Re-emergence of Parechovirus: 2017–2022 National Trends of Detection in Cerebrospinal Fluid

Abstract

Increasing parechovirus (PeV) infections prompted a Centers for Disease Control and Prevention Health Advisory in July 2022. We retrospectively assessed national PeV trends in cerebrospinal fluid and observed unexpected viral dynamics from 2020 to 2022 with regional variance. These findings may be due to mitigation strategies aimed at severe acute respiratory syndrome coronavirus 2. PeV testing can benefit ill patients, particularly children.

Parechoviruses (PeV) are nonenveloped RNA viruses in the Picornaviradae family that are transmitted by respiratory and fecal–oral routes [1]. Six species have been identified to date in the Parechovirus genus, though only Parechovirus A (PeV-A) causes disease in humans [2]. Most cases of PeV-A infection are subclinical, with minor respiratory or gastrointestinal symptoms. However, in infants <3 months old, PeV-A infection can cause severe diseases. These include a sepsis-like syndrome and meningoencephalitis, which may result in neurodevelopmental sequalae [1]. Severe PeV-A infections in adults have also been reported [3]. Differing PeV species and genotypes have varying epidemiologic dynamics. PeV-A3, the genotype that causes the majority of severe disease, usually circulates at a biennial cycle with peaks observed in even-numbered years [1, 4]. In July 2022, the US Centers for Disease Control and Prevention (CDC) issued a Health Advisory warning of increased PeV circulation in the United States, encouraging clinicians to include PeV in the differential diagnosis of infections presenting with fever, sepsis-like syndrome, or neurologic illness [5]. We concurrently reported 23 cases of PeV meningoencephalitis in infants aged 5 days to 3 months at Monroe Carrel Jr. Children's Hospital at Vanderbilt, diagnosed during April 12 to May 24, 2022, using a multiplex molecular panel (BIOFIRE® FILMARRAY® Meningitis/Encephalitis Panel (ME panel), bioMérieux) [6]. Although our report indicated a peak of PeV central nervous system (CNS) infections in young infants in our region, it was not clear whether this increased detection of PeV was occurring nationwide. Accordingly, we retrospectively investigated national epidemiologic trends of PeV detected in CSF specimens using data generated by the BIOFIRE ME panel.

METHODS

Counts for the total number of CSF ME panels and number of panels positive for PeV were collected by bioMerieux BIOFIRE® Syndromic Trends (Trend) and obtained on request from bioMérieux. Associated metadata included the testing week date and census region (Northeast, South, Midwest, or West) where the test was performed; no patient-level data or data on testing institutions were provided. Counts for the number of panels positive for Enterovirus (EV), a virus with comparable transmission routes and seasonal trends, and for HSV-2, a virus with differing transmission routes, were obtained as comparators [7, 8]. These viruses are also detected on this panel. Detection of PeV and EV was not expected to be limited by this assay, as the BIOFIRE ME panel is a Food and Drug Administration (FDA)–cleared multiplex molecular assay capable of detecting PeV-A serotypes 1–8, as well as all species and serotypes of EV. Weekly data obtained from Trends spanned January 1, 2017, to September 30, 2022. Percent positivity was calculated by dividing the number of tests positive for the target analyte by the total number of tests. For the purposes of this study, a major peak for PeV and EV was defined as reaching ≥10.0% positivity at any point or ≥3.0% positivity for ≥4 consecutive weeks. Minor spikes are defined as percent positivity above baseline but not meeting the definition of a major peak.

Statistical analyses were conducted using Microsoft Excel, version 16. Comparisons between different groups were performed using the Fisher exact test or chi-square test. Statistical significance was determined as P < .05.

RESULTS

A total of 75 665 BIOFIRE ME panel results were included in the Trends database during the study period. PeV was detected in 791 (overall positive rate of 1.05%). Detection of PeV in CNS specimens by time is presented in Figure 1A. A major peak began in May 2018 and persisted through November 2018, with minor spikes occurring in September 2017 and September 2019. PeV was not detected in this data set from the week beginning on May 2, 2020, until the week beginning on January 30, 2021. Thereafter, a minor spike was detected in April 2021, and a major peak began in April 2022.

