Chapter 4: The Second Lens—Make Infections Not War

It is somewhat taken to be an axiom that infectious diseases eventually taper in their ability to cause severe disease over time as they evolve to incite less physiological mayhem in the species they infect.

This is not an axiom but a complicated phenomenon that is very context dependent, the relevant context being the transmission mode of the pathogen, the teleology (or goal) of the pathogen, and what countermeasures the host species is deploying (either through evolution or consciously when it comes to humans). In this chapter, I am going to explore this concept and, by doing so, give you my second lens for looking at the pandemic, catastrophe, and extinction potential of any agent of infectious disease.

How Transmission Modes Matter

Thinking anthropomorphically, an infectious disease pathogen “wants” to flourish, complete its life cycle, and continue the propagation of its genetic lineage. To do so, it will need a suitable environment that is conducive to the completion of these tasks. Such an environment might be the gut of mosquito, the nasopharynx of a human, the digestive system of a cat, or even a combination of multiple hosts for different hosts for different life stages. Some pathogens do not need anything, but the conditions present in a pond, the detritus on the forest floor, or the soil. This last group is a special case I will discuss separately later in the chapter.

Pathogens, therefore, need to traverse the chasm from one host to another and, to do so, need to be carried from host A to a suitable place in host B via some medium. Suitable mediums and mechanisms include skin-to-skin contact, body fluids such as saliva, respiratory droplets, blood, sexual-activity related fluid, feces, nasal mucus, ingestion, via a tick or mosquito bite, or through exhaled air.

Additionally host A and host B need to be in close enough proximity or networked enough to be above a threshold degree for this to be successful.

Differing modes of transmission will lead to different proximity thresholds. For example, a pathogen like measles which spreads efficiently through the air just needs two humans to share the same air, even separated by a couple of hours. By contrast, Ebola requires close proximity for body fluids carrying viral particles to pass fairly directly from one human to another human. Certain other pathogens need humans to be in a network such as one that shares water sources, shares food sources, or shares an environment with the same pool of mosquitoes or ticks.

In general, a pathogen that requires people to be in close proximity to be transmitted by blood or body fluids is, in the modern world, going to be constrained in its spread. Additionally, the modern world can be thought of as very pathogen-proof (not foolproof of course) in the sense that modern sanitation, food handling processes, vector control measures against mosquitoes and ticks, and hand washing really make the terrain difficult for many pathogens.

What’s left for pandemic prone pathogens, as I concluded in the last chapter, are those that spread via the respiratory route either through respiratory droplets or via exhaled air. A pandemic pathogen not only needs to be able to spread, but it also has to spread prolifically, universally, and uncontainably. It has to easily overwhelm modern societal anti-infection measures. In short, it needs hosts in close proximity who are not apprised or unaffected by the respiratory droplets or contaminated air to which they are exposed.

Even though healthcare (or nosocomial) infections are a critical and devastating problem, they are not conducive to starting a global pandemic let alone something worse. This is because a hospitalized patient with a respiratory infection is, by definition, not in the most conducive environment to spread to the majority of the humans on the planet. A bedridden person, in the hospitalize or at home, is going to have less proximity to others and, because of the severity of the illness, is also likely to raise caution level of those that visit with the patient delimiting spread.

However, if a person is out and about performing their daily tasks— not changing the landscapes of their contacts with others because of unawareness of their illness, because the severity of the experienced infection insufficient to keep them home, and/or because the illness resembles an every-day baked in risk of daily living like stepping in a mud puddle, getting caught in the rain, or twisting one’s ankle stepping off of a curb, or transmitting or acquiring the common cold—transmission will be efficient and widespread.

Therefore, a pandemic prone pathogen is likely to be a respiratory virus that spreads efficiently between humans secondary to causing a spectrum of illness that is heavily weighted towards mild or clinically inapparent — yet contagious — manifestations.

A respiratory virus that causes fulminant symptoms too frequently is going to confine a significant portion of its transmissibility period to the bed-bound or hospitalized which is inefficient if a pandemic is the end game. It is also the case that fulminant symptoms occurring too frequently will eventually change enough of the behavior of humans to one that is more avoidant of individual risks.

The above is not meant to mean that a pandemic pathogen can’t evolve to be incrementally more dangerous to humans such as the delta variant of SARS-CoV-2 represents, but that a respiratory route-dependent pathogen cannot be on a path to kill all humans if it “wants” to be prolific and join the pantheon of pandemic pathogens. 

