Building on what I’ve written in prior chapters, this very short chapter serves to concretize an important principle of infectious diseases: solving the puzzle of what is making someone sick.

In the early days of a burgeoning pandemic, epidemic, or outbreak the key task is to identify the inciting pathogen. What type of pathogen is it? A virus, fungi, bacteria, prion, parasite, etc.? What species is it? What does it resemble? All these questions are aiming to understand the identity of the pathogen. While this might sound very obvious and simple, knowing the identity of a pathogen gives humans a very powerful tool. It illuminates what I call “biological dark matter” — all the unidentified pathogens that lurk behind infectious syndromes of all severities that are not completely identified (more on this in a later chapter).

Every sniffle, every UTI, every sore throat, every pneumonia, every gastroenteritis, every ear infection starts out as biological dark matter that may or may not yield a final specific diagnosis (often because diagnostic tests might not be deemed necessary).

However, when one grasps the entity’s identity and is able to categorize it, a whole host of related knowledge one has accumulated can then be applied to it. For example, if one knows that some clinical syndrome is due to an infecting bacterial species that will lead to general treatment and diagnostic principles such as the use of certain types of antibiotics, certain types of culture media, and anticipating certain types of transmission. Similarly, if something is known to be caused by a virus it will lead to unique considerations specific to viruses.

This reasoning can be extended, for example, to knowing a virus is of a specific viral family or if a bacterial species is of a certain type (e.g., gram stain positive or gram negative). What comes along with each iterative step of identification is a whole slew of information that can be applied to the problem based on what has been learned in the past regarding entities of this type. If the unidentified pathogen is subsumed by an already known concept, all that prior knowledge can now be applied to the new instance of it.

Knowing, to any degree of specificity, what kind of thing the culprit organism is conveys explanatory power which can then be wielded for therapeutic, prognostic, or other purposes.

A little digression

I am someone who shamelessly loves the Ghostbusters and am always at the ready to equate infectious disease physicians to the Ghostbusters or the Men in Black (”We're your first, last and only line of defense against the worst scum of the universe”; “'Cause we see things that you need not see and we be places that you need not be”).

But I sometimes think a better analogy is to a science-based “exorcist”. After all, infection is a type of possession or infestation in which the host’s normal physiology can be severely altered by the invader It then becomes the infectious disease physician’s task to identify the invader and develop a plan to remove its influence on the host by killing it with medications and modulating the host’s immune response to it.

Maybe I’m making too much of this and it’s just the indelible 9 years of Catholic school I attended as an atheist child who was intrigued by the mythology of the dark side.

But, an aspect of all the exorcist demonic possession movies I have watched is the power that the exorcist (infectious disease physician) gains by learning the demon’s name (the identity of the pathogen).

In the movie The Rite, it is explained that:

“It is the job of an exorcist...
...to determine the number of
possessing demons and their names...
...something the demons protect
with great ferocity.
And when the exorcist has a name...
...he can then begin to
assert control over the entity...”

Like the German fairytale character Rumpilztilksen, the evildoer hides its name lest it lose the power it possesses. Once the name is known, it seems like child’s play to rid the person of the demon. Quoting again from the movie, The Rite, when the priest discovers the demon’s name he states:

“I know you, Ba'al.
And I command you, retire therefore.
Depart from this place. Leave!
Surrender now.”

To complete the analogy: in the case of, for example, severe septic shock, once the inciting cause is discovered the clinician can start a specific treatment plan and gain some control back (“Well I guess we're gonna have to take control”). While this may or may not be ultimately successful in rescuing the patient by ridding them of the infection, at a minimum, explanatory power is obtained.

***

Having the capacity to determine the etiology of the unknown unknown making someone, a city, a country, or the world sick is a critical aspect of pandemic preparedness and response. You have to know the demon’s name. However, to be able to do this adeptly in an emergency situation requires aiming for specific microbiologic diagnoses (and not ceasing investigation at the level of, for example, “pneumonia” or “viral syndrome”) to be the norm during day-to-day medical care, the topic for the next chapter.

The grand challenge of pandemic preparedness is how to develop and maintain a proactive stance against a foe whose current identity and timeframe of attack is unspecified. The sea of microorganisms that can inflict harm on humans is vast and every changing. It reminds of the problem faced in the world of The Three Body Problem: preparing for the unspecified alien threat that is coming at sometime in the future.

