EEE: Rare, Deadly, and Headline-grabbing

With the recent news that the Eastern Equine Encephalitis (EEE) virus has been identified in Pennsylvania birds, has prompted me to get a few inquiries about this deadly mosquito-borne virus. (Here is a link to a television interview I did on the topic and a print interview is here). A recent summary published in STAT really provides a great primer for what you need to know about EEE and I have little to add to it. However, I wanted to emphasize several points.

1. EEE is a rare infection: Though headlines are announcing what sounds like a lot of EEE cases it is important to remember that it is rare. The average number of cases that occurs is about 7 and this clearly has seen an uptick with 28 cases in 7 states (there are no human cases in Pennsylvania this year — one did occur between 2009-2018) with 8 deaths. When it comes to mosquito borne infections, it is important to remember that West Nile is, by far, more common.

2. Not everyone who acquires the virus will have symptoms. In fact, only about 20% have a flu-like illness and of these, half will develop brain infection. If one develops encephalitis, the fatality rate can reach 33% and those that survive may be left with permanent disability. The mechanism of how EEE evades immune responses to get to the brain is fascinating and involves the silencing of host miRNAs. There is no human vaccine or antiviral treatment.

3. The virus is spread of mosquitoes that thrive in swampy areas and operates in a cycle between birds and mosquitoes. Eastern and Gulf coast states are where human cases are most commonly reported. Horses, for whom there is a vaccine for, can enter this cycle and become infected (the virus was first identified in horses in the 1930s). when other types of mosquitoes, which are less ornithophilic (e.g. Aedes, Culex, Coquillettidia) serve as “bridging vectors”. These mosquitoes can allow the virus to find its way to humans, swine, and other animals such as dogs.

4. In the absence of a vaccine, the best defense against this virus — like other mosquito-borne viruses — is to avoid mosquitoes, wear repellents, wear appropriate clothing, and remove mosquito breeding grounds from one’s property (e.g. standing water).

It is unclear, to me, what is behind the increased incidence this year. Some possibilities include: better detection/awareness, a change in the behavior of the virus causing more encephalitis cases, a change in the behavior of the vector or the bridging vector, or some other explanation. Understanding what is behind this rise will an important task (which the US Senate is interested in). Also, the heightened case burden may spur EEE vaccine development which, thus far, has been pursued virtually exclusively because of the potential for its use as a biological weapon.

The risk of EEE should trigger vigilance, not panic.

5 Questions for DA Henderson 3 Years After His Death

It’s been 3 years since DA Henderson died. As I’ve done each year since, I try to remember this giant of infectious disease and public health by thinking about how much worse off our field is without his towering presence and all the wisdom he so easily imparted. For those that don’t know, DA was the architect of the smallpox eradication campaign — arguably one of mankind’s greatest achievements — and a pioneer in myriad other public health campaigns, the dean of the premier school of public health, and eventually founded what became the Center for Health Security, where I met him and was mentored by him.

One way to acutely concretize the gap in the field, is to pose 10 questions to DA about current infectious diseases problems and try and ask yourself “What would DA do?” Here are 5 I came up with for this year:

1. How would you manage the current Ebola outbreak? This outbreak, the 2nd largest in history, is particularly challenging not because the virus has changed but because of the security situation and distrust of health authorities has made control impossible, despite the use of a very effective vaccine. I remember during 2014, how we offered the idea of focusing on the most contagious individuals — those with severe symptoms, emanating body fluids. However, in this outbreak some of the cases are not showing up at treatment centers (where experimental treatments are seeing great success) and a shadow outbreak is occurring. What would you do? Get aggressive like with smallpox eradication, finding the cases and treating them.

2. What do you think about the US on the cusp of losing its measles elimination status? This one is embarrassing and I suspect you would be furious as all the hard work you did in building expanding programs for immunization is being squandered. When elimination status passes, what do we do next? Should the US try to eliminate it again or is the anti-vaccine movement to strong and our voices in favor of vaccines too weak to win back the country from measles?

3. Is polio eradication feasible any longer? I know this is something that you had strong opinions on — when didn’t you have a strong opinion? — and things have only gotten worse. Wild polio is still spreading in Afghanistan and Pakistan with numbers increased this year over last. It doesn’t seem like the Taliban is every going to be in support of this program which is costing more and more money. People are still chasing vaccine-derived polio — something which you convinced me should be a separate task from wild polio.