It is important to recognize that in the above discussion and thought experiment I am confining myself to pandemic pathogens (in the modern era) and this does not apply to epidemic pathogens or outbreak pathogens. Recall the way the fecal-oral spread bacterium that causes cholera can evolve to more ferocity in certain situation when that is conducive to more extensive spread.

What about HIV?

An astute reader would be thinking that the above is skirting over probably the most devastating pandemic in our lifetimes — that of the Human Immunodeficiency Virus (HIV). HIV is the subject of a later chapter, but it is important to delineate some aspects its pandemicity now. HIV has killed at least 40 million people in the past 40 years, spread to every habitable niche of the planet, and infected around 100 million. Until around 1996 with the development of potent combination anti-retroviral therapy, it was essentially 100% fatal.

Why was HIV with its horrific case fatality ratio of 1.0 able to cause a still ongoing pandemic and defy what I take to be a general rule about pandemic-prone pathogens? It is a legitimate question to ask whether HIV qualifies as a pandemic because it differs from an unequivocal pandemic pathogen such as the 1918 influenza A virus, whose death toll exceeded 40 million plus in about year— not over 40 plus years.

Make no mistake, HIV has arguably been the most pressing infectious disease challenge in the past 100 years and its emergence was a seminal event in my profession. HIV was and remains a disruptive event that changed society indelibly (and probably eternally) when it comes to certain practices such as universal precautions, blood supply safety issues, safe sex, and safe injection drug use practices. However, the very attribute that allowed it to infect over 100 million humans is what makes it different than traditional pandemic pathogens (and also the same when viewed in a certain context) — its clinical latency or chronic period.

The time period after HIV initially infects someone, the occurrence of which will cause a severe flu-like illness, and when a person has overt symptoms due to the opportunistic infections that HIV predisposes to, involves a period of about a decade. We know that during this time, HIV is not biologically silent and physiologic damage is occurring, but it is often clinically silent..until enough damage is done that the immune system is so wrecked it cannot serve its purpose any longer and AIDS (Acquired Immunodeficiency Syndrome) ensues. Throughout this period of clinical silence a person is contagious to others via their blood and body fluids. This is why the virus spread around the world even before it was first noticed and continues to infect individuals who are asymptomatic and do not know their status. This asymptomatic period is what gave HIV its pandemic potential. However, the clinical latency and its blood/body fluid transmission mode also staggered cases temporally and did not overwhelm society (though some hospitals in the 1980s did have considerable burden of patients at once suffering from HIV) in the manner of 100 million cases occurring over a period of a year or two. Its slow silent spread gave HIV a prolific reach that other blood and body fluid infections could never attain but also did not cause a universal, all-at-once calamitous response or have the same velocity of risk that the 1918 influenza or COVID pandemics did. [A similar analysis could be applied to both hepatitis B and hepatitis C which followed similar trajectories but are even more silent and subtle, causing fatal liver disease and carcinoma over a period of multiple decades].

The Idea of a perfect pathogen

I have argued that pathogens have to “care” about what they do to their hosts if they want to spread. This is known as the host-density theorem: there must be enough density of hosts present for the pathogen to successively infect; if it kills too many it will extinguish itself. But what about a pathogen that just doesn’t care because finding itself in a human or some other species is a detour from its normal lifestyle, just a brief fling, a species to which the host density theorem does not apply?  Think of a fungus, for example, that normally lives on the dying or dead vegetation in a pond. It, through whatever means, now finds itself in the body of a frog which summarily succumbs to the infection that ensues. In fact, imagine that this happens to every frog that happens upon the fungus. The fungus after killing the frog just leeches out if its body and goes back to its ordinary life cycle in the specific environment it is suited for. This type of pathogen can pose extinction level pandemic threats because of its non-relationship with the frog host, it is environmentally stable and can thrive irrespective of a frog being present or not. This is what is known as a sapronoticinfection and they are basically exclusively confined to the realm of fungi, and, in the case of humans, the environmental source can be removed or avoided, and anti-fungal therapies can be developed (many frogs are left without defenses of any sort as attested to the devastation their species has faced from the chytrid fungus). I have already discussed why I don’t think humans face this threat from fungi in an earlier chapter and will return to it again in a later chapter.  

