Cascading Human Error: COVID-19

I explicitly chose to not focus this book on COVID-19 — there are plenty of excellent books that do this, and I have lectured on it countless times — as my aim is to really outline general principles as well my thoughts on infectious diseases and pandemics. However, COVID-19, in addition to being the greatest infectious disease threat the human species has faced in over 100 years, concretizes many of the points that I think this book makes clear about infectious diseases. In this chapter, I do not intend to rehash the details of the pandemic but to highlight some of the most salient aspects of it. These highlights will be in the form of what I take to be general principles.

 

Principle 1: An efficiently spreading respiratory pathogen with an animal host cannot by eliminated or eradicated.

 

SARS-CoV2, the cause of COVID-19, is a coronavirus. It is the 7th human coronavirus discovered and of those 7, 4 cause about 25% of cases of the common cold (there are reports of sporadic cattle related coronavirus infections in humans as well). The other two cause SARS and MERS.

It is critical to recognize that for any pathogen to be a cause of the common cold it has to possess a few key attributes: the capability to be able to spread efficiently, cause a spectrum of illness shifted towards the mild side (to facilitate transmission), and be able to get around immunity to some degree in order to re-infect. There are myriad viruses that cause the common cold. Some of them include rhinoviruses, adenoviruses, and parainfluenza viruses.

 When it became clear that SARS-CoV2 — unlike MERS and SARS — was able to efficiently transmit from person to person, it was a foregone conclusion that it would infect virtually everyone over time and settle in to eventually become the 5th seasonal coronavirus. Even before the virus was discovered, it had already spread from China and was likely mixed in with flu and other respiratory viruses unbeknownst to anyone.

 A corollary to this principle is that if a pathogen has the ability to spread before symptoms develop, it is extremely — if not impossible to contain — as the infected unknowingly go about their activities of daily life spreading the infection. This phenomenon, characteristic of influenza, was not something known to occur with coronaviruses justifying the lack of early mask recommendations for the asymptomatic. In the first months of the pandemic, it became clear that SARS-CoV-2 behaved in a different manner than its other family members in terms of the potential for pre-symptomatic spread prompting major guidance changes to reflect the new context of knowledge. It is still unclear what underlies this divergence from other coronaviruses. Perhaps with the 4 common cold causing coronaviruses the rigor of study on pre-symptomatic spread was not high enough to firmly exclude it (although with SARS and MERS it was). As SARS-CoV-2 behaves, in terms of transmission, rather unlike SARS and MERS it could be that the genetic traits conferring this enhanced transmissibility profile also confer a propensity for pre-symptomatic spread.

What invariably unfolded, because there was zero immunity in the population and a marked ability of the virus to cause severe disease in those with high-risk conditions, was death and destruction, even if the case fatality ratio was about 0.6 — a small number multiplied by a large number is still a large number. This is what underlies the 1 million plus U.S. deaths that resulted from the millions and millions of cases that occurred here.

 Because of the biology of the virus, in my analysis, the objective should never have been to pursue a flawed “COVID-zero” program or to have some expectation that the post-pandemic world be anything like 2019. The goal should have been to prevent severe disease and develop and distribute medical countermeasures that tamed the virus in high-risk populations. It should have included a frank conversation with the world’s population about the destined endemicity of the virus and the need to develop methods of risk calculation to reduce the harm the virus could cause. This is how individual patient-level thinking smoothly integrates with population-level thinking.

 A critical component among the required activities would be preventing hospitals from getting overrun by augmenting capacity, ensuring supply of medical equipment and personal protective equipment, facilitating regional load-balancing of patients, and provisions for adequate staffing. Also, because we understood early on the predilection for this virus to devastate the elderly, nursing homes should have been fortified significantly. There also would be a need to sustainably buttress long-standing deficits in public health infrastructure required for testing, tracing, and isolating. Most nations of the world failed — repeatedly — to do this, but notable exceptions like Taiwan and South Korea exist.

 Taiwan avoided lengthy stay-at-home orders and societal disruption because they proactively jumped into action on December 31, 2019. 2019! They were able to test, trace, and isolate meeting cases as they occurred. This is not just because it is an island nation, it is because they prepared for infectious disease threats almost like no other nation. I was part of a team who, in 2013, evaluated their infectious disease preparedness because sadly Taiwan is not permitted to be a member of the World Health Organization (WHO). Infectious disease preparedness is an activity that is interwoven with national security in Taiwan, and they have even had a Vice President with a PhD in epidemiology. Sadly, during COVID-19, the U.S. Vice President was not an epidemiologist, and the results speak for themselves.

 Similarly, South Korea was able to muster their diagnostic companies in an all-hands-on-deck approach in early 2020. The U.S. government, by contrast, willfully erected bureaucratic barriers that virtually precluded diagnostic companies and laboratories engaging in the testing enterprise.

 Today, our rapid tests, vaccines, monoclonal antibodies, antivirals and, most notably, our knowledge of the virus, its epidemiology, its clinical features, its complications, and its treatment have succeeded in taming the virus. The remaining task is to get more people to be accepting of the pathbreaking tools scientists have developed.

 Principle 2: If you can’t test, you’re blind.

