A Case Series of Infants 60 Days of Age or Younger With Human Parechovirus (PeV) Meningitis From a New York City Pediatric Emergency Department

Introduction

Starting in the late spring of 2022, there has been an outbreak of infants infected with human parechovirus (PeV). Parechovirus is a virus of the Picornaviridae family, often found in the gut and spread via the fecal-oral route. ¹ There are multiple strains of PeV, with the most prevalent strains being PeV-A1 and PeV-A3. ¹ The Center for Disease Control (CDC) has found that all of the specimens it has recently tested were PeV-A3, a strain that can result in severe manifestations of disease in infants less than 3 months old, including meningitis and encephalitis.^2,3 There are few case studies written about this virus, whether that be because it is a relatively new cause of morbidity and mortality in children, or because it has just started to be included in infectious testing panels in 2015. ⁴ In addition, it is unclear how this outbreak compares to prior seasons. ²

At one children’s hospital in Tennessee, there were only 7 reported cases of PeV from 2019 to 2021, but in April and May of 2022, there were 23 infants between the ages of 5 days and 3 months admitted to the hospital with PeV meningoencephalitis. Four (17%) of these patients were admitted to the intensive care unit and had a magnetic resonance imaging (MRI) brain performed, which all showed white matter diffusion consistent with typical PeV meningoencephalitis. Despite this, only 1 of the patients had seizures, and 1 will require future evaluation for possible late-onset hearing loss. ⁵ Prior studies have shown that long-term neurodevelopmental deficits have been reported in patients with PeV-A3 infections. ⁶ Since this PeV outbreak in Tennessee, the CDC has released a health advisory warning providers that the virus is spreading throughout the United States. ²

Methods

We conducted a retrospective chart review of all patients less than or equal to 60 days of age with a positive cerebrospinal fluid (CSF) polymerase chain reaction (PCR) panel (BioFire FilmArray Meningitis/Encephalitis Panel) for human PeV from one community hospital in Brooklyn, New York, between June 1, 2022, and August 15, 2022. The 60 days of age cutoff was based on the American Academy of Pediatrics (AAP) guidelines for evaluation of febrile infants, as patients in this age range typically undergo a laboratory workup for the investigation of sepsis. ⁷ The CSF PCR panel tests for multiple viral pathogens including PeV, but is not specific for which strain of PeV. It is routinely obtained as part of the febrile infant sepsis evaluation, as per AAP guidelines. ⁷ Information on age, gender, medical history, sick contacts, and symptoms at the time of presentation were collected from the patient’s charts. The pediatric emergency department (PED) and hospital courses were reviewed, including vital signs, examination findings, laboratory findings, interventions, and hospital length of stay. The study received institutional board review exemption status at our institution prior to data collection.

Results

Four patients tested positive for PeV on CSF PCR (Table 1). Two of the patients (patients #1 and 3) had CSF testing as they were less than 21 days old with a fever. Patient #2 was ill-appearing upon presentation, prompting CSF testing. Patient #4 initially had blood and urine cultures drawn at his first visit but then was called back to the PED the next day for a more extensive infectious workup including CSF testing after his urine culture resulted positive. Patient #3 had reported respiratory distress in the form of grunting at home, but had no evidence of respiratory compromise in the PED. Two of the 4 appeared well, while the other 2 (patients #2 and 3) were either ill-appearing or irritable. Two patients presented with a maculopapular rash and 2 with mottling, but no other major physical exam abnormalities were found, including weakness, hypotonia, or other neurologic deficits.

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Table 1.

Demographics and Results for Hospitalized Infants Tested Positive for Human Parechovirus Meningitis.

No. of patient	1	2	3	4
Age at PED presentation	8 days	33 days	20 days	54 days
Sex	Female	Male	Male	Male
Gestational status	Term	Term	Term	Term
Comorbid conditions	None	None	None	None
Symptoms at time of presentation	Fever, decreased feeding	Fever, crying, decreased feeding, tired-appearing, irritable	Fever, crying, grunting, tired-appearing	Fever
Household sick contacts	No	Yes	No	Yes
Temperature (°C)	38.4	38.2	38.9	39.1
Heart rate (beats per minute)	195	164	204	185
Respiratory rate (breaths per minute)	42	48	32	58
Oxygen saturation %	100%	95%	99%	97%
Positive PE findings	Diffuse maculopapular rash, irritable	Ill-appearing, mottled, cool lower extremities, macular rash on neck and chest	Mottled	None
WBC count (×103/uL)	5.04	3.39	3.62	3.74
Absolute neutrophil count (×103/uL)	1510	1590	1390	2980
Absolute lymphocyte count (×103/uL)	2220	1090	1470	5210
CRP (mg/L)	<2.9	<2.9	11.2	6.6
CSF PCR	Positive for parechovirus	Positive for parechovirus	Positive for parechovirus	Positive for parechovirus
CSF cell count	2	25	21	25
CSF glucose (mg/dL)	71	84	55	61
CSF protein (mg/dL)	255	50	80	80
Blood culture	Negative	Negative	Negative	Negative
Urine culture	Negative	>100 000 Enterobacter species	Negative	>100 000 Enterobacter cloacae
CSF culture	Negative	Negative	Negative	Negative
Respiratory pathogen PCR panel	Negative	Negative	Negative	Negative
Head ultrasound	No abnormal findings	No abnormal findings	Subependymal Cysts (sequela of prior GMH)	Not performed
Level of hospital care	PICU	General pediatric inpatient unit	PICU	General pediatric inpatient unit
Hospital LOS	6	6	4	3

Vital signs measured at triage on arrival to the PED.

