Update on nonpolio enterovirus and parechovirus infections in neonates and young infants.

PURPOSE OF REVIEW: To review the epidemiology, clinical manifestations, and treatment strategies of nonpolio enterovirus and parechovirus (PeV) infections, and identify research gaps. RECENT FINDINGS: There is currently no approved antiviral agent for enterovirus or PeV infections, although pocapavir may be provided on a compassionate basis. Elucidation of the structure and functional features of enterovirus and PeV may lead to novel therapeutic strategies, including vaccine development. SUMMARY: Nonpolio human enterovirus and PeV are common childhood infections that are most severe among neonates and young infants. Although most infections are asymptomatic, severe disease resulting in substantial morbidity and mortality occurs worldwide and has been associated with local outbreaks. Long-term sequelae are not well understood but have been reported following neonatal infection of the central nervous system. The lack of antiviral treatment and effective vaccines highlight important knowledge gaps. Active surveillance ultimately may inform preventive strategies.

Disruption of seasonal enterovirus and parechovirus detections in the CSF and plasma of children during the COVID-19 pandemic.

BACKGROUND: Enteroviruses (EV) and parechovirus (PeV) are a common cause of CNS infection in children. Both viruses demonstrate consistent seasonal patterns, with detections mainly in the summer-fall months. While research has shown COVID-19 pandemic-related disruption of traditional seasonality of respiratory pathogens, the pandemic's impact on non-respiratory pathogens is less understood. The aim of this study was to quantify the EV/PeV seasonal variations during pre-COVID years compared to variations observed during the COVID pandemic. METHODS: Patients with EV/PeV testing of CSF/plasma between January 2012 through September 2022 were identified. Restricted cubic spline methods were used to model the detections. Poisson models were utilized to model pre-COVID (2012-2019) EV/PeV detections. The expected seasonal trends from these models were then compared to the observed EV/PeV detections during the COVID pandemic (2020-2022). RESULTS: A total of 5199 patients were included. The annual pre-pandemic proportion of EV detections ranged between 7.5%-20.3%. PeV exhibited a biennial pattern with peak proportions between 8.0%-16.3%. EV/PeV detections during the COVID pandemic period, especially during 2020 and 2021, were considerably lower than would have been expected based on pre-pandemic modeling. However, PeV detections from January through September 2022 nearly reached the pre-pandemic modeled expectation, including instances of exceeded expectations. CONCLUSIONS: A significant disruption in expected seasonal EV/PeV detections was observed during the early phases of the COVID-19 pandemic. However, testing that occurred during summer-fall of 2022, when social mitigation initiatives were relaxed, showed a rapid increase in detections. Additional data are needed to further understand which public health initiatives are effective at decreasing EV/PeV transmission.

Effects of COVID-19 and Social Distancing on Rhinovirus Infections and Asthma Exacerbations.

Since their discovery in the 1950s, rhinoviruses (RVs) have been recognized as a major causative agent of the "common cold" and cold-like illnesses, accounting for more than 50% of upper respiratory tract infections. However, more than that, respiratory viral infections are responsible for approximately 50% of asthma exacerbations in adults and 80% in children. In addition to causing exacerbations of asthma, COPD and other chronic lung diseases, RVs have also been implicated in the pathogenesis of lower respiratory tract infections including bronchiolitis and community acquired pneumonia. Finally, early life respiratory viral infections with RV have been associated with asthma development in children. Due to the vast genetic diversity of RVs (approximately 160 known serotypes), recurrent infection is common. RV infections are generally acquired in the community with transmission occurring via inhalation of aerosols, respiratory droplets or fomites. Following the outbreak of coronavirus disease 2019 (COVID-19), exposure to RV and other respiratory viruses was significantly reduced due to social-distancing, restrictions on social gatherings, and increased hygiene protocols. In the present review, we summarize the impact of COVID-19 preventative measures on the incidence of RV infection and its sequelae.

High prevalence and clinical characteristics of respiratory infection by human rhinovirus in children from Lima-Peru during years 2009-2010.