 One of the most basic ingredients to any infectious disease response on both the individual and regional level is to be able to actually know who is infected. From the early days of the pandemic up to the minute I am writing this line, testing has been the original sin of the pandemic. In the early days of the pandemic, the U.S. deployed a flawed test manufactured by the Centers for Disease Control and Prevention (CDC) that was only able to be performed at state health departments and only on those who met strict testing criteria. Paradoxically, as the public health emergency was declared it eliminated a pathway, used every day for many infectious diseases, for university and commercial labs to make their own laboratory-developed tests ensuring supply would be no where sufficient to keep up with even a modicum of cases. The market needed to be flooded with tests in South Korean fashion then, (and even now) but what was delivered was a trickle. It is also true that restricting testing to those from China long after the virus had departed and those with lower respiratory symptoms only was a perfect recipe for allowing chains of transmission to get out of control and land on vulnerable populations, including nursing home residents.

 When it is not clear who is infected, it is difficult to determine how they were infected and, subsequently, what activities are at higher and lower risk. This type of risk differentiation is needed for risk calculation guidance and is a key component of harm reduction.  

 In recent years, the advent of home tests — long delayed and resisted by some — has somewhat rectified the problem but shortages and short-sightedness continued to restrain testing from being deployed optimally. The myriad regulatory constraints on home tests underlie why they were initially far from ubiquitous, and these regulations served as a major barrier to entry for manufacturers. The resistance to home tests is long-standing in the U.S. and is responsible for the fact that pre-COVID only an HIV test was available to use in the home (this itself was the result of about a decade of regulatory wrangling). The paternalism over testing stems from an inability to imagine a layperson operating testing material and is ridiculous on its face. Laypersons operate all sorts of devices more complicated than a lateral flow assay everyday. Home testing puts the public back into public health, as it has been shown that people modify their behavior based on results. These tests should be seen as public health tests akin to the cheap fentanyl test strips with which injection drug users test their materials with.

 Principle 3: A long range approach is needed

With an endemic infectious disease is mandatory that any control plan be long-range in nature, not something expedient and in response to public panic. The danger of short-range solutions to COVID is everywhere you look. Privileging one type of Illness over all other illnesses and everything else in the world leads to cascading consequences that must be dealt with some time in the future. This is the folly of using blunt tools such as lock-downs — which were indicated in some places for a short and defined period of time in the very early days of the pandemic to preserve hospital capacity — because they treat all activities as equivalent for transmission. Categorizing some economic activity and those who perform it as essential and others as non-essential is also a consequence of short-range thinking that ignores the fact that without productive activity life ceases. As Elon Musk bluntly stated, “if you don’t make stuff, there is no stuff”.

In the future, it will not be surprising to see the aftershocks of COVID on cancer diagnoses, substance abuse, mental illness, and other chronic infections. The amount of economic disruption will be incalculable as we will not know what could have been where it not for the pandemic-induced disruption.

 Another aspect of long-term thinking that was absolutely required was to deal with the hospital capacity problems that regularly recurred. Hospital emergency preparedness is perennially neglected and an afterthought for most hospital executives. Financial considerations have incentivized hospitals to be similar to hotels as empty beds mean less revenue. While hospital preparedness exists for short term emergencies like a mass casualty event, preparedness for a sustained surge like a pandemic requires much more effort. A pandemic is very different than dealing with acute surges from a mass casualty incident and beyond the scope of much what is done in hospital emergency preparedness.

 Infectious disease emergencies, by their very nature, spread and hospitals in a given region need to act in a coordinated manner to withstand the onslaught of patients. Hospitals, though nominally part of coalitions with other hospitals, seldom acted like coalition members to load-balance during the pandemic. The convening of regular conference calls to check a box is not sufficient. It also must be emphasized that it is near impossible to build a hospital rapidly (or even semi-rapidly) in the U.S. — just think of all the municipal government officials that would need to sign off just on the land zoning issues.

 This short-range thinking also was evident in the way public health infrastructure was managed during the pandemic. State, county, and municipal health departments have been woefully underfunded and understaffed trapped in a cycle of panic/neglect and boom/bust for decades. Long shorn from their core function of communicable disease control, some health departments budgets are more non-infectious disease focused than infectious disease focused as elected leaders value headline grabbing health threats like vaping, obesity, or pollution more than the actual functions that health departments were constituted to address. Throughout the pandemic, it was mind-boggling that political leaders seemed befuddled about cases escalating and unknown chains of transmission when they failed, over and over, to actually hire the case investigators and contact tracers required to keep cases to a manageable level. We also see short-range thinking on display when resources for testing were shifted to vaccination and, when testing resources were again needed, consternation ensued.

 Much of this stems from the fact that political leaders are, by their very nature, short-ranged thinkers whose vision is bound by the next election cycle. They are unprincipled, range-of-the-moment, and, especially in today’s context, view things through the narrow lens of what political tribe they have sworn allegiance. They also possess an irresistible urge to been seen taking action, doing something, even if it is the wrong thing (the Biden administration’s South African travel ban in response to the Omicron variant is a paradigmatic example).

 Principle 4: Infectious disease subject matter experts are not policymakers.

 As I wrote above, political leaders are a major factor in why the pandemic went the way it did. These events can only be viewed as a failure of the government at all levels from federal to state to local to school board. Those that occupy our elected offices, at all levels, do not want to be blamed for anything and often abuse subject matter experts tasking them with activities that they themselves defaulted on. Subject matter expertise involves analyzing a situation and presenting scenarios and options. It is the responsibility of a policymaker to take the subject matter expert’s analysis and integrate it with countless other considerations such as laws, individual rights, feasibility, negative impacts, practicability, and sustainability. For much of COVID-19, political leaders leaned heavily on subject matter experts to make these calls and abdicated their responsibilities. For a communicable infectious disease that thrives on social interaction, minimizing social interaction surely will diminish transmission but is it the correct solution to forbid people to leave their residences for extended periods of time? What metrics should govern the order? What is the legal framework for such action? Does it apply to the infected and uninflected alike? What about people’s liberty? What about the survival of people’s businesses? All of these questions are to be weighed by a policy maker before implementation, it is not the role of a subject matter expert.