Abbreviations: PED, pediatric emergency department; PE, physical exam; WBC, white blood cell; CRP, C-reactive protein; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; GMH, germinal matrix hemorrhage; PICU, pediatric intensive care unit; LOS, length of stay.

With regard to laboratory studies, 3 of the 4 patients were leukopenic with a white blood cell (WBC) count <5 K/uL and 2 had lymphopenia, with an absolute lymphocyte counts <1.75 K/uL; however, a third patient (patient #1) had a low lymphocyte count found on repeat laboratories the next day. All 4 had normal WBC counts at the time of discharge. On CSF studies, 1 patient had elevated protein level (normal for age is 35-189 mg/dL). Three of the 4 patients had elevated CSF cell counts (normal for age is <10 cells per mm³). ⁸

Two infants (patients #1 and #3) were transferred to the pediatric intensive care unit after initial admission to the general pediatric inpatient unit, one (patient #1) because of oxygen-level desaturation as low as 88%, and the other (patient #3) after developing respiratory distress with grunting. One patient (patient #2) was noted to be producing bloody stools, with a negative stool culture, and one other patient (patient #3) developed nonbloody diarrhea. None of the 4 patients had any neurologic deficits or were noted to have seizure activity. Three of the 4 patients had a head ultrasound performed. Only patient #3 had clinical findings, which were subependymal cysts that were thought to be sequela of prior germinal matrix hemorrhage, and repeat ultrasound 3 months later showed resolution of these cysts.

Overall, all 4 patients were febrile for 3 days during their hospitalization. All 4 had otherwise uneventful hospital courses with no further complications, and none of the 4 patients returned to our PED within 8 months of discharge.

Discussion

Historically, PeV has been associated with nonspecific presentations, physical exams, and laboratory findings. It manifests biennially, usually during the late summer and fall. Patients may present with fever and mild respiratory or gastrointestinal (GI) symptoms, or severe disease including seizures and other neurologic deficits.^3,4 All of the patients in this case series presented with fever, 2 presented with GI findings, and 2 presented with respiratory findings. The physical exam of patients with PeV may only reveal irritability and maculopapular rash and have been described as “red, hot, angry babies.” ³ Two of our infants presented with both irritability and a maculopapular rash, while the other 2 presented with neither. Historically, laboratory results include peripheral blood lymphopenia and CSF studies with elevated protein levels, lack of pleocytosis, and a positive viral panel for PeV. ⁴ Of the 4 patients in our case series, 3 of the 4 had lymphopenia and CSF pleocytosis, and only 1 had elevated CSF protein levels.

Fever, respiratory and GI findings, maculopapular rash, lymphopenia, and elevated CSF protein levels are all commonly seen in viral infections and are not specific to PeV. What may separate PeV from other viral infections is its predilection to cause neurologic deficits. A recent systematic review and meta-analysis evaluating for neurological and neurodevelopmental outcomes of infants with PeV CNS (central nervous system) infections showed that seizure and lethargy were reported clinical symptoms at presentation in 60% of studies. ⁹ While all 4 patients in our case series had positive CSF PCR tests for PeV, none of the 4 patients presented with seizures, lethargy, or focal neurologic deficits. Two patients did present as irritable, but this is a common presentation in infants with non-specified viral infections. The results of this review are consistent with the Tennessee study outbreak, where only 2 patients out of 23 were found to have neurologic deficits, making PeV difficult to suspect clinically without definitive testing. ³ None of our 4 patients underwent an MRI during their hospital admissions. Despite the effectiveness of MRI in evaluating for white matter diffusion consistent with meningoencephalitis, there are no specific guidelines recommending which infants should have an MRI performed, though imaging should be considered for those infants presenting with neurological manifestations. ¹⁰

Although all 4 patients in our case series had uneventful hospital courses, the development of neurological dysfunction should be a long-term consideration. van Hinsbergh et al ⁹ showed that 27% of pooled patients with PeV CNS infections developed neurological sequelae at 12 months or more of long-term follow-up, including visual problems, gross motor function delay, speech and language delay, and cognitive impairment, among other issues. We successfully obtained phone follow-ups with either the family or primary medical doctor for all 4 patients 8 months after hospital discharge. There were no reported significant medical problems or the development of neurological defects, and all 4 were all reaching their developmental milestones appropriately. None of the infants had an MRI performed after discharge.

Conclusion

Human PeV is a rare cause of infection in infants and children but may present as meningitis or encephalitis in young infants less than 3 months old. There is currently an ongoing outbreak throughout different areas of the United States, surging in the late spring and early summer. We have seen since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that spikes in cases of various viral pathogens, like RSV, have occurred at unexpected times of the year, which could be why we are seeing PeV present earlier in the year than expected. ¹¹ Many institutions did not routinely evaluate for PeV RNA on CSF PCR testing until the last few years, which could explain the recent uptick in positive results. Human PeV has a nonspecific presentation similar to other viral infections but should be suspected in any infants less than 2 months of age with fever. Long-term neurological sequelae from PeV meningitis and encephalitis are possible, and since findings may not present themselves for months after initial infection, close follow-up should be recommended.

Author Contributions

GP: Contributed to conception and design; contributed to analysis; drafted the manuscript; revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. ND: Contributed to conception and design; contributed to analysis; drafted the manuscript; revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.