When I first started thinking about the ideas contained in this book, one of the questions I was trying to answer for myself was “what does it take for a pathogen to cause a pandemic?”— let alone a GCBR or extinction event. Not everything can cause a pandemic despite how breathless each outbreak, especially post-COVID, renders the press.
In this task, I wanted to go back to first principles and clarify my thinking. I could not just think about scary pathogens that were put on some list without thinking about why they were on the list. Could all bacteria, fungi, parasites, or viruses equally cause a pandemic? What traits would be absolutely necessary?
For an infectious disease to become anything near an extinction level threat it first has to be able to cause infection in a large — very large — swath of the population. This is independent of its ability to cause severe or fatal disease. It must first be capable of infecting a large proportion of the population and causing some degree of symptomatic infection. In essence, an existential risk pathogen would be something that has the characteristics needed to render it pandemic-worthy.
In my estimation a pandemic can only be caused by an agent that transmits between people. I do not think an agent that uses an intermediate animal or insect to get to humans would be able to cause a world-wide pandemic and would be limited to an outbreak or epidemic. This is also true for environmentally acquired pathogens like tetanus. This fact is because all other forms of transmission can be halted much easier than transmission between humans. For example, once a contaminated food was discovered people would stop consuming it or once an animal species was found to be the source of infection people could change their interaction with it or cull it. Though an animal reservoir makes eradication of the pathogen from the planet impossible—and provides a source for new pathogens to enter the human species—this feature is not related to pandemic potential, which is almost entirely related to how efficiently it transmits between humans.
The concept pandemic literally means “all people” and does not denote any level of severity. Pandemics can be relatively mild in the number of deaths such as 2009 H1N1 or intermediate like COVID-19. Although the concept has some psychological connotation or association with severity, it is not part of the concept.
In this chapter I will detail my thoughts on this question, most of which are derived from a project I led in 2018, The Characteristics of Pandemic Pathogens.
Being Agnostic
Most people associate pandemics and viruses together for good reason, but in this exercise, I want to be agnostic about and ask the question if any category of the myriad infectious microbes, in the modern era, has this capacity.
Dividing the infectious disease world up into categories yields 7 major categories (by my count):
1. Viruses
2. Bacteria
3. Fungi
4. Protozoa
5. Helminths (i.e., worms)
6. Prions
7. Ectoparasites (e.g., lice, botflies, etc.)
All of these categories are awesome in their own right and each exact a considerable toll on humans, but are all of them equal when it comes to causing a pandemic in the 21st century?
Let’s discuss some of these in turn.
Bacteria
Bacterial infections are formidable and today, post-COVID, the number one infectious disease killer of humans is again a bacterial agent: Mycobacterium tuberculosis, the cause of tuberculosis. Antimicrobial resistance continues to be a vexing problem with physicians increasingly being in the situation of having no good anti-bacterial options to treat a patient with due to overwhelming levels of resistance in certain bacterial species. The Black Death, mentioned, earlier wiped out one-third of Europe’s population.
However, when looked at with a discerning eye one can see that bacterial infections since the advent of penicillin and the age of antibiotics have lost much of their edge. It is true that endemic bacterial infections such as tuberculosis exact a horrific toll on the population of certain parts of the world and antibiotic-resistant bacteria plague the immunocompromised and debilitated with serious and fatal infections. Antibiotic resistance does threaten modern medicine with a hint of the pre-penicillin era as antibiotics to treat and prevent secondary infections facilitate everything from cancer chemotherapy to organ transplantation to joint replacement. But this is a far cry from a pandemic. The U.S. average lifespan in 1944 had already reached over 60 years, before antibiotics were commercialized.
It is also the fact that antibiotics tamed much of the bacterial world of infectious disease that led to bacteria not possessing the pandemic potential they once had. While it is critical to not view the struggle against bacterial infections as anywhere near over and to continue to advocate for a robust antibiotic pipeline, a pandemic is not — in my estimation — possible with a bacterial species any longer. The direst untreatable bacterial infections are not capable of causing disease in most members of the population. These bacteria rely on compromised hosts with little by way of defenses who are often in and out of various medical facilities and, thus, have multiple medical-related exposures (where antimicrobial resistant organisms abound). We are even able to craft together (sometimes not so elegant treatment regimens) for some of these patients.
So, if not bacteria, what about fungi?
