Human Parechovirus Infections Research Articles

Human Memory B Cells Producing Potent Cross-Neutralizing Antibodies against Human Parechovirus: Implications for Prevalence, Treatment, and Diagnosis.

The family Picornaviridae is a large and diverse group of positive-sense RNA viruses, including human enteroviruses (EVs) and human parechoviruses (HPeVs). The human immune response against EVs and HPeVs is thought to be mainly humoral, and an insufficient neutralizing antibody (Ab) response during infection is a risk factor and can ultimately be life threatening. The accessibility of different antigenic sites and observed cross-reactivity make HPeVs a good target for development of therapeutic human monoclonal antibodies (MAbs). In this study, we generated two different human MAbs specific for HPeV by screening culture supernatants of Ab-producing human B cell cultures for direct neutralization of HPeV1. Both MAbs showed HPeV1-specific neutralization as well as neutralization of HPeV2. One antibody, AM18, cross-neutralized HPeV4, -5, and -6 and coxsackievirus A9 (CV-A9). VP1 capsid protein-specific assays confirmed that AM18 bound VP1 of HPeV1, -2, and -4 with high affinity (11.5 pM). In contrast, the HPeV1-specific MAb AM28, which neutralized HPeV1 even more efficiently than did AM18, showed no cross-reactivity with HPeV3 to -6 or other EVs and did not bind any of the capsid proteins, suggesting that AM28 is specific for a conformation-dependent, nonlinear epitope on the virus. The discovery of MAbs that are cross-reactive between HPeVs may help development of HPeV treatment options with antibodies and vaccine design based on epitopes recognized by these antibodies. HPeV infections are widespread among young children and adults, causing a broad range of disease. Infections can be severe and life threatening, while no antiviral treatment is available. Given that the absence of neutralizing Abs is a risk factor for severe disease in infants, treatment of picornavirus infections with MAbs would be a therapeutic option. To study antibody neutralization of HPeV in more detail, we generated two different HPeV1-specific human MAbs. Both MAbs show HPeV1-specific neutralization and cross-neutralized HPeV2. One MAb also cross-neutralized other HPeVs. Surprisingly, this MAb also neutralized CV-A9. These MAbs provide a unique tool for further research and for the diagnosis (antigen detection) and possible treatment of HPeV infections.

Human parechovirus infection in neonatal intensive care.

Approximately 5-6% of all infective episodes in neonatal intensive care unit (NICU) are of viral origin. Previous studies suggest that human parechovirus (HPeV) infection presents most commonly in term infants, as a sepsis-like syndrome in which meningoencephalitis is prominent. Our aim was to study the infection rate and associated features of HPeV. Blood samples were taken from NICU babies older than 48 hours, who were being investigated for late onset sepsis. Clinical and laboratory data were collected at the time of the suspected sepsis episode. Samples were tested using universal primers and probe directed at the 5'-untranslated region of the HPeV genome by reverse transcriptase polymerase chain reaction (RT-PCR). Results were confirmed by electrophoresis and DNA sequencing. HPeV was detected in 11 of 84 samples (13%). These infants had a mean [interquartile range (IQR)] gestational age of 28.9 (26.9-30.6) weeks and mean birth weight of 1.26 (SD = 0.72) kg. The median day of presentation was 16 (IQR: 11-27). These characteristics were similar to the infants without positive viral detection. Six infants presented with respiratory signs. One infant presented with signs of meningitis. Six of the 11 episodes of HPeV infection occurred during the winter months (December to February). No HPeV positive infants had abnormal findings on their 28-day cranial ultrasound examination. We found an HPeV infection rate of 13% in infants being tested for late onset sepsis. HPeV should be considered as a possible cause of sepsis-like symptoms in preterm infants.

