2 Years and 10 Questions: Remembering DA Henderson

It’s been 2 years since the founder of the Center for Health Security, DA Henderson, died. Like I wrote then and last year, it is an incalculable loss to the field of infectious disease that such a giant voice speaks no more. Personally, it’s rare that I go a day without thinking about him and the wisdom he always about all things infectious.

Last year to commemorate DA, and concretize how pressing public health and infectious disease issues are, I listed things that happened since he died that I — and the world — desperately needed his expert opinion about. So in that spirit, here are my new set of questions for DA.

1. What do you think about Russia and the current state of their former bioweapons program? There’s been a recent book about this topic and you personally debriefed some of the highest level defectors from the Soviet Union. Also, Putin has shown no qualms about using Novichok agents (as well as dioxin and polonium) so is their anything different about biological agents?

2. What’s your take on the number of food borne outbreaks? We had cyclospora and a big E.coli outbreak this year. Is it that surveillance is capturing what we never knew about or is the risk increasing or is it both?

3. The cholera outbreak in Yemen is the biggest ever and compounded by war. How would you tackle it? You dealt with conflict when you eradicated smallpox. Would you advise vaccines? Antibiotics? 

4. Back-to-back Ebola outbreaks have occurred in the DRC. The first one came and went but the second is a lot more scary because of the conflict zone in which it occurred. The vaccine seems excellent and was used in the ring vaccination manner — which you developed to beat smallpox — but they can’t find the contacts of cases so well in this 2nd outbreak. Should they just blanket immunize ? What priority should vaccination have when you can’t do contact tracing? 

5. Measles elimination in the Americas is no more. Venezuela and their totalitarian government have seen outbreaks of malaria, diphtheria, and now measles transmission for over a year. How can we fix this? You were never a fan of eradication and now it seems measles, which was on the list, is slipping away. 

6. We had a bad seasonal flu year and it had hospitals inundated. We seem no where near able to cope with a pandemic and H7N9 looms. I know you don’t have an easy answer but when this pandemic occurs not having you to lead will make it much worse.  

7. We have a new smallpox antiviral. I know you had issues with this drug and didn’t have a good idea for how it would be used and definitely opposed it’s research program being used as an excuse not to destroy the samples of the virus but it’s here now. How should we use it? Individual cases? The vaccine should still be the cornerstone of response, right? 

8. Horsepox was artificially synthesized in the quest for a better vaccine. I know you would  have something to say about that. The standard vaccine’s cardiac side effects weren’t something you thought was significant enough to scrap it and this is the reason cited for the horsepox version. There’s also the debate about this event lowering the threshold for those who want to synthesize smallpox. What do you think about all this? We really missed your voice on this.

9. Polio eradication is still faltering. Just Afghanistan and Pakistan have wild cases and it looks like type 2 polio is gone the way of 3 and we’re just contending with type I. The Taliban hasn’t stopped their anti-vaccine push either. People are getting hyper about vaccine-derived cases and we’re still using the Sabin vaccine in many parts of the world. I know you taught me to think of vaccine-derived cases entirely separately and I’ve been saying that to people. This is the way to do it right? Wild polio first then switch to Salk and deal with vaccine-cases separate, right?

10. What do you think about my Pandemic Pathogens report? I know this is my own vanity but I spent a lot of time thinking about this topic and really want it to impact the field. It hopefully would be something that would make you proud of the time you spent teaching me. 

As is apparent, DA’s intellect is needed just as much now as it was when he beat smallpox off the planet. I don’t know if humans will ever produce another DA. It seems like a dream that he existed, but we should all remember him and how the insoluble problems of infectious diseases fell away when his mind faced them. 

Why People Wore Penile Sheaths: A Review of Deadly Companions

I recently read a book that somehow escaped my attention when it was first released 11 years ago: Deadly Companions: How Microbes Shaped Our History. This book, by the University of Edinburgh's microbiology professor Dorothy Crawford, was just released in an updated edition. To someone like me who is completely obsessed with this subject, I increasingly approach books in this genre with a bit of apprehension because the value-added aspect of each additional books is less and less. However, Deadly Companions is a book which I found valuable. The book consists of 8 chapters plus a preface, introduction, and conclusion. Chapters are not organized around specific microbes, but forces that propel microbes to cause epidemics and disease such as crowding and famine; other chapters are devoted to explaining the dominance of microbial life on this planet. 

