hMPV Infection Research Articles

The Upper Respiratory Tract Exhibits Reduced Interferon Response that Contributes to Limited CD8 +T Cell Recruitment and Delayed Clearance of Human Metapneumovirus

Abstract Human metapneumovirus (HMPV) is a leading cause of acute upper and lower respiratory infections. Although nearly everyone is infected during early childhood, re-infections occur often, highlighting difficulty in building long-term immunity. We employed a mouse model of HMPV infection to elucidate differences in upper and lower tract immune responses, and address why upper airway infection does not establish durable protective immunity. We found HMPV burden was higher in nasal airways and exhibited delayed clearance compared to lung. Additionally, there was low nasal expression of antiviral interferons (IFN) and inflammatory cytokines. Key innate immune cells, including macrophages, monocytes, and dendritic cells, were present in the nose at baseline but were not upregulated by infection. We previously showed HMPV-specific lung CD8 +T cells (T CD8) are impaired, exhibiting sustained high PD-1 levels and reduced functionality. Despite higher HMPV viral load, there were few HMPV-specific nasal T CD8and they did not exhibit impairment. To test whether low nasal IFN led to this phenotype, we administered type I IFN in an upper airway-restricted fashion early post-infection. This led to lower HMPV nose titers, increased cell number, higher PD-1 expression, and reduced functionality in HMPV-specific nasal T CD8. Despite the subdued nasal immune response, intranasal vaccination with a small-volume HMPV dose elicited modest reduction of lung and nose titers on challenge but no improvement in clinical disease. Our findings reveal a quiescent nasal immune landscape despite high HMPV burden that contributed to slow clearance and was modulated, in part, by low IFN expression. Supported by NIH R01 AI085062-06 (JVW), T32 AI138954-4 (JS), and UPMC Children's Hospital of Pittsburgh Research Advisory Council Graduate Fellowship (JS).

Clinical significance of human metapneumovirus detection in critically ill adults with lower respiratory tract infections

BackgroundUnlike other viruses, the pathogenicity of human metapneumovirus (hMPV) in adults remains uncertain. To address this question, a retrospective monocentric cohort including all patients admitted to ICU with hMPV infection between January 1, 2010, and June 30, 2018 was performed. The characteristics of hMPV infected patients were studied and compared to matched influenza infected patients. Consecutively, a systematic review and meta-analyses investigating PUBMED, EMBASE and COCHRANE databases was conducted to explore the hMPV infections in adult patients (PROSPERO number: CRD42018106617). Trials, case series, and cohorts published between January 1, 2008 and August 31, 2019 compiling adults presenting hMPV infections were included. Pediatric studies were excluded. Data were extracted from published reports. Primary endpoint was the rate of low respiratory tract infections (LRTIs) among all hMPV infected patients.ResultsDuring the study period, 402 patients were tested positive for hMPV. Among them 26 (6.5%) patients were admitted to the ICU, 19 (4.7%) for acute respiratory failure. Twenty-four (92%) were immunocompromised. Bacterial coinfections were frequent 53.8%. Hospital mortality rate was 30.8%. In the case–control analysis, the clinical and imaging characteristics were not different between hMPV and influenza infected patients. The systematic review identified 156 studies and 69 of them (1849 patients) were eligible for analysis. Although there was heterogeneity between the studies, the rate of hMPV LRTIs was 45% (95% CI 31–60%; I2 = 98%). Intensive care unit (ICU) admission was required for 33% (95% CI 21–45%; I2 = 99%). Hospital mortality rate was 10% (95% CI 7–13%; I2 = 83%) and ICU mortality rate was 23% (95% CI 12–34%; I2 = 65%). Underlying malignancy was independently associated with increased mortality rate.ConclusionsThis preliminary work suggested that hMPV may be associated with severe infection and high mortality in patients with underlying malignancies. However, regarding the small size of the cohort and the heterogeneity of the review, more cohort studies are warranted.

Human Metapneumovirus (hMPV) Infection and MPV467 Treatment in Immunocompromised Cotton Rats Sigmodon hispidus.