INTRODUCTION: Human rhinovirus is a major cause of acute respiratory infections (ARIs) worldwide. Epidemiological data on human rhinovirus (RV) in Peru is still scarce, as well as its role in respiratory infections in children. Therefore, the aim of this study was to describe the prevalence of rhinovirus and to identify the circulating species in nasopharyngeal swabs from children with acute respiratory infections. MATERIALS AND METHODS: We analyzed nasopharyngeal swab samples that were collected from children younger than 17 years old, who had a clinical diagnosis of ARI from the "Hospital Nacional Cayetano Heredia" between May 2009 and December 2010. The original study recruited 767 inpatients with ARI, 559 samples of which were included and analyzed in the current study. Detection of rhinovirus and determination of rhinovirus species were characterized by PCR. RESULTS: Rhinovirus was detected in 42.22% samples (236/559), RV-A was detected in 10.17% (24/236) of the cases, RV-B in 16.53% (39/236), and RV-C in 73.31% (173/236). The age group with the highest number of cases was the 0-5 months group with 45.97%, followed by the 1-5 years group with 25.22%. Most of the positive RV cases, i.e., 86.44% (204/236), were hospitalized. The most common signs and symptoms found in patients who tested positive for RV were cough (72.88%), fever (68.64%), rhinorrhea (68.22%), and respiratory distress (61.44%). Infection with RV-A was associated with wheezing (p = 0.02). Furthermore, RV-C was related to cough (p = 0.01), wheezing (p = 0.002), and conjunctival injection (p = 0.03). A peak in RV-C cases was found in March (32 cases in 2010); June (18 cases in 2009 and 12 cases in 2010), which corresponds to the fall season in Peru; and also November (17 cases in 2009 and 4 cases in 2010), which corresponds to spring. RV-A and RV-B cases were constant throughout the year. CONCLUSION: In conclusion, we found a high prevalence of rhinovirus C infection among pediatric patients with acute respiratory infections in Lima, Peru. This viral infection was more common in children between 0 to 5 months old, and was associated with cough, wheezing, and conjunctival injection. Epidemiological surveillance of this virus should be strengthened/encouraged in Peru to determine its real impact on respiratory infections.

Retrospective evaluation of viral respiratory tract infections in a university hospital in Ankara, Turkey (2016-2019).

INTRODUCTION: Viruses are responsible for two-thirds of all acute respiratory tract infections. This study aims to retrospectively detect respiratory tract viruses in patients from all age groups who visited the hospital. METHODOLOGY: A total of 1592 samples from 1416 patients with respiratory tract symptoms were sent from several clinics to the Molecular Microbiology Laboratory at Gazi University Hospital from February 2016 to January 2019. Nucleic acid extraction from nasopharyngeal swabs, throat swabs or bronchoalveolar lavage (BAL) samples sent to our laboratory was done using a commercial automated system. Extracted nucleic acids were amplified by a commercial multiplex-real time Polymerase Chain Reaction (PCR) method, which can detect 18 viral respiratory pathogens. RESULTS: Among 1592 samples, 914 (57.4%) were positive for respiratory viruses. The most prevalent were rhinovirus (25.2%) and influenza A virus (12.1%), the least prevalent was the bocavirus (2.6%). Rhinovirus was the most detected as a single agent (21.2%, 194/914) among all positive cases, followed by coronavirus (9.3%, 85/914). The detection rates of coronavirus, human adenovirus, respiratory syncytial virus A/B, human parainfluenza viruses, human metapneumovirus-A/B, human parechovirus, enterovirus and influenza B virus were 9.9%, 8%, 7.7%, 5%, 3.4%, 3.1%, 3%, and 2.8%, respectively. CONCLUSIONS: The most detected viral agents in our study were influenza A virus and rhinovirus. Laboratory diagnosis of respiratory viruses is helpful to prevent unnecessary antibiotic use and is essential in routine diagnostics for antiviral treatment. Multiplex Real-time PCR method is fast and useful for the diagnosis of viral respiratory infections.

Genetic diversity and epidemiology of human rhinovirus among children with severe acute respiratory tract infection in Guangzhou, China.

BACKGROUND: Human rhinovirus (HRV) is one of the major viruses of acute respiratory tract disease among infants and young children. This work aimed to understand the epidemiological and phylogenetic features of HRV in Guangzhou, China. In addition, the clinical characteristics of hospitalized children infected with different subtype of HRV was investigated. METHODS: Hospitalized children aged < 14 years old with acute respiratory tract infections were enrolled from August 2018 to December 2019. HRV was screened for by a real-time reverse-transcription PCR targeting the viral 5'UTR. RESULTS: HRV was detected in 6.41% of the 655 specimens. HRV infection was frequently observed in children under 2 years old (57.13%). HRV-A and HRV-C were detected in 18 (45%) and 22 (55%) specimens. All 40 HRV strains detected were classified into 29 genotypes. The molecular evolutionary rate of HRV-C was estimated to be 3.34 × 10-3 substitutions/site/year and was faster than HRV-A (7.79 × 10-4 substitutions/site/year). Children who experienced rhinorrhoea were more common in the HRV-C infection patients than HRV-A. The viral load was higher in HRV-C detection group than HRV-A detection group (p = 0.0148). The median peak symptom score was higher in patients with HRV-C infection as compared to HRV-A (p = 0.0543), even though the difference did not significance. CONCLUSION: This study revealed the molecular epidemiological characteristics of HRV in patients with respiratory infections in southern China. Children infected with HRV-C caused more severe disease characteristics than HRV-A, which might be connected with higher viral load in patients infected with HRV-C. These findings will provide valuable information for the pathogenic mechanism and treatment of HRV infection.