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The two lenses I employ prompt two questions for any outbreak and concretize why an extinction level event from an infectious disease in humans is not plausible. These questions are:

1. Is the etiologic agent a respiratory-borne pathogen?

2. Is it efficiently spreading?

If the answers are no, it is at most, capable of causing an epidemic and be regionally restricted. If the answers are yes, it will be pandemic capable. However, an efficiently spreading respiratory virus — the only pandemic prone pathogen according to my analysis — will fall far short of an extinction level event. To not fall short would contradict the prerequisite needed to be a pandemic pathogen: an efficient spreader requiring a wide spectrum of illness tilted towards the mild or asymptomatic.

Chapter 3: The Alchemy of a Pandemic Pathogen

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.

Chapter 2 The nature of the microbial world and infectious diseases

It’s a Microbial World After All

The realm of infectious disease is so ripe and attractive as a backdrop for contemplating the catastrophic decimation of populations of species because of its very nature of the microbial world.

We live on a planet dominated—in terms of species biomass—by microbes. This ubiquity is not accidental but the result of the causal forces responsible for the nature of life. The earth was formed 4.6 billion years ago, and life began 1 billion years later. For the majority of that time, life on earth was exclusively microbial species. Mammals represent only a sliver of that nearly 4-billion-year epoch, with humans representing just a sliver of a sliver.

 What that microbial multi-billion-year advantage has done is allow microbes time to evolve and diversify to inhabit every niche of this planet, including areas inhospitable to any other form of life. Such environs including radiation-laden environments and undersea heat vents, which are home to extremophile bacteria that are “extreme” in a manner very different than human extreme sports participants.

 Viewing the planet in this context, you can see how foolish it is to try and over sterilize one’s life with antibacterial hand sanitizer, respect the 5-second rule for food dropped on the floor, and memorize articles cataloging the density of “germs” in various public locations. Everything is germy and always will be.

 Even the human body, soon after birth, becomes virtually melded to its microbial colonizers. These constitute the human microbiota or human microbiome. This patina of microbes has become so essential for life that disruption or alteration of the microbiome has been linked with adverse health outcomes such as Clostridium difficile infection, gastro-esophageal reflux disease (GERD) and possibly will help unravel the mysteries of autism.

 We are really unable to live without bacteria. The symbiotic relationship we have with bacteria provides essential physiological support for our life. From synthesizing the vitamin K needed for adequate blood clotting to fending off potential nefarious bacteria by leaving them no space to set up shop, our microbiome is our protector. A disrupted microbiome is not conducive to good health.

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Bacteria, though mere single-celled organisms, are not simple in any sense. They possess many sophisticated genetic and metabolic components. For example, certain bacteria can flip a genetic switch when they sense enough others of their species are present to constitute a quorum. Such quorum sensing provides a massive survival advantage to bacteria that possess the faculty, which, in effect, allows a bacterial colony to operate like a super-organism reminiscent of the societal structure advocated in Plato’s Republic. These bacterial super-organisms can take the form of a biofilm, an impregnable slime layer, that in the certain setting such as the infection of a prosthetic hip, can stymie the power of antibiotics to the great detriment of the patient.

In fact, if looked at from the perspective of an alien race, as I frequently say, the Earth could be described as a planet of bacteria with a spattering of other species that, as Eula Biss puts it in her excellent book, bacteria use to travel about. Of course, this is hyperbole, because bacteria, though ubiquitous, cannot be thought to dominate the planet in the manner in which humans do but it is a perspective that is based on significant and under-appreciated facts.

 A similar analysis could be applied to other major members of the microbial world such as fungi and protozoa. It is more complicated with viruses, of which a quadrillion quadrillion exist on earth, because viruses exist on the chasm between animate and inanimate. As such, they do not have the a “life” cycle akin to bacteria or fungi. In fact, some hypotheses have been put forward postulating that viruses are devolved bacteria that have given up some of the trappings of life and the related energy upkeep costs in favor of a simpler existence. In fact, there exist some viruses which are endogenously present in our DNA and are literally part of us, along for the ride of life.

Standing on the Shoulders of Darwin

The veracity of Darwin’s observations and inductions, which coalesced from hypothesis into the theory of evolution by natural selection, are — in the modern context — apparent to anyone who just looks with an active mind. However, there is no better setting in which to witness evolution unravel real time than in the microbial world where the equivalent of world wars and a struggle for existence are occurring continuously.

Any microbe has to fight for its life, competing for sources of food in order to survive, reproduce, and flourish. Some environments are luscious resource-replete locales in which life is relatively easy with little effort required to meet needs. However, situations can be temporary and drastically change for any number of reasons, including cleaning out the fridge some bacteria call home.

