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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children. During the COVID-19 pandemic, a significant change in the epidemiology of RSV and other viruses occurred worldwide, leading to a reduction in the circulation of these infectious agents. After the pandemic, the resurgence of seasonal respiratory viruses occurred, but some features of these infections contrast to those registered prior to the pandemic. In the present work, we studied 390 children <5 years old admitted to the hospital to determine the contribution of RSV, SARS-CoV-2, human metapneumovirus (hMPV), and influenza viruses to acute respiratory infections during the 2023–2024 winter season in Mexico. RSV was the most frequently detected virus (n = 160, 41%), followed by SARS-CoV-2 (n = 69, 17.7%), hMPV (n = 68, 17.4%), and influenza A or B (n = 40, 10.26%). Fourteen patients required admission to the intensive care unit, including six (42.8%) with RSV infection. Four children died (1%). At least one of the four viruses was detected in all deceased patients: SARS-CoV-2 in one; SARS-CoV-2 and hMPV in two; and RSV, influenza A, and SARS-CoV-2 in one. The high impact of RSV and other respiratory viruses indicates the need to implement specific preventive programs to reduce the morbidity and mortality associated with them. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (HMPV) is a significant respiratory pathogen, particularly in vulnerable populations. Background: No vaccine for the prevention of HMPV is currently licensed, although several subunit vaccines are in development. Saponin-based adjuvant systems (AS), including QS-21, have transformed the field of subunit vaccines by dramatically increasing their potency and efficacy, leading to the development of several licensed vaccines. However, naturally sourced tree bark-extracted QS-21 faces supply and manufacturing challenges, hindering vaccine development. Objective: This study reports on an alternative plant cell culture system for the consistent production of highly pure QS-21. Method: We evaluated the efficacy of cultured plant cell (cpc)-produced QS-21 in a novel HMPV vaccine, formulating a recombinant pre-fusion stabilized HMPV F protein (preF) with cpcQS-21 and a synthetic toll-like receptor 4 (TLR4) agonist adjuvant formulation. Results: In mice, TLR4 agonist containing adjuvant formulations with plant cell-produced QS-21 performed equally to licensed adjuvant AS01 containing tree-bark-extracted QS-21 and demonstrated a significant increase in immunogenicity against HMPV preF compared to the unadjuvanted control. Conclusion: Our findings pave the way for a reliable, scalable, and sustainable source of pure QS-21, enabling the development of highly effective HMPV and other vaccines with significant public health impact. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (HMPV) is a leading cause of respiratory infections in children, older adults, and those with underlying conditions (K. M. Edwards et al., N Engl J Med 368:633-643, 2013, https://doi.org/10.1056/NEJMoa1204630; A. R. Falsey et al., J Infect Dis 187:785-790, 2003, https://doi.org/10.1086/367901; J. S. Kahn, Clin Microbiol Rev 19:546-557, 2006, https://doi.org/10.1128/CMR.00014-06; N. Shafagati and J. Williams, F1000Res 7:135, 2018, https://doi.org/10.12688/f1000research.12625.1). HMPV must evade immune defenses to replicate successfully; however, the viral proteins used to accomplish this are poorly characterized. The HMPV small hydrophobic (SH) protein has been reported to inhibit signaling through type I and type II interferon (IFN) receptors in vitro in part by preventing STAT1 phosphorylation (A. K. Hastings et al., Virology (Auckl) 494:248-256, 2016, https://doi.org/10.1016/j.virol.2016.04.022). HMPV infection also inhibits IL-6 signaling. However, the mechanisms by which SH inhibits signaling and its involvement in IL-6 signaling inhibition are unknown. Here, we used transfection of SH expression plasmids and SH-deleted virus (SH) to show that SH is the viral factor responsible for the inhibition of IL-6 signaling during HMPV infection. Transfection of SH-expression vectors or infection with wild-type, but not SH virus, blocked IL-6-mediated STAT3 activation. Furthermore, JAK1 protein (but not RNA) was significantly reduced in cells infected with wild-type, but not SH virus. The SH-mediated reduction of JAK1 was partially restored by the addition of proteasome inhibitors, suggesting proteasomal degradation of JAK1. Confocal microscopy indicated that infection relocalized JAK1 to viral replication factories. Co-immunoprecipitation showed that SH interacts with JAK1 and ubiquitin, further linking SH to proteasomal degradation machinery. These data indicate that SH inhibits IL-6 and IFN signaling in infected cells in part by promoting proteasomal degradation of JAK1 and that SH is necessary for IL-6 and IFN signaling inhibition in infection. These findings enhance our understanding of the immune evasion mechanisms of an important respiratory pathogen. IMPORTANCE Human metapneumovirus (HMPV) is a common cause of severe respiratory illness, especially in children and older adults, in whom it is a leading cause of hospitalization. Prior research suggests that severe HMPV infection is driven by a strong immune response to the virus, especially by inflammatory immune signals like interferons (IFN). HMPV produces a small hydrophobic (SH) protein that is known to block IFN signaling, but the mechanism by which it functions and its ability to inhibit other important immune signals remains unexplored. This paper demonstrates that SH can inhibit another related immune signal, IL-6, and that SH depletes JAKs, which are critical proteins involved in both IL-6 and IFN signaling. A robust understanding of how HMPV and related viruses interfere with immune signals important for disease could pave the way for future treatments aimed at mitigating severe infections. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (HMPV) is a member of the genus Metapneumovirus in the family Pneumoviridae of the order Mononegavirales that can cause upper and lower respiratory tract disease. This retrospective study describes the epidemiology of hMPV based on community viral surveillance results from sentinel sites across Taiwan from 2013 to 2023. A total of 114 hMPV strains were isolated and analyzed to assess viral evolution through sequencing of their fusion protein genes. This study revealed that hMPV cases occur almost year-round in Taiwan, with a peak occurring during spring (March to May). Of the 114 infected patients, 68.4% were children under 4 years old. The geographical distribution of hMPV positivity was highest in Penghu County, followed by Changhua County and Hsinchu County. The clinical symptoms of hMPV infection are nonspecific, with fever (56.1%), cough (44.7%), rhinorrhea (21.1%), and sore throat (14.9%) being the most common. However, a few patients also developed severe central nervous system symptoms (1.8%) or dyspnea (0.9%). Phylogenetic analysis revealed genetic diversity among the 114 isolated hMPV strains, with the A2 lineage (57.9%) being the most frequently observed, followed by the B2 lineage (33.3%), in the Taiwanese community from 2013 to 2023. In conclusion, hMPV causes a serious acute respiratory disease in Taiwan that should not be neglected. Further epidemiological surveillance and investigations of the clinical characteristics of hMPV should be performed continually for prevention and control of this virus. [ABSTRACT FROM AUTHOR]

Objective. To study the characteristics of severe acute bronchiolitis (AB) caused by hMPV (hMPV-AB). Materials and Methods: This retrospective comparative study included 27 patients aged 2 to 12 months, who were hospitalized from 2021 to 2023 in the Intensive Care Unit (ICU) of the «Kommunarka» Moscow Multidisciplinary Clinical Center. The etiology of AB was determined using polymerase chain reaction. Results. Patients with hMPV-AB had a longer stay in the ICU compared to patients with AB of another etiology (9.0 [5.0; 11.0]; 3,0 [2.0; 4.0] days, p = 0.007). Ratio SpO2/FiO2 was lower in patients with hMPV-AB (190.2 [131.0; 203.3]) compared to patients with AB of another etiology (275.0 [253.0; 340.0], p = 0.001). Rating on the Pediatric Sequential Organ Failure Assessment (pSOFA) was higher in patients with hMPV-AB (5.0 [3.45; 11.0] vs. 1.0 [0.54; 1.93], p = 0.002). One lethal outcome was recorded in the hMPV-AB group. Conclusions. hMPV-AB in children is characterized by a more severe course and requires more intensive treatment compared to AB of other etiologies.

