What Should Our Public Health and Health Care Organizations be Doing in Response to the HPAI A(N5H1) Outbreak in Cattle in the U.S.?

Dr. Ted Epperly and I wrote a book that was released one year ago in which we provided 117 recommendations based upon lessons learned from the COVID-19 pandemic that should better prepare us for the next pandemic. https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak. One only has to review the recent history of global outbreaks and pandemics to see that we should expect the next pandemic before this decade is over. We had an influenza pandemic in 2009, the first SARS in 2002 – 2003, MERS in 2012 and SARS-CoV-2/COVID-19 in 2019 – present. Even during the COVID-19 pandemic, we had a global outbreak of Mpox (formerly known as Monkeypox).  We must fight off the pandemic fatigue and ensure that we incorporate the learnings and recommendations we make in our book to each new threat we face.

A recent article (Reference 2) tees up the most recent threat well: “The recent confirmation by the United States Department of Agriculture (USDA) of the detection of Highly Pathogenic Avian Influenza (HPAI) A(H5N1) strain in dairy cattle herds across several states, including Texas, Kansas, Michigan, New Mexico, and Idaho (https://www.science.org/content/article/us-dairy-farm-worker-infected-as-bird-flu-spreads-to-cows-in-five-states), has ignited significant concern and raised pertinent questions regarding the implications of this unprecedented occurrence. This divergence from the typical avian host raises alarms, as avian influenza rarely infects cattle.”

If you have been a long-time follower of my blog or have read my book, you know that novel viruses that make the jump from animal species to humans (zoonotic transmission) arguably represents the biggest threat for a pandemic with a high mortality rate. The reasons for that include the facts that if it is a novel (new) virus, especially one not closely related to a virus to which we have previously been exposed:

1. There will be no preexisting population immunity;
2.  It would likely take us at least 6 – 9 months to develop, test and authorize new vaccines under the best of circumstances;
3. We would be less likely to have any off-the-shelf treatments available.

This HPAI virus has infected people in close contact with infected birds and poultry since we identified it. Fortunately, we have seen no evidence of forward transmission (we did not see evidence that those infected humans in turn infected their family members or others with whom they were in close contact). Unfortunately, the case fatality rate of these infections has been in excess of 50 percent.

What the authors in the above quotation are pointing out is that when we see a dangerous virus like this begin infecting new hosts (species of animals that can be infected) that we previously have not seen get infected, or as in this case, when it is suddenly infecting large numbers of a species (cows) that previously it only infected uncommonly and sporadically without forward transmission, we have to consider:

1. Has the virus mutated in a way that enhances its ability to infect that species of animal;
2. Has the virus mutated and become more fit in a way that now allows it to transmit among the new species (i.e., from cow to cow);
3. Have any of these new mutations now enhanced the ability of the virus to infect humans and transmit between them?

Even before the recognized infections among dairy cattle on 3/25/24, many of us were concerned by the increasing range of mammals, including aquatic mammals, that had been infected over the past two years, often evidenced by large numbers of carcasses discovered on land or washed up on shores. The concern about the third question above became heightened when we saw an outbreak of HPAI among mink on a mink farm in Spain, as mink have respiratory tracts that more resemble ours than most of the mammals we had seen infected to that point, and we had seen reverse zoonotic events (human-to-mink infections followed by mink-to-human infections with significant mutations adapted to the mink) with the SARS-CoV-2 virus.

One mutation that has believed to be necessary for mammalian transmission of this virus, which would also be necessary, but not sufficient for infection of humans and forward transmission is the PB2 E627K mutation. This is a mutation on the PB2 protein (see prior blog post for an explanation of this protein) and represents a single nucleotide substitution at the 627 position. Interestingly, this mutation was not found in any of the birds or cattle sampled in the U.S. However, it was present in the human who was infected in Texas. What that tells us is that the mutation was an “in-host” mutation, meaning that it was not in the virus he was infected with, but rather the mutation occurred as it was replicating in his body.

To some degree this is reassuring, however, it also suggests that there are likely other mutations that we may not yet have identified that tend to promote fitness of the HPAI virus in mammals, and in fact, Reference 2 provides some evidence that there have indeed been genetic changes that may be contributing to this spread.

Another reassuring finding from sequencing of birds, animals and humans is that “the genetic distance between groups is very small (0.002 – 0.144) for both genes [i.e., the genes that code for the hemagglutinin and neuraminidase proteins], especially considering that Influenza A, along with other RNA viruses, reproduces with minimal accuracy.” (Reference 2) Readers will recall that there is marked genetic distance between the original or wild-type SARS-CoV-2 virus and the variants that we are dealing with today.

Be sure to read my prior two blog pieces on the HPAI epizoonosis (epidemic in animals) for additional background.

So, at this point, what should our public health and health care organizations be doing? I am reminded of the old saying, “Hope for the best, but prepare for the worst.” At this point, the assessment is that the risk to the public health is low, however, this is a rapidly evolving situation and that assessment could change. Thus, there is no need to open emergency command centers and escalate matters, however, there are important steps that should be taken that are not only helpful to prepare if we should see sustained human-to-human transmission in the future (“the worst” scenario), but is simply a helpful exercise to go through as a continuous evolution of our pandemic planning.

