Is EV-D68 causing mysterious polio-like symptoms in children?

Bubble fun at the Santa Fe Renaissance Fair © EEG 

One of the twists in my latest book, Gene Cards, is an unknown pathogen threatening the fictional city of Liasis. I confess that when I came up with the idea I was a little nervous. My story is set in the future, and with all the state-of-the-art technology we already have, is it feasible to think that we will still deal with diseases without a known causative agent? The thing is, new viruses and new pathogens arise all the time. Take the flu, for example. Every time it jumps from one species to another, it has the potential to recombine in new strains and create a new virus. Influenza viruses are usually recognizable from their surface proteins, hemagglutinin and neuraminidase. But the point is that for as long as there are pathogen that thrive in animal reservoirs and then suddenly jump to humans, these pathogens could potentially lead to unknown organisms. And it's hard to test for something you don't know. Another issue with viruses is that they can "hide" in cells (like neurons) that are not accessible through standard test, making them harder to detect unless one resolves to invasive techniques.

One thing is to theorize that it's possible, and one thing is to find it's happening, as you can read in this post from TWiV:

"In February 2014 I wrote about children in California who developed a poliomyelitis-like paralysis, also called acute flaccid paralysis or AFP. However, the cause of this paralysis was not known. The CDC has released its study of these cases and concludes 'The etiology of AFP with anterior myelitis in the cases described in this report remains undetermined'."

The CDC report is available online, and perhaps the most striking quote is the following:

"Additional laboratory testing for infectious diseases conducted at the CDPH Viral and Rickettsial Disease Laboratory did not identify a causative agent to explain the observed clinical syndrome reported among the patients."

So, what is the story, here?

Acute flaccid paralysis happens when muscles become weak or limp and can no longer contract. In order to be diagnosed as AFP, the symptoms must arise spontaneously and not be caused by a trauma. A number of viruses can cause this condition, including polio. When caused by polio, the paralysis is associated with inflammation of the spinal cord, and the whole condition takes the name of "acute flaccid paralysis associated with anterior myelitis." A total of 23 cases of acute flaccid paralysis associated with anterior myelitis have been reported in California between June 2012 and May 2014.

"Affected patients resided in diverse geographic areas throughout California with no indication of clustering. During the 30-month inquiry, no indication of seasonality or temporal trends in disease onset was established."

Twelve patients had been vaccinated against polio, two hadn't, and for the rest no information was available. Nineteen of the 23 patients had been tested for the "usual suspects" (polio, enteroviruses, West Nile virus, rabies, etc.), but only two tested positive for Enterovirus EV-D68, which in most cases actually manifests as a respiratory disease. The CDC report excludes polio as a cause of the 23 cases in the study and concludes that no common etiology could be found.

[. . .] whether these cases represent an actual increase from baseline incidence of AFP with anterior myelitis in this population is unclear. A study examining AFP in children aged 15 years in California during 1992-1998 reported an incidence of 1.4 AFP cases per 100,000 children per year, with the most common diagnoses being Guillain-Barre syndrome (23%), unspecified AFP (21%), and botulism (12%). None of the 245 reviewed cases had recognized anterior myelitis, which is characteristic of paralytic poliomyelitis.

If you do a quick search on PubMed, you'll see that the most common etiology for AFP is polio, and in those cases it's usually associated with anterior myelitis. A Korean study carried over the span of 10 years (from 2001 to 2010) found a total of 285 AFP cases, for which Guillain-Barre syndrome was the major leading causes [1]. Usually triggered by an infection, Guillain-Barre syndrome is a disorder that affects the peripheral nervous system. With prompt treatment, it is 100% curable, though if not treated promptly, it can cause life-threatening complications.

What about the two patients who tested positive for Enterovirus D68? EV-D68 was first isolated in 1962. Since then, there have been rare reports of clustered cases, particularly in summer. However, this summer, there has been an unusual increase in reported cases of severe respiratory diseases, and most of these cases tested positive for EV-D68. Here are the latest numbers from the CDC:

"From mid-August to October 8, 2014, CDC or state public health laboratories have confirmed a total of 664 people in 45 states and the District of Columbia with respiratory illness caused by EV-D68."

What makes this virus worrisome is that it affects young children (usually under the age of 10) and that currently there is no vaccine or treatment against it. And while it normally manifests as a respiratory disease, in some rare instances, the virus can affect the nervous system. In the two California AFP cases that tested positive for EV-D68, the virus was found through nasal swabs. There is a possibility that in the other cases the virus was not found because it was elsewhere, namely in the nervous system (where it would be found only through invasive procedures).

In a different report, the CDC describes

"a cluster of nine children evaluated at Children's Hospital Colorado with acute neurologic illness characterized by extremity weakness, cranial nerve dysfunction (e.g., diplopia, facial droop, dysphagia, or dysarthria), or both. Neurologic illness onsets occurred during August 8‚ September 15, 2014."

Four of eight Colorado children tested were positive for EV-D68. And even though these symptoms are not quite equivalent to AFP, they still fall within the spectrum of acute neurologic illnesses.

Bottom line: we can't quite hold EV-D68 as responsible of the mysterious AFP cases, but we can't exclude it either. Viruses tend to target specific cells in the body, and sometimes they can spread beyond their usual "hunting grounds." When a pathogen is symptomatic (or manifests certain symptoms) only in one particular subset of the population, the reported cases appear to be unrelated, making it very hard to reconstruct the etiology of the outbreak.

Yes, sometimes reality is weirder than fiction. Ad if you are curious about the premise of my new book Gene Cards, you can read the first chapter here.

[1] Kim H, Kang B, Hwang S, Lee SW, Cheon DS, Kim K, Jeong YS, & Hyeon JY (2014). Clinical and enterovirus findings associated with acute flaccid paralysis in the Republic of Korea during the recent decade. Journal of medical virology, 86 (9), 1584-9 PMID: 24114945

[2] Zangwill KM, Yeh SH, Wong EJ, Marcy SM, Eriksen E, Huff KR, Lee M, Lewis EM, Black SB, & Ward JI (2010). Paralytic syndromes in children: epidemiology and relationship to vaccination. Pediatric neurology, 42 (3), 206-12 PMID: 20159431