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.