A few important tidbits that particularly stood out to me from the book include:

• The use of penile sheaths to protect against schistosomiasis which was erroneously, but reasonably, thought to enter the body through the penile opening (it really enters via penetration of the skin)
• An enlightening discussion of the fungal-caused potato blight responsible for the Irish famine
• A great thought experiment concretizing the impact of travel on infectious disease: charting the travel patterns of your great-grandparents, grandparents, parents, and yourself

I recommend Deadly Companions for a short and enlightened -- but still comprehensive -- overview of infectious diseases of the past, present, and future. 

Where the Wild Things Are: Polio and Vaccine-Derived Polio are Distinct Issues

One of my major pet peeves with infectious disease reporting is the conflation of polio with vaccine-derived polio. While both conditions can be severe and paralyzing, there's an important distinction that is missing from headlines announcing the "return of polio." 

Vaccine-derived polio is a known and expected risk so long as the Sabin oral polio vaccine is used. The Sabin oral polio vaccine has many advantages that have favored its use: it's given orally (no needles), it's cheaper, and it's "live". This last is important since the vaccine is given orally and replicates in the GI tract -- just like the untamed wild strain of polio -- it more closely mimics natural infection. It is also shed in the stool and others are, in effect, vaccinated upon exposure. On the contrary, the injectable Salk vaccine does not prevent viral spread as the vaccinated are protected against paralytic polio but are still able to be infected with the wild virus, but only in their intestine, and are able to pass the virus along.

However, these advantages are a double-edged sword as the virus, which has been weakened, can mutate its way back to its original virulence level and paralyze someone (vaccine-associated paralytic polio, VAPP) In rare circumstances, the altered vaccine virus can circulate and cause outbreaks as a circulating vaccine-derived poliovirus (cVDPV) -- this last usually requires recombination with a non-polio enterovirus. Usually the impact of cVDPVs is delimited because of population immunity. This paper provides a great overview of the phenomenon. 

The risk of VAPP, in the US, became too much to bear and the US slowly changed recommendations and moved to an all injectable Salk regimen several years ago. The global eradication program will eventually phase out the oral vaccine as well.

What is missed by the recent headlines is the fact that so long as oral polio vaccine is used there will always be a risk of VAPP and the emergence of cVDPVs. I think that the eradication of polio should be restricted to the eradication of the wild virus -- something my mentor and smallpox eradicator DA Henderson insisted upon. cVDPVs and wild polio are distinct problems. Wild polio continues to spread in only two countries: Pakistan and Afghanistan, where a dozen cases have occurred so far this year. cVDPV outbreaks in the DRC, Somalia, and Papua New Guinea are important problems but should not, in my opinion, be considered on the same level as wild polio virus infections. 

Antibiotic Resistant Infections Kill More than Car Accidents: A Review of Superbugs

I often say that the biggest infectious disease problem humans face is that of antimicrobial resistance. I am not alone in this assessment and today there are myriad books describing  this problem and its many facets. However, a recent book I read on this topic, Superbugs: An Arms Race Against Bacteria, provides a unique lens to view the problem: economics. Below I give a short overview of the prime value I took from this book.

Superbugs is a book that stems from a high level review of antimicrobial resistance commissioned by then UK prime minister David Cameron and is written, not by scientific subject matter experts, but by economists and policymakers (Jim O'Neill, William Hall, and Anthony McDonell).

I think it is not difficult for anyone to see that a drug-resistant infection will be, on average, more expensive to treat than a drug-sensitive one. This cost disparity exists for several reasons that include the expense of switching therapy to a an appropriate regimen, the expense of isolation of patients with drug resistant infections, and the increased severity of illness because time to appropriate antibiotic therapy is delayed. 

