Introduction

Human Parechovirus (HPeV) is a common cause of infections occurring especially during the first years of life. It may present with a broad spectrum of manifestations, ranging from a pauci-symptomatic infection to a sepsis-like or central nervous system (CNS) disease, with possible neurological involvement, particularly among the youngest, that may even require intensive care unit assistance. The cytopathic effect, the rapid viral replication in neuronal cells, in combination with the likely lack of maternal protective antibodies and the immaturity of the immune system in toddlers may explain the potential danger related to HPeV infections in the youngest and the risk of sequelae [1].

Aim of the study is to review the current literature on HPeV meningitis in order to highlight the actual knowledge on epidemiology, clinical presentation, laboratory findings and imaging as well as therapeutic indication and need to follow up.

Materials and methods

This systematic review followed the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) guidelines [2]. The literature research was performed through four different electronic databases: PubMed, Embase, Scopus and Web of Science, on 13th February 2023. For the aim of the study, the keywords used were “Parechovirus Meningitis”, and filters were added to limit the research to a paediatric population (< 18 years old), to reports written in English, and to limit the time spam to the last 5 years (2018–2023). Each research performed on each database was downloaded and then uploaded to the web tool “Rayyan web application” [3], a website used to analyse and appoint articles, specific for writing reviews.

Eligibility criteria

To be included in the review, reports should satisfy the following inclusion criteria:

th February 2023.

The exclusion criteria are:

− Issues not pertinent to the field of investigation;

− Reports including adults, without age distinction;

− Reports without data.

Selection process

The selection process was conducted following the PRISMA guidelines, and it was assisted using the web application “Rayyan” [3].

First, the duplicates, produced by the research on four databases, were identified by the web application, Rayyan. Then, two authors checked the accuracy of the duplicates detected and excluded the unnecessary copies.

To limit errors and bias, two authors independently screened titles and abstracts produced by the research and defined those articles clearly irrelevant to the review. Afterward, full texts were retrieved and assessed for eligibility by the two screening authors. If full text articles couldn’t be found, an attempt of contacting authors was performed, to obtain the full text.

Finally, following PRISMA guidelines, references not included in the original search but relevant to the review were examined. Disagreements regarding inclusion/exclusion were settled through discussion between the researchers and a third author.

Data Collection process and data items

Relevant articles were selected on the web application Rayyan and grouped together based on the different issues they dealt with.

Afterwards, data was compiled in a Microsoft Excel spreadsheet to evaluate the main topics reported in the last years about HPeV meningitis. The information extracted from the full-text reports included epidemiological, clinical, laboratories, radiological, therapeutic data, and outcome results.

Data synthesis

Using the information gathered from the included studies, an updated review was achieved. The characteristics of the included studies were reported using descriptive statistics. No meta-analysis could be made with statistical work because of the variability of the studies. These results were then elaborated on in the discussion.

Results

The search of the selected electronic databases produced 304 studies. Diagram 1 presents the flow chart of the selection process, adapted from the PRISMA guidelines [4] (Fig. 1).

Out of them, 127 were the duplicates and 4 were not written in English. Then, according to PRISMA guidelines, all abstracts were analysed, and 63 records were discharged because they dealt with different topics, or with other types of HPeV infection, or with an adult population. Also, another duplicate article was found, not previously identified by the Rayyan web application.

Afterwards, 109 records were eligible to be analysed by reading their full-length text; however, 8 articles could not be retrieved. Therefore, 101 full-length reports were assessed for eligibility, and 21 were excluded because they did not display any data (n. 15), or no age subgroups could be found in a study population including adults and children (n. 5). In two cases the study reported had already been described in other articles. Finally, two relevant reports cited in other studies were added to this research.

In conclusion, 81 records were included in the revision.

Fig. 1
figure 1

Flow chart of the selection process

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Table 1 below shows the main issues found in this scoping review. Epidemiology was discussed in 39 reports, clinical manifestations in 47 reports, laboratory findings in 36 reports, imaging in 23 reports, therapy in 11 reports and outcome in 24 reports.

