Another chapter from my book project
Based upon what I have written in prior chapters, a focused approach to preparedness — even if nothing rises to an existential threat —is critical for to minimize the disruption and mortality that will occur with the inevitable infectious disease threats we face.
As I have argued preparation for pandemic — as opposed to outbreak or epidemic — by governments, non-governmental agencies, and other organizations threats should focus on those viral families most likely to cause a pandemic, as outlined in the prior chapter. Preparation translates into 2 major categories: surveillance/diagnosis and therapeutic/preventative medical countermeasures.
Biological Dark Matter
As we try to prepare for the next infectious disease emergency and decide how best to invest limited resources in early warning systems for detection of future viral threats, it is critical to prioritize surveillance activities that: (1) are most likely to uncover actual, rather than hypothetical, threats and (2) are practical and add value every day to preparedness, even between outbreaks.
Too often, our limited surveillance dollars are funding overly broad surveillance and basic analysis that includes a vast collection of animal samples with the goal of finding potential infectious diseases emanating from animals in spillover, or zoonotic events. Given the history of viruses such as SARS-CoV2, Nipah, Ebola, and HIV, zoonotic spillover events is a suitable priority. However, focusing our surveillance efforts on the constant sampling of animals can be like looking for a needle in a never-ending haystack. While this type of surveillance can play a part in early warning systems and it helps us to improve our understanding of disease in animal species, we should be careful not to place an overemphasis on viral cataloging efforts. These are, indeed, essential virological and scientific tasks but none should construe them to be synonymous with early warning or a substitute for pandemic preparedness activities.
We should complement the broad sampling of animal species with a more targeted type of surveillance focused on sampling of viruses present in patients in clinical environments. A microbe most likely to cause a pandemic or a disruptive outbreak is one that can infect humans now (even if only to a diminished extent). These are infections that are occurring in humans by pathogens that could do so now. Such a microbe may go unnoticed, mistaken for other causes, or occur in populations where diagnostic technology is not available. The pathogen may spread via the respiratory route and cause a respiratory infection such as pneumonia. It may also have characteristics that can cause a brain or central nervous system infection like meningitis. And, critically, it is likely to result in sepsis or septic shock as the final common pathway to severe disease and death.
These types of syndromes occur all over the world every day, even in the US. In some cases, we discover that the cause was a known pathogen such as pneumococcus, influenza, or the like. But most of these cases go without identification of the virus and without a specific diagnosis. The empiric treatment either works or it does not. This is something I commonly see in the hospitals in which I round in the Pittsburgh area--it is much more common internationally.
This passive status quo of our surveillance systems makes us much more vulnerable to infectious disease threats. This vulnerability derives from the fact that we lack full situational awareness of the microbial threats that we are facing now and will face in the future. Testing people already sick to aggressively pursue a specific microbiologic diagnosis is not only practical, but high yield as it aims at uncovering, not theoretical threats that have not yet materialized, but ones already present.
As I wrote earlier, I liken the undiagnosed syndromes to biological dark matter which holds key information about what is making people sick — some deathly — today, right now, everywhere. The first COVID-19 cases in Wuhan camouflaged in with influenza and, because the two syndromes are clinically indistinguishable, clinicians missed them. This caused weeks delay in digging into more about this emerging novel virus. Imagine having even a few weeks head start on this pandemic: it would have translated to even faster scientific understanding, faster medical countermeasures, less economic disruption. A few weeks would have saved lives. The first U.S. cases of the novel influenza H1N1 virus that sparked the last flu pandemic in 2009 became known only because the young children the virus infected happened to go to a medical facility that was part of a U.S. Navy study that strived to figure out what viruses were making people sick, even mildly sick.
In many international locations infectious disease diagnosis is based on a generic syndrome such as pneumonia and clinicians prescribe first line medications without a specific microbial diagnosis -- the organism responsible -- but arrived at by local epidemiology (what is common) and clinical presentation. While this is valuable and astute clinicians are extremely valuable it is not enough. For example, during the 2013-2014 West African Ebola outbreak it was often emphasized that West Africa had not seen Ebola before (save one isolated case in the Ivory Coast) but by analyzing blood samples of those thought to have another viral hemorrhagic fever, Lassa Fever, revealed Ebola had been present for over a decade mixed in with Lassa. Imagine how useful that information would have been when health authorities in Guinea took 3 months to realize it was Ebola they were dealing with and not some virulent form of cholera. Lives saved, epidemic curves bent, and spill into other countries prevented by an early warning followed by prompt containment strategies deployed successfully in every prior Ebola outbreak.
