Landscape of respiratory syncytial virus.

ABSTRACT: Respiratory syncytial virus (RSV) is an enveloped, negative-sense, single-stranded RNA virus of the Orthopneumovirus genus of the Pneumoviridae family in the order Mononegavirales. RSV can cause acute upper and lower respiratory tract infections, sometimes with extrapulmonary complications. The disease burden of RSV infection is enormous, mainly affecting infants and older adults aged 75 years or above. Currently, treatment options for RSV are largely supportive. Prevention strategies remain a critical focus, with efforts centered on vaccine development and the use of prophylactic monoclonal antibodies. To date, three RSV vaccines have been approved for active immunization among individuals aged 60 and above. For children who are not eligible for these vaccines, passive immunization is recommended. A newly approved prophylactic monoclonal antibody, Nirsevimab, which offers enhanced neutralizing activity and an extended half-life, provides exceptional protection for high-risk infants and young children. This review provides a comprehensive and detailed exploration of RSV's virology, immunology, pathogenesis, epidemiology, clinical manifestations, treatment options, and prevention strategies.

Genomic characteristics of human respiratory syncytial virus from children in China during 2017-2020.

Acute lower respiratory tract infections (ALRTIs) are a leading cause of mortality in young children worldwide due to human respiratory syncytial virus (RSV). The aim of this study was to monitor genetic variations in RSV and provide genomic data support for RSV prevention and control. A total of 105 complete RSV genome sequences were determined during 2017-2020. Phylogenetic analysis showed that all of the RSVA sequences were of genotype ON1, and all of the RSVB sequences were of genotype BA9. Notably, a phylogenetic tree based on the whole genome had more branches than a tree based on the G gene. In comparison to the RSV prototype sequences, 71.43% (50/70) of the ON1 sequences had five amino acid substitutions (T113I, V131N, N178G, H258Q, and H266L) that occurred simultaneously, and 68.57% (24/35) of the BA9 genotype sequences had 12 amino acid substitutions, four of which (A131T, T137I, T288I, and T310I) occurred simultaneously. In the F gene, there were 19 amino acid substitutions, which were mainly located in the antigenic sites Ø, II, V, and VII. Other amino acid substitutions were found in the NS1, NS2, P, SH, and L proteins. No significant evidence of recombination was found in any of the sequences. These findings provide important data that will be useful for prevention, control, and vaccine development against RSV.

Dysfunction of γδ T cells in pediatric chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a progressive and life-threatening disease characterized by persistent or recurrent EBV activation. It has been reported that, γδ T cells, a type of cytotoxic lymphocyte, play a critical role in restricting EBV. However, the functional status of γδ T cells in pediatric CAEBV patients has not yet been described. In this study, flow cytometry analysis was conducted to explore the cytokine production capacity of γδ T cells in CAEBV patients. A diminished frequency of γδ T cells and decreased expression of cytolytic molecule granzyme B were found in CAEBV patients, suggesting a dysfunction in the immune regulatory function of γδ T cells in this disease.

Genetic characteristics of human parainfluenza viruses 1-4 associated with acute lower respiratory tract infection in Chinese children, during 2015-2021.