4. How would you gauge recent activities with Russia and North Korea? Your prescient warnings about biological weapons and the expertise you leveraged to build US biosecurity programs are unmatched. You debriefing Soviet defectors and changed the way the world approached this threat. Now, we face belligerent actions with Russia using Novichok agents on British soil (a word that was classified when you were alive) and North Korea using VX in plain daylight. Syria has employed chemical weapons in war as. This use of chemical weapons so brazenly likely means that biological weapons are not necessarily a taboo for state-actors and indeed there are reports of increased interest in their use. What should we do to prepare? How would you augment activities??

5. Is HIV transmission elimination possible in the US? You worked on the early days of HIV when it was an incurable death sentence and saw it become an eminently treatable infection. Now with the concepts of U=U and PrEP, there is the prospect of halting transmission. How would you direct this program? Right now, it appears the HIV epidemic in the US is non-homogenous with certain counties accounting for the majority of new transmission. Would this be the thrust of the best approach ? How do we increase PrEP use? Make it over the counter?

These were just a selection of 5 questions I would desperately want to know DA’s thoughts on. It’s been 3 years since I could just walk several feet to his office, gaze at all his presidential citations and awards, and see that giant sitting there eagerly answering question after question that occurred to me.

His portrait looms large at the Center, but his spirit looms even larger.

A Philosopher Looks at Antibiotic Resistance

The antibiotic crisis and its cascading impact is a well-characterized seemingly insoluble infectious disease problem. There is a large context of factors that impact antibiotic and exacerbate the problem which include: the ever present threat of evolved resistance and consequent antibiotic stewardship concerns, the low relative price of antibiotics (versus more lucrative pharmaceutical products), the outrage that accompanies any attempt to raise the price of an antimicrobial, the fact that one individual’s (or animal’s) use of an antibiotic can impact another individual’s future use, and the general societal undervaluing of infectious disease control, prevention, and treatment.

In recent years, one of the biggest legislative effort to incentivize antibiotic development has been The GAIN Act, which is “pull” incentive that provides an additional 5 years of market exclusivity for certain qualified infectious disease products (QIDPs) that is stacked upon other market exclusivity that may exist because of its novel chemical nature, its applicability to pediatric patients, or its niche in treating a rare (orphan) disease. Importantly this market exclusivity is not intellectual property based, but instead results from the FDA not allowing any generic versions to be marketed for that period of time. Other pull initiatives include special technology payments to hospitals that use certain “breakthrough” antibiotics that use them as well as proposals to reimburse hospitals higher for drug-resistant infections and to carve antibiotics out of bundled payments for hospitalization (removing the incentive to use cheaper antibiotics when more expensive and more effective ones may be indicated). There are also “push” initiatives that fund early development such as CARB-X.

Given this context, it is clear that there is a real problem to solve — one that is often blamed on markets. Gregory Salmieri — a philosopher and friend of mine dating back to when he was a graduate student at the University of Pittsburgh’s philosophy program — has recently published an innovative and creative solution in the George Mason University Law Review.

In his piece, Salmieri first presents the current situation in a very comprehensive manner addressing legislation and new proposed business models (such as decoupling/delinking revenues from sales volume). Next, he makes a convincing case that antibiotics suffer from a “tragedy of the commons” in which “a resource of immense value” is “being used myopically in a way that destroys existing stocks of the resource” with little “being done to find or develop new stocks of it.”

The proposal Salmieri advances is one premised upon enabling “creators of drugs to profitably exercise their rights over the drugs in a manner that preserves the drugs’ effectiveness over time—ideally into the indefinite future.” By tying patent life explicitly to resistance rates of target organisms to a predetermined threshold (e.g. remaining below 20%), a patent could exist in perpetuity (like a trademark). Such a mechanism incentives the judicious use of the antibiotic in order to preserve its profitability at higher patent-protected prices that could also reflect a premium placed on drugs-of-last resort, increasing return on investment over a longer term horizon.

Salmieri also addresses certain complications including cross resistance to drugs developing and issues related to how other countries steward antibiotics.

I think that this is an excellent paper to read — irrespective of whether you agree with the solution —because it offers a clearly reasoned solution that looks at this problem through a different lens and allows one to better conceptualize a problem that has been looming since the time of Alexander Fleming’s prescient warning. I hope it finds a large audience and sparks the debate it merits.

What do Legionnaire's, Parrots, and Sharks Have in Common: A Review of The Pandemic Century

The latest book on pandemics and infectious disease that I’ve made my way through is Mark Honigsbaum’s The Pandemic Century: 100 Years of Panic, Hysteria, and Hubris, “a book about these events and processes, and the reasons why, despite our best efforts to predict and prepare for them, they continue to take us by surprise.” That theme is an important one that deserves attention as time and again, a new infectious disease threat appears and calamity ensues. This cycle repeats over and over.