 A subject matter expert is tasked with controlling the infection and, naturally, might provide options that are the most devastating for the pathogen. In this task they are not, as Dr. Anthony Fauci once stated, “talking about liberties”. Similarly, former NIH director Dr. Francis Collins, stated:

If you’re a public health person and you’re trying to make a decision, you have this very narrow view of what the right decision is, and that is something that will save a life. Doesn’t matter what else happens. … You attach zero value to whether this actually totally disrupts people’s lives, ruins the economy, and has many kids kept out of school in a way that they never quite recover from.

These exchanges called to mind an interesting exchange from the movie The Siege in which an army general is asked about using the military in an American city to capture a terrorist. He replies:

 

The Army is a broadsword, not a scalpel. Trust me, senator, you do not want the Army in an American city.

Make no mistake, Senator. We will hunt down the enemy, we will find the enemy, and we will kill the enemy. And no card-carrying member of the ACLU is more dead set against it than I am. Which is why I urge you - I implore you. Do not consider this as an option.

 This is the unenviable position our political leaders put subject matter experts in.

 Principle 5: Don’t underestimate the anti-vaccine movement

 The reason why the U.S. remains mired in pandemic purgatory is surprising to many because vaccine availability is unrivaled. The signature achievement of the Trump administration is inarguably the delivery of vaccines through Operation Warp Speed in record time — I wish they were delivered even faster. However, even before the vaccine was developed the anti-vaccine movement sprang into action sowing misinformation and distrust. Using the tools of the 21st century, the voice of the Dark Ages hit a note with many Americans, including those who possessed risk factors for severe disease. So, even over a year after the availability of the vaccine, hospitals were still held hostage by high-risk unvaccinated individuals who reside in their communities and choose to keep hospital capacity in their cross hairs.

 The threatening intimidation to which vaccine advocates have been subject to, including myself, seems to be at record levels. The cowardice of hospital administrators in the face of unvaccinated healthcare workers who were holding their heads high while the vaccinated were on the defensive is something many did not anticipate. What has been needed is a proactive approach to addressing the anti-vaccine movement and illustrating to all that they are, for all intents and purposes, a nihilistically motivated movement that eschews rationality, reason, and evidence. The attacks on science, if they go forcefully unanswered, will come back to haunt us.

 

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Integrating the COVID-19 pandemic with the theme and message of the book, it should be clear that COVID-19 is no where near an extinction level event and is a perfect illustration of how human factors magnified a threat to greater proportions than it could ever have achieved without blunder after blunder. Coronaviruses will continue to be an infectious disease threat, but they are not an extinction level threat or even a 1918 level threat if they are met with the appropriate response.

 

 

Attack from Another Kingdom

It was a normal day rounding on this Monday, a few cases of contaminated fractures, a lady extremely sick with a necrotizing infection, a couple of post-neurosurgical meningitis cases and I was done for the day.

 Driving home, I was thinking about the cases making sure I considered all variables and made the appropriate recommendations. I arrived home and decided to binge watch a television series I’d been waiting to see for a while. It was Labor Day and I hate holidays—I hate the quiet, I hate everything being closed, I hate the faux events that occur.

 Then the pager went off. On the other line a hospital doctor was asking for my assistance in managing a patient who was in the emergency department with an unknown illness with fever. Usually, there are algorithms and empiric treatments that could be tried, but this was more complicated than that because of who the patient was.

The patient was a mechanic – but not an ordinary mechanic. He lived in Hawaii and was in Pittsburgh for the Labor Day weekend. The chief machine he worked on was not a car, an airplane, or dishwashers—he worked on underwater deep-sea exploration vehicles.  He presented to the emergency department with chills and a lesion on his hand where he had scraped it while cleaning some “gunk” out of one of the pieces of a vehicle a week or so ago. 

He stated that it began like an ordinary cut but then developed redness and pain with accompanying fevers. The area was not red, painful, and hot. I gave a recommendation to send blood cultures, have a surgeon take a look at the arm, and start some basic antibiotics.

 By the time the surgeon was done seeing the patient, they infected area had progressed from just his hand to his forearm with the fever being unbreakable. His routine blood work revealed his body was fighting this infection as his white blood cell count was markedly elevated. The patient’s blood pressure, which usually ran high, was hovering around 90/50, requiring intravenous fluids to be administered. The surgeon didn’t like the rapid progression of the infection, which reminded him of necrotizing fasciitis, known in the lay press as a “flesh-eating” bacterial infection, so he was eager to take the patient to the operating room quickly to achieve source control—that is cut away all the infected tissue before it spread further.

 In the operating room, the patient’s arm was sliced open and an extensive infection was seen rapidly moving up tissue planes. Pus, debris, and necrotic tissue was seen and removed. It looked like streptococcus, the surgeon noted. Routine cultures were obtained and sent to the microbiology lab.

 The patient’s course was rocky, and he was kept on the ventilator post-op as the surgeon planned to take a 2nd look the next day.

