Enterovirus D68: The Virus Behind AFM

In August 2014, pediatric hospitals across the United States began reporting a surge of children struggling to breathe, many of them with asthma. Testing pointed to Enterovirus D68 (EV-D68), a respiratory virus first reported in California in 1962 and confirmed in only 699 people worldwide before 2014. Weeks later, clusters of children with sudden limb weakness appeared in several states. This article explains what EV-D68 is, how it makes some children severely ill, and how strong the evidence is that it can cause paralysis.

Educational content, not medical advice. Talk to your doctor before changing any medication, treatment, or routine. Information here reflects current research but every person's situation differs. A child with sudden weakness in an arm or leg, trouble swallowing, or drooping eyelids needs urgent medical evaluation.

What is Enterovirus D68?

EV-D68 belongs to the family Picornaviridae and the genus Enterovirus, the same genus that includes poliovirus and dozens of other viruses that circulate every year. To understand how any of them works at a basic level, see how viruses work: from infection to replication.

Like its relatives, EV-D68 is a non-enveloped virus with a genome made of a single strand of RNA. "Non-enveloped" means it has no fatty outer membrane; the genetic material sits inside a hard, geometric shell of protein called a capsid. Think of it as a tiny dice-shaped vault: durable on surfaces, but dependent on one specific kind of lock to get into a cell. The genome is translated into one long polyprotein, which the virus then cuts into the individual proteins it needs.

The lock is the interesting part. A 2015 study in Nature Communications found that sialic acid, a sugar molecule found on the surface of many human cells, is essential for EV-D68 to bind and infect susceptible cells (Liu et al., 2015). Crystal structures showed that sialic acid analogues sit in a "canyon" on the capsid surface, and that binding triggers a conformational change that ejects a fatty molecule stabilizing the shell, a first step toward unpacking the virus inside the cell.

Sialic acid is abundant on airway cells, which fits the virus's behavior. EV-D68 spreads in respiratory secretions and behaves more like a rhinovirus, the cause of many common colds, than like poliovirus. It was originally grouped with rhinoviruses before genome analysis moved it into the enterovirus genus. For the cold-causing cousin, see rhinovirus and the common cold explained. Researchers have proposed other receptors on neurons and other cell types, and the receptor question is still being worked out.

How does EV-D68 spread?

The Centers for Disease Control and Prevention (CDC) says the virus is found in respiratory secretions such as saliva, nasal mucus, and sputum, and likely spreads from person to person through coughing, sneezing, or touching surfaces that others then touch. Infections are more likely in summer and fall, but can happen year-round (CDC, EV-D68). That is why handwashing and staying home when sick are the standard advice, covered further below.

A rare virus becomes a national emergency

EV-D68 was first found in California in 1962 and was reported only rarely for the next five decades. A systematic review of 70 papers in The Lancet Infectious Diseases put it starkly: before 2014, infections had been confirmed in only 699 people worldwide (Holm-Hansen et al., 2016). The virus was probably circulating more widely than that, but few laboratories tested for it, and routine hospital panels often lump rhinoviruses and enteroviruses together without typing them.

That changed in August 2014. Hospitals in Missouri, Illinois, and Colorado saw sharp increases in children admitted with severe respiratory illness, and CDC investigators began testing specimens from severely ill patients across the country. Of 1,529 patients tested, 699 (46%) were confirmed as EV-D68. Among the 614 hospitalized patients with confirmed EV-D68, the median age was 5 years, and the most common symptoms were shortness of breath, cough, and wheezing (Midgley et al., 2015).

The outbreak was not confined to one country. The same systematic review found more than 2,000 EV-D68 cases reported in 20 countries in 2014, with spread to Canada, Europe, and Asia. It also noted that clusters of children with acute flaccid paralysis of unknown cause appeared in several US states and in Europe, and that EV-D68 was confirmed in some of those children but not all.