Background Unlike influenza, information on the burden of human metapneumovirus (HMPV) as a cause of hospitalizations in adults with acute respiratory illness (ARI) is limited. Methods We compared the population-based incidence, seasonality, and clinical characteristics of these 2 viral infections among adults aged ≥20 years with ARI hospitalizations in Auckland, New Zealand, during 2012–2015 through the Southern Hemisphere Influenza Vaccine Effectiveness Research and Surveillance (SHIVERS) project. Results Of the 14 139 ARI hospitalizations, 276 of 6484 (4.3%) tested positive for HMPV and 1342 of 7027 (19.1%) tested positive for influenza. Crude rates of 9.8 (95% confidence interval [CI], 8.7–11.0) HMPV-associated and 47.6 (95% CI, 45.1–50.1) influenza-associated ARI hospitalizations were estimated for every 100 000 adult residents annually. The highest rates for both viruses were in those aged ≥80 years, of Māori or Pacific ethnicity, or living in low socioeconomic status (SES) areas. HMPV infections were more common than influenza in those with chronic medical conditions. Conclusions Although HMPV infections accounted for fewer hospitalizations than influenza in adults aged ≥20 years, HMPV-associated ARI hospitalization rates were higher than influenza in older adults, Māori and Pacific people, and those of low SES. This highlights a need for vaccine/antiviral development. [ABSTRACT FROM AUTHOR]

A key mediator of T cell impairment during respiratory virus infection is the inhibitory receptor PD-1. PD-1 is induced on T cells following antigen exposure, whereas proinflammatory cytokines upregulate the ligands PD-L1 and PD-L2. Respiratory virus infection leads to upregulation of PD-L1 on airway epithelial cells, dendritic cells, and alveolar macrophages. However, the role of PD-L1 on different cell types in acute respiratory virus infections is not known. We sought to determine the role of PD-L1 on different cell types in CD8+ T cell impairment. We found that PD-L1-/- mice challenged with human metapneumovirus or influenza showed a similar level of CD8+ T cell impairment compared to wild-type (WT) mice. Moreover, virus clearance was delayed in PD-L1-/- mice compared to WT. CD8+ T cells from PD-L1-deficient mice expressed higher levels of inhibitory receptors both at baseline and after respiratory virus infection. The antibody blockade of PD-L2 failed to restore function to the impaired cells. While reciprocal bone marrow chimeras between WT and PD-L1-/- mice did not restore CD8+ T cell function after the respiratory virus challenge, mice that received the PD-L1-/- bone marrow had higher inhibitory receptor expression on CD8+ cells. This discrepancy in the inhibitory receptor expression suggests that cells of the hematopoietic compartment contribute to T cell impairment on CD8+ T cells. [ABSTRACT FROM AUTHOR]

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Objectives: We aim to investigate the prevalence of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) among pediatric patients with acute respiratory tract illness (ARTI) in southern China both pre- and post-COVID-19 pandemic, as well as identify associated risk factors for severe infections. Methods: The study conducted a real-time PCR analysis on hospitalized children with ARTI from 2012 to 2023, specifically targeting RSV, hMPV, and other respiratory pathogens. Additionally, demographic data was collected during this analysis. Results: The prevalence of RSV occurs triennially, and likewise, the temporal pattern of hMPV outbreaks mirrors that of RSV. The peak infection rates of RSV and hMPV occurred during and following the implementation of COVID-19 epidemic prevention and control measures. The incidence of RSV infection exhibited bimodal peaks in 2022, while hMPV demonstrated seasonal peaks during the spring, fall, and winter periods post-COVID-19 pandemic. After the COVID-19 outbreak, there has been an upward trend in the proportion of female patients and patients aged one year and older presenting with ARTI, RSV infections, and hMPV infections. Infant (OR = 4.767, 95%CI: [3.888-5.846], p < 0.0001), presence of coinfection (OR = 0.540, 95%CI: [0.404-0.722], p < 0.0001), and existence of comorbidities (OR = 1.582, 95%CI: [1.285-1.949], p < 0.0001) was the risk ratio for the severity of RSV infection. Children infected with hMPV under the age of 1 year (OR = 0.322, 95%CI: [0.180 - 0.575], p < 0.0001), as well as those with comorbidities (OR = 8.809, 95%CI: [4.493 - 17.272], p < 0.0001), have a higher risk of developing severe illness. Conclusion: The changing epidemiological patterns have the potential to lead to widespread severe outbreaks among children, particularly those with underlying medical conditions who may experience more severe symptoms. Conducting surveillance for pneumoviridae viruses in children is an imperative measure to establish a robust foundation for future epidemic prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Respiratory viral infections remain a leading cause of morbidity and mortality. Using a murine model of human metapneumovirus, we identified recruitment of a C1q-expressing inflammatory monocyte population concomitant with viral clearance by adaptive immune cells. Genetic ablation of C1q led to reduced CD8+ T-cell function. Production of C1q by a myeloid lineage was necessary to enhance CD8+ T-cell function. Activated and dividing CD8+ T cells expressed a C1q receptor, gC1qR. Perturbation of gC1qR signaling led to altered CD8+ T-cell IFN-γ production, metabolic capacity, and cell proliferation. Autopsy specimens from fatal respiratory viral infections in children exhibited diffuse production of C1q by an interstitial population. Humans with severe coronavirus disease (COVID-19) infection also exhibited upregulation of gC1qR on activated and rapidly dividing CD8+ T cells. Collectively, these studies implicate C1q production from monocytes as a critical regulator of CD8+ T-cell function following respiratory viral infection. [ABSTRACT FROM AUTHOR]

BackgroundInteractions of Streptococcus pneumoniae with viruses feature in the pathogenesis of numerous respiratory illnesses.MethodsWe undertook a case-control study among adults at Kaiser Permanente Southern California between 2015 and 2019. Case patients had diagnoses of lower respiratory tract infection (LRTI; including pneumonia or nonpneumonia LRTI diagnoses), with viral infections detected by multiplex polymerase chain reaction testing. Controls without LRTI diagnoses were matched to case patients by demographic and clinical attributes. We measured vaccine effectiveness (VE) for 13-valent (PCV13) against virus-associated LRTI by determining the adjusted odds ratio for PCV13 receipt, comparing case patients and controls.ResultsPrimary analyses included 13 856 case patients with virus-associated LRTI and 227 887 matched controls. Receipt of PCV13 was associated with a VE of 24.9% (95% confidence interval, 18.4%-30.9%) against virus-associated pneumonia and 21.5% (10.9%-30.9%) against other (nonpneumonia) virus-associated LRTIs. We estimated VEs of 26.8% (95% confidence interval, 19.9%-33.1%) and 18.6% (9.3%-27.0%) against all virus-associated LRTI episodes diagnosed in inpatient and outpatient settings, respectively. We identified statistically significant protection against LRTI episodes associated with influenza A and B viruses, endemic human coronaviruses, parainfluenza viruses, human metapneumovirus, and enteroviruses but not respiratory syncytial virus or adenoviruses.ConclusionsAmong adults, PCV13 conferred moderate protection against virus-associated LRTI. The impacts of pneumococcal conjugate vaccines may be mediated, in part, by effects on polymicrobial interactions between pneumococci and respiratory viruses.

