Despite the tremendous work of the Global Polio Eradication Initiative (GPEI), polio is still a serious disease in many parts of the world. Though the eradication effort succeeded with wildtype poliovirus everywhere other than Afghanistan and Pakistan, many countries still struggle with other strains of poliovirus and polio-like diseases caused by various enteroviruses.
Polio manifests as poliomyelitis, with distinct paralysis in the extremities spreading to the truncal and respiratory muscles. Alternatively, polio-like diseases are comparable clinical manifestations without detection of polioviruses. These diseases can have various causes, with enteroviruses – a family related to polioviruses – being one of the main culprits.
Thea Kølsen Fischer
The existing surveillance of non-polio enterovirus is sporadic at best and no global system is currently tracking the spread of these viruses or the number of people hospitalized due to them each year. This means that infection rates for non-enterovirus are local or outbreak based, which was shown in Europe’s increased cases of severe and fatal neonatal infections with echovirus 11 (E11) in 2022 and 2023 (1).
Unfortunately, a lot of prevailing belief among healthcare professionals is that poliovirus is associated with previous epidemics and remains in the history books with black and white photos from the 1950s. But this perception is far from reality. In fact, some people reading this article might unknowingly be infected with polio. Of course, some areas of the world still consider polio a great concern – especially developing countries with low vaccination coverage. This is evident in Afghanistan and Pakistan, where poliovirus remains an epidemic.
Caroline Klint Johannesen
Past outbreaks
In recent years, we’ve also seen outbreaks of vaccine-derived poliovirus (VDPV) in areas with low vaccination rates (2), such as VDPV type 2 in the Sub-Saharan African region and VDPV type 1 in the Democratic republic of Congo and Madagascar in 2023. Of course, vaccination campaigns and surveillance efforts continue to detect and respond to outbreaks of polio in hopes of eradicating the threat of the disease.
Another enterovirus strain that continues to plague the world is EV-A71, causing similar paralysis-like disease as polio in the 21st Century, which was first detected in the US in the 1960s. In Asia, the virus caused large outbreaks of hand, foot, and mouth disease (HFMD) in children, with severe cases causing neurological and cardio-pulmonary illnesses, and sometimes death.
In 2015, there was a significant change when a strain of EV-A71 was detected with major genetic changes following recombination with other enteroviruses. Before the COVID-19 pandemic, this new strain caused outbreaks of encephalitis and other neurological diseases (such as AFM, AFP, and acute meningitis) in Spain (2016) and France (2016, 2019). In the present day, this new virus continues to circulate across Europe and has been detected in Asia and North and South America.
But it’s not only EV-A71 that’s taking the world by storm. EV-D68 has always been present but was overlooked due to its respiratory nature. While most non polio enteroviruses are commonly detected in feces, EV-D68 is one of few that targets the respiratory system. This makes samples like nasopharyngeal aspirates the best for detecting EV-D68, but current surveillance systems for poliovirus rarely test respiratory samples for enteroviruses – limiting detection.
It wasn’t until respiratory surveillance and diagnostic testing included enterovirus testing and typing that EV-D68 gained attention. The increased detection of EV-D68 in AFM cases in 2014 (3) and the COVID-19 pandemic led to more testing and typing of respiratory samples for enteroviruses. New EV-D68 lineages have been observed over time, but it's unclear if they are linked to more severe illnesses.
Kim Benschop
Enterovirus diagnostics today
But why are we still struggling with enterovirus diagnostics? In the past, we’ve used laborious and time-consuming cell culture methods, followed by type identification in neutralization assays using a range of specific antisera. Over the past few decades, we’ve used faster and more sensitive molecular methods, improving speed and sensitivity of enterovirus detection, but challenges remain. Despite good sensitivity in molecular diagnostics of patient specimens, the specificity of differentiating enteroviruses from closely related rhinoviruses and enterovirus type identification requires more extensive genome sequence analysis.
Over 110 different non-polio enteroviruses are known to infect humans. With rapidly changing and diverse genetics, this makes it difficult to develop antivirals. With this in mind, new approaches targeting different viral or cellular components could be broad-spectrum and less prone to drug resistance. It’s also important to note that over 90 percent of all viral meningitis cases in infants under three months old and the most severe enterovirus infections occur in vulnerable newborns. Therefore, the safety and delivery of antivirals for these populations must be carefully considered.
Various studies have shown that certain enterovirus types might present a challenge, which increases demand for fast and reliable enterovirus differentiation and type identification. Looking ahead, The European Non-Polio Enterovirus Network (ENPEN) network has already taken the first step towards improved diagnostic accuracy and is writing an up-to-date guideline on diagnostic and characterisation of enteroviruses. This guideline reflects the shift from slow, labor-intensive virus-culture methods to innovative molecular techniques.
Heli Harvala
The next generation of diagnostics
The next step involves implementing high-throughput (complete) genome sequencing to quickly identify any enterovirus type. Many university hospitals are equipped for next-generation sequencing, allowing them to detect and characterize enterovirus strains from diagnostic samples. It's crucial to share these methods and data across the community.
As genomic diagnostics advance, we should also recognize the importance of maintaining specific diagnostic skills, such as virus isolation and histopathological investigations, which are essential to studying newly emerging, less characterized, and rare enteroviruses.
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References
- M Grapin et al., Eurosurveillance, 28, 22 (2023). PMID: 37261730.
- Global Polio Eradication Initiative (2024). Available at: https://polioeradication.org/polio-today/
- S Kidd et al., Emerg Infect Dis, 26, 10 (2020). PMID: 32833616.
