Novel Human Parechovirus 3 Diversity, Recombination, and Clinical Impact Across 7 Years: An Australian Story

Abstract

Background: A novel human parechovirus 3 Australian recombinant (HPeV3-AR) strain emerged in 2013 and coincided with biennial outbreaks of sepsis-like illnesses in infants. We evaluated the molecular evolution of the HPeV3-AR strain and its association with severe HPeV infections.

Methods: HPeV3-positive samples collected from hospitalized infants aged 5-252 days in 2 Australian states (2013-2020) and from a community-based birth cohort (2010-2014) were sequenced. Coding regions were used to conduct phylogenetic and evolutionary analyses. A recombinant-specific polymerase chain reaction was designed and utilized to screen all clinical and community HPeV3-positive samples.

Results: Complete coding regions of 54 cases were obtained, which showed the HPeV3-AR strain progressively evolving, particularly in the 3' end of the nonstructural genes. The HPeV3-AR strain was not detected in the community birth cohort until the initial outbreak in late 2013. High-throughput screening showed that most (>75%) hospitalized HPeV3 cases involved the AR strain in the first 3 clinical outbreaks, with declining prevalence in the 2019-2020 season. The AR strain was not statistically associated with increased clinical severity among hospitalized infants.

Conclusions: HPeV3-AR was the dominant strain during the study period. Increased hospital admissions may have been from a temporary fitness advantage and/or increased virulence.

Keywords: Australia; HPeV3; community; infants; parechovirus; pediatric; picornavirus; recombination; sepsis; viral evolution.

Figure 1.

Seasonality of hospitalized human parechovirus (HPeV) cases across the Queensland, Australia, spring/fall period. The solid lines represent total diagnosed HPeV cases within the state within that outbreak period, and the smaller, dashed lines underneath represent the respective cases captured for the study, which were genotyped as HPeV3. Note all 2013–2014 samples that were diagnosed were also captured for the study. Y-axis shows number of cases.

Figure 2.

Maximum likelihood phylogenetic analyses using 1000 bootstraps of all available Australian human parechovirus 3 (HPeV3) genomes’ coding sequence regions upstream of the recombination breakpoint (nt 1–3114), including 2 non-AR, non-Australian (Yamagata-2008 and CAU14/82015/KR) HPeV3 reference strains. Node colors indicate strain genomes generated in this study and are color coded by Australian state where they were collected: blue, Queensland hospital; green, Western Australian hospital; orange, Queensland community; gray, previously published Australian AR genomes collected during 2014–2016 from New South Wales, Victoria, and Tasmania.

Figure 3.

Maximum likelihood phylogenetic analyses of available human parechovirus 3 Australian recombinant (AR) strains coding sequences as a function of time and categorized by geographic area of origin. The Nextstrain plot shows the progressive evolution of the AR strain for most of the disease outbreak periods.

Figure 4.

Total human parechovirus 3 (HPeV3) and Australian recombinant (AR) strain prevalence in the Queensland community (blue) and hospital-based (peach) cohorts each month over an interval period spanning the first observed HPeV disease outbreak. Only an overlap of several months from November to January was available for both datasets. Red bar indicates duration of the first HPeV3 disease outbreak; the dashed line portion indicates uncertainty in when the outbreak began. Y-axis shows number of cases.

Figure 5.

Clinical features relating to Australian recombinant status over the 4 sampled epidemic periods. Abbreviations: MRI, magnetic resonance imaging; N, no; PICU, pediatric intensive care unit; Y, yes.