Human parainfluenza viruses (HPIVs) are a significant cause of acute lower respiratory tract infections (ALRTIs) among young children and elderly individuals worldwide. The four types of HPIVs (HPIV1-4) can cause recurrent infections and pose a significant economic burden on health care systems globally. However, owing to the limited availability of complete genome sequences, the genetic evolution of these viruses and the development of vaccines and antiviral treatments are hampered. To address this issue, this study utilized next-generation sequencing to obtain 156 complete genome sequences of HPIV1-4, which were isolated from hospitalized children with ALRTIs in six regions of China between 2015 and 2021. This study revealed multiple clades, lineages, or sublineages of HPIVs circulating in mainland China, with a novel clade D of HPIV1 identified as geographically restricted to China. Moreover, this study identified the endemic dominant genotype of HPIV3, lineage C3, which has widely spread and continuously circulated in China. Bioinformatic analysis of the genome sequences revealed that the proteins of HPIV3 possessed the most variable sites, with the P protein showing more diversity than the other proteins among all types of HPIVs. The HN proteins of HPIV1-3 are all under negative/purifying selection, and two amino acid substitutions in the HN proteins correspond to known mAb neutralizing sites in the two HPIV3 strains. These findings provide crucial insights into the genetic diversity and evolutionary dynamics of HPIVs circulating among children in China and may facilitate research on the molecular diagnosis, vaccine development, and surveillance of HPIVs.IMPORTANCEPhylogenetic analysis revealed the prevalence of multiple clades, lineages, or sublineages of human parainfluenza viruses (HPIVs) circulating in mainland China. Notably, a unique evolutionary branch of HPIV1 containing only Chinese strains was identified and designated clade D. Furthermore, in 2023, HPIV3 strains from Pakistan and Russia formed a new lineage within clade C, named C6. The first HPIV4b sequence obtained in this study from China belongs to lineage C2. Evolutionary rate assessments revealed that both the HN and whole-genome sequences of HPIV3 presented the lowest evolutionary rates compared with those of the other HPIV types, with rates of 6.98E-04 substitutions/site/year (95% HPD: 5.87E-04 to 8.25E-03) and 5.85E-04 substitutions/site/year (95% HPD: 5.12E-04 to 6.62E-04), respectively. Recombination analysis revealed a potential recombination event in the F gene of an HPIV1 strain in this study. Additionally, all the newly obtained HPIV1-3 strains exhibited negative selection pressure, and two mutations were identified in the HN protein of two HPIV3 strains at monoclonal antibody-binding sites.

Human adenovirus type 4 (HAdV-4) associated acute respiratory tract infection in children & genetic characteristics of HAdV-4 in China: a prospective multicenter study.

BACKGROUND: Human adenovirus (HAdV) is an important pathogen causing acute respiratory infection (ARI) in children. Many countries, including China, have experienced sporadic or outbreaks related to HAdV-4, and death cases were reported. However, there is little research on HAdV-4 and the epidemic situation of HAdV-4 in China is little known. This study was designed to comprehend the prevalence and genetic characteristics of HAdV-4 in ARI children in China. METHODS: Respiratory tract samples from ARI children hospitalized in six hospitals of Northern and Southern China from 2017 to 2020 were collected for HAdV detection and typing. Clinical information was collected from HAdV-4 positive patients for clinical characteristics and epidemiological analysis. The main capsid proteins and the whole genome sequences were amplified and sequenced for bioinformatics analysis. RESULTS: There were 2847 ARI children enrolled, and 156 (5.48%) HAdV positive samples were detected. Eleven HAdV-4 positive samples were identified, accounting for 0.39% of the total samples and 7.05% of the HAdV positive samples. The main manifestations were fever and cough. Two children had conjunctivitis. Two children were diagnosed with severe pneumonia and developed respiratory failure. One of them developed hemophagocytic syndrome and checked in pediatric intensive care unit (PICU). This child had ventricular septal defect. All the children recovered. The isolated strains of HAdV-4 obtained in this study and the reference strains from China located in the same phylogenetic branch (HAdV-4a), while the prototype strain and vaccine strains formed another branch (HAdV-4p). Upon comparison with the prototype strain, there were a few amino acid mutations existing in three major capsid proteins. According to recombination analysis, no new recombination was found. CONCLUSIONS: The detection rate of HAdV-4 in children hospitalized with ARI was 0.39% in the total samples and 7.05% of all HAdV positive samples. HAdV-4 isolates obtained in this study and other reference strains from China belonged to the HAdV-4a subtype. Our data provided reference for the monitoring, prevention and control of HAdV-4, as well as the research and development of vaccines and drugs.

A multi-center study on genetic variations in the fusion protein of respiratory syncytial virus from children with Acute Lower Respiratory Tract Infections in China during 2017-2021.