Fungi can cause a range of infections from the banal athlete’s foot to fulminant necrotizing infections in lungs or sinuses of the immunocompromised. Probably the major fungal threat is the multi-drug resistant fungi Candida auriswhich is currently causing human infections that are extremely difficult to treat. Valley fever, caused by Coccidiodes, has expanded its range likely in response to temperature changes making more of the world hospitable to it. Even the construction of the Panama Canal and the occurrence of tsunamis were exploited by fungi to settle in different environs where humans were infected. Fungi are also regularly destroying reptilian and amphibian species where they are an existential threat. Despite these facts, and the popularity of the Last of Us television series, I do not believe they have pandemic potential for several reasons.
First, human fungal diseases outside of some minor skin ailments like ring worm or athlete’s foot are not really transmissible between people outside of healthcare facilities. They are not highly communicable, but primarily environmentally acquired through inhalation of spores or sometimes through direct inoculation of the skin (as happened with post tornado debris). Fungi abound in the environment and each of us inhale countless fungal spores daily with no untoward effect. It is really only in the immunocompromised, critically ill, or those with severe lung disease that serious fungal disease is commonly found.
Healthcare facilities themselves confer increased risk of fungal disease as evidenced by the multi-drug resistant C.auris which has become a critical problem in nursing homes that house frail patients. Fungi can also exploit shoddy sterilization procedures be transmitted through medical procedures such as contaminated steroids used for spinal injection (Exserohilum), contaminated anesthetic agents, or via injection drug use.
Why is this the case? Interestingly, fungi thrive at temperature lower than we do. The normal human temperature of around 98.6F/37.5C is not hospitable to most fungal species — they are not thermotolerant. There is even a hypothesis that mammals were provided this temperature by natural selection — a mammalian filter — as a way to avoid fungal infections that had major consequences for our colder amphibian and reptilian relatives. This biological barrier, though not insurmountable (as the evolution and dissemination of the multi-drug resistant and somewhat thermotolerant C.auris demonstrates), coupled to the constrained person to person transmission of most fungal species really delimits pandemic potential from this kingdom of infectious agents.
The cast of others
Protozoa and helminths as more complicated organisms are often geographically restricted and have complex lifecycles for which humans are often a dead-end host. A dead-end host is one from which no further transmission can occur. The infection chain dies with the host. As such, these often lead to a very niche type of infection that is not conducive to a worldwide pandemic. The protozoa that cause malaria are a notable exception worth noting as they are purported to have killed half of all humans that have ever lived. This face alone merits its consideration as an existential or pandemic risk. But, with the understanding of how the disease is transmitted (via mosquitoes) the disease became much more controllable when resources were deployed. For instance, malaria’s reliance on a mosquito vector for transmission opens up another avenue — beyond vaccines and treatment — for control which can be as simple as an insecticide-impregnated bed net. The development of effective anti-malarial compounds, a vaccine, and even genetically modified mosquitoes have considerably delimited malaria’s prowess. Highly drug resistant malaria species spreading out of the Mekong Delta to Africa would be a continent-wide emergency, but still not an existential or pandemic level crisis.
Prions, the infectious protein particles responsible for bovine spongiform encephalopathy (BSE) or Mad Cow Disease, are probably the most fascinating class of infectious agents to me. They may play a role not only in Creutzfeld-Jakob disease but also Alzheimer’s and Parkinson’s Disease as well as Lewy Body Dementia. But despite these roles, prions are not easily transmissible between people outside of medical procedures or cannibalism, as occurred in Papua New Guinea and was responsible for kuru. If people have resorted to cannibalism on a mass scale, I think a pandemic would be the least of our problems.
Viruses, Viruses, Viruses
Surveying the microbial world, it becomes quickly clear that a pandemic pathogen is most likely to be a virus. The reason for this is several-fold and should be no surprise given my treatment of the other classes of infectious agents.
First, viruses have the ability to quickly spread with shorter generation times — the time it takes an infected person to become contagious — on average than other classes of pathogens. Some viruses replicate into the billions each day and people can become infectious to others in a matter of days. That replication capacity also gives viruses the ability to evolve at a much faster pace than other types of infectious agents that are, comparably, much slower.
Second, there are no broad-spectrum anti-viral agents the way there are broad-spectrum antibacterial and antifungal and antiparasitic agents. Viruses are bad news coated in protein, to borrow a famous analogy. The “news” they contain is very sparse and very specific to the virus. This means that viruses have just a few targets for antivirals to interfere with as it is host cell machinery that the virus relies on to go through its “life cycle” and host targets are, for obvious reasons, not suitable targets. Additionally, what targets viruses do have are often exquisitely specific to an individual virus type or even a subtype or strain of a virus. For example, some antivirals only work on one subtype of a subtype of a virus and have no cross reactivity against other agents. There are no off-the-shelf antivirals that can be rapidly deployed with large effects on a virus that is genetically distinct. Accordingly, there are very few antivirals that work on multiple viruses in a single family let alone disparate families.
