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Parechoviruses: Past, present and future
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In this Ask the Experts feature, José R. Romero, MD, reviews what he hopes to learn about parechoviruses in the future.
Please discuss the history of human parechoviruses.
These viruses were first identified in the 1950s, when investigators were looking for strains of poliovirus. They were initially classified as enteroviruses and given the designation echoviruses 22 and 23. Early on, there were data from a number of different investigators that indicated these particular viruses were not typical of the echoviruses that were identified at that time. They had a different cytopathology from the other enteroviruses. As the age of molecular virology came about, investigators began to realize that they didn’t act as the prototypical enterovirus — poliovirus — did in certain cell culture systems. Early genomic characterization demonstrated the human parechovirus genome was different from that of the enteroviruses.
José R. Romero
When molecular technology really took off and investigators had the opportunity to sequence their genomes to figure out what their RNA sequence and structure was, it was clear that they didn’t have a nucleotide sequence similar to the polioviruses or their cousins, the enteroviruses. Around the turn of the century, a number of investigators suggested they be placed in a genus unto themselves; thus were born these new viruses, parechoviruses.
Parechoviruses are not detected through the routine cell cultures that we use, so they were hidden for a long time. With the development of molecular methods for detection of parechoviruses, came an explosion of new isolates. It is likely that they are going to find more than the 16 that have been identified already. We suspect that there will be a significant increase in these viruses in the near future as more are identified. We are starting to look for them specifically.
How will identifying these viruses impact the clinician?
Many of us have seen babies who we suspect have an enterovirus infection. These infants had fevers or aseptic meningitis, for example. But tests for enteroviruses would come back negative. We wondered why. Maybe the amount of enterovirus in the spinal fluid was so low that it couldn’t be detected through current methodology. Or perhaps, it is possible that some or many of these infants had parechovirus infections. These viruses would not be detected by tests used to detect the enteroviruses.
More accurate identification of the parechoviruses will add to our knowledge of the different causes of aseptic meningitis in infants and children. Parechoviruses account for about, on average, 5% of all cases of aseptic meningitis in infants in the United States and in other parts of the world where there are other sites that have begun to detect them. If they can be diagnosed, the impact will be shorter hospital stays, less antibiotic use and lower actual health care costs.
Identifying these viruses will also add to our body of knowledge of certain severe encephalitis cases in neonates. Among the most severe disease comes from the parechovirus group. There is no therapy for it, but we can begin to at least put a name on some of the causes of severe encephalitis in neonates. Further studies of these cases of encephalitis may also allow us to offer better prognostic predictions to the parents and, perhaps, begin early intervention in order to maximize their outcome.
Better identification will also allow us to see if these viruses play a role in other diseases. So, in defining them, we will be able to better manage children suffering infections caused by the parechoviruses.
What about the costs of identification and diagnosis?
Because many of the parechoviruses grow poorly in cell culture, detection of the parechoviruses relies on the use of nucleic amplification tests such as reverse transcription-polymerase chain reaction (RT-PCR). If you incorporate this diagnostic test in a RT-PCR assay at the same time you are diagnosing enteroviruses, it should not add tremendously to the cost. We can now identify enteroviruses in the spinal fluid, blood and host of other body fluids and tissues. It would not be much more to add a specific test for the parechoviruses. There would be a cost involved, but it has been shown over and over again that early detection of enteroviral infections that cause central nervous system (CNS) infections lowers the hospital cost, antibiotic use and health care cost in general because you are able to get the child out of the hospital quickly. Most infections caused by enteroviruses are self-limited and have a favorable outcome.
The same appears to be true of the parechoviruses. So if we identify an enterovirus infection in an infant or child and they are doing well, we can send them home in a day, instead of 3 or 4 days. A similar approach can be taken with the parechoviruses.
Could you highlight the differences between CNS infections and other infections associated with human parechoviruses from those caused by the enteroviruses?
One of the characteristics of parechovirus infections is that the vast majority, more than that seen with the enteroviruses, occur in children aged younger than 2 years. Few cases seem to occur in older children and adults.
The CNS disease most commonly associated with the parechoviruses is primarily aseptic meningitis, which is generally a benign viral disease. The majority of cases are due to human parechovirus type 3. The overwhelming majority of individuals with aseptic meningitis will recover completely. It presents clinically similarly to enteroviral aseptic meningitis. However, the findings in the cerebrospinal fluid (CSF) are different. Unlike the enteroviruses, where most cases have a CSF pleocytosis, in parechovirus aseptic meningitis, the CSF cell count and protein concentration is normal in most cases. An evaluation of reports seeking the presence of parechovirus genome in archival CSF specimens showed that it was found in 2% to 7% of samples — as opposed to 5% to 25% of enteroviruses samples. It should be kept in mind that considerable annual variation may be observed in the prevalence of CSF specimens that test positive for parechovirus (0% to 17%), depending on the study.
The other major syndrome within the CNS is encephalitis. Among this group of viruses, parechovirus type 3 tends to cause profound neurologic insults to babies who become infected around the time of birth. Encephalitis caused by parechoviruses tends to be a much more severe disease that is not generally seen with the enteroviruses. It is a unique syndrome.
The other CNS manifestation of parechovirus is acute flaccid paralysis, which is like that caused by the polioviruses, but this is very rare.
As for the other diseases caused by the parechoviruses, that is where it is a little confusing. In part, this is because we have not actively sought to identify them and, in part, because we are just beginning to understand their epidemiology. A comparison of symptoms from longitudinally followed infants showed that no symptom was significantly associated with parechovirus detection in stool when compared with children not shedding virus. So we are not quite sure if these viruses actually are a major cause of epidemic gastrointestinal (or respiratory) disease.
A European study linked them to endemic cases of community gastroenteritis but not epidemic outbreaks of disease, and it appears to be restricted to infants and young children. Similar confusion exists as to their role in respiratory diseases. A large Scottish study analyzed respiratory specimens from 2,200 patients and detected parechovirus in 1%. In counterpoint, reports for different parts of the world, including the United States, have detected parechoviruses from respiratory samples. So, broadly speaking, there seems to be no specific association between parechovirus and any specific gastrointestinal or respiratory syndrome.
Reports of parechoviruses in association with other conditions do exist, including undifferentiated febrile illness in neonates and infants; hemorrhage-hepatitis syndrome in neonates; necrotizing enterocolitis; myocarditis; herpangina; and sudden unexplained infant death. However, further studies are necessary to conclusive link them with many of these. — by Rob Volansky