Why asthma matters

The Midgley investigation found that patients with a history of asthma or reactive airway disease (a tendency toward wheezing) were more likely to need intensive care and breathing support. Among those patients, 66% needed intensive care compared with 51% of children without such a history, and 32% needed ventilator support compared with 24%.

A useful analogy is a garden hose that is already partly kinked. A child with asthma starts with narrowed, twitchy airways; a virus that inflames the lining and triggers wheezing can push a marginal situation over the edge. The CDC's current advice for families reflects this: children and adults with asthma should keep their asthma action plan current, take prescribed medications, and get an annual flu vaccine.

Acute flaccid myelitis: polio's shadow

Beginning in late summer 2014, clinicians in the United States began reporting children with sudden limb weakness and characteristic spinal cord changes on magnetic resonance imaging (MRI). The syndrome is called acute flaccid myelitis (AFM). "Flaccid" means the weak limb is floppy rather than stiff; "myelitis" means inflammation of the spinal cord.

According to the CDC, the most common signs of AFM are sudden arm or leg weakness, loss of muscle tone, and loss of reflexes. Some patients also have facial droop or weakness, drooping eyelids, difficulty moving the eyes, or trouble swallowing or speaking. More than 90% of cases have occurred in young children. AFM is uncommon, but it is serious (CDC, About AFM).

What the first national count showed

A CDC-led analysis of nationwide surveillance for August through December 2014 identified 120 AFM cases from 34 states, with 16 more cases from 13 states found in 2015 (Sejvar et al., 2016). The median age was 7.1 years and 59% of patients were male. Most had a respiratory illness (81%) or fever (64%) before limb weakness began. MRI showed lesions mainly in the cervical (neck) portion of the spinal cord in 103 of 118 scans, nearly all patients were hospitalized, and no deaths occurred in that group.

Table 1 collects the main events in the EV-D68 and AFM story that are documented in published surveillance reports.

Year	Event	Source
1962	First EV-D68 detection, California	Holm-Hansen et al., Lancet Infect Dis, 2016
Before 2014	Only 699 confirmed infections worldwide	Holm-Hansen et al., 2016
2014	Nationwide US outbreak; 699 of 1,529 tested severe-illness patients confirmed as EV-D68	Midgley et al., Lancet Respir Med, 2015
2014	120 AFM cases, 34 states (Aug-Dec)	Sejvar et al., Clin Infect Dis, 2016
2016	29 EV-D68-associated AFM cases in 12 European countries	Knoester et al., Pediatr Infect Dis J, 2019
2014, 2016, 2018	US AFM case increases	CDC, About AFM
2021	139 EV-D68 cases in 8 European countries (late July to mid-October)	Benschop et al., Euro Surveill, 2021
2022	Rise in US pediatric respiratory visits and EV-D68 positivity	Ma et al., MMWR, 2022

Why "polio-like"?

Poliovirus, a close relative in the same genus, damages motor neurons in the anterior horn, the front part of the spinal cord's gray matter where the cells that command muscles sit. When those neurons are destroyed, the muscles they control lose their signal and weaken. AFM produces a similar pattern: limb weakness with lesions concentrated in spinal cord gray matter. For a closer look at the polio mechanism, see poliovirus: how it works.

The resemblance is one reason investigators test children with sudden limb weakness for poliovirus too. In its 2022 report, the CDC advised clinicians to consider AFM in children with acute limb weakness, especially after a respiratory illness or fever, to arrange prompt hospitalization and specialty referral, and to test for poliovirus. Poliovirus remains the pathogen that must never be missed, even though routine vaccination makes it very rare in the United States.

What happens to children afterward

Recovery is variable. A clinical review of US cases from 2012 to 2015 reported that some patients improved in muscle strength and function, but most still had residual weakness a year or more after onset (Messacar et al., 2016). The CDC states there is no specific treatment for AFM; clinicians may recommend interventions case by case, such as physical or occupational therapy, and early physical rehabilitation might improve long-term outcomes.