The book is divided into two parts that focus, respectively, on the problem and solutions to drug resistance. To me, the chief value of the book is the authors attempt to quantify the problem of antimicrobial resistance because as they note a whole different audience -- beyond the health one -- is more receptive to a quantitative analysis. Several of their estimates are worth noting.

• 1.5 million people die of antimicrobial resistant infections annually (more than die i automobile accidents)
• Total worldwide costs (direct and lost productivity) are approximately $864 billio

The book provides a comprehensive overview of the economic challenges inherent with antibiotics: namely, stewardship programs that diminish revenue from new antibiotics, low prices of antibiotics vs. other pharmaceuticals, and the ability to substitute antibiotics.

One of the most valuable portions of the book, to me, is their discussion of diagnostic tests. Much of inappropriate antibiotic prescribing is done for viral infections. It is thus obvious that by employing diagnostic tests to determine whether a patient's symptoms are caused by a virus or a bacteria and which virus it might be could curtail injudicious antibiotic prescribing (and provide valuable epidemiological information) however they are seldom employed despite their availability. Superbugs delves into the dilemma that has stifled the routine use of diagnostics for infectious disease contrasting it the use of advanced diagnostics tests that are standard of care for cancer. 

Chief amongst these obstacles, as they note and I have experienced first hand, is the hospital siloing of costs. Because a multiplex point-of-care molecular diagnostic test deployed during an office visit for bronchitis is more than the entire cost of the visit plus the inappropriate antibiotic prescription that will likely result, testing is foregone. But economics is not only about the seen, but also the unseen, and taking a wider perspective allows one to realize that the costs of antimicrobial resistance driven by the inappropriate prescribing outweighs the cost of running a diagnostic test. 

The book concludes with policy recommendations to solve what the authors believe to be a tractable problem that are informed by a thorough analysis of the problem that are familiar to those that follow this issue and include increasing awareness, increased R&D, and the inclusion of all relevant parties (including agriculture). 

I recommend Superbugs to those who would like an up-to-date holistic analysis of a pressing public-- and individual -- health threat. 

Viral Cataloging ≠ Pandemic Preparedness

When my Johns Hopkins Center for Health Security colleagues and I were working on our pandemic pathogens project, the report of which has been released, one of the more contentious issues we had to face was separating the task of pandemic preparedness from viral discovery and cataloging. One of the participants in our round table meeting on the topic colorfully referred to viral cataloging as "stamp collecting"! 

On its face, it might seem very reasonable to believe that knowing all the viruses "out there" will by design lead us to new pathogens that have the capacity to cause pandemics, but that is not a foregone conclusion for two main reasons:

1. Most viruses on the planet are innocuous to humans and do not have the capacity to cause damage 
2. While it is most likely that pandemics in the modern age are exclusively the province of viruses, it is possible a non-viral agent could, under certain circumstances and in certain contexts, be the cause of a pandemic

For pandemic preparedness purposes, we proposed focusing on ensuring specific diagnosis and enhanced surveillance of infectious syndromes such as respiratory infections, sepsis, and central nervous system infections in all parts of the world. By focusing on what has unequivocally demonstrated the ability to infect humans -- what would be level 2 and 3 pathogens according to an insightful paper by Woolhouse, the yield of uncovering a potential pandemic pathogen will be much higher. Such activities will have salutary effects on other activities such as antibiotic and antiviral stewardship as well as improving the epidemiology around well-characterized pathogens.

It is undeniable that viral discovery will enormously advance our understanding of virology and is very valuable but it is not synonymous with pandemic preparedness -- it is distinct. 

A new commentary published in Nature by three eminent researchers in the field, Eddie Holmes, Andrew Rambaut, and Kristian Anderson, provides some additional validation for the above conclusion we drew. The piece, entitled "Pandemics: spend on surveillance, not prediction," makes the point that:

“Broad genomic surveys of animal viruses will almost certainly advance our understanding of virus diversity and evolution. In our view, they will be of little practical value when it comes to understanding and mitigating the emergence of disease.”

Pandemic preparedness is a daunting task with many facets and varied approaches. It is only in the modern era with the sharp tools of biology coupled to advances in information and communication technology that we are even able to truly prepare for pandemics. It is essential that these powerful tools be directed at the right task.