This Pig is not a PERV: Major Xenotransplantation Advance

One of the most exciting fields of medicine which represents the integration of several disciplines is organ transplantation. The advances that have made such an innovative and life-enhancing feat possible were the result of breakthrough insights by heroic pioneers in the life sciences. However, despite the feasibility and almost routine nature of solid organ transplantation today, the full benefits have not been achieved. It is basically universally known that there are not enough organs procured per year to meet the needs of those on waiting lists. Several partial solutions have been proposed including more efficient allocation algorithms, increased public outreach campaigns to increase organ donation, and the use of "high risk" organs but even with all these initiatives combined demand is still outpacing supply. 

Using organs from animals closely related to humans -- such as pigs -- has been a proposed fix that has, unfortunately, not been able to reach fruition for several reasons. One reason xenotransplantation from pigs has been stalled is the presence of viruses integrated into the chromosomes of the pig. The fear is that porcine endogenous retroviruses (PERVs) could reactivate in the transplanted human, as several viruses can do in the presence of immunosuppression, and cause unknown effects which may be benign or not. A xenozoonosis would have major implications as it would virtually unprecedented, with no treatment protocol (though HIV drugs may work), and unknown contagiousness. To date, pig heart valves, pig skin, pig-derived insulin, and encapsulated pig islet cells are being used in humans with no evidence of PERV infection. 

A team from Harvard, which included the visionary George Church, recently harnessed the power of CRISPR to clean pig DNA of these viruses and allow PERV-free piglets to be borne. The study was published in Science. This is an unequivocally major achievement and has removed a major roadblock while illustrating the enormous value of CRISPR in furthering human life. 

Now that this hurdle has been cleared, it will be necessary to ensure that the human immune system is not too aggressive in rejecting the organ, which will need some further genetic modification in order to not tip off the immune system to its origin.

There is no timeline for how long it will be before pig xenotransplantation is adopted on a larger scale as protocols and regulations that govern these procedures will have to be rewritten, but each step forward should be applauded. 

Exploration, Integration: A Review of An Unnatural History of Emerging Infections

One of the best aspects of infectious disease is the grand scope which they encompass. It can be very hard to tell the story of just one infectious disease let alone the entire field. A 2013 book which I just finished attempts to do that and, in my view, is highly successful. Emory University professors Ron Barrett and George Armelagos's An Unnatural History of Emerging Infections is a must read for anyone interested in the field of emerging infectious disease. 

The book is written from a philosophical viewpoint that seeks to integrate the microbiological world with the human world. The human world, characterized by a litany of changing conditions, is shown to be very explanatory when it comes to the infections we contract. A key theme of the book is understanding human epidemiological transitions of which there have been three: from  a nomadic lifestyle to a sedentary one 10,000 years ago; the Industrial Revolution; and the modern era of urbanization/globalization coupled to population aging. Through these epidemiologic transitions disease patterns change from an age of pestilence to a period of receding epidemics to an era of manmade/degenerative diseases. It is important to realize that a nomadic lifestyle is not one in which large infectious disease outbreaks can flourish given the low population density and the constant movement. "Heirloom" infections (those that infected hominid species pre-humans) and "souvenir" infections (acquired in activities of daily living) were likely the majority of infections during these times.

From this lifestyle humans increasingly moved to agricultural societies which provided many advantages over the prior lifestyle -- principally in the ability to store calories via agriculture. On balance, this was the right choice for our ancestors but it did create kindling for infectious disease outbreaks as population density increased, contact with animals became more frequent, and food sources changed. This new set of conditions was conducive to zoonotic spread of infections as well as the persistence of endemic infections. Only with the advent of sanitary and, later, medical innovations characterized by the Industrial Revolution would these pestilences be tamed. 

There are countless additional pearls in this book that include a discussion of the competing Attenuation and Virulence Hypotheses and the role of non-human primates in human diseases. 

To me, this book is a valuable resource that I thoroughly enjoyed reading. It greatly deepened my understanding of the field reinforcing my knowledge and helping me make wider integrations with history and anthropology. I highly recommend it.

Chimeric Outbreak: Low Risk and Indolent but Nonetheless Deadly

To me one of the more underappreciated forms in which an outbreak can take hold is through contaminated medical equipment. There are several unique aspects of these types of outbreaks I believe makes them particularly difficult to detect and control. First, is the fact that the individuals getting infected are accessing the healthcare system for some reason that may mask the signs and symptoms of infection. These patients can also be at higher risk for ordinarily acquired infections making it less likely that someone would attribute their infection to a specific medical procedure and when infection occurs in these patients, it may be more difficult to treat because of coexisting conditions or, because of the nature of exposure, a deep-seated invasive location. Another factor is that the dose a patient may be exposed to may be small enough that a clinical latency period may occur before exposure and onset of symptoms, making linkage difficult. Indeed some exposures may not result in infection at all. Finally, these infections may not necessarily be clustered geographically and disparate locations may take a while to be knitted together delaying recognition of the outbreak. 