 Because of the sheer number of bacteria and their ability to reproduce rapidly, mutations will occur routinely. Some mutations may not be beneficial, some will have no effect, and some will be advantageous. Advantageous mutations could allow a microbe to utilize a new food source, withstand extremes of temperature, expand an ecological niche, or develop a weapon to use against competitors.

 All of this dynamism of evolution is occurring all the time in the microbial world, irrespective of humans. Remember, humans have only existed for a brief segment of the time that microbes have flourished on this planet. It is only when humans and other organisms appeared that this evolution had implications for health.

 For instance, the weapons some bacteria evolve to use against each other and other microbes, sometimes take the form of what we know as antibiotics. Antibiotics are the missiles microbes use against each other to keep outsiders away from their niche and its treasures. In response to these weapons, some bacteria develop anti-weapons systems or antimicrobial resistance mechanisms—naturally, in order to survive.

 Antibiotic resistance is often framed as a novel threat because of the role of injudicious antibiotic prescribing (which is a real issue). However, antibiotic resistance is truly almost as old as the planet itself. It has been detected in bacteria that reside within caves in which no human has set foot and also in tribes of remote peoples who have never received an antibiotic prescription. Following this line of reasoning, it becomes clear that our tit-for-tat war with microbes is doomed to end in failure if an antibiotic arms race is our chosen tactic, for the microbes can evolve much faster than we can develop new antibiotics, which ultimately are often derived from them. We are playing on their field using tools they themselves developed.

 It is important to recognize that evolutionary pressures do not always select for more virulent or dangerous microbes and, in some cases, may select for less virulence. It all depends on the context. For example, the bacterium that causes the diarrheal illness cholera might be very deadly in one setting but in another much milder. For instance, it has been hypothesized that the level of sanitation has an influence on the volume of the diarrhea produced by Vibrio cholerae, which is spread via the fecal-oral route. In certain situations, voluminous diarrhea gives it the best chance to pass from person-to-person where in others just a little diarrhea can go a long way.

 The forces of evolution are manifest in the microbial world and, because of the magnitude of reproduction achievable by microbes (compare the 20-minute doubling time of an E.coli cell vs. that of a human) have real-time consequences for disease and health. Accordingly, these forces play a major role in how we think about and respond to these threats. Conversely, even though we are also indisputable products of evolution, our reproductive time leaves us woefully without an ability to rapidly develop an intrinsic species level adaption, though over centuries, we do fairly well—and better than the Christmas Island rat—as I will discuss at several later points in the book.

 There are three touchstone infectious disease emergencies in our species’ past (and present) that highlight important threads that I will draw out and integrate throughout the book. A context-setting thumbnail sketch of each follows.

The Black Death and the Power to Reshape Society

 The Black Death, which occurred in the 14th century, is arguably the most important infectious disease outbreak in history. Not only did it shake medical foundations to their core, but it also literally reshaped societal structure in medieval Europe by culling a large swath (1/3rd!) of the population.

 The Black Death was an outbreak of plague, a disease caused by infection with the flea-associated bacteria Yersina pestis. This bacteria spreads from fleas to humans and then between humans when it reaches the lungs. It has always been well recognized in its bubonic form in which the lymph nodes in the groin and armpit become markedly swollen.

 There have been countless books written about the Black Death as well as extemporaneous accounts such as Boccaccio’s The Decameron and I don’t seek to recapitulate the intricate details. For our purposes, it is important to realize that The Black Death, by killing 1/3 of Europe’s population, is a touchstone in understanding how infectious diseases impact history, world events, geopolitics, and national security. No war or weapon (save biological ones) could ever deliver such a blow as this tiny bacterium did.

 With one-third of Europe’s population dead, labor shortages abounded and because of the demand for labor and its reduced supply, it is thought that peasant laborers were able to change the terms of employment via The Peasant’s Revolt—an event that dramatically changed the structural relationship between landlords and their tenants who worked the land. The other element of The Black Death worth emphasizing is the deadly anti-Semitism that sought to blame European Jews for the outbreak. Jews were repeatedly accused of having poisoned wells and were consequently killed in large numbers using horrific means. Societal disruption during such an existential crisis, how The Black Death clearly must have been viewed by those experiencing it, is a major factor in infectious disease outbreaks. You might think that humans have jettisoned something as prejudicial and arbitrary as blaming certain members of society for a disease outbreak, but in large part they haven’t. Just recall HIV/AIDS, Ebola, and even the 2009 H1N1 influenza pandemic, in which North Americans faced stigma.