True to the panic and calamity aspect, Honigsbaum begins his book discussing shark attacks occurring in the North Atlantic, a supposed venue in which such attacks were not known to occur. Sound familiar? We’ve heard that a lot: Ebola doesn’t occur in West Africa, Zika doesn’t occur in the Western Hemisphere, Chikungunya is restricted in its geographic spread, etc etc

Infectious diseases — though we try to find strict laws of nature to confine them — are fluid physical phenomena whose dynamics are influenced by countless factors that are very hard to account for in models and cannot be dogmatized. It is not a foregone conclusion that each pandemic threat can be easily beaten back as we have seen with malaria, tuberculosis, influenza, and HIV (to name a few prominent ones). As New York Times science journalist Carl Zimmer notes in his review of the book: “What made this past century unusual was not pandemics per se, but our expectations about beating them. The germ theory of disease and other scientific advances in the 19th century fostered a sense of mastery over the microbial world.”

Honigsbaum’s book is divided into several chapters recounting various outbreaks and pandemics. Some of these are familiar such as the 1918 influenza pandemic, the 1976 Legionnaire’s Disease outbreak, SARS, and HIV. However, some are less familiar such as the parrot fever (psittacosis) outbreak that occurred in 1930s America. Of this outbreak, Honigsbaum colorfully writes:

Perhaps the most important factor of all, however, had been the popularity of lovebirds with American consumers and the lucrative interstate trade that saw itinerant peddlers going door-to-door offering parakeets to widows and housewives. In 1930, the idea that these cute American-bred birds might be the avian equivalent of Trojan horses was too disturbing to contemplate.

I recommend this book to those who want an easily digestible account of pandemics and outbreaks that are not only headline-grabbing but reveal holes in our preparedness and knowledge regarding infectious disease and microbiology. When each outbreak occurs, it is invariably followed by conspiracy theories, fake news, panic, sometimes disregard, and a whole host of other human responses that are driven by the uncertainty that characterizes the early days of a response. This is nothing new and is something that will continue but will hamper response and containment activities. The value of learning the history contained in this book is as Carl Zimmer notes in his review, “Surely the value of understanding history is that it gives us a chance to stop repeating our mistakes.”

5 Feet Apart: A Movie About Social Distancing, Cystic Fibrosis, Burkholderia

Cystic fibrosis (CF) is a genetic disease that every medical student becomes familiar with because it is common, causing by a single amino acid substitution, and has a clear link with severe lung (and other organ system) disease that can result in the need for transplantation,. LIfespan of patients with CF is severely curtailed and CF patients are plagued with infection after infection as their lungs are clogged with thickened secretions. It is the third leading cause of lung transplantation. Often, these infections involved highly drug resistant — as an ID fellow I vividly recall a twentysomething female die of a totally drug resistant Pseudomonas fluorescens infection — and ominous bacteria.

Infection with the Burkholderia cepacia complex, however, is the most significant of these infections. This gram negative bacteria targets those with cystic fibrosis and immunosuppressive conditions. When a cystic fibrosis patient is colonized with this complex, their chances of survival diminish. This fact leads some transplant centers to refuse to transplant patients with this recalcitrant infection.

The complex consists of a group of bacteria (one is even called B.metallica), with varying degrees of importance. Genoserovar III — B.cenocepacia — is the most dangerous and only two institutions in North America including one in the US (not surprisingly UPMC) will offer transplants to these individuals because the mortality post-transplant can be exceedingly high.

With these facts as context, I wanted to draw attention to a movie that, surprisingly to me, focused on this bacterial complex. Five Feet Apart is a 2019 movie that tells the story of young cystic fibrosis patients struggling with their disease, holding out for new treatments, and hoping for transplants. As part of their regimen they are forbidden to be close to other CF patients to avoid transmission of infections, which is difficult when there are romantic connections developing. One character suffers from B.cepacia and the movie details the efforts of medical professionals to try new treatments on him while also preventing it from spreading to other patients, particularly the protagonist. Not surprisingly, this story was inspired by a real life couple who were transplanted at — again no surprise — UPMC.

While the movie is not a medical documentary, the fact that it highlights the social aspect of infectious disease — the social (and emotional) distancing that can occur with an transmissible infection and how hard that can be to cope with for patients makes it particularly compelling to medical professionals. I think it is a film well worth watching for this aspect.

Hopefully, better CT treatments — drugs that modulate the function of the abnormal gene such as lumacaftor and ivacaftor — will diminish the need for transplantations and increase lifespans.