by Joseph Cabral
figures by Rebecca Senft
cover by Nick Youngson CC BY-SA 3.0 Alpha Stock Images

In the middle of the 20th century, poliovirus could be found in every country of the world. Infection by poliovirus can lead to a severe disease called poliomyelitis, or simply polio, in which the patients become paralyzed when poliovirus inflames the spinal cord. To great public relief, the first polio vaccine was licensed in 1955 and mass vaccination campaigns began immediately. As a result, the last known case of poliomyelitis in the US was recorded in 1979, and the US was declared polio-free in 1994. Decades of aggressive worldwide vaccination campaigns have driven poliovirus to the brink of extinction. Today, poliovirus can only be found in 3 countries: Afghanistan, Pakistan, and Nigeria. According to the World Health Organization, only 22 cases of polio were reported worldwide in 2017.  However, recent reports of children exhibiting a polio-like paralytic condition has sent health officials and researchers scrambling for answers.

The condition is called acute flaccid myelitis, or AFM. With over 300 reports of AFM from this year alone (158 confirmed cases as of Dec 14), the Center for Disease Control and Prevention (CDC) has recently launched an AFM Task Force to investigate this very serious disease.

Acute Flaccid Myelitis: The Replacement Polio

Taking health officials off guard, a spike in polio-like disease was first described in a Morbidity and Mortality Weekly Report from the CDC in October of 2014. The report detailed clusters of children in California and Colorado suffering from acute flaccid paralysis (AFP), a neurological illness that results in the sudden onset of paralysis (Figure 1). AFP can have a wide range of causes including environmental toxins, genetic conditions, and infection by viruses. Using magnetic resonance imaging (MRI) to peer inside the body, investigators discovered that all of the patients exhibited inflammation of the spinal cord (referred to as myelitis) in a specific neuron-dense region known as grey matter. This specific form of myelitis is usually the calling card of poliovirus infection. Surprisingly, though, investigators found no evidence of poliovirus. There have been a few reports of polio-like myelitis also occurring during West Nile virus and adenovirus infections, but investigators could not find evidence of infection by these viruses either. With no suspect to blame for the sudden spike in polio-like paralysis, the term acute flaccid myelitis (AFM) was coined to encompass all AFP conditions that display polio-like myelitis.

Figure 1. AFP. Acute flaccid paralysis (AFP) is a broad classification of disorders defined by the rapid onset of limb weakness. AFP can be caused by complications from neurotoxic snake venom, tick bites, HIV infection, and genetic disorders such as Guillain-Barre syndrome. Acute flaccid myelitis (AFM) is a specific kind of AFP that is linked to infection by a number of different viruses such as poliovirus, EV-D68, West Nile virus, and adenoviruses. The paralysis in AFM is thought to result from inflammation in the grey matter (a thick bundle of motor nerves) of the spinal cord caused by viral infection. The classic example of AFM is poliomyelitis (“Polio”) that is caused by the poliovirus.

If Not Poliovirus, Then What is Causing AFM?

While the CDC has yet to publicly confirm what is driving the sudden spike of AFM, viral infection is suspected to be the likely cause. Poliovirus belongs to a group of viruses known as enteroviruses. Enteroviruses usually replicate in the gastrointestinal tract of infected humans and spread person-to-person through the fecal-oral route. It’s one of the reasons why we should really remember to wash our hands after using the restroom. Infections by most enteroviruses, including poliovirus, usually present with mild or no symptoms at all. Sometimes, though, enterovirus infections can spread to motor neurons, which are the cells that control muscle movement. This type of infection is actually a rare event, a fluke in the viral lifecycle. In fact, fewer than 1% of poliovirus infections ever spread to motor neurons, and only a handful of enteroviruses have the capacity to infect neurons at all. But when they do, the results are dramatic and severe, often involving paralysis. So, when cases of AFM began to suddenly appear in the absence of poliovirus, investigators turned their eyes toward another enterovirus making its own dramatic entrance.

