Part I
I have previously written about the outbreak of avian influenza among mammals, and particularly the dairy farm outbreaks that were first noted in late March. We now have a lot more information.
The U.S. Department of Agriculture (USDA), the U.S. Food and Drug Administration (FDA), and the CDC as well as state agencies have been investigating more than 30 outbreaks in 8 states (including two dairy farms in Idaho) of highly pathogenic avian influenza (HPAI) virus [HPAI is a designation for any influenza virus that is avian (bird) in its origin and causes very high mortality rates in domestic birds and poultry. Historically, HPAI viruses have either been of the H5 or H7 variety, a reference to the antigenic nature of one of the key proteins of the influenza virus – hemagluttinin] on U.S. dairy farms that was first detected March 25, 2024 in Texas. It was initially discovered as a result of investigation into cows with signs of illness, such as decreased milk output, discolored and altered texture milk that more resembled colostrum, and decreased appetite. Updates on Highly Pathogenic Avian Influenza (HPAI) | FDA
The specific HPAI involved in these outbreaks is A(H5N1), often referred in shorthand to H5N1. The A refers to the fact that these avian influenza viruses are of the A type. There are four types of influenza viruses, conveniently named A, B, C, and D. A (other than the avian influenza viruses) and B viruses circulate across the globe in humans and generally cause seasonal epidemics annually. Influenza C generally causes very mild illness, and therefore, is not seen as a public health threat, nor is its activity tracked. Influenza D viruses circulate primarily in cattle, and we have not identified spillovers into humans. https://www.cdc.gov/flu/about/viruses/types.htm
The influenza vaccine provides protection against the specific strains of A and B viruses that we see evidence of as likely ones to cause our fall/winter influenza epidemic and usually covers 3 (trivalent) or 4 (quadrivalent) specific ones. Influenza A viruses are the only influenza viruses that have been identified as causing pandemics in the past (1918 – 1919, 1957, 1968, and 2009).
When dealing with influenza A viruses, we can further identify the strain by characterizing two key proteins that make up that particular strain of virus. By now, most people are aware of the spike protein of the SARS-CoV-2 virus, which is a key protein in binding to host cells to cause infection, but also a key target of the antibodies produced by immunization or by our bodies in response to infection. So, while the influenza virus does not have a spike protein, they all have two key proteins – hemagluttinin and neuramidinase, for which we refer to more conveniently as “H” and “N,” respectively. We then can refer to a specific influenza A virus by which particular H protein it has – there are 18 known subtypes and we conveniently designate the specific subtype as H1 – H18 – and the particular N protein it has – there are 11 known subtypes and they are similarly designated – N1 – N11. So, each particular influenza A virus will have one of the eighteen H proteins and one of the eleven N proteins, and thus far, more than 130 different combinations have been identified. https://www.cdc.gov/flu/about/viruses/types.htm
Thus, when we want to refer to a specific influenza A virus, you will see designations such as A(H_N_), with the specific protein subtype numbers filled in. Most of what we deal with in the U.S. with our usual influenza virus seasons, such as the one we just wrapped up, are A(H1,N1) and A(H3N2), and to a lesser extent one of the influenza B viruses. We saw infections with all three viruses this past flu season. With the pandemics of the past century, we saw H1N1 in 1918, H2N2 in 1957, H3N2 in 1968, and H1N1 in 2009.
To wrap this little primer up, we can refer to types of influenza viruses by their A, B, C, or D designation. Influenza A and B viruses that contribute to our yearly flu seasons are types of influenza viruses. Then, we can get more specific about the particular influenza virus by using its subtype designation A(H_N_) if we are referring to an A type virus or its lineage, such as B/Yamagata or B/Victoria when are referring to a B type virus. We can go further into characterizing influenza viruses by their specific genetic sequences (you may recall that with SARS-CoV-2, we have used their genetic sequences to identify them as specific variants, for example, JN.1 that caused our most recent huge surge in COVID-19 cases). The specific genetic sequences that we identify for influenza viruses, especially when we are doing outbreak investigations as we currently are, allow us to assign these viruses to clades, and even subclades. More on this later.
And, now, to get back to current events, the virus we are dealing with in these dairy farm outbreaks is A(H5N1).