Human parechovirus infections and child myositis cases associated with genotype 3 in Osaka City, Japan, 2014

Human parechovirus (HPeV) infects humans early in life and typically causes asymptomatic or mild diseases such as gastrointestinal and respiratory illness but sometimes leads to more serious consequences in neonates and young infants. In 2014, we detected HPeV from 38 patients by real-time reverse transcription-PCR in Osaka City, Japan, and 33 HPeV strains were genotyped based on their VP1 sequences. HPeV genotype 3 (HPeV-3) was the most prevalent and accounted for 22 cases (66.7%) followed by nine HPeV-1 (27.3%), one HPeV-2 (3.0%) and one HPeV-4 (3.0%). Phylogenetic analysis revealed that detected HPeV-3 strains were divided into three genetically distinct groups. One was characterized by a novel single amino acid deletion mutation at the N terminus of the 2A protein as well as the VP1 sequence, whereas the others were closely related to HPeV-3 strains detected in Japan in either 2008 or 2011. These HPeV-3 groups were detected from patients with various symptoms including three myositis cases. Recent papers have demonstrated that HPeV-3 was the aetiological agent for epidemic myalgia exclusively among adults from Yamagata Prefecture in Japan. Here, we provide clinical details and episodes of three myositis patients including an adult and two children in Osaka City, Japan. Our results suggest that HPeV-3 is a causative agent of myositis not only in adults but also in children.

Characteristics and outcomes of human parechovirus infection in infants (2008-2012).

Human parechoviruses (HPeVs) cause a spectrum of disease ranging from self-limiting illness to severe disease and, sometimes, death. We describe the clinical characteristics and outcomes of HPeV infection in infants. The study describes the clinical and laboratory characteristics and outcomes of infants with HPeV infection during 2008-2012, from three paediatric hospitals in London each with a paediatric intensive care unit. The infants were retrospectively identified through laboratory and patient discharge databases and diagnosed through HPeV PCR. Fifty infants were identified. Half required admission to PICU. Infants less than 3 months were more likely to require PICU (16/25: p < 0.01). Clinical signs at presentation were often indistinguishable from those of bacterial sepsis and meningitis, but inflammatory markers were nearly always (95 % of cases) within normal ranges. Brain MRI showed white matter changes in 10/12 infants. Three of 19 infants with follow-up data (16 %) had significant neurological sequelae. HPeV may cause severe disease and long-term neurological sequelae in young infants. HPeV should be considered in infants with clinical features of sepsis/meningitis with normal CSF microscopy. Prospective observational studies are warranted to better define the epidemiology of infection and thus inform future treatment trials.

Human Parechovirus Infection in Neonate and Neurological Disorder: A New Disease

There are many new emerging viral diseases that become the new problem in neurology. In neonate, the viral neurological infection is a common problem and the disease caused by the new virus should be specially focused. Of several new diseases, human parechovirus infection is a new disease that can cause neonatal neurological infection. The pathogenic virus is a picovirus that can cause clinical problem including to the neurological infection in neonate [1].

Parechovirus Sepsis and Meningitis in a Neonatal Intensive Care Unit

The majority of febrile neonates have negative bacterial cultures and presumed viral infections. During November 2014, four febrile neonates in southeastern Wisconsin required intensive care admission for human parechovirus (HPeV) infection in the blood and/or cerebral spinal fluid (CSF). Both vertical and horizontal transmission led to disease, and a variety of signs and symptoms, including tachycardia, hypotension, neutropenia, rash and irritability accompanied fever. All neonates recovered clinically, although concern for neurodevelopmental delay remains for those with meningoencephalitis. This case series describes the presentation and short-term outcomes of neonates requiring intensive care for HPeV infections.

Human parechovirus as a minor cause of acute otitis media in children

Human parechoviruses (HPeVs) cause mild upper respiratory infections, gastrointestinal symptoms, central nervous system infections and some studies have linked them with acute otitis media (AOM). The aim of the present study was to study further the role of HPeV infections in AOM by detecting these viruses directly from middle ear fluid (MEF), respiratory and stool samples collected from children during AOM episodes. A total of 91 MEF samples, 98 nasal swab (NS) samples and 92 stool samples were collected during 100 AOM episodes in a total of 87 children aged between five to 42 months. All specimens were analyzed by real time RT-PCR for the presence of HPeV RNA. HPeV infection was diagnosed in 12 (14%) patients. HPeV RNA was detected in altogether 13 samples, including four MEF samples, three NS samples and six stool samples. One patient was positive in both stool and MEF samples. The results suggest that HPeV may play a role in some AOM cases, but it is not a major cause of AOM in children.

