VCOM Carolinas Research Day 2023

Clinical Case-Based Reports

Human Parechovirus (HPeV) Meningoencephalitis in an Eight-day Old Infant Nicole A. Ivan, OMS-III 1 ; Katlin M. Hencak, OMS-III 1 ; Hanna S. Sahhar, MD, FAAP, FACOP 1,2 1 Edward Via College of Osteopathic Medicine, Carolinas Campus, Department of Pediatrics, Spartanburg, SC 2 Spartanburg Regional Healthcare System, Department of Pediatrics, Pediatric Intensive Care Unit, Spartanburg, SC Abstract Case Presentation i i

Abstract # CBR-6

i

Discussion

Human parechovirus (HPeV) infections have been increasing in the United States since May 2022, according to the Center for Disease Control and Prevention (CDC). Human parechoviruses are a member of the Picornaviridae family and share similarities with enteroviruses. HPeV commonly affects children, with disease manifestations ranging anywhere from asymptomatic infection to severe disease. HPeV typically affects the gastrointestinal and respiratory tracts but may also cause severe infection of the central nervous system (CNS), leading to sepsis-like illness, meningitis, and encephalitis. Of the 19 established serotypes of HPeV, serotypes A1 and A3 are most commonly identified in humans. HPeV serotype A3 is of particular importance as it more commonly causes sepsis and CNS infection, especially in young children. In the United States between 2014-2016, a total of 2,758 cases of enteroviruses and parechoviruses were reported to the National Enterovirus Surveillance System. Of those cases, 2.3% were distinguished as HPeV A3. This case details the clinical course of an eight-day old infant with human parechovirus meningoencephalitis. The infant initially presented with fever and other nonspecific symptoms, which later progressed to include diffuse blanching erythroderma and seizure activity. Although current management of HPeV meningoencephalitis involves supportive care and close monitoring, determining HPeV as a cause of infection is important due to the long-term sequelae that patients may develop. Potential complications of infection include white matter lesions of the brain, cerebral palsy, developmental delay, and visual impairment. This case was documented to increase awareness of the rising incidence of HPeV infections in children in the United States, as well as detail the signs and symptoms of HPeV meningoencephalitis in a neonate. An 8-day old female presented to her primary care physician for new-onset fever of 101.4 ° F, decreased oral intake, and loose stools. The patient was born at 40w1d gestational age via spontaneous vaginal delivery to a group B-streptococcus-positive mother. The mother received adequate antibiotic coverage prior to delivery. APGAR scores at 1- and 5-minutes following delivery were documented as 8 and 9, respectively. The infant had no recent sick contacts, and review of systems were negative for cough, rash, or vomiting. Physical exam findings were significant for prolonged capillary refill, jaundice, and dry mucous membranes. The patient was admitted to the hospital for workup of a fever in an infant less than 30 days old. A full septic workup was performed including lumbar puncture and meningitis panel. The patient was placed on empiric ampicillin and gentamicin and was monitored for worsening symptoms. A film-array meningitis panel performed on the patient’s cerebral spinal fluid (CSF) was positive for human parechovirus, formally diagnosing this infant with human parechovirus meningitis. On hospital day 2, the patient developed blanching erythroderma. The patient was monitored closely and noted to improve steadily over the course of 72 hours. The patient was afebrile following admission and CSF and blood cultures remained negative. Case Presentation