Figure 1.

National positive rate of Parechovirus, Enterovirus, and herpes simplex virus 2 from a multiplex molecular meningitis/encephalitis panel from January 2017 to July 2022. A, Positive rate of Parechovirus by time. B, Positive rate of Parechovirus in “circulating” years. C, Positive rate of Enterovirus by time. D, Positive rate of herpes simplex virus 2 by time. E, Positive rate of Parechovirus in different regions by year. Data at the top of the columns are labeled as number of Parechovirus positive tests/number of total tests for each year. ^aIncomplete data for 2022; data from January 1 to September 31 were collected.

A major peak was expected in 2020 given the biennial epidemiology of PeV-A3. However, comparing the monthly positivity rate in even years with anticipated biennial PeV peaks reveals the absence of a peak in 2020 (Figure 1B). A major peak was detected in 2022, and the average positive rate of PeV from January 1 to September 30, 2022, is comparable with the same date range in 2018 (2.33% vs 2.21%; P > .05). However, the onset of the 2022 major peak was shifted to an earlier date range. The percent positivity was significantly higher from April 1 to June 30, 2022, than over the same dates in 2018 (2.89% vs 0.64%; P < .001). The 2022 positive rate remained high at 3.5% from July 1 to September 30, 2022.

We compared Trend data for the BIOFIRE ME panel for EV and HSV-2 to assess CSF positivity of viruses with similar (EV) and differing (HSV-2) transmission routes and virology. Annual major peaks of EV were observed in 2017, 2018, and 2019 (Figure 1C). Akin to PeV, transmission dynamics differed after 2019 as only spikes were present in 2020 and 2021. A developing major spike began in 2022. In contrast, detection of HSV-2 remained overall consistent with intermittent spikes throughout the study period (Figure 1D).

We further investigated the increase of PeV cases in different regions of the United States to determine if regional variation was present (Figure 1E). The patterns of PeV positivity in different regions from 2017 to 2022 are similar, with 2018 and 2022 being the most prevalent years. Consistent with national data, the predicted peak of PeV in 2020 was absent from all regions. The overall prevalence of PeV from 2017 to 2022 in the Northeast region was lower than all other regions. During this time period, the PeV positive rate was 0.71% (105/14 873) in the Northeast, compared with 1.09% (203/18 672; P < .001) in the West, 1.13% (310/27 343; P < .001) in the Midwest, and 1.20% (168/14 053; P < .001) in the South. Regional data per month spanning January 1–September 30, 2022 (Table 1), demonstrate that the majority of detected PeV from January 1 to May 31 clustered in the South and Midwest regions. Lower positivity was detected in the West, and almost no PeV was detected in the Northeast during the same period. From June 1 to September 30, positivity increased in the Midwest, West, and Northeast, whereas it decreased in the South.

Table 1.

2022 Positive Rate of Parechovirus in US Census Regions

	Positive Rate, %
	South	West	Midwest	Northeast
Jan	0.59 (3/512)	0 (0/439)	0.45 (2/449)	0 (0/231)
Feb	0.19 (1/526)	0 (0/392)	0 (0/432)	0 (0/171)
Mar	0.8 (4/497)	0 (0/366)	0.47 (2/426)	0.55 (1/181)
Apr	2.88 (20/695)	0.22 (1/450)	0.78 (4/513)	0 (0/225)
May	6.21 (35/564)	0.82 (3/367)	3.00 (13/433)	0 (0/163)
Jun	4.35 (27/621)	3.37 (13/386)	6.11 (30/491)	0 (0/138)
Jul	1.73 (13/751)	4.07 (22/541)	5.43 (30/552)	2.83 (6/212)
Aug	0.52 (3/580)	6.45 (26/403)	3.95 (17/430)	4.76 (8/168)
Sep	2.72 (14/514)	4.00 (17/425)	5.88 (27/459)	3.98 (8/201)

DISCUSSION

In the summer of 2022, the CDC raised concern for potentially increased numbers of severe PeV infections due to reports from health care providers in multiple states. Utilizing Trend data from CSF testing using a broadly employed and FDA-cleared multiplex molecular assay, we demonstrate increased detection of PeV nationwide in 2022 as compared with any year since 2018. We additionally demonstrate earlier PeV detection in 2022 compared with 2018, with regional variation of the positive rate.