Malaria: This Leaves a Mark

 If something killed half of all humans that ever lived, it is safe to say it is something that would leave its mark on history both literally and figuratively on the human genome. Such is the “achievement” of malaria.

 This mosquito-borne scourge of mankind, caused by the Plasmodium species of parasites, still kills at an amazing clip of 1 million humans per year. Though most of the industrial world is now free of malaria—thanks in part to DDT—the planet on the whole is still malarious. In areas in which malaria is endemic, it exacts an enormous toll on the people, robbing parents of their children, confining productive people to their beds, and diverting precious resources to beat back what could’ve been just a problem of the past, as it is in many parts of the world.

 Because of the incredible ability of malaria to cull the population of humans, it can be thought of as a Darwinian selection pressure on the population. In other words, because of the myriad, often subtle, genetic differences (i.e., mutations) that exist between humans there may be some that, for whatever reason, are advantageous to those who are infected with malaria. Such an advantage may be that the possessor of the mutation is unable to be infected by the malaria parasite or has only a mild case if infected. Over time those that are resistant to dying from malaria would have more of a chance to reproduce and pass on the protective genes to their offspring. As more and more time passes, a proportion of the population who descended from these “mutants” would exist and be able to flourish in an area that other humans would find inhospitable.

 The above is a brief explanation for why such mutations as the one that causes sickle cell anemia was preserved by natural selection. In this case, if one possesses just one of two mutant genes and is only a carrier, they are resistant to malaria and not affected by sickle cell anemia (whereas those with both genes mutated suffer the effects of sickle cell anemia). The offspring of carriers, who would have at least a 50% chance of inheriting the gene from one of its parents, would be evolutionarily privileged in malarious areas where those not so preferred would have a higher chance of succumbing to malaria. Similar mechanics underlie the propagation of other malaria-resistant genetic diseases such as glucose-6-phosphate deficiency (G6PD), thalassemia, hereditary spherocytosis, hereditary elliptocytosis, and the Duffy blood group. To indelibly concretize the point, one just has to superimpose maps of where malaria has been present on the planet and where these genetic mutations are highly prevalent and see the perfect overlap.

 The lesson I draw from such a prolific killing machine as malaria is that even when it appears bleak—a 50% kill rate of the human population can’t be described, even if you’re a glass half-full type, as anything but bleak—there is inherent resiliency in humans derived from their genomes.

1918: The Great Influenza

 For most of human history, globalization was not fathomable as people tended to locate in one geographic area and not move far from it because of the cost, difficulty, and danger incurred when leaving one’s enclave. That all changed with Christopher Columbus’ path-breaking, heroic, and pioneering voyage of 1492. Indeed, I believe our modern perspective of “a small world”, when viewed in terms of fundamentals, can be traced back to that pregnant voyage that changed so many things.

 Fast-forward 400 or so years in the future to the early 20th century and we find ourselves in the midst of the world’s first global conflict in which nations, literally separated by oceans, are engaged in an unprecedented war with each other.

 Inserted into the melee was the influenza virus.

 This small virus, which hadn’t even been discovered, embarked on a killing spree that dwarfed war casualties. It charted up to 50 to 100 million deaths in its deadly yearlong circumnavigation of the globe, aided by mass global troop movements.  By comparison HIV is estimated to have killed 39 million people in its decades of existence.

 While debate exists to the original origin of this virus—Kansas vs. China vs. somewhere else—this pandemic concretized for many the ability of an infectious disease, in the modern era, to literally wreak havoc.

 There are many books that have been written about this incident detailing the utter calamity the human race was in during the pandemic with shortages, curfews, closures, masks, casket piles, mass graves, and the like becoming a normal part of life. With “just” an estimated 1-2.5% fatality rate with infection, the sheer scope of the respiratory virus’s infectiousness exacted a staggering toll killing about 5% of the extant population of 1 billion humans on Earth in what is really just a blink of time.

 Though fictional portrayals of a post-apocalyptic world inhabited by zombies, monsters, and mystery abound in popular culture, one need not delve into the world of science-fiction fantasy to understand pandemics and infectious disease emergencies. One can simply study the course of The Black Death, malaria, and the 1918 influenza pandemic to see worst case scenarios.

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 From the above it should, hopefully, be apparent that the human race has been through major infectious disease emergencies that took a horrendous toll on the species who, not knowing the power that laid within their genes, must have thought the end of the universe was at hand (and for those who succumbed indeed it was the end). However, the human race persisted—even in an era before widespread availability of effective supportive medical care, not to mention vaccines, antibiotics, and antivirals. These were not even close to existential or “x-risks” even though they were the biggest foes our ancestors faced from the microbial world.