Severity in Europe was similar in kind. In the 2016 European series of 29 EV-D68-associated AFM cases, most patients were children (median age 3.8 years), only 3 patients fully recovered, and 2 died (Knoester et al., 2019). The authors noted this was probably an undercount, since detection depends on clinician awareness, respiratory sampling, and laboratory capacity to type enteroviruses.

Does EV-D68 really cause AFM?

This is the question that makes EV-D68 scientifically interesting, and the honest answer is "very probably, but the proof is indirect." The classic way to blame a pathogen for a neurological disease is to find it in the affected tissue, usually the cerebrospinal fluid (CSF) that bathes the spinal cord. In AFM, that almost never works.

In the national 2014 analysis, EV-D68 was found in the CSF of just one patient, and that sample was heavily contaminated with blood. EV-D68 was, however, the most common virus in upper respiratory samples: 20% overall, rising to 47% when specimens were collected within 7 days of illness onset. The authors concluded that timing and epidemiology suggested a link to the EV-D68 respiratory outbreak, but that laboratory evidence directly tying AFM to EV-D68 was inconclusive.

Think of a burglary where the thief has left before the police arrive. Fingerprints on the front door (virus in the nose) and a pattern of break-ins on the same nights as the neighborhood's EV-D68 surge are suggestive, but nobody caught the burglar in the house. Enteroviruses often clear from the nervous system quickly, and spinal cord tissue is almost never sampled in living children, so direct evidence is naturally scarce.

The case for causation

Investigators have built the case from several directions:

• Epidemiology: AFM cases in the United States rose in 2014, 2016, and 2018, years of EV-D68 activity, according to the CDC. A 2018 analysis in Eurosurveillance applied the nine Bradford Hill criteria (a standard checklist for judging causation from observational evidence) and found six fully met, two partially met, and the dose-response criterion minimally met. It concluded that the criteria support a causal relationship (Dyda et al., 2018).
• Strain evolution: Genomic studies of the 2014 outbreak identified a genetically distinct clade, B1, linked to the AFM clusters. As described below, contemporary outbreak strains, but not the old 1962 prototypes, were neuropathic in animal models.
• Animal experiments: In a 2017 mouse study, four of five 2014 outbreak strains caused paralysis resembling human AFM, while the 1962 prototype strains (Fermon and Rhyne) caused little or none. Paralysis was linked to infection and loss of motor neurons in the spinal cord's anterior horn, virus recovered from paralyzed mice caused disease in naive mice (satisfying Koch's postulates in that model), and immune serum protected against paralysis (Hixon et al., 2017).
• Cell studies: A 2018 mBio study found that only a subset of contemporary strains, including some from the 2014 outbreak, could infect a neuronal cell line, a pattern that held in primary human neuron cultures and a mouse paralysis model (Brown et al., 2018).

The limits of the evidence

Each line of evidence has weaknesses. The mouse experiments used neonatal mice, which are far more susceptible to enteroviruses than a school-age child. Cell-culture neurons are not a spinal cord. And epidemiology cannot prove that any individual child's paralysis came from EV-D68 rather than another enterovirus, a different virus, or an immune reaction. Other viruses, including West Nile virus, Japanese encephalitis virus, herpesviruses, and adenoviruses, are also linked to AFM according to the CDC, and researchers are still working to learn why a small number of people develop AFM after a common infection. For a related mosquito-borne cause of neurological disease, see West Nile virus explained.

A fair summary is that most researchers treat EV-D68 as the leading explanation for the AFM waves of 2014, 2016, and 2018, while acknowledging that proof in an individual patient is usually out of reach.

Why EV-D68 comes in waves

One of the most striking features of EV-D68 is its pattern of larger and smaller years. US AFM cases rose in 2014, 2016, and 2018, which gave rise to the idea of a two-year cycle. A tidy explanation is easy to imagine: a big outbreak leaves many children immune, so the next year is quiet, but a new crop of babies and waning immunity set up another big year after that.