Purpose: The objective of this study was to examine the molecular epidemiology and clinical characteristics of HMPV infection among children with ARIs in Nanjing. Methods: The respiratory samples were collected from 2078 children (≤ 14 years) with acute respiratory infections and were tested for HMPV using real-time RT-PCR. Amplification and sequencing of the HMPV G gene were followed by phylogenetic analysis using MEGA 7.0. Result: The detection rate of HMPV among children was 4.7% (97/2078), with a concentration in those under 5 years of age. Notably, the peak season for HMPV prevalence was observed in winter. Among the 97 HMPV-positive samples, 51.5% (50/97) were available for characterization of the HMPV G protein gene. Phylogenetic analysis indicated that the sequenced HMPV strains were classified into three sublineages: A2c111nt − dup (84.0%), B1 (2.0%), and B2 (14.0%). Conclusion: There was an incidence of HMPV among hospitalized children during 2021–2022 in Nanjing with A2c111nt − dup being the dominant strain. This study demonstrated the molecular epidemiological characteristics of HMPV among children with respiratory infections in Nanjing, China. [ABSTRACT FROM AUTHOR]

Numerous viruses have been found to exploit glycoconjugates expressed on human cells as their initial attachment factor for viral entry and infection. The virus-cell glycointeractome, when characterized, may serve as a template for antiviral drug design. Heparan sulfate proteoglycans extensively decorate the human cell surface and were previously described as a primary receptor for human metapneumovirus (HMPV). After respiratory syncytial virus, HMPV is the second most prevalent respiratory pathogen causing respiratory tract infection in young children. To date, there is neither vaccine nor drug available to prevent or treat HMPV infection. Using a multidisciplinary approach, we report for the first time the glycointeractome of the HMPV fusion (F) protein, a viral surface glycoprotein that is essential for target-cell recognition, attachment, and entry. Our glycan microarray and surface plasmon resonance results suggest that Galβ1-3/4GlcNAc moieties that may be sialylated or fucosylated are readily recognized by HMPV F. The bound motifs are highly similar to the N-linked and O-linked glycans primarily expressed on the human lung epithelium. We demonstrate that the identified glycans have the potential to compete with the cellular receptors used for HMPV entry and consequently block HMPV infection. We found that lacto-N-neotetraose demonstrated the strongest HMPV binding inhibition in a cell infection assay. Our current findings offer an encouraging and novel avenue for the design of anti-HMPV drug candidates using oligosaccharide templates. IMPORTANCE All cells are decorated with a dense coat of sugars that makes a sugar code. Many respiratory viruses exploit this sugar code by binding to these sugars to cause infection. Human metapneumovirus is a leading cause for acute respiratory tract infections. Despite its medical importance, there is no vaccine or antiviral drug available to prevent or treat human metapneumovirus infection. This study investigates how human metapneumovirus binds to sugars in order to more efficiently infect the human host. We found that human metapneumovirus binds to a diverse range of sugars and demonstrated that these sugars can ultimately block viral infection. Understanding how viruses can take advantage of the sugar code on our cells could identify new intervention and treatment strategies to combat viral disease. [ABSTRACT FROM AUTHOR]

• VLP associated RSV-F and hMPV-F immunogens properly display pre-fusion epitopes. • VLP associated immunogens induce better neutralizing responses than soluble ones. • The VLP platform benefits manifest primarily during prime immunization. Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) vaccines have been long overdue. Structure-based vaccine design created a new momentum in the last decade, and the first RSV vaccines have finally been approved in older adults and pregnant individuals. These vaccines are based on recombinant stabilized pre-fusion F glycoproteins administered as soluble proteins. Multimeric antigenic display could markedly improve immunogenicity and should be evaluated in the next generations of vaccines. Here we tested a new virus like particles-based vaccine platform which utilizes the direct fusion of an immunogen of interest to the structural human immunodeficient virus (HIV) protein Gag to increase its surface density and immunogenicity. We compared, in mice, the immunogenicity of RSV-F or hMPV-F based immunogens delivered either as soluble proteins or displayed on the surface of our VLPs. VLP associated F-proteins showed better immunogenicity and induced superior neutralizing responses. Moreover, when combining both VLP associated and soluble immunogens in a heterologous regimen, VLP-associated immunogens provided added benefits when administered as the prime immunization. [ABSTRACT FROM AUTHOR]

Background: Influenza, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) are common respiratory viruses causing similar symptoms. Optimal tools to assess illness severity for these viruses have not been defined. Using the Hospitalized Acute Respiratory Tract Infection (HARTI) study data, we report symptom severity by clinician‐rated clinical severity scores (CSS) in adults with influenza, RSV, or hMPV and correlations between CSS and patient‐reported outcomes (PROs). Methods: HARTI was a global epidemiologic study in adults hospitalized with acute respiratory tract infections. Patients were assessed at enrollment within 24 h of admission with CSS and twice during hospitalization with CSS, Respiratory Infection Intensity and Impact Questionnaire™ (RiiQ™), and EQ‐5D‐5L. Data were summarized descriptively, stratified by pathogen and baseline and hospitalization characteristics. Domain (general, upper respiratory, and lower respiratory) and sign/symptom subscores are presented for CSS; sign/symptom subscores are presented for RiiQ™ results. Results: Data from 635 patients with influenza, 248 with RSV, and 107 with hMPV were included. At enrollment, total CSS and general and lower respiratory signs/symptoms (LRS) scores were higher for RSV and hMPV than influenza. Between‐pathogen differences were greatest for LRS scores. Dyspnea, rales/rhonchi, wheezing, and shortness of breath scores trended higher for RSV and hMPV than influenza. RiiQ™ scores for cough, fatigue, and short of breath were strongly correlated with corresponding clinician‐rated symptoms. Conclusions: These findings support the use of PROs (e.g., the RiiQ™) correlating with clinician assessments to gauge patient well‐being and aid patient management by accurately assessing respiratory illness severity due to RSV, hMPV, or influenza. [ABSTRACT FROM AUTHOR]

Background: In addition to the well-known Whipple's disease (WD), Tropheryma Whipplei (TW) can also lead to acute pneumonia. There is no unified consensus on the susceptible population, pathogenesis, clinical manifestations, diagnostic criteria, and treatment options for TW pneumonia. Clinical Presentation and Intervention: This is an elderly patient with multiple injuries caused by falling from a building, and was transferred to intensive care unit (ICU) for mechanical ventilation and empirical anti-infection treatment due to severe pneumonia, and then the results of targeted next-generation sequencing (tNGS) in patient's bronchoalveolar lavage fluid (BALF) suggested TW and human metapneumovirus (HMPV) infection, and after switching to anti-infective therapy for TW, the patient was successfully extubated and transferred out of the ICU. Conclusion: This is the first case of using tNGS to diagnose severe pneumonia caused by TW and HMPV. We hope that our study can serve as a reference for the diagnosis and treatment of related cases in the future. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (hMPV) is a respiratory pathogen that can cause lower respiratory tract infections and pneumonia in immunocompetent adults. Pneumonia caused by hMPV is reportedly more likely to cause bronchial wall thickening and ground-glass opacity (GGO). A 44-year-old woman with no significant medical history developed fever, cough, and nausea. Computed tomography of the chest showed scattered GGOs in the right upper lobe and infiltrating shadows with air bronchograms in the left lingual and bilateral lower lobes. The patient was admitted to our hospital for further evaluation. Atypical pneumonia was suspected and lascufloxacin (LSFX) was started. Multiplex polymerase chain reaction (PCR) detected hMPV on hospital day 2 using the FilmArray Respiratory Panel 2.1. Pneumonia due to hMPV was suspected and LSFX was discontinued. The patient subsequently showed spontaneous improvement and was discharged on hospital day 6 after admission. After discharge, pneumonia continued to improve. Early detection of respiratory pathogens using multiplex PCR can help determine the appropriate treatment strategy. As hMPV can also cause lobar pneumonia, we should consider pneumonia due to hMPV in the differential diagnosis of lobar pneumonia.

