Kiss A Frog, Fight the Flu

There is always speculation about particular compounds that exist naturally in the wild that may have benefits for human health. Indeed, history is full of stories like this from quinine to aspirin. New research from Emory shows that frog mucus contains a potentially flu-fighting antimicrobial peptide. 

For the study peptides contained in the mucus from Hydrophylax bahuvistara frogs were screening for both anti-influenza activity and non-toxicity to human cells. Of these screens, one peptide, named urumin, emerged as the leading candidate. Urumin was noted to interact directly with the influenza virus at an important site: the conserved stalk area of the H1 hemagglutinin. Because it is a "conserved" region (i.e. one not highly mutable) the frog peptide retained activity against drug-resistant variants. This region is one of the targets of the long sought after universal flu vaccine. In the study, urumin worked not only in vitro but also in a mouse model.  The peptide was specific for just H1 variant influenza A viruses.

I found the paper to be very interesting and the discoveries may have wide-ranging implications not only for novel antivirals but for understanding influenza. As the authors note, innate defense mechanisms are less likely to be prone to resistance because they presumably were selected  via natural selection for their durability against their target. It is unclear what role amphibians have with influenza A epidemiology but it appears they can be infected and perhaps urumin is one of its natural defenses against the virus. Future studies with ferrets will be important to perform as they are important surrogates for humans.

Clinical Care Gaps in US Zika Cases

Today, the CDC released important new information on the Zika outbreak and its impact on pregnant women. The report, which details approximately 1300 US pregnancies, contains several important points:

• The risk for fetal malformation is the highest in the 1st trimester with 15% of confirmed 1st trimester infections having this horrific result
• Overall, the risk of fetal malformation appears to be 10% with confirmed maternal infection
• The vast majority of babies with possible Zika infection or brain malformation did not get further testing (either for diagnosis or brain imaging)

This last point is the most ominous as it shows just how hard it is for crucial public health and medical messaging to find its way to the front line clinicians. Diffusion of knowledge in ordinary care is a difficult decade long process -- clearly not something that can be tolerated in the midst of an infectious disease emergency like Zika. 

Winning Isn't Everything: A Review of Have Bacteria Won?

I recently finished the next infectious disease book on my long list -- I think I've been reading these books non-stop since 1996 and probably will forever -- University of Aberdeen microbiology Professor Hugh Pennington's Have Bacteria Won? 

This short book, part of the New Human Frontiers series, was published in 2016 and is packed with a lot of good information and narrative from an expert in the field. Being written by a UK expert is a large value to the American reader as it is recounts many UK-based infectious disease outbreaks that may not be so familiar but nonetheless contain important lessons. 

His introductory chapter is entitled "Why We Are so Worried About Bacteria" and provides an overview of some headline-grabbing infectious diseases. The most popularized UK-based outbreak (which is non-bacterial in origin), of course, is bovine spongiform encephalopathy (BSE, Mad Cow Disease) and its human form, vCJD, which Dr. Pennington details noting that no new human cases have been diagnosed in those born after 1989. In addition to BSE, the chapter highlights other important infectious diseases such as necrotizing fasciitis (flesh-eating bacteria)  that, despite media attention, has been known to medicine since at least 1924.

In the chapter's treatment of Ebola, Dr. Pennington includes a very revealing and interesting quote from the court proceedings against heroic nurse Kaci Hicox who was forcibly -- and unjustifiably-- detained by government agents:

“the court is fully aware of the misconceptions, misinformation, bad science and bad information being spread from shore to shore in our country with respect to Ebola. The Court is fully aware that people are acting out of fear and that this fear is not entirely rational. However, whether that fear is rational or not, it is present and it is real Respondent's actions at this point, as a health care professional, need to demonstrate her full understanding of human nature and the real fear that exists. She should guide herself accordingly.”

The quote, from a Maine judge, shows just how far we've fallen that despite acknowledging the irrationality of the mob in their fear of Ebola the judge still advises Hicox to placate it!

Other aspects I particularly concepts that I found particularly notable included: "sewer socialism", a defense of pasteurization (unpasteurized products have a 150-fold increased risk of being involved in outbreaks), the significance of mutant broiler chickens, "allowable" Salmonella levels in chocolate, the "trans-science" of influenza prediction, and Paul Ehrlich's work with pneumococcus and the quinine-derivative optochin in 1911 and its fate foretelling the modern antibiotic resistance crisis which he deems not a scientific problem but an anthropological one.

Have bacteria won? We know Pasteur said microbes would have the last word but reading Dr. Pennington's words is nonetheless highly recommended.