Respiratory Transmission is Critical
Above, I discussed why transmissibility is critical between humans for an agent to be pandemic capable but not all types of transmission are equal.
Communicable infectious diseases are transmitted in a variety of ways: surface/mucosal contact, blood/body fluids, fecal-oral, and via the respiratory route. Of these, as has become evident with COVID-19, the ease with which a respiratory spread pathogen can traverse the world is unrivaled. That is not to say major calamities won’t ensue with different transmission modes but in the 21st century it is the respiratory route that is paramount to pandemic causation. For example, blood and body fluid transmission — exemplified by Ebola and HIV — can be interrupted with simple barrier protections and fecal-oral transmission by sanitation. Something transmitted by mosquitoes, flies, ticks, or fleas can be outran as many of these vector species have a geographic range to which they are best suited or the vectors themselves can be targeted.
It is only the respiratory route which cannot be interrupted by simple measures as talking, coughing, laughing, sneezing, singing, and breathing are not easy to interdict. The respiratory route of transmission is best understood as a continuum that ranges from larger droplets to aerosols with many pathogens alternating between modes based on the context. For example, measles is the paradigmatic airborne pathogen, in which the air in the room in which a measles infected individual was in remains contagious for an extended period of time, while influenza and COVID are better considered to be opportunistically airborne.
Contagious Before Symptoms
It may be an axiom in infectious disease that a pathogen that is able to move from person-to-person before a person knows that they are ill is basically not containable. This is so because if a person does not recognize they are ill or are not disruptively ill, they are able to go about their activities of daily living all the while spreading an infection to their contacts. This explains why respiratory viral illnesses such as the common cold are so prolific. If an infection spreads efficiently between humans via the respiratory route and is contagious during a period when only mild or no symptoms are present, containment becomes a fantastical goal.
This is a critical trait that evolution would select for in many pathogens especially those that thrive on social interaction which requires people to be well enough to interact. As such, in the early days of an outbreak, a pathogen can be all over the globe before it is even noticed, traveling at the speed of a jet, seeding outbreaks in all corners of the globe. Indeed, this was likely the case with COVID-19 and with the 2009 H1N1 influenza pandemic virus.
No Pharmacologic Countermeasures or Population Immunity
In the current era, a pandemic pathogen is likely to be something that cannot be met with off-the-shelf antimicrobial agents or vaccines or even with significant immunity in the population. Though the speed with which vaccine platform technologies such as mRNA vaccines, monoclonal antibodies, viral-vectored vaccines (i.e., the Johnson & Johnson and Astra-Zeneca COVID vaccines), and other platform medical countermeasure technologies can be developed is truly revolutionary and the lead time is shrinking, there will always be some lag before vaccines are developed, made in mass quantities, and administered to the population. This last is critical because a vaccine is not a vaccination and if there is sufficient vaccine hesitancy, control may be elusive until widespread antivirals — which take substantially more time to develop — are available.
The Controlling Families
What the above boils down to is a select cluster of traits that can be mapped onto known viral families spread through the respiratory route. Not every virus can cause a pandemic and many members of high risk viral families may not be capable either. However, I believe it is likely that the next pandemic pathogen will emerge from one of the following families: adenoviridae, picornaviridae, paramyxoviridae, orthomyxoviridae, pneumoviridae, or coronaviridae. These families contain many familiar diseases such as the common cold, RSV, influenza, and smallpox but also many other members (some in animals, some undiscovered), one or more of which could pose a pandemic threat. It is these families that I believe merit special emphasis which will be discussed in detail in later chapters.
The First Lens to View Infectious Diseases
The above is my first lens when studying an infectious disease outbreak and projecting its potential to cause a pandemic.
The question I ask myself is: is this a respiratory-borne virus that spreads efficiently between humans, contagious with mild or no symptoms, to which the population has little immunity without existing vaccines or treatment?
If yes, there is pandemic potential; if no, it is containable.
As an exercise apply this rubric to the US 2022 monkeypox outbreak one sees why cases fell so precipitously in the US — despite doomsday predictions in the press - once testing, vaccines, and behavior change recommendations were put in place.
Using this lens is powerful because it allows one to cut through much of the noise in the early days of an outbreak and focus on the most salient aspects. One develops the ability to have a way to make one of the most important distinctions in the infection disease field which will have cascading impacts on the public, the healthcare industry, and policy makers: pandemic prone or not.
Next, we will explore my 2nd lens which, when combined with the first, will hopefully relegate the extinction event, or as the hip are wont to call them “X-events”, to apocalyptic science fiction and allow real progress on long neglected but less shiny pandemic preparedness tasks to continue.