Enteroviral Infections Pathogenesis, Clinical Manifestations, and Management

Introduction

Enteroviral infections are among the most common viral illnesses affecting humans globally, particularly in children. These infections are caused by enteroviruses, a genus within the Picornaviridae family, which includes polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses such as EV-D68 and EV-A71. Enteroviruses are non-enveloped, positive-sense single-stranded RNA viruses that primarily replicate in the gastrointestinal tract but can disseminate to other organs, leading to diverse clinical syndromes ranging from mild respiratory illness to severe neurological and cardiac complications. Their global impact, coupled with their potential to cause outbreaks, makes them an important subject of public health and medical research.

Virology and Pathogenesis

Enteroviruses are small, icosahedral viruses measuring approximately 30 nm in diameter. Their genome encodes structural proteins (VP1–VP4) forming the viral capsid and non-structural proteins involved in replication and immune evasion. Transmission occurs mainly via the fecal–oral route, although respiratory transmission is also possible, particularly for coxsackievirus A and enterovirus D68.

After entering the host, the virus initially replicates in the lymphoid tissue of the pharynx and intestines. The infection may remain localized or progress to viremia, allowing the virus to reach secondary sites such as the central nervous system, heart, or skin. Host immunity, especially humoral responses mediated by neutralizing antibodies, plays a crucial role in limiting viral spread and conferring long-term protection. However, cellular immunity and innate immune responses, including interferon production, are also vital in controlling infection.

Epidemiology

Enteroviruses are distributed worldwide and cause seasonal outbreaks, particularly during summer and early autumn in temperate climates. Infants and young children are most susceptible due to immature immune systems and close contact in communal settings. Poor sanitation, overcrowding, and inadequate hygiene practices contribute to transmission, especially in developing countries. Non-polio enteroviruses account for millions of infections annually, with outbreaks of EV-A71 and EV-D68 posing significant challenges in Asia and North America.

The introduction of the poliovirus vaccine dramatically reduced poliomyelitis cases globally. However, other enteroviruses have emerged as significant pathogens. For example, enterovirus A71 is a major cause of hand, foot, and mouth disease (HFMD) in Asia, occasionally leading to severe neurological complications. Similarly, enterovirus D68 has been linked to outbreaks of respiratory illness and acute flaccid myelitis (AFM).

Clinical Manifestations

Enteroviral infections exhibit a wide spectrum of clinical manifestations depending on the virus type, host immune status, and target tissues. Common clinical presentations include:

1. Mild Illnesses:
   • Herpangina – caused mainly by coxsackievirus A, characterized by vesicular lesions on the soft palate and tonsillar pillars.
   • Hand, foot, and mouth disease (HFMD) – primarily caused by coxsackievirus A16 and enterovirus A71, presenting with vesicular lesions on hands, feet, and oral mucosa.
2. Respiratory Diseases:
   Enterovirus D68 has been associated with outbreaks of severe respiratory infections, especially in children with asthma or chronic respiratory conditions.
3. Neurological Complications:
   • Aseptic meningitis – commonly caused by echoviruses and coxsackieviruses, presenting with headache, fever, and neck stiffness.
   • Encephalitis and acute flaccid paralysis (AFP) – rare but serious complications, resembling poliomyelitis.
   • Acute flaccid myelitis (AFM) – linked to enterovirus D68, leading to limb weakness and paralysis.
4. Cardiac and Muscular Diseases:
   • Myocarditis and pericarditis – typically caused by coxsackievirus B, resulting in chest pain, arrhythmia, and in severe cases, heart failure.
   • Pleurodynia (Bornholm disease) – characterized by severe chest or abdominal pain due to coxsackievirus B infection.
5. Neonatal and Systemic Infections:
   Neonates are particularly vulnerable to severe enteroviral infections due to limited maternal antibody protection. Systemic infections may lead to myocarditis, hepatitis, or meningoencephalitis with high mortality.