Table 2 displays all the reports included and their major findings.

Table 1 Main issues found in this scoping review
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Discussion

Epidemiology

Of 81 reports analysed, 39 dealt with the epidemiology of HPeV meningeal infection [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43].

Incidence

The reported percentage of HPeV positivity on Cerebrospinal Fluid (CSF) in children with meningeal involvement varied in American patients from 0.4 to 8.9%, with epidemic waves being occasionally reported [5,6,7,8,9,10]. HPeV type 3 was the most frequently detected single viral type [9].

As for Europe, many European Countries have been involved in epidemiological studies and highlighted the HPeV meningitis outbreak as well [11, 12]. The reported incidence in European patients varied as well from 0,04 to 10% [13,14,15,16,17,18,19,20,21,22,23,24,25,26].

Incidence of HPeV meningitis in the Asian continent has been studied mainly in Japan and Korea [27,28,29,30,31,32,33,34]. A multicentre study, conducted in Japan identified 240 infants with HPeV type 3 infection, of which 14.2% diagnosed with acute CNS infection [28]. Among 216 patients aged less than 4 months and hospitalised for fever, 110 were found to have a viral infection on serum or CSF, caused by HPeV in 60 cases [30]. In Korea the reported incidence varied from 8,6 to 37% [31,32,33,34].

As well as for other Continents, in Oceania incidence was varying from 5,4% to 25,8%, depending on the case series and period time considered [38,39,40].

Incidence of HPeV meningitis in the African continent seemed to be low. In Sudan, between December and August 2010 no patient was found positive for HPeV on CSF, out of 503 children aged 0 to 15 years presenting with fever, seizures, and a suspicion of neuroinfection [42]. Nine years later in the Comoros archipelago, HPeV RT-PCR were performed on 122 CSFs, of which 77 were collected from children, and only a 30-days-aged infant presented with a CSF HPeV infection (0,8%) [43]. The Countries involved in the studies are represented on the Map in Fig. 2.

Fig. 2
figure 2

Countries involved in the studies are shown in blue on the World map. They were Argentina, Australia, Canada, Comoros, France, Germany, Greece, Ireland, Israel, Italy, Japan, Netherlands, New Zealand, Poland, Portugal, Qatar, Singapore, South Korea, Spain, Sudan, Taiwan, Turkey, United Kingdom., USA.

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Seasonality

Some reports described the seasonality of the HPeV infection, with most of the cases presenting in the warmer months of the year [8,9,10,11,12, 18, 19, 27, 34, 43]. Whereas other studies didn’t find evidence of seasonality connected to HPeV meningitis [13,14,15,16,17,18,19,20,21,22,23,24,25,26].

HPeV genotypes

Regarding the molecular epidemiology of HPeV infection, HPeV type 3 was the predominant genotype, as reported by most studies analysed by this review [8, 9, 11, 17, 19, 21, 26, 27, 40]. Chamings A et al. described two cases of HPeV meningitis caused by the recombinant HPeV type 5 [41].

Clinical manifestations

Of 81 reports analysed, 47 dealt with the clinical presentation of HPeV meningeal infection [1, 8,9,10,11,12, 14, 17, 21, 23, 25,26,27,28, 32, 33, 41, 44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73].

Almost all reports showed that the youngest (under 3 months of age and in particular neonates) were the most affected patients. [9,10,11,12, 14, 21, 23, 26,27,28, 32, 33, 59,60,61,62, 64,65,66,67,68, 70]. Of note, an exceptional adolescent onset was reported in an immunosuppressed 17-year-old girl [58].

Most studies reported a higher incidence in males (56.4–91%) than in females [9,10,11, 17, 21, 27, 59, 60, 62, 65, 66]. Only two Korean studies reported a female prevalence (57.1-80%) [32, 33].