Human parechovirus type 3 and 4 associated with severe infections in young children.

The symptoms observed in children with human parechovirus (HPeV) infection vary widely from asymptomatic or mild gastrointestinal infections to more severe central nervous system infections and sepsis-like disease. Many of the disease associations are, however, only suggestive. In this study, we examined the connection between HPeV and acute otitis media, lower respiratory infections and suspected central nervous system infections. An HPeV specific real-time reverese transcriptase polymerase chain reaction was used to detect HPeV RNA. We analyzed altogether 200 middle-ear fluid samples, 192 nasopharyngeal aspirates, 79 cerebrospinal fluid specimens and 50 serum and 5 fecal or fecal culture samples. Positive samples were typed by sequencing the VP1 region. Seven (8%) of 85 children with suspected central nervous system infections were positive for HPeV. Of these, 4 (all in autumn 2012 and from children <3 months of age) were typed to be HPeV4, whereas 1 child had HPeV3. HPeV4 was detected from stool, serum and cerebrospinal fluid. The children with acute otitis media tested HPeV positive in 2.5% episodes. In the lower respiratory cases, HPeV was absent. The findings reported in this study suggest that HPeV4 can cause sepsis-like disease in young infants and be present in cerebrospinal fluid. Furthermore, this report shows that HPeV findings in children with more severe symptoms occur also in Finland.

Epidemiology of human parechovirus, Aichi virus and salivirus in fecal samples from hospitalized children with gastroenteritis in Hong Kong.

BackgroundEmerging human picornaviruses, including human parechovirus (HPeV), Aichi virus (AiV) and salivirus (SalV) were found to be associated with gastroenteritis, but their roles in enteric infections are not fully understood. In addition, no report on the circulation of these viruses in Hong Kong is available. The objective of this study was to investigate the prevalence and genetic diversity of HPeV, AiV and SalV in fecal samples from hospitalized children with gastroenteritis in Hong Kong.MethodsFecal samples from hospitalized children with gastroenteritis were subject to detection of HPeV, AiV and SalV by RT-PCR using consensus primers targeted to their 5′UTRs. Positive samples were subject to capsid and/or 3CD region analysis for genotype determination. The epidemiology of HPeV, AiV and SalV infections was analyzed.ResultsAmong 1,708 fecal samples subjected to RT-PCR using primers targeted to 5′UTR of HPeV, AiV and SalV, viruses were detected in 55 samples, with 50 positive for HPeV only, 3 positive for AiV only, 1 positive for both HPeV and AiV, and 1 positive for both HPeV and SalV. Phylogenetic analysis of the partial VP1 gene of the 33 HPeV strains revealed the presence of genotypes of HPeV- 1, 3, 4, 5, 7, 10, among which HPeV-1 was the predominant genotype circulating in our population. The peak activity of HPeV infection was in fall. Of the 3 children with AiV infection, the 3 AiV strains were found to belong to genotype A based on the phylogenetic analysis of their partial VP1 and 3CD regions. The genotype of a SalV strain detected in this study could not be determined. Co-detection of different pathogens was observed in 24 samples (43.6%) of 55 fecal samples positive for HPeV, AiV and SalV.ConclusionsHPeV, AiV and SalV were detected in fecal samples of hospitalized children with gastroenteritis in Hong Kong, with the former having the highest prevalence. HPeV-1 was the predominant genotype among HPeVs, while genotype A was the predominant genotype among AiVs in this study.

Sepsis-like disease in infants due to human parechovirus type 3 during an outbreak in Australia.

