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Human metapneumovirus infections

Human metapneumovirus infections
Author:
James E Crowe, Jr, MD
Section Editors:
Martin S Hirsch, MD
Sheldon L Kaplan, MD
Deputy Editor:
Sheila Bond, MD
Literature review current through: Jun 2022. | This topic last updated: Feb 09, 2021.

INTRODUCTION — In 2001, investigators from the Netherlands discovered a new virus associated with respiratory disease in children and designated it human metapneumovirus (hMPV) [1]. Data suggest that hMPV has been responsible for respiratory tract infections for at least 60 years with a worldwide distribution [1-4].

The virology, pathogenesis, epidemiology, clinical manifestations, diagnosis, and treatment of hMPV will be discussed here. Other common respiratory viruses are reviewed separately. (See "Respiratory syncytial virus infection: Clinical features and diagnosis" and "Seasonal influenza in children: Clinical features and diagnosis" and "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Parainfluenza viruses in children" and "Parainfluenza viruses in adults" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections".)

VIROLOGY — HMPV is classified as a member of the family Pneumoviridae, which comprises large enveloped negative-sense RNA viruses. This taxon was formerly a subfamily within the Paramyxoviridae family but was reclassified in 2016 as a separate family with two genera, Metapneumovirus (which includes hMPV) and Orthopneumovirus (which includes respiratory syncytial virus).

HMPV is an enveloped virus with a nonsegmented negative-sense RNA genome. HMPV is most closely related phylogenetically to avian metapneumovirus (APV) [1]. The complete genome sequence reveals a high level of homology with APV [5]. Phylogenetic analysis has identified two subgroups of hMPV, subgroups A and B, and two clades within each of these subgroups (designated A1, A2, B1, and B2), which often circulate concurrently [6,7]. A study of 727 Australian hMPV isolates was undertaken from 2001 to 2004 to determine the epidemiologic profile of genetic subtypes associated with acute respiratory tract infections [7]. Concurrent annual circulation of all four hMPV subtypes was common, although a single, and usually different, hMPV subtype predominated each year.

Given the close relationship between hMPV and APV, it was speculated that hMPV might have originated from birds [1]. Although genetically similar, animal experiments have shown that hMPV is not an avian virus, since it does not infect chickens or turkeys. In contrast, inoculation of macaque monkeys with hMPV did lead to significant viral replication restricted to the respiratory tract with the subsequent development of upper respiratory symptoms [8].

Circulating virus strains exhibit minor genetic diversity, but there is no evidence to date that strains vary significantly in their virulence. A large-scale, 10-year study in South Korea between 2007 and 2016 identified 1275 instances of hMPV infection and classified 94 percent of the strains into 5 genotypic subtypes (A1, A2a, A2b, B1, and B2); a correlation between hMPV subtype and clinical outcome was not observed [9].

PATHOGENESIS — Viral replication has been demonstrated in the respiratory tracts of experimentally infected chimpanzees and monkeys and is associated with mild upper respiratory tract signs [8]. The integrin alpha-V-beta-1 has been identified as a receptor that facilitates infection of epithelial cells [10]. In a mouse model, viral RNA and significant airway inflammation were prolonged [11]. Infection also was associated with mucus hyperproduction and hyperplasia of the respiratory epithelium, with resultant airway obstruction and hyperresponsiveness after methacholine challenge. These data are consistent with those from studies of other respiratory viruses, suggesting that the pathogenesis of severe respiratory infections in childhood may be associated with the development of, or susceptibility to, asthma [12].

TRANSMISSION — It is likely that transmission occurs by direct or close contact with contaminated secretions, which may involve large particle aerosols, droplets, or fomites but not small particle aerosols. Physical separation at distances ≥6 feet therefore interrupts aerosol transmission. Nosocomial infections have been reported in hospitalized children [13], including in a pediatric hematology-oncology ward [14], and in hospitalized adults [15] as well as adults in skilled nursing facilities [16].Some reported hMPV outbreaks of severe lower respiratory tract infection in residents of long-term care facilities have shown attack rates of 34 to 72 percent [16,17].

INCUBATION PERIOD — The incubation period is not fully defined but is thought to be five to nine days in most cases [13,14]. In one study, transmission to family members appeared to be very efficient when an index case became ill, with an estimated five-day interval (range four to seven days) between the onset of symptoms in the index patient and the onset of symptoms in contacts [18].