Human metapneumovirus (hMPV) is an important cause of respiratory disease in immunocompromised individuals, yet hMPV infection has not been modeled before in immunocompromised animals. In this work, cotton rats S. hispidus immunosuppressed by cyclophosphamide were infected with hMPV, and viral replication and pulmonary inflammation in these animals were compared to those in normal hMPV-infected S. hispidus. The efficacy of prophylactic and therapeutic administration of the anti-hMPV antibody MPV467 was also evaluated. Immunosuppressed animals had higher pulmonary and nasal titers of hMPV on day 5 post-infection compared to normal animals, and large amounts of hMPV were still present in the respiratory tract of immunosuppressed animals on days 7 and 9 post-infection, indicating prolonged viral replication. Immunosuppression was accompanied by reduced pulmonary histopathology in hMPV-infected cotton rats compared to normal animals; however, a delayed increase in pathology and pulmonary chemokine expression was seen in immunosuppressed cotton rats. Prophylactic and therapeutic MPV467 treatments protected both upper and lower respiratory tracts against hMPV infection. The lung pathology and pulmonary expression of IP-10 and MIP-1α mRNA were reduced by therapeutic MPV467 administration. These results indicate that immunosuppressed cotton rats represent a useful model for studying hMPV pathogenesis and for evaluating therapeutics that could alleviate hMPV-induced disease in immunocompromised subjects.

A nationwide survey of human metapneumovirus-associated encephalitis/encephalopathy in Japan

BackgroundAs there have been no comprehensive reports of human metapneumovirus-associated encephalopathy (hMPVE), this study examined the clinical features of hMPVE in children in Japan. MethodA nationwide survey of children with hMPVE was conducted using a structured research form. An initial survey asked pediatricians about children with hMPVE treated between 2014 and 2018. A second survey obtained patient information from hospitals that responded to the initial survey and those identified as having treated cases from a literature search. We collected demographic data, symptoms of hMPV infection, neurological symptoms, laboratory data, treatment, and outcomes. Outcomes were determined using the Pediatric Cerebral Performance Category Score. ResultClinical information was available for 16 children. Their median age was 37 months. Six had preexisting neurological disorders. The interval between the onsets of infection and hMPVE was 4 days. Outcomes were good in 11 patients and poor in 5. There were no significant differences in demographic data, neurological symptoms, or laboratory data between the patients with good and poor outcomes. The encephalopathy subtypes were acute encephalopathy with biphasic seizures and late reduced diffusion in 3, clinically mild encephalitis/encephalopathy with a reversible splenial lesion in 3, hemorrhagic shock and encephalopathy syndrome in 2, and others in 8. ConclusionThe outcomes of children with hMPVE were not very different from those of acute encephalopathy due to other viruses. We found no factors associated with poor outcomes.

Epidemiological profile of hospitalized human metapneumovirus in a capital of central-west of Brazil from 2017 to 2019: high lethality at extremes of age

Human metapneumovirus (hMPV) is a paramyxovirus that causes airway infections. hMPV symptoms range from mild infections of the upper respiratory tract to infections as serious as bronchiolitis and pneumonia. From 2018 to 2019, there was a high incidence of severe acute respiratory syndrome (SARS) in the State of Goiás with a relative increase in hMPV incidence. This study aimed to assess the hMPV epidemiology of cases treated at tertiary hospitals of Goiás, as there are not significant published data from hMPV infection in Brazil. We performed a retrospective and descriptive analysis of a case series of patients infected with hMPV diagnosed by PCR (16 individuals), through medical records review from 2017 to 2019. The observed age distribution was bimodal, with the disease affecting individuals at extremes of age (median of 3.5 years old in the first stratum and median of 52 years in the second stratum). The time between the onset of flu-like symptoms and the first medical assessment had an average of 5 days. The most frequent severe symptoms were respiratory distress/dyspnea and oxygen saturation <95% (93.7% as media), even in patients without comorbidities. The most frequent complications were acute renal failure (18.7%) and healthcare-associated infections (43.7%). Death occurred in 37.5% of patients. hMPV may cause upper and lower respiratory tract infections in patients of all age groups, but the symptomatic disease occurs more frequently at extremes of age. In the pandemic caused by a new coronavirus (SARS-CoV-2), which is known to lead to influenza-like and SARS, the differential diagnosis of the etiologic agent becomes paramount. KEY WORDS: Respiratory tract infections; paramyxoviridae infections; acute disease.