Infections with human parechoviruses (HPeVs) are associated with a wide range of clinical presentations in children, ranging from mild or asymptomatic infections to severe sepsis-like presentations or meningoencephalitis. We reviewed medical records of infants admitted to 5 hospitals in New South Wales, Australia, during an outbreak of HPeV-3 infection. Data were collected on clinical presentation, laboratory markers, and outcome of infants with HPeV infection confirmed by reverse transcription polymerase chain reaction. We identified 118 infected infants. Most presented with an acute sepsis-like syndrome with high fever, tachycardia, poor perfusion, and severe irritability. Other common features were erythrodermic rash, abdominal distension, edema, and hepatitis. The age range of infants was 4 days to 9.5 months; 75% were <2 months old, including all but 1 of the 30 infants (25%) admitted to intensive care units (ICUs), who as a group, were significantly younger than infants not admitted to ICUs. Only 4% of evaluable cerebrospinal fluid samples had pleocytosis, but HPeV was detected in 95%. Brain magnetic resonance imaging on a small number of children demonstrated white matter changes and diffusion restriction. Sequencing of the VP1 gene confirmed HPeV-3 in all samples tested. All children recovered without ongoing complications at last follow-up. We report the largest series of HPeV-3 infection in infants, and the first outbreak in Australia. Infants presented with a severe sepsis-like syndrome with a high rate of ICU admissions, but all recovered from the acute infection without complications. Long-term sequelae are unknown.

Molecular and epidemiological study of human parechovirus infections in Taiwan, 2007-2012.

As routine diagnostic assays for human parechoviruses (HPeVs) have not been included in the enteroviruses surveillance network in Taiwan, HPeVs may be the actual pathogens of hundreds of untypeable enteroviruses-suspected isolates. In this study, these untypeable isolates collected from 2007 through 2012 were examined by reverse transcription-polymerase chain reaction (RT-PCR)-based methods to survey the epidemiology of HPeVs in Taiwan. Thirty-eight HPeV isolates were identified from 575 untypeable isolates, including 23 HPeV type1 (HPeV1), 13 HPeV3, and two HPeV6. Most of the patients were Taiwanese children under 5 years of age and their infections were generally prevalent in summer and autumn, with the highest peak occurring in September. The ratio of male to female patients was 1.56 and 2.25 for HPeV1 and HPeV3, respectively. Fever and respiratory symptoms were reported in significantly more patients infected with HPeV1. The results of phylogenetic analyses showed that HPeV isolates between 2007 and 2012 belonged to different lineages, indicating that endemic circulation of HPeV existed in Taiwan. This study showed that HPeVs have been endemic in Taiwan for some years despite a low positive rate. The detection tests of HPeVs are needed to correct a diagnostic deficit in the surveillance system. The epidemiological and genetic information obtained from the present study would contribute to the understanding of the etiology and epidemiology of HPeVs.

Diversity and recombination of human parechovirus in children with acute gastroenteritis in Guangzhou, China.

Human parechovirus (HPeV), a member of Picornaviridae family, is a widespread pathogen causing a wide spectrum of diseases. Like other picornaviruses, HPeV genome recombination has been detected. A total of 322 fecal samples were collected from children outpatients in Guangzhou, China, including 42 (13.0%, 42/322) HPeV-positive samples detected in most of the infected children less than two years old. Seven HPeV genotypes (HPeV1, HPeV3, HPeV4, HPeV5, HPeV6, HPeV8 and HPeV14) were detected, among which, HPeV14, a rare genotype, was reported for the first time in children with acute gastroenteritis in China. This study revealed recombination events in eight samples. Clinical profiles did not yield statistical significance between children with HPeV infection alone and cases without pathogens detected. In conclusion, this study demonstrated that HPeV circulated in Guangzhou, China is diverse genetically, which provided evidence of recombination in HPeV in China.

Human parechovirus-3 infection in a neonate with fever and suspected sepsis

The human parechovirus (HPeV) are viruses of the recently described Picornaviridae family and are causing several infections in young children. The pathology associated with these viruses is beginning to emerge. The HPeV type 3 has been described particularly in association with sepsis-like febrile syndromes, meningitis and encephalitis in very young infants and neonates. We report the case of a 14-day-old girl with a fever and clinical sepsis that required hospitalisation and in which HPeV-3 was identified in the cerebrospinal fluid. The blood, urine and cerebrospinal fluid bacterial cultures were negative, and the patient improved. This case illustrates the usefulness of investigating parechovirus infection in neonates with fever or suspected sepsis. Los parechovirus humanos (HPeV) son virus de la familia Picornaviridae recientemente descritos y causantes de numerosas infecciones en niños pequeños. La afección asociada a estos virus se está empezando a conocer. El HPeV tipo 3 se ha descrito especialmente asociado a síndromes febriles, sepsis-like, meningitis y encefalitis en lactantes muy pequeños y neonatos. Presentamos el caso de una niña de 14 días de vida con un cuadro de fiebre que precisó hospitalización por sospecha de sepsis y en la que se identificó en líquido cefalorraquídeo un HPeV-3. Las pruebas analíticas (leucocitos, fórmula diferencial y procalcitonina en sangre) fueron normales. Los cultivos bacterianos de sangre, orina y líquido cefalorraquídeo fueron estériles. La paciente evolucionó favorablemente. Este caso ilustra la utilidad de investigar la infección por parechovirus en los recién nacidos con fiebre o sospecha de sepsis.

