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. 

Repurposing Drugs to Fight Zika: Putting it into Context

Bursting through the almost continual parade of negative Zika headlines was news that 3 drugs -- one of which (niclosamide) was once FDA approved for another indication have the potential to combat this virus and its severe complications. This study was done in vitro in a laboratory setting and is unequivocally promising. The discoveries center on two drugs with antiviral effects and one which acts as a neuroprotectant. However, as I elaborated on in this interview with Healthday, there several important questions and caveats needed to put this finding in the proper context, two of which I discuss below.

1. In vitro needs to become in vivo: The most obvious next step to be taken with this finding is to see if it holds up--and provides a clinically meaningful benefit--in animal models. Can effective doses be achieved? How robust is the response in an animal model? Do they cross the placenta? Are they safe in pregnancy (at least niclosamide is)? These are the types of questions that would be pursued with an animal model and provide an ability to gauge the feasibility of these drugs as actual treatment options.

2. Concept of Operations: Anytime a new countermeasure is being evaluated for its use in the treatment, prevention, or control of an infectious disease the use case for how it is to optimally used must be part of the discussion. With Zika, an antiviral strategy is difficult for several reasons including, chiefly, the fact that the vast majority of people do not know they are infected and therefore wouldn't be prompted to seek treatment. Secondly, Zika is largely a fleeting virus that comes and goes and in that short process, in certain circumstances, causes fetal harm in pregnant women. Can pharmaceutical intervention occur quickly enough?  Can these compounds make an actual impact on complications? 

If I were to think of a possible concept of operations it would have to center around using these drugs prophylactically to prevent or blunt infection -- if the drugs have that ability in vivo. For only with high drug levels in one's body pre-infection could one have a good chance at preventing the virus from taking hold, spreading to the fetus, or causing other complications like Guillain-Barre Syndrome.

Overall, the repurposing of existing drugs in the face of an emerging infectious disease outbreak is a major effort that provides the fastest path forward to developing new countermeasures. This is especially true if the drug being repurposed has already been FDA approved for another indication such as niclosamide was. When an already approved drug can be used "off label" for a new clinical problem, the burden of funding large clinical trials and complying with FDA regulations is substantially lower.

Until a vaccine is available for Zika, it will be worthwhile to explore potential uses of antiviral therapy but building a concept of operations in which these compounds can be used optimally is essential.

Zika Owns 1 Square Mile of America

By now, everyone knows there are 14 cases of local mosquito-borne transmission of Zika in Florida, some symptomatic and some asymptomatic. What is interesting about this small, and completely expected, outbreak is that it is, thus far, seemingly confined to one specific neighborhood of the city of Miami (in Miami-Dade) called Wynwood. This conglomeration of cases has caused the CDC to issue a travel advisory for pregnant women traveling to just that neighborhood of Miami which spans about 1 square mile. 

That this first documented outbreak of Zika within the 50 states is hyper-localized comes as no surprise as the Aedes aegypti mosquitoes responsible for the spread of the virus are not big commuters, preferring to stay around 150 meters from where they hatched. Also, neighborhoods have differing capacities for supporting mosquitoes in terms of ready access to blood meals and ample standing water for breeding. 

This hyper-locality made me recall a conversation I had months ago with a top Mexican public health official who lamented his entire country getting slathered with Zika-colors and a travel advisory when it was truly a specific region that was conducive to Zika spread.

The CDC, by sticking to real-time date and the evidence, was able to issue -- for the time being -- a very specific travel advisory so as to delimit panic and derail an economy heavily reliant on tourism. This type of highly actionable and precise advisory should be the norm (when possible).

Zika: An Increasingly Frustrating Unknown Unknown

The last few days in Zika-land have been quite calamitous. Major changes in how the disease is conceived occurred. The first revolves around the sexual transmission of the virus from female to male. While male to female and male to male transmission had been known to take place for some time, female to male transmission was not really thought to occur though the virus has been found in the female genital tract and prolonged maternal viremia has been noted. This case, which occurred in NYC, illustrates that such transmission events are possible, though may be more rare than male to female transmission events. HIV, for example, is about half as likely to jump from female to male as it is from male to female.

The other big Zika news involves transmission of the virus in Utah from a fatal case to one of his caregivers. There is much to learn about this incident and it is difficult to hypothesize in such a context but several facts are known: the deceased had an extraordinary level of virus in his blood, the caregiver did not have sexual contact with the patient, mosquitoes in Utah are not known to harbor the virus, and the deceased was diagnosed with Zika post-mortem. 

This case, in my estimate, likely represents a chance transmission event that was facilitated by an extraordinary case of Zika in which the patient died (from Zika or from underlying illnesses) and possibly unique characteristics of the caregiver. It is unclear how generalizable this case may be but the mechanism as to how the caregiver was infected does carry important implications for the trajectory of the virus including the requisite infection control measures needed in the face of a virus that is present in multiple body fluids (blood, urine, semen, saliva).

Zika, more and more, is becoming an unknown unknown.

A Snapshot of a Storm -- A Review of Zika: The Emerging Epidemic by Donald McNeil

It is a difficult task to write a book about an ongoing event in which what are believed to be facts are regularly found out to not be so when truths are constantly modified by new contexts. Such is the case with the current Zika epidemic and the task that The New York Times' stellar global health reporter Donald McNeil Jr. took on with his newly released book Zika: The Emerging Epidemic. McNeil superbly executed his task.

This short book is an expertly written guided tour of not only the ongoing epidemic and its vicissitudes, but also the history of this once relegated virus. Throught the work, McNeil covers unfolding events play-by-play, something that is extremely useful to those who, unlike me, do not follow outbreaks like sports games (it is useful to those who do as well). McNeil delves into the controversy that truly existed regarding the causal role of Zika in the development of microcephaly prior to the virus's meeting of the definitive Shepard's Criteria.

One of the chief values of the book, to me (beside the fact his reference 160 is to the work of my colleagues and me), is that McNeil provides a much needed exploration of the issues surrounding the recommendations, issued by some countries, for women in Zika-laden areas to delay pregnancy and the hesitancy of others to not follow suit for various reasons.

This book is must reading for those following the Zika outbreak, those wanting to learn about it, and those wanting to immerse oneself in excellent scientific writing.