The Parechovirus genus includes six species (A-F), with only Parechovirus-A (PeV-A) species infecting humans. To date, 19 PeV-A genotypes have been identified having distinct clinical and epidemiological profiles [1], [2]. While many genotypes, including PeV-A1, A5, and A6, are predominantly associated with non-systemic illnesses such as mild respiratory or gastrointestinal infections, others exhibit neuroinvasive potential, causing severe systemic disease in neonates and young infants [3], [4], [5], [6]. Among these, PeV-A3 has been the most frequently implicated genotype in central nervous system (CNS) infections, presenting with fever, irritability, sepsis-like illness, and meningitis [3], [5], [7], [8], [9]. A previous 10-year surveillance study (2007–2016) conducted by our group identified PeV-A3 as the leading picornavirus genotype causing viral CNS infections in pediatric population of Kansas City. PeV-A3 was detected in 26 % of all cerebrospinal fluid (CSF) samples that tested positive for enterovirus (EV) or parechovirus (PeV), surpassing the combined detections of each enterovirus type [9].

The epidemiology of PeV-A genotypes, however, continues to evolve. In 2019, we reported the first USA cluster of PeV-A4 CNS infections in eleven infants. These cases of PeV-A4 infected patients had similar clinical characteristics with PeV-A3 infected patients, such as fever, irritability, and systemic manifestations [10]. This emergence underscored the need for vigilance toward non-PeV-A3 genotypes in severe pediatric infections. Within this manuscript, we report the first USA cluster of PeV-A5 CNS infections in Kansas City infants.

Historically, PeV-A5 is a genotype that is linked to non-systemic infections and commonly detected from stool and respiratory samples [11], [12], [13], [14], [15], [16]. Formerly classified as echovirus 23 strain 86-6760, PeV-A5 was first identified in the stool of a 2-year-old girl in Connecticut [19]. Thereafter, the evidence of sterile site involvement of PeV-A5 has only been sporadically shown with reports from Canada in 2018–19 (n = 12; 12 CSF) [17], European countries between 2015–21 (n = 14; 11 CSF, 3 blood) [4], [18], and Australia in 2019 (n = 7; 6 CSF, 1 plasma) [19]. Our findings reveal the capacity of PeV-A5 to invade the CNS, mirroring the neurotropism of PeV-A3 and PeV-A4. This is the highest number of PeV-A5 sterile site detections from infants within the USA in a single year.