The evidence for this model is suggestive rather than settled. The 2014 outbreak was followed by European AFM clusters in 2016 and a US increase in 2018, and the COVID-19 pandemic then disrupted the usual circulation of most respiratory viruses. In Europe, 139 EV-D68 cases from eight countries were reported between late July and mid-October 2021, which the authors linked to the virus's typical seasonal pattern boosted by the reopening after lockdowns (Benschop et al., 2021). In the United States, the CDC reported rising emergency department visits for pediatric respiratory illness and asthma in late summer 2022, along with rising EV-D68 positivity in sentinel surveillance (Ma et al., 2022).

Evolution keeps changing the target

Population immunity is only half of the story because the virus itself changes. A 2022 analysis in PLoS Pathogens of 2018 samples found multiple subgroups within subclades B3 and A2 with different origins, and reported that variants began diversifying up to 18 months before their first diagnostic detection in an EV-D68 season. The authors also found continuous change in putative neutralizing epitopes (the parts of the capsid that antibodies recognize) and hypothesized that rapid evolution combined with high geographic mixing could be explained by substantial reinfection of adults (Hodcroft et al., 2022).

An evolving virus is like a key whose teeth keep being filed slightly, so the locks that antibodies built last year may no longer fit perfectly. That makes forecasting hard. It also helps explain why the age pattern can shift: the same analysis found that patients infected with A2-lineage viruses were significantly older than those with B3-lineage viruses, with a two-peaked age distribution in children and the elderly.

Seasonality and climate

Enteroviruses as a group peak in summer in the United States. A 2018 study in PNAS using CDC surveillance data from 1983 to 2013 found that the peak typically falls between July and September, that the seasonal pattern resembled that of historical polio, and that climate, but not demography, was likely to drive it, with dew point temperature alone explaining roughly 30% of the variation in transmission intensity (Pons-Salort et al., 2018). That study covers non-polio enteroviruses broadly, not EV-D68 alone, so it describes the seasonal backdrop rather than the two-year rhythm.

EV-D68 compared with polio and the common cold

Comparisons across the enterovirus genus help explain why a respiratory virus can sometimes reach the nervous system.

Feature	EV-D68	Poliovirus	Rhinovirus
Main site of illness	Respiratory tract	Gut, then nervous system in a minority	Upper respiratory tract
Entry molecule	Sialic acid (established); other receptors under study	CD155 (polio receptor)	ICAM-1 or other receptors, depending on type
Paralysis	Rare (AFM, strongly associated)	Yes (poliomyelitis)	Not a feature
Vaccine	None licensed	Yes (oral and injected)	None
Typical season	Summer and fall	Summer and fall historically	Year-round with seasonal peaks
Treatment	Supportive only	Supportive only	Supportive only

Table 2 is a simplification. Poliovirus and rhinoviruses are well studied, and their receptors are textbook knowledge, while the EV-D68 receptor landscape is still being mapped.

Who is at risk?

According to the CDC, infants, children, and teenagers are most likely to become infected and ill because they lack prior immunity. Adults can be infected but are more likely to have no or mild symptoms. Children with underlying medical conditions may be at higher risk of severe illness, and children with asthma may be at higher risk of severe symptoms.

Severe respiratory disease and AFM are different outcomes. The 2014 hospitalized patients had a median age of 5, while the national AFM cohort had a median age of 7.1, and the 2016 European series had a median age of 3.8. These numbers describe who was diagnosed in particular outbreaks, so they should not be read as fixed rules about who can be affected.

Adults are not immune from the virus. The 2022 genomic analysis described above found an older, bimodal age pattern for A2-lineage infections. Even so, AFM remains overwhelmingly a childhood problem: the CDC reports that more than 90% of cases occurred in young children.

