Parechovirus on the brain

Two recent papers have added to growing recognition that long-term neurological outcomes can follow severe parechovirus (HPeV) infection of the central nervous system (CNS), in the very young.[1,2]

The first HPeVs to be discovered (formerly classified as enteroviruses, Echovirus 22 and Echovirus 23) were mostly found to cause infections of the gut and airways. Seldom these HPeVs thought to threaten the central nervous system. This comment from a 1998 study nicely summarizes this…

“..EV22 causes more gastrointestinal and respiratory but fewer CNS signs and symptoms than, for example, typical EVs. Most EV22 infections are still probably mild or asymptomatic. However, our knowledge about EV22 and EV23 infections may be rather incomplete since these viruses were only recently recognized to be biologically different from other enteroviruses”

HPeV-3 has our attention

However, the next one of the 17 HPeVs we know of today,[9] has been increasingly recognized as a different beastie.

What causes these differences remains unknown.

HPeV-3 was described in a 2011 study as the most commonly detected HPeV among over 4,000 cerebrospinal fluid (CSF) specimens taken from hospitalized children.[4] In a 2015 study, HPeV-3 was described as the most frequent single virus type to cause neonatal sepsis/meningitis in summer-autumn seasons since 2005 in the United States.[5]

It has been hypothesized that the increased findings of HPeV-3s are due to better testing methods, relatively recent introduction of the virus,  more recent changes to the virus, or a drop in the proportion of mums with antibodies to protect against HPeV-3 infection.[4] A Dutch study found that use of an HPeV-specific RT-PCR  (standard lab method to detect viruses) increased detection of a viral cause of newborn sepsis by 31%.[6] Testing is a big driver of us hearing more about HPeV-3 cases.

Two recent studies

Study 1.

One of two recent studies describes the course of a newborn male who became ill days after birth. Initially, with acute gut disease, the newborn developed sepsis (system-wide inflammation) a few days later and was diagnosed with meningitis.[1] No bacteria were identified in the blood, urine or CSF but HPeV-3 infection was diagnosed after detection of HPeV-3 RNA in the CSF and faeces using RT-PCR.

At 37 weeks, no abnormal neurological findings were apparent. After a year, an assessment found that his gross motor skills (GMF) were delayed (fine motor skills, communication and social-emotional development were normal). GMF developmental delay became more obvious at 2-years of age (yoa) as did delays in social-emotional development and was diagnosed with cerebral visual impairment. At 5-yoa he developed epilepsy and was diagnosed with mild cerebral palsy.

Study 2.

The second study followed 91 children under 2yoa for 2 years. Of these children, 11 (13-114 days of age) had early HPeV CNS infections. All children were offered gross motor function (GMF) testing at 6, 12 and 24 months after becoming part of the study. Enrolled children had a fever, or signs of meningitis or other signs of infection, upon examination. None developed GMF anomalies.

The authors note that 90% of the children in this study were older at disease onset, less severely ill at presentation, had shorter hospitals stays and were not cared for in a paediatric intensive care setting.

I think these differences explain the absence of GMF differences. We know that most HPeV-3 infections do not end up in severe disease. And while true that we haven’t seen studies following up mild or non-CNS HPeV-3 disease, GMF anomalies are not as common as HPeV-3 infection must be to remain an endemic human virus.  We can make an educated guess here that it is disease severity – and the brain-damaging inflammation and cell damage associated with those more severe outcomes – that result in long-term neurodevelopmental issues among a small proportion fo CNS infections. 

The need to include HPeV testing and follow up of newborn meningitis and sepsis-like illness

 

HPeV (Kalynych et al [12]

Reports usually describe no short-term developmental issues following most HPeV-3 infections. But recent Australian studies have solidified the importance of following up certain young children with CNS disease due to severe  HPeV-3 infection.[10,11]

There was already past evidence of neonatal brain injury brain alongside detection of HPeV but now there’s a growing body of evidence that highlights the need for professional follow-up and support of cases with CNS symptoms and sepsis.[11] This is important considering that HPeVs now make a sizable contribution to sepsis-like illness and meningitis in very young children.[6] This association has been described in the literature for a decade and more.[6]

The inclusion of laboratory testing and careful follow-up evaluation by a paediatrician is likely to apply for other acute childhood viral infections that cause systemic infection and inflammation as much as it is clearly essential for HPeV cases. 

If there is any good news here it is that GMF developmental delay only seems to be associated with the most severe of HPeV-3 infections of the CNS; a small proportion of total HPeV infections.

References…

  1. Human Parechovirus Meningitis with Adverse Neurodevelopmental Outcome: A Case Report
    https://www.ncbi.nlm.nih.gov/pubmed/29561512
  2. Longitudinal Association Between Human Parechovirus Central Nervous System Infection And Gross-motor Neurodevelopment in Young Children
    https://www.ncbi.nlm.nih.gov/pubmed/29601457
  3. Diagnosis and Epidemiology of Echovirus 22 Infections
    https://www.ncbi.nlm.nih.gov/pubmed/9675466
  4. Comparison of human parechovirus and enterovirus detection frequencies in cerebrospinal fluid samples collected over a 5-year period in Edinburgh: HPeV type 3 identified as the most common picornavirus type
    https://www.ncbi.nlm.nih.gov/pubmed/21412796
  5. Human Parechovirus 3: The Most Common Viral Cause of Meningoencephalitis in Young Infants
    https://www.ncbi.nlm.nih.gov/pubmed/26188604
  6. Human Parechoviruses as an Important Viral Cause of Sepsislike Illness and Meningitis in Young Children
    https://academic.oup.com/cid/article/47/3/358/315141
  7. Cluster of human parechovirus infections as the predominant cause of sepsis in neonates and infants, Leicester, United Kingdom, 8 May to 2 August 2016
    https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2016.21.34.30326
  8. Human parechovirus causing extensive white matter brain injury in a neonate
    https://www.ncbi.nlm.nih.gov/pubmed/18825694
  9. Parechovirus A
    http://www.picornaviridae.com/parechovirus/parechovirus_a/parechovirus_a.htm
  10. Severe parechovirus infection in infants: adding to the case for a role in later neurodevelopmental issues…
    http://virologydownunder.com/severe-parechovirus-infection-in-infants-adding-to-the-case-for-a-role-in-later-neurodevelopmental-issues/
  11. Parechovirus: an important emerging infection in young infants
    https://www.mja.com.au/journal/2018/208/8/parechovirus-important-emerging-infection-young-infants
  12. The Structure of Human Parechovirus 1 Reveals an Association of the RNA Genome with the Capsid
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719609/

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