In September of 2014, a month before the initial reports of AFM, an outbreak of a previously rare enterovirus, EV-D68, resulted in severe respiratory infections and many hospitalizations across the US. A possible link between EV-D68 and AFM was uncovered when 67% of the samples from the Colorado AFM cluster in 2014 tested positive for EV-D68.

EV-D68: A Misfit Enterovirus Learns New Tricks

First identified as causing bronchitis in California in 1962, EV-D68 is a little different than most enteroviruses. EV-D68 is unstable in acidic conditions. This means that EV-D68 is unable to survive exposure to stomach acid and does not replicate in the gastrointestinal tract of humans like most enteroviruses. EV-D68 preferentially replicates at a temperature around 33°C (91.4°F) and has adapted to infect the upper respiratory pathway where the body temperature is cooler because of breathing (Figure 2). Infection results in cold-like symptoms. Rather than spreading by the fecal-oral route like poliovirus, EV-D68 spreads from respiratory tract secretions like the common cold or flu. Interestingly, greater than 90% of AFM patients were reported to have a mild respiratory illness or fever shortly before the onset of paralysis. Moreover, like AFM, most cases of EV-D68 are reported in the fall, and outbreaks of both EV-D68 and AFM have been following the same biennial pattern: 2014, 2016, 2018 (Figure 3).

Figure 2. EV-D68 infection. An enterovirus, EV-D68, is suspected to be the leading cause of AFM outbreaks since 2014. Unlike poliovirus and most other enteroviruses, EV-D68 infects the upper respiratory passages and presents symptoms similar to those of a common cold. For reasons that are not clearly understood, it is thought that EV-D68 can infrequently move from the upper respiratory passages to the spinal cord. This results in myelitis, or inflammation of the spinal cord. The inflammation can damage the motor neurons and lead to limb weakness or even paralysis.

Given the appearance of cold-like symptoms just prior to the onset of AFM and the outbreak pattern shared by EV-D68 and AFM, research groups from around the world have been investigating the link between AFM and EV-D68. In January of this year, a study from the University of New South Wales in Australia demonstrated a causal relationship between EV-D68 infection and AFM using the Bradford Hill criteria, the same set of 9 epidemiological tests the CDC used to link zika virus infection to developmental defects in children.

Figure 3. The pattern of AFM and EV-D68 outbreaks. Following a biennial pattern, diagnosed cases of AFM spiked in the fall of 2014, 2016, and 2018 (red). These AFM cases peaked during times of high EV-D68 circulation which follows the same biennial pattern (green). So far in 2018, an outbreak of EV-D68 has been reported in New York State, and several AFM patients have tested positive for EV-D68.

Supporting this relationship, a study released in October of 2018 by scientists at the University of California San Diego showed that at least one of the currently circulating strains of EV-D68 can infect nerve cells and cause paralysis in mice. Conversely, a strain of EV-D68 isolated in 1962 could not induce paralysis. Uncovering clues as to why EV-D68 has only recently developed into a public health concern, the same group of researchers identified 21 mutations in this newer strain. These mutations are thought to contribute to the increased severity of respiratory illness caused by EV-D68 infection and the ability of EV-D68 to infect neurons and cause paralysis.

AFM is a Global Health Concern

There is currently no vaccine for EV-D68 in humans, but a group of researchers in China recently reported that an inactivated form of EV-D68 could protect mice against the virus, giving hope to future vaccine research and development. Until a vaccine can be developed, the best line of defense is hygiene, public awareness, and continued surveillance by the CDC and other monitoring organizations in countries where AFM has been linked to EV-D68. So far, that list includes France, Norway, Canada, the UK, Sweden, Spain, the Netherlands, and Japan. Recognizing AFM and EV-D68 as global public health concerns now and proactively putting resources into research and vaccine development may help avert a public health crisis in the future. While AFM is a dramatic and debilitating condition, it is fortunately rare. However, the biennial pattern of outbreaks is likely to continue. Expect to hear about EV-D68 and AFM again in 2020.

Joseph Cabral is a fifth-year PhD candidate in the Program in Virology at Harvard University.

Rebecca Senft is a fourth-year Program in Neuroscience PhD student at Harvard University who studies the circuitry and function of serotonin neurons in the mouse

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