Comparison of the clinical features of human bocavirus and metapneumovirus lower respiratory tract infections in hospitalized children in Suzhou, China.

We compared the clinical data of hospitalized children with lower respiratory tract infections caused by human bocavirus (HBoV) and human metapneumovirus (hMPV). In total, 8,430 children admitted to the Department of Respiration, Children's Hospital of Soochow University for lower respiratory tract infections from January 2017 to October 2021 were enrolled. Seven common respiratory viruses, including respiratory syncytial virus, influenza virus A, influenza virus B, parainfluenza virus (PIV) I, PIV II, PIV III, and adenovirus, were detected by direct immunofluorescence assay, whereas human rhinovirus and hMPV were detected by reverse transcription-polymerase chain reaction. Mycoplasma pneumoniae (MP) and HBoV were detected by real-time fluorescence quantitative polymerase chain reaction. Bacteria was detected in blood, nasopharyngeal secretion, bronchoalveolar lavage specimen or pleural fluid by culture. In parallel, MP was detected by enzyme-linked immunosorbent assay. In addition, we performed metagenomic testing of alveolar lavage fluid from some of the patients in our study. The detection rate of HBoV was 6.62% (558/8430), whereas that of hMPV was 2.24% (189/ 8430). The detection rate of HBoV was significantly higher in children aged 1 to <3 years than in other age groups, but there were no significant differences in positivity rates for hMPV by age. Before 2020, the incidence of HBoV infection peaked in summer and autumn, whereas that of hMPV peaked in spring. The epidemiology of both HBoV and hMPV has changed because of the impact of the novel coronavirus. Among the positive cases, the HBoV mixed infection rate was 51.6%, which was similar to that for hMPV mixed infection (44.4%). Comparing clinical characteristics between HBoV and hMPV single infection, the median age of children was 17 months in the HBoV group and 11 months in the hMPV group. In the HBoV single infection group, 31 patients (11.5%) had pulse oxygen saturation of less than 92% on admission, 47 (17.4%) had shortness of breath, and 26 (9.6%) presented with dyspnea. Meanwhile, four patients (3.8%) in the hMPV single infection group had pulse oxygen saturation of less than 92% on admission, eight (7.6%) displayed shortness of breath, and three (2.9%) had dyspnea. The proportion of patients requiring mechanical ventilation and the rate of PICU admission were higher in the HBoV group than in the hMPV group. The prevalence of HBoV infection is higher than that of hMPV infection in children with lower respiratory tract infection in Suzhou, and HBoV is more likely to cause severe infection than hMPV. Public health interventions for COVID-19 outbreaks have affected the prevalence of HBoV and hMPV.

Epidemiology and Acute Respiratory Distress Syndrome Propensity of Viral Respiratory Infections in Pediatric Intensive Care Units Prior to the Coronavirus Disease 2019 Pandemic

Abstract Objective This study aimed to determine the epidemiology and acute respiratory distress syndrome (ARDS) propensity of common respiratory viruses in a tertiary pediatric intensive care unit (PICU) among hospitalized children who were tested for respiratory viruses by polymerase chain reaction (PCR) prior to the coronavirus disease 2019 (COVID-19) pandemic. Methods Respiratory tract samples were collected from patients who were followed up in the Dokuz Eylul University Hospital pediatric intensive care unit between March 2015 and March 2020 and tested for viral pathogens. The results of 269 patients between 1 month and 18 years of age were evaluated retrospectively. Results In the 5 years preceding the COVID-19 pandemic, 269 patients with a lower respiratory infection were admitted to the PICU. A positive viral PCR result was detected in 160 patients (59.5%). Human rhinovirus was the most common virus (40%), followed by respiratory syncytial virus (26.3%), human bocavirus (10%), and seasonal coronaviruses (10%). Five (33.3%) of the fifteen children who developed ARDS were infected with influenza A/B, while four (26.7%) were infected with human metapneumovirus (hMPV). Conclusion Although rhinovirus was the most common viral agent in critically ill children, the incidence of ARDS was higher in children aged over 1 year who had influenza or hMPV infection.