Abstract Background In the aftermath of the COVID-19 pandemic, there has been a surge in human metapneumovirus (HMPV) transmission, surpassing pre-epidemic levels. We aim to elucidate the clinical and epidemiological characteristics of HMPV infections in the post-COVID-19 pandemic era. Methods In this retrospective single-center study, participants diagnosed with laboratory confirmed HMPV infection through Targeted Next Generation Sequencing were included. The study encompassed individuals admitted to Henan Children's Hospital between April 29 and June 5, 2023. Demographic information, clinical records, and laboratory indicators were analyzed. Results Between April 29 and June 5, 2023, 96 pediatric patients were identified as infected with HMPV with a median age of 33.5 months (interquartile range, 12 ~ 48 months). The majority (87.5%) of infected children were under 5 years old. Notably, severe cases were statistically younger. Predominant symptoms included fever (81.3%) and cough (92.7%), with wheezing more prevalent in the severe group (56% vs 21.1%). Coinfection with other viruses was observed in 43 patients, with Epstein–Barr virus (EBV) (15.6%) or human rhinovirus A (HRV type A) (12.5%) being the most common. Human respiratory syncytial virus (HRSV) coinfection rate was significantly higher in the severe group (20% vs 1.4%). Bacterial coinfection occurred in 74 patients, with Haemophilus influenzae (Hin) and Streptococcus pneumoniae (SNP) being the most prevalent (52.1% and 41.7%, respectively). Severe patients demonstrated evidence of multi-organ damage. Noteworthy alterations included lower concentration of IL-12p70, decreased lymphocytes percentages, and elevated B lymphocyte percentages in severe cases, with statistical significance. Moreover, most laboratory indicators exhibited significant changes approximately 4 to 5 days after onset. Conclusions Our data systemically elucidated the clinical and epidemiological characteristics of pediatric patients with HMPV infection, which might be instructive to policy development for the prevention and control of HMPV infection and might provide important clues for future HMPV research endeavors.

Abstract Human metapneumovirus (HMPV) is a newly identified pathogen causing acute respiratory tract infections in young infants worldwide. Since the initial document of HMPV infection in China in 2003, Chinese scientists have made lots of efforts to prevent and control this disease, including developing diagnosis methods, vaccines and antiviral agents against HMPV, as well as conducting epidemiological investigations. However, effective vaccines or special antiviral agents against HMPV are currently not approved, thus developing early diagnosis methods and knowing its epidemiological characteristics will be beneficial for HMPV control. Here, we summarized current research focused on the epidemiological characteristics of HMPV in China and its available detection methods, which will be beneficial to increase the public awareness and disease control in the future.

Human metapneumovirus (HMPV) is a significant respiratory pathogen, particularly in vulnerable populations. Background: No vaccine for the prevention of HMPV is currently licensed, although several subunit vaccines are in development. Saponin-based adjuvant systems (AS), including QS-21, have transformed the field of subunit vaccines by dramatically increasing their potency and efficacy, leading to the development of several licensed vaccines. However, naturally sourced tree bark-extracted QS-21 faces supply and manufacturing challenges, hindering vaccine development. Objective: This study reports on an alternative plant cell culture system for the consistent production of highly pure QS-21. Method: We evaluated the efficacy of cultured plant cell (cpc)-produced QS-21 in a novel HMPV vaccine, formulating a recombinant pre-fusion stabilized HMPV F protein (preF) with cpcQS-21 and a synthetic toll-like receptor 4 (TLR4) agonist adjuvant formulation. Results: In mice, TLR4 agonist containing adjuvant formulations with plant cell-produced QS-21 performed equally to licensed adjuvant AS01 containing tree-bark-extracted QS-21 and demonstrated a significant increase in immunogenicity against HMPV preF compared to the unadjuvanted control. Conclusion: Our findings pave the way for a reliable, scalable, and sustainable source of pure QS-21, enabling the development of highly effective HMPV and other vaccines with significant public health impact.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children. During the COVID-19 pandemic, a significant change in the epidemiology of RSV and other viruses occurred worldwide, leading to a reduction in the circulation of these infectious agents. After the pandemic, the resurgence of seasonal respiratory viruses occurred, but some features of these infections contrast to those registered prior to the pandemic. In the present work, we studied 390 children

This study aims to analyze the epidemiological and pathogenic characteristics of an outbreak primarily caused by respiratory syncytial virus (RSV), human rhinovirus (HRV), and human metapneumovirus (HMPV) in a kindergarten and primary school. The outbreak was investigated by field epidemiological investigation, and the common respiratory pathogens were screened by RT-PCR detection technology. The attack rate of this outbreak was 63.95% (110/172). Main symptoms included cough (85.45%), sore throat (60.91%), and sneezing (60.00%). Multifactorial logistic regression analysis revealed that continuous handwashing and mouth and nose covering when sneezing were protective factors. All 15 collected throat swab specimens tested positive for viruses, with HMPV as the predominant pathogen (80.00%), followed by HRV (53.33%), and two cases of positive respiratory syncytial virus (13.33%). Among them, six samples showed coinfections of HMPV and HRV, and one had coinfections of HMPV and RSV, resulting in a coinfection rate of 46.67%. Genetic sequencing indicated that the HMPV genotype in this outbreak was A2c, and the HRV genotype was type A, resulting in a coinfection outbreak of HMPV, HRV, and RSV in schools and kindergartens, suggesting that multi-pathogen surveillance of respiratory tract infections should be strengthened. [ABSTRACT FROM AUTHOR]