 The specimens were stained in the lab and revealed a few types of bacteria: gram negative and gram positive. The culture was plated and incubated. In about a day, when the plates where examined, the familiar rounded colonies of bacteria weren’t present, but a circular mold-like growth was present.

 The microbiology tech popped off the cover of the plate to take a closer look and examine the color, texture, and grab a sample to look at more closely under a microscope.  John, the microbiologist who literally had a nose for fungi, was brought the plate as he ate lunch in the break room. He peered at it and looked at the slides and offered some ideas as to what fungus it might be. Often fungal diagnosis is based solely on morphology (how it looks under a microscope) but this one didn’t look anything seen before so was set up for definitive identification using the laser MALDI machine that figures everything out.

 Fast-forward two days: the MALDI result was equivocal as no species level identification was possible. Based on the presence of mold, the original patient was placed on a powerful antifungal drug, but his condition had continued to deteriorate after his second trip to the OR where the infection continued with only minor, if any, abatement. The patient was no requiring medications to support his blood pressure and was in shock.

 Interestingly, the original lab tech had now developed a wheezy cough over the last few hours. Fast forward a few days, the original laboratory technician is now hospitalized with pneumonia, 3 of his coworkers are sick with respiratory symptoms and no one has identified the mold yet. Now, because there is a cluster of illness hospital infection control is involved because the original tech breeched biosafety by opening the plate in an open area in the lab and not under a special hood. He presumably inhaled fungal spores and contaminated the whole lab. The spores also entered the hospital’s ventilation system and were hopefully stopped by HEPA filters. But cases are expected to occur in other areas as spores likely contaminated clothing.

 The original patient, meanwhile, has succumbed to his illness and an autopsy revealed extensive invasion of multiple organs with the unknown fungus. Mycologists at the hospital pre-emptively tested the organism against all known anti-fungal compounds and found none that were effective against it.

 

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The above is a semi-functional scenario (I do, for the most part, hate holidays) and it might not strike one as more captivating than Ebola, bird flu, MERS, or whatever one can find in the headlines. But in each of those cases—even including novel viruses like MERS—the path to discovering the cause was clear cut and straight-forward as the usual rules for pathogen discovery could be applied. Electron microscopy, culture, PCR and other tests are applied in succession or simultaneously with the tacit assumption that something will lead to the correct answer. Sure, there might be missteps, like when SARS was misidentified as a parainfluenza virus, but they were in the right ballpark.

 An unknown unknown, by contrast, has no ballpark to be in. It is in a different league where the rules don’t apply. Dealing with these types of agents is, in many ways, similar to the way in which, before viruses were discovered, physicians and scientists could rule out a bacterial cause but knew a “filterable agent” must be present, as it passed through a filter too small for bacteria to pass and eluded the limited means of detection of the day. Similarly, a modern unknown unknown would have a high bar to clear to reach such status, but such a scenario remains a possibility, though distant.

 However, such a scenario does find similarities in the modern world. For example, the 2012 Exserohilum fungal meningitis outbreak, which was linked to the contamination of a steroid product, injected into the spine of patients was for a time an unknown unknown. That this outbreak was occurring was only appreciated after 14,000 people were injected with the contaminated steroid. Initially a well-known fungus was implicated after being identified in the index case, but that was found to be a blind alley and only later was the true culprit identified (though not in the index case!). Exserohilum was not a fungus well known to the medical community and prior to this outbreak—which led to 751 cases and 64 deaths in 23 states—there was a real paucity of human infections reported.

 In many ways the Exserohilum outbreak, which has long faded from the general public and the press’s mind, is something that was scarier than Ebola but was never appreciated for what it was. Just consider a few aspects of the outbreak: an organism that was not really linked to human disease in the past causing severe illness, an organism being spread through the healthcare system via unknowingly contaminated injections, the sheer number of injections of the contaminated material that occurred prior to recognition, the wide distribution network of the contaminated product, the direct injection of this pathogen into the body, the initial false identification and so on.  Such a scenario, to someone who studies these types of events on a day-to-day basis, is chilling. Imagine if the contamination was intentional or if it went unnoticed because of lack of situational awareness or information exchange and you can see how the problem becomes exponentially worse.

 Lastly, fungi are often overlooked but when thinking of human global catastrophe scenarios, we would do well to appreciate this kingdom of life even if it may fall short of a human pandemic threat. Fungi have literally decimated other species on the planet such as the frog in the Sierra Nevada Mountains (chytrid fungus disease) concretizing this kingdom’s destructive prowess in certain contexts. The popular television series The Last of Us (sensationalistically) dramatizes such a threat to humans. Certain human fungal diseases have notably emerged in recent years while traditional geographic distributions of certain species have been revised. Close to 4 million humans die from fungal infection annually.

 The reason fungi are often discounted is that they do not flourish at the human body temperature – they prefer cooler temps such as that seen in the reptiles and amphibians they decimate. However, the planet teems with fungi, and we live among them. Fungal organisms live on our skin, in between our toes, and in our gastrointestinal tract but are largely harmless unless some predisposing condition exists. The one mammalian species they can infect and threaten are bats, but white nose syndrome occurs during hibernation when the animal’s body temperature drops to a more hospitable level for the fungi.

 In recent years, the rise of a multiple-drug resistant fungi called Candida auris, which lurks in nursing homes, is extremely lethal (mostly due to the debilitated people it infects) and challenging to treat (though usually some antifungal therapy regimens can be effective. It can be nightmare for infection control practitioners as it can contaminate large swaths of a healthcare facility. Fascinatingly, the rise of this fungus began to increase its prevalence in human infections simultaneously on 3 different continents and has likely evolved to flourish at higher temperatures. There is some speculation that the rising temperatures of the globe may have put evolutionary pressure on this organism to develop heat tolerance capacities.