EPIDEMIOLOGY — Based upon reports from the Netherlands [1], the United Kingdom [19], Finland [20], Australia [3], Canada [2,4], Kenya [21], China [22], Norway [23], and many other countries, the virus is ubiquitous and has been associated with infection for at least 60 years [1,24]. The global burden of infection is large. Worldwide, models estimate that there were 14.2 million hMPV-associated acute lower respiratory infections in children <5 years in 2018 [25].

HMPV can cause upper and lower respiratory tract infection in patients of all age groups, but symptomatic disease most often occurs in young children or older adults. In a Canadian series of 37 patients, 35 percent occurred in children under the age of 5 and 46 percent in adults above the age of 65 [2]. Many infected children are under the age of one year [26-28].

HMPV has seasonal variation: late winter and early spring in the United States, the Netherlands, the United Kingdom, Norway, and Finland, and late spring and summer in Hong Kong [1,13,26,29,30]. However, one summer outbreak of respiratory hMPV illnesses was described in 26 residents and 13 staff members in a United States–based long-term care facility [31].

Neutralizing antibodies in the serum of patients that cross-neutralize these viruses are difficult to study, but the isolation of human monoclonal antibodies that neutralize both respiratory syncytial virus and hMPV suggests that partial cross-immunity for these two viruses may occur [32,33].

Trends in hMPV infections in the United States are monitored by the National Respiratory and Enteric Virus Surveillance System and can be found on the Centers for Disease Control and Prevention website [34].

Children — First infections occur early in life. Seroprevalence data suggest that most children are infected by the age of five [1]. In studies of children with acute respiratory illnesses, hMPV has been detected in approximately 5 to 15 percent of patients, most commonly in infants <1 year [26-29,31-33,35-37].

Younger age may be associated with hMPV disease requiring hospitalization. In population-based surveillance studies in the United States, hMPV was detected in 13 percent of children hospitalized with pneumonia [38,39]. In one study, the incidence was higher in children <5 years of age than children ≥5 years of age [38]. In approximately half of cases, it was detected alone, and in half it was detected together with another pathogen. In children less than 3 years of age who were hospitalized or who presented to a clinic with hMPV infection, factors independently associated with hospitalization included age <6 months and the presence of three or more children in the household [40]. Among children who were hospitalized, factors independently associated with severe disease were female sex, prematurity, and genotype B infection.

The prevalence of hMPV was higher in children less than three years of age who were hospitalized for wheezing compared with hospitalized controls without wheezing (8.9 versus 1.3 percent); however, hMPV did not play a significant role in wheezing respiratory disease in children older than three years of age [41]. History of prematurity is a risk factor for hospitalization with hMPV [42]. In another study, the majority of inpatients and outpatients less than five years of age with hMPV infection had no underlying conditions, although premature birth and asthma were more frequent among hospitalized children with hMPV than among those without hMPV [28]. Children hospitalized with hMPV infection (as compared with those hospitalized without hMPV infection) were older and more likely to receive a diagnosis of pneumonia or asthma, to require supplemental oxygen, and to have a longer stay in the intensive care unit. HMPV can cause fatal respiratory illness; a cluster of severe disease was reported in which most patients were Native American, a group that may be at increased risk [43].

Adults — HMPV upper respiratory tract infection occurs in adults, but its frequency as a cause of an acute lower respiratory illness appears to be lower than in children [19,44-47]. In population-based surveillance studies in the United States, hMPV was detected in about 4 percent of hospitalized adults with community-acquired pneumonia; hMPV was detected primarily as a single pathogen, although coinfection with other pathogens was common [39,47]. Frail older adult patients with hMPV infection are most likely to require medical care [19]. HMPV has also been detected from asymptomatic individuals.

CLINICAL MANIFESTATIONS — Serosurveys suggest that hMPV is usually associated with mild, self-limited respiratory infections in children and adults [19,26,27,29,44]. The kinetics of virus shedding and the relationship between virus shedding and clinical symptoms are not known with precision because human challenge studies have not been performed with wild-type virus. The typical course of mild disease probably involves an asymptomatic period of several days after inoculation, followed by a week of upper respiratory symptoms, with gradual resolution. The typical peak of virus shedding is likely to be about one week after inoculation, and the peak day of symptoms likely follows within a day or two of peak shedding. In severe disease involving the lower respiratory tract, the typical course appears to involve a brief asymptomatic period after inoculation, followed by a day or two of upper respiratory symptoms, which progress to wheezing and/or other signs of lower respiratory tract involvement. In many patients, the wheezing lasts for several days; however, individuals with a predisposition to reactive airway disease may exhibit prolonged airway dysfunction, with recurrent mild wheezing and cough for days or even several weeks.