Background: Pneumonia is a leading cause of morbidity and mortality in children < 5 years. We describe nasopharyngeal carriage of respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and influenza virus among children with fast‐breathing pneumonia in Karachi, Pakistan. Methods: We performed a cross‐sectional analysis of nasopharyngeal swabs from children aged 2–59 months with fast‐breathing pneumonia, enrolled in the randomized trial of amoxicillin versus placebo for fast‐breathing pneumonia (RETAPP) (NCT02372461) from 2014 to 2016. Swabs were collected using WHO standardized methods, processed at the Aga Khan University, Pakistan. Viral detection was performed using LUMINEX xTAG respiratory viral panel assay and logistic regression identified clinical and sociodemographic predictors. Findings: Of the 1000 children tested, 92.2% (n = 922) were positive for viral carriage. RSV, hMPV, and influenza virus were detected in 59 (6.4%), 56 (6.1%), and 58 (6.3%) children and co‐infections in three samples (two RSV‐hMPV and one influenza‐hMPV). RSV carriage was common in infants (56%), we observed a higher occurrence of fever in children with hMPV and influenza virus (80% and 88%, respectively) and fast breathing in RSV (80%) carriage. RSV carriage was positively associated with a history of fast/difficulty breathing (aOR: 1.96, 95% CI 1.02–3.76) and low oxygen saturation (aOR: 2.52, 95% CI 1.32–4.82), hMPV carriage was positively associated with a complete vaccination status (aOR: 2.22, 95% CI 1.23–4.00) and body temperature ≥ 37.5°C (aOR: 2.34, 95% CI 1.35–4.04) whereas influenza viral carriage was associated with body temperature ≥ 37.5°C (aOR: 4.48, 95% CI 2.53–7.93). Conclusion: We observed a high nasopharyngeal viral carriage among children with WHO‐defined fast‐breathing pneumonia in Pakistan. Fever, difficulty in breathing, hypoxia and vaccination status are important clinical predictors for viral nonsevere community‐acquired pneumonia. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (hMPV) is an important pathogen that causes both upper (URTIs) and lower respiratory tract infections (LRTIs) in children. The virus can be implicated in severe bronchiolitis and pneumonia, necessitating hospitalization, with certain cases requiring intensive care unit intervention. As part of a retrospective observational study, we aimed to identify indicators of severe hMPV respiratory tract infections in children referred to the University Children's Hospital Ljubljana and the Department of Infectious Diseases Ljubljana, Slovenia, during a recent outbreak. We analyzed clinical data from November 2022 to January 2023 and compared the characteristics of children presenting with URTIs and LRTIs. We also examined the characteristics of children with hMPV LRTIs, distinguishing between children with and without LRTI-associated hypoxemia. Of 78 hMPV-PCR-positive pediatric patients (mean age 3.1 years; 60.3% boys), 36% had a URTI, and 64% had an LRTI. Hospitalization was required in 64% (50/78), with 42% (21/50) requiring oxygen therapy. LRTI-associated hypoxemia was more common in patients with atopy who showed dyspnea, tachypnea, crackles, and wheezing on lung auscultation. In a multivariable logistic regression analysis, wheezing detected on lung auscultation was a significant predictive factor for hypoxemic hMPV-LRTI. Specifically, children presenting with wheezing were found to be ten times more likely to experience hypoxemia. Prematurity and chronic conditions did not influence the presentation or severity of hMPV infection. This study highlights wheezing and atopy as crucial indicators of severe hMPV LRTI in children, emphasizing the importance of early recognition and intervention. [ABSTRACT FROM AUTHOR]

There is increasing recognition that respiratory viral infections such as influenza, respiratory syncytial virus, parainfluenza virus, adenovirus, and SARS‐CoV‐2 can promote the development of invasive fungal pulmonary coinfections, particularly invasive aspergillosis, both in immunocompetent and immunocompromised patients. To date, there are no case reports exploring the role of human metapneumovirus as a risk factor for fungal coinfection. Below, we describe the case of a 63‐year‐old woman who received a kidney transplant and developed invasive pulmonary aspergillosis after a human metapneumovirus infection and discuss the possible phenomena that could favor this association [ABSTRACT FROM AUTHOR]

Background: Human metapneumovirus (hMPV) is one of the leading respiratory viruses. This prospective observational study aimed to describe the clinical features and the outcomes of hMPV-associated lower respiratory tract infections in adult inpatients. Methods: Consecutive adult patients admitted to one of the 31 participating centers with an acute lower respiratory tract infection and a respiratory multiplex PCR positive for hMPV were included. A primary composite end point of complicated course (hospital death and/or the need for invasive mechanical ventilation) was used. Results: Between March 2018 and May 2019, 208 patients were included. The median age was 74 [62–84] years. Ninety-seven (47 %) patients were men, 187 (90 %) had at least one coexisting illness, and 67 (31 %) were immunocompromised. Median time between first symptoms and hospital admission was 3 [2–7] days. The two most frequent symptoms were dyspnea (86 %) and cough (85 %). The three most frequent clinical diagnoses were pneumonia (42 %), acute bronchitis (20 %) and acute exacerbation of chronic obstructive pulmonary disease (16 %). Among the 52 (25 %) patients who had a lung CT-scan, the most frequent abnormality was ground glass opacity (41 %). While over four-fifths of patients (81 %) received empirical antibiotic therapy, a bacterial coinfection was diagnosed in 61 (29 %) patients. Mixed flora (16 %) and enterobacteria (5 %) were the predominant documentations. The composite criterion of complicated course was assessable in 202 (97 %) patients, and present in 37 (18 %) of them. In the subpopulation of pneumonia patients (42 %), we observed a more complicated course in those with a bacterial coinfection (8/24, 33 %) as compared to those without (5/60, 8 %) (p = 0.02). Sixty (29 %) patients were admitted to the intensive care unit. Among them, 23 (38 %) patients required invasive mechanical ventilation. In multivariable analysis, tachycardia and alteration of consciousness were identified as risk factors for complicated course. Conclusion: hMPV-associated lower respiratory tract infections in adult inpatients mostly involved elderly people with pre-existing conditions. Bacterial coinfection was present in nearly 30 % of the patients. The need for mechanical ventilation and/or the hospital death were observed in almost 20 % of the patients.

ABSTRACTHuman metapneumovirus (HMPV) is a primary cause of acute respiratory infection, yet there are no approved vaccines or antiviral therapies for HMPV. Early host responses to HMPV are poorly characterized, and further understanding could identify important antiviral pathways. Type III interferon (IFN-λ) displays potent antiviral activity against respiratory viruses and is being investigated for therapeutic use. However, its role in HMPV infection remains largely unknown. Here, we show that IFN-λ is highly upregulated during HMPV infection in vitro in human and mouse airway epithelial cells and in vivo in mice. We found through several immunological and molecular assays that type II alveolar cells are the primary producers of IFN-λ. Using mouse models, we show that IFN-λ limits lung HMPV replication and restricts virus spread from upper to lower airways but does not contribute to clinical disease. Moreover, we show that IFN-λ signaling is predominantly mediated by CD45- non-immune cells. Mice lacking IFN-λ signaling showed diminished loss of ciliated epithelial cells and decreased recruitment of lung macrophages in early HMPV infection along with higher inflammatory cytokine and interferon-stimulated gene expression, suggesting that IFN-λ may maintain immunomodulatory responses. Administration of IFN-λ for prophylaxis or post-infection treatment in mice reduced viral load without inflammation-driven weight loss or clinical disease. These data offer clinical promise for IFN-λ in HMPV treatment.IMPORTANCEHuman metapneumovirus (HMPV) is a common respiratory pathogen and often contributes to severe disease, particularly in children, immunocompromised people, and the elderly. There are currently no licensed HMPV antiviral treatments or vaccines. Here, we report novel roles of host factor IFN-λ in HMPV disease that highlight therapeutic potential. We show that IFN-λ promotes lung antiviral responses by restricting lung HMPV replication and spread from upper to lower airways but does so without inducing lung immunopathology. Our data uncover recruitment of lung macrophages, regulation of ciliated epithelial cells, and modulation of inflammatory cytokines and interferon-stimulated genes as likely contributors. Moreover, we found these roles to be distinct and non-redundant, as they are not observed with knockout of, or treatment with, type I IFN. These data elucidate unique antiviral functions of IFN-λ and suggest IFN-λ augmentation as a promising therapeutic for treating HMPV disease and promoting effective vaccine responses.