Distinct systemic and central nervous system disease patterns in enterovirus and parechovirus infected children

Enteroviruses (EV) and human parechoviruses (HPeV) infections are increasingly identified in neonates and young children with sepsis, meningitis and encephalitis. We investigated EV and HPeV viral loads in plasma and cerebrospinal fluid (CSF) among those presenting with sepsis or central nervous system (CNS) disease to gain understanding of the nature of these infections. Detections frequencies and viral loads of EV and HPeV RNA were compared in plasma and CSF obtained from infected children originally identified on sepsis or CNS screening. Two distinct infection profiles were identified; 11 subjects with CNS disease, showed higher or similar viral loads in CSF than in plasma (median plasma:CSF ratio 0.5), whereas 14 children with sepsis showed low or undetectable viral loads in CSF and high viral loads in plasma (mean ratio 5700). HPeV type 3 and one EV serotype (coxsackievirus B2) were primarily associated with the latter presentation. Simple detection of EV or HPeV RNA in CSF is not predictive of CNS disease, especially in the absence of clinical markers (i.e. pleocytosis). Screening of plasma can identify EV and HPeV RNA in a substantial proportion of sepsis cases, some of which will be missed if CSF samples alone are screened.

Infection sévère à paréchovirus de type 3 chez un nourrisson de 6 semaines

Febrile infants under 3 months of age are often treated with broad-spectrum intravenous antibiotics while awaiting culture results, to prevent mother-to-child bacterial infections. Human parechoviruses (HPeV) have recently been described as etiologic agents of meningitis and severe sepsis in neonates and young infants. They are rarely investigated and are therefore probably underestimated. They cause acute clinical symptoms that can incorrectly suggest a bacterial infection. In the present case, a 6-week-old infant infected with HPeV developed severe sepsis, complicated by hepatic cytolysis, meningitis, acute renal failure, and mild hemophagocytic lymphohistiocytosis. HPeV type 3 was found by routine specific RT-PCR in cerebrospinal fluid, stools, and plasma. The outcome was spontaneously favorable after 4 days. Early diagnosis of the HPeV infection by routine specific RT-PCR reduces unnecessary antibiotic use and extended hospitalization in febrile young infants.

Human enterovirus and parechovirus infections in newborns with sepsis-like illness and neurological disorders

Enterovirus (HEV) and parechovirus (HPeV) infections are common in the neonatal period, and account for a large portion of febrile illnesses during the summer season. HEV infections appear clinically and seasonally similar to HPeV infections. In this study, we present the virological and clinical data from neonates infected with HEV or HPeV and hospitalized in a neonatal intensive care unit for sepsis-like illness or neurologic disorders. In the period January 2010 to October 2013, 54 cerebrospinal fluid (CSF) and 10 plasma samples were obtained from 60 newborns aged <30 days. A total of 7/60 (11.6%) patients were positive for HEV infection and 3 (5.0%) were positive for HPeV infection as determined by specific real-time RT-PCR. The most common clinical signs were fever, irritability, hyporeactivity and, in a few cases, rash. All infections were observed during the summer-fall period. In conclusion, HEV and HPeV were shown to account for a significant portion of febrile illnesses in neonates requiring hospitalization.

Human Parechovirus Infection, Denmark

Human parechoviruses (HPeVs) often cause severe illness among young children. National surveillance with routine testing of all cerebrospinal fluid, fecal, and tissue samples was conducted during January 2009-December 2012 in all counties in Denmark (6,817 samples from 4,804 children were screened for HPeV). We detected HPeV RNA in 202 (3.0%) specimens from 149 persons. Young infants were at highest risk for HPeV, and 9 (6%) of the HPeV-infected children died, probably of their HPeV illness. HPeV3 was the most common genotype identified, and 5 closely related clades of HPeV3 circulated in Denmark throughout the study period. Our study adds perspective on the prevalence and clinical and molecular virologic characteristics of HPeV infection.