Respiratory syncytial virus (RSV) is a significant cause of acute lower respiratory tract infection (ALRTI) in children under five years of age. Between 2017 and 2021, 396 complete sequences of the RSV F gene were obtained from 500 RSV-positive throat swabs collected from ten hospitals across nine provinces in China. In addition, 151 sequences from China were sourced from GenBank and GISAID, making a total of 549 RSV F gene sequences subjected to analysis. Phylogenetic and genetic diversity analyses revealed that the RSV F genes circulating in China from 2017 to 2021 have remained relatively conserved, although some amino acids (AAs) have undergone changes. AA mutations with frequencies ≥ 10% were identified at six sites and the p27 region: V384I (site I), N276S (site II), R213S (site Ø), and K124N (p27) for RSV A; F45L (site I), M152I/L172Q/S173 â€‹L/I185V/K191R (site V), and R202Q/I206M/Q209R (site Ø) for RSV B. Comparing mutational frequencies in RSV-F before and after 2020 revealed minor changes for RSV A, while the K191R, I206M, and Q209R frequencies increased by over 10% in RSV B. Notably, the nirsevimab-resistant mutation, S211N in RSV B, increased in frequency from 0% to 1.15%. Both representative strains aligned with the predicted RSV-F structures of their respective prototypes exhibited similar conformations, with low root-mean-square deviation values. These results could provide foundational data from China for the development of RSV mAbs and vaccines.

Current antiviral agents against human adenoviruses associated with respiratory infections.

Human adenoviruses (HAdVs) are important pathogens responsible for respiratory infections. In children and immunocompromised patients, respiratory infections can cause considerable morbidity and mortality. Currently, there are no approved effective and safe antiviral therapeutics for the clinical treatment of HAdV infections, even those that have undergone preclinical/clinical trials. However, many compounds and molecules with anti-HAdV activity have been explored, and some candidates are undergoing clinical development. Here, we reviewed the reported in vitro and in vivo efficacies, as well as the therapeutic potential of these antiviral compounds, providing an overview and a summary of the current status of anti-HAdV drug development.

Clinical epidemiology of Epstein-Barr virus-associated Lymphoproliferative Disorders (EBV-LPDs) in hospitalized children: A six-year multi-institutional study in China.

BACKGROUND: Epstein-Barr virus-associated lymphoproliferative disorders (EBV-LPDs) are a group of disorders involving lymphoid tissues or lymphocytes. The epidemiology and economic burden of hospitalized children with EBV-LPDs in China have not been well studied. This study aimed to reveal the epidemic characteristics and disease burden of EBV-LPDs among the Chinese hospitalized children, providing strategies for the prevention and management. METHODS: This study was based on the FUTang Updating medical REcords (FUTURE) database of China and collected the medical records from 27 tertiary children's hospitals between January 2016 and December 2021 in China, counting five types of EBV-LPDs, namely EBV-positive T-cell lymphoproliferative disease, NK/T cell lymphoma, extranodal NK/T-cell lymphoma (nasal type), systemic EBV-positive T-cell lymphoproliferative disease of childhood and posttransplant lymphoproliferative disorders. We conducted a retrospective syhthesis and analysis of the epidemiological characteristics, expenses, length of stay (LOS), as well as complications among hospitalized children diagnosed with five types of EBV-LPDs and compared parameters using appropriate statistical tests. RESULTS: The study described 153 children aged 0-18 years hospitalized with EBV-LPDs from 2016 to 2021 in the FUTURE database. The male-to-female ratio was 1.10:1, and more than half of the age distribution was in the 6-12 y group. Among EBV-LPDs cases, EBV+ T-LPD accounted for the largest proportion (65.36%). Complications were presented in 93 children with EBV-LPDs, mainly hemophagocytic lymphohistiocytosis (HLH). The median LOS of NKTL was 26.5 days [interquartile range (IQR) = 3-42], which was the longest among EBV-LPDs. The median hospitalization cost of PTLD was 10 785.74 United States dollars (IQR = 7 329.38-16 531.18), which was the heaviest among EBV-LPDs. CONCLUSIONS: Compared with the total number of hospitalized children in China during the same period and in the same age group, the proportion of EBV-LPD is very low. EBV-LPD can develop in all age groups, but it is more common in school-age children. Among 5 EBV-LPDs, the disease with the highest proportion is EBV+ T-LPD. The overall disease burden of EBV-LPD was heavy, especially the economic burden. HLH was one of the most common complications, which could directly affect the burden of patients because of prolonged hospitalization. These data are taken from a very large database, illustrating the epidemiological and economic burden of EBV-LPDs hospitalized children in China, which enriched the existing epidemiological and disease burden content of EBV-LPDs.

