Enterovirus D68 and Acute Flaccid Myelitis

April 25, 2022

Enterovirus-D68 virions under transmission electron microscope.
Enterovirus-D68 virions under transmission electron microscope.
Children and young adults frequently acquire respiratory tract infections during respiratory season, when viruses like influenza circulate and bacterial pharyngitis is common. However, when an unprecedented surge of children with asthma-like respiratory illness presented in the typically calm summer-to-fall season of 2014, it was clear something unusual was occurring. In the midst of this unusual, nonseasonal respiratory outbreak, a previously healthy young adult presented to their provider with a fever, congestion, cough and sore throat. Due to the relatively mild symptoms, and no other significant concerns, the patient was diagnosed with tonsillitis and sent home with a prescription for steroids.

Five days later, things took a turn for the worse when the patient started experiencing headaches, a stiff neck and the inability to move their left arm. After admission to the hospital, an MRI revealed lesions in the brainstem and spinal cord. As the patient's symptoms progressed, they were intubated for airway protection, received a gastrostomy tube for feeding and nutrition and were ultimately hospitalized for several weeks of intensive care, followed by inpatient rehab. Unfortunately, the patient was left with persistent left arm paralysis and muscle atrophy 8 years later.

Mysterious Paralysis 

This may seem like a unique case study, but it became the personal experience of several families across the United States in 2014. In 2012, sporadic cases of acute paralysis, later called acute flaccid myelitis (AFM), a condition in which limbs become extremely weak and lose muscle tone in conjunction with inflammation of the spinal cord, were reported in children in California. At the time, California was the only state performing active surveillance for AFM. These sporadic cases led to increased surveillance of acute flaccid myelitis in the United States from 2012 onward. The mysterious condition seemed to mimic polio, yet most AFM patients had received their regularly scheduled poliovirus vaccines and tested negative for poliovirus (a serotype of the species Enterovirus C), making it an unlikely culprit. From 2014-2018, cases of AFM were reported in an every-other-year pattern, with the highest case numbers occurring during even-numbered years.

Linking Enterovirus D68 to AFM 

At the same time cases of AFM were popping up across the U.S., a record number of Enterovirus D68 infections were also being reported in the U.S. Enterovirus D68 (EV-D68) was first identified in California in 1962, one of hundreds of non-polio enteroviruses. While small numbers of cases have been reported since 1987, over 1,153 confirmed cases were reported in 2014. Like most respiratory viruses, EV-D68 causes symptoms like runny nose, cough, sneezing and body aches, and can spread via contact with respiratory secretions or contaminated surfaces. 

Geographic and Temporal Evidence

Across the country, epidemiologic evidence for the association between EV-D68 infection and development of AFM began to build. The EV-D68 outbreak geographically and temporally matched the increase in AFM in California, Colorado and Utah in 2014. At one Colorado children’s hospital, the number of AFM cases reported during the EV-D68 outbreak of 2014 was 3 times higher than the maximum number of cases ever previously reported, and studies demonstrated that the odds of EV-D68 detection in the nasopharynx of a patient with AFM was significantly higher than outpatient controls.

EV-D68 Can Cause ‚ÄčNeurologic Disease

Furthermore, studies have demonstrated the potential for EV-D68 to cause neurological disease, similar to other members of the enterovirus family, like the polioviruses and enterovirus A71, which both cause acute flaccid paralysis. EV-D68 has also been identified in cerebrospinal fluid (CSF) of patients with acute flaccid paralysis, and studies have demonstrated the virus' potential to cause damage to the anterior spinal cord. 

Demonstrating Causality Between EV-D68 and AFM

Finally, it is essential to note that while other viruses can cause AFM, researchers have demonstrated a possible causal relationship between infection with EV-D68 and AFM in children, which might explain the increase in AFM cases during the 2014 EV-D68 outbreak. Over the years, epidemiologic evidence, paired with experimental mouse models and isolation of virus from central nervous system tissue, proved causation between neurologic disease and the polioviruses as well as enterovirus A71. This proved to be a much more difficult task with patients who had AFM during the 2014 outbreak, because EV-D68 was rarely detected in the CSF of patients with AFM. To demonstrate causality between EV-D68 infection and AFM, researchers used The Bradford Hill Criteria, which are used to help determine if observed epidemiologic associations are causal, similar to Koch’s Postulates.

Diagnosing EV-D68 

There is no routine test to specifically detect EV-D68, and the diagnosis remains primarily clinical. While standard respiratory tests may detect enterovirus, they do not differentiate between enteroviruses. In cases of severe, unexplained respiratory illness, reverse transcriptase-polymerase chain reaction (rRT-PCR) may be performed at public health laboratories or the Centers for Disease Control (CDC). Many infections with EV-D68 will be mild and self-limiting, and supportive care is recommended. Preventative measures include hand washing, covering the mouth and nose when coughing or sneezing and avoiding others when ill.

The Future of AFM Research

Children's Hospital Colorado is one of several sites dedicated to studying the underlying cause and lasting impact of AFM. Through a pediatric nervous system infection research program led by Drs. Kevin Messacar and Sam Dominguez, the first cluster of EV-D68-associated AFM was described in 2014.

Furthermore, collaborative efforts undertaken by researchers in infectious disease, neurology, radiology and rehabilitation medicine at the University of Colorado Anschutz Medical Campus have generated new evidence for the relationship between EV-D68 and AFM. This research has helped determine the pathophysiology of EV-D68 infection. Once a person is infected, the virus infects motor neurons of the anterior horn of the spinal cord and subsequently leads to motor neuron inflammation and death. Muscles that become completely denervated will remain paralyzed forever. This process is nearly identical to the process seen in poliomyelitis due to infection with poliovirus.

While cases of AFM caused by EV-D68 can occur in adults, particularly in those who are immunocompromised, most cases occur in children. In 2019, the National Institutes of Health (NIH) awarded the University of Alabama $10 million over 5 years to study the natural history of acute flaccid myelitis in children. This international multi-site study aims to discover how the disease develops and progresses. The CDC also constructed an AFM task force that includes 16 multidisciplinary experts from across the U.S. The task force has identified the following priorities as crucial next steps in the fight against AFM:
  • Strengthening and expanding education and communication outreach to clinicians for the diagnosis and rapid reporting of cases.
  • Providing more resources at the state and local levels to improve case identification and AFM monitoring and collecting more long-term data on cases and outcomes.
  • Implementing studies that can help establish potential risk factors.
  • Further distinguishing the symptoms or group of symptoms associated with diagnosed cases of AFM.
  • Developing a system for collecting, processing, storing and sharing clinical specimens (e.g., blood, tissue, CSF) to support future scientific investigation and collaboration. 
  • Advancing the ability to detect and identify potential causes of AFM using cutting-edge laboratory technologies, such as enhanced gene sequencing.
Additionally, CDC offers a route for families or individuals interested in participating in AFM research. Continued EV-D68 research and surveillance is crucial to infection prevention and management of both acute respiratory infections and AFM.

Interested in learning more about the connection between EV-D68 and AFM? Check out this Microbial Minutes, which covers an mBio paper from Aug. 2019, about the discovery of antibodies to enteroviruses in the CSF of patients with acute flaccid myelitis.

Author: Andrea Prinzi, Ph.D., MPH, SM(ASCP)

Andrea Prinzi, Ph.D., MPH, SM(ASCP)
Andrea Prinzi, Ph.D., MPH, SM(ASCP) is a field medical director of U.S. medical affairs and works to bridge the gap between clinical diagnostics and clinical practice.