Just when you thought it was safe to come out again

I have been preparing for pandemics for more than two decades in my roles as a leader of a major teaching hospital in the Texas Medical Center and subsequently as the President and CEO of the largest health system in Idaho.

In pandemic planning, I have found it useful to consider past outbreaks, epidemics and pandemics to consider which pathogens were not eliminated and have the potential to recur. For example, I didn’t spend much effort worrying about smallpox (the only virus we have eliminated from the world as a natural infection) because the only way we would see that would be as a result of a state-sponsored bioweapon attack. I also crossed the original SARS virus (2003) off my list because to our knowledge, that virus never was introduced into an animal reservoir before we contained the spread of the outbreak in humans (very much unlike what has happened with the second SARS virus – SARS-CoV-2 (2019). Further, while we still have cholera outbreaks in the world, they tend to be isolated to locations without proper water treatment and in locations following natural disasters that lead to flooding and disruption of the infrastructure. Further, person-to-person transmission of cholera is minimal and unlikely to propagate the spread to other areas of the world.

We must keep in mind that the majority of emerging infectious diseases in humans are the result of zoonotic transmission (animal à human). More than 70% of these pathogens arise in wildlife.

Looking a past epidemics and pandemics, the pathogen that would rise to the top of the list for causing a new pandemic would be an influenza A virus with zoonotic transmission to humans and mutations that would increase its virulence as well as its efficient spread from person-to-person. That has happened three times in the 20^th century – 1918 (the so-called Spanish flu – H1N1), 1957 (the so-called Asian flu- H2N2), and 1968 (the so-called Hong Kong flu- H3N2). Currently, we are watching the alarming spread of H5N1 avian influenza among multiple species of mammals causing significant mortality. Normally, there is a genetic protection of humans from these avian viruses, however, with increasing transmission among mammals, the potential for significant mutations (specifically, influenza viruses tend to develop the most profound genetic modifications from reassortment of their genes – a swab of genes from one virus to another), is concerning for the potential to develop a new mechanism by which the virus can infect humans with better onward human-to-human transmission.

As I wrote in Preparing for the Next Global Outbreak, https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak, we must expand our readiness and preparedness for novel viruses as:

• the frequency of human-wild animal interactions increases with:
  • human expansion into wild animal habitats;
  • wet markets continue to operate in various countries;
  • non-domesticated animals are exported for research purposes or as part of black-market trade; and
  • the world becomes increasingly interconnected through international travel.

In addition, we must also anticipate diseases showing up in the US that were previously endemic only to poor and developing countries due to the increase in international travel. One example was the case of a man who traveled from an African country to the U.S. with Ebola virus disease who developed symptoms once he was in the U.S. and subsequently presented to a hospital in Dallas on September 25, 2014. This one patient had 48 contacts, 6 of whom would be considered close contacts, prior to his death from Ebola. Two nurses caring for this patient before he was diagnosed became infected. Ultimately, 147 health care workers were involved in the care of the initial patient and the two infected nurses. It is easy to see from this how one person can potentially expose many people if the person is not so sick as to be incapacitated or the disease has not been identified and people are not using proper protection. Just last year, we had another wake-up call. Monkeypox was first identified in 1958. There have been outbreaks of disease in humans since 1970, primarily in African countries. With lack of appreciation of the global risk presented by novel viruses that first appear in low income and developing countries, the world largely ignored these outbreaks and did little to study the virus, to develop antiviral treatments and to develop vaccines. Then, in 2022, a global outbreak with monkeypox developed.

Finally, health care leaders must also consider diseases endemic to countries in the southern hemisphere that may now present in the U.S. due to climate change (e.g., Chikungunya outbreaks in Florida and Texas in 2014 and Zika in 2015 and 2016, and malaria in 2023).

For the past three years, I have been warning that SARS-CoV-2 (COVID-19) will not be our last pandemic. Just in the past two decades we have had an epidemic or pandemic with novel viruses at intervals of 6 years, 3 years, and 7 years.

The World Health Organization prepared a list of pathogens that it considers to pose the highest risk for a future outbreak or potentially, a pandemic in 2018. That list turned out to be quite prescient (as you can see that outbreaks with almost every virus listed have occurred since then) and contains the following infectious diseases:

• Crimean-Congo hemorrhagic fever (there is currently an outbreak in Afghanistan involving more than 100 people, with 6 deaths reported so far);
• Ebola virus disease (there was an outbreak from September 20, 2022 until January 10, 2023 in Uganda with more than 160 people infected, 77 of whom died);
• Marburg virus disease (an outbreak was declared on 2/13/23 in Equatorial Guinea. It infected 16 people, 12 of whom died. It was contained and declared over on May 15, 2023);
• Lassa fever (there have been outbreaks in Nigeria and in Ghana. The outbreak in Ghana began in February 2023 and was contained rapidly with no new cases since March 2023, with 27 people in total infected, one of whom died);
• Middle East respiratory syndrome (MERS) (there were three cases reported between December 2022 and May 2023, involving 1 death);
• Nipah virus disease (between January 4, 2023 and February 13, 2023, there have been 11 cases resulting in 8 deaths in Bangladesh);
• Rift Valley fever (there was an outbreak in Mayotte, France between November 2018 to July 2019 involving 142 confirmed cases); and
• Zika (in March 2015, Brazil reported a large outbreak that was soon thereafter determined to be Zika virus disease. In 2015 and 2016, there was widespread transmission of Zika in Puerto Rico and the U.S. Virgin Islands, as well as limited local transmission in Florida and Texas. Only counting cases that were locally acquired (not cases in travelers from other countries to the U.S., between 2015 and 2017 when the last case occurred in the continental U.S., there were a total of 231 cases in the continental U.S. and 37,041 cases locally acquired in U.S. territories (Puerto Rico and US Virgin Islands).