506. Neonatal CD8+ T Cells Demonstrate PD-1 Dependent Impairment Following Human Metapneumovirus Infection

Abstract Background Human metapneumovirus (HMPV) is a leading cause of pediatric acute respiratory illness, accounting for 14.2 million acute lower respiratory tract infections and 500,000 hospitalizations per year in children less than 5 years of age globally. Infants and neonates are particularly susceptible to severe HMPV disease. Our prior studies in adult mice demonstrated CD8+ T cells were critical for clearance of HMPV infection, although these cells show impaired function due to PD-1:PD-L1 signaling. However, the immune system in the neonatal lung skews towards an anti-inflammatory and tolerogenic response when compared to adults. We therefore sought to explore the roles CD8+ T cell and PD-1 signaling in neonatal mice to recapitulate the population at highest risk. Methods C57BL/6 or Pdcd1-/- pups were infected intranasally with 1.0x106 PFU/g of a clinical isolate of HMPV (TN94-49) on day of life 4-6. Viral burden was assessed via plaque assay and cellular responses were characterized by multispectral flow cytometry. Results HMPV infection led to stunted weight gain in pups compared to mock-infected controls. HMPV-infected neonatal mice had a robust innate immune response comprised of neutrophils, CD103+ dendritic cells, and interstitial macrophages, all of which demonstrated upregulation of PD-L1. From an adaptive perspective, neonatal mice mounted an antigen-specific CD8+ T cell response and resolved HMPV infection by day 8 post-infection. Similar to our prior studies in adult mice, neonatal CD8+ T cells upregulated expression of several inhibitory receptors, such as PD-1, LAG-3, and TIM-3. Neonatal CD8+T cells demonstrated limited effector cytokine production, such as IFN-γ and granzyme B, following ex vivo stimulation with a class I HMPV-specific peptide. Pdcd1-/- mice (lacking PD-1) also mounted an antigen-specific CD8+ T cell response, but had markedly increased production of IFN-γ and granzyme B. Conclusion These data demonstrate that PD-1 signaling on CD8+ T cells constrains the antiviral response in a novel model of neonatal respiratory viral infection. Understanding the mechanisms that inhibit neonatal anti-viral responses could present opportunities for novel therapeutic strategies for common infections with high morbidity and mortality in neonates and infants. Disclosures John Williams, MD, GlaxoSmithKline: Advisor/Consultant|Quidel: Advisor/Consultant.

Retrospective comparison of respiratory syncytial virus and metapneumovirus clinical presentation in hospitalized children.

Respiratory syncytial virus (RSV) and Human metapneumovirus (hMPV), members of Pneumoviridae family are common causes of acute respiratory tract infections (ARTI) among children. Study material includes routine nasopharyngeal samples obtained during 8-year period for hMPV and one single season for RSV in children hospitalized for ARTI between 0 and 15 years at the Center Hospitalier Universitaire (CHU) Saint Pierre in Brussels. Positive samples for RSV or hMPV identified by viral culture, lateral flow chromatography test for RSV or direct fluorescent assay for hMPV were selected retrospectively. Characteristics of children hospitalized for RSV or hMPV infections were compared. Children hospitalized for RSV infection were significantly younger and requiring more respiratory support, longer hospital stay and transfers in Pediatric intensive Care Unitsthan those hospitalized for hMPV infection. Pneumonia diagnostic and antibiotics therapies were more significantly associated with hMPV infections.In conclusion, despite their genetic similarities, RSV, and hMPV present epidemiological and clinical differences in pediatric infections. Our results should be confirmed prospectively.