1. Public health organizations, schools and health care organizations should update their pandemic plans taking into consideration all of the lessons that were learned through the pandemic. To assist in making that an easier and less time-consuming endeavor, we have outlined a summary of planning tips at the end of our book for each type of entity or organization.
2. I was very pleased to see that the CDC is being proactive. Last Friday, CDC officials were on the phone with members of the Association of State and Territorial Health Officials (ASTHO), the Council of State and Territorial Epidemiologists (CSTE), and the Association of Public Health Laboratories (APHL) recommending that state public health officials engage with their state veterinarians and agriculture department officials to ensure that they have up-to-date operational plans to respond to avian influenza at the state level. For example, CDC emphasized the importance of having plans in place to quickly test and provide treatment to potentially impacted farm workers following positive results among cattle herds. (Reference 3)
3. On that same day, the CDC sent out a Health Alert Advisory to clinicians. (Reference 4).
4. I commend the CDC. It is essential that they communicate clearly, promptly and frequently while the situation is evolving. But, they have more work to do (see below).
5. When testing is a key element of our surveillance and planning (as it is here), and there is suspicion that the virus has mutated and evolved (as it has), it is important that we test to ensure that our rapid tests still detect the virus with sufficient sensitivity and specificity. Researchers conducted a study last year and concluded: “In the laboratory, the rapid tests detect all 18 avian influenza viruses with 16 different H subtypes, including highly and low pathogenic influenza viruses with subtype H5 or H7.” (Reference 5) Note these are rapid tests for Influenza A in general that will show a positive result for these avian influenza viruses which are Influenza A viruses, but it will not identify them as avian influenza viruses or by their H or N subtypes. Obviously, we should monitor this and continue to assure that the tests are effective, but this is very reassuring.
6. The CDC does have a stockpile of avian influenza vaccines, but given how long ago they were produced, tests need to be conducted to ensure that these vaccines would be effective against currently circulating strains. Nevertheless, I applaud the CDC that they have provided high quality samples to vaccine manufacturers so that they can be prepared to manufacture vaccines if necessary. [Note: our seasonal influenza vaccines are not protective against this avian influenza, however, our commonly used antivirals for influenza A appear to be.)
7. HHS has not (to my knowledge) informed hospitals as to whether the National Strategic Stockpiles have been replenished since they were largely depleted early in the COVID-19 pandemic. I suspect the answer to this question is “no,” but it is important for hospitals to know this so that together with their supply chains, they can do their own planning without relying on the federal government for assistance.
8. It is possible that this has been done and just not made public, but hopefully the FDA, or other appropriate agency, is assessing the adequacy of antiviral availability and the ability of pharmaceutical companies to significantly increase production in short order if needed.
9. The recommendations that have come out from the USDA and CDC appear to be reasonable, but I have seen no reference to measures to prevent spillover to pigs (for the significance of this, see my first blog post on avian influenza), nor to surveillance and testing of pigs. Given the potential for this to be the first evidence for a new strain that has enhanced fitness for infection of and transmission among humans, this seems important.
10. There also needs to be consideration given to an animal vaccination program to decrease infection and transmission among animals.
11. If, as has been reported, the USDA and CDC are convinced that spread among cows is occurring through contamination of milking equipment, recommendations for stopping this spread need to be promulgated.
12. The CDC also needs to determine whether virus in unpasteurized milk is infectious to humans. In the meantime, the CDC should do the testing to ensure that the pasteurization process is inactivating the virus.
13. Hospitals should also use this as the opportunity to update and revise their pandemic plans.
14. Hospital planning and preparedness should also include an assessment of their own inventories of medications, equipment and PPE. Protocols for screening, testing and reporting need to be prepared including instructions for how patients will be isolated, what infection control measures will be put in place, how specimens are to be handled, admission criteria and where patients in the ED and those hospitalized will be placed. Unfortunately, this planning also needs to contemplate two topics that are unpleasant to think of – how would excess be created for children if necessary, and given the high mortality rate for this infection, how should bodies be handled. Further, how can hospitals, urgent care centers and medical offices ramp up quickly to vaccinate people once a vaccine becomes available.

Hopefully, we would never need to put this plan into effect, but it is always better to contemplate these matters in advance as opposed to during the crisis itself.

References:

1. Preparing for the Next Global Outbreak: A Guide to Planning from the Schoolhouse to the White House, Pate D. and Epperly T. Johns Hopkins University Press 2023.
2. Emerging Threats: Is Highly Pathogenic Avian Influenza A(H5N1) in Dairy Herds a Prelude to a New Pandemic? – ScienceDirect.
3. The latest from CDC on preparing for a bird flu epidemic | Sharyl Attkisson
4. https://emergency.cdc.gov/han/2024/han00506.asp
5. 653286 (wur.nl) (This article is written in Dutch).