Background: Human metapneumovirus(hMPV) is one of the most common viruses that cause acute lower respiratory tract infections. Interleukin-1β (IL-1β) has been reported to play an important role in multiple virus replication. Patients with hMPV infection have increased levels of IL-1β which reminds IL-1β is associated with hMPV infection. However, the mechanism by which IL-1β affects hMPV replication remains unclear. In this study, we explore the effect of IL-1β on hMPV replication and investigate its specific mechanism of action. Methods: We established an hMPV infection model through Human bronchial epithelial cells (16HBE). qRT-PCR and Western Blot were used to detect the expression levels of IL-1β, cyclic GMP-AMP synthase (cGAS), and interferon stimulating factor (STING). Regulating IL-1β expression by small interfering RNA (siRNA) or exogenous supplementary to study the influence of hMPV replication. The selective cGAS inhibitor RU.521, G150, and STING inhibitor H-151 were utilized to detect hMPV replication in 16HBE cells. Results: The level of IL-1β protein increased in a time-dependent and dose-dependent manner after hMPV infection. The mRNA and protein levels of cGAS and STING were significantly up-regulated. Knockdown of IL-1β could contribute to the decreased viral loads of hMPV. While the exogenous supplement of recombinant human IL-1β in cells, replication of hMPV was significantly increased. Additionally, the level of cGAS-STING protein expression would be affected by regulating IL-1β expression. Inhibitors of the cGAS-STING pathway led to a lower level of hMPV replication. Conclusion: This study found that IL-1β could promote hMPV replication through the cGAS-STING pathway, which has the potential to serve as a candidate to fight against hMPV infection, targeting IL-1β may be an effective new strategy to restrain virus replication.

Objectives: This study aimed to determine the epidemiological and genetic features of human metapneumovirus (HMPV) infection in children in southern China, and the effect of meteorological factors on infection. Methods: 14,817 children (≤14 years) with acute respiratory tract infections from 2010 to 2019 were examined for HMPV and other respiratory viruses by real-time quantitative polymerase chain reaction. Full-length F gene of 54 positive samples were sequenced and subjected to phylogenetic analysis. The correlation between the HMPV-positive rate and meteorological factors was analyzed by linear regression analysis. Results: HMPV was detected in 524 (3.5%) children, who were mostly younger than 1 year. The seasonal peak of HMPV prevalence mainly occurred in spring. Respiratory syncytial virus was the most common virus coinfected with HMPV (5.3%). Phylogenetic analysis revealed that the sequenced HMPV strains belonged to four sublineages, including A2b (1.9%), A2c (31.5%), B1 (50.0%), and B2 (16.7%). After adjusting for all meteorological factors, sunshine duration was inversely correlated with the HMPV-positive rate. Conclusion: HMPV is an important respiratory pathogen that causes acute respiratory tract infections in children in southern China, particularly in children ≤5 years old. The prevalence peak of HMPV in this area appeared in spring, and the predominant subtype was B1. Meteorological factors, especially long sunshine duration, might decrease the HMPV prevalence.

Abstract Background Acute respiratory infections (ARIs) are one of the most common causes of mortality and morbidity worldwide. Every year millions of children suffer from viral respiratory tract infections (RTIs) ranging from mild to severe illnesses. Human Metapneumovirus (HMPV) is among the most frequent viruses responsible for RTIs. However, HMPV infections and their severity among children have not been explored yet in Nepal. Purpose Therefore, the study was focused on HMPV infections and other potential viral etiologies or co-infections using multiplex PCR among children attending Kanti Children’s Hospital and assessed the clinical characteristics of the infections as well as found the co-infections. A hospital-based cross-sectional study was designed and a convenience sampling method was used to enroll children of less than 15 years with flu-like symptoms from both outpatients and inpatients departments over three months of the study period. Results HMPV infection (13.3%) was the most predominant infection among the different viral infections in children with ARIs in Kanti Children’s Hospital. The HMPV was more prevalent in the age group less than three years (21.8%). Cough and fever were the most common clinical features present in all children infected with HMPV followed by rhinorrhea, sore throat, and wheezing. HMPV-positive children were diagnosed with pneumonia (42.9%), bronchiolitis (28.5%), upper respiratory tract infections (14.3%), and asthma (14.3%). The prevalence of HMPV was high in late winter (14.3%) followed by early spring (13.5%). Conclusions This study provides the baseline information on HMPV and associated co-infection with other respiratory viruses for the differential diagnosis based on molecular methods and also the comparison of clinical presentations among the different respiratory syndromes.

ABSTRACT Human metapneumovirus (HMPV), a member of the Pneumoviridae family, causes upper and lower respiratory tract infections in humans. In vitro studies with HMPV have mostly been performed in monolayers of undifferentiated epithelial cells. In vivo studies in cynomolgus macaques and cotton rats have shown that ciliated epithelial cells are the main target of HMPV infection, but these observations cannot be studied in monolayer systems. Here, we established an organoid-derived bronchial culture model that allows physiologically relevant studies on HMPV. Inoculation with multiple prototype HMPV viruses and recent clinical virus isolates led to differences in replication among HMPV isolates. Prolific HMPV replication in this model caused damage to the ciliary layer, including cilia loss at advanced stages post-infection. These cytopathic effects correlated with those observed in previous in vivo studies with cynomolgus macaques. The assessment of the innate immune responses in three donors upon HMPV and RSV inoculation highlighted the importance of incorporating multiple donors to account for donor-dependent variation. In conclusion, these data indicate that the organoid-derived bronchial cell culture model resembles in vivo findings and is therefore a suitable and robust model for future HMPV studies.IMPORTANCEHuman metapneumovirus (HMPV) is one of the leading causative agents of respiratory disease in humans, with no treatment or vaccine available yet. The use of primary epithelial cultures that recapitulate the tissue morphology and biochemistry of the human airways could aid in defining more relevant targets to prevent HMPV infection. For this purpose, this study established the first primary organoid-derived bronchial culture model suitable for a broad range of HMPV isolates. These bronchial cultures were assessed for HMPV replication, cellular tropism, cytopathology, and innate immune responses, where the observations were linked to previous in vivo studies with HMPV. This study exposed an important gap in the HMPV field since extensively cell-passaged prototype HMPV B viruses did not replicate in the bronchial cultures, underpinning the need to use recently isolated viruses with a controlled passage history. These results were reproducible in three different donors, supporting this model to be suitable to study HMPV infection.