An Expert Play-by-Play of Emerging Infectious Disease: A Review of The Next Pandemic

In order to have an understanding of the field of emerging infectious disease and be able to make some sense of the daily vicissitudes of outbreaks, odd cases, and long-standing endemic infections one has to have some sense of the context and history of the field. Having a first person tour guide would be indispensable. That is the role that former CDC official, and now University of Nebraska Medical Center College of Public Health dean, Dr. Ali Khan, plays in his book The Next Pandemic: On the Front Lines Against Humankind's Gravest Dangers. 

Drawing on a wealth of on-the-ground experience Dr. Khan uses carefully selected cases to illustrate several key concepts that are fundamental to the field. Though the incidents described in each of the chapters were all very familiar to me, they still held a lot of value as they contained Dr. Khan's expert perspective and insights. For example, when describing the management of avian influenza outbreaks on poultry farms, I found the  detailed explanation of the business arrangements between farmers and poultry farmers very useful. Similarly, I found Dr. Khan's narrative of the anthrax bioterrorist attacks and Hurricane Katrina (specifically his incisive criticism of then Louisiana governor Blanco and New Orleans mayor Nagin) to also hold much value.

Dr. Khan's harrowing experiences involving sketchy planes, dense customs agents (including those in the US), and goats are also entertaining to read about and give the reader the sense of adventure that is inherent in the field -- Dr. Khan describes himself as a "geek version of Indiana Jones." His discussion of his famous zombie campaign is also very fun to read about.

By providing an play-by-play analysis of some of the most significant emerging infectious disease outbreaks in recent decades, the book will hopefully have many reader and inspire others to the endlessly enthralling and intellectually stimulating world of infectious disease. 

Sepsis: Untangling Bundles, Goals, Measures

Probably one of the of the most paradigm-changing papers in the fields of emergency medicine, critical care medicine, and infectious disease was Rivers, Nguyen and colleagues early goal directed therapy for sepsis paper published in The New England Journal of Medicine in 2001. 

Sepsis, the common final pathway for infectious syndromes and what your grandma called "blood poisoning", is a dysregulated immune response to infection that causes organ dysfunction.  Severe sepsis carries a mortality rate of approximately 25% and is a cause or contributor to many deaths. 

The EGDT paper, with its spectacular results showing a 16% mortality reduction, spurred the development of international consensus guidelines, the Surviving Sepsis campaign, and elevated sepsis to the medical emergency that it is. The bundle of interventions included in EGDT (aggressive fluid resuscitation, prompt antibiotic administration, vasoactive medication administration, blood transfusions)  has quickly come to be regarded as the standard of care.

However, there has been growing concern regarding just how powerful the bundle is and which components are essential and which have less importance. The ARISE, ProCESS, and ProMISe trials failed to replicate the results of the initial trial and there is a strong argument that sepsis care has advanced so much, because of EGDT, that "usual" care incorporates much more than it did in 2001 (because of the results of the initial trial) and later trial patients got many of the interventions of EGDT before randomization. As quality measures and reporting increasingly hone in on the bundle, it is essential to unpack the bundle and not grade providers and facilities negatively if not all components of the bundle contribute positively.

A pair of new papers provide some insight that may help to disentangle the various component of the bundles. The first, by Khalil and colleagues, was published in Critical Care Medicine and is focused on explaining the discordant results between Rivers's study and observational studies that support EGDT and the three negative randomized trials. The conclusion reached was that in the observational studies time to antibiotic administration was substantially faster in the EGDT arms and in the randomized trials very similar arguing that timing of antibiotics explained the discordant results. Interestingly, they also noted increased mortality with EGDT in the sickest group of patients.

The second paper is a patient level meta-analysis of the ARISE, ProCESS, and ProMISe trials. This type of analysis adds increased power to detect effects. The results again show no effect of EGDT on mortality and in subgroup analyses controlling for how aggressive a given center is in resuscitation -- addressing the "usual care" conjecture -- no difference was found. The investigators did find EGDT being associated with higher costs, however. 

So what to make of all this ? A few thoughts:

• The bundle needs to be unbundled: as third-party payors have focused on bundle compliance as a quality measure that may influence payment it will be crucial to make sure they are measuring something that unequivocally matters
• Antimicrobials are of paramount importance: sepsis is a response to infection and taming the infection with antibacterials, antivirals, antifungals, and/or antiparasitic medications as quickly as possible may make the biggest difference (even the order in which one gives antibiotics may matter, depending on the inciting organism)
• As the PRISM investigators note, individualized sepsis care based on variables particular to the patient being treated, rather than a one-size-fits-all approach, is likely the correct manner to treat sepsis

Sepsis is an important diagnosis to make and aggressive care, even if non-formulaic, should be the norm. The Rivers trial was pathbreaking and changed the dialogue regarding this condition. I am sure that these latest salvos in the medical literature will be answered and more elucidation will be forthcoming,