Histone methylation in Epstein-Barr virus-associated diseases.

Epstein-Barr virus (EBV) infection is linked to various human diseases, including both noncancerous conditions like infectious mononucleosis and cancerous diseases such as lymphoma and nasopharyngeal carcinoma. After the initial infection, EBV establishes a lifelong presence and remains latent in specific cells. This latent infection causes changes in the epigenetic marks known as histone methylation. Many studies have examined the role of histone methylation in different EBV-associated diseases, and understanding how EBV affects histone methylation can help us identify potential targets for epigenetic therapies. This review focuses on the research progress made in understanding histone methylation in well-studied EBV-associated diseases, intending to provide insights into potential strategies based on histone methylation to combat EBV-related ailments.

This review focuses on histone methylation in EBV-associated diseases, offering potential strategies to combat EBV-related ailments. #EBV #histonemethylation #epigenetics #medicalresearch.

Efficacy and safety of robot-assisted deep brain stimulation for Parkinson's disease: a meta-analysis.

Objective: This meta-analysis aims to assess the effectiveness and safety of robot-assisted deep brain stimulation (DBS) surgery for Parkinson's disease(PD). Methods: Four databases (Medline, Embase, Web of Science and CENTRAL) were searched from establishment of database to 23 March 2024, for articles studying robot-assisted DBS in patients diagnosed with PD. Meta-analyses of vector error, complication rate, levodopa-equivalent daily dose (LEDD), Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS II, UPDRS III, and UPDRS IV were performed. Results: A total of 15 studies were included in this meta-analysis, comprising 732 patients with PD who received robot-assisted DBS. The pooled results revealed that the vector error was measured at 1.09 mm (95% CI: 0.87 to 1.30) in patients with Parkinson's disease who received robot-assisted DBS. The complication rate was 0.12 (95% CI, 0.03 to 0.24). The reduction in LEDD was 422.31 mg (95% CI: 68.69 to 775.94). The improvement in UPDRS, UPDRS III, and UPDRS IV was 27.36 (95% CI: 8.57 to 46.15), 14.09 (95% CI: 4.67 to 23.52), and 3.54 (95% CI: -2.35 to 9.43), respectively. Conclusion: Robot-assisted DBS is a reliable and safe approach for treating PD. Robot-assisted DBS provides enhanced accuracy in contrast to conventional frame-based stereotactic techniques. Nevertheless, further investigation is necessary to validate the advantages of robot-assisted DBS in terms of enhancing motor function and decreasing the need for antiparkinsonian medications, in comparison to traditional frame-based stereotactic techniques.Clinical trial registration: PROSPERO(CRD42024529976).

Changes in the epidemiology and clinical characteristics of viral gastroenteritis among hospitalized children in the Mainland of China: a retrospective study from 2016 to 2020.