We propose that epidemiologic measures beginning in 2020 in response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic led to the unexpected viral dynamics reported here. A PeV peak was expected in 2020 [1, 10], yet the case number of PeV CNS infections was dramatically reduced in that year as compared with prior years (Figure 1A, B). Notably, the same impact was also observed for detection of EV (Figure 1C), a similar virus in the Picornaviridae family with shared transmission routes. EV peaked annually from 2017 to 2019, but the pattern was disrupted in 2020 and 2021. No disruption in detection was observed for HSV-2, a dissimilar DNA virus in the Herpesviridiae family without seasonal peaks (Figure 1D) and presence in the CSF primarily due to reactivation of latent infection. The disruption of PeV and EV dynamics occurred concurrently with social distancing measures intended to limit the spread of SARS-CoV-2, suggesting that the transmission of these viruses was similarly influenced by these measures. In tandem with national relaxation of SARS-CoV-2 mitigation measures, PeV CNS infections began increasing as well. An earlier peak of PeV CNS infection was observed in the South and Midwest regions (Table 1), possibly due to quick relaxation of the measures in these regions. However, other factors beyond those intended to mitigate the spread of SARS-CoV-2 may have contributed to this trend. These include uneven distribution of PeV across the United States, regional climate variations, differences in population density, and reduced care-seeking behavior during the height of the coronavirus disease 2019 pandemic. Additional factors include more susceptible infants following the pandemic-related birth rate increase or potentially an “immunity debt” incurred by the relative lack of primary caregiver exposure to PeV.

Continued monitoring of this trend will benefit epidemiologic understanding and alert providers to PeV as a potential explanation for neonatal aseptic meningitis. Detection of PeV infection in young infants with fever and sepsis-like syndromes is beneficial for patient management. Several studies report a positive impact of PeV detection on shortening antimicrobial use in young infants [6, 9, 10]. In addition, neurodevelopmental delay can occur in young infants after severe PeV CNS infection [11, 12, 13]. The detection of PeV in these patients is therefore essential in identifying individuals that require close monitoring of neurodevelopment and who may benefit from possible early intervention. Additional research documenting long-term outcomes of neonates with PeV CNS infections is needed. PeV CNS infection is not a notifiable condition, though a local increase in detection could prompt focused infection prevention interventions to limit spread. Detecting PeV in infants is helpful for infection prevention purposes to prevent inpatient transmission [14].

This study provides an estimate of current and recent PeV CNS infection regionally in the United States, and by extension a view into transmission. However, this study is retrospective and not population based. It is limited by the lack of associated patient-level metadata including patient age, disease severity, and testing institution. However, we assume that patients undergoing lumbar puncture for CSF acquisition demonstrated signs and symptoms consistent with meningitis and/or encephalitis or underwent this procedure as a component of neonatal fever workup. Further, differing institutional testing practices could lead to incomplete data. As CSF pleocytosis can be absent from cases of PeV CNS infection in infants <3 months old [6], the incidence of PeV infection can be underestimated if CSF pleocytosis is used as an indicator for infectious disease testing. As such, some cases may have been missed if an ME panel was not ordered based on testing algorithms or if differing levels of diagnostic stewardship were employed. Additionally, this study was retrospective and focused on CNS infection. As such, it does not assess transmission, subclinical infection, or other clinical syndromes caused by PeV. The data were collected using a single assay and as such do not include PeV cases detected by other methods. Finally, the assay cannot determine the PeV genotype, though this is an ongoing area of research.

In conclusion, PeV CNS infections increased nationally in 2022, with seasonal variations between regions following a relative lack of expected infections in 2020. This may be due to variations in PeV transmission dynamics given the temporal correlation with initiation and relaxation of public health measures intended to limit spread of SARS-CoV-2. PeV testing should be considered in young infants with severe symptoms as detection of virus has implications for patient management and follow-up.