Female offspring gestated in hypothyroxinemia and infected with human Metapneumovirus (hMPV) suffer a more severe infection and have a higher number of activated CD8+ T lymphocytes.

Maternal thyroid hormones (THs) are essential for the appropriate development of the fetus and especially for the brain. Recently, some studies have shown that THs deficiency can also alter the immune system development of the progeny and their ability to mount an appropriate response against infectious agents. In this study, we evaluated whether adult mice gestated under hypothyroxinemia (Hpx) showed an altered immune response against infection with human metapneumovirus (hMPV). We observed that female mice gestated under Hpx showed higher clinical scores after seven days of hMPV infection. Besides, males gestated under Hpx have higher lung viral loads at day seven post-infection. Furthermore, the female offspring gestated in Hpx have already reduced the viral load at day seven and accordingly showed an increased proportion of activated (CD71+ and FasL+) CD8+ T cells in the lungs, which correlated with a trend for a higher histopathological clinical score. These results support that T4 deficiency during gestation might condition the offspring differently in males and females, enhancing their ability to respond to hMPV.

Characterization of prefusion-F-specific antibodies elicited by natural infection with human metapneumovirus.

Human metapneumovirus (hMPV) is a major cause of acute respiratory infections in infants and older adults, for which no vaccines or therapeutics are available. The viral fusion (F)glycoprotein is required for entry and is the primary target of neutralizing antibodies; however, little is known about the humoral immune response generated from natural infection. Here, using prefusion-stabilized F proteins to interrogate memory B cells from two older adults, we obtain over 700 paired non-IgM antibody sequences representing 563 clonotypes, indicative of a highly polyclonal response. Characterization of 136 monoclonal antibodies reveals broad recognition of the protein surface, with potently neutralizing antibodies targeting each antigenic site. Cryo-EM studies further reveal two non-canonical sites and the molecular basis for recognition of the apex of hMPV F by two prefusion-specific neutralizing antibodies. Collectively, these results provide insight into the humoral response to hMPV infection in older adults and will help guide vaccine development.

Pediatric burden and seasonality of human metapneumovirus over 5 years in Managua, Nicaragua.

Human metapneumovirus (hMPV) is an important cause of pediatric respiratory infection. We leveraged the Nicaraguan Pediatric Influenza Cohort Study (NPICS) to assess the burden and seasonality of symptomatic hMPV infection in children. NPICS is an ongoing prospective study of children in Managua, Nicaragua. We assessed children for hMPV infection via real-time reverse-transcription polymerase chain reaction (RT-PCR). We used classical additive decomposition analysis to assess the temporal trends, and generalized growth models (GGMs) were used to estimate effective reproduction numbers. From 2011 to 2016, there were 564 hMPV symptomatic infections, yielding an incidence rate of 5.74 cases per 100 person-years (95% CI 5.3, 6.2). Children experienced 3509 acute lower respiratory infections (ALRIs), of which 160 (4.6%) were associated with hMPV infection. Children under the age of one had 55% of all symptomatic hMPV infections (62/112) develop into hMPV-associated ALRIs and were five times as likely as children over one to have an hMPV-associated ALRI (rate ratio 5.5 95% CI 4.1, 7.4 p &lt; 0.001). Additionally, symptomatic reinfection with hMPV was common. In total, 87 (15%) of all observed symptomatic infections were detected reinfections. The seasonality of symptomatic hMPV outbreaks varied considerably. From 2011 to 2016, four epidemic periods were observed, following a biennial seasonal pattern. The mean ascending phase of the epidemic periods were 7.7weeks, with an overall mean estimated reproductive number of 1.2 (95% CI 1.1, 1.4). Symptomatic hMPV infection was associated with substantial burden among children in the first year of life. Timing and frequency of symptomatic hMPV incidence followed biennial patterns.