BACKGROUND: Acute gastroenteritis (AGE) causes significant morbidity in children worldwide; however, the disease burden of children hospitalized with viral gastroenteritis in China has been rarely described. Through this study, we analyzed the data of hospitalized children with viral gastroenteritis to explore the changes in the epidemiology and clinical characteristics of viral gastroenteritis in the mainland of China. METHODS: Data were extracted from Futang Children's Medical Development Research Center (FRCPD), between 2016 and 2020, across 27 hospitals in 7 regions. The demographics, geographic distribution, pathogenic examination results, complications, hospital admission date, length of hospital stays, hospitalization charges and outcomes were collected and analyzed. RESULTS: Viral etiological agents included rotavirus (RV), adenovirus (ADV), norovirus (NV) and coxsackievirus (CV) that were detected in 25,274 (89.6%), 1,047 (3.7%), 441 (1.5%) and 83 (0.3%) cases. There was a higher prevalence of RV and NV infection among children younger than 3 years of age. RV and NV had the highest detection rates in winter, while ADV in summer. Children with viral gastroenteritis were often accompanied by other diseases, such as myocardial diseases (10.98-31.04%), upper respiratory tract diseases (1.20-20.15%), and seizures (2.41-14.51%). Among those cases, the co-infection rate with other pathogens was 6.28%, with Mycoplasma pneumoniae (M. pneumoniae), Epstein-Barr virus (EBV), and influenza virus (FLU) being the most common pathogens. The median length of stay was 5 days, and the median cost of hospitalization corresponded to587 US dollars. CONCLUSIONS: This finding suggests that viral gastroenteritis, especially those caused by RV, is a prevalent illness among younger children. Co-infections and the presence of other diseases are common. The seasonality and regional variation of viral etiological agents highlight the need for targeted prevention and control measures. Although viral gastroenteritis rarely leads to death, it also results in a significant economic burden on healthcare systems.

Activation of the NLRP3 inflammasome by human adenovirus type 7 L4 100-kilodalton protein.

Human adenovirus type 7 (HAdV-7) is a significant viral pathogen that causes respiratory infections in children. Currently, there are no specific antiviral drugs or vaccines for children targeting HAdV-7, and the mechanisms of its pathogenesis remain unclear. The NLRP3 inflammasome-driven inflammatory cascade plays a crucial role in the host's antiviral immunity. Our previous study demonstrated that HAdV-7 infection activates the NLRP3 inflammasome. Building upon this finding, our current study has identified the L4 100 kDa protein encoded by HAdV-7 as the primary viral component responsible for NLRP3 inflammasome activation. By utilizing techniques such as co-immunoprecipitation, we have confirmed that the 100 kDa protein interacts with the NLRP3 protein and facilitates the assembly of the NLRP3 inflammasome by binding specifically to the NACHT and LRR domains of NLRP3. These insights offer a deeper understanding of HAdV-7 pathogenesis and contribute to the development of novel antiviral therapies.

Clinical epidemiology of adenovirus pneumonia among Chinese hospitalized children.

Adenovirus pneumonia is a prevalent form of community-acquired pneumonia among children. Research on the epidemiology and economic burden of this disease is crucial for public health, yet comprehensive data remains scarce, making it crucial to highlight on this topic. In this study, the data were extracted from the face sheet of discharge medical records collected from 26 tertiary children's hospitals from January 2016 to December 2021. In total, 1854 children with laboratory-confirmed adenovirus pneumonia were hospitalized, accounting for 0.13% of the total number of hospitalized for pneumonia in the database during the period. In addition, this figure represents a meager 0.027% when compared to the total number of hospitalized children. The male-to-female ratio was 1.78:1. The 1-3-year age group had the highest number of inpatients for adenoviral pneumonia and the largest proportion of the total hospitalizations in the same age group. Overall, winter is the primary season for the prevalence of adenovirus pneumonia, however, in southern China, there are two peak seasons, winter and summer. Although patients with 3/4 adenovirus pneumonia had no significant complications, some patients had complications such as respiratory failure, diarrhea, and myocardial damage. The median length of stay of adenovirus pneumonia was 8 d [interquartile range (IQR) 6-11], and the median hospitalization cost was 1293.83 United States dollars (IQR 811.81-2472.51). These valuable epidemiological insights into adenovirus pneumonia in Chinese children can help direct the development of targeted prevention and control strategies and surveillance measures for HAdV infections in this demographic.