Clinical presentation was nonspecific, mainly in neonates, so that the diagnosis may be challenging. At onset, patients appeared with sepsis-like symptoms and poor general conditions. Fever was the most frequent presenting sign [1, 41, 44,45,46,47, 49, 50, 52,53,54,55,56,57,58]. In fact, fever occurrence ranged between 80% and 100% [8, 10,11,12, 14, 17, 21, 23, 25,26,27,28, 32, 33, 60,61,62,63,64, 69, 70]. However, in an American retrospective study, 2% of patients reported hypothermia (TC < 35 °C) instead of hyperthermia [68].

Other frequent symptoms included irritability, from 40 to 100%, poor feeding, from 42 to 81.8%, and tachycardia ranging from 63.6 to 77% [12, 14, 26, 41, 44,45,46, 51,52,53,54, 58, 60, 62,63,64, 67,68,69,70]. In a few cases lethargy was the presenting symptom, with a prevalence between 14% and 51% [1, 12, 14, 26, 60, 69].

Many clinical cases of HPeV CNS infection included a cutaneous sign, as macular or maculo-papular rash, involving mainly truncus and extremities [14, 23, 41, 45, 47, 54,55,56,57,58, 62]. The occurrence of a rash as a presenting sign ranged from 20 to 60% [1, 8, 11, 12, 17, 21, 52, 53, 60, 64, 68, 69].

Moreover, 15 reports evidenced the presence of seizures [1, 10, 11, 21, 26, 28, 45, 50, 58, 62, 65,66,67,68, 70]. Their occurrence may vary from 3.1 to 65.2% [10, 11, 21, 26, 28, 62, 65,66,67,68, 70].

Gastrointestinal symptoms were described as concomitant to meningitis, usually as diarrhoea, with a variable occurrence, ranging from 15 to 30% [12, 23, 52].

Other symptoms involving the respiratory system have been described, including coryza, cough, breathing difficulties, apnea and tachypnea. Their reported occurrence varied from 37.5 to 18.2% [11, 64, 68, 70].

Congenital HPeV Infection

Three cases of congenital/in utero transmission had been described in recent literature, leading to neonatal meningitis at birth, requiring intensive care unit support. The onset presentation symptoms were hypotonia, respiratory distress with desaturation, bradycardia, fever and abnormal movements [71,72,73].

Laboratory findings

Out of the 81 articles included in this review, 36 focused on the laboratory findings [1, 8, 12, 14, 17, 18, 21, 23, 26, 27, 31, 33, 36, 38, 41, 44, 45, 48, 51,52,53, 55,56,57, 61,62,63, 67, 69, 70, 72,73,74,75,76].

Blood analysis

In children with HPeV meningitis, peripheral leukocyte count, haemoglobin and platelets were within normal value range [51, 52]. Leukopenia was found especially in neonates and infants aged < 3 months [1, 55, 63, 67]. Low values of haemoglobin were occasionally described [12, 56].

General chemistry was unremarkable [41], although some authors described an increase of the transaminase, lactate dehydrogenase (LDH) values and hyponatremia [27, 51, 67, 70].

Inflammation markers were generally in the range of normality or mildly elevated [1, 12, 18, 31, 41, 52, 53, 55,56,57, 63, 69, 70]. Of note, compared with Enterovirus (EV) positive infants, infants with HPeV meningitis had lower values of blood white blood cells [27, 33] and infection indices [17].

Blood cultures were reported as negative [1, 41, 48, 62].

CSF analysis

CSF samples of children with HPeV meningitis were clear and pleocytosis characteristically mild or absent [1, 8, 12, 14, 21, 26, 27, 36, 38, 41, 45, 51, 53, 55, 57, 62, 67, 69, 70, 72, 74].