Whether what is lurking in the biological dark matter is the first human foray for an emerging pathogen, a change in behavior of a known pathogen, or an ordinary infection that went undiagnosed it is valuable information. We need to commit and spend more time diving deep to understand this dark matter. It is a no regret investment because it is most likely to uncover actual, rather than hypothetical, threats and it is practical adding value every day to preparedness, even between outbreaks.
This focus finds synergies with home testing for infectious diseases. Building on the momentum of COVID home testing, I have a vision of the future that includes a device in many people’s homes that allow them to swab their nose of throat and figure out if the symptoms that they have are due to COVID, influenza, RSV, strep throat, and other causes. This will improve antibiotic overuse issues, minimize contagion, and enhance surveillance, and provide vital intelligence. Imagine an outbreak of a respiratory pathogen in a city in which some proportions of people can test themselves for a variety of pathogens and it all comes back negative — that would be a signal that public health practitioners should pursue further investigation. It is much more precise than watching sales of cough and cold medicine at drug stores.
I also want to emphasize that to make these diagnostic capabilities routine does not require sophisticated futuristic machines. The technology and tools exist today, and clinicians are using them in healthcare facilities every day. In the past several years, technology has improved to such a degree that sophisticated molecular detection techniques such as PCR or the equivalent, that an untrained person can perform them at home. Diagnostic panels that check for a multitude of organisms all at once are not only available in an ordinary hospital lab, but even at the point-of-care. These machines exist now for routine use in many hospitals and medical facilities around the globe. Some of them are point-of-care requiring little training. As such, they will not need constructions of fancy labs but could be as simple as just augmenting diagnostics laboratories that already exist. The ability to improve routine infectious disease care will, as I have argued, naturally, also have major implications for early detection of all infectious disease hazards. The interconnection and dependency of U.S. domestic infectious disease response on international detection and characterization of COVID-19 variants such as Omicron, achieved through ordinary sampling of people ill with COVID-19, concretizes this fact.
Proactivity
In the past, much of medical countermeasure development for biosecurity and emerging infectious disease has been reactive. For instance, after the anthrax attacks of 2001, it became clear that medical countermeasures against biothreat agents were sorely deficient. The U.S. government put forth a concerted effort to remedy this problem. Bioshield, the name for this program, has been an unequivocal success. However, the model that this program used was based on a list of threat agents weaponized by the Soviet Union—it was reactive. For emerging infectious diseases, there exists no definitive list of potential pathogens. Therefore, we cannot rely on this approach. If we want resiliency, we must push for more. In the prior chapters, I have sketched out what a proactive pandemic approach would amount to in a research and development agenda that is not exclusive to a particular virus, but to viral families.
It is also important to include medical countermeasures against common immune system pathways that trigger in people post-infection. These host-directed approaches aimed at the immune system have seen remarkable success with COVID-19. Potential threat agents also will also trigger these and similar pathways. Having medical countermeasures that focus on changing the aberrant dysregulated immune responses that various viruses set off could provide early means of ameliorating some of the negative consequences of infection before more specific medications are available. The success of medications like dexamethasone and tocilizumab in the treatment of COVID-19 illustrates the value of these types of treatments.
At the policy level, this type of programmatic shift would primarily involve a transition in the categories of disease for which organizations provide funding. Instead of funding R&D specific diseases, grants would target whole categories of disease, thereby facilitating a broader approach to the program than in the past. Additionally, this new program would involve educating policymakers about the importance of proactively and sustainably funding not just what is in headlines but also what will be in headlines. Situations such as waiting for Congress to distribute specific funding for Zika because it was not a virus pre-specified in prior funding cycles would never occur. The programs would be pathogen agnostic but still recognize that focus on pathogens with pandemic-requisite traits merit prioritization.
Following COVID-19, it has become clear that we, as a species, cannot tolerate what has happened ever again because of our own willful inaction. For decades many in my field have advocated proactive preparation for both natural and intentional infectious disease threats. However, while earlier attempts to dislodge the reactive, boom-boost, panic-neglect cycle that typifies how society has dealt with these threats, an opportunity now exists to reconfigure our thinking and our methods. We must not squander this chance.