Role of human metapneumovirus glycoprotein G in modulation of immune responses.

Human metapneumovirus (hMPV) is an important pathogen responsible for acute respiratory tract infections in children, the elderly, and immunocompromised patients, with no effective treatment or vaccine currently available. Knowledge of virus- and host-specific mechanisms contributing to the pathogenesis of hMPV infection is still limited. Studies have shown that hMPV surface glycoprotein G is an important virulence factor, by inhibiting innate immune signaling in airway epithelial cells and immune cells. In this study, we investigated the role of G protein in modulating innate and adaptive immune responses in mice infected with a recombinant virus with deletion of G protein (rhMPV-ΔG). Results show that rhMPV-ΔG was strongly attenuated, as it did not induce significant clinical disease, airway obstruction and airway hyperresponsiveness (AHR), compared to infection with a control strain (rhMPV-WT). By analysis of cells in bronchoalveolar fluid and lung tissue, as well as cytokine production, we found that G protein mediates aspects of both innate and adaptive immune responses, including neutrophils, dendritic cells, natural killer cells and B cells. Lung T cells recruited in response to rhMPV-ΔG had a significantly higher activated phenotype compared to those present after rhMPV-WT infection. Despite highly attenuation characterized by low levels of replication in the lung, rhMPV-ΔG was able to induce neutralizing antibodies and to protect mice from a secondary hMPV challenge. However, challenged mice that had received rhMPV-ΔG as primary infection showed some signs of lung disease at the earliest time points, which were less evident in mice that had received the rhMPV-WT strain as primary infection. These results demonstrate some of the mechanisms by which G protein could contribute to airway disease and modulate immune response to hMPV infection.

Profiling of hMPV F-specific antibodies isolated from human memory B cells

Human metapneumovirus (hMPV) belongs to the Pneumoviridae family and is closely related to respiratory syncytial virus (RSV). The surface fusion (F) glycoprotein mediates viral fusion and is the primary target of neutralizing antibodies against hMPV. Here we report 113 hMPV-F specific monoclonal antibodies (mAbs) isolated from memory B cells of human donors. We characterize the antibodies’ germline usage, epitopes, neutralization potencies, and binding specificities. We find that unlike RSV-F specific mAbs, antibody responses to hMPV F are less dominant against the apex of the antigen, and the majority of the potent neutralizing mAbs recognize epitopes on the side of hMPV F. Furthermore, neutralizing epitopes that differ from previously defined antigenic sites on RSV F are identified, and multiple binding modes of site V and II mAbs are discovered. Interestingly, mAbs that bind preferentially to the unprocessed prefusion F show poor neutralization potency. These results elucidate the immune recognition of hMPV infection and provide novel insights for future hMPV antibody and vaccine development.

CD8+ T cell impairment drives severe human metapneumovirus respiratory disease in aged mice.

Abstract Objective Human metapneumovirus (HMPV) is a leading cause of severe respiratory disease in children &amp;lt;5, adults &amp;gt;65, and the immunocompromised. CD8+ T lymphocytes are the primary cell responsible for clearing HMPV infection in the lung. We tested the hypothesis that CD8+ T cell impairment in the aged host drives severe respiratory infection and delayed viral clearance. Methods B6 aged 72–73wk mice and young 6–7wk mice were infected with 2×106 PFU HMPV. Seven days post infection, mice were euthanized and lung, bronchoalveolar lavage (BAL), spleen, and draining lymph nodes were collected for flow cytometry. Lung and BAL supernatant was collected for viral titer, histology, and cytokine measurement. Results Aged mice lost more weight, had delayed viral clearance, and increased clinical scores and lung histopathology. Aged mice produced fewer HMPV-tetramer+ cells in lung and BAL. Aged CD8+ T lymphocytes in BAL co-expressed inhibitory receptors PD-1, TIM-3, LAG-3, and 2B4. Aged CD8+ T lymphocytes also upregulated senescence markers, T-bet and EOMES. Upon ex vivo peptide stimulation, aged CD8+ T cells produced significantly less granzyme B compared to young CD8+ T cells. Adoptive transfer of young T cells into aged mice rescued this severe disease phenotype. Young CD8+ cells in the aged host produced more tetramer+ cells and granzyme B and had less senescent marker expression. Conclusion Aged mice exhibit more severe respiratory disease when infected with HMPV. Aged CD8+ T cells appear to be impaired and upregulate senescence markers that contribute to severe HMPV infection in the aged host. Supported by: NIH/NIAID 5R01 AI085062-09, John V. Williams, MD NIH T32GM008208 Medical Scientist Training Program, University of Pittsburgh School of Medicine

