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.

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.  

 

*****

 

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.