Expert consensus on the diagnosis, treatment, and prevention of respiratory syncytial virus infections in children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading global cause of respiratory infections and is responsible for about 3 million hospitalizations and more than 100,000 deaths annually in children younger than 5 years, representing a major global healthcare burden. There is a great unmet need for new agents and universal strategies to prevent RSV infections in early life. A multidisciplinary consensus development group comprising experts in epidemiology, infectious diseases, respiratory medicine, and methodology aims to develop the current consensus to address clinical issues of RSV infections in children. DATA SOURCES: The evidence searches and reviews were conducted using electronic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, using variations in terms for "respiratory syncytial virus", "RSV", "lower respiratory tract infection", "bronchiolitis", "acute", "viral pneumonia", "neonatal", "infant" "children", and "pediatric". RESULTS: Evidence-based recommendations regarding diagnosis, treatment, and prevention were proposed with a high degree of consensus. Although supportive care remains the cornerstone for the management of RSV infections, new monoclonal antibodies, vaccines, drug therapies, and viral surveillance techniques are being rolled out. CONCLUSIONS: This consensus, based on international and national scientific evidence, reinforces the current recommendations and integrates the recent advances for optimal care and prevention of RSV infections. Further improvements in the management of RSV infections will require generating the highest quality of evidence through rigorously designed studies that possess little bias and sufficient capacity to identify clinically meaningful end points.

Development and evaluation of a multiplex digital PCR method for sensitive and accurate detection of respiratory pathogens in children.

The emergence of multiplex digital polymerase chain reaction (dPCR) and other detection technologies for respiratory pathogens in recent years has facilitated greater understanding of respiratory virus epidemics. In this study, a multiplex dPCR method was developed and evaluated as a means of detecting five respiratory pathogens in children with acute lower respiratory tract infection (ALRTI). With 139 nasopharyngeal swabs collected from children with ALRTI, pathogens were detected using dPCR and quantitative real-time PCR (qPCR) methods. Of those specimens, dPCR detected 86 positive cases, while qPCR identified 84. Moreover, dPCR exhibited higher sensitivity than qPCR, and displayed no cross-reactivity with common respiratory pathogens. These findings suggest that dPCR-based method could become one of the most promising options for acute respiratory pathogen detection.

Clinical epidemiology and disease burden of adenoviral encephalitis in hospitalized children in China: A nationwide cross-sectional study.

Importance: Adenovirus encephalitis is a significant infectious disease of the central nervous system that commonly affects children under the age of 5 and has a profound impact on the health of infants and young children throughout China. National multicenter epidemiological studies have significant public health implications. Objective: This study aims to report the epidemiology of adenovirus encephalitis in hospitalized children in China, providing valuable guidance for clinicians. Methods: The data utilized in this study were extracted from the comprehensive Futang Update Medical Records database, which comprises discharge medical records collected by 27 tertiary children's hospitals between January 2016 and December 2018 in China. Specifically, the face sheet of discharge medical records encompassed critical sociodemographic variables and basic medical care details. Results: In this database, a total of 544 children were hospitalized due to adenoviral encephalitis. The male-to-female ratio was 1.62:1, with more boys being affected across different age groups and places of residence. Of the children hospitalized, the highest number of hospitalizations occurred in the 1-3-year age group and the number of hospitalizations decreased each year from 2016 to 2018. The disease exhibits seasonal characteristics with a pronounced peak in the summer months of June and July. While most children (58%) did not have any significant complications, one-third of them developed respiratory complications, including pneumonia and acute bronchitis. The median length of stay for adenoviral encephalitis was 7 days, and the median cost of hospitalization was 2145.56 US dollars. Interpretation: This study highlights the prevalence of adenovirus encephalitis in hospitalized children in China. Children aged 1-3 years were found to be the main demographic hospitalized due to this condition, with boys being significantly more affected than girls. The seasonal variations of adenovirus encephalitis were also found to be significant. Fortunately, the fatality rate associated with this condition was low, and the prognosis was generally favorable.