Despite that, some case-reports described pleocytosis in children, predominantly neonates, with HPeV meningitis [44, 48, 57, 61, 73]. Compared with EV meningitis, HPeV meningitis determined a lower rate of CSF pleocytosis [14, 17, 27, 32, 33, 61]. In case of pleocytosis, white cell count was lower in the HPeV meningitis than in the EV group, and other viral meningitis, such as Human Herpes 6 and Herpes Simplex Virus-2 meningitis [23, 32].

As for the remaining CSF biochemistry, in HPeV meningitis proteins were normal or slightly elevated [1, 8, 14, 18, 21, 27, 45, 55, 56, 61, 62, 70, 72]. Moreover, glucose values were generally normal [1, 8, 21, 27, 41, 51, 55, 61, 62, 70, 72]. Of note, low glucose concentration has been described just in few cases, mainly in neonates [57, 63].

CSF cultures were negative [1, 41, 45, 48, 51,52,53, 62].

Cytokine Profile on serum and CSF

Measurement of cytokines levels revealed high levels of interleukins (IL): IL-6, IL-17 and TNF alpha on serum and of IL-2, IL-4, IL-7 and IL-13 in CSF [31, 75].

Compared to EV, a higher serum level of proinflammatory cytokine/chemokine was present in HPeV, likely related to the more severe clinical manifestations in the former [76].

Imaging

HPeV meningitis was diagnosed by clinical manifestations and laboratory findings. Instrumental diagnostic exams were used as complementary and to investigate HPeV’s clinical complications and outcomes. Twenty-three publications analysed instrumental exams in patients affected by HPeV meningitis [1, 10, 12, 25, 26, 28, 45, 48,49,50, 56,57,58, 62, 65,66,67,68, 71,72,73, 77, 78].

Head ultrasound and cerebral magnetic resonance imaging (MRI) were the most used diagnostic exams; few cases reported head Computerised Tomography (CT) scan finding.

Head ultrasound

Head ultrasound was used in reports as it is a fast, non-invasive and economic diagnostic exam. Nevertheless, it generally resulted in normal finding [1, 12, 25, 45, 48, 50, 56, 62, 77, 78].

Magnetic resonance imaging

When performed in patients with HPeV neuro-infections, MRI resulted in white matter anomalies. Common findings included restricted diffusion in deep white matter and periventricular white matter involving mainly the frontal zones [48,50,65, 6872]. Involvement of parietal and temporal lobes, corpus callosum and thalamus have been described as well [58, 71, 73, 77, 78]. Hyperintensity in the T2/FLAIR was also a possible presentation of HPeV neuro-infection [28]. These findings were typically bilateral, either asymmetrical or symmetrical [50, 58, 65]. Other findings, such as unilateral lesions, low signal intensity on T2 and hyperintensity on T1 or just a leptomeningeal enhancement were also described [28, 50].

Some authors reported that MRI abnormalities were usually detected in a minority of children with HPeV CSF infections [1, 10, 12, 26, 57, 65]. Conversely, other authors demonstrated that the majority of patients in the study populations had positive MRIs findings [28, 66].

There’s evidence that most of the patients with white matter alterations on MRI developed more severe diseases, with seizures or necessity of ventilations and vasoactive infusion [67].

When performed weeks or months after the acute infection, MRI scan might be normal, with no evidence of white matter lesions [49, 58]. Persistence of the lesions had been proved in a minority of patients [28, 65].

White matter MRI anomaly had been also used as a prognostic sign of neurodevelopmental concerns. By the way, some authors found neurodevelopmental impairment at clinical follow-up in children with initial MRI alterations [28, 65, 66].

Bucci S. et al. showed that children with MRI abnormalities in the HPeV acute infection scored lower, but still in the range of normality, on cognitive Bayley III (Bayley Scales of Infant and Toddler Development, Third Edition) subscale at Neurodevelopmental assessment at 1 year of age compared with children with normal MRI [25]. Whereas Abe Y. et al. reported that the totality of the patients (6/6) with MRI negative findings had a neurological good prognosis [28].

Other investigations

Electroencephalography (EEG) demonstrated seizure activity or encephalopathy signs [67, 68, 72,73,7868].