 With these basic facts and a little bit of history at hand, we can now turn to unraveling the alchemy of a pandemic pathogen — the first lens for how I evaluate every infectious disease outbreak.

Chapter 1: When to Worry

This is the first installment of what was a book project of mine. It is written for a general scientifically interested audience and the style reflects that. Feedback on my ideas is always welcome.

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“You’ll tell us when you’re worried, right?” This was a question I was frequently asked by reporters, colleagues, and even my barista during the height of the 2014 West African Ebola outbreak — the deadliest in history — when, drawing on my work in infectious diseases and pandemic preparedness, I was called upon to serve as a media expert.

Throughout the hysteria and the 24-hour news cycle, I repeated one statement: “Ebola is a deadly scary disease, but it is not that contagious and will not find the United States (or other industrialized nations) to be a hospitable environment.” In the end, this was borne out, increasing my credibility with those who had heard my predictions.

But my predictions were not based on some overly rosy outlook on the landscape of infectious disease. How could I have a rosy outlook on infectious disease with serial killers such as HIV, malaria, and tuberculosis presently threatening the human race, and diseases such as MERS and SARS emerging as deadly threats? We had just experienced a pandemic of a novel influenza virus that took the world by storm and surprise. Meanwhile, its highly lethal avian cousins, including to this day, seem to be waiting for the right opportunity to pounce. In 2014, abetted by the primal scream of the anti-vaccine movement, the US had a record number of measles cases (in the post-vaccine era) and just 4 years later the Americas lost their measles elimination status and the US broke measles records. Perpetually lurking in the background of all these explosive outbreaks, antibiotic resistant bacteria threatened to collapse the entire structure of modern medicine.

 In short, I know just how deadly and disruptive infectious diseases have been, both historically and presently, as well as what it takes for an infectious disease to be included in the pantheon of pandemic causing pathogens.

Despite almost no chance of contracting Ebola, ordinary people in industrialized nations took extreme, unwarranted measures – such as buying spacesuit-like apparatuses for what they believed was the coming apocalypse – that would not make them any safer from the disease. Though many people truly feared the world was poised to become a dead zone inhabited by Ebola-stricken zombies, their fears have not come true.

 Indeed, in the midst of the unprecedented Zika outbreak in 2016, I echoed a similar message to dampen fear. Drawing on historical examples such as rubella – which caused similar devastating fetal anomalies – I tried to explain that Zika, notwithstanding its considerable public health impact, doesn’t measure up to a widespread pandemic threat.

 What some actually fear, with each outbreak of emerging infectious disease, is the arrival of an extinction event. Hypothetically, such an event would cause such a large proportion of the human race to succumb to infection, leaving few or no survivors, that the population would cross a critical threshold, beyond which the species cannot be sustained. The extinction event concept activates the human imagination like nothing else: our minds fill with dinosaur images, science fiction narratives, and post-apocalyptic scenarios.

This focus on extinction or existential level infectious disease threats may be intellectually stimulating, has synergy with ordinary pandemic preparedness, catches the eye of prominent philanthropists such as those involved in the Effective Altruism movement, but is often hyperbolic and distracts away from actual infectious disease and public health tasks that are tractable and merit attention. As we have learned through COVID-19, hyperbolic pronouncements sow mistrust between public health authorities and the public and often create false alternatives for policymakers.

 The most famous extinction event is, of course, that of the dinosaurs 66 million years ago. Though we tend to associate it exclusively with dinosaurs, the truth is that three quarters of animal and plant species perished during this period, formally known as the Cretaceous-Paleogene extinction event. The leading hypothesis, which has amassed enough supportive evidence to reach the level of a theory, points to an asteroid impact. It is important to note that the impact alone, rather than cause mass extinctions in itself, created changes in planetary conditions that made life impossible for those species unable to adapt and ill-equipped to a markedly different habitat.

 Such a cataclysmic result is not surprising, since many species would not have developed resiliency mechanisms to cope with a major habitat change. Natural selection would not have produced superfluous traits (in the absence of an asteroid strike) on a large scale. In essence, the Cretaceous-Paleogene extinction event was a great culling, the survivors of whom possessed, by chance mutations, the characteristics that allowed them to survive.