Human rhinoviruses prevailed among children in the setting of wearing face masks in Shanghai, 2020.

BACKGROUND: Human rhinovirus (HRV) is the predominant etiological agent of the common cold in children and adults. A recent study showed that the inhibitory effect of face masks on viral shedding of HRV was less prominent than that on other respiratory viruses. Considering that most Chinese people have worn face masks in public area since the outbreak of coronavirus disease 2019, we aimed to find out whether HRV prevailed among children in 2020 and demonstrate the details of the epidemiological features of HRV under such a special circumstance. METHODS: We summarized the incidences of various respiratory virus infections in patients who visited the Children's Hospital of Fudan University during 2018-2020, and genotyped HRV positive nasopharyngeal specimens collected from 316 inpatients and 72 outpatients that visited the hospital in 2020. RESULTS: There was a major prevalence of HRV among children in the latter half of 2020, with a clear seasonality that HRV-As prevailed in summer while HRV-Cs in autumn. HRV-As were more prone to cause severe lower respiratory tract infections (LRTI), while HRV-Cs were closely associated with childhood wheezing. The predominant genotypes were A11, A28, A47, A82, A101, C40 and C43. Notably, A21, A82 and A101 took up larger proportions in severe cases than in non-severe cases. CONCLUSIONS: Our findings described a major prevalence of HRVs among children in 2020, which highlight the unique transmitting pattern of HRV and help to narrow the targets for antiviral strategies.

Hospitalized Children With Common Human Coronavirus Clinical Impact of Codetected Respiratory Syncytial Virus and Rhinovirus.

BACKGROUND: The clinical impact of common human coronavirus (cHCoV) remains unclear. We studied the clinical manifestations of pediatric cHCoV infections and the possible modifying effects of codetected human rhinovirus (RV) and respiratory syncytial virus (RSV). METHODS: We used data from an 11-year-long prospective study of hospitalized children with community-acquired respiratory tract infections. Nasopharyngeal aspirates were analyzed with real-time polymerase chain reaction assay for cHCoV OC43, NL63, HKU1 and 229E, and 15 other respiratory viruses. We assessed disease severity based on the clinical factors hospitalization length, oxygen requirement, other respiratory support and supplementary fluids. RESULTS: cHCoV was detected in 341 (8%) of 4312 children. Among 104 children with single cHCoV detections, 58 (56%) had lower respiratory tract infection (LRTI) and 20 (19%) developed severe disease. The proportion with severe disease was lower among single cHCoV detections compared with single RSV detections (338 of 870; 39%), but similar to single RV detections (136 of 987; 14%). Compared with single cHCoV, codetected cHCoV-RSV was more often associated with LRTI (86 of 89; 97%) and severe disease (adjusted odds ratio, 3.3; 95% confidence interval: 1.6-6.7). LRTI was more frequent in codetected cHCoV-RV (52 of 68; 76%) than single cHCoV, but the risk of severe disease was lower (adjusted odds ratios, 0.3; 95% confidence interval: 0.1-1.0). CONCLUSIONS: cHCoV was associated with severe LRTI in hospitalized children. Viral codetections were present in two-thirds. Codetections of cHCoV-RV were associated with lower proportions of severe disease, suggesting a modifying effect of RV on HCoV.

Incidence and Outcome of Coinfections with SARS-CoV-2 and Rhinovirus.