References HPeV infections are uncommon in the continental United States, especially those severe enough to cause CNS infection. With a recent increase in HPeV infections in the United States, it may be beneficial to include this virus in the differential diagnosis for children presenting with acute viral illness. Although care for HPeV infection is mostly supportive, it is important to consider the potential CNS complications associated with this virus. HPeV more commonly affects the gastrointestinal and respiratory tracts, but may spread hematogenously to affect other organ systems, including the central nervous system. HPeV subtype A3 more commonly causes severe systemic disease when compared with other subtypes. Of the children infected with known HPeV-A3, those presenting with severe systemic disease tend to be younger in age compared to those presenting with milder gastrointestinal or respiratory symptoms. Most severe cases of HPeV infection occur in infants younger than 3 months of age. This has important implications in the neurodevelopment of young children with HPeV infection and warrants close monitoring for long-term neurological complications. Inflammation and cytotoxicity associated with infection of the brain and spinal cord may cause irreversible neurological damage. Infection of the CNS increases the risk of cerebral palsy, anoxic brain injury, and white matter lesion development. This may subsequently result in neurodevelopmental delay, visual impairment, delays in motor development, recurrent seizures, and even death. Diagnosis of HPeV as the cause of infection in children is important when considering that young infants are at increased risk for severe disease. The increase in incidence of HPeV cases in the United States should encourage testing for this virus in infants less than 90 days old presenting with a fever as well as children presenting with gastrointestinal and respiratory illnesses. Close monitoring and follow-up is important in young infants with HPeV infection and may aid in earlier detection of CNS manifestations and improve neurodevelopmental outcomes. 1. Abedi GR, Watson JT, Nix WA, Oberste MS, Gerber SI. (2018, May 11 Enterovirus and Parechovirus Surveillance — United States, 2014 – 2016. MMWR Morb Mortal Wkly Rep 2018;67:515 – 518. DOI: http://dx.doi.org/10.15585/mmwr.mm6718a2 2. Britton PN, Jones CA, Macartney K, & Cheng AC. (2018). Parechovirus: An important emerging infection in young infants. Medical Journal of Australia , 208 (8), 365 – 369. https://doi.org/10.5694/mja18.00149 3. CDC Health Alert Network. (2022, July 11). Recent Reports of Human Parechovirus (PeV) in the United States — 2022 . Centers for Disease Control and Prevention. Retrieved November 8, 2022, from https://emergency.cdc.gov/han/2022/han00469.asp 4. Modlin JF. (2022, August 1). Enterovirus and parechovirus infections: Epidemiology and pathogenesis. Hirsch, MS (ed) & Bogorodskaya, M (ed). UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com/contents/enterovirus-and-parechovirus-infections-epidemiology-and-pathogenesis (Accessed January 15, 2023). 5. Olijve L, Jennings L, & Walls T. (2018). Human parechovirus: An increasingly recognized cause of sepsis-like illness in young infants. Clinical Microbiology Reviews , 31 (1). https://doi.org/10.1128/cmr.00047-17 No relevant financial affiliations or conflicts of interest. If the authors used any personal details or images of patients or research subjects, written permission or consent from the parent (or legal guardian) was obtained. This work was not supported by any outside funding. Acknowledgements

On examination prior to discharge, a focal clonic movement of the left arm was noted. Later in the day, the clonic movement evolved to include the right arm along with eye twitching and lip smacking. An electroencephalogram (EEG) was obtained, and evidence of seizure-like activity was recorded. At this time, a consult was made for evaluation by pediatric neurology. Following their recommendations, the patient was initiated on phenobarbital and transferred to their care. Figure 2. Blanching erythroderma. Infants with severe HPeV infection are often described as "red, hot, angry babies" in literature due to the triad of fever, rash, and irritability.

IMPRESSION: Abnormal EEG secondary to infrequent repetitive brief generalized high amplitude polyspike discharges with slow wave

Following initiation of phenobarbital, the patient remained in stable condition. No focal neurologic deficits were present on physical exam at that time, and she was placed on seizure precautions. A long-term EEG was performed, which revealed epileptic potential in the right central and temporal lobes, however, no seizures were recorded during the study. Levetiracetam was initiated with an initial loading dose and the patient was continued on twice daily dosing. The patient tolerated the medication well and no further seizure activity was observed during the admission. Magnetic resonance imaging (MRI) was obtained with findings suggestive for cytotoxic injury, likely due to parechovirus encephalitis. The patient was discharged with parent education and strict return precautions. A follow-up with pediatric neurology was recommended one month following discharge for repeat EEG and medication management. The parents were encouraged to establish care with a neurodevelopmental pediatrician to closely monitor the patient’s development due to the MRI findings. Follow-up exam was unremarkable for focal deficits. Repeat magnetic resonance angiography of the brain was unremarkable. Figure 3. Video evidence of focal clonic seizure activity (QR code, left). Abnormal EEG showing polyspike discharges and slow waves (right) .

Complete Blood Count with Differential Component

CSF Cell Count with Differential

Patient's CSF Reference Value

Ref Range & Units Patient's Values

Color CSF

Colorless

Clear/Colorless

White Blood Cells

5.0 - 21.0 x 10*3/uL

7.4

Number of Cells, CSF

12

RBC

3.60 - 6.20 x 10*6/uL

5.39 18.2 53.8 99.8 33.7 33.8

Hemoglobin Hematocrit

12.5 - 20.0 g/dL 39.0 - 63.0 % 86.0 - 124.0 fL 28.0 - 40.0 pg 28.0 - 38.0 g/dL

Red Cell Count

7

0-5

WBC, CSF

5

< 20/mm3

MCV MCH

Segmented Neutrophils

0

MCHC

Lymphocytes

36

70%

RDW

16.4 (High)

11.8 - 15.2 %

Monocytes

64

30%

Platelets

141 - 359 x 10*3/uL

233

Glucose CSF

46

50-80 mg/dL

nRBC

0.0 - 0.0 %

0

Nucleated RBC Absolute

Protein CSF

44

15-45 mg/dL

0.01 (High)

0.00 - 0.00 x 10*3/uL

Figure 4 . MRI of the brain without contrast (left) and with contrast (middle) show multifocal diffusion restriction throughout the periventricular white matter of both cerebral hemispheres concerning for recent ischemia. MRA of the head (right) showed no major arterial intracranial vascular abnormality.

Figure 1. Complete blood count with differential (left). Film-array meningitis panel from CSF sample (middle). CSF cell count with differential (right).

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