 An interesting footnote to this event is the idea that drastic reductions in the amount of sunlight killed those plants that relied on photosynthesis for life, resulting in the proliferation of non-photosynthetic organisms such as fungi. If, like me, you try to find an infectious cause in every event, you may wonder if the increase of fungi led to widespread fungal infections, magnifying the devastation posed by the loss of nutritious vegetation relied upon by most species. Today, fungal infections are responsible for annihilating species of reptiles and amphibians.

 Whatever the mechanics, the Cretaceous-Paleogene extinction event is the most widely known of its kind, but it is decidedly not akin to something an infectious disease pathogen could do. I mention this event only to draw a distinction between an actual mass extinction event and what a severe human pandemic is capable of doing.

For many species – unequipped by evolution for changes in habitat, predator-prey relationship variations, and myriad other factors – micro-extinction events occur continuously.

Amongst these micro-extinction events, there has been only one semi well-established infectious disease extinction event—that of the Christmas Island rat by Trypanosoma lewisii, a mosquito-borne protozoan (related to the causes of the human infectious diseases African Sleeping Sickness and Chagas Disease). In this instance, the poor rodent, stuck on an island and unequipped to leave it, had nowhere to run. Incidentally, there is an effort to de-extinct this rat using modern technology.

However, between a fleeting infectious disease outbreak and an extinction level event there is a lot of room for disaster. I agree with most experts who do not think an extinction event is possible. However, there is a concern for what are termed global catastrophic biological events (GCBRs). These events, which are caused by infectious disease outbreaks, have the capacity to lead to dire consequences for modern industrial society as the resources needed to contain them outstrip national governments and the private sector.

The COVID-19 pandemic, with its relatively low mortality ratio of <1%, has proved to be such a case. The early failures to see it as the looming threat it was — and eventually became — reflect either a degree of evasion or a failure to understand the threat matrix of infectious diseases. The events of this pandemic exposed major vulnerabilities in what were deemed the world’s most prepared nations. There have been several times that I have been baffled and frustrated by the response. This was especially true in the early stages where inaction followed by wrong actions could not have been more perfectly calibrated to orchestrate disaster if they were planned. For example, ineffectual travel bans, flawed testing criteria, the lack of testing capacity, the lack of personal protective equipment (PPE), the failure to fortify nursing homes, and the general reactive evasive nature of the response set the stage for the million plus deaths that followed in the U.S.

When it comes to infectious diseases, it is events such as these that induce people to worry about the future of the species, societal collapse, and economic ruin.

The human species, for the vast majority of its existence, has struggled against infectious diseases of one sort or another. And the explosive increase in our average life span, a very recent occurrence, can be directly attributed to the control of infectious diseases through sanitation, vaccination, and antimicrobial therapies. So, for most of mankind’s history, infectious diseases were the existential threat. And time after time, they have proven their success at killing humans and impacting civilizations. The emotion of fear, given this context, is quite understandable. The luxury of death from cancer, heart disease, or stroke in our eighth decade of life has only emerged in the modern era, when industrialized societies learned to mitigate many infectious diseases. Idyllic childhoods – free from watching siblings and friends die from outbreaks of typhoid, scarlet fever, smallpox, or measles – were not the norm for most of our ancestors. Even today, some parts of the world still face such threats.

Extinction Event is the result of my daily engagement in this field which ranges from treating patients, to speaking to the media, to thinking deeply about the role of infectious diseases and human societies. My aim is to provide you, the reader, with an important context by which to gauge any infectious disease outbreak by providing you a grounding in the key factors that govern an infectious disease’s trajectory, grasping the significance of certain facets of historical outbreaks, understanding other variables that set boundaries for infectious disease outbreaks, and recognizing the key tasks of pandemic and emerging infectious disease preparedness.

In what follows, I will alternate between discussing outbreaks, epidemics and pandemics, because much can be gleaned from looking at extreme and varied cases to elucidate, and set limit conditions, of what will be most likely to occur. Also, and crucially, preparations for the mitigation of these events are similar, utilize the same infrastructure, and engender expertise in outbreak response fundamentals. By executing the right actions for the most minute threat such as a limited salmonella outbreak or the occurrence of a single case of a high consequence pathogen, the threat of larger occurrences is lessened.

It is important to emphasize that when it comes to humans and infectious disease outbreaks, we cannot evolve our way out of them. Whether it is influenza, COVID-19, or plague, the key question to ask is how to diminish the societal disruption that will be engendered. This can only be accomplished by knowing the key questions to ask, acquiring knowledge iteratively, and ultimately taking the right actions.