I have never advocated for living in fear. But, worse, in my opinion, is living in ignorance. I believe in doing risk assessments and then prioritizing those risks based upon the likelihood of the threat coming to pass versus the magnitude of harm that would result if the risk materialized. I illustrate how to do this and make decisions based upon this assessment on pages 277 – 280 in the book – Preparing for the Next Global Outbreak.

Fortunately, some of the viruses with the highest mortality rates (70+%) are less likely to cause pandemics than other viruses with lower mortality rates. However, that is for viruses that we know about today, and even if that were still the case for all new emerging novel viruses, there are still plenty of viruses that have mortality rates 10 – 20 times what we saw with SARS-CoV-2 that under the right circumstances could efficiently spread and cause a pandemic.

We must increase our surveillance, improve our response to outbreaks and promote cooperative international research into passive immunity treatments, vaccines that can provide durable, mucosal immunity; antiviral therapies that are effective against an entire family of viruses; rapid and inexpensive tests for these viruses that can be rapidly deployed, and research to identify the main antigenic targets for each of these vaccines that might allow for the rapid development of effective vaccines.

There has rightly been a lot of focus on bats, particularly in southern China and in Saudi Arabia because 3 novel coronaviruses capable of causing severe acute respiratory syndrome have been identified in those countries in the past 20 years – SARS-CoV (2003) – China, MERS-CoV (2012) – Saudi Arabia and SARS-CoV-2 (2019) – China. We know that bats often carry coronaviruses and that we have only yet begun to sample and characterize al the coronaviruses they carry and can transmit to animals such as palm civets, raccoon dogs, camels, pangolins, and many others that can then serve as potential intermediate hosts for zoonotic transmission to humans.  A major route of transmission of coronaviruses from bats to animals is thought to be through fruit. The bats feast on fruit and in doing so can contaminate the fruit with coronaviruses, or alternatively can contaminate the ground with coronaviruses passed through their guano (excrement). The partially eaten fruit often falls to the ground, where animals, such as those mentioned above, forage for food, eating the residual fruit or ingesting the guano-contaminated vegetation exposing themselves to coronaviruses left by the bats.

Recently, researchers have reminded us that not all worrisome coronaviruses will necessarily arise out of Asian or Middle Eastern countries. A team of researchers from the Imperial College of London and the University College of London sampled 48 fecal specimens from 16 of the 17 species of bats that reside in the UK.

From these 48 specimens, they recovered 9 whole coronavirus genomes (i.e., a complete copy of their genetic material), which allows for identification of the coronavirus. Coronaviruses are divided into 4 genera based upon certain biological characteristics– alpha- and beta-coronaviruses infect mammals and gamma- and delta-coronaviruses primarily infect birds, but there is a gamma-coronavirus that infects whales and a delta-coronavirus that infects pigs.) Of these 9 coronaviruses:

• 4 were alpha-coronaviruses (you may recall my earlier blog piece discussing human coronaviruses in which I indicated that common cold coronaviruses 229E and NL63 are alpha-coronaviruses)
• 5 were beta-coronaviruses:
  • One was a merbecovirus – (the sub-genus to which MERS-CoV belongs)
  • 4 were sarbecoviruses, which are in a sub-genus to which SARS-CoV and SARS-CoV-2 belong. At least one of the novel sarbecoviruses can bind the ACE-2 receptor to infect human cells as SARS-CoV-2 does, though it does so sub-optimally. In addition, these sarbecoviruses were only one mutational step away from a development (a furin cleavage site) that would significantly enhance virus receptor binding and potentially infectivity. (Note that it was the fact that SARS-CoV-2 did have a furin cleavage site that many used to justify that SARS-CoV-2 was genetically engineered or modified, but this (and other findings) demonstrate that a furin cleavage site can be a result of natural viral evolution.)

2 of the coronaviruses identified were previously unknown coronavirus strains – i.e., novel coronaviruses (one of the alpha-coronaviruses and the merbecovirus).

The key takeaways are these:

1. There will continue to be future outbreaks, epidemics and even pandemics.
2. Outbreaks that occur anywhere in the world threaten every other part of the world due to international travel and trade.
3. Most new, emerging infectious diseases are zoonotic in origin (transmitted by animals to humans).
4. Increasing human expansion into wildlife areas is increasing the risk for zoonotic events.  
5. Climate change is causing introductions of infectious diseases into some more northern geographic locations where these infectious diseases had previously not been circulating.

We must prepare now. For a full discussion of preparation see Preparing for the Next Global Outbreak, https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak. Preparation includes increased surveillance, improvement in our response to outbreaks and promotion of cooperative international research into passive immunity treatments; vaccines that can provide durable, mucosal immunity; antiviral therapies that are effective against an entire family of viruses; rapid and inexpensive tests for these viruses that can be rapidly deployed, and research to identify the main antigenic targets for each of these vaccines that might allow for the rapid development of effective vaccines.