How doctors diagnose and manage it

Diagnosis of EV-D68 relies on laboratory tests of respiratory specimens that can identify the virus type, since standard panels often report only "rhinovirus/enterovirus" without further typing. The European series found that 99% of EV-D68-positive samples reported by 16 laboratories came from respiratory specimens, which also explains why the virus is rarely found in CSF.

Treatment is supportive. The CDC says there is no specific treatment or antiviral for EV-D68, and that people with serious respiratory illness may need hospitalization and intensive supportive care. There is also no vaccine. For AFM, the CDC notes that treatment is individualized and may include physical and occupational therapy. Because evidence on drugs for AFM is limited, decisions about any medication belong with the child's neurology team.

Prevention is general. The CDC points families to its Respiratory Virus Guidance, which includes practical steps such as washing hands, staying home when sick, and cleaning high-touch surfaces. People with asthma should keep their management plan current. For a broader look at how the immune system handles respiratory viruses, see how the human immune system fights viruses, step by step.

Common misconceptions

"EV-D68 is the same as polio." It is a relative, not the same virus. Poliovirus is a different enterovirus with its own receptor, a vaccine, and a long history of paralysis in unvaccinated children. EV-D68 is primarily a respiratory virus, and AFM after infection is uncommon.

"Every EV-D68 infection risks paralysis." The CDC describes AFM as uncommon, and most infections cause mild or no symptoms. The 2014 national count of 120 AFM cases occurred alongside an outbreak with many more infections than were ever tested.

"It only happened in 2014." Published reports document EV-D68 activity and AFM clusters in Europe in 2016, a US AFM increase in 2018, European re-emergence in 2021, and a US pediatric respiratory increase in 2022. The CDC page on the virus notes that enterovirus season recurs each year.

"A vaccine will arrive soon." The CDC says no vaccine is available. Researchers are studying the virus's capsid and antibody targets, but a licensed product is not in use. Because the virus keeps evolving, designing one that works across lineages is a real scientific challenge.

"Paralysis always heals." Outcomes vary. Some children improve, but a review of US cases found that most had residual weakness a year or more after onset, and the 2016 European series found only 3 of 29 patients recovered fully.

Open questions worth watching

Several uncertainties remain. Researchers do not know why only a small fraction of infected children develop AFM, whether certain lineages are more neuropathic, or how often adults experience subclinical reinfection that keeps population immunity patchy. The receptor story is still being refined, so the molecular picture of how the virus enters respiratory and nerve cells continues to develop.

Surveillance is the practical answer. Wastewater testing, sentinel respiratory surveillance, and laboratory typing of rhinovirus/enterovirus positives can catch an upswing earlier than hospital admissions alone. The CDC's 2022 report is a good example: clinicians in several areas flagged more hospitalizations of children with severe rhinovirus or enterovirus illness in August, and national laboratory and emergency department data showed the same upswing. The same alertness is why clinicians are reminded to consider AFM in any child with new limb weakness, especially after a respiratory illness or fever.

What this means

EV-D68 shows how a virus can look familiar and still surprise us. For nearly 50 years it was a laboratory curiosity, confirmed in only 699 people worldwide; then a single late-summer outbreak revealed a respiratory pathogen with a strong link to severe asthma exacerbations and a rare but devastating association with paralysis. Evidence for causation is strong in animals and strong epidemiologically in humans, but it remains indirect in individual patients because the virus is almost never found where the damage occurs.

For families, the takeaway is calm and practical rather than alarming. Most EV-D68 infections are ordinary respiratory illnesses. Children with asthma deserve attention to their action plans during enterovirus season, and any child with sudden limb weakness, trouble swallowing, or facial droop warrants immediate medical care, because early rehabilitation may improve outcomes. For scientists, the unanswered questions about receptors, lineages, and immunity make EV-D68 one of the more instructive emerging respiratory viruses to watch, alongside better-known threats such as influenza and adenovirus.