Unlike poultry, and domestic birds in the typical outbreaks of HPAI infections, and more recently, what we have seen with many more mammalian species that have been infected over the past couple of years where the infected animals appeared to have, in many cases, developed neurological impairments followed by rapid decline and death, reports thus far have suggested that dairy cows have suffered relatively minor illness and seem to be making a full recovery.
There have been concerns about the safety of the commercial milk supply because it appeared that the infection primarily manifested as mastitis (infection of the milk glands) as demonstrated by the finding of very high levels of virus in the milk of infected cows. [Note: when you buy a carton or jug of milk at the store, that is not milk from a single cow and often not even from a single dairy farm, but rather pooled from many cows. If infections are sporadic and few, then pooling of milk does increase the chances that some of the milk might be from an infected cow, but it would also result in diluting of any virus that came from a single cow.] The USDA and FDA provided reassurance to the public that the pasteurization process (a rapid heating of the milk for a specific, but short, amount of time) is known to kill both bacteria and viruses and that it should be effective in killing (so as not to offend the sensibilities of any virologists or microbiologists who read this, it is not really killing because viruses were not “alive” to begin with, so technically, we are referring to inactivating the virus so that it is no longer infectious) should make any milk that made it to the market from diseased cows safe for human consumption, but as an additional precaution, diseased cows were being isolated from the other cattle and their milk was being discarded.
Nevertheless, this begs a number of questions that I will try to address below – (1) are we confident that the pasteurization process does inactivate all of the virus? (for extra credit, this question gets at the question as to whether pasteurization for A(H5N1) is equivalent to sterilization.) (2) If not (i.e., if pasteurization in this case does not result in sterilization), does it at least inactivate enough virus that there would not be enough present to cause infection in humans (technically, the amount of remaining infectious virus would be less than the infectious dose) (3) If the pasteurization process doesn’t inactivate all of the virus, but does reduce the amount of infectious virus below the infectious dose, might it still pose risk to immunocompromised patients or patients whose guts are disrupted by disease? (4) Do we even know that this virus can infect humans through ingestion? Would the virus survive the low pH (acidic) environment of our stomachs? Do we even have the right kind of receptors in our GI tracts to allow the virus to bind to cells, infect them and then cause disease?
So why is this concerning and why should anyone be interested?
- Avian influenza viruses do not transmit to humans efficiently, because we don’t have the correct biochemically structured receptors in our nose, throat and respiratory tract that allows the virus to bind with high affinity to infect our cells and cause disease (details on this below). However, we do have the correct biochemically structured receptors in the lining of our eyes, so human infection is possible, in fact, over years and across the world, slightly less than 1,000 people have been infected with this virus, usually when their occupation places them in close contact with infected birds or other animals for extended periods of time (farm hands, slaughterhouse workers, animal health workers, etc.).
Unlike the annual, seasonal influenza viruses that cause human disease, the mortality rate when human cases of avian influenza have been detected has been over 50%. On one hand, it is quite possible that we are only identifying more severe cases since many farm workers and slaughterhouse workers do not have great access to health care around the world and because, to my knowledge, there has not been any significant screening of workers to know whether there may be many more infections that are asymptomatic or causing mild illness. On the other hand, one would expect that most of these workers are likely to be young and healthy given the difficulty of this work, thus the high mortality rate is quite concerning.
- Until the past couple of years, avian influenza viruses are generally spread by waterfowl to domestic birds and poultry. There have certainly been sporadic and isolated cases of infection in mammals, but generally this has been attributed to the mammal also being in close contact to domestic birds, coming into contact with the excrement of infected birds, or feasting on the carcasses of diseased birds. In the past two years, it has been absolutely astounding to see the vast range of mammalian species and numbers of animals that have been infected, clearly representing a change in the behavior of the virus or a change in the environment that is promoting transmission of the virus, or both.
The recent and wide-spread infection in U.S. dairy farms and the infection of a farm worker in Texas has increased the concern that the virus may be adapting to enhanced transmission in mammals and that with the diverse species being infected and large numbers being infected, the risk for mutations and reassortments that might promote transmission to and among humans is increasing. This could pose a pandemic threat if the virus were to develop the changes necessary to transmit efficiently among humans because the entire population would likely be susceptible to infection since we are not expected to have any preexisting immunity to this virus (prior influenza A infections and immunizations in humans are with virus strains that are not similar enough to confer any significant degree of protection to our current knowledge).
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