Background Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. Methods This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. Results We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. Conclusions These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections worldwide, particularly in young children. In Bhutan, respiratory disease continues to be among the top 10 diseases of morbidity for several years. This study aimed to estimate the prevalence of RSV among hospitalized patients with severe acute respiratory infection (SARI) in Bhutan. Method: Respiratory specimens were collected from SARI patients of all ages in 2016 and 2018 following influenza surveillance guidelines. Specimens were tested for influenza and RSV, human metapneumovirus, adenovirus, and human parainfluenza virus types 1, 2, and 3 using real‐time reverse‐transcription polymerase chain reaction assay. Descriptive statistics were used to analyze the result in STATA 16.1. Result: Of the 1339 SARI specimens tested, 34.8% were positive for at least one viral pathogen. RSV was detected in 18.5% of SARI cases, followed by influenza in 13.4% and other respiratory viruses in 3%. The median age of SARI cases was 3 (IQR: 0.8–21 years) years. RSV detection was higher among children aged 0–6 (Adj OR: 3.03; 95% CI: 1.7–5.39) and 7–23 months (Adj OR: 3.01; 95% CI: 1.77–5.12) compared with the children aged 5–15 years. RSV was also associated with breathing difficulty (Adj OR: 1.73; 95% CI: 1.17–2.56) and pre‐existing lung disease, including asthma (Adj OR: 2.78; 95% CI: 0.99–7.8). Conclusion: Respiratory viruses were detected in a substantial proportion of SARI hospitalizations in Bhutan. [ABSTRACT FROM AUTHOR]

• Human metapneumovirus (HMPV) is an important respiratory pathogen that causes acute respiratory tract infection in children ≤5 years old. • The prevalence peak of HMPV in southern China appeared between March and May. • Respiratory syncytial virus is the most common respiratory virus coinfected with HMPV in children. • The predominant subtype of HMPV in this area is B1, followed by A2c subtype. • Long sunshine duration might decrease the HMPV prevalence. This study aimed to determine the epidemiological and genetic features of human metapneumovirus (HMPV) infection in children in southern China, and the effect of meteorological factors on infection. 14,817 children (≤14 years) with acute respiratory tract infections from 2010 to 2019 were examined for HMPV and other respiratory viruses by real-time quantitative polymerase chain reaction. Full-length F gene of 54 positive samples were sequenced and subjected to phylogenetic analysis. The correlation between the HMPV-positive rate and meteorological factors was analyzed by linear regression analysis. HMPV was detected in 524 (3.5%) children, who were mostly younger than 1 year. The seasonal peak of HMPV prevalence mainly occurred in spring. Respiratory syncytial virus was the most common virus coinfected with HMPV (5.3%). Phylogenetic analysis revealed that the sequenced HMPV strains belonged to four sublineages, including A2b (1.9%), A2c (31.5%), B1 (50.0%), and B2 (16.7%). After adjusting for all meteorological factors, sunshine duration was inversely correlated with the HMPV-positive rate. HMPV is an important respiratory pathogen that causes acute respiratory tract infections in children in southern China, particularly in children ≤5 years old. The prevalence peak of HMPV in this area appeared in spring, and the predominant subtype was B1. Meteorological factors, especially long sunshine duration, might decrease the HMPV prevalence. [ABSTRACT FROM AUTHOR]

Following the coronavirus disease 2019 (COVID‐19) outbreak in February 2020, incidences of various infectious diseases decreased notably in Hokkaido Prefecture, Japan. However, Japan began gradually easing COVID‐19 infection control measures in 2022. Here, we conducted a survey of children hospitalized with human metapneumovirus (hMPV), influenza A and B, and respiratory syncytial virus infections in 18 hospitals across Hokkaido Prefecture, Japan, spanning from July 2019 to June 2023. From March 2020 to June 2022 (28 months), only 13 patients were hospitalized with hMPV, and two patients had influenza A. However, in October to November 2022, there was a re‐emergence of hMPV infections, with a maximum of 27 hospitalizations per week. From July 2022 to June 2023 (12 months), the number of hMPV‐related hospitalizations dramatically increased to 317 patients, with the majority aged 3–6 years (38.2%, [121/317]). Influenza A also showed an increase from December 2022, with a peak of 13 hospitalizations per week in March 2023, considerably fewer than the pre‐COVID‐19 outbreak in December 2019, when rates reached 45 hospitalizations per week. These findings suggest the possibility of observing more resurgences in infectious diseases in Japan after 2023 if infection control measures continue to be relaxed. Caution is needed in managing potential outbreaks. [ABSTRACT FROM AUTHOR]

Before the COVID‐19 pandemic, common community‐acquired seasonal respiratory viruses (CARVs) were a significant threat to the health and well‐being of allogeneic hematopoietic cell transplant (allo‐HCT) recipients, often resulting in severe illness and even death. The pandemic has further highlighted the significant risk that immunosuppressed patients, including allo‐HCT recipients, face when infected with SARS‐CoV‐2. As preventive transmission measures are relaxed and CARVs circulate again among the community, including in allo‐HSCT recipients, it is crucial to understand the current state of knowledge, gaps, and recent advances regarding CARV infection in allo‐HCT recipients. Urgent research is needed to identify seasonal respiratory viruses as potential drivers for future pandemics. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (HMPV) is a nonsegmented, single-stranded negative RNA virus and a member of the Pneumoviridae family. During HMPV infection, macrophages play a critical role in defending the respiratory epithelium by secreting large amounts of type I interferon (IFN). MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that play an essential role in regulating gene expression during normal cellular homeostasis and disease by binding to specific mRNAs, thereby regulating at the transcriptional and post-transcriptional levels with a direct impact on the immune response and other cellular processes. However, the role of miRNAs in macrophages and respiratory viral infections remains largely unknown. Here, we characterized the susceptibility of THP-1-derived macrophages to HMPV infection and the effect of hsa-miR-4634 on these cells. Transfection of an miRNA mimic and inhibitor demonstrated that hsa-miR-4634 regulates the IFN response in HMPV-infected macrophages, suggesting that HMPV induces the expression of the miRNA as a subversion mechanism of the antiviral response. This effect was not limited to macrophages, as a similar effect was also observed in epithelial cells. Overall, our results demonstrate that hsa-miR-4634 is an important factor in regulating the IFN response in macrophages and epithelial cells during HMPV infection. [ABSTRACT FROM AUTHOR]

ObjectiveTo analyze genetic characteristics of human metapneumovirus (hMPV) strains isolated in Ningxia Hui Autonomous Region (Ningxia) for providing relevant data to construct hMPV genome database in China. MethodsTwo hMPV strains isolated from throat swab specimens were collected from the positive sample bank of 2021 for respiratory disease pathogen monitoring in Ningxia and whole genome sequencing was performed for the two strains. Informatics analysis was conducted with 27 representative strains of hMPV genotypes downloaded from the National Biotechnology Information Center (NCBI). MEGA7.0 was used to construct phylogenetic tree and calculate genetic distance and MegAlign 7.1 in DNAStar 7.1 software package was adopted to analyze amino acid and nucleotide homology of the strains. ResultsThe results of phylogenetic tree of G protein genome sequencing, F protein genome sequencing and whole genome sequencing showed that the two hMPV strains belong to the same branch of B2 type. The amino acid distance (nucleotide distance) between the whole genome sequence of the two strains (hMPV/NX01/2021 and hMPV/NX02/2021) and the whole genome sequence of the Australian strain (MW221994) in 2020 are the nearest, with the distance of 0.005 (0.002) and 0.006 (0.003), respectively. The two hMPV strains had the highest homology with the average amino acid and nucleotide of hMPV-B2 in the whole genome sequence and sequences of each protein genome (N, P, M, F, M2-1, M2-2, SH, G, L). ConclusionThe genome of the two respiratory human metapneumovirus stains isolated in Ningxia region has the genetic characteristics of hMPV, and both belong to the hMPV-B2 genotype.

