Neuroinvasive Human Parvovirus 4 is associated with increased mortality in children: a multiyear retrospective observational study

Background: Infections of the central nervous system (CNS) in children remain a major cause of mortality and long-term disability globally, particularly in low- and middle-income countries (LMICs), where a high proportion of cases lack an identified pathogen. Sporadically, human parvovirus 4 (PARV4) has been detected in a small number of cerebrospinal fluid (CSF) from children with CNS infections, but its pathogenic role is unclear. We investigated the prevalence, clinical impact, and genomic characteristics of PARV4 in children with suspected meningitis. Methods: We retrospectively analyzed CSF samples collected from children with WHO-defined suspected meningitis at the largest pediatric hospital in Bangladesh between 2015-2022. All samples underwent routine diagnostics, including bacterial culture and serological testing. Additional testing for PARV4 and parvovirus B19 was performed using qPCR of samples with >9 white blood cell (WBC)/ul followed by metagenomic sequencing of a subset. Clinical and laboratory data were extracted from patient records. Associations between PARV4 detection and mortality were assessed using logistic regression, adjusting for age, WBC count, and co-infections. Genomic and phylogenetic analyses were conducted on PARV4-positive samples. Findings: Among 2,793 CSF samples with >9 WBC/ul, 526 (18.8%) were PARV4-positive. The median age of PARV4-positive cases was lower than that of PARV4-negative cases (4 vs 7 months, p<0.001). Co-infections were more common among PARV4-positive cases (49.6%) than PARV4-negative cases (16.4%). PARV4 positivity was independently associated with increased in-hospital mortality (adjusted odds ratio 2.09, 95%CI:1.46-2.96; p<0.001). Phylogenetic analysis indicated most strains belonged to genotype 2, with two sequences forming a distinct clade. Interpretation: PARV4 is frequently detected in the CSF of children with suspected meningitis and is associated with increased in-hospital mortality. Its high prevalence, detection early in life, and frequent co-infection with other pathogens highlight the need to investigate PARV4 as an emerging CNS pathogen in LMICs. Funding: Gates Foundation