 Another fungus to watch is Cryptococcus gattii, this soil-based fungus is largely confined to the Pacific Northwest but has the ability to infect healthy humans – many serious fungal diseases are concentrated in the immunosuppressed. The appearance of this fungus in the Northern Hemisphere has been hypothesized to have been related to the Panama Canal allowing the subtropical fungus to utilize cargo ships to reach new geographic environs (a tsunami may have played a role in allowing them to reach shore – other fungal infections such as Valley Fever and Mucormyosis have synergized with natural disasters too).

 

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In summary, this is the kind of thing that scares me: a microbe that is unknown as a pathogen whose identification, even using our most significant diagnostic techniques, is challenged. That I grounded this scenario on earth, albeit with a deep-sea water twist, is an important point to emphasize as one doesn’t have to travel to outer space to find these pathogens, they live amongst us. The Exserohilum outbreak should serve as a concretization of that threat and deserves much more attention than it has received. Humans are aware of just a speck of the microbial diversity on the planet and the constantly churning and evolving genetically promiscuous microbial world lays largely undiscovered all around us.

 

What’s Alive in the Superunknown?

Up until now I have talked about diseases and conditions with which all readers are likely familiar, have some experience with, and can conceptualize. I know want to give some attention to a flavor that, to varying degrees, will have the opposite effect on readers and even on physicians and scientists.

I want to introduce the idea—well accepted by the microbiological community—that much of this field is unknown and what we do know is but a sliver of what is yet to be discovered. Throughout the chapter I will introduce interesting, and sometimes provocative, topics that are on the cutting edge of microbiological science. The purpose is not just to merely list all the cool things out there but to begin to sketch out an answer to the question with which I began this book by developing an enhanced framework with which to approach the field of infectious disease.

The Final Frontier

When people contemplate extraterrestrial life, they immediately think of creatures like ET or other Hollywood creations, but a more sober thought would be of microorganisms as the first type of extraterrestrial life that humans might encounter.

Indeed, the panspermia hypothesis argues life on Earth originated after the planet was seeded with microbes from a comet, asteroid, or meteoroid that crashed to the planet. If, and it is still a major if, panspermia is more than a hypothesis, what would that mean?

It may be surprising to many that the US government takes the possibility of extraterrestrial life very seriously—but not in an X-Files Area 51 way.

There have been 6 manned landings on the moon and in each of these situations humans interacted with a vastly different environment than anything before. Not only did the astronauts return to Earth after their heroic adventures, but they also brought back moon rocks and equipment “contaminated” with mysterious dust.

Biosafety (a common buzzword in the modern era due to highly visible lapses involving anthrax, smallpox, and bird flu popularized by the media) was a major component of lunar missions and is a fascinating topic in this context. Not only were astronauts quarantined prior to the mission to minimize the risk that they would contract an earthly infection prior to liftoff, but there were serious concerns regarding what would happen to them upon return.

 The human microbiome—the symbiotic bacteria and other microbes that are part of our bodies—is a fragile thing.  Antibiotics can severely disrupt it and the consequences can be dire (e..g., Clostridiodes difficile infection) as the microbiome is part of our defense against pathogenic microbes. In general, any alteration in the milieu can change the microbiome whether it’s antibiotics, social isolation, or stress hormones.

 Knowing these facts decades ago, scientists conducted simulations of the spaceship environment prior to prolonged spaceflight. The results revealed microbiome changes did occur (including a shift toward more virulent microorganisms) causing many to speculate whether upon return to earth a pathogenic microbe might gain a foothold while the microbiome defenses of the astronaut were still altered, and a fatal “microbial shock” ensue. Thankfully, such an event never came to pass, though certain fungi overgrew in the mouths of returned astronauts—an intriguing finding given that fungi, such as Aspergillus, stowing away from Earth, also flourished on the Russian space station Mir.

In addition to the threat of microbial shock, there was a slight—but real—concern of the astronauts bringing back a moon contagion and quarantine was imposed on the returning astronauts through the Apollo 14 mission. There is even a famous picture of President Nixon visiting the pioneering Apollo 11 astronauts who are safely behind a window in their quarantine trailer. The same sorts of precautions were also taken with lunar rocks. There is even an Outer Space Treaty(1966) and a NASA Policy Directive (8020.7G) that stipulates that care must be taken so as to not contaminate the earth with extraterrestrial material. Various microbiological studies were conducted and did not reveal the presence of any lunar microorganism—one wonders what the results would be with our current microbiological diagnostic tools.

The proposed Mission to Mars has also prompted some concern regarding the threat of Martian microbes, especially given the presence of subsurface ice and possibly organic Martian meteorite contents. There are currently debates about what types of biosafety procedures should be used so as not to damage any potential biological samples yet still render them relatively safe.

The solar system is often described as desolate, radiation-laden, and subject to large variations in temperature. On its face that doesn’t appear to be all that conducive to supporting a fragile organism, even a tiny bacterium. However, tiny microbes—the predominant form of life on Earth—aren’t as invariably dainty as they may seem.