Among patients who require hospitalization, clinical manifestations can range from bronchiolitis or asthma exacerbation to severe pneumonia and acute respiratory distress syndrome [37,44,48-50].

No specific clinical features distinguish hMPV from other viral causes of bronchiolitis or pneumonia.

Children — A number of studies have described the clinical manifestations of hMPV infection in children [26,27,29,49,51,52]. The range and frequency of symptoms and signs was illustrated in three series that included approximately 150 children with hMPV infection [26-28]:

Cough – 68 to 90 percent

Rhinitis – 44 to 77 percent

Fever – 52 to 86 percent

Wheezing – 51 to 56 percent

Symptoms of upper respiratory infection include rhinopharyngitis and laryngitis [26,29].

The clinical diagnoses that were made among 49 children with lower respiratory tract infection in one of the above reports were bronchiolitis (59 percent), croup (18 percent), exacerbation of asthma (14 percent), and pneumonia (8 percent) [26].

An association with wheezing and exacerbation of asthma has been noted in other studies [20,27,29,52]. As an example, in a Finnish study, which assessed 132 consecutive admissions for wheezing in children who had not taken glucocorticoids in the preceding four weeks, hMPV was detected by polymerase chain reaction (PCR) in 10 cases (9 percent) [20].

The most common reasons for hospitalization in hMPV-infected children are acute bronchiolitis and pneumonia [37,49]. The median total hospitalization cost per patient in one study was over five thousand dollars, with significantly higher costs for patients with chronic medical conditions [53]. Disease severity may be increased when there is coinfection with respiratory syncytial virus (RSV). Among RSV-infected children less than two years of age, coinfection with hMPV has been associated with severe RSV bronchiolitis [54,55], the need for admission to the intensive care unit [56], and a 10-fold increase in the need for mechanical ventilation [55]. Other studies, however, have not identified a high rate of coinfections in hospitalized patients, so the clinical significance of finding RSV and hMPV RNA in the same sample is uncertain. It is not known if primary hMPV infection that is severe or early in life predisposes to asthma or to a higher frequency of subsequent wheezing-associated respiratory illnesses [41]. (See "Evaluation of wheezing in infants and children".)

In one study, immunization of HIV-infected children with pneumococcal vaccine reduced the prevalence of hMPV-associated lower respiratory tract illnesses, suggesting an interaction between hMPV and bacteria in severe disease [57].

Encephalitis has been reported rarely in children with upper respiratory tract hMPV disease [58,59]. In one report of fatal encephalitis in a 14-month-old boy, reverse-transcriptase PCR tests of both brain and lung tissue during the postmortem were positive for hMPV [58]. In another report, hMPV was detected by PCR from the cerebrospinal fluid and nasal washings of a 10-year-old girl with severe acute encephalitis [59]. Magnetic resonance imaging of both patients demonstrated multifocal cortical and subcortical lesions [58,59]. It is not clear whether hMPV is causative in these cases, since virus replication is thought to be limited to the respiratory tract.

Adults — The clinical manifestations of hMPV infection in adults are similar to those seen in children. In a review cited above, the following frequency of symptoms was noted [44]:

Cough – 100 percent

Nasal congestion – 85 percent

Rhinorrhea – 75 percent

Dyspnea – 69 percent

Hoarseness – 67 percent

Wheezing – 62 percent

Fever occurred in only one patient (4 percent). Dyspnea and wheezing were more common in older adult patients, while hoarseness was more common in young adults. In one population-based surveillance study that evaluated 88 adults hospitalized with hMPV pneumonia, fever and cough were the most common presenting symptoms. Clinical features of hMPV pneumonia were similar to pneumonia caused by other pathogens, although bacterial pneumonia and RSV pneumonia were associated with greater severity [39].

Possible role in COPD and asthma exacerbations — The role of hMPV in exacerbations of chronic obstructive pulmonary disease (COPD) is controversial. One group identified the agent to be associated with exacerbations in about 5 percent of cases, whereas another series could not identify a single patient with hMPV in this context [60,61]. HMPV infection has been associated with acute exacerbation of asthma in adults [62].

Recurrent infection — Limited data suggest that recurrent infection is common. Since all children become infected in the first years of life, all adult infections represent reinfections. Reinfections appear to be mild, although immunocompromised patients may be at risk of severe disease during reinfection. In a case report, for example, a young child with acute lymphoblastic leukemia developed recurrent infections with distinct hMPV strains during two consecutive winters [63].

Antigenic drift, