five-part therapeutic strategy governments and physicians can institute to reduce H5N1 morbidity and mortality. It explains what they should be aware of as the world eventually moves into this decades-long anticipated pandemic, probably sometime during the next two years. Part 1 suggests therapies that in addition to vaccination, can be used prophylactically to reduce the chance of infection or serious disease. It proposes early therapies that will help prevent disease progression. If implemented correctly, will prevent the need for most hospitalizations. Part 2 will review additional approaches to buttress the current official anti-influenza medical paradigm that provides only a weak layer of protection.

No one can accurately predict when the dam of HPAI contagion that has already affected dozens of other mammal species will transcend the species barrier into human transmissibility. Although it is obviously important to treat the cause of this disease directly with antiviral drugs, it is far more important to retard, prevent and suppress the resulting immunological conflagration of the cytokine storm, sepsis, and multiorgan-failure that follows initial infection. This can be accomplished with well-chosen, appropriate, immunomodulators and anti-inflammatories. Within a week after the virus strikes the proverbial match igniting inflammation, fever, chills, fatigue, frequently pneumonia and sometimes encephalitis, viral replication itself has mostly subsided. (    ) Thus, physicians must know how to effectively suppress the cytokine and chemokine drivers that result in the hypercytokineamic cytokine storm that triggers sepsis, multiorgan failure and death. If the safe, affordable, easy to understand recommendations presented here are implemented, mortality rates from the eventual H5N1 pandemic could conceivably be reduced 80% to 90%. Morbidity and the incidence of post avian influenza syndrome (PAIS) will be significantly reduced. It should be noted that the neurological manifestations of this B3.13 variant in mammals are quite severe, including seizures, blindness, encephalitis and death. (Eisfeld) As with so many other diseases, immediate early therapy for H5N1 will be the best therapy. Given the threat of encephalitis and early onset pneumonia, the earlier the therapy begins, the better. America cannot allow what happened with SARS-2 to occur again. Then health officials claimed no effective early therapies existed. In fact, those therapies did exist and are described in this essay.      

An updated H5N1 vaccine for B3.13 will take time to develop, test, approve, and distribute. Many Americans will remain skeptical of vaccination until they realize the frequently deadly consequences of their ill-founded fear. Although flu vaccines provide great benefit, they are never 100% effective in preventing infection. However, they are excellent in reducing mortality rates, the incidence of severe illness, the chances of long H5N1 syndrome – PAIS - and blindness. Vaccines are especially critical due to the potentially severe effects on the central nervous system and brain caused by the 2.3.4.4b clade. Scientists at the NIH estimate that up to 50% of the world’s population can be infected in the first year of an influenza pandemic (Taubenberger), especially by H5N1 that exhibits a much higher rate of replication than other flu viruses (Li) and a high viral load (de Jong) and therefore is likely to be extremely transmissible. With a normal distribution lead time of eight  months, tens of millions of Americans could be infected before they are able to receive an initial vaccination. Thus, there must be a backup Plan B to the currently underpowered medical scheme to defend against H5N1, both prophylactically and therapeutically. This essay presents Plan B. It does not replace the current plan for pandemic preparedness but instead complements it with science-based, effective therapies to meet the challenge of this new pandemic age. Instead of offering only a one or two wall protective strategy, it offers five complementary mechanisms of defense. In any war, five lines of defense are always superior to just two somewhat deficient ones.   

            It is sobering to recall that medical workers – physicians, nurses and others – are always among the first and hardest hit occupations in any new lethal pandemic. Healthcare workers and all Americans need to know what therapies can help save their lives once this virus finally jumps the species barrier. Immediate early therapy is essential the first day an infection is recognized. It should be started the moment the telltale symptoms of a sudden spike in fever and fatigue or other symptoms are recognized. To achieve that goal of early therapy the public should be instructed to assemble a home influenza first aid kit of safe, approved, effective antiviral medicines including aspirin, selenium, and naproxen that can be used even before a physician’s appointment can be made. The cost of this home flu first aid kit would be about $25 per person. Particularly because how rapidly H5N1 replicates and the early neurological damage it can cause, every hour’s delay in beginning to suppress that exponential escalation of viral replication that eventually triggers the deadly cytokine storm is critical. Delaying hours or days before seeing a physician to get a prescription for the additional benefit of OTV/BXM could be fatal, result in blindness or long-H5N1 syndrome. If one does have the flu, a physician should be consulted as soon as possible but delays invariably occur. With HPAI H5N1 that can result in serious illness, the intensive care unit, the need for ventilation, or death. 

            The U.S. and the world cannot afford to repeat the fatal mistakes made with the Covid-19 pandemic when health officials denied that potential effective early therapies existed to treat that disease. Taking early effective treatments against Covid-19 could have reduced the need for hospitalization and suppressed the onset of the cytokine storm, sepsis and the need for ventilation. Those early treatments existed but were ignored by medical officials so were not used. The nation’s medical establishment cannot afford to be so cavalier or elitist in its approach to therapeutics this time. Physicians need to use what works based on an understanding of science, not medico-scientific procrastination or science denialism. Thus, public health officials should begin to establish a plan to instruct the public how to assemble and use a SAN influenza first aid kit containing a bottle of selenium, a bottle of aspirin, a bottle of naproxen, plus safety instructions. We must learn from our previous mistakes that cost far too many thousand excess deaths during the Covid-19 pandemic. Those who fail to learn from recent history are doomed to repeat it. Perhaps this time with many more casualties.          

Part one of this essay considers the utility of safe and effective prophylactic drugs to reduce the chance of infection, the need to institute infectious first aid and early therapy, and the possibility of delaying disease progression, serious illness, and long H5N1 syndrome - PAIS. Part 2 discusses the later stage of the disease and additional pharmaceutical interventions physicians can use clinically to further reduce morbidity and mortality in seriously ill patients.                     

2.      The characteristics and epidemiology of H5N1 highly pathogenic avian influenza (HPAI).

            The H5N1 flu virus is extremely lethal. In the past two decades almost a thousand people worldwide have been confirmed infected with H5N1. (A. Johnson) But now after the virus has infected so many mammal species the rate of human infections is beginning to increase significantly, at least in the United States. Historic H5N1 influenza mortality rates have been calculated at 52%. (A. Johnson) That is comparable to the Ebola-Zaire virus. Like Ebola-Zaire, H5N1 has a remarkably rapid replication rate. (Korteweg) Comparing the reported mortality rates, I estimate the recent 52% mortality rate for H5N1 is forty times as deadly as SARS-CoV-2 (SARS-2, Covid-19), and more than twenty times as lethal as the 1918-20 H1N1 Spanish flu that was estimated at a 2% case fatality rate. (Starko) The Spanish flu killed an estimated 675,000 Americans out of a population of 106 million (Beach) and between 50 and 100 million worldwide with mortality rates in some countries of between 5% and 10% of the entire population. (Johnson N.) People can only hope past H5N1 virulence and mortality rates will moderate and evolve after human-to-human transmission commences, as often is the case with contagious viral disease. There is a chance that may already have occurred because of the several dozen confirmed infections in the U.S. As of October 2024, none of the 54 confirmed patients have died yet. However, that may be due to a different means of transmission. Once it establishes human-to-human transmissibility, that could change entirely.   

            As with the SARS-2 corona virus that has transmuted through many variants with differing disease characteristics, other RNA viruses including H5N1 influenza also mutate rapidly. Flu viruses change via two different processes. First, they change gradually through point mutations that occur continuously, each time a virus replicates. As an RNA virus, influenza A virus (IAV) lacks the genetic proofreading ability DNA virus-based copying has. Because it cannot correct the mistakes H5N1 makes each time it copies its genes, IAV incorporates those mistakes as mutations. Unlike less common but highly stable DNA viruses, RNA viruses exhibit antigenic drift as point mutations accrue though repeated replication. As a second mechanism of change, flu viruses also occasionally undergo a more dramatic antigenic shift, or reassortment. That occurs when two different strains of influenza occasionally infect the same cell allowing the two strains to exchange segments of RNA genetic material with each other. Then they change more drastically, shuffling their genetic makeup like a pack of cards, creating wholly different variants or clades of the virus. In antigenic shift or reassortment, viruses trade whole sections of viral genomes causing a major shift in their genetic makeup creating a new flu strain with different disease characteristics. That frequently happened with SARS-CoV-2 in Covid-19, but scientists say H5N1 engages more readily in reassortment than most flu viruses.    

             According to the CDC, “Since 2005 HPAI A (H5N1) viruses have undergone extensive genetic diversification including the formation of hundreds of genotypes following reassortment with other avian influenza A viruses.” Clade 2.3.4.4b first appeared in the U.S. in late 2021, imported by birds that flew from Northern Europe. (CDC ‘23) These numerous mutations may or may not have influenced how lethal the current clade or strain is. Although the virus has apparently gained the ability to transmit between some mammals such as ferrets (Gu) and sea lions, (Plaza) until a mutation or genetic shift affects the HA hemagglutinin gene that controls the ability of the virus to easily enter human cells in the upper respiratory track, human to human transmission will not become common. (CDC ‘23) However, since the virus has gained this function in some mammal species it may be getting closer to doing so among humans too. The more people H5N1 infects, the more chances it has to gain this capability, especially if it infects someone who already is infected with another flu strain like H1N1 and genetic reassortment occurs. The reassortment could happen much more easily in swine or ferrets that carry receptors for both avian and human influenza. Potentially that might even be possible with cows, but that has not been determined yet.        

            H5N1 was first detected in Southern China in geese in 1996 and in people there in 1997. (Greger) Now endemic in bird species worldwide, it has infected over 200 mammalian species, (CDC) killing up to 90% of some animal colonies - for instance over 17,000 sea lions and elephant seals in South America. (Johnson) Recently the virus has shown the ability to transmit mammal-to-mammal in minks, ferrets, and sea lions, indicating it may be coming closer to mutating to being able to transmit between people because ferret lungs are quite similar to human lungs.(Belser) Virologists and epidemiologists have long anticipated this final adaptation and agree it is almost inevitable H5N1 will eventually reassort to allow human transmission as it has among some mammals. Yet no one can predict exactly how soon that may happen - or if the virus might mutate to become less lethal in humans when it does so - or may already have done so. Due to its rapid replication rate and resultant higher viral load, epidemiologists expect transmission rates to be high once it does finally jump the species barrier into humans. Flu strains that are designated either H5 or H7 are considered highly pathogenic or highly lethal compared to strains that carry an H number different from 5 or 7.         

            Since early 2024, H5N1 has been confirmed in over 500 dairy herds in fifteen U.S. states. This number is increasing rapidly. (CDC 10/24) Cow-to-cow transmission has occurred through use of milking machinery and the interstate transport of infected livestock. More than 20% of milk on U.S. grocery shelves currently contain noninfectious H5N1 viral particles (Anthers) indicating the H5N1 epidemic among U.S. dairy herds is more widespread than currently detected. Most milk remains safe to drink because it has been pasteurized but it is not safe if it has not been. Most U.S. states allow the sale of unpasteurized milk. Given the immediate danger of a pandemic and knowing how one might start, it would be wise to pass a national law banning the sale of raw unpasteurized milk. Otherwise, Murphy’s Law that explains “what can go wrong will go wrong” will come back to haunt us.

Initially, H5N1 may have jumped the species barrier into cattle from feces from the natural host of the virus, waterfowl, who contaminated their grazing pasture, silage, or water. Although over half of dairy cattle survive the infection, some develop severe symptoms quickly and must be put down within three days. (Halwe) Drinking unprocessed milk from infected cows kills mice and barn cats within a few days so it would probably sicken people as well – or worse. (Mandavilli 5/24) Widespread human consumption of commercially available unpasteurized milk in the U.S. could spark an outbreak that would endanger national and world health.

Another possible source of transmission to people are wet animal markets in U.S. cities that slaughter and sell chickens, ducks, and geese – all potential carriers - along with other small and larger animals. New York City alone has seventy such storefront markets, often in residential neighborhoods. Over a dozen of these businesses have been closed after testing positive for bird flu, but after cleaning they were allowed to reopen. (Mandavilli 9/24) H5N1 may be even more widespread in India. An Australian child recently returned from there with the disease. (Johnson) The first young person in Canada was reported severely ill with H5N1 in early November. They had no contact with animals except for domestic pets, - cats and dogs. Cats are easily infected by H5N1 when they eat infected birds and there have been many reports of cats dying of Avian flu worldwide – some that feed on infected chickens. Pet cats may become a vector leading to more human infections – perhaps through their feces - for example in kitty litter.       

            Since April 1st, 2024, over forty dairy workers have been infected (Branswell 12/24) by handling milking machinery and diseased cows whose udders and milk concentrate the virus (Halwe). Many have been infected by milk splashing in their eyes or by touching their eyes with milk residue on their hands. The conjunctiva of the eye includes receptors that allow for flu infection. (Olofsson) Due to the uncharacteristic, non-respiratory route of infection, some dairy workers apparently only suffered conjunctivitis, red eye, but some have also developed respiratory symptoms. Nine additional farm workers have been infected after culling chickens as poultry farmers try to slow the spread of the disease and the resulting economic damage to their industry. The American poultry industry has been hit hard. Over 92 million fowl have been destroyed in forty-eight states since 2022 (Johnson), raising the price of eggs. No one has died yet, perhaps due to the unusual routes of transmission, or perhaps the virus has mutated to be less virulent. Humanity may soon discover exactly how lethal this virus remains or can reassort to become.

            Health news correspondents report that the National Institutes of Health (NIH) and the Center for Disease Control (CDC) assure them there is nothing for the public to worry about until the virus develops the ability to transmit between humans. However, once it does, scientists say nothing can be done to avoid an almost immediate pandemic. Developing, producing, and distributing a vaccine widely will take six to eight months. The U.S. Biomedical Advanced Research and Development Authority (BARDA) has developed several candidate vaccines based on the current H5N1 molecular structure and has 4.8 million doses stored in the Department of Health and Human Services’ National Pre-Pandemic Influenza Vaccine Stockpile. However, those vaccines are not an exact fit for the new Missouri variant that includes two new mutations. (Branswell) Yet those would still be better than nothing. Even when vaccines work perfectly, they mostly protect from severe disease and death. They do not always protect a person from getting infected by or from spreading a virus. Unfortunately, as with Covid-19, by the time enough vaccine can be produced and distributed the virus may have swept twice around the globe, infected one or two billion people, and mutated and reassorted with other flu viruses innumerable times. Normally flu vaccines contain three flu strain inoculants. Today it would be wise to add the current variant of H5N1 into the next vaccine formula that goes into production.      

3.      What are the disease characteristics of highly pathogenic avian influenza?

            H5N1 has a short incubation period of as little as one day and is transmissible within hours, before symptoms appear. (    ) Viral replication peaks about 48 hours after initial infection and then declines rapidly, completely tapering off by day 8 or 10 of infection. Thus, the window for effective antiviral intervention is extremely short. However, by the time most people see a physician to get a prescription, Tamiflu is only marginally effective. Avian influenza causes typical flu symptoms including fever, cough, congestion, fatigue, headache, aches and pains, sore throat, lack of appetite, chills and sweats, and difficulty breathing. Sometimes it also exhibits gastrointestinal symptoms including vomiting and diarrhea. Some develop pneumonia quickly, within several days – faster than with regular flu. Central nervous system symptoms may also occur with encephalitis, blindness or shaking. By increasing platelet aggregation, H5N1 causes micro-clotting in the lungs, and hypoxia by reducing oxygen transfer to the blood. Common seasonal influenza primarily affects the pulmonary or respiratory system. However, like SARS-2, H5N1 also directly affects other organ systems. Those include the intestines, kidneys, liver, spleen, lymphatic system, central nervous system, and the brain. (de Jong, Zhou)

            Again, as with Covid-19, a key aspect of H5N1 infection is a highly dysregulated immune system. Lung infection may result in acute lung injury (ALI). Six to eight days after infection this may lead to acute respiratory distress syndrome (ARDS). ARDS both causes and is caused by the cytokine storm that contributes to widespread cell death. (Hojyo, Bhatia) Apoptotic and necrotic cell death release internal cellular toxins into the blood circulation, damaging tissues and organs, especially the kidneys. Those toxins intensify the positive feedback loop of ever increasing proinflammatory cytokine release and cell damage. The resulting hyper-generation of dysregulated cellular messenger signaling including both cytokine-influenced inflammation and chemokine attraction of macrophages and neutrophils to the scene of infection in the lungs, expands from a localized to a systemic challenge after it enters the circulatory system. This cytokine storm or hypercytokineamia often results in sepsis or septic shock. Widespread cell death damages vital organs leading to multiorgan-failure and death. Even when using the current standard of care therapy, mortality frequently occurs ten to twelve days after initial flu symptoms appear. (    ) Tamiflu and Zofluza are not highly effective when patients are not treated within 48 hours or at maximum four days after initial symptoms. Unfortunately, many patients do not get to the hospital or clinic in time for that. Waiting to start treatment more than 48 hours after symptoms commence may frequently result in mortality. With H5N1 HPAI, time is of the essence.        

4.      How does the H5N1 influenza-A virus (IAV) kill? Does the virus kill directly, or does the overactive immune response to viral infection kill a person?

            As one author succinctly explained, “much of the morbidity and mortality associated with influenza infection can be attributed to an over exuberant immune response leading to excessive production of cytokines and excessive inflammation” (Carey) That describes the cytokine storm, technically called hypercytokineamia.

            By the time a person dies from H5N1 infection, the virus is often found only at extremely low levels or even not at all in the body, yet the damaging hyperactive immune response continues unabated even after the virus has subsided or been cleared. (    ) Thus, it is obvious that the uncontrolled overreaction of the immune system with its hyperinflammatory cytokine storm that leads to sepsis and multi-organ-failure are the real killers. That hyper-oxidative pro-inflammatory immune overreaction and the resulting spillage of toxins from inside dying cells damages the body’s organs to the point of failure. Mortality ensues. Unlike with most other viral cytokine storms, H5N1’s ability to attack the nervous system and brain adds an additional battle front that must be faced in the fight against avian flu compared to Covid-19. Thus encephalitis, pneumonia, and kidney, liver and heart failure are all common causes of death from H5N1.   

            Immune dysregulation is a complex phenomenon, far too detailed to explain in Part 1 of this essay. However, the final downward spiral of the cytokine storm, sepsis, multiorgan-failure and death follow an almost identical path in the end stage of AIDS, Ebola, SARS-1, SARS-2/Covid-19, H5N1 and most lethal viral diseases. Since this cytokine storm pathway is similar in all these deadly viral infections, preventing, delaying, or even reversing this fatal trajectory frequently can be accomplished by applying the same strategy, skillfully combining anti-inflammatory drugs with immunomodulating therapies. Restoring the body’s prooxidant/ antioxidant homeostasis and correcting immune dysregulation with high dose selenium supplements has proved successful in pulling many patients out of the steep dive towards sepsis driven mortality the above mentioned deadly viral infections cause. This was clearly demonstrated in Ebola-Zaire patients in Monrovia, Liberia in 2014. (personal observation)

A keen observer of the improving scientific understanding of the cytokine storm and disease pathogenesis over several decades of global viral pandemics and epidemics would have noticed that attendant to the downward spiral of immune factors and physical health is a parallel steep decline in bodily selenium levels caused by the depletion of this essential trace element due to increasing viral replication. Just as every cell in the human body requires selenium, most viruses also need selenium. That is because those viruses genetically encode selenium containing proteins that form part of their outer envelope protective sheafing. If health officials ignore this underlying, parallel molecular phenomenon that rapidly causes a severe nutritional deficiency of selenium, they ignore a fundamental clue pointing towards an improved paradigm for solving the challenge of severe viral disease. If health experts fail to more closely examine and appreciate some of the most powerfully influential immunological factors hidden in plain sight, they are unlikely to learn from that costly mistake. If that continues, their strategic failure in the war against viral and respiratory disease will end up unnecessarily costing millions more lives in the approaching H5N1 pandemic, not only in the U.S. but worldwide. Ignoring that the replication of many, especially enveloped RNA viruses cause rapid and severe selenium depletion ignores a gigantic piece of the puzzle laying at the heart of the riddle of how to cut the Gordian Knott of overcoming the global challenge of viral pandemics that are emerging at an ever-faster pace. But selenium depletion through viral replication is only one critical although mostly unrecognized process at the heart of a hundred-piece immunological puzzle.

5.      What are the current recommended treatments for influenza?  

            Currently there are three classes of drugs that were specifically developed to treat influenza. The first category of anti-influenza drugs is adamantane derivatives including rimantadine and amantadine. They inhibit the viral M2 ion channel that assists in viral entry into cells. Influenza strains have become almost completely resistant to this class of antiviral drug. M2 ion channel inhibitors also have more adverse side effects than the second class of anti-flu drugs. Thus, health officials no longer recommend M2 ion channel inhibitors (M2Is) because today they are 99% ineffective against flu.

            First approved in 1999, the second class of antivirals specifically developed against the influenza A virus (IAV) are neuraminidase inhibitors (NIs). They inhibit the NA gene of IAV and include oseltamivir (OTV), commercially sold as Tamiflu or Relenza, as well as peramivir and zanamivir. For it to be effective, a patient must start Tamiflu treatment within 48 hours after symptoms develop. Then it can only be used for five days. Started later than 48 hours after symptoms appear, the drug rapidly loses effectiveness because flu replication declines naturally, and it has already lit the immune system fire.

            Unfortunately, even less virulent strains like the now tame H1N1 seasonal flu virus also rapidly develop resistance to neuraminidase inhibitors like OTV/Tamiflu. Although oseltamivir has proved moderately effective in treating many flu cases, frequently the virus becomes resistant to the drug within five days, even when started within 48 hours of symptoms appearing. That combination of ineffectiveness and rapid development of viral resistance is why many respected scientists claim Tamiflu does not work. In a pandemic situation when resistant virus is passed from person to person, within one month, Tamiflu would likely be almost completely useless as monotherapy against H5N1, despite it currently being described in medical journals as the standard of care. Population-wide development of resistance to Tamiflu was seen in the 2009 pandemic of H3N2 flu when after six months 90% of viruses were resistant. (Jefferson) Although the U.S. government has a stockpile of tens of millions of courses of Tamiflu, those years old stocks may not be as effective as they once were. Even if Tamiflu was newly manufactured, H5N1 would quickly become resistant. It only takes one common mutation to make flu viruses OTV resistant.

Even before it was first approved in 1999, many scientists questioned oseltamivir’s effectiveness. However commercial interests and the lack of alternatives prevailed over the limited, questionable scientific evidence and the objections of many regulatory experts to its approval. Once the FDA approved it, the WHO and many governments established massive stockpiles. (Cohen) Those Tamiflu stockpiles remain. Yet oseltamivir’s inadequacy to meet the exigencies of a potential world population threatening flu pandemic lingers on menacingly. Unfortunately, a decades old therapeutic white elephant - the biggest pharmaceutical-commercial boondoggle since AZT - will soon come home to roost. Oseltamivir/OTV/Tamiflu is the only drug the NIH, CDC, and various state departments of health publicly promote as providing a shield to protect the public against highly pathogenic avian influenza. It is the proverbial promise of false hope posed against a looming tsunami-like HPAI pandemic when an ultra-pathogenic-strength pharmaceutical antiviral safety-net is urgently needed but is so sorely lacking. The question is – how can scientists weave a safe and effective therapeutic safety-net to protect lives from recurring respiratory disease pandemics?  H5N1 will not be the last respiratory pandemic in our time. That is guaranteed.      

             An article in the British Medical Journal reviewed the results of the 2014 Cochrane Database Systemic Review of oseltamivir and concluded:

            “Given that oseltamivir is now recommended as an essential medicine for the treatment of seriously ill patients or those in higher risk groups with pandemic influenza, the issues of mode of action, lack of sizable benefits, and toxicity are of concern. This is made worse by the record and stated intentions of governments to distribute oseltamivir to healthy people to prevent complications and interrupt transmission on the basis of a published evidence base that has been affected by reporting bias, ghost authorships, and poor methods.

            We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion in the WHO list of essential drugs and its use in clinical practice as an anti-influenza drug.” (Jefferson)

            However, when health authorities have nothing else, they use what they have, even if it is only marginally effective, does not work for long, and like oseltamivir, it occasionally causes dangerous neuropsychiatric adverse effects. (Jefferson)    

            Due to its obvious inadequacies as an antiviral drug, the approval of oseltamivir by the FDA in 1999 was highly contentious from the start. (Cohen) To call Tamiflu the standard of care for influenza verges on the oxymoronic. It only emphasizes the current, almost empty shelf in the medical armamentarium of the global defense against one of humanity’s greatest historic killer diseases. The vacant storehouse of knowledge concerning effective approaches to treating respiratory viral disease is due to an official therapeutic failure of concept that has focused on using specific, virus-targeted medicines against a rapidly mutating moving viral target. As with Covid-19, the viral strategic defense plan is profit and new-drug-research driven instead of focused on protecting the public’s health. That failing, virus-focused paradigm dangerously ignores safe, long-lasting, effective, broad-spectrum antiviral medications, against which the virus cannot develop resistance. The continual effectiveness of broad-spectrum antivirals is based on the fact they target human cellular proteins and immune system pathways that are not subject to viral mutation. Even gene-shuffling IAV cannot become resistant to a barrage of several classes of broad-spectrum antiviral drugs used in combination against cellular targets. Many scientists have highlighted the official failure to focus on the real cause of flu-related death, the cytokine storm. That begs the question. Why do health authorities fail to utilize broad-spectrum antiviral drugs against viruses when they do use broad-spectrum antibacterial drugs against bacteria, even though those drugs are subject to the development of bacterial resistance? Why use one broad-spectrum therapeutic approach but totally ignore another? Is Tamiflu the medical standard of care, or has it become the standard of not caring – health officials refusing to think outside the specific antiviral drug box? There certainly are many safe, approved, effective pharmaceutical drugs ready for repurposing as the H5N1 pandemic approaches ever closer. Others are reviewed in Part 2 of this essay.

            Fortunately, a third specific class of anti-influenza drug has been developed and was approved by the FDA in October 2018. This newer drug is baloxavir marboxil or BXM, sold as Zofluza by Genentech. BXM/Zofluza works by inhibiting the influenza cap-dependent endonuclease (CEN) and is effective against both influenza A and B. BXM works similar to how integrase inhibitors work against HIV. (Dufrasne)

            BXM is even more effective against influenza than NIs like oseltamivir because BXM reduces the level of proinflammatory cytokines such as interleukin-6 (IL-6) and gamma interferon (INF-g) in the lungs. BXM also reduces the number of inflammatory macrophages and neutrophil cells in the lungs, limiting lung damage. Older NIs do not provide that benefit. BXM reduces the time it takes to end flu-related fever, hours faster than oseltamivir. And it is effective against NI resistant viruses. (Dufrasne) Another benefit BXM has is a long half-life. It can be used as a single, one-time dose. BXM reduces influenza viral load more than NIs like OTV/Tamiflu. Should BXM be considered the new standard of care against influenza? Overall, it is superior to the previous NI Tamiflu standard of care. Just one problem remains. Viral Resistance. (Dufrasne)

            As with M2Is and NIs before them, because BXM targets a continually changing viral enzyme, Zofluza is subject to the rapidly mutating IAV becoming resistant to it. That is because influenza is so highly mutable. Every time it replicates it changes ever so slightly, and it only takes one specific, common mutation for the virus to become resistant to BXM. Only one common mutation is needed for resistance to develop against BMX, so resistance can develop quite rapidly. (Ikematsu) In some clinical trials flu viruses develop resistant resistance to BXM at between 9.7% in adults (Hayden) and 23.4% in children within one week. (Omoto)    When that happens it soon makes the drug totally ineffective. As one scientist warned, “resistances could arise in the future if BXM is too extensively prescribed, especially without limiting its use to the most fragile patients.” (Dufrasne) Once H5N1 also becomes resistant to BXM that would leave most people totally unprotected from an eventual rampaging flu pandemic.    

            Like Ebola-Zaire, H5N1 replicates at an extremely high rate, more rapidly than other IAV strains. That contributes to its greater virulence, pathogenicity, and lethality, and suggests H5N1 may become resistant to both NIs and BXM faster than other flu strains do. As many knowledgeable scientists recognize, Tamiflu, the “standard of care”, simply does not work - at least not for long on a population basis. That is true with BXM too. Drugs targeting the highly mutable IAV do not stand the test of time, or of a pandemic. If health officials really want to help Americans survive the approaching H5N1 super-pandemic, they need to shift their antiviral strategy. Too many lives are on the line to continue depending on the current logical fallacy that relies solely on specific viral targeted drugs that quickly become worthless yet ignore durable broad-spectrum antivirals that target cellular factors. The current therapeutic, virus target-focused strategy is destined to fail miserably once H5N1 becomes transmissible. That is no way to win a war against any viral disease. That is like fighting a two-front war on only the less defensible specific drug front while completely ignoring the more defensible broad-spectrum antiviral battlefront. Continuing to follow that blinded, vacuous strategic antiviral defense plan will surely end in national and international pandemic catastrophe, adding to even more public distrust of government and the international health system. Who will people blame? Politicians, health officials, the pharmaceutical industry, the medical establishment - or all of them? The result will be a cynical public, overflowing cemeteries, a tanking economy, and a skyrocketing budgetary deficit.     

6.      If neuraminidase inhibitors – NIs - like oseltamivir/Tamiflu and the newer class of CEN inhibitors BMX/Zofluza cannot sustainably protect American citizens from an approaching H5N1 pandemic, what can physicians and individuals use to protect themselves? What safe, effective, approved treatments are available to protect one’s health and sustain life? What can help to both prevent and treat viral respiratory disease?

            That is simple. Use broad-spectrum antiviral drugs directed against factors inside human cells and immune system pathways. These drugs can be used prior to and with the current pharmaceuticals like OTV and BMX that are specifically targeted only against constantly mutating viral enzymes. Approved cell-function targeted, broad-spectrum antiviral medicines include variously potent NF-kappaB inhibitors (NF-kBIs) listed below, most of which possess multiple immunological effects beyond just the anti-viral, anti-inflammatory ability to inhibit the powerful NF-kB protein. People recognize most NF-kBIs as non-steroid anti-inflammatory drugs (NSAIDs), although some are steroids.      

            What is nuclear-factor kappaB – also referred to as NF-kB, or NF-kappaB? NF-kappaB is a protein discovered in 1986 that is found in every human cell. This powerful protein is the primary stimulant that increases both viral replication within the cell and tissue damaging inflammation. If a drug inhibits NF-kB as both non-steroid and steroid anti-inflammatory drugs do, it kills two birds with one stone. NF-kB inhibitors work as both antivirals and as anti-inflammatories. Who knew that what physicians commonly refer to as anti-inflammatory drugs also act as antiviral drugs? Now we do. However, drugs in this large class of pharmaceuticals do not all work solely as NF-kBIs. Some like aspirin and naproxen and the nutritional supplement selenium affect multiple mechanisms and numerous immunological pathways, as do some other NSAIDs. Each NF-kBI drug is unique demonstrating additional varied effects and side effects, so they are not interchangeable.  Aspirin, naproxen and selenium are all immunomodulators. They exhibit wide ranging beneficial effects in the immune system, but to the detriment of national health during pandemics, they are mostly overlooked by health officials because they are cheap, off-patent, and do not require a physician’s prescription.     

            Nevertheless, because NF-kB is a cellular protein and the human cell does not mutate like RNA viruses do, when physicians use NF-kBIs as antiviral drugs, these steroid and non-steroid anti-inflammatories work consistently and are not subject to viruses developing resistance against them because they target human cellular factors, not shape-shifting viral enzymes. NF-kBIs relative strength as anti-inflammatories only partly reflect their individual strength against viral disease. Many of these drugs also work through multiple other immune mechanisms, not just as NF-kBIs. Thus, their ranking power as NF-kBIs, shown below, do not fully represent their entire value as anti-IAV therapies. Some are more effective against some viruses than others, but they all inhibit damaging inflammation. However, they should be used with caution. The ones fully detailed here are the safest and best against flu infections – selenium, aspirin and naproxen.    

NF-kappaB inhibitors:

            The referenced article in the journal Oncogene by Yasunari Tanaka of the Cytokine Research Laboratory of the University of Texas Cancer Center provides the following comparative ranking of a selection of NF-kBIs tested to determine their ability to inhibit the viral replication factor nuclear-factor kappaB. Unfortunately, selenium and nimesulide were not included among those tested. The rankings below are based on a comparison to the strength of aspirin that was rated as 1.0. They do not necessarily reflect the overall impact each drug may have in ameliorating the effects of H5N1 infection and the cytokine storm since there are many cellular and immune factors. This ranking only relates to inhibiting the NF-kB protein.  

Aspirin 1.0; ibuprofen 1.6; sulindac 1.9; phenylbutazone 4.5; naproxen 6.0: indomethacin 9.5; diclofenac 14.9; resveratrol 67.5; curcumin 131; dexamethasone 210; celecoxib 236; tamoxifen 567.          

            During the 2020-21 Covid Crisis, many physicians used the broad-spectrum, steroid antiviral immunomodulator dexamethasone to treat patients. As a powerful corticosteroid NF-kB inhibitor, dexamethasone exhibits immunosuppressive qualities many less potent NSAIDs do not. Dexamethasone’s potency and immune depressive side effects limited its use against Covid-19 to a mere five days. Still, it reduced the mortality rate of those who used it by 33%, (     ) more than any other drug used against Covid-19 prior to the extremely delayed introduction of the double protease inhibitor Paxlovid that may or may not be entirely superior to dexamethasone. Due to a conceptual failure of the current medical antiviral paradigm, a multitude of broad-spectrum NSAID drugs that could have been used against SARS-2/Covid-19 infection to reduce both viral replication and damaging inflammation from the start of infection were never used. This commercially induced medical blind-spot led to a tragic failure of concept and excessive loss of life in the fight against Covid-19 that could have been avoided. That blind spot must be eliminated if health officials want to save more lives and reduce the incidence of expensive, post avian influenza syndrome – PAIS - during the approaching, eventual H5N1 potential holocaust.

7.       Early therapy - A reasonable proposed therapeutic solution to save lives from the initial impact of HPAI   H5N1 infection.

 SAN - A Respiratory Disease Home First Aid Kit Consisting of Selenium, Aspirin and Naproxen.  

            Every dad, mom, camper, sportsperson, scout leader or military veteran knows about first aid kits. They contain basic medical supplies that are needed if someone gets injured, before they can reach a proper medical facility for professional care. That is exactly what is needed for contagious respiratory viral disease. The CDC and America’s fifty state departments of health should educate the public about broad-spectrum antiviral drugs that people can safely take from the first sign of flu symptoms. Viral first aid would slow the exponential growth of viral replication that reaches its peak about 48 hours after infection. Respiratory viral first aid will reduce viral replication and the damage it causes to cells and tissues. It will moderate the overactive immune response, reducing its hyperinflammatory reaction and significantly suppress the initiation of the cytokine storm. Maintaining and using a respiratory disease first aid kit at home provides a sense of personal health security and well-being and initial infection intervention until a person can reach a clinic or hospital if they become ill. The most important considerations for a home respiratory viral first aid kit is for it to do no harm, be safe, effective, and easy to understand.  It should include a leaflet of safety instructions and contraindication.  In practice, how would this therapeutic combination work for H5N1 infection?

            Treating most viral diseases using a combination of different therapies working together and complementing each other via different immune mechanisms provides a better result than monotherapy using only one drug directed at one target. Advantages of combination therapy are addressed in Part 2 of this essay.

            Based on the known science as reported below, I propose a five-way combination-therapy for H5N1 avian flu and other contagious respiratory diseases like Covid-19. It consists of:

            1/2) Tamiflu or Relenza – (oseltamivir, OTV) - an NI - plus BXM/Zofluza – a CEN inhibitor. These       two drugs are specifically intended for influenza only. They both require a physician’s           prescription. Thus, they are not considered “first aid” since it usually takes several days until                  these are accessible. The cost of OTV is about $70 and the cost of BXM is about $170.

           

3) Selenium (Se) supplement to boost selenium levels. Se is an NF-kBI and immunomodulator. It                 helps maintain the body’s oxidative balance and reduces the chance of sepsis. With well-known                    prophylactic activity to reduce the chance of viral infection, selenium could be considered an                          “inner mask”, boosting the immune system and its ability to produce antibodies to reduce                             the chance of or intensity of respiratory viral infection and disease. Suggested dosage for early flu         therapy is 400-600mcg daily. The long-term use, prophylactic dosage against influenza is              100mcg to 200mcg daily. The cost is $5-10 per bottle.    

4) Aspirin, acetylsalicylic acid, ASA - 325mg daily to prevent platelet activation and aggregation.             ASA is an NF-kB inhibitor, immunomodulator, and a COX-1 inhibitor. It provides some                    symptomatic relief against fever, aches and pains. Aspirin also may provide some prophylactic                     protection against respiratory infection. The cost is $5-10 per bottle.   

            5) Naproxen is a COX-2 inhibitor and an NF-kBI. It provides specific, direct inhibition of viral               replication of influenza A and B by fitting tightly into the viral groove, thereby “blocking” viral                 replication. It also provides some symptomatic relief. Suggested dosage for early therapy is                 440-660mg daily. In case of imminent threat of infection low dose 220mg naproxen can be                        used prophylactically for immediate short-term prophylaxis. The cost is $10-15 per bottle. 

            All five of the above medicines are approved, safe, effective, available and affordable. When H5N1 eventually jumps the final molecular barrier and becomes transmissible among humans, having the ability to access most of these medications from the first hour symptoms occur could save millions of lives. Three of these medications are proven broad-spectrum antivirals while oseltamivir and BXM are specific for influenza, but both of these prescription drugs are subject to resistance. Because oseltamivir rapidly loses it antiviral effectiveness on an almost hourly basis beginning 48 hours after first flu symptoms appear, the sooner a person can start the above combination of antiviral drugs the greater the chance they will survive H5N1 HPAI and reduce their chance of developing post avian influenza syndrome - PAIS. SAN first aid for influenza is especially important considering that for various reasons, most people do not visit a physician until two to four days after the onset of flu symptoms when oseltamivir/Tamiflu has already lost much of its effectiveness. Having Tamiflu available at home as part of an influenza first aid kit would eliminate that dangerous therapeutic delay, but because it occasionally has neurologic negative effects and requires a prescription, that is not possible. However, selenium, aspirin and naproxen have all been shown scientifically to help against viral infection and these can be used from the first moment a flu infection is recognized. If TAN home first aids kits are provided in an organized program, they should include an advisory sheet explaining how to tell the difference between a cold, flu, covid, or respiratory syncytial (RSV) infection, as well as information concerning contraindications and potential adverse effects of the drugs included.      

            Homeowners keep a fire extinguisher in their home because they know it takes the fire department some minutes before they arrive in case of fire. Every minute counts. With influenza it often takes a person hours before they realize they are having flu symptoms instead of just a common cold or Covid-19. Of course, with minor adjustments, this SAN viral first aid kit is equally applicable to colds and Covid, so even if the illness is not influenza, it is still safe and beneficial. Thus, it pays to have an influenza first aid kit at home because, just like a real fire, with the inflammatory fire and fever of influenza, every hour counts. Early therapy is the best therapy. That includes reducing the chance of post avian influenza syndrome – PAIS.

            Once an H5N1 pandemic eventually starts, the medical system will be overwhelmed, potentially far worse than it was with Covid-19. If every American is advised to assemble and maintain a SAN influenza first aid kit at home and is trained how to use it at the first sign of a fever or other distinguishing flu symptom, that will take some strain off an overworked health care system. Since these three SAN medicines can be used as prophylaxis, that also should help slow the spread of the pandemic. Can such a practical, common-sense solution be accepted by government health officials? That is the real test of a competent, responsible and responsive national health system - its willingness to accept a simple workable community, family and science-based partial solution to an expensive, complex, public health problem. Government should educate and empower people to understand how to protect their own health and the health of their families, not stand in their way of doing so.           

8.      What are the broad-spectrum drugs and medications that can be used to protect people from H5N1 infection once the pandemic finally arrives? Especially, what can be used against early disease in the first 48 hours of infection before a person gets to see a physician – and continue using after that?          

a.       Selenium (Se) – NF-kBI rating (?x)

Selenium is an NF-kBI inhibitor, an immunomodulator, an antioxidant, a broad-spectrum antiviral, a platelet antagonist, and an anti-inflammatory – among other things. (Hatfield) It also works as a protease inhibitor against both the SARS-2 Mpro (Jin) and the H5N1 protease enzyme. (      ) Selenium is the keystone chemical element for both the immune system and the cellular antioxidant network. It has proven to significantly reduce sepsis and septic shock-related death (Alhazzani, Forceville) and is the strongest agent to increase critical CD4 white blood cell count. (Odunukwe) Loss of selenium due to viral replication contributes to the depletion of CD4 cells. That causes a decline in both immune function and immune system regulation. (Rayman) Selenium deficiency results in the loss of the critical prooxidant-versus-antioxidant homeostatic balance in the body. (     )

      In her 2000 landmark article in The Lancet medical journal, “The Importance of Selenium to Human Health”, Margret P. Rayman of the University of Surry explained, “More than 20 papers report a progressive decline in plasma selenium in parallel with the on-going loss of CD4 cells in HIV-1 infection.” She noted that “selenium-deficient HIV patients are nearly 20 times more likely to die from HIV-related causes than those with adequate levels.” Moreover, “low plasma selenium is a significantly greater risk factor for mortality than low helper-T-cell count by a factor of 16…” (Rayman) This same immunological phenomenon applies equally to other fatal viral diseases that genetically encode selenium proteins. Among many others, those include Ebola, SARS-1 and -2, and H5N1. Variable factors that can affect a viral disease include how many selenium atoms are required to form each virion, how rapidly a virus replicates, and total viral load. A critical determinative factor influencing immune function versus dysfunction in the body is the level of selenium. (Hatfield) Once a person’s selenium reserves decline below a critical level, the person expires. (Taylor) Thus, supplementing selenium prior to and during the critical, severe stage of viral disease is essential to preventing mortality. It is unconscionable for public health officials to continue to ignore this basic fact of human immunology. It is a fatal mistake that society pays the cost of in increased morbidity, excess mortality, and higher incidence of post pandemic syndromes.    

      Selenium’s benefits against IAV disease have been studied for over twenty-five years. In 2001 Melinda Beck of the University of North Carolina wrote a keystone article titled, “Selenium Deficiency Increases the Pathology of an Influenza Virus Infection.” The title could not be more self-explanatory. Beck explains that selenium deficiency has “been associated with an increase in the severity of infectious disease.” She notes that “The mouse has long been used to study influenza virus infection and pathogenesis.” The experiments her groups conducted showed that “Se-adequate mice infected with influenza A develop a relatively mild inflammatory response. However, the inflammation is much more severe in the Se-deprived animals.” Her abstract revealed that “Infected Se-deficient mice developed much more severe interstitial pneumonitis than did Se-adequate mice. This increase in pathology was associated with significant alterations in mRNA levels for cytokines and chemokines involved in pro-inflammatory responses.” Lung pathology showed that “mice fed the Se-deficient diet had significantly more inflammation at days 4,6,10 and 21 post-infection than mice fed the Se-adequate diet.” “The lung pathology in the Se-adequate mice began to diminish after day 6, whereas the Se-deficient mice still had severe pathology even 21 days post-infection.” While the inflammation and thus the disease was much more under control in the Se-adequate mice, the virus itself was not cleared any faster in Se-adequate mice compared to deficient mice. (Beck ’01)

Like so many other experts, Beck reports that “The lung inflammation induced by influenza virus is the major cause of the tissue damage, rather than direct viral damage to the lung cells.” She mentions the “importance of CD8+ T cells in viral clearance” and explains that “Se-deficient mice had impaired recruitment of CD8+ cells to the lungs.” Thus, “a deficiency in total numbers of CD8+ T cells likely contributed to the inability of the Se-deficient mice to clear the virus faster”. “The continuing inflammation noted in the Se-deficient animals at a time when the pathology was resolving in the Se-adequate mice suggests that the overexpression of the pro-inflammatory chemokines contributed to the continued influx of inflammatory cells in the lungs.” As is obvious to scientists, “the increased lung pathology in the Se-deficient animals may be due to an excess activation of NF-kB”. In conclusion Beck writes, “Our work points to the importance of adequate antioxidant defense mechanisms for protection against viral infection and demonstrates that Se-dependent GSH-Px may play an important role during an influenza-induced inflammatory process.” (Beck ’01)          

      As another researcher, Australian Harsharn Gill wrote in 2008, “Selenium deficiency has also been associated with increased incidence, severity (virulence) and/or progression of viral infection such as influenza, HIV and Cocksackie virus. For example, infections with influenza are known to cause significantly greater lung pathology in Se-deficient mice compared with Se-adequate mice; number of inflammatory cells and the pathology score were significantly higher in Se-deficient mice compared with Se-adequate mice.” ”increased severity of viral infections in Se-deficient mice could be the result of increased oxidative stress caused by impaired GPx [glutathione peroxidase] activity. Excessive inflammation may be the result of viral induced tissue damage and an increased expression of NF-kB because of increased oxidative stress” (Gill)   

      In their article titled “High-dose selenium reduces ventilator-associated pneumonia and illness severity in critically ill patients with systematic inflammation” William Manzanares and his group at the University Hospital in Montevideo, Uruguay showed that after ten days, adding a dose of 1.6mg of selenite daily following an introductory bolus of 2.0mg Se significantly reduced the sequential organ failure assessment (SOFA) score by 86% compared to only a 52% reduction in systemic inflammatory response syndrome (SIRS) patients who only received standard  therapies. In addition, selenium supplemental therapy reduced the number of SIRS patients who developed ventilator-associated pneumonia (VAP) by more than half  compared to those who only received standard care. The authors suggested that “this therapeutic approach is sufficiently robust to seek confirmation in a more adequately powered clinical trial…” (Manzanares)       

      In 2013 a group of Australian researchers at the University of Melbourne headed by Selcuk Yatmaz reiterated that current influenza treatment strategies are misguided and instead should be directed toward “investigating mechanisms that modulate host responses which lead to lung inflammation and pathology.” They report that a selenium-based compound drug “Ebselen has been shown to have therapeutic benefit in various disease states involving ROS [reactive oxygen species] including lung inflammation.” (Yatmaz) They suggest that a selenium-dependent antioxidant enzyme glutathione peroxidase-1 (GPx-1) “reduces influenza A virus-induced lung inflammation.” And “may represent a novel means of controlling influenza infections.” “Our data provide new evidence for a protective role of GPx-1 in influenza A virus-induced lung inflammation and suggest the potential therapeutic utility of supplementing GPx-1 activity in vivo.” One might as well change their “GPx-1” to “selenium” because GPx-1 is a selenium-based enzyme. Yatmaz explains that “The absence of GPx-1 [or selenium] leads to a dysregulation of the immune response to influenza.” “this altered immune response may be due to an oxidant/antioxidant imbalance, resulting in oxidative stress”. That results in the activation of NF-kB and the “up-regulation of a number of proinflammatory genes, including IL-6, GM-CSF, MCP-1, and TNF-a.” (Yatmaz)    

      In 2014 in a small clinical trial at ELWA-2 Ebola treatment unit (ETU) in southern Monrovia organized by Dr Jerry Brown with the Liberian Ministry of Health, a moderately high-dose of selenium in the form of 1.2mg of sodium selenite daily reduced mortality rates due to Ebola-Zaire virus infection in advanced patients by 43.6%. (personal communication from Dr John Fankhouser). A higher dose of 2.0mg daily that other physicians have used to treat hemorrhagic fever viruses would have achieved significantly better results.

       Selenium also improves blood flow. The depletion of selenium through viral replication may be the fundamental cause of developing life-threatening distributed intravascular coagulation – DIC - that clogs blood vessels throughout the body and accompanies hemorrhagic fevers. As one medical journal article explained, “Selenium supplementation has been suggested as a possible therapeutic agent to decrease clotting, especially that of disseminated intravascular coagulopathy (DIC) that accompanies Ebola hemorrhagic fever…” (Abd-El Moemen). DIC is a common symptom of Ebola (Geisbert) and an occasional symptom of H5N1 influenza. (Writing Committee WHO) In 2020, during the Covid Crisis, a laboratory screening of over 10,000 drugs and molecules determined that Ebselen, a selenium-based compound, was the number one most effective drug to treat SARS-2. (Jin) Surprisingly, health officials ignored that critically timed life-saving research and failed to use Ebselen or related selenium supplements to save lives from Covid-19. However, Ebselen or a similar alternative like sodium selenite should be almost equally effective against H5N1 HPAI. If health authorities fail to learn from their historic mistake with SARS-2 by failing to recognize and utilize the multiple benefits of selenium against the cytokine storm of H5N1, millions more Americans than necessary may die in the coming H5N1 pandemic. The suggested dose of selenium for highly pathogenic influenza depends on body weight and the severity of the disease, but it should normally range between 1mg and 2mg daily when treating severe disease or cytokine storm. For most people it should be approximately 2.0mg if sepsis or organ failure begin to occur. 200-400mcg daily is adequate for early therapy while 100-200mcg is sufficient for prophylaxis.        

As a part of their envelope structure, many RNA viruses genetically encode a selenium containing protein, selenocysteine, an analogue of the universal antioxidant glutathione peroxidase (GPx). (Taylor) The selenocysteine selenoprotein has been confirmed as a component of a number of RNA viruses including HIV-1, molluscum contagiosum (MCV), fowlpox virus, canarypox virus (CPV), Japanese encephalitis virus (JEV) and likely in JEV-related viruses including dengue fever virus (DENV) West Nile virus (WNV) and yellow fever virus (YFV). (Guillin) Margaret Rayman extends that list to include HIV-2, coxsackie virus B3, hepatitis B and C viruses, and measles virus. She suggests polio virus and influenza viruses type A and B probably also do so. (Rayman). Ebola-Zaire and Hantavirus also encode selenoproteins. (Taylor)

By genetically incorporating selenoproteins as they replicate, these viruses progressively deplete selenium from the cells, tissues, and organs they infect. Selenium deficiency reduces interleukin-2 (IL-2) and the IL-2 receptor, thereby reducing CD4 lymphocyte production by the thymus. That eventually leads to the loss of CD4 helper cells, immune deficiency, and immune system dysregulation. Health officials have ignored selenium depletion due to viral replication as a central key aspect of the pathogenesis of viral infection that often leads to inflammatory generation of a cytokine storm and sepsis. The health of Americans and the world has suffered greatly during viral epi-pandemics because of that neglectful oversight.

As Olivia Guillin of France’s National Institute of Health explained in 2019, “The link between selenium and viral infection has been reported for many viral groups.” “Most of the beneficial effects of selenium is due to its incorporation in the form of selenocysteine into an essential group of proteins that are called selenoproteins.” Among its many attributes selenium inhibits the NF-kB stimulatory protein “which is necessary for viral replication”. (Guillin) She reports that “selenium deficiency of the host promotes rapid genomic evolution of the virus in HA and NA genes”. That results in rapid generation of viral resistance. She continues “selenium deficiency is an important virulence factor” and “a rapid change in the pathogenicity of the virus in selenium deficient host has been also reported for influenza virus.” (Guillin) That means if selenium levels decline due to viral replication, the virus can more easily mutate, escaping the antiviral effect of drugs such as oseltamivir and increasing its replication rate. She reports that in influenza experiments, selenium deficient mice suffer more severe pathology and have a longer term of lung inflammation. (Guillin) As another scientist observed, “selenium deficiency results in greater lung pathology and altered immune function in mice infected with influenza virus.” (Sheridan)       

      The effect of viral replication-induced selenium deficiency as a primary cause of sepsis and the ability of selenium supplementation to reduce the incidence of sepsis, multiorgan failure and death has been addressed by numerous researchers. K Mertens wrote that “Concentrations of selenium were very low in plasma from all patients, lowest in patients with sepsis, and strongly associated with peak CRP and IL-6 concentrations.” (Mertens) Waleed Alhazzani reported that in “Nine trials…selenium supplementation in comparison to placebo was associated with lower mortality.” “In patients with sepsis, selenium supplementation at doses higher than daily requirements may reduce mortality.” (Alhazzani) Jiri Valenta explained that “studies exploring selenium supplementation were extremely successful …found a decrease in the frequency of multiple organ failure and a decrease in mortality from 40% to 15%.” And reported “lower mortality with selenium supplementation in the most critically ill patients”. (Valenta) Y. Sakr of Germany observed that “minimum selenium concentrations were the strongest predictive factor for ICU mortality” “critically ill patients…administration of 1000mcg of sodium selenite for 15 days was associated with improved survival”. “Lower plasma selenium concentrations were associated with …organ dysfunction/ failure, and with increased ICU mortality.” (Sakr). French researcher Xavier Forceville noted that “high dose selenium administration…decrease the mortality in septic shock or similar SIRS patients.” He reported that two clinical trials of septic shock had shown “a 90% and 35% mortality decrease [with selenium supplementation] respectively.” (Forceville) Finally, WA Angstwurm of Germany explained that the “Mortality rate was inversely correlated with…selenium concentrations” and “high-dose selenium supplementation reduced the mortality rate in patients with severe sepsis and especially septic shock.” (Angstwurm). Based on the preceding quotes from medical journal articles, it is obvious that the depletion of selenium through viral replication contributes to the development of sepsis and that the use of moderately high dose selenium supplementation can save lives. Although selenium alone is not a cure for sepsis, it should be required adjunct therapy and included as part of the standard of care with other drugs used to treat sepsis and multiorgan failure. Selenium is as essential to the health of every human cell – and every human – as water is. Severe deselenization is as lethal as severe dehydration. To save lives, both need to be detected and corrected as soon as possible.

      There are four common forms of selenium nutritional supplements. Two are organic, selenomethionine and selenocysteine; and two are inorganic, selenate and selenite. “The chemical form of selenium is an important factor influencing biological activity.” (Kieliszek) As Marek Kieliszek relates, “selenium supplementation has been shown to strengthen the immune system against the influenza virus.” And selenium plays a role in reducing oxidative stress by inhibiting NF-kB, the “activator of many proinflammatory cytokines, including interleukin-6 (IL-6) which may contribute to the intensification of inflammation and cytokine storm.” (Kieliszek) Although all four forms of selenium should demonstrate some benefit as prophylaxis and treatment of H5N1, the form that is most proven in the treatment of viral infection and therefore ideally should be recommended against H5N1 is sodium selenite, the form that was used successfully against Ebola-Zaire in Liberia in 2014. (personal knowledge) As noted, failing to provide supplemental selenium to those in danger of dying from viral disease is like failing to provide water to those dying of dehydration. During a viral pandemic it would be a historic medical blunder to fail to acknowledge and remedy one of the fundamental underlying causes and drivers of viral disease pathogenesis – deselenization.   

      Selenium is as fundamental to health as water. Providing the basic building block for most cellular antioxidants, selenium is essential to the health of every cell in the body. Likewise, selenium plays a central role in the functioning of the immune system. To paraphrase one scientist who summarized the influence of selenium on immunity - if you have enough selenium the immune system will be strong. If you do not, then it will be weak. (Taylor)

      In my book Understanding Covid-19, How 500,000 American Lives Could Have Been Saved there is a chapter titled “Unheeded Science: Scientists Explain How Selenium Affects Covid-19.” Covid-19 provided scientists another chance to observe how selenium affects viral respiratory disease. The same lessons learned about SARS-2 and Covid by some attentive scientists are applicable now against H5N1. Below are additional quotes from medical journal articles about selenium and Covid taken from that chapter “Unheeded Science”. Together with the science referenced above, they demonstrate how deep and wide this knowledge base concerning the usefulness of selenium supplementation against viral respiratory disease is. Many of these quotes from medical journals are also found in my second book, Dear Bill Gates, How to End Serial Pandemic Failure, HIV-1 to Covid-19.

       In 2020 in the journal Redox Biology Jinsong Zhang writes “Significant clinical benefits of selenium supplementation have been demonstrated in a number of viral infections…” Selenium supplementation “significantly restored the antioxidant capacity of the lungs…and meaningfully improved respiratory mechanics.” “Selenium adequacy prevents excessive cytokine activation”. Zhang explains that “supernutritional levels of selenium might suppress…organ damage and the cytokine storm”, and there is “an association between…selenium intake/status and higher cure rate.”  (Zhang)

      Because the SARS-CoV-2 pandemic started in central China, Chinese scientists witnessed its danger first and had a slight lead in the race to find and develop anti-Covid treatments. Scientists at the Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology and the Drug Discovery and Design Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences were about the first to respond with an effective solution. They had developed a high-throughput chemical assay that could test many drugs and pharma-active compounds quickly against a pathogen to see which drugs might work. (Jin) Within days they were able to run all 10,000 drugs in their pharmaceutical library and found six that had enough effect to reduce viral replication by more than half. However, one far surpassed any of the others, a selenium-based compound drug named Ebselen. (Jin) Ebselen was developed in Japan in the 1990s but was never fully commercially exploited. It is now off-patent but not available in pharmacies because it is not currently manufactured. However, it was by far the best drug to inhibit SARS-2 replication out of the 10,000 that were tested. The characteristics of Ebselen are remarkably similar to some other forms of supplemental selenium, so perhaps that is why it was never exploited. Some selenium supplements can achieve a similar effect. Nevertheless, Ebselen would still be a good drug to treat Covid-19. It is approved and it is effective. But it is not manufactured. Zhenming Jin and his large research group submitted their results in a paper on 9 February 2020, about three weeks after Chinese authorities had announced to the world that a previously unknown virus of mysterious origin was causing people to die of pneumonia. On April 9^th the prestigious journal Nature published their article titled “Structure of Mpro from SARS-CoV-2 and Discovery of its Inhibitors”.    

      How does Ebselen work? It works as a protease inhibitor to strongly inhibit viral replication, although it might also work through additional mechanisms that are not discussed in the article. As the authors explain, “the development of a single antiviral agent targeting Mpro, or such an agent used in combination with other potential therapies, could provide an effective first line defense against all diseases associated with coronaviruses.” (Jin) While this important discovery could have been used immediately to reduce the mortality rate of Covid-19, it was not. Approximately twenty months later another protease inhibitor drug was introduced to the public to treat Covid - Paxlovid. Thus, although a very effective off-market drug existed to treat not only SARS-2 but also all other coronaviruses (Jin) Americans and the world had to wait until an American developed protease inhibitor was introduced.

      As Jin’s group explained “The timely development of effective antiviral agents for clinical use is extremely challenging because conventional drug development approaches normally take years of investigation and cost billions of dollars. The repurposing of approved pharmaceutical drugs and drug candidates provides an alternative approach that allows for the rapid identification of potential drug leads to manage rapidly emerging viral infections.”(Jin) [italics added] One might ask how many people worldwide died of Covid-19 or developed long Covid while public health officials failed to use an approved drug with low side effects like Ebselen and the public was misled to believe that no drugs existed to treat early Covid-19 infection and even those with more advanced disease were not informed about Ebselen. Will this historic failure to save lives from Covid-19 be repeated with H5N1 influenza? Yes. However, unless something changes it may result in much more massive mortality.                         

      Continuing the story of research… in the journal Frontiers in Nutrition Laurent Hiffler relates that “Selenium deficiency is associated with …more severe disease outcomes.” He reports that “Intense viral replication would…induce a selenium deficiency.” And “with Covid-19…the lowest serum selenium were strongly associated with mortality.” Finally, there is a “strong correlation with low selenium status and poor outcomes in hospitalized [Covid-19] patients.” (Hiffler)

      Another article by selenium expert Ethan Will Taylor explains that there is “a consistent pattern of a role for selenium that has been reported over several decades for a variety of RNA viruses…” Taylor continues that “NF-kB is an activator of cytokines… contribute to increased inflammation and the cytokine storm observed in Covid-19 and is a significant basis of pathogenic effects associated with SCoV-2 infection of various tissues, including the lung, gastrointestinal tract and cardiovascular system.” (Taylor ‘20)

      In his article “Selenium Deficiency is Associated with Mortality Risk from Covid-19” Arash Moghaddam remarks that there is a “vast body of literature on declining selenoprotein biosynthesis under acute phase conditions, in inflammation and hypoxia.” “a longer stay in the ICU…may cause an elevated selenium requirement due to ongoing selenium loss” and “selenium status was significantly higher in samples from surviving Covid patients as compared with non-survivors.” (Moghadam)

      In his apply titled article “The Pathogenesis and Treatment of the Cytokine Storm in Covid-19” Qing Ye writes “reducing viral load through interventions in the early stages of the disease and controlling inflammatory responses through immune-modulators are effective measures to improve the prognosis of [SARS-CoV-2] infection.” He continues, “Timely control of the cytokine storm in its early stage through such means as immunomodulators…is the key to improving the treatment success rate and reducing the mortality rate of patients with Covid-19.” (Ye) Ye reconfirms a major point of this essay.

      Writing in the journal Molecules, Minkyung Bae observed, “selenium deficiency increased… vasoconstriction and blood coagulation. This might explain the mechanism for venous thromboembolism in selenium-deficient Covid-19 patients.” “Selenium deficiency exacerbates virulence and progression of viral infections.” “A low plasma selenium…increased mortality in ICU patients.” “Selenium deficiency may be a risk factor for Covid-19 mortality.” (Bae)     

      As for prophylaxis, Jan Alexander writes that “an adequate pre-infectious status of selenium would represent a protective measure against…corona viral infections.” (Alexander) Soodeh Jahromi reports “Supplementation of selenium for the institutionalized elderly was found to reduce the infection rate significantly.” (Jahromi) And Sojit Tomo details how selenium helps inhibit infection in that “selenium also interferes with the attachment of the virus to the host by inhibition of disulfide exchange reaction.” (Tomo)

      Another article reveals how SARS-CoV-2 affects selenium-based antioxidants in the body and how that affects Covid-19 progression. A top team of British, American, and Chinese experts wrote that “Higher selenium status has been shown to improve the clinical outcome of infection caused by a range of evolutionary diverse viruses, including SARS-CoV-2.” Selenium is “a significant factor affecting the incidence and severity of a number of viral diseases in both animals and  humans.” (Y. Wang) They explain that “The Stimulator of Interferon Genes (STING) is pivotal in initiating innate immune responses against viral infection.  GPX4 [A selenium-based antioxidant, glutathione-peroxidase-4] is required for facilitating STING activation. [Thus] SARS-CoV-2 may exploit evasion of the immune system by suppressing GPX4.” (Y. Wang) “SARS-CoV-2 may benefit more from targeting GPX4 [because] …GPX4 specifically protects against ferroptotic cell death which normally occurs in cells of the immune system.” (Y. Wang) By reducing the GPX4 antioxidant protection for white blood cells, the virus pushed those lymphocytes towards iron oxidation induced cell death. “Thus SARS-CoV-2 infection may cause both tissue depletion of selenium and transcriptional inactivation of GPX4, thereby synergistically destroying GPX defenses.” (Y. Wang)

Wang et.al. also found that SARS-CoV-2 may boost virus production by reducing production of TXNRD3, a selenium-based antioxidant strongly expressed in the lung. By reducing the level of TXNRD3 “SARS-CoV-2 may boost virus production in the lung, the major site of SARS-CoV-2 replication.” “SARS-CoV-2 targets TXNRD3” reducing both its antioxidant and antiviral protection. “Our study found that SARS-CoV-2 …significantly lowered mRNA concentration of TXNRD3 by 36.9%.” “SARS-CoV-2 may target [the TXNRD3] selenoprotein to promote [its own] viral life cycle.” (Y. Wang) Reduction of TXNRD3 by the virus allows reactive oxygen species (ROS) oxidants to “accelerate SARS-CoV-2 replication. Treatment by antioxidants…substantially inhibits SARS-CoV-2 replication.” (Y. Wang)         Thus, by suppressing the production of both the GPX4 and TXNRD3 selenium-based antioxidants in the body, the SARS-2 virus not only reduces the protection those antioxidants provide and thus increases the death of white blood cells, it also hijacks the selenium resources it requires to facilitate its own replication. (Y. Wang)            

      Finally, in a preprint version of his paper titled, “RNA viruses vs. DNA synthesis: a general viral strategy that may contribute to protective antiviral effects of selenium”, Ethan Will Taylor elaborates that selenium is a “natural antagonist of RNA viruses…linking selenium to the incidence, morbidity and mortality of a number of RNA viral infections.” “Increased mortality risk associated with low selenium status or reduced intake…was significantly reduced by selenium supplementation.” Taylor concludes, “Rarely has a simple and affordable dietary factor shown such promise to contribute to our ability to withstand an entire class of …deadly diseases.” (Taylor ’21)                     

      When I wrote Understanding Covid-19, How 500,000 American Lives Could Have Been Saved 500,000 was a conservative number. Based on the additional research conducted for this essay, reading over 450 additional medical journal articles, today I believe that conservative number should be 800,000 lives that could have been saved in the first two years of the Covid Crisis of 2020-2021 when 1.2 million Americans died of the disease. Those lives could have been spared if physicians and public health officials had informed the public about the benefits of selenium, aspirin, and naproxen as outlined in this essay and people had been instructed how to use early therapy from the start against respiratory disease. Instead, Americans were repeatedly misinformed and told by the highest, most respected health authorities that no early therapies existed to treat Covid-19. As the research quoted here confirms, that simply was not true.      

      The pathological sequence of events – pathogenesis - that transpires in H5N1 avian influenza and Covid/SARS respiratory infections are remarkably similar. First, in response to infection there is a rush of immune cells to the lungs, where they and activated platelets both emit and attract cytokines and chemokines and additional types of immune cells to flood the pulmonary zone – causing damage as they do. Then, micro-clotting of the blood occurs in alveola lung cells and capillaries. That causes hypoxia – depriving the blood, tissues, and organs of oxygen. These events frequently trigger an immune overreaction, a cascade that causes widespread cellular death, a cytokine storm, sepsis, multiorgan failure, and is ultimately lethal. That sequence is essentially the same in both Covid and H5N1. While SARS-CoV-2 might use a viral match to ignite its conflagration, H5N1 may use a proverbial cigarette lighter to do the same. After a week or ten days, viral replication has faded, but the immune overreaction of the cytokine storm rages on burning, consuming all in its path, killing cells that spew out toxins as they disintegrate.  

      Although there is little difference in the above pathogenic sequence between SARS-CoV-2 and H5N1, according to its observed effects in other mammal species, HPAI H5N1 generally provokes much more involvement of the central nervous system and brain than SARS-2. That is because at least some genotypes or variants of H5N1 are neurotropic and infect the nerves. (Chothe) That adds blindness and often fatal encephalitis to the usual HPAI engendered sequelae of pneumonia, sepsis, and organ failure. What remains consistent in AIDS, Ebola, SARS-1 and -2 and H5N1 is the progressive loss of selenium. That loss is central to all these disease processes, yet it is ignored, one might even say covered up by those who claim to do no harm and are employed by the government to protect public health. Instead, they have ignored critically beneficial science. In the end that cost the U.S. government trillions of dollars that citizens are left on the hook to eventually pay. If he were here today, Hippocrates of Cos would agree when I say “Doctor, use what works.” But first check the science – as reported here – or review the voluminous journal science yourself. But please do not ignore the science, and lacking wisdom, allow the people to perish. 

      As briefly touched on here, selenium is central to an understanding of how viruses replicate and how they cause disease. Thus, one must ask why public health officials ignore this fundamentally essential element? Is it only because it is a basic element - a nutrient, and as such physicians are not taught much about it in medical school because that is left to nutritionists? Is it because Se is a nutritional supplement, not a drug, and so it is disregarded since it does not require a prescription? When a patient is in the hospital they are provided water. Then why are they not provided selenium when most ill patients would also require that? Do physicians not consider selenium and the immunity and cellular oxidative balance it helps restore important? Or do they fail to test for its deficiency or not recognize how much needs to be supplemented? How can something so essential to life at all levels be so ignored?

Selenium is the strongest booster of immunity because it has been shown to be the strongest agent to increase CD4 count.  Se provides benefits against many diseases and conditions. Many of those including trauma, viral and bacterial infections, and cancer deplete selenium, causing its deficiency. Thus, most people who are ill would benefit from supplementing it. At proper doses recommended here, Se is absolutely safe and is not contraindicated to any other drug. So, what is the problem that in epidemic after pandemic, from HIV/AIDS to Ebola, to SARS-CoV-1 and -2, health officials fail to check under the hood of the immune system to recognize that the loss of selenium correlates closely with disease progression, the development of sepsis, and eventual organ failure and death? Why is knowledge about this life saving medicine swept under the rug, ignored, and people are allowed to die due to the failure to apply this simple science? If the Father of Medicine, Hippocrates of Cos were alive today and saw what was happening after medical doctors take their sacred oath in his name to do no harm, he would turn over in his grave and shed a tear seeing what modern medicine has become - in this case a barrier to the beneficial use of advanced scientific knowledge. That harms those who need the benefit of this knowledge the most – those whose health is threatened by respiratory illness and residual autoimmune-like syndromes caused by viral infection. This neglected science results in hundreds of thousands more deaths in pandemics than are necessary. These facts are not medical misinformation, disinformation, or pseudoscience dredged from the rabbit hole or from beyond the looking glass. It is established medical science. Why do health officials continuously fail to apply it? What is their excuse when innumerable excess people perish in a botched war against an unseeable viral enemy? Their silence is deafening. For those with H5N1 it may be blinding.                         

The approaching epochal challenge of a potential once in a millennium highly pathogenic influenza pandemic should give pause to health authorities and prod them to reevaluate and apply this well-established science to save lives. Failure to do so would represent an unpardonable repeat of the failure to convert known science to save lives in the last disastrous pandemic. But after American and international health officials failed to apply this laboratory and clinical science to save lives during the Covid Crisis of 2020-21 they may “forget” to do so again. That begs the question. How can state, national, and international health officials learn from their mistakes if they fail to recognize them in the first place? How many hundreds of thousands or even millions of people must suffer because of the mistakes of health officials and their failure or refusal to recognize and correct their mistake by failing to apply known science?   

b.      Aspirin (ASA) - NF-kBI rating – (1x) (Tanaka)

      Aspirin is an immunomodulator. First used against flu in its herbal form in Egypt over 3,550 years ago, it has been used as salicylate since the 1850s and as acetylsalicylic acid (aspirin - ASA) since 1899. (Di Bella) Aspirin has been used worldwide to treat symptoms of colds and flu since 1899, including by American physicians and mothers for over 100 years. ASA can help reduce the incidence of hypoxic low-oxygen levels in the body by preventing micro-clotting in the lungs, as well as circulatory systemwide DIC mega-clotting. To reduce platelet aggregation/clotting, the recommended aspirin dosage against flu should be one tablet, 325mg daily. Higher doses of aspirin should be avoided in H5N1 because at higher doses it inhibits cyclooxygenase 2 (COX-2) more than COX-1, so it offers slightly different benefits. Due to the fear of Reye’s syndrome, aspirin use should be avoided in children under the age of 14. One might ask, when did American physicians and national medical authorities forget about the obvious usefulness of aspirin against respiratory diseases such as influenza and Covid-19? It is one of the best therapeutic weapons in the anti-respiratory disease pharmaceutical armamentarium because it prevents initial platelet activation. However, people need to know exactly how to use it best.   

      Hippocrates of Cos used the willow bark herbal antecedent of aspirin against flu-like fevers in the Fourth Century BC, as did American Indians and ancient Chinese. However, during the 1918-20 Spanish flu pandemic when aspirin was less well understood than today, American military medical officers recommended extremely high doses of aspirin. Many1918-20 flu deaths can be attributed to overdosing of ASA when some patients consumed aspirin by the handful to fight the fearsome flu and suffered death from ASA overdose instead – probably by hemorrhage. (Starko) That was not the last pandemic in which medical authorities missed the therapeutic mark. Misunderstood, one might say aspirin was the oseltamivir of its day – the one great hope for effective therapy. During the Covid Crisis government health officials misjudged the standard of care, especially the benefits of and possibilities for early therapy for respiratory disease. They prioritized new drug research over the practical clinical application of existing medications that could have provided immediate benefit to patients. Thus, officials again missed their most important goal – preservation of people’s health and lives. Hard working, caring physicians can only be as effective as the tools they have to work with – primarily the drugs in the pharmaceutical armamentarium. When they were told no beneficial drugs existed to treat early Covid, they were at a loss as to how to treat their patients. The tragedy of excess deaths during the Covid-19 Crisis was the result.         

Since the first alert by the World Health Organization (WHO) in 2006 that the world might face a pandemic of highly pathogenic H5N1 avian influenza, and especially because flu viruses rapidly develop resistance to current anti-flu medications, many scientists have focused on exploring additional therapeutic approaches to overcome the ultimately mortal challenge of highly pathogenic avian influenza A - HPAI. With aspirin’s ability to inhibit both NF-kB and platelet activation and potentially ameliorate many of the obvious symptoms of flu, the scientific search for repurposing therapeutics has included aspirin and aspirin-like drugs.

The medical literature explaining how aspirin can assist against respiratory illness is extensive. In 2007 German researchers led by Igor Mazur at the Institute of Molecular Virology focused on aspirin’s ability to “block” flu virus replication by inhibiting NF-kB. They cited the “urgent need for new and amply available antiviral drugs” and suggested that “salicylate-based aerosolic drugs may be suitable as anti-influenza agents.” They noted that NF-kB “controls expression of a variety of antiviral cytokines and is also a regulator of apoptotic [cellular self-destruction] gene expression.” They reported that aspirin inhibits the H5N1 virus, but interestingly, indomethacin does not. They explain that although aspirin’s “anti-influenza virus activity directly correlates with its inhibiting effect on NF-kB, other cellular signaling mediators may also be targeted.” Aspirin “results in retention of viral RNP complex in the nucleus of the infected cell.” Finally, they state that “Besides the direct antiviral effect of ASA, an infected patient may further benefit from the analgesic and anti-inflammatory properties of the compound that makes it already today a preferred drug to treat flu-like symptoms.” (Mazur)

Mexican physicians at Oasis of Hope hospital in Tijuana led by Mark McCarty spoke to the obvious fatal flaw in the current therapeutic approach against influenza when they wrote, “The most foolproof way to promote survival in epidemics is to target, not highly mutable viral proteins, but rather intracellular signaling pathways which promote viral propagation or lung inflammation.” They point out that “salicylates, which suppress NF-kappaB activation, have been shown to reduce the lethality of H5N1 avian-type influenza in mice.” Emphasizing the need for immediate commencement of therapeutic intervention they write, “salicylate [aspirin] initiated as soon as feasible during infection, might be expected to have life-saving potential during dangerous flu epidemics.” (McCarty)

ALI, SIRS and ARDS are all names for aspects of the cytokine storm. They are technical terms to describe the same phenomena of the out-of-control hyper-immune response that is technically referred to as hypercytokinemia – the cytokine storm. Stronger respiratory infections cause platelets in the lungs to activate and initiate a flood of proinflammatory immune factors into the lungs that eventually develop into a cytokine storm. Infections that can cause a cytokine storm include more pathogenic strains of influenza like H5N1, and SARS-CoV-1 and -2. Those severe infections can initiate this storm of cytokine messages in the immune system that cause cell death and often culminates in sepsis, septic shock, multiple-organ-failure and death.

   ALI stands for acute lung injury. ARDS is acute respiratory distress syndrome, a more serious form of ALI. SIRS is systemic inflammatory response syndrome. These are all stages of or other names for what we commonly call the cytokine storm. The cytokine storm occurs when an infection causes proinflammatory factors to increase out-of-control, and anti-inflammatory immune factors that normally moderate the immune response fail to do so because they are overwhelmed, often weakened due to comorbidities or nutrient deficiencies. Both highly pathogenic respiratory disease and other severe diseases like AIDS or Ebola can initiate cytokine storms.  

Cytokines are messenger signals that communicate between cells – intercellular text messages. They can be either proinflammatory, anti-inflammatory, or neutral. Different cytokines signal cells to maintain themselves, energize their action, shut down, move, or even commit suicide via apoptosis – programmed cell death. Although there are dozens of cytokines, two of the key cytokines that cause or increase the cytokine storm are the proinflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a). Another key inflammatory factor related to the cytokine storm that is internal to cells is NF-kB, nuclear-factor kappa B. When these three immune factors are excessive, the destructive cytokine storm rages. When they are suppressed either naturally by anti-inflammatory factors in the immune system gaining the upper hand or through using external anti-inflammatory agents like selenium, aspirin, and naproxen, the destruction brought about by the cytokine storm can safely resolve. ALI represents the start of this stormy process when platelets are initially activated in response to viral infection. Platelets that are activated in response to severe viral infection trigger the proinflammatory immune response that frequently results in an uncontrolled hyperactive response. The antiplatelet action of aspirin prevents platelet activation, helping prevent ignition of the cytokine storm before it gets started. The important role platelets play in the immune system was not appreciated until the last two decades. Understanding that helps explain one more critical aspect of how aspirin works as a powerful immune modulator.    

As physicians from Harvard and the Mayo Clinic observed in 2011, “ALI is a multifactorial disease where immune cell migration and activation within the lung ultimately result in injury to the alveolar-capillary membrane.” They reported that organ dysfunction can often be prevented when aspirin “is taken before an event that causes hospitalization and ICU treatment.” In their study they found that patients that were already taking aspirin prior to hospitalization were “associated with a reduced incidence of ALI/ARDS” by 54.6%. Thus, taking a low or moderate dose of aspirin, for instance for the prevention of heart attack or cardiovascular disease, also provides a significant reduction in the chance of suffering ALI/ARDS and organ dysfunction if a person has a lung infection as with influenza or Covid. (Erlich)

The next year an  Australian research group reviewed the hospital records of over 5,500 patients who had been admitted to the hospital for the first time with systemic inflammatory response syndrome (SIRS). They found that patients who were given aspirin within 24 hours of when SIRS was recognized after they had been admitted, had a 36.6% reduced chance of mortality compared to those who did not receive aspirin therapy. They concluded that “Our study shows a strong association between [aspirin] and survival in intensive care unit systematic inflammatory response syndrome and sepsis patients.” (Eisen)   

In 2013 another group of Harvard physicians showed that aspirin triggered a factor named resolvin D1 (RvD1) that promotes resolution of ALI. They reported that “Retrospective analyses of patients with ARDS have identified aspirin as a protective exposure that decreases ARDS morbidity and mortality. In addition to inhibiting platelet function, aspirin triggers the formation of specific pro-resolving mediator [Aspirin triggered resolving D1].” Resolvin D1 that is triggered or induced by aspirin “is a potent regulator of mucosal inflammation and promote an array of protective responses for lung catabasis after ALI.” (Eickmeier) Thus, by inducing RvD1, aspirin therapy can help reduce or resolve the negative impact of ALI and ARDS and reduce or resolve the cytokine storm.    

Another research group at Vanderbilt University showed a slightly smaller benefit for taking aspirin prior to hospitalization for ARDS. They found that “Patients with prehospital aspirin had significantly lower incidence of ARDS 27% versus 34%” for those who had not taken aspirin, even though the aspirin group had many more comorbidities – presumably the reason they were already on aspirin therapy. That 20.6% reduction in the incidence of ARDS due to aspirin pretherapy was added to an even stronger benefit against sepsis. As the authors explained, “Platelet activation plays an active role in the pathogenesis of acute respiratory distress syndrome (ARDS).” “aspirin can prevent ARDS by decreasing neutrophil activation, TNF-alpha expression…and platelet sequestration in the lungs.” Aspirin “was associated with a decreased risk of lung dysfunction and multiple organ failure”. “In addition, aspirin also has potent effects on treatment and prevention of sepsis via anti-platelet and anti-inflammatory effects”. (Chen)    

An Irish group explained how serious ARDS truly is by defining it as a “devastating clinical syndrome characterized by life-threatening hypoxaemic respiratory failure, often requiring mechanical ventilation and frequently leading to multiple organ failure. ARDS is a major cause of morbidity and mortality within the ICU and causes long-term reduction in quality of life for survivors.” “The accompanying widespread activation of the coagulation cascade leads to microvascular thrombosis and fibroproliferation.” They elaborate that “delayed neutrophil apoptosis [cell death] is a feature of ARDS that aspirin can ameliorate to promote resolution of persisting inflammation.” By reducing neutrophile cell death “aspirin therapy can decrease severity and augment resolution of ARDS.” They claim, “This is the first report to find aspirin therapy is associated with reduced ICU mortality in patients with established ARDS.” And the most common result of ARDS is sepsis but “studies have shown reduced mortality when aspirin is administered during the course of illness.” (Boyle) Obviously this knowledge should have been but was not applied in the fight against Covid-19. It should be used against H5N1 and all future pandemics.          

A consortium of European scientists spearheaded by Vuong Ba Le in 2015 focused on the key role platelets play in lung inflammation and influenza pathogenesis. Their ground-breaking research showed that “Lungs of infected mice were massively infiltrated by aggregates of activated platelets.” They explain that “platelet activation promoted influenza A virus pathogenesis” and “worsens the severity of lung injury.” They showed that “Activated platelets release potent inflammatory molecules and play a key role in leukocyte recruitment.” (Le) Le notes that the centrally important part platelets play in influenza pathogenesis has not been investigated previously, and like macrophages, “platelets engulfed IAV particles, fragments of IAV, or viral proteins.” “On activation platelets become immobilized, secrete their granule content, and aggregate.” “On infection, platelet counts increased in a time-dependent manner, peaked on Day 3, and stayed elevated until Day 8.” Neutrophils and monocytes then attach to platelet aggregates. That causes the formation of micro clots in the lungs and through the “release of an arsenal of potent proinflammatory molecules” significantly damages the lung. They theorize that “Altogether, the data indicate that platelets regulate IAV pathogenesis.” Finally, like others, they reiterate that “Targeting the host rather than the virus would not easily lead to resistance, drugs regulating inflammation are appealing as potential new therapeutics for IAV symptoms.” In this regard they suggest aspirin is “known to inhibit platelet activation.” (Le) This points to the critically important role moderately low dose aspirin therapy can play in reducing the pathogenicity of H5N1 infection.

In 2016 a research group at the University of Toronto headed by Michael Sugiyama again addressed the previously underappreciated part platelets play in lung injury in influenza. They showed that “Inhibition of platelets using acetylsalicylic acid [ASA] significantly improved survival, a finding confirmed by using a second antiplatelet agent.” Thus, “The inhibition of platelets may constitute a practical adjunctive strategy to the treatment of severe infection and influenza.” (Sugiyama) Considering the inadequacy of current anti-IAV therapies they explain, “While antiviral drugs exist, they only partly reduce mortality, they must be administered early to be maximally effective, and their use is complicated by the rapid development of resistance.” Sugiyama noted that “numerous reports describe pulmonary thrombi [clots] as an important complication of severe infection with influenza.” Their experiments on mice demonstrated that while the M2 ion channel inhibitor amantadine alone reduced mortality by 10%, adding aspirin to amantadine reduced deaths by 80%. (Sugiyama) That enormous difference is worth noting and points not only to the potency of aspirin, but also the value of combining therapies. Sugiyama concluded by making the important points that “treatment with ASA improved survival, increased arterial oxygenation, and did not impact viral clearance.” This research shows that aspirin can reduce inflammation in flu through at least two different mechanisms; both as an NF-kB inhibitor, and as a platelet activation/aggregation inhibitor. Based on that, aspirin may be effectively applied against IAV at the moderately low dose of 325mg daily as a platelet antagonist, which inhibits lymphocyte attraction, and cytokine and chemokine generation through that pathway. It is best to use aspirin against influenza at the dose of 325mg daily to inhibit COX-1, platelet activation and clotting, and rely on naproxen as the primary inhibitor of NF-kB. However, to varying degrees, all three SAN medicines inhibit NF-kB, viral replication, inflammation and the many immune-response genes NF-kB stimulates.

In  2009 Xiu-ren Gao of Zhong-Shan University in Guangzhou, China and Zhi-yi Zuo of the University of Virginia published an interesting paper in the Journal of Pharmacy and Pharmacology titled “Efficacy of Different Doses of Aspirin in Decreasing Blood Levels of Inflammatory Markers in Patients with Cardiovascular Metabolic Syndrome.” They compared the effect of two different doses of aspirin – 100mg vs 300mg daily - on four indicators of inflammation levels in the body. Those indicative markers included thromboxane B2 (TXB2) that indicates the level of platelet aggregation, interleukin-6 (IL-6) that is a cytokine of central importance in the cytokine storm, tumor necrosis factor-alpha (TNF-a) another major proinflammatory cytokine, and  high-sensitivity C-reactive protein (hs-CRP). “hs-CRP appears to be one of the best indicators of the presence of a proinflammatory state [as in influenza] because it provides an integrated indication of the total level of circulating inflammatory cytokines.” (Gao) In other words, CRP can be used as an overall measure of the intensity of the cytokine storm that TNF-a and IL-6 play central roles in instigating and perpetuating. Likewise, thromboxane B2 is an indicator of platelet activation and relates to the potential for cardiovascular disease (CVD) events. In fact, higher levels of all four of these factors indicate an increased risk for CVD, heart attack, and stroke. However, “TNF-a also may participate in the development of insulin resistance and type 2 diabetes mellitus.” Given that this clinical trial was conducted in China, one could label these four markers the Gang of Four because along with NF-kB, they all play a plethora of negative roles in the pathogenesis of dozens of diseases. Thus, in general, it is best to have them all moderately suppressed if possible. Aspirin does that. Gao’s clinical trial had patients on aspirin for two weeks prior to measuring the effect. It produced the following results shown here as a percentage reduction of each factor compared to the level in CVD patients prior to starting aspirin.

                                    ASA Dose        hs-CRP             TNF-a              IL-6                 TXB2

                                    100mg             -5.3%               -2.5%               -1.5%               -8.0

                                    300mg             -24.1%             -12.2                -15.7                -12.1

         It is obvious that to varying degrees, the 300mg dose of aspirin provided a significantly greater level of suppression of all these proinflammatory indicators than the 100mg dose. And it is critical to suppress all these factors in influenza since they constitute the major drivers of the cytokine storm. The authors explain “that aspirin in a broad range of doses from 75mg to 1500mg daily is beneficial in reducing the risk of cardiovascular events.” But they continue “Aspirin, especially at low doses, may preferentially inhibit COX- [1] in the platelets…” (Gao) The importance of allowing aspirin to inhibit COX-1 in the platelets is why this  essay recommends using aspirin at a relatively low dose of 325mg and allow naproxen that is six times as    strong an NF-kBI as aspirin to do the heavy antiviral lifting working through two mechanisms against IAV  while it inhibits COX-2 as well. My analysis of Gao and Zuo‘s research also suggests that physicians who  have recommended low dose 80mg ASA daily to prevent heart attack and stroke also may have missed the  therapeutic mark missing out on many of the other benefits of aspirin including its anti-carcinogenic effects  that are not addressed in this essay. In this essayist’s opinion, 325mg rather than 80mg daily of ASA should be the standard dose recommended for CVD prophylaxis. The multiple immunological benefits of this moderately low daily dose of aspirin have been underappreciated by the medical community and its adverse effects exaggerated for many years.      

A group at the Institute of Immunology in Vienna led by Bernadette Glatthaar-Saalmuller tested the ability of aspirin to inhibit viral replication against many different viruses in the laboratory. They found that while aspirin inhibits RNA viruses, it might have less effect against most DNA viruses. They showed that aspirin inhibits viral replication in a dose dependent manner and effective inhibition of replication can be achieved with aspirin against IAV within the range achieved at moderate anti-inflammatory doses of 1.5 grams per day – below the level of toxicity. (Glatthaar-Saalmuller) This in vitro laboratory research did not consider the anti-platelet effect of aspirin but confirms that ASA can be moderately effective as an antiviral against IAV and can be used at a moderately high dose when other drugs are not available. Thus, ASA can be used initially as first-aid to slow initial IAV infection. Obviously, adding aspirin as adjunct therapy at either low or moderate doses, combined with other therapies, will improve overall clinical outcomes in HPAI. However, the current essayist recommends its use at low dose in combination with naproxen. Doing so obviates the need to use aspirin at a higher dose.    

In 2022 Italian researchers at the University of Trieste headed by Stephano Di Bella reviewed research on the use of aspirin across many infections mentioning that “During the last few decades, evidence of the anti-infective [prophylactic] properties of aspirin has emerged.” They reported that “ASA reduced cardiovascular events after pneumonia” and when added to antibiotics it reduced mortality in patients with pneumonia. They claim, “The beneficial effects of ASA against the mechanisms protracting pulmonary damage in pneumonia are quite well recognized.” (Di Bella) Thus, in mice co-infected with pneumonia and IAV, aspirin therapy reduced the number of monocytes and macrophages invading the lungs by approximately 50%. Importantly, they mention that “The bidirectional relationship between cardiovascular (CV) disease and lower respiratory tract infection is of growing interest. ASA could be a promising candidate for the prevention of CV events after pneumonia.” In fact, a Turkish trial of 300mg of ASA daily against community-acquired pneumonia – CAP - demonstrated a reduction of cardiovascular events from 11% in the placebo group to 1% in the aspirin group. That is truly impressive.  They also suggested aspirin “may be a promising molecule to limit the severity of sepsis.” (Di Bella)                                 

Regarding aspirin and Covid-19 the same authors suggest “A strong pathophysiological rationale for a potential therapeutic role for ASA in Covid-19 has been advocated because of its anti-inflammatory, antiplatelet aggregation and anticoagulant effects, as well as its modulation of the immune system and possible inhibition of viral replication and/or entry.” (Di Bella) That exact same rationale applies to the use of aspirin to save lives against almost every highly lethal viral respiratory disease – H5N1, Covid-19, SARS-1, MERS, or otherwise.  

The benefits aspirin provides critically ill patients are also relevant in the context of severe respiratory diseases that cause sepsis including Covid-19 and highly pathogenic avian influenza. Chinese researchers working with Fangbing Du addressed this in a meta-analysis of 22 relevant studies. They explained that “an increasing number of clinical studies have suggested that anti-platelet therapy might be associated with better outcomes in critically ill patients, such as lower hospital mortality, lower in-ICU mortality, reduced incidence of ALI [acute lung injury] or ARDS [acute respiratory distress syndrome] and reduced incidence of sepsis.” (Du) They concluded that the benefit of antiplatelet therapy was not seen in all critically ill patients but only those with sepsis, with a reduction in hospitalized mortality of 29% and a reduction in ICU mortality of 35%. Concerning which antiplatelet drugs provided the greatest benefit they wrote, “Network meta-analysis shows that the probability of being the best antiplatelet therapy for critically ill patients was aspirin.” Remarkably, that suggests aspirin was about as effective in saving lives from Covid-19 as dexamethasone was. Du explained that “platelets play significant roles in immune defense. Once activated, platelets acting as inflammatory cells contribute to host defense against infection involving the recruitment of neutrophiles and macrophages. For example, platelets… release a wide variety of inflammatory mediators to activate inflammatory cells… [contributing to] severe disseminated intravascular coagulation (DIC) and participates in the development of multiple organ dysfunction syndrome (MODS).” “Platelet activation causes the expression of P-selectin, which increases platelet-leucocyte interactions, which are associated with the severity of sepsis and septic organ dysfunction.” They emphasized that “aspirin presented the greatest likelihood of having lowest hospital mortality rate.” And “there was evidence aspirin downregulates proinflammatory signaling pathways including NF-kB and AP-1”. (Du)

Previously another Chinese group under Lijun Wang had reported their meta-analysis of nine cohort studies including 14,612 critically ill patients. They determined that “Antiplatelet therapy was associated with decreased mortality” of 39% and a reduction in ARDS/ALI of 36%. “Antiplatelet therapy is associated with reduced mortality and lower incidence of ARDS/ALI in critically ill patients, particularly those with predisposing condition such as high-risk surgery, trauma, pneumonia and sepsis.” (L.Wang) They mentioned that sepsis has a usual mortality rate of about 30% and ARDS about 25-38%. Wang found that “mortality rates in critically ill patients did not appear to be substantially influenced by heparin”, a strong anti-platelet-aggregation drug, and there was “no survival benefit of ibuprofen in sepsis.” “Therefore, the antithrombosis function [of aspirin] may not be the only possible mechanism of the benefit of anti-platelet treatment in critically ill patients.” These researchers observed that “In the pathogenesis of ARDS, for instance, both an uncontrolled inflammatory response and dysregulated coagulation are key pathways. ARDS is largely predicted on the key role for platelets in these two pathways.” They explain that “delayed neutrophil apoptosis is a remarkable feature of ARDS” and “aspirin-triggered production of the anti-inflammatory lipid mediator 15-epi-lipoxin A4 restores neutrophil apoptosis and promotes the resolution of alveolar inflammation.” (L.Wang) Could the stimulation of the 15-epi-lipoxin A4 mechanism be the key to why aspirin proves far more effective in saving lives in sepsis, acute lung injury, and acute respiratory distress syndrome than ibuprofen, heparin, or other platelet antagonists? That is an interesting research question.  

The Covid-19 pandemic provided an opportunity for many research groups to conduct studies of aspirin against Covid-19 and dozens of studies were published. Several careful reviews and meta-analysis of those efforts provides a greater understanding of how potent an effect aspirin has in lowering the morbidity and mortality of viral respiratory disease and if the danger of the adverse effect of bleeding should be a significant concern.

 In 2021 Januar Martha and researchers in Indonesia conducted an early meta-analysis of the use of ASA in relation to survival of Covid-19 it included six studies and 13,993 patients and concluded, “Use of low dose aspirin is independently associated with reduced mortality in patients with Covid-19. People who were taking low dose ASA prior to infection reduced their risk of mortality by 54% and those given low dose ASA once hospitalized reduced their risk of death by 61%. (Martha) They also reported other research that showed, “In critically ill individuals without Covid-19, the use of aspirin was associated with a lower risk of acute respiratory distress syndrome (ARDS) and death.” They mention that “Aspirin has been found to reduce the generation of C-reactive protein, interleukin-6 and macrophage-stimulating factor, and therefore helps in mitigating the cytokine storm.” (Martha)

A second systematic review and meta-analysis of “The effects of aspirin on the outcome of Covid-19” was conducted in Indonesia in 2021, this time led by Indra Wijaya. Wijaya’s team reviewed seven studies that included 34,415 patients and found that aspirin therapy demonstrated a reduction in mortality of 44% compared to those who were not taking aspirin. She reports that “Aspirin was previously reported as capable in reducing RNA synthesis and replication of human coronavirus-299E (CoV-229E) and Middle East Respiratory Syndrome (MERS)-CoV”. Thus, aspirin appears to work as a broad-spectrum antiviral drug against numerous coronaviruses. However, Wijaya also mentions that “antiviral properties of aspirin have previously been documented in both DNA and RNA viruses, including cytomegalovirus, varicella-zoster virus, rhinovirus, coxsackie virus, hepatitis C virus, H1N1 influenza virus, SARS-CoV, and CoV-229e.” Besides aspirin’s direct antiviral effect that they report is primarily exerted through inhibition of NF-kB, the authors suggest that aspirin should be beneficial in both the early phase of Covid-19, helping prevent development of severe Covid-19, as well as in the later stage of the disease. They note that “in the late phase of illness where hyperinflammation and hypercoagulable state ensue, introducing aspirin might probably reduce the severity of cytokine storm syndrome through modulation of inflammation, and may prevent fatal thrombosis via several pathways, including…impairing the neutrophil extracellular traps.” As for adverse effects of aspirin, “the incidence of major bleeding between aspirin and non-aspirin users” was 7.6% with aspirin users compared to 6.1%, a negligible difference. (Wijaya)

In 2022 a Chinese and American research team spearheaded by Shaodi Ma conducted yet another meta-analysis of aspirin’s effect on mortality in Covid-19 including seventeen studies totaling 49,041 subjects. They found “that aspirin use was associated with a reduction in Covid-19 mortality” of 31%, but that “low-dose” aspirin use “was associated with a reduced Covid-19 mortality” of 36%. They also found that “aspirin use was not associated with bleeding risk.” They noted that “it is well-known that coagulation dysfunction plays a central role in the pathology of Covid-19, which leads to end-organ complications and death.” “Covid-19 has been associated with growing incidence of thromboembolic complications such as venous thromboembolism (VTE), stroke and myocardial infarction.” They explain that “thrombo-inflammation turns out to be a major cause of morbidity and mortality in patients with Covid-19…[and] aspirin is associated with a reduction in death from acute respiratory distress syndrome in critically ill patients with non-coronavirus diseases.” Finally, they observe that “different dosage of aspirin seems to have different effects on the risk of death in Covid-19. It is indicated that low doses of aspirin have mainly antiplatelet effects while high doses exhibit anti-inflammatory effects.” (Ma)

After all that evidence has been considered, it appears that the antiplatelet effect is aspirin’s most critical contribution against the pathogenesis of respiratory disease, and it should be used at a low dose  between 80mg to a maximum of 325mg daily. Naproxen and selenium should cover the task of inhibiting viral replication primarily through inhibition of NF-kB, plus in the case of naproxen preventing replication by blocking the influenza viral groove. It is also apparent that if a person is taking low dose aspirin prior to infection with a corona or an influenza virus, they will stand a much better chance of survival than if they were not. This suggests low-dose aspirin therapy might be recommended not only for cardiovascular disease but also as prophylaxis against highly pathogenic viral diseases such as Covid-19 and especially H5N1 influenza.           

It is now scientifically well-established that aspirin is quite effective in reducing mortality from ARDS/ALI/MODS and sepsis. Others have also questioned what dosage of aspirin achieves the best results – low dose (75mg to 150mg per day), moderate dose (300-700mg/d), or high dose (1,000-1,500mg/d)? High doses of ASA can cause significant adverse effects while moderate dose aspirin is usually well tolerated in most people. Aspirin has a half-life of 4 hours in the body. German researchers also addressed the question of dosage in 2001. (Muller)

Dominik Muller and his group at the Center for Molecular Medicine in Berlin reported that low dose aspirin was not sufficient to significantly inhibit NF-kB and gain the benefits thereof, but “High-dose aspirin reduced mortality, cardiac hypertrophy, fibrosis, and albuminuria independent of blood pressure, whereas both [high and low ASA] doses reduced cyclooxygenase activity. High-dose aspirin inhibited NF-kB and AP-1 activation and inflammation in heart and kidney.” (Muller) Like NF-kB, AP-1 is a key protein that stimulates viral replication. Technically, it is a replication factor. Thus, moderately high-dose ASA adds a boosted antiviral component to therapy that low-dose aspirin does not. Low-dose aspirin reduces the proinflammatory effects platelets generate but may be insufficient to inhibit NF-kB stimulated inflammation that “activates the genes for IL-1, IL-6, TNF-a, intracellular adhesion molecule-1 vascular cell adhesion molecule (VCAM)-1, and others participating in inflammation.” (Muller) These German authors report that aspirin “protects from angiotensin II-induced organ damage”. Angiotensin II “is a potent activator of AP-1 regulating vascular growth and fibrosis.” They reiterate that “High dose aspirin reduced NF-kB binding, whereas low-dose aspirin had no effect.” “High-dose aspirin also inhibited AP-1 DNA binding activity in the kidney.” (Muller) The high dose of aspirin referred to in Muller’s article approximates 1.5-2.0 grams of aspirin daily. That dose could be achieved by taking one aspirin every four hours. Although that might be a reasonable therapeutic strategy to take where naproxen might not be available, such as rural Africa, high dose aspirin should be avoided when it can be safely and usefully combined with naproxen and selenium.   

Other findings that may be relevant to subgroups infected with H5N1 include that “low dose aspirin is safe in pregnancy and is used to prevent preeclampsia.” “ASA may prove a promising treatment for averting the significant vascular complications associated with influenza infection and pregnancy.” (Coward-Smith) Flu infection during pregnancy increases the chance of “hospitalization, preterm birth, and low birth weights as well as miscarriages, stillbirths, and early neonatal disease and death.” This Australian Irish group showed that low dose aspirin helped prevent “vascular dysfunction associated with maternal IAV infection” and reported that aspirin crosses the placental barrier. (Coward-Smith.)

Obviously, aspirin, one of the oldest and most available drugs worldwide, that even at low doses can provide significant benefits against influenza, should be considered part of any anti-IAV combination therapy or standard of care – except for prepubescent children. Years ago, I ran into the famous Dr Robert Gallo, the most referenced scientist in the history of medicine, while attending the 1995 International Conference on Virology at the Moscone Center in San Francisco. I asked Dr Gallo what he thought about my observation in early 1991 concerning aspirin’s effect in increasing CD4 count and its effect against HIV disease that I had published in an abstract at the Amsterdam International AIDS Conference in 1992. Gallo reflected for a moment and replied, “Aspirin? Aspirin? Aspirin is the greatest drug of all time. I take it every day for the heart.” Indeed, after researching this essay and discovering aspirin’s potent effect against viral respiratory diseases and knowing of all its other effects including as prophylaxis against cancer, I cannot help but agree with that great scientist, “Aspirin is the Greatest Drug of All Time”.

Based on the above review of the relevant science and in consideration of its use in combination therapy with selenium and naproxen, 325mg of aspirin a day should be the best dose for physicians to recommend for early flu therapy and to save lives from HPAI H5N1 or similar viral respiratory diseases. Every combination therapy used against the potential approaching pandemic tsunami should include this underappreciated little white tablet that no longer receives the respect it deserves from the medical community. It is just too common, cheap, multipurpose, superannuated – and powerful! Indeed, in the Age of Respiratory Pandemics, aspirin is a life saver. When used correctly, its benefits are impressive. They are especially so in light of its effect in retarding the powerful part platelets play in triggering the immune response.                      

c.       Naproxen – NF-kBI rating – (6x). COX-2 inhibitor.

      In 2013 French scientists led by Nathalie Lejal at the National Institute of Agricultural Research conducted a laboratory screening of over 100,000 drugs and molecules and determined that naproxen was the most effective against replication of both the H1N1 and H3N2 flu viruses. (Lejal) That is because the naproxen molecule fits snuggly into the IAV RNA groove binding site whose configuration is well conserved among different IAV species. This viral groove is common to all influenza A and B species and does not mutate. Thus, unlike with current specific anti-influenza drugs like OTV and BXM, IAV and IBV (influenza B virus) do not become resistant to naproxen. By filling that viral groove naproxen blocks the protein that normally upregulates influenza replication. (Lejal) In other words, naproxen targets the influenza A nucleoprotein and inhibits its binding to the well-conserved RNA viral groove, thereby inhibiting viral replication. Naproxen is nontoxic at the dosage needed to treat IAV. It quickly reduces the viral titer - viral load - and reduces weight loss related to influenza. (Lejal) Those qualities would make naproxen almost surely the most effective antiviral drug directed against H5N1- far more effective than OTV or BXM. In their experiments Lejal’s group showed that “naproxen reduced the [viral] titers to 7% relative to controls”. That is a 93% reduction. “Thus, the naproxen antiviral effect was significantly more potent than those of nimesulide and the other COX-2 inhibitors tested. Naproxen presents a reasonable selectivity index compared to other antivirals”. “Besides its antiviral effect, naproxen reduced lung bleeding.” (Lejal) Lejal concludes by explaining “the efficacy of a drug is improved by reaching more than one target while being nontoxic, naproxen has the advantage of inhibiting both COX-2 and the nucleoprotein of influenza A virus. Naproxen is more potent than COX-2 inhibitors such as nemesulide against influenza A virus challenge. Importantly, naproxen is a safe, potential pharmaceutical readily available for cases of resistance to antiviral and if an IAV infection pandemic emerges.” (Lejal) To note that naproxen inhibits NF-kB six times as strongly as aspirin would be redundant. (Tanaka)      

 

      Two years later in 2015 another French research group confirmed that influenza viruses do not become resistant to naproxen. They ran Tamiflu treated viruses through cell culture four times and they all became resistant. But after running naproxen treated cells through that same type of culture eight times, none of them developed resistance. They suggested that a naproxen analogue they referred to as C0 might work even better than naproxen (Tarus). But that analogue drug may not have been tested yet. A different French group led by Sebastian Dilly emphasized that naproxen is “a dual inhibitor of [the IAV nuclear protein] and cyclooxygenase COX-2, thus combining antiviral and anti-inflammatory effects.” (Dilly) They thought their naproxen analogues 2 and 4 were superior to naproxen, but progress on those derivative drugs is uncertain. They noted, “bi-therapy is more effective with drugs addressed to two targets”. (Dilly)       

 

      Extending its reach as a broad-spectrum antiviral, in 2018 Chinese scientists at Sun Yat-Sen University showed that naproxen inhibits Zika virus (ZIKV) replication. Naproxen and some other “NSAIDs exerted this inhibitory effect by potently reducing the expression of AXL, the entry cofactor of ZIKV.” (Pan) This may have implications for other viruses in the Zika family of Flaviviridae viruses that include dengue, yellow fever, West Nile, and Japanese encephalitis. Led by Ting Pan, this group tested several NSAIDs including lornoxicam, acetaminophen, ibuprofen, aspirin, and naproxen. Naproxen proved to be most potent at downregulating the AXL entry cofactor in Zika-targeted cells, and at safe concentrations. (Pan) The authors explain that “the potent inhibitory effect of NSAIDs on ZIKV infection via AXL targeting may efficiently prevent the transmission of ZIKV from the maternal compartment to the fetal compartment.” (Pan)    

 

       In 2019 researchers led by Weinan Zheng from the Chinese Academy of Sciences and the Chinese CDC demonstrated that naproxen was superior to oseltamivir in fighting IAV. “We show that naproxen is a potential broad, multi-mechanistic anti-influenza therapeutic” and one way it works is by antagonizing the export of the nuclear protein (NP) out of the nucleus “by the host export protein CRM1.” “This study reveals a crucial mechanism of broad-spectrum anti-influenza virus activity of naproxen, suggesting that the existing drug naproxen may be used as an anti-influenza drug.” (Zheng) Zheng’s group explained that naproxen works as an antiviral thorough multiple mechanisms and they “examined the effect of naproxen on influenza viral replication at both the early and late stages of viral infection”. They compared the survival of B-Yamagata-[flu strain]-infected mice and showed that with oseltamivir 75% survived. With high dose naproxen 87.5% survived, and with low dose naproxen 100% of mice survived. Naproxen therapy also “reduced the lung indices and virus titers”. (Zheng) Detailing their work they showed that “ANP and BNP were overwhelmingly found in the cytoplasm in nearly all infected cells without naproxen, whereas they were clearly retained in the nucleus in naproxen treated cells.” “Thus, naproxen administration suppressed ANP and BNP nuclear export during virus infection.” They found “naproxen inhibited the replication of influenza A and B viruses by blocking CRM1-mediated NP nuclear export.” (Zheng) They tested whether this had the same effect on other viruses and determined that “naproxen is likely to affect the nuclear export of vRNP complex [of similar viruses].” “Our results suggest a crucial antiviral mechanism of naproxen through targeting NP nuclear transport, which is especially intensified by the facts that NP is highly conserved among different influenza isolates, and nucleocytoplasmic transport of NP is one of the key steps for the replication of influenza viruses.” (Zheng) Finally they suggest that naproxen “could be implemented into influenza treatment protocols more quickly than other antivirals in development.” (Zheng) Recognizing the critical importance of this well-established science should require immediate action by American public health officials to stockpile naproxen for current and future respiratory pandemics.

 

      In 2021 another high-level French collaboration led by Olivier Terrier of the International Center for Infectious Research addressed how beneficial naproxen is against Covid-19. They demonstrated that “naproxen specifically inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2-induced damage.” “we assume that impeding N function associated with viral replication would be the main mode of action explaining the observed antiviral effect of naproxen.” “the N protein drives virus assembly and budding.” (Terrier) “Naproxen’s mechanism of action demonstrated here involved the inhibition of N oligomerization associated with its antiviral effect. Nevertheless, we cannot rule out that naproxen might bind other viral targets, such as the viral 3C-like protease, as suggested by some modeling studies”. Touting the “Broad-spectrum antiviral activity of naproxen” and importantly that it “protected the pulmonary epithelium from the pandemic virus induced damage”, they recommended “Naproxen addition to the standard of care [for Covid-19] could be beneficial in a clinical setting.” (Terrier) “Naproxen, being an easily affordable drug, could help in the worldwide, long-lasting pandemic crisis [of Covid-19] we have already been experiencing for a year.” They also noted that ibuprofen and celecoxib do not show the same antiviral effect against SARS-2 as naproxen does. (Terrier) Thus, if governments and the WHO had used naproxen as early therapy against Covid-19, hundreds of thousands of lives could have been saved. The science was there, but the bureaucratic will of  national and international public health officials who should have been paying attention to the research was missing in action. The tragic failure to do so was distressing, painful, and costly in lives and finances for everyone worldwide.   

 

      Finally, in 2024 a group of scientists in Hong Kong led by Han Wang showed how naproxen could prevent the cytokine storm caused by acinetobacter baumannii (Ab) bacterial infection in the lung. This should also apply to respiratory diseases such as SARS-1 and -2 and H5N1 influenza and bacterial infections that also generate cytokine storms – starting in the lung. Wang “highlighted the critical role of alveolar and interstitial macrophages of Ab during the infection process. These cells were found to undergo polarization towards M1 phenotype, triggering a cytokine storm that eventually caused death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-kB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen was shown to confer full protection of mice from lethal infection.” (H. Wang) “We showed that the drug naproxen could effectively suppress excessive inflammatory response in infected mice, thereby protecting the infected mice from death.” Naproxen “protected 100% of the infected mice from death within 120 hours, indicating its superior effectiveness compared to” dexamethasone, cyclosporin A, aspirin or azathioprine. (H. Wang) They explain that “the TLR2/MyD88 pathway activates the transcription factor NF-kB and promotes M1 macrophage polarization, thereby inducing over-production of inflammatory factors IL-1b, IL-6 and TNF-a. As a result, a severe cytokine storm is triggered, producing a systemic inflammatory response syndrome which is often associated with systemic organ failure and even death”. (H. Wang) They showed that both aspirin and naproxen “exhibited relatively high efficacy as a therapeutic agent that acts by inhibiting the Ab-triggered cytokine storm, with naproxen being the most effective.” Finally, they mention that “COX-2 has been regarded as the most suitable target for anti-inflammatory drugs.” “the therapeutic anti-inflammatory effect of NSAIDs is achieved by inhibiting COX-2, whereas the adverse side effects are primarily associated with COX-1 inhibition.” Their study revealed “a critical link between macrophage polarization, neutrophil activation, cytokine storm and host mortality.” (H. Wang)    

 

      After the above evidence is weighed and fully considered, it is easy to conclude that although OTV, BXM, Se, and ASA are all effective against IAV, naproxen is probably the most effective. However, the more of these antiviral medications we can combine as therapy, the more we can reduce the morbidity, and mortality associated with H5N1. A reduction in deaths of up to 80-90% is not unreasonable to expect if people begin combination therapy as quickly as possible after flu symptoms are clearly apparent. That should emphasize the need to provide affordable, life-saving, SAN antiviral home first aid kits, plus quality face masks, to every home, once a pandemic begins, along with instructions how to use them safely.              

9.      When will a H5N1 vaccine be available?

            The Food and Drug Administration (FDA) has already approved several vaccines for H5N1, and the U.S. has a stockpile of almost five million vaccine doses with additional precursor chemicals stored, ready to quickly produce more. (Mandavilli 4/24) The U.S. Biomedical Advanced Research and Development Authority (BARDA) is on top of the situation. Working with its partners in the vaccine industry BARDA can quickly develop a vaccine to match a particular variant that gains the ability to transmit between people. (CDC) However, as with Covid-19, the world saw that vaccines are lifesaving yet still imperfect since they cannot prevent all infections, secondary infections or illnesses. As with SARS-2, mutant variant viral species can rapidly emerge with slightly different disease characteristics. Thus, just like with Covid-19, updated vaccines will be required on a regular basis. Several hundred million doses will be needed in the U.S. alone.

            According to the American Medical Association seasonal flu vaccines are usually 40% to 60% effective in preventing initial flu infection, although this range can vary. However, they also help prevent more severe disease and mortality. (Berg) Like Covid-19 vaccinations, flu shots primarily prevent or limit severe disease and death. That includes reducing the chance of developing “long-influenza” - post avian influenza syndrome (PAIS). However, H5N1 flu inoculations are not available yet. They will not be available for most people for an estimated six to eight months after a pandemic is officially declared. As with SARS-2, by the time most people get vaccinated, the first wave of bird flu will have flown around the world more than once, mutating and reassorting as it goes - just as it did in 1918, or Covid-19 did in 2020 - killing millions. As in both 1918 and 2020, densely populated, hygiene challenged India may suffer the greatest losses.  

            A European company, CLS Seqirus is already producing thousands of H5N1 vaccines to protect farm workers. Once a pandemic is announced they will ramp up production to provide 150 million vaccine doses within six months. (Johnson) Many multiples of that will be needed. However, given the continuing appearance of individual cases in the U.S. and the historically extremely high mortality rate of 52% (Johnson), it would be a wise precaution for the U.S. government to immediately begin producing an emergency supply of H5N1 vaccines based on the B3.13 genotype to protect frontline medical workers such as physicians, nurses, and other health care professionals, even if those contingency vaccines are not of the precise eventual breakout variant of H5N1 that goes pandemic. Regardless, those initial clade-based vaccines should provide some protection. Hospital, clinic, and nursing home workers are always the hardest hit at the onset of a contagious respiratory pandemic. The time for action is now, not six months from now. It takes at least six to eight months to formulate, test, manufacture, and distribute vaccines. Given that most humans have no innate retained historic immunity to this highly pathogenic H5N1 strain, if vaccines are not quickly available, an unimaginable worst-case scenario may unfold. Although some virologists theorize that there may be some limited natural immunity already in the population because other flu strains have included the N1 component of H5N1, given the extreme virulence and lethality this particular clade has shown among other mammal species, health agencies should prepare for the worst even while hoping for the best. Applying the above detailed scientific knowledge about how early therapy can help save lives should avoid another catastrophe like Covid-19.           

10.   Can any medicine be used prophylactically against H5N1 to reduce the chance of infection and the severity of disease?

            Given its moderately high toxicity profile and its rapidly diminishing effectiveness when used, oseltamivir/OTV should not be considered as first choice for prophylaxis against H5N1. Its cost-benefit-risk ratio is misjudged by those who propose Tamiflu as prophylaxis against flu. Selenium, low dose aspirin and low dose naproxen would each probably be as effective or more effective than Tamiflu. In combination they definitely would be.      

            Based on multiple scientific reports, having lower levels of selenium in the body significantly increases viral infectivity and the chance of contracting enveloped RNA viral infections, including colds, influenza, Covid-19, or even Ebola. (Luty-Franckiewicz, Beck, Taylor, Rataan) In the 2014 Ebola epidemic in West Africa, selenium was used widely in Liberia as prophylaxis against Ebola virus disease. (personal knowledge) Although we may not know precisely how effective it is against IAV, the scientific literature is replete with evidence that selenium is an effective antiviral and that it can be used prophylactically to reduce susceptibility to respiratory viral infection. Se is used as a food supplement in the poultry and livestock industries, in part to do exactly that, and to improve farm animal health, reproduction, and growth. Selenium supplements are extremely safe and affordable. There are no pharmaceutical contraindications, and they provide ancillary health benefits besides a reduction in susceptibility to contagious viral infection.  

            As an immune booster, taking one 325mg aspirin a day also theoretically should provide prophylactic protection from H5N1. Most people should be able to take either selenium, aspirin, or both as prophylactic protection during pandemic times, reducing the odds of infection and reducing the chance of severe infection if they do become infected. However, these do not replace the need for vaccines. Naproxen can also be used prophylactically. However, naproxen is more appropriate when there is a substantial risk of immediate infection as when a housemate is infected, there is another close contact who is ill, or if one works in close contact with H5N1 patients and lacks protection like masks or vaccines. Naproxen would be most useful over a brief time such as two weeks while low dose aspirin or selenium can be used by most people continuously, for years if necessary. In cases of close contagion when living or working closely with those who are infected, a combination of selenium  and aspirin should be used to reduce the chance of and impact of infection. As an example, I have used both 325mg ASA plus 200mcg Se daily for over 25 years because I want to maximize the strength of my immune system, avoid additional viral infections, and gain the other health benefits of selenium.           

11.   Will there be a post H5N1, “long influenza” syndrome like long Covid?

            Yes, almost assuredly. The previous influenza pandemic most comparable to H5N1 was the 1918-20 H1N1 Spanish avian influenza that had an estimated mortality rate of approximately 2% worldwide, killing between 50 and 100 million people. (Beach) That pandemic was followed by a widespread post-infection syndrome that included symptoms similar to long Covid. Those symptoms included depression, tremors, nervousness, listlessness, fearfulness, and inability to work. (Tufekei)

 

            Scientists have theorized that a sudden dip in the selenium level in the body caused by severe viral diseases such as SARS-2, H5N1 or pregnancy, or physical trauma severely impacts immunity. That sudden shock to the selenium supply and the physiological dysregulation it causes may trigger the onset of autoimmune disease. (Schomburg) Lutz Schomburg of Humbolt University in Berlin suggests that “The risk for dropping into the danger zone of severe Se deficiency and immune system failure can be reduced by early Se supplementation.” “A decline below a certain threshold may tip the balance from regular lymphocyte function to disruption of self-tolerance, triggering autoreactive processes.” “In view that severe Covid-19 causes very strongly decreasing Se status, high mortality risk, and newly developing autoimmunity, it may also be hypothesized that severe Se deficiency may be related to post-acute sequelae and long Covid symptoms.” (Schomburg) This should also hold true for H5N1 and development of PAIS – post avian influenza syndrome. Other viruses that have provoked post infection syndromes include, Ebola virus disease (EVD), the 1918-20 H1N1 Spanish flu, SARS-1, Covid-19, and West Nile, Zika, Chikungunya, and Epstein Barr viruses.

 

            As Lillian Santos writes, “The “selenostasis” maintenance seems to contribute to the prevention of immune mediated thyroid disorders.” She explains that “The thyroid gland, in particular, is characterized by a high concentration of selenium, which is incorporated in several selenoproteins with key functions in the gland. Not surprising, selenium deficiency may impair thyroid function.” This must be due in part because selenium is more concentrated in the thyroid gland than in any other part of the body. Thus, if the United States wants to avoid another healthcare budget burdening follow-on pandemic of a post-viral disease, autoimmune-related syndrome with tens of millions affected, as it endured following Covid-19 with PASC/long Covid, it would be wise to start treating H5N1 infections from day one of symptoms with highly affordable, safe, selenium supplements and a combination of drugs that can be used as early therapy against H5N1. Failing to implement sensible precautions with SAN will significantly increase society’s disease burden of the follow-on pandemic of PAIS and the tremendous additional healthcare costs that will entail.          

12.   Pandemic Preparedness:

            How can health officials reduce the problem of medical misinformation and improve their response to the approaching H5N1 pandemic compared to their problematic response to Covid-19? To avoid reliving the previous self-inflicted tragedy, health officials should acknowledge the slightly arcane but obviously well-established science and recommend SAN home viral first aid medication for early therapy instead of injudiciously offering nothing at all and then discovering that resistance generating Tamiflu briefly works not too effectively before it does not work at all. Although Tamiflu and BXM are somewhat beneficial, the failure to inform the public about early therapy they can  use to reduce the symptoms and progression of H5N1 disease will end in a disastrous excessive toll in morbidity/illness and mortality/death. That can and should be avoided by having the CDC and state departments of health inform people how they can protect themselves and their families by preparing early therapy kits to survive what will most likely eventually be a catastrophic HPAI pandemic. Unfortunately, once patients receive a prescription for Tamiflu and Zofluza several days after initial infection, the viral horse is already out of the barn. By then the immune system is starting to shift into overdrive into the second phase of the illness that causes most of the problems associated with HPAI – the extreme overreaction of the immune system – the cytokine storm.             

 

            In the Covid Crisis of 2020-21 American health authorities lost control of the narrative and the confidence of a significant portion of the public by trying to maintain too close control over information at a time when people logically wanted understandable, actionable medical facts that would allow them to protect their health. When imminent danger threatens a community, a country, or the world, people want to know how they can maintain some degree of personal autonomy and choice and take informed, science-based action to save their lives. When a lethal pandemic threatens them and their families, people want more than just a facemask and hand sanitizer and an order to quarantine at home waiting for vaccines to be developed, tested, approved, produced and distributed. People want a safe and effective prophylactic drug, even if it is not perfect, plus information on what pill to take if they begin to experience symptoms. With thousands of drugs developed over the last 125 years, surely something must be effective against flu or Covid. If health officials fail to provide guidance pointing to at least some minimal remedy, people inevitably resort to do their own “research”. Then they end up following others down the misinformation/disinformation rabbit hole grasping onto ill-founded quasi-medical solutions such as chloroquine and ivermectin, not appreciating that what works against parasites probably does not work against viruses that are a million times smaller. In the early days of Covid-19, based on both antiquated and more recent third-rate science that had been published but often then retracted, some legitimate scientists did suggest that chloroquine might help against SARS-2, unaware it increases NF-kB and promotes viral replication and disease progression. Without appreciating the greater scientific context, based on shoddy research chloroquine looked good theoretically, even to some few physicians. But in the end, those who took chloroquine (CQ) or hydroxychloroquine (HCQ) experienced negative adverse effects that advanced disease progression instead of retarding it. Those medical doctors did not recognize how CQ and HCQ affect the immune system and increase viral replication.       

 

The failure by health officials including the NIH, CDC and WHO to provide at least minimal helpful directions to people based on known immunological and virologic principles while those same authorities coordinated with their pharmaceutical industry partners to develop “new” drugs for a “new” disease while millions worldwide died waiting, led to understandable mistrust and resentment that the people welding institutional power do not really care about the citizens they are supposedly entrusted to protect. This lack of trust by people who see national and international health institutions appearing not to be acting in the public’s best interests spilled over into the public’s greater disregard, even rejection of messages coming from those institutions and resulted in a worse overall outcome for society. Countries where there was more trust in government and science fared better in the Covid-19 pandemic than the U.S. where people were more skeptical, cynical, or sci-phobic. This seems like an impossible problem to solve. It cannot be solved completely or quickly. But one giant step can improve that situation. That is by providing better, more honest information about what existing drugs or medicines can be used at home to reduce the chance of transmission and to help slow progression of the disease if one starts to experience symptoms of H5N1. Repetition of “There is no treatment. There is no cure” or offering only a treatment like oseltamivir that quickly will become mostly ineffective in a pandemic does not build trust. After more than a century of progress in virology and immunology research and pharmaceutical development, there should be some protective beneficial therapy to offer the public, even if it is not perfect. A hundred years ago “Take two aspirin and call me in the morning” was good advice from the family doctor. Today pairing ASA with selenium and naproxen provides a complete home action plan that people can believe in – because it is safe, available, affordable and 100% supported by science. Individually, all three of these broad-spectrum antiviral medicines have been shown scientifically to work against influenza and many other viral infections. SAN provides benefits against both influenza A and B, Covid-19 and probably RSV – not to mention the list of viruses previously named in this essay. Denying or ignoring that science or trying to cover it up does not build trust. It only leads many more to the threshold of the misinformation rabbit hole. Untrained amateurs doing their own research is not healthy for society in the Age of Pandemics. That is why the U.S. had the second worst mortality rate of any advanced nation during the Covid Crisis. Trying to hide the fact that naproxen is more effective in inhibiting influenza than Tamiflu will not build trust in a health establishment that is no longer trusted by too many already. In the end, covering up life saving science serves no one except the undertaker.      

 

            During the Covid Crisis of 2020-21 the leadership at the NIH repeatedly misinformed the public and medical professionals alike that there was nothing at all they could take for early SARS-2 infection. It was if they said, “Sorry folks, you’ll have to try to recover from your initial infection without our help. And good luck if you end up with long Covid. But if you eventually do become seriously ill, come to the clinic or hospital and we’ll give you strong medicine, like dexamethasone. That may save your life. Until then, good luck. You’re on your own.” No wonder people scrounged information from Mexico, Peru, India and Egypt where people commonly take ivermectin for worms, or hydroxychloroquine for malaria. Individuals and local physicians in those nations looked to their lowest common denominator of pharmaceuticals and thought, “Why not try this? It is on the shelf. What do we have to lose?” Indeed, there had been medical journal articles suggesting chloroquine or ivermectin might work. But on average, 10% of all published medical journal articles, even peer reviewed ones, are not 100% correct – or just plain wrong. Mistaken science sometimes slips into the system. Americans who followed the dream of “Do your own research” were entranced to follow along and promote the antimalarial chloroquine, an NF-kB promoter that increases inflammation, viral replication and disease progression. They had no idea. But nature abhors a vacuum and that is exactly what the NIH created. Their thinking must have been “any pharmaceutical port in a storm” no matter how ill considered. Even President Trump repeatedly touted hydroxychloroquine as if it were a miracle cure and informed everyone he was taking it. Someone must have been profiting. Two years later, a final meta-analysis determined that 97% of those who used chloroquine or hydroxychloroquine against Covid had worse outcomes than average. (    ) The failure of the U.S. health bureaucracy to offer any rational alternative ended up doing tremendous harm causing untold deaths. Taking no action ended up doing far more harm than providing at least some minimal common-sense guidance based on science, even if it might have been imperfect and obviously not an absolute cure. Realistically, neither perfection nor absolute cures are often achieved in medicine. But serious harm was done during the Covid Crisis when existing science published in reputable medical journals over the previous two decades confirming the benefits of aspirin, selenium and NF-kBIs like naproxen was ignored by the medical establishment in favor of the siren song of blockbuster new drug development. “Just wait a little longer, then a little longer, and soon we might have a miracle cure for you. Just keep waiting. It will be great. Just wait and see.”  

 

            Likewise, a meta-analysis of ivermectin eventually found no benefit against morbidity. Although one  systematic review and meta-analysis detected a 3% reduction in mortality rates compared to average but no other symptomatic benefit against the disease, that finding was not highly significant. Two later meta-analyses found no benefit at all from the use of ivermectin against Covid-19. (Hernandez, Marcolino) That was not a great if one took ivermectin instead of dexamethasone that reduced Covid-19 deaths by between 17% and 33% (    ) and saved more lives than any other drug during the pandemic. (Barry) It is not as good as aspirin would have been if aspirin had been used at the correct dose. What can only be correctly labeled as propaganda from Dr Anthony Fauci and the NIH was that there was nothing available to treat early Covid-19. (Kim)  “There is no treatment…” That misinformation resulted in more than doubling of the mortality rate in the U.S and probably doubling the incidence of long Covid – post acute sequelae of Covid (PASC). Both Covid-19 mortality and long Covid would have been substantially reduced if medical authorities had recommended a simple program of known broad-spectrum antiviral drugs that people could have taken as outlined here. The antiviral benefits of aspirin, naproxen, and selenium were all known to science prior to the outbreak of Covid-19. However, the NIH, CDC and WHO failed to do their own research. It is incredible that after over one hundred years of new drug development since the 1918-20 Spanish Flu epidemic killed 675,000 Americans, there was still nothing health officials could offer those frightened to death by Covid-19, despite over twenty-five years of research and accumulated knowledge about the cytokine storm. Had science not made any progress against respiratory disease in that entire century? Even in 1918 people knew about aspirin - just not how to apply it correctly. Instead of mini-dosing ASA as recommended here, in 1918 they grossly overdosed it based on the advice of the then medical establishment – U.S. Army doctors.   

 

            “There is no treatment. There is no cure.” was the same Orwellian mantra that was chanted at the beginning of the AIDS Crisis in the early 1980s, then again when the West African Ebola epidemic hit in 2014, then for Zika and again for Covid-19. Mind numbingly propagandistic, meant to cover up the existence of broad-spectrum antiviral drugs, that mantra was only half true. While health officials appear to continually protect the interests of their partners in research and the pharmaceutical industry, average Americans are left in the lurch without a single tablet or pill to protect their lives or the lives of their parents, children or loved ones. No wonder people tried to do their own research. The NIH and CDC failed to do it for them. What is government for anyway? When was common sense and caring banished from government service? During the Covid Crisis of 2020-21 health officials failed miserably in their primary mission to protect the health of the people. They failed to provide guidance to at least some initial partial antiviral protection or immune support. They failed to think outside the profitable pharmaceutical new drug development box. As a result, people suffered, died, and millions ended up with long Covid. In fact, I contacted Dr Anthony Fauci’s assistant at the National Institute for Allergy and Infectious Disease (NIAID), Dr Clifford Lane three times by email in March 2020 and attached my essays recommending the use of broad-spectrum antivirals, aspirin and selenium against SARS-CoV-2. If they had used even that simple dual combination therapy as early therapy, the scientific articles referenced in this essay suggest that should have reduced mortality rates by 50% to 70% or more. In Liberia in 2014, adding 1.2 mg of selenium alone to supportive care reduced mortality rates due to Ebola-Zaire by 43.6% compared to supportive care alone. If physicians had added naproxen to ASA and Se against Covid-19, mortality rates might have been reduced by up to 80% to 90% - or at a minimum 60%. To repeat a medical truism – early therapy is the best therapy. Why did we fail to use it? Were potential pharmaceutical profits more important than people’s lives? The eventual cost to society was immeasurable.    

 

            Although the NIH mantra was “There is no treatment. There is no early therapy.” After twenty years observing health systems in Africa my own advice has always been, first do not harm – but in the end, “Doctor, use what works.” Often, too much harm is done when nothing is done, or existing science is simply ignored.  U.S. health authorities failed to even try to use what works or what the science referenced here already had shown works. Why? But when those who are in responsible positions do not even try, they are guaranteed to fail. As hard as it is to admit, an excess of hundreds of thousands of Americans died of Covid-19 as a result. America’s top health institutions failed the nation. As exemplars of science, they also failed the world. Americans must never allow that to happen again. It could happen again – soon – only  worse.            

 

            Indeed, the NIH and CDC should learn from their mistakes. But how can they if they fail to recognize them? Perhaps it is not in their financial interest to do so? Instead, they need to recognize and apply the overlooked or covered up simple science of broad-spectrum antivirals and improve their performance against N5N1 HPAI. Otherwise, if the H5N1 pandemic is as lethal as indications suggest it might be, there will not be enough cemetery plots left in the nation to bury all the dead – healthcare workers included. I have seen the expansive graveyards of South Africa, the legacy of the AIDS crisis. Here as there, pandemic negligence has consequences. We live in a world of viruses. We need to stop ignoring how we can protect ourselves from the consequences of living in the virosphere. Pretending our troubles all come from an imagined lab leak in China when a million birds with H5N1 fly above our cities is the essence of scientific obliviousness.   

 

             Due to lack of enlightened guidance from the NIH, during the first year of Covid-19 many physicians were as confused and directionless as the public was. A continued failure today to provide or inform the public about the possibility of a simple, scientifically based, common sense, home action plan to stock medicines people can take if they start to feel sick with the flu would call into question the competence, good faith and responsiveness of government. As explained here, the often-repeated message that “There are no medicines to treat early Covid” was a lie. It led many who resorted to doing their own research to end up in the confusing medical misinformation cul-de-sac of chloroquine/ivermectin. The NIH/CDC created the problem of misinformation which they then decried after they failed to offer a better solution which they could have based on a sound understanding of the established science presented here. The resulting information vacuum from the top of the scientific ladder was filled by those who promoted ivermectin as prophylaxis against Covid from the bottom of the ladder of medical knowledge. That was dangerous. Ivermectin is essentially parasitic worm poison. It becomes a people poison if too much is ingested. The NIH and CDC could have recommended something safe and simple that works, like naproxen, aspirin and selenium. But that was too cheap and simple – and did not require a physician’s prescription. The NIH and CDC failed “to do their own research” and ignored the scientific facts reported here so misinformation and confusion filled the public square that health officials had abandoned, leaving an information vacuum waiting to be filled. I knew selenium and aspirin would help against Covid and wrote about it in the first two weeks after Covid was announced. The public demands better from a health bureaucracy that could have done better but did not. That falls on the deaf ears of politicians who should not be expected to know this information but lacked the political will to question expert opinion and demand better. In 2020 the NIH and its industry partners looked forward to developing novel, hoped-for solutions instead of utilizing he already known science-based solutions discussed here. After almost two years and ordering tens of thousands of ventilators, the NIH finally developed an expensive double protease inhibitor, Paxlovid. Paxlovid has numerous pharmaceutical contraindications and unfavorable adverse effects. Today, only 16% of those who should benefit from it  for Covid find it acceptable. (    ) The time it took to develop that novel pharmaceutical was highly problematic. It cost hundreds of thousands of Americans’ lives who waited for it to be developed while they were not informed about simple drugs that science had previously shown could be effective in slowing the progress of viral respiratory disease. The eventual death toll of 1.2 million Americans was problematic indeed. That was more than all the American combat deaths in all the wars this nation has fought. We lost the war against Covid-19. We can’t afford to lose the war against H5N1.                      

              

            So, what is the solution to the pandemic dilemma we now face with H5N1?  As I often advised during my 20 years in Africa where appropriate resources were often in short supply and I still do, “Doctor, use what works.” In this case SAN first aid kits for the home will help save lives from the rapid onset of H5N1 influenza. Without SAN home first aid kits the healthcare system quickly will be overwhelmed, and people will wonder why no one informed them how to reduce the chance they would fall seriously ill. Encephalitis can strike on the first day of H5N1 infection so people being prepared to take immediate action to prevent that is essential. When the pandemic eventually emerges, public health officials immediately will be confronted with the disinformation chorus hyping chloroquine/ivermectin and the ultra-confusion and science questioning attitude that will ensue. If so, government health authorities again will have recreated their own self-generated, medical misinformation Pandora’s Box.    

 

            The Hippocratic Oath includes much more than just the words, “First, do no harm.” Not informing people what kind of first aid measures they should have available and ready to use to protect themselves against the initial symptoms of H5N1 HPAI would seriously harm millions. Health authorities should do everything they can to save lives and reduce the potential for a follow-on pandemic of long influenza/PAIS that may make the number of people long Covid has affected pale in comparison. Safe, affordable SAN influenza first aid kits for the home should be a key tool in the national medical pandemic planning toolbox, complementing vaccines, personal protective equipment, face masks, and clinical and hospital care. Affordable $25 SAN home first aid kits will eventually save the government billions, perhaps trillions of dollars, and thousands if not millions of lives. If these kits are provided to people by health agencies additional educational material about how to stay healthy and survive the pandemic can be packaged with them. They should be an indispensable tool in the public health pandemic tool kit.

 

            The solid science is clear. Now physicians just need to use what works and health officials need to act responsibility and inform and instruct the public how they can protect themselves and their families before the pandemic strikes. Providing lifesaving, science-based information should not be too much for citizens to ask of their government. The question is, do public health officials and the medical establishment trust people enough to use their common sense and follow instructions how to use SAN if they are informed about it? It is about as simple and safe as using a fire extinguisher. If people cannot be trusted to even take an aspirin or selenium tablet on their own to protect their health, then it is time to order a million new ventilators because they will be needed. That is the choice. Early therapy to help prevent hospitalization - or overtime pay for those working in the ICU. Early therapy is the best therapy. With Covid-19 why did the health establishment drop the ball when we the people needed its protection the most? As President George W. Bush said, “Fool me once, shame on you. Fool me twice…well, you better not try to fool me a second time.” Appeal to authority while failing to examine the evidence is a common logical fallacy. Unless people take a hard look at the science as presented here and not just rely on “expert opinion”, America and the world will become the victim of a pandemic much worst that anyone has ever lived through before.               

13.   Conclusion:

            The current specific viral-targeted therapeutic paradigm for treating influenza that depends on only NIs and MXB is comparable to trying to protect humanity from a herd of charging elephants with a two-foot-high picket fence, building a house with only one wall, or a nation going to war depending on only a single type of rusty weapon. It is ill-conceived, myopic, scientifically outmoded, and wholly inadequate. Current, specific, antiviral drugs directed only at viral enzyme targets will be quickly overtaken by resistance from a hyper-replicating, rapidly mutating, highly pathogenic influenza A virus. Although IAV infection initiates the disease process, like most other severe respiratory diseases, the symptoms and resultant physiological damage, morbidity and mortality are caused not by the virus directly, but rather by the uncontrolled, overpowering immune response to the virus that precipitates the cytokine storm. Trying to arrest the H5N1 viral firebug that ignites the inflammatory fire while failing to control and extinguish the cytokine and NF-kB fueled inflammatory conflagration itself, is to fail conceptually in the face of an approaching, probable, once-in-a-millennium mega-lethal pandemic whose emergence, after person-to-person transmission begins, cannot be predictably timed.  

            The NIH, CDC and WHO need to reassess their approach to pandemic respiratory disease or otherwise millions of excess lives will be lost again instead of just the hundreds of thousands of excess lives unnecessarily lost in the U.S. alone due to a negligent, myopic governmental response to Covid-19. We can no longer afford to follow the mistaken paradigm that has insisted in Covid-19, the West African Ebola epidemic, and the AIDS pandemic, that for every new disease, we must develop a new drug. That course takes years and costs millions of lives. Respiratory pandemics are not like HIV disease that is caused by a lentivirus – a slow virus. Respiratory pandemics are mostly finished before new drugs even can be developed. Yes, obviously everyone wants to inhibit the cause of the disease – the virus. More importantly, however, we also must treat the disease itself by both preventing and suppressing the cytokine storm and sepsis that leads to multiorgan failure and death. Everyone wants new and better drugs, but not at the price of a million lives lost while waiting.

            Medical authorities should utilize these proposed possibilities for therapeutic prophylaxis against H5N1, even if they are not perfect. Prophylactics seldom are. Neither are vaccines. Health officials should open both eyes and focus on combating the main threat to life and health, the cytokine storm, instead of focusing only on the virus. Rather than denying they exist, authorities should educate and alert the public about how people can plan to prepare and use first aid for viral infection based on applying broad-spectrum antiviral medicines from the first hour flu symptoms occur with approved, safe, effective, available, affordable medications including low-dose aspirin, naproxen, and selenium supplements. They can layer on prescription Tamiflu and Zofluza after they visit their physician. Based on historic clinical trial data referenced in this essay, used correctly in combination, SAN plus OTV/BMX could possibly reduce H5N1 pandemic deaths by up to 80-90%. The CDC should educate people and trust them to use affordable, available SAN first aid until they are able to see their physician or reach a hospital where additional therapy can be added with prescription COX-2 inhibitors, S1P-1 agonists or other approved remedies. Those late-stage disease therapies will be reviewed in Part 2 of this essay.

Faced with a hyper-replicating virus that increases exponentially, every hour counts. To delay access to or deny knowledge about broad-spectrum antiviral first aid that people themselves can safely use would constitute unconscionable medical negligence. Otherwise, the knowledge gap will again be filled with misinformation and the dangerous misapplication of the ersatz-science touting malaria tablets and worm poison. Public health authorities should be mindful of the delays most people have before arranging physician appointments or emergency room visits. Failing to inform people about science-based, effective medicine and how they can protect themselves to save their own lives is bureaucratic medical malfeasance. Unlike in the Covid-19 Crisis, medical officials need to put the health of the American people first, ahead of the pharmaceutical industry’s special interests in new drug development, gross profits, and researchers’ royalties.      

            Like an ancient Greek drama, the competing choruses chanted – “There is no early treatment. There is no cure.” The counter-chorus responded, “Do your own research.” Around the national public health forum they marched, ad infinitum. Now it is time to cut the Gordian Knott, end the competitive chanting, and sincerely ask physicians and health officials to simply “use what works”. Use what has been proved to work scientifically. Hippocrates himself would surely agree. That would do no harm.       01/07/25

         This essay was written in response to a request from a U.S. Senator’s office to review H5N1 influenza. 

            The above preliminary report is based on a review of over 450 medical journal articles related to H5N1 influenza, its pathogenesis, and therapeutic treatments. 99% of the above statements can be supported by medical journal articles or reports from authoritative or respected sources such as university research departments, the CDC and NIH. A more complete referencing of statements is in progress as indicated by (  ). [  ] denotes essayists comments or clarifications. Part 2 of this medical essay that will address additional, effective medical interventions against H5N1and more about the pathogenesis of H5N1and the cytokine storm will be forthcoming in early 2025.

Howard Armistead has a BA in government from Hampden-Sydney College and an MA in international relations from the University of Virginia. He has been HIV+ since 1983, has studied the interaction of viral disease and the immune system since 1989, and has attended over 57 AIDS and virology conferences worldwide. He served as an unpaid consultant to the Ministry of Health of Zambia in 2006 for H5N1 HPAI and authored the “Report of the Technical Working Group on Selenium” for that ministry. In 2014 the Liberian Ministry of Health asked him to bring selenium to test against Ebola virus disease. Sodium selenite was the only highly effective anti-Ebola drug used during the entire 2014-15 West African Ebola epidemic. 1.2mg Se daily reduced the mortality rate by 43.6%. Mr. Armistead has written two self-published books – Understanding Covid-19, How 500,000 American Lives Could Have Been Saved and Dear Bill Gates, How to End Serial Pandemic Failure, HIV-1 to Covid-19. Both are available at Amazon.com

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