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Frequently Asked Questions

Q: What is Enterovirus D68 and why does it matter? A: EV-D68 is a respiratory virus in the same genus as poliovirus. It usually causes cold-like illness, but in 2014 it caused a large US outbreak of severe breathing problems in children, and it has been strongly linked to acute flaccid myelitis (AFM), a rare condition causing sudden limb weakness.

Q: Does EV-D68 definitely cause acute flaccid myelitis? A: The evidence is strong but indirect. In the national 2014 analysis, EV-D68 was found in the CSF of only one patient, and that sample was contaminated with blood. Epidemiology, a Bradford Hill analysis, and mouse experiments support causation, but proof in any individual child is usually out of reach.

Q: Why do children with asthma get sicker? A: In the 2014 investigation, children with a history of asthma or reactive airway disease were more likely to need intensive care (66% vs 51%) and ventilator support (32% vs 24%). Narrowed, reactive airways appear to have less reserve when a virus inflames the lining.

Q: Is there a vaccine or specific treatment for EV-D68? A: No. The CDC states there is no vaccine and no specific antiviral. Care is supportive, including oxygen and hospital care for severe breathing problems, and for AFM it focuses on individualized rehabilitation such as physical and occupational therapy.

Q: Does EV-D68 really cycle every two years? A: US AFM cases rose in 2014, 2016, and 2018, which suggests a rhythm, but the pattern was disrupted by COVID-19 measures and re-emerged in Europe in 2021 and in the United States in 2022. Waning immunity, new susceptible children, and viral evolution are all proposed contributors, and no single explanation is settled.

Q: How is EV-D68 different from polio? A: Both can damage motor neurons in the spinal cord, causing flaccid weakness. Poliovirus uses its own receptor, a vaccine exists, and it is a gut-associated virus. EV-D68 spreads mainly through the respiratory tract, uses sialic acid for cell entry, and is not preventable by vaccine.

Q: What should parents watch for? A: According to the CDC, signs of AFM include sudden weakness in an arm or leg, loss of muscle tone and reflexes, neck or limb pain, trouble swallowing or speaking, trouble moving the eyes, drooping eyelids, and facial weakness. These need urgent medical attention.

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Sources

• Centers for Disease Control and Prevention. Enterovirus D68 (about). https://www.cdc.gov/non-polio-enterovirus/about/ev-d68.html
• Centers for Disease Control and Prevention. About Acute Flaccid Myelitis. https://www.cdc.gov/acute-flaccid-myelitis/about/index.html
• Midgley CM, et al. "Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014)." Lancet Respir Med. 2015;3(11):879-887. https://pubmed.ncbi.nlm.nih.gov/26482320/
• Holm-Hansen CC, Midgley SE, Fischer TK. "Global emergence of enterovirus D68: a systematic review." Lancet Infect Dis. 2016;16(5):e64-e75. https://pubmed.ncbi.nlm.nih.gov/26929196/
• Sejvar JJ, et al. "Acute flaccid myelitis in the United States, August-December 2014: results of nationwide surveillance." Clin Infect Dis. 2016. https://pubmed.ncbi.nlm.nih.gov/27318332/
• Messacar K, et al. "Acute flaccid myelitis: a clinical review of US cases 2012-2015." Ann Neurol. 2016. https://pubmed.ncbi.nlm.nih.gov/27422805/
• Hixon AM, et al. "A mouse model of paralytic myelitis caused by enterovirus D68." PLoS Pathog. 2017. https://pubmed.ncbi.nlm.nih.gov/28231269/
• Dyda A, et al. "The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68): what is the evidence for causation?" Euro Surveill. 2018. https://pubmed.ncbi.nlm.nih.gov/29386095/
• Ma KC, et al. "Increase in acute respiratory illnesses among children and adolescents associated with rhinoviruses and enteroviruses, including enterovirus D68, United States, July-September 2022." MMWR. 2022. https://pubmed.ncbi.nlm.nih.gov/36201400/

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• Poliovirus: How It Works and Why It Paralyzes
• Rhinovirus and the Common Cold Explained
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