As I have emphasized, ours is a microbial world and in areas of the globe where it would appear inhospitable to life, microbes can be found. Undersea high temperature vents, acid-laden environments, and environs with high levels of ionizing radiation are all home to extremophile – extreme loving -- microorganisms of various types. Extremophiles have even been found in the highest reaches of the Earth’s atmosphere. Such resiliency to harsh conditions argues that microbes don’t require the cozy environment of sweat gym socks or grandma’s potato salad to thrive. In fact, these extremophiles, by flourishing in their respective environments, have evolved traits that make it impossible for them to be displaced from the safety of the nasty places they call home.

Despite the existence of extremophiles, I think it is unlikely that a microbial organism that evolved to survive in an environment entirely disparate from that of Earth’s is unlikely to find our planet hospitable.

 The Third Domain

 Traditionally, pre-1990, the domains of life were broken into two: bacteria and the eukaryotes, which included everything from malaria parasites to humans. The division was based upon the presence of a certain cellular features including a nucleus. Now, the accepted division includes a third domain: the Archaea. Archaea were once included in the bacterial domain and share many features with them, including a one-celled nature and the absence of a nucleus. However, upon deeper investigation, it became apparent that they were as different from bacteria, despite superficial similarities, as the eukaryotes are. These differences include distinct biochemical attributes, such as the structural components of cell walls, as well as a divergent evolutionary lineage.

It is unclear what the full evolutionary relationship is between Archaea, Bacteria, and Eukaryotes. However, I believe the answer will unlock many mysteries of the origin of life on the planet.

Many Archaea are extremophiles, but species of these microbes can also be found living, rather peacefully, inside us. An open question has been whether Archaea can cause human disease and the answer is somewhat mixed. While most Archaea can be thought of as gentle components of the human microbiome there is suggestive evidence of their role in dental disease (periodontitis) where the density of their presence in those with certain dental infections correlates with disease severity.

Biological Dark Matter

 In a way, what I am focusing on in this chapter is the prospect of biological dark matter—though Archaea are by no means dark. By dark matter I mean microorganisms that we are unable to culture or see. More broadly speaking, biological dark matter includes genetic material we recover from various locations (including our own bodies!) that doesn’t match with any known entity. The field of metagenomics explores these haunting sequences.

What might have been considered biological dark matter in infections gets a little brighter when we bring new technologies to bear. From a plain light microscope to routine culture to an electron microscope, the diagnosis and treatment of infectious diseases have gotten both simpler and more complex. As routine culture, with its clean and often binary (growth or no growth) answers is increasingly supplemented with mass spectrometry and genetic sequencing, the clinician is faced with a zoo of organisms some of whose names require the consulting of a reference book. What was once a straightforward case of a Staphylococcal blood stream infection is now a polymicrobial swarm of organisms, as what was dark to routine culture is now blindly bright. In these settings, the clinician—me included—sometimes wishes to be left in the dark because patients did well enough when treated according to ordinary culture results…usually. However, this type of paradigm cannot continue to exist if our species is to become more resilient to microbial threats.

One corner of the biological dark matter world that merits deep exploration are the ordinary infections in which no culprit organism is found. Ranging from pneumonia to encephalitis (infection of the brain) to septic shock, many cases defy a specific microbiologic diagnosis. People get better, or they don’t. Antibiotics are often given empirically with a hope they will counteract whatever is occurring. Part of this gap in diagnosis is due to the fact that pursuing diagnostic testing after a few standard methods come up empty is not the standard of care in many conditions. Hospitals are loathe to incur costs on such endeavors as they falsely believe the answer is likely inconsequential and won’t change treatment. However, I think this is short sighted as having a specific diagnosis for conditions with high mortality such as septic shock provides valuable epidemiological insight, has implications for hospital infection control, and could engender more judicious use of antibiotics. It also saves lives. The continued rise and widely recognized value of antibiotic stewardship programs – which improve outcomes by countering antibiotic resistance trends, preventing antibiotic associated infections such as C.difficile, and optimizing the treatment of infections—will hopefully displace this type of thinking.

The advent of COVID-19 saw many hospitals purchase equipment allowing the identification of many respiratory viruses so, if this equipment continues to be employed routinely, many more viral infections will be identified and add to our knowledge of their circulation and impact. This will increase interest in developing antivirals and vaccines for those seen to have significant impacts. The same trend can be hoped to the rise of at-home diagnostic testing for COVID-19 allowing more individuals to conduct home testing for respiratory infections such as influenza. Prior to the COVID-19 pandemic, only HIV could be tested for in the home. I envision a day when many households have a device in their bathroom that can identify common causes of sniffles, coughs, sexually transmitted infections (STIs) and sore throats allowing expeditious treatment and helping people make judgements about whether to social distance or not.

So far, these pseudo-dark matter infections represent what we can identify, classify and label. However, true biological dark matter is much darker, and, in many cases, there are no clues to its origin. It might represent esoteric members of known life or could be hints of an undiscovered 4th domain of life. The existence of such dark matter, what its origin may be, and what its impact is should give pause to those who devote all their efforts to warning of the dangers of synthetic biology and genetic engineering while ignoring the fact that these techniques operate on what is known while this shadow life operates unbeknownst to all.

Similarly mysterious, within our own human genome exist large gene sequences whose origins are viral. The role and function of these endogenous retroviruses, integrated into our chromosomes, and which compromise nearly 10% of our genetic material, are only beginning to be unraveled. These viral genes are also present in pigs (porcine endogenous retroviruses, PERVs) and the nascent field of xenotransplantation — using organs from pigs in humans— is complicated by their presence.