BACKGROUND: We aimed to compare the clinical severity in patients who were coinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rhinovirus or monoinfected with a single one of these viruses. METHODS: The study period ranged from 1 March 2020 to 28 February 2021 (one year). SARS-CoV-2 and other respiratory viruses were identified by real-time reverse-transcription-PCR as part of the routine work at Marseille University hospitals. Bacterial and fungal infections were detected by standard methods. Clinical data were retrospectively collected from medical files. This study was approved by the ethical committee of our institute. RESULTS: A total of 6034/15,157 (40%) tested patients were positive for at least one respiratory virus. Ninety-three (4.3%) SARS-CoV-2-infected patients were coinfected with another respiratory virus, with rhinovirus being the most frequent (62/93, 67%). Patients coinfected with SARS-CoV-2 and rhinovirus were significantly more likely to report a cough than those with SARS-CoV-2 monoinfection (62% vs. 31%; p = 0.0008). In addition, they were also significantly more likely to report dyspnea than patients with rhinovirus monoinfection (45% vs. 36%; p = 0.02). They were also more likely to be transferred to an intensive care unit and to die than patients with rhinovirus monoinfection (16% vs. 5% and 7% vs. 2%, respectively) but these differences were not statistically significant. CONCLUSIONS: A close surveillance and investigation of the co-incidence and interactions of SARS-CoV-2 and other respiratory viruses is needed. The possible higher risk of increased clinical severity in SARS-CoV-2-positive patients coinfected with rhinovirus warrants further large scale studies.

Effects of human immunodeficiency virus status on symptom severity in influenza-like illness in an otherwise healthy adult outpatient cohort.

The impact of HIV on influenza-like illness (ILI) has been incompletely described in the era of combination antiretroviral therapy, particularly in the post-H1N1 pandemic period. This analysis informs on ILI in an otherwise healthy, predominantly outpatient cohort of adults with HIV in the USA. From September 2010 to March 2015, this multisite observational cohort study enrolled otherwise healthy adults presenting to a participating US military medical center with ILI, a subset of whom were HIV positive. Demographics, clinical data, and self-reported symptom severity were ascertained, and enrollees completed a daily symptom diary for up to 10 days. 510 men were included in the analysis; 50 (9.8%) were HIV positive. Subjects with HIV were older and less likely to be on active duty. Rhinovirus and influenza A were the most commonly identified pathogens. Moderate-severe diarrhea (p<0.001) and fatigue (p=0.01) were more frequently reported by HIV-positive men. HIV positivity was associated with higher gastrointestinal scores, but not other measures of ILI symptom severity, after controlling for age, race, military status, and influenza season. Few were hospitalized. HIV-positive subjects had more influenza B (p=0.04) and were more likely to receive antivirals (32% vs 6%, p<0.01). Antiviral use was not significantly associated with symptom scores when accounting for potential confounders. In this predominantly outpatient cohort of adult men, HIV had minimal impact on ILI symptom severity. Despite similar illness severity, a higher percentage of subjects with HIV reported undergoing antiviral treatment for ILI, likely reflecting differences in prescribing practices.Trial registration number: NCT01021098.

The Reemergence of Seasonal Respiratory Viruses in Houston, Texas, after Relaxing COVID-19 Restrictions.

Measures intended to limit the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus at the start of the coronavirus disease 2019 (COVID-19) pandemic resulted in a rapid decrease in other respiratory pathogens. Herein, we describe the trends of respiratory pathogens in a major metropolitan health care system central microbiology reference laboratory before and during the COVID-19 pandemic, with attention to when COVID-19 mitigation measures were implemented and relaxed. During the initial lockdown period, COVID-19 was the primary respiratory pathogen detected by multiplex respiratory panels. As COVID-19 containment measures were relaxed, the first non-COVID respiratory viruses to return to prepandemic levels were members of the rhinovirus/enterovirus family. After the complete removal of COVID-19 precautions at the state level, including an end to mask mandates, we observed the robust return of seasonal coronaviruses, parainfluenza virus, and respiratory syncytial virus. Inasmuch as COVID-19 has dominated the landscape of respiratory infections since early 2020, it is important for clinicians to recognize that the return of non-COVID respiratory pathogens may be rapid and significant when COVID-19 containment measures are removed. IMPORTANCE We describe the return of non-COVID respiratory viruses after the removal of COVID-19 mitigation measures. It is important for the public and physicians to recognize that, after months of COVID-19 being the primary driver of respiratory infection, more typical seasonal respiratory illnesses have returned, and this return is out of the normal season for some of these pathogens. Thus, clinicians and the public must now consider both COVID-19 and other respiratory illnesses when a patient presents with symptomatic respiratory illness.

Upsurge of human rhinovirus infection followed by a delayed seasonal respiratory syncytial virus infection in Thai children during the coronavirus pandemic.