重篤化した乳児期ヒトパレコウイルス感染症の2例

ヒトパレコウイルス（Human parechovirus, HPeV）は，新生児や乳児期に感染すると敗血症性ショックや中枢神経感染を来し，死亡例や重篤な神経学的後遺症を残す症例が報告されている。今回，重篤化した乳児期のHPeV感染の2例を経験したため報告する。症例1は，生後1ヶ月の男児で，敗血症性ショック，脳症，腸閉塞を認めた。7日間の人工呼吸器管理と，9日間の集中治療管理を要した。症例2は，生後1ヶ月の男児で，敗血症，脳症を認め，3日間の集中治療管理を要した。2症例ともに退室時に明らかな後遺症は認めなかった。新生児や乳児期のHPeV感染は重篤化し，かつ中枢神経後遺症を残す可能性があるため，確定診断のうえ適切な集中治療管理および中長期的な経過観察が必要である。

Hyperferritinemia in neonatal and infantile human parechovirus-3 infection in comparison with other infectious diseases

Human parechovirus-3 (HPeV-3) has been associated with severe clinical manifestations in neonates and infants in the form of sepsis or hemophagocytic lymphohistiocytosis (HLH)-like illness. To clarify the clinical features of HPeV-3 infection, we compared clinical signs and laboratory findings among enteroviruses (EVs), HPeV-3, and other infections. Participants were 26 febrile infants in whom EVs (n=20) or HPeV-3 (n=6) were isolated from throat swab or fecal specimens. Clinical and laboratory data were compared among EVs, HPeV-3, respiratory syncytial virus (RSV) infection (n=15), and bacterial meningitis (n=8) groups. Apnea was frequently seen in the HPeV-3 group although there were no significant differences in other clinical symptoms. Leukocyte count was significantly lower in the HPeV-3 group than in the EV and RSV group. Platelet count was significantly lower in the HPeV-3 group than in the RSV group. Serum ferritin levels in the HPeV-3 group (mean, 2437ng/ml) and EV group (mean, 552ng/ml) were significantly higher than in the RSV group (mean 237ng/ml; P=0.008 and P=0.002, respectively). The frequency of patients with clearly high ferritin levels ≥1000ng/ml was comparatively higher in the HPeV-3 group (4/6) than the EV group (3/20) (P=0.03). In the HPeV-3 group, ferritin levels were high on Days 4-5. Elevated ferritin levels, decreased leukocyte and platelet counts could offer diagnostic clues to HPeV-3 infection in infant. These laboratory findings might be associated with aberrant immune response to HPeV-3, which could contribute to the development of sepsis or HLH-like illness in neonates.

Genotyping of human parechoviruses in Iranian young children with aseptic meningitis and sepsis-like illness

Human parechoviruses (HPeV) are classified into 14 genotypes. HPeV1 and HPeV2 are the most prevalent genotypes in young children, which have been associated with mild to severe diseases. This study was conducted to investigate the involvement of HPeVs in aseptic meningitis and sepsis-like illness in Iran. Viral RNA was extracted from 148 cerebrospinal fluid samples from children <8 years old with primary diagnosis of aseptic meningitis and/or sepsis-like illness. Specific HPeV, HEV real-time PCR and HPeV typing were done to identify the infection rate of these viruses. HPeV and HEV were detected in 64 (43.24 %), 31 (20.94 %) of 148 patients with 10 (6.75 %) coinfection. VP1/VP3 junction region was successfully sequenced from 12 of the HPeV-positive specimens, and all of them were identified as HPeV1. HPeV was more prevalent than HEV in both aseptic meningitis and sepsis-like illness, so further studies are needed to understand the disease burden of HPeV infections, and clinical manifestations especially in specific illnesses of possible viral etiology. Direct detection of these viruses leads to reduce hospitalization and use of antibiotic, which are often followed by other complications in neonates and young children.