ABSTRACTHuman metapneumovirus (hMPV) is a leading cause of viral lower respiratory tract disease in children and adults. The hMPV fusion protein F is a trimeric class I fusion protein that is initially synthesized as a precursor (F0) and requires proteolytic activation by a host cell protease to generate the metastable, fusion-competent prefusion conformation of F. hMPV F is considered the main target of the neutralizing antibody response against hMPV infection. We isolated single-domain antibodies (sdAbs) directed against hMPV F that potently neutralize hMPV A and B strains. One of these sdAbs, sdHMPV16, specifically bound to cleaved and uncleaved prefusion F. Co-crystal structure analysis revealed that sdHMPV16 binds to a site located at the trimer interface of prefusion F. Moreover, prophylactic treatment with a sdHMPV16-Fc fusion protein reduced viral titers in the lungs of hMPV-infected cotton rats. In summary, sdHMPV16 broadly neutralizes hMPV, can be turned into a candidate biologic that restricts hMPV replication in an in vivo model, and, unexpectedly, binds to an unconventional epitope at the prefusion F trimer interface.IMPORTANCEHuman metapneumovirus (hMPV) is an important respiratory pathogen for which no licensed antivirals or vaccines exist. Single-domain antibodies represent promising antiviral biologics that can be easily produced and formatted. We describe the isolation and detailed characterization of two hMPV-neutralizing single-domain antibodies that are directed against the fusion protein F. One of these single-domain antibodies broadly neutralizes hMPV A and B strains, can prevent proteolytic maturation of F, and binds to an epitope in the F trimer interface. This suggests that hMPV pre-F undergoes trimer opening or “breathing” on infectious virions, exposing a vulnerable site for neutralizing antibodies. Finally, we show that this single-domain antibody, fused to a human IgG1 Fc, can protect cotton rats against hMPV replication, an important finding for potential future clinical applications.

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause a high burden of disease, particularly in children and the elderly. With the aim to add knowledge on RSV and HMPV infections in Italy, a prospective, multicenter study was conducted by eight centers of the Working Group on Respiratory Virus Infections (GLIViRe), from December 2018–April 2019. Weekly distribution and patients' demographic and clinical data were compared in 1300 RSV and 222 HMPV-positive cases. Phylogenetic analysis of the G-glycoprotein coding region was performed to characterize circulating strains. RSV positivity ranged from 6.4% in outpatients of all ages to 31.7% in hospitalized children; HMPV positivity was 4–1.2% with no age-association. RSV season peaked in February and ended in mid-April: HMPV circulation was higher when RSV decreased in early spring. RSV was more frequent in infants, whereas HMPV infected comparatively more elderly adults; despite, their clinical course was similar. RSV-B cases were two-thirds of the total and had similar clinical severity compared to RSV-A. Phylogenetic analysis showed the circulation of RSV-A ON1 variants and the predominance of RSV-B genotype BA10. HMPV genotype A2c was the prevalent one and presented insertions of different lengths in G. This first multicenter Italian report on seasonality, age-specific distribution, and clinical presentation of RSV and HMPV demonstrated their substantial disease burden in young patients but also in the elderly. These data may provide the basis for a national respiratory virus surveillance network. [ABSTRACT FROM AUTHOR]

Acute bronchiolitis is a leading cause of hospitalization in infants. In this retrospective study, 645 patients with acute bronchiolitis diagnosed as respiratory syncytial virus (RSV; n = 538) or human metapneumovirus (HMPV; n = 107) were compared in terms of demographic, clinical, and laboratory findings. The HMPV patients presented later in the winter, were older (20 vs 7.55 months; P <.001)), had higher levels of C-reactive protein (4.55 vs 3.03 mg/dL; P =.007), and a higher prevalence of complications (43.9% vs 32.7%; P =.03). This study highlights the similarities and differences between these 2 common respiratory viral pathogens and shows that HMPV has a slightly more severe disease course than RSV. These findings can help guide approaches to these 2 common viruses that cause bronchiolitis. [ABSTRACT FROM AUTHOR]

The non-pharmaceutical interventions implemented to prevent the spread of COVID-19 have affected the epidemiology of other respiratory viruses. In South Korea, Human metapneumovirus (HMPV) typically occurs from winter to the following spring; however, it was not detected for two years during the COVID-19 pandemic and re-emerged in the fall of 2022, which is a non-epidemic season. To examine the molecular genetic characteristics of HMPV before and after the COVID-19 pandemic, we analyzed 427 HMPV-positive samples collected in the Gwangju area from 2018 to 2022. Among these, 24 samples were subjected to whole-genome sequencing. Compared to the period before the COVID-19 pandemic, the incidence rate of HMPV in 2022 increased by 2.5-fold. Especially in the age group of 6–10 years, the incidence rate increased by more than 4.5-fold. In the phylogenetic analysis results, before the COVID-19 pandemic, the A2.2.2 lineage was predominant, while in 2022, the A2.2.1 and B2 lineage were observed. The non-pharmaceutical interventions implemented after COVID-19, such as social distancing, have reduced opportunities for exposure to HMPV, subsequently leading to decreased acquisition of immunity. As a result, HMPV occurred during non-epidemic seasons, influencing the age distribution of its occurrences. [ABSTRACT FROM AUTHOR]

Respiratory virus infections are the main causes of pediatric diseases. Human metapneumovirus (hMPV) is an enveloped RNA virus similar to severe acute respiratory syndrome coronavirus type 2, both of which have emerged as important new respiratory viruses. Recent studies have found that interleukin-4 (IL-4) is involved in the replication of a variety of viruses, and its role differs in different viruses. The purpose of this study was to investigate the effect of IL-4 on hMPV and to elucidate its mechanism of action. We found that hMPV infection promoted the expression of IL-4 in human bronchial epithelial cells. The replication of the virus was reduced using small interfering RNA knockdown of IL-4 expression, while the addition of exogenous recombinant human IL-4 to IL-4 knockdown cells restored viral replication ability. These results demonstrate that the expression of IL-4 is closely related to the replication of hMPV; moreover, further experiments revealed that IL-4 promotes the replication of hMPV through a mechanism dependent on the Janus kinase/signal transductor and transcription activator 6 signaling pathway. Therefore, anti-IL-4 strategies may be a promising avenue for the treatment of hMPV infection, representing an important breakthrough for children at risk from hMPV infection. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory infections (ARIs) are one of the most common causes of mortality and morbidity worldwide. Every year millions of children suffer from viral respiratory tract infections (RTIs) ranging from mild to severe illnesses. Human Metapneumovirus (HMPV) is among the most frequent viruses responsible for RTIs. However, HMPV infections and their severity among children have not been explored yet in Nepal. Purpose: Therefore, the study was focused on HMPV infections and other potential viral etiologies or co-infections using multiplex PCR among children attending Kanti Children's Hospital and assessed the clinical characteristics of the infections as well as found the co-infections. A hospital-based cross-sectional study was designed and a convenience sampling method was used to enroll children of less than 15 years with flu-like symptoms from both outpatients and inpatients departments over three months of the study period. Results: HMPV infection (13.3%) was the most predominant infection among the different viral infections in children with ARIs in Kanti Children's Hospital. The HMPV was more prevalent in the age group less than three years (21.8%). Cough and fever were the most common clinical features present in all children infected with HMPV followed by rhinorrhea, sore throat, and wheezing. HMPV-positive children were diagnosed with pneumonia (42.9%), bronchiolitis (28.5%), upper respiratory tract infections (14.3%), and asthma (14.3%). The prevalence of HMPV was high in late winter (14.3%) followed by early spring (13.5%). Conclusions: This study provides the baseline information on HMPV and associated co-infection with other respiratory viruses for the differential diagnosis based on molecular methods and also the comparison of clinical presentations among the different respiratory syndromes. [ABSTRACT FROM AUTHOR]