Human metapneumovirus prevalence during 2019-2021 in Israel is influenced by the COVID-19 pandemic

To compare infection rates and circulating subtypes of human metapneumovirus (hMPV) before (2019-2020) and after the emergence of coronavirus disease 2019 (COVID-19) (2021) in Israel. In total, 12,718 respiratory samples were collected from hospitalized patients of all ages during the years 2019 to 2021 at the Sheba Medical Center in Israel and subjected to reverse transcription-polymerase chain reaction analysis. In addition, whole-genome sequencing was performed to characterize the subtypes of hMPV circulating in Israel between 2019 and 2021. A total of 481 samples were found positive for hMPV. Before the emergence of COVID-19, hMPV peaked in winter months and declined thereafter. In sharp contrast, during the COVID-19 pandemic, we observed a delayed peak in hMPV infection cases and higher infection of young children. Viral sequencing showed a shift in the most prevalent circulating hMPV strain from A2b to B1 during the years 2019, 2020, and 2021. Compared with the years before the COVID-19 pandemic, in 2021, hMPV mostly affected young children, and the most prevalent circulating subtype shifted from A2b in 2019 to B1.

Molecular investigation of human metapneumovirus in children with acute respiratory infections in Chennai, South India, from 2016-2018.

Human metapneumovirus (hMPV) has emerged as a frequent cause of acute respiratory infections (ARI) among young children. The prevalence and genetic diversity of hMPV circulating in Chennai, Southern India, has not been studied yet. Hence, this study was aimed to investigate the prevalence, co-infection with other respiratory viruses like HRSV A and B, influenza A and B, hRV and HPIV 1-4 viruses, socio-demographic associations, and genotypes of hMPV among children in Chennai. A total of 350 nasal swab specimens were collected from children with ARI during April 2016 to August 2018 and tested for hMPV by real time PCR method. In this study, hMPV was detected in 4% (14/350) of the samples. One hMPV positive sample was found to be co-infected with influenza B virus. The mean and median ages of the children with hMPV infection were 61.5months (5.1years) and 83months (6.9years), respectively. Phylogenetic analysis of the partial F gene revealed the presence of A2c subcluster among the study strains as well as with B1 and B2 lineages. The prevalence data obtained in this study is important in evaluating the role of hMPV in childhood ARI and emphasizes the importance of routine viral diagnosis in hospitals. To the best of our knowledge, this is the first study to report the prevalence, seasonality, and genetic diversity of hMPV in Chennai as well as the first study to report A2c subcluster of hMPV among children in India.

Comparative Analysis of Epidemiology, Clinical Features, and Cytokine Response of Respiratory Syncytial and Human Metapneumovirus Infected Children with Acute Lower Respiratory Infections.