Though I will argue against an infectious disease being able to cause an extinction or even a global catastrophic biological event for humans it should not be construed as minimizing the impact and importance of extreme resiliency against infectious disease threats. What my discussion does provide is a framework to better focus preparedness on the most crucial elements. How can we minimize the chance that infectious disease threats cause disarray? If a low lethality pandemic like COVID-19 can wreak such havoc, what would happen if something far more dangerous took hold.

As part of my argument, I will introduce several themes or principles that will provide a framework that I, personally, rely on as a lens to understand past infectious disease events, gauge the impact of current threats, and try and predict those that lie in the future. Whether or not they are exhaustive, at minimum this framework provides an integrated and principled way of thinking about this field. I consider the below points my primaries, first principles, or starting points:

1.    For an extinction level event to occur, an infectious disease will have to possess certain attributes that allow it to first cause a pandemic. Not every infectious disease has pandemic potential.

2.    By its very nature a pandemic pathogen must be capable of transmitting efficiently between humans, putting bounds on which of the myriad members of the microbial world are capable of this feat.

3.    The human immune system, which evolved in the midst of our microbial planet, is a major constraining factor on the impact of infectious disease threats because of how it operates.

4.     The human mind’s ability to develop new tools to attenuate the impact of infectious disease threats — in increasingly more rapid fashion — has grown increasingly formidable through our species’ existence.

Any human pathogen — whether pandemic, epidemic, or outbreak worthy — will have to overcome these factors.

So, here again is the crucial question I began with, but reformulated: why couldn’t an infectious disease constitute an existential level threat to humans?

Holding Out For a Hero: A Long 6 Years without DA Henderson

It’s been six years since DA Henderson died and I think it is painfully obvious to everyone — not just those in infectious disease and public health — how much he’s needed. As has become my tradition, I am going to list several questions I have for him. Thought it is a pale comparison to the terms when I could just walk through the office and find him at his desk reading and just ask him, I find it useful to refine my own thinking on the issues of the day and wonder how his unrivaled mind might approach the problem. Sometimes, it just makes me appreciate just what it was like to be in the presence of such a person.

Interestingly, just a few days ago I was excited and not surprised to see DA’s name in print in the Washington Post as an anecdote from over 20 years ago in which he warned of the threat of monkeypox was recounted.

So here are my questions for DA.

1. What do you think the trajectory of monkeypox will be? Is this something that will burn itself out as people become immune through vaccination and prior infection while also changing their behavior? Do you think sustained spread is possible in the US outside of men-who-have sex with men? Is this clustering among MSM akin to how meningococcus can do the same thing?

2. What do you think of Jynneos’s effectiveness? I know you always swore by Dryvax and it’s modern equivalent, ACAM2000, because it — with you driving its use — banished smallpox from the planet. Would you favor the use of ACAM2000 in select cases (I know I would). Also, what about Lc16m8, the Japanese 2nd generation vaccination you favored. I remember a story you told me about how after the anthrax attacks the Jynneos (or MVA) was prioritized over the existing Lc16 m8 for reasons you never quite understood (a good story for a journalist to try to uncover)

3. As COVID-19 becomes more manageable with all the medical countermeasures that have been developed how do you help people risk acclimatize to a never-abating threat?

4. What should be done about circulating vaccine derived polio viruses (cVDPVs) ? Following what you taught me I draw a distinction between wild poliovirus and these Sabin-vaccine derived strains. Should we just move to full Salk for the rest of the world to eliminate this problem? Why do people conflate wild polio — which exists in just Afghanistan, Pakistan, and Mozambique -0 with cVDPVs?

5. Do you think that waning immunity against ordinary respiratory viruses due to decreased social interaction because of COVID is responsible for pediatric hepatitis cases and off season RSV? What will happen with flu as some strains have become extinct ?

6. How do you think the CDC should be reformed? What was your final impression of it’s promise after spending so much time there? I think there was a reason you didn’t ever direct the organization that stemmed from who “they” wanted at the helm vs. who is best qualified.

These are just 6 questions I want to know DA’s answer to — there are so many more.

One last point to make. As infectious diseases have, understandably, taken center stage DA’s presence and voice would be unequalled. His would be an intransigent voice that spared no one’s feelings, one that would not be carefully calibrated to curry favor with any political party, leader, or administration, and one that provide a resolute direction for clinicians, the public health workforce, and the whole country and planet. Would that a DA-like figure emerge again — I hope his qualities are not a once in a century appearance.