However, amongst the plethora of microorganisms that have the capacity to pose pandemic level threats to the human species in the modern era, several characteristics are prerequisites. Disease X, the conceptual tool being used to foster proactive pandemic preparedness, should be informed by the fact that a pathogen’s ability to constitute a pandemic threat will be constrained and grounded by its biological attributes. As previously outlined and argued for in a project I led that aimed to derive pandemic preparedness first principles, the essential attributes of such a pathogen will include:

1. A viral etiology

2. Predominant and efficient respiratory/airborne mechanism of transmission

In the absence of these two factors, pathogens may rise to epidemic status and be regionally disruptive but will fall short of the pandemic threshold.

Historically, pandemic potential status was reserved — almost exclusively — for influenza viruses. Pandemic preparedness was considered to be synonymous with influenza preparedness. This equivalence was not without basis as the only occurring pandemics for almost a century (spanning from at least 1918 to 2009) were all caused by influenza A viruses. However, this solo focus on influenza constituted an unwarranted freezing of the concept of pandemic pathogen in the mind. The advent of SARS—CoV-1 in 2003, MERS-CoV in 2012, and, most recently and obviously, SARS-CoV-2 in 2019-2020 highlighted, in dramatic fashion, how a non-influenza virus could not only pose a pandemic threat but foment one.

An alternative approach is to focus pandemic preparedness on pathogens that possess the requisite traits by mapping those traits onto the known viral families. Of approximately 2 dozen viral families that are known to infect humans, there are 6 that warrant special attention. These families are:

1. Orthomyxoviridae (the influenza virus family)

2. Coronaviridae

These viral families all include members that have the capacity for efficient human-to-human spread via the respiratory route, seasonal endemic members, and zoonotic analogues.

Honing pandemic preparedness activities to focus on these 6 viral families serves as a razor or an operative principle to simplify the task by focusing efforts on areas with the highest yield. As such, it is akin to a lens or conceptual tool with which to survey the microbial world. As such, this lens will, by necessity, include certain viral families (some of which such as the adenoviridae that have been completely discounted as pandemic threats) and exclude others.

In the wake of the rise of the coronaviridae as a pandemic threat, several groups have adopted the term “prototype pathogen” as a mechanism to facilitate work in viral families on a specific member that could serve as the basis for further accelerated work if a pandemic was incited by a member of that family. This approach is correct however its full impact is diluted as there is a tendency to focus — not just on the 6 respiratory viral families — but on all the 24-25 extant human infecting viral families, conflating outbreak, epidemic, pandemic, and as Osterholm has identified, pathogens of critical regional importance.

Moreover, even while better approaches have supplanted prior thinking and created an improved paradigm that recognizes preparedness should be focused on viral families in addition to specific agents, it must be protected from the tendency to slip into the familiar mode of making lists of pathogens that are members of the high consequence viral families.

Specifically, it is not necessarily the case that a pandemic pathogen will be a known human pathogen in a viral family. For instance, it is unlikely that parainfluenza virus 1 will develop pandemic potential in the future. What is more likely to be the case is that a fellow member of the viral family that includes parainfluenza virus 1, one that is infecting animals and not currently causing documented infections in humans, could acquire the capacity to cause a pandemic in humans. Similarly, Nipah virus has been infecting humans with some regularity yet not risen to pandemic level. This phenomenon suggests that it is not Nipah, but perhaps a Nipah-adjacent henipavirus that is the true pandemic threat. The epidemiological history of the sarbecovirus coronaviruses SARS-CoV-1 and MERS-CoV juxtaposed to their relationship to the pandemic causing sarbecovirus SARS-CoV-2 is a concretization of this point.

As such, a pandemic threat will be most likely to emerge from a zoonotic member of those respiratory viral families whose other members are well-characterized and/or ubiquitous human pathogens.

This means that working on list of known human pathogens in these viral families too narrowly focuses the scope of pandemic preparedness. It is undoubtedly critical to work on Nipah, for example, but not only because it is a threat in itself but also because a related virus that may be exclusively in bats today may emerge. If a Nipah vaccine becomes available, it will not necessarily remove the threat of a Nipah-like virus (although it would lessen it if there were cross protection and provide critical information for targeted vaccine development). It is necessary to delve into the full breadth of the family, particularly its zoonotic potential members, and work to develop a pathophysiological understating of the family (including immune system targets, organ tropism, etc.) and to develop countermeasures that have impact on one or more family members.

An optimized viral family approach to pandemic preparedness recognizes that well-characterized human-infecting members of respiratory viral families are the most likely pandemic threat. While it is a truism that a pandemic viral family will hail from the 25 viral families that have the capacity to infect humans. Once this prerequisite is met, however, it will be higher yield to pare the task down using the razor of respiratory viral families. The great conceptual value of this approach is that it is a means of systematically approaching pandemic preparedness.

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