Existing in this netherworld are even more entities, each more puzzling than the next. There are viroids, the basically naked infectious RNA molecules that have some properties of viruses and can infect plants; satellite and defective viruses that require the presence of another virus to be infectious (the human hepatitis D virus/virusoid is one such example); and virophages, viruses that infect other viruses and cause their function to be altered (an interesting vampire virus has been described). New massively sized (relatively speaking) amoeba-infecting viruses have even been isolated from the desolate tundra—reminiscent of the manner in which scientists recovered the deadly 1918 H1N1 influenza virus from human remains in the permafrost.

For those who think of infectious disease and microbiology as dry and boring subjects this chapter should serve as a concretization for how dynamic and intellectually challenging these fields are. To paraphrase Isaac Newton, we are as children playing on the seashore, diverting ourselves now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before us.

Why it won't be HIV?

If I were to describe a viral illness that infects people surreptitiously, lingers in their bodies for 10 years almost silently, is contagious throughout its silent years, and is uniformly fatal I would be describing a potential human extinction level pathogen. For the astute reader, it is obvious that what I am describing is the human immunodeficiency virus (HIV). For the reasons I enumerate below, I do not believe even this prolific killer has the capacity to cause and extinction level event.

A Snapshot of a Prolific Pathogen

When you look at HIV in terms of its global impact, it has a very impressive record. It has been the #1 infectious disease killer in the world, won major victories in every corner of the planet, made medical science turn on a dime to confront it, prompt society to explore sometimes taboo social mores, and elude—thus far—any and all attempts to cure or prevent it through vaccination, though one vaccine which reduced rates of acquisition by about 30% provides proof-of-concept that an efficacious vaccine may be possible.

But looking at its record in terms of the statistics and facts I just listed does not do this class A killer justice.

HIV as the Perfect “Form” of the Emerging Infectious Disease

When the infectious disease community discusses the need to better deal with emerging infectious diseases, exotic diseases like Hendra, Nipah, and chikungunya spring to mind. HIV is not one that makes the list in 2021. The general public, in many ways, views HIV as passé and a known quantity but, when looked at in the appropriate context, HIV is the emerging infectious disease par excellence, unequivocally demonstrates almost every attribute of this class of disease and dwarfs all other members of the category.

HIV is a zoonosis – an infection that originated in animals –that spilled into humans from other primate species: chimpanzees for HIV-1 and sootey mangabey monkeys for the less common HIV-2 strain.  The precise manner in which this event occurred is something that is lost to history, but through genetic techniques it can be determined when and where this occurred.

Though HIV burst onto the infectious disease main stage in the early 1980s it was, like a small-town comedian, making important advances on second stages around the world since the early 20th century.

The way I explain HIV’s emergence is that it spilled into sentinel humans in Africa, such as bush meat hunters in Cameroon, but had a stultified spread. HIV was unable to make major inroads into the human population until aided and abetted by industrialization that allowed regular contact—especially sexual—between peoples in remote villages where HIV was present and burgeoning metropolitan cities. Even in this brief encapsulation of HIV’s emergence, the crucial actions needed to track emerging infectious diseases (the exotic infectious disease zebras as opposed to the ordinary horses whose hoofbeats we always hear when evaluating patients) become apparent. These include:

1.     Understanding what infectious diseases are prevalent in animal species: Since almost all infectious diseases arise in animal species prior to infecting humans, it is important to know what is out there and will serve as the substrate for future human threats to health. Indeed, the entire “one health” movement, which seeks to meld human and veterinary health and epidemic intelligence, is devoted to this point. This is not a call for what was once derided as “viral stamp collecting” but a need to understand which minute proportion of the countless animal viruses that exist has the capacity to infect humans.

2.     Monitoring sentinel populations: not every human has the same risk of acquiring novel infectious diseases. Just as not everyone skydives, not everyone hunts chimpanzees, works in an abattoir, goes spelunking, injects drugs, or works in a brothel. When an individual’s unique activities place them at the vanguard of what the human species does, they become the tip of the spear that first pokes into new microbial jungles. As such, these special populations are studied in detail in order to predict the next trend in microbial threats to humans as a whole.

3.     The dynamics of social interaction can make or break a disease. If a disease is only present in an isolated society—say a remote village in the DRC—it may have little opportunity to spread beyond that population, especially if it is rapidly fatal and leaves little to no mechanism for widespread contagion to occur. However, if a contagious person has access to larger populations through buses, airplanes, trains, or crowded hospital waiting rooms, the microbe does too. This phenomenon is behind all the (mostly misguided) calls for travel bans, quarantines, vigilance at airports, and emphasis on travel history taking.

While HIV may be a staid representative of an established infectious disease and glossed over by those in the emerging infectious disease field, it can be viewed as, to use a Platonic metaphor, the “Form of the Emerging Infectious Disease” of which others are mere diluted versions.

Blood and Body Fluids

Generally speaking, if a microbe is spread through blood and body fluids it has a major problem it will always need to overcome: how to find easy access to new hosts. Unlike something that can spread through the air or through droplets in a sneeze, a virus like HIV requires close contact between individuals for transmission to occur because it is spread through blood and body fluids.

The ways in which humans exchange blood and body fluids are rather obvious: sexual intercourse, sharing of injection material, blood and blood product transfusions, breast-feeding, and in utero.

Again, the role of technological progress (i.e., blood transfusions) is something that viruses can exploit. HIV, with its long latent period, was able to contaminate blood banks before anyone even knew it existed. The latency period was also instrumental in allowing spread via the sexual route. Asymptomatic yet contagious vectors are a major boon for an ambitious infectious disease that is poised for world dominance.