Therapy

Out of the included reports, eleven focused on the therapeutic approach [10, 21, 45, 50, 56, 57, 62, 68, 69, 73, 79]. Authors agree on supportive therapy, including paracetamol and fluids. Antibiotics as well as antivirals were prescribed at onset and then discontinued as soon as the diagnosis of HPeV infection was confirmed [21, 56, 57, 62, 69, 73].

In case of seizures, antiepileptic therapy was considered [10, 45, 68, 73].

In case of critical conditions or unresponsiveness to therapy, intravenous immunoglobulin and/or methylprednisolone have been prescribed [10, 21, 50, 69]. Finally, posaconazole was used against HPeV type 3, acting as an early-stage inhibitor of viral replication: it binds the capsid interfering with virus-cell attachment and entry [79].

Outcome

We identify 24 publications dealing with clinical outcome of HPeV meningitis, in term of hospital stay and long-term outcome [1, 12, 21, 25, 26, 28, 44, 48, 49, 56, 57, 59, 60, 62, 65, 66, 70, 73, 74, 80,81,82,83,84].

Hospital Stay

Hospitalisation has been analysed in 9 reports [1, 12, 21, 48, 49, 56, 57, 62, 70].

Hospitalisation ranged from 2 days to 5 weeks. The high variability was depending on various factors, including the clinical course and the need of intensive care in case of respiratory distress, apnoea, seizures, and hemodynamic instability [1, 12, 21, 48, 49, 56, 57, 62, 70].

All but one otherwise healthy 11-days old neonate affected by HPeV type 3 meningoencephalitis survived. The neonate’s autopsy showed bilateral multicystic cavitation of the fronto-parietal white matter as well of temporal and occipital asymmetric cavitation [78].

Long-term outcome

The long-term outcome was analysed in 21 reports.

Even if HPeV is one of the main identified etiological agents of viral meningitis in infants, poor attention has been reserved to it from the Scientific Community in the past, mainly due to the high survival range. Examining scientific reports from all over the world are increasing awareness of the risk connected to a severe parechovirus infection. In fact, out of the revised literature, cerebral palsy, vision and neuropsychomotor development impairment were reported in a high percentage of case series [65, 80, 83]. The appropriate duration of post hospitalisation follow-up is still being debated. Evidence supported clinical follow-up until at least the second year of life, with a recommended longer-term follow-up in case of further potential risk factors, such as prematurity, early onset of infection (neonatal period), MRI abnormalities, severe clinical course (seizures, apnoea) with necessity of paediatric Intensive Care Unit [1, 25, 28, 48, 6566]. Evidence suggested an ameliorating of clinical sequelae with a normal development in most cases by the age of three [65]. Anyway, as neurodevelopmental impairment is often difficult to detach at an early stage, prior to school-age, families should be aware of potential neurological, behavioural, and learning impairments in childhood in order to eventually seek assessment.

Conclusion

HPeV infection is very common in paediatric age and may have a severe course mainly among neonates and toddlers less than 3 months of age when it manifests as meningitis. Symptoms may be non-specific, including fever, irritability, poor feeding, skin rash, or seizures. Although several authors described favourable outcome with high probability of survival, reported neurodevelopmental outcomes at discharge suggest a specific follow up and the family awareness on the risk of sequelae.

Evidence supported clinical follow-up until at least the second year of life, with a recommended longer-term follow-up in case of further potential risk factors, such as prematurity, early onset of infection (neonatal period), MRI abnormalities, severe clinical course (seizures, apnoea) with necessity of paediatric Intensive Care Unit. Of note, we emphasise the need for surveillance to define the disease burden, evaluate strategies and interventions to prevent and manage cases, and to respond to the potential first early signals of sequelae developing. Finally, defying and following the global epidemiology of HPeV infection may be useful for considering the opportunity of vaccine development mainly for those with risk factors for a severe course.

Table 2 Reports included and the major finding
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