Enterovirus D68: Symptoms, Types, Causes and Treatment

Enterovirus D68 (EV-D68) has gained international attention over the past decade as an emerging respiratory virus, with outbreaks leading to severe illness in children and, in rare instances, neurological complications like acute flaccid myelitis (AFM). This article provides a comprehensive, evidence-based overview of EV-D68, synthesizing the latest research on its symptoms, types, causes, and current and emerging treatment strategies.

Symptoms of Enterovirus D68

Enterovirus D68 primarily affects the respiratory system, but its full clinical spectrum is broader and sometimes severe. Since the major outbreaks in 2014, clinicians and parents alike have grown more aware of its diverse manifestations.

Symptom	Frequency/Pattern	Severity	Source
Wheezing	Common in children	Mild to severe	3 4 8
Asthma Exacerb.	Frequent in those w/ asthma	Can require ICU	1 3 4
Bronchiolitis	Especially in young kids	Moderate to severe	3 8
Pneumonia	Not uncommon	Moderate to severe	3 8
Acute Flaccid Myelitis (AFM)	Rare, post-respiratory	Severe, polio-like paralysis	1 2 5 9 12 13
Meningitis/Encephalitis	Rare	Severe	5 6 9

Table 1: Key Symptoms

Common Respiratory Symptoms

EV-D68 is notorious for causing respiratory illness ranging from mild cold-like symptoms to severe respiratory distress. Children, especially those with pre-existing asthma, are at higher risk for severe symptoms such as:

• Wheezing and shortness of breath: These are hallmark symptoms, especially notable during outbreaks. Children with asthma are disproportionately affected, often requiring hospitalization or intensive care 1 3 4 8.
• Asthma exacerbations: EV-D68 is strongly associated with sudden and severe asthma attacks. In some outbreaks, nearly half of infected children presented with asthma exacerbations, sometimes necessitating mechanical ventilation 3 4.
• Bronchiolitis and pneumonia: Young children commonly develop lower respiratory tract infections like bronchiolitis and pneumonia, which can be moderate to severe and may lead to increased oxygen demand 3 6 8.

Neurological Complications

Though rare, EV-D68 can cause severe neurological manifestations:

• Acute Flaccid Myelitis (AFM): This polio-like syndrome presents as sudden limb weakness, sometimes accompanied by cranial nerve dysfunction or bulbar symptoms. AFM is often preceded by a respiratory illness and disproportionately affects children 2 5 9 12 13.
• Meningitis and encephalitis: Less commonly, EV-D68 can lead to central nervous system infections, presenting as headache, altered mental status, or seizures 5 6 9.

Severity and Risk Factors

• Children under five and those with underlying lung disease (especially asthma) are most susceptible to severe EV-D68 disease 1 3 4 8.
• Severe cases may require intensive care, particularly during large outbreaks 3.
• Neurological complications, while rare, have been associated with long-term disability or even death in a small number of cases 2 9 13.

Types of Enterovirus D68

EV-D68, like many enteroviruses, exists in multiple genetic forms, known as clades and subclades. Tracking these types is crucial for understanding outbreaks and guiding diagnostic efforts.

Type/Clade	Geographic Spread	Outbreak Years	Source
Clade A	Early Asian outbreaks	Pre-2014	7
Clade B (B1, B2, B3)	US, Europe, China, Spain	2014, 2016, 2018	3 5 7 8 9 10
Clade D1	Europe, Spain	2017–2018	5 7

Table 2: Major EV-D68 Types

Genetic Diversity and Clades

• Clades A, B, and D: EV-D68 is divided into several clades based on genetic analysis, especially of the VP1 region. Clade B has further subdivisions like B1, B2, and B3 3 5 7 8 9 10.
• Evolution and Spread: The 2014 outbreak in the US was largely due to the B1 and B2 subclades, while subsequent outbreaks in Europe and China have seen the emergence of B3 and D1 5 7 8 10.
• Geographical Patterns: Clade B variants have been most widespread, causing outbreaks across North America, Europe, and Asia 3 5 7 8 10. Clade D1 emerged later, notably in Europe and Spain 5 7.

Why Do Types Matter?

• Outbreak prediction: Understanding clade circulation helps predict and monitor outbreaks.
• Vaccine and therapy development: Genetic variation may influence susceptibility to potential treatments and future vaccines 7 16 18.
• Potential for recombination: EV-D68 shows evidence of genetic recombination, which could lead to new strains with different clinical or epidemiological features 7.

Causes of Enterovirus D68

How does EV-D68 spread, and what makes certain individuals more vulnerable? Understanding the causes and transmission routes is key to prevention and control.