Diagnosis

Diagnosis of enteroviral infections is primarily based on clinical presentation and laboratory confirmation. Laboratory methods include:

• Polymerase Chain Reaction (PCR):
  Real-time reverse transcription PCR (RT-PCR) is the gold standard for detecting enteroviral RNA in cerebrospinal fluid (CSF), blood, throat swabs, or stool samples.
• Viral Culture:
  Although historically used, culture methods are less sensitive and time-consuming compared to molecular assays.
• Serology:
  Detection of virus-specific IgM or rising IgG titers may assist in diagnosis, especially in retrospective studies.
• Imaging:
  MRI can be useful in identifying central nervous system involvement, particularly in cases of AFM or encephalitis.

Management and Treatment

Currently, there is no specific antiviral therapy for most enteroviral infections; management is largely supportive. This includes hydration, pain control, and antipyretics for mild cases. Severe infections, especially those involving the central nervous system or heart, require hospitalization and intensive supportive care.

Pleconaril, an antiviral that targets the viral capsid, showed promise against enteroviruses in clinical trials but has limited approval due to resistance concerns. Other agents under investigation include capsid inhibitors and viral protease inhibitors. Intravenous immunoglobulin (IVIG) has been used in severe neonatal and chronic enteroviral infections with variable success.

Prevention and Control

Preventive measures focus on interrupting transmission and strengthening immunity:

1. Vaccination:
   • Poliovirus vaccines (OPV and IPV) are highly effective and have nearly eradicated poliomyelitis worldwide.
   • Vaccines against enterovirus A71 have been developed and licensed in China, showing significant efficacy in preventing severe HFMD.
2. Hygiene Practices:
   Regular handwashing, disinfection of contaminated surfaces, and avoidance of close contact with infected individuals are crucial for controlling outbreaks.
3. Public Health Surveillance:
   Surveillance programs help detect outbreaks early, allowing for timely public health interventions. Molecular typing of enteroviruses assists in tracking emerging strains and guiding vaccine development.

Complications

Severe enteroviral infections may result in lasting complications, including neurological sequelae such as paralysis or cognitive impairment, chronic myocarditis leading to dilated cardiomyopathy, and neonatal multi-organ failure. Early recognition and supportive management are essential in reducing morbidity and mortality.

Conclusion

Enteroviral infections represent a significant public health concern due to their widespread prevalence, diverse clinical manifestations, and potential for severe complications. While most infections are self-limiting, outbreaks of neurotropic and cardiotropic enteroviruses underscore the need for continued surveillance, vaccine development, and public awareness. Advances in molecular diagnostics have improved detection, but the lack of specific antiviral therapy highlights the importance of preventive strategies. Strengthening global surveillance and vaccine research remains vital to mitigate the burden of enteroviral diseases.

References

1. Pallansch, M. A., & Roos, R. P. (2013). Enteroviruses: Polioviruses, Coxsackieviruses, Echoviruses, and Newer Enteroviruses. In Fields Virology (6th ed.). Lippincott Williams & Wilkins.
2. Huang, C. C., Liu, C. C., Chang, Y. C., Chen, C. Y., Wang, S. T., & Yeh, T. F. (1999). Neurologic complications in children with enterovirus 71 infection. New England Journal of Medicine, 341(13), 936–942.
3. Holm-Hansen, C. C., Midgley, S. E., & Fischer, T. K. (2016). Global emergence of enterovirus D68: A systematic review. Lancet Infectious Diseases, 16(5), e64–e75.
4. Solomon, T., Lewthwaite, P., Perera, D., Cardosa, M. J., McMinn, P., & Ooi, M. H. (2010). Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infectious Diseases, 10(11), 778–790.
5. Verboon-Maciolek, M. A., Krediet, T. G., Gerards, L. J., et al. (2008). Severe neonatal enterovirus infections: Case series and review of the literature. Pediatrics, 122(5), e923–e928.
6. American Academy of Pediatrics. (2021). Red Book: Report of the Committee on Infectious Diseases (32nd ed.). American Academy of Pediatrics.

Tapparel, C., Siegrist, F., Petty, T. J., & Kaiser, L. (2013). Picornavirus and enterovirus diversity with associated human diseases. Infectious Genetics and Evolution, 14, 282–293.