Marginalized Populations

Who is first infected is almost as important how a person is infected. When the first victims of a disease are those that the world can empathize with, we are quicker to to action. When the first victims are far away, have special risk factors that are not seen as universal, or otherwise stigmatized, it may take longer for the world to notice and even longer for decisive action. All of this applied to the early years of HIV.

Though HIV was silently coursing through the African continent infecting many heterosexually, through birth, and through breast milk, it may have been hard to tease apart from the myriad other infectious diseases that perpetually plague those in non-industrialized settings. Indeed, there are early clues to HIV in African patient logs in certain areas in which mysterious opportunistic infections, a telltale sign of HIV-induced immune deficiency, were clustering.

The first descriptions of HIV occurred in men who had sex with men, injection drug users, Haitian immigrants, and hemophiliacs. Infectious diseases are taboo in many ways, even today, because of who they are thought to infect. When is the last time you say a hospital billboard advertising their infectious disease physician in a manner they do their dermatologists, surgeons, or oncologists? Any billboards that read “Got Hepatitis C, We Have Your Back?” in your hometown?

Such groups as those who doctors first diagnosed with HIV were not considered “mainstream” victims and therefore the outbreak response was slowed. This slowing did not affect all aspects of the management of the HIV pandemic and clearly does not characterize the rapid-fire discovery of the actual virus, the development of the test to diagnose it, and the elucidation of its transmission properties, all of which occurred in record time. The slowing was more of a general lassitude with which the general population and its leaders viewed the disease. Some of this is captured in the musical Rent. Yet, despite this general sentiment, HIV was subject to a travel ban by the United States until 2009.

HIV thrived on this neglect and even in the modern era, with our 5th generation HIV tests and robust anti-retroviral therapies can roar back when societal safeguards such as needle exchange for injection drug users are neglected. The 2015 Indiana HIV and hepatitis C outbreak is one powerful case to keep in mind in which then Governor Mike Pence had to be persuaded about the benefits of harm-reduction and clean needles.

Elusive Maneuvers

In the over 3 decades we have been actively battling this virus, the landscape has changed unrecognizable. HIV is no longer a death sentence, and a normal lifespan can be had if one is on treatment. HIV is a chronic infection that can be, in most cases, easily controlled with medication. Not only does treatment keep a person healthy, but one also becomes less contagious on treatment—treatment is prevention. Treatment can even render someone non-contagious, the U=Uparadigm (undetectable viral load means untransmittable virus sexually). There are even techniques that prevent people from acquiring HIV if they engage in behaviors that place them at risk, almost like pseudo-vaccines. Pre-exposure prophylaxis (PReP) — taking a daily antiviral pill or an injection every few months to prevent infection upon exposure — holds great promise, if implemented correctly, to changing how readily HIV can find new victims.

However, none of the above should be mistaken for a cure. There is currently no cure for HIV and no vaccine available. All attempts at a vaccine have fallen short and ingenious attempts to cure the infected with early treatment and other techniques have failed (save innovative and dangerous bone marrow transplants done for other reasons--the exception that proves the rule). Also, like any microbe, HIV can become drug-resistant if treatment is not judicious and these resistant strains can be transmitted rendering first line therapies ineffectual.

It Isn’t the One to Cause Human Extinction

With all the doom and gloom that is the HIV pandemic, it won’t be an extinction event for the human species for many reasons many of which I discuss above. Current treatment regimens, though not curative, are game-changers allowing a normal lifespan and even the ability for those with diagnosed HIV to give birth to uninfected children. A person with an undetectable viral load is unable to transmit the virus (U=U). Pre-exposure prophylaxis (PrEP) with antiretrovirals can prevent infection and long acting injectable antiretrovirals make treatment much simpler. In many important ways, becoming a diabetic is more life altering than becoming HIV positive (obviously one must ignore the social stigma in this calculation).

Human genetic variation also poses challenges for HIV as a proportion of the population is naturally resistant to infection. A specific human mutation (CCR5-Δ32), for which tantalizing hypotheses are devoted to, is present in a high enough frequency in certain areas of the world to provide a mechanism for the human race to survive HIV even if it were much more widespread. Ingenious physicians exploited the facts surrounding CCR5-Δ32 in the treatment of the Berlin Patient, Timothy Brown. His was the first of just a few durable cures of HIV to have been achieved and was accomplished via a bone marrow transplant for a concomitant leukemia containing the requisite mutation (though there is a hypothesis that a complication known as graft-versus host disease in which the transplanted bone marrow attack the recipient’s cells may be part of the actual curative process). Additionally, and even prior to the advent of therapies, mother to child transmission of the virus was never 100%.

While vaccine progress has been disappointing, there have been important advances. The most promising vaccine candidate today is the RV 144 vaccine (“The Thai vaccine”) that demonstrated a 31% protection rate in those vaccinated. While 31% isn’t perfect, it is substantial (compare it to the 2014-2015 23% efficacy of the seasonal influenza vaccine) and serves as the basis for newer vaccines.

HIV, like Ebola, is delimited in how it spreads. It is not measles. It requires close and intimate contact between individuals. Because of this limitation, behavior change is a key means to prevent infection. Countermeasures as simple as condoms, clean needles, limiting sexual partners—especially concurrent ones—and, in certain contexts, male circumcision (before sexual debut) can significantly make inroads into HIV’s spread.