Factor	Description	At-Risk Population	Source
Respiratory Spread	Droplets, close contact	Children, especially <5; asthmatics	1 3 4 11 12
Sialic Acid Receptor	Required for cell entry	Universal; children more exposed	11
Immunity Gap	Lack of prior exposure, waning maternal antibodies	Young children, post-pandemic populations	13
Seasonal/Biennial Pattern	Outbreaks in late summer/fall, every 2 years	Population-wide	1 13

Table 3: Key Causes and Risk Factors

Transmission and Entry

• Respiratory Route: Unlike many other enteroviruses that primarily spread via the fecal-oral route, EV-D68 is mainly transmitted through respiratory droplets and close contact—more akin to rhinoviruses 1 3 4 11 12.
• Viral Entry Mechanism: The virus attaches to sialic acid receptors on the surface of respiratory epithelial cells, initiating infection 11.

Risk Factors

• Children: Young children, especially those under five, are most frequently affected, likely due to less developed immunity 1 3 13.
• Asthma and lung disease: Pre-existing respiratory conditions dramatically increase the risk of severe disease 1 3 4.
• Immunity gap: Outbreaks often follow periods where population immunity wanes, such as after birth cohorts are replenished or after pandemic interventions reduce virus circulation 13.
• Prematurity: Some studies suggest preterm infants may be at greater risk of severe respiratory complications 6.

Outbreak Patterns

• Biennial Peaks: Since 2014, EV-D68 outbreaks in North America and Europe have shown a tendency for biennial (every other year) peaks, often in late summer and early autumn 1 13.
• Influence of Pandemic Measures: Non-pharmaceutical interventions during COVID-19 suppressed the predicted 2020 EV-D68 outbreak but may have increased the subsequent pool of susceptible individuals, raising the risk for larger future outbreaks 13.

Treatment of Enterovirus D68

Currently, there is no approved antiviral therapy or vaccine for EV-D68. Treatment remains largely supportive, but promising research is underway.

Treatment	Mechanism / Use	Evidence/Status	Source
Supportive care	Oxygen, ventilation, ICU	Standard of care	1 3 4 12
IVIG	Neutralizing antibodies	Some benefit in animal models	14 16
Monoclonal Antibodies	Virus neutralization	Promising in animal studies; clinical trials needed	16 18
Antivirals (e.g., guanidine, quinolines)	Inhibit viral replication	Effective in mice; not yet human-approved	15 17
Steroids (e.g., dexamethasone)	Anti-inflammatory	May worsen outcomes in AFM	14

Table 4: Treatment Strategies

Supportive Care

• Mainstay of treatment: Most patients require only supportive care, including fluids, oxygen, and monitoring. Severe cases, especially those with respiratory distress or neurological symptoms, may need intensive care and mechanical ventilation 1 3 4 12.
• No specific antiviral: There are currently no licensed drugs or vaccines for EV-D68 12 15 16 18.

Immunoglobulin and Monoclonal Antibodies

• IVIG (Intravenous Immunoglobulin): Contains neutralizing antibodies and has shown benefit in animal models, reducing paralysis and viral load in the spinal cord 14. Its efficacy in humans, especially for AFM, is still uncertain.
• Monoclonal antibodies: Recent studies have isolated human and murine monoclonal antibodies with potent cross-clade neutralizing activity. These have protected mice from both respiratory and neurological EV-D68 disease and are promising candidates for future human therapy 16 18.

Antiviral Drugs

• Guanidine: Demonstrated efficacy in mouse models, reducing viral replication and preventing progression to severe disease 17.
• Quinoline analogues: Some newly developed compounds have shown potent antiviral activity in lab and animal studies, warranting further investigation 15.

Ineffective or Harmful Therapies

• Steroids (e.g., dexamethasone): Contrary to their use in other neurological or inflammatory conditions, steroids have been shown to worsen outcomes in animal models of EV-D68-associated AFM, increasing viral load and mortality 14.
• Fluoxetine: Despite in vitro activity, did not improve outcomes in animal models 14.

Future Directions

• Vaccine development: No vaccines are currently available, but preclinical work is ongoing 12 16 18.
• Immunological surveillance: Enhanced real-time immune monitoring and rapid response pipelines are being advocated to facilitate the development of vaccines and therapeutics for EV-D68 and other pandemic threats 13.

Conclusion

Enterovirus D68 remains a significant global health concern, particularly for children and those with underlying respiratory disease. Its ability to cause both respiratory and neurological disease, coupled with a lack of specific treatments or vaccines, underscores the need for ongoing surveillance and research.

Key Takeaways:

• EV-D68 primarily causes respiratory illness, especially in children, with symptoms ranging from mild cold-like complaints to severe asthma, wheezing, and pneumonia.
• Neurological complications like acute flaccid myelitis (AFM), though rare, are severe and have lasting consequences.
• Multiple genetic clades (notably B1, B2, B3, D1) circulate globally, with shifting patterns during outbreaks.
• Transmission is mainly respiratory, facilitated by close contact and droplet spread. Children, especially those with asthma, are most at risk.
• Treatment is currently supportive; no approved antivirals or vaccines exist. Monoclonal antibodies and novel antivirals show promise in preclinical studies.
• Ongoing surveillance and research are vital to prepare for future outbreaks and to develop effective countermeasures.

By staying informed and supporting research, clinicians, public health officials, and caregivers can better protect vulnerable populations from the evolving threat of EV-D68.