BACKGROUND: Respiratory syncytial virus (RSV) and human rhinovirus (HRV) commonly cause influenza-like illness in young children. The global coronavirus pandemic beginning in 2020 altered the seasonality and prevalence of these respiratory infections in Thailand. We aimed to characterize the upsurge of HRV and the subsequent RSV infection observed among young children who sought medical care at a hospital in Bangkok. METHODS: From July to December 2020, nasopharyngeal swabs from children ≤5 years of age presented with influenza-like illness were tested for RSV and HRV using reverse-transcription polymerase chain reaction. Positive samples were Sanger sequenced. Genotyping was performed using sequence and phylogenetic analysis. RESULTS: Upsurge of HRV infection began in July and was subsequently replaced by a surge of RSV infection from September onward. In 6 months, HRV was detected in 27.5% (158/574) of the samples, of which 44% (69/158) were HRV-A, 7% (11/158) were HRV-B, and 36% (57/158) were HRV-C. Meanwhile, RSV was detected in 40.4% (232/574) of the samples, of which 78% (181/232) were RSV-A and 6% (14/232) were RSV-B. RSV peaked in October 2020, approximately 2 months later than typically seen in previous years. All RSV-A were of subgenotype ON1. Codetection of HRV and RSV was found in 5.1% (29/574). CONCLUSIONS: HRV and RSV infection among young children coincided with relaxed local coronavirus public health measures, including the return to in-class schooling. The delayed RSV season in 2020 was predominantly associated with RSV-A.

Rhinovirus spread in children during the COVID-19 pandemic despite social restrictions-A nationwide register study in Finland.

Social restrictions during the coronavirus disease 2019 pandemic strongly affected the epidemiology of influenza and respiratory syncytial virus (RSV). As rhinovirus seemed to spread despite the restrictions, we aimed to analyze rhinovirus epidemiology in children during the pandemic. This register-based study used data from the Finnish Infectious Disease Register. Nationwide rhinovirus findings from July 2015 to March 2021 were included and stratified by age (0-4, 5-9, and 10-14). Cumulative 14-day incidence per 100000 children was calculated. Four thousand five hundred and seventy six positive rhinovirus findings were included, of which 3788 (82.8%) were among children aged 0-4. The highest recorded incidence was 36.2 among children aged 0-4 in October 2017. The highest recorded incidence during the pandemic period was 13.6 in November 2020. The impact of the restrictions was mostly seen among children aged 0-4 years of age in weeks 14-22 in 2020. The incidence has since remained near reference levels in all age groups. Strict restrictions temporarily interrupted the circulation of rhinovirus in spring 2020. Rhinovirus incidence returned to normal levels soon after the harsh restrictions were lifted. These looser social restrictions prevented RSV and influenza seasons but failed to prevent the spread of rhinovirus.

Increased risk of rhinovirus infection in children during the coronavirus disease-19 pandemic.

BACKGROUND: Coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level. METHODS: To investigate the impact of COVID-19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020. RESULTS: The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella-zoster virus) was appreciably reduced among all patients during the COVID-19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID-19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children. CONCLUSIONS: Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID-19 pandemic and viral interference with SARS-CoV-2.

Respiratory viruses and febrile response in children with febrile seizures: A cohort study and embedded case-control study.

OBJECTIVE: There are limited data on the pathogen-related and host-related factors in the pathogenesis of febrile seizures (FS). We designed a controlled study to compare the role of different respiratory viruses and febrile response in FS. METHODS: In a prospective cohort study of 1899 pediatric emergency room patients aged 6 months-6 years with a positive respiratory virus multiplex PCR, we identified 225 patients with FSs. We first compared the distribution of respiratory viruses in age-stratified patients with FSs with that in other patients. In an embedded case-control study, we compared the febrile response in patients with FSs with that in the controls matched for age, season and the same respiratory virus. RESULTS: The relative risk for FS was the highest for coronavirus OC43, 229E, and NL63 infections [RR: 3.2, 95 % confidence interval (CI): 1.4-7.2) and influenza A and B [RR: 2.5, 95 % CI: 1.4-4.7] as compared to those with other respiratory viral infections. The patients with FSs had a stronger febrile response of 39.2 °C (difference: 0.8 °C, 95 % CI: 0.5-1.2) later during hospitalization after acute care than the controls matched for the same respiratory virus. CONCLUSIONS: Influenza and coronaviruses caused relatively more FS-related emergency room visits than other respiratory viruses. Furthermore, the febrile response was stronger in the patients with FSs than in the controls matched for the same respiratory virus. The results suggest that the pathomechanism of FSs includes modifiable pathogen-related and host-related factors with possible potential in the prevention of FSs.