This was all very apparent in the deadly Exserohilum steroid contamination meningitis outbreak and is also apparent in the Mycobacterium chimaera outbreak linked to contamination of heater-cooler units used in cardiac surgery. This outbreak involves at least 79 patients, 17 of whom have died -- a fairly high fatality rate.

Mycobacterium chimaera, a non-tuberculous mycobacterium (NTM), is an indolent slow growing pathogen that can be difficult to diagnose. In this outbreak devices were contaminated during manufacture (in a very large manner) and, because of the fact that the majority of cardiac surgeries in the US use this type of machine, the breadth of exposure is large. However, the complicating factor is that despite exposure to this particular organism the risk of infection is low and symptoms can be non-specific. CDC advises hospitals should consider notifying patients who had exposure to this device after January 1, 2012. Some facilities have notified patients, others have not given the nuances (including the medicolegal implications) of this low risk exposure. A recent piece in the Tribune Review details one patient's experience with his possible exposure and subsequent symptoms.

When people think of outbreaks, it is often in the setting of explosive case counts and calamity. However, medical device outbreaks -- which can carry high fatality rates --  are an important species of outbreaks that are no less impactful or disruptive. Like the two-headed Greek monster that the bacteria is named after, this outbreak possesses a dual nature: both indolent/low-risk but but potentially deadly.

Kaci Hickox: From Ebola Nurse to Liberty Defender

A very significant development in the world of infectious disease policy occurred earlier this week. Nurse Kaci Hickox settled her lawsuit against the state of New Jersey which irrationally detained her for an erroneous forehead temperature reading as she returned home after battling Ebola in West Africa. The detention she suffered was a prominent part of the news cycle and her struggle to have her individual rights respected was something I intransigently defended in the press. Ms. Hickox never had Ebola and never posed a risk to any individual. 

The most significant aspect of Ms. Hickox's lawsuit settlement is that she got the state to establish a sort of bill of rights for those detained under New Jersey's quarantine power including the right to counsel, the right to contest the detention, the right to be notified of hearings, and to send/receive correspondence. The terms of the settlement will form the basis to hopefully change other states quarantine policies.

The government, as the protector of individual rights with a legal monopoly on the use of force, should and does have the power of quarantine. This power is exercised to protect individuals from infection from others in the context of a contagious infectious disease that poses a demonstrably serious threat to health. In this context, infectious agents must be viewed as projectiles emanating from the body and, as such, when they impact others, are violation of their rights compelling government to act.

However, the government cannot arbitrarily wield this power and it must be based exclusively on the actual threat posed. To quarantine someone is to delimit their liberty and must absolutely be justified and exercised in a stepwise fashion based on risk and compliance for the absolute minimal time possible. What cannot enter into this decision -- and unfortunately it does and will -- is political expediency, pandering to public fear, or an "abundance of caution" overreaction.

Ms. Hickox's work moves us closer to this ideal and she deserves praise for her heroic struggle to reform quarantine laws that were used capriciously, irrationally, and unjustly against her.

Don't Finish Your Antibiotics -- They Probably Weren't Necessary

It's a tale as old as time: when you're prescribed a course of antibiotics, finish it no matter if you feel better after a few doses. The implicit rationale behind that maxim was that if one is being prescribed antibiotics, it is because they have been accurately diagnosed with a bacterial infection in which antibiotic treatment will be helpful. 

Every antibiotic one takes has two aspects to its nature. Antibiotics, even narrow spectrum ones, impact not only the offending bacteria but also others who are bystanders. Those bystanders are reduced in population opening up space for more dangerous bacteria as well as putting pressure on bacterial populations to select for and evolve resistance (collateral selection). Broad spectrum antibiotics do this on a larger scale and that's why they should be used only when the clinical situation warrants it (i.e. wide uncertainty about the cause of a patient's symptoms). 

There is a risk benefit calculus that must occur with each dose of an antibiotic. Does the risk of antibiotic resistant bacteria developing and antibiotic side effects occurring outweigh the benefit of the antibiotic. Obviously, in a viral infection the risk strongly outweighs the benefit.

The other aspect of this issue is that often antibiotic courses, even when they are needed, are prescribed for arbitrary amounts of time. Courses of 7 days, 10 days, 14 days may have little to no rationale behind them. More and more studies are showing shorter course therapies are optimally effective and there has been a movement to shorten courses of antibiotics as much as possible. A new piece in the British Medical Journal is a tour de force  as is this excellent piece by Brad Spellberg. 

The point is that if an antibiotic is prescribed injudiciously -- as most are -- each unnecessary dose one takes is harmful. Also, each prolonged course of antibiotics that exceeds what is necessary confers unneeded risk. Of course, when a course is appropriately and rationally constructed to ameliorate the infection one should take the prescribed dose so as not to foster recrudescence of the infection with possibly resistant organisms (targeted selection).

Antibiotics are a precious resource that changed the face of medicine and improved human life immeasurably. The threat of antibiotic resistance is one of the most pressing problems medicine faces. Exploding arbitrary dogma to optimize antibiotic use will be essential.