Both human respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause immune-mediated under-five acute respiratory infections (ARIs), but differences in their disease pathogenesis, if any, are not well-known. This study was undertaken to analyze the epidemiological and immunological features of RSV and hMPV infections. Nasopharyngeal aspirates from children (aged 2 months to 5 years) with ARI, presenting to our tertiary care center between December 2013 and March 2016, were subjected to real-time polymerase chain reaction for the detection of RSV and hMPV. Positive samples were analyzed for co-infection and cytokine levels. Of the 349 nasopharyngeal aspirates, RSV was detected in 40.68% (142/349), hMPV in 6.59% (23/349), and both in 1.4% (5/349). Co-infections were common, with rhinovirus being the most common co-offender. The demographic and clinical parameters of RSV- and hMPV-infected children were comparable. The MMP-9/TIMP-1 ratio was significantly higher in RSV-mediated ARI and IFN-γ in hMPV-mediated ARI. Both RSV and hMPV are common among North Indian children with ARI, and coinfections are common. Their clinical features are non-discriminatory, and molecular diagnosis should be utilized to ascertain their individual epidemiology. The differences in their immune-pathogenesis (MMP-9/TIMP-1 ratio in RSV and IFN-γ in hMPV) could serve as useful tools for developing newer drugs.

Evaluation of children diagnosed with a lower respiratory tract infection due to Human metapneumovirus.

Human metapneumovirus (hMPV) is one of the leading causes of acute respiratory infections and bronchiolitis in infants. A history of prematurity and chronic diseases such as congenital heart disease or asthma/reactive airway disease (RAD) increases the risk of severe lower respiratory tract infection (LRTI) due to hMPV. In this cross-sectional study, we aimed to analyze the clinical outcome and risk factors for severe disease in children with LRTI due to hMPV. The current cross-sectional study included children between 28 days and 18 years of age with the diagnosis of hMPV-associated LRTI hospitalizations, over two years from January 2016 to September 2018 in Health Science University Dr. Behçet Uz Child Disease and Pediatric Surgery Training and Research Hospital. hMPV virus was detected by the multiplex polymerase chain test (PCR) (Commercial Multiplex Real-Time PCR: FTD Respiratory 21 plus, Fast Track Diagnostics, Luxembourg) from a nasopharyngeal swab. Patients who had positive results in multiplex PCR tests with other viral agents simultaneously were not included in the study. Data were retrospectively collected from the computerized hospital system. In this cross-sectional study, 62 patients who were hospitalized with the diagnosis of LRTI due to hMPV infection were included. Thirty-five (55.7%) of the patients were male. The median age was one year (2 months-15 years). Fifty-one (82.2%) patients were younger than two years. The median hospital length of stay was found to be 10 days (2-33 days) in patients with an underlying disease and 7,5 days (ranging from 2 to 20 days) in the patients without an underlying disease, this difference was significant (p=0.031). Clinicians should consider hMPV as an important pathogen of LRTI even in healthy children, although we expect a poor course of disease in children with an underlying disease.

Human Metapneumovirus Infection in a Children’s Hospital – It Should Get More Attention

Respiratory syncytial virus (RSV) and influenza infections are a major cause of hospitalization and intensive care unit (ICU) admission to children's hospitals and are closely tracked. We compared data over 6 seasons of human metapneumovirus (hMPV), RSV and influenza infections. During the 2014-2019 winter viral seasons, hMPV, RSV and influenza infections were tracked. For hMPV admissions, rates of hospitalizations, ICU admissions, hospital-acquired infections (HAIs) and mortalities were assessed and compared with RSV and influenza admissions. Retrospective data was used to study patients infected with hMPV. During the winter seasons of 2014-2019, the rates of hospitalization due to hMPV were significantly higher than both RSV and influenza. ICU admissions, deaths and HAIs for hMPV were similar to RSV and influenza.Of the 471 total cases with hMPV, 58 (12.3%) had chronic lung disease (CLD) and 23 (4.9%) were tracheostomy dependent. Among 104 hMPV ICU admissions from 2013 to 2019, 86 (82%) had an underlying medical diagnosis, 30 (29%) had CLD, 21 (20%) had tracheostomies and 33 (32%) required mechanical ventilation. The average age of hMPV infected children in our ICU is 3 years and 10 months. Our large descriptive study of hMPV infected children over 6 seasons showed higher rates of hospitalization compared with RSV and influenza, similar ICU and HAI rates, and deaths. ICU admitted children often had associated co-morbidities, including CLD. Further studies for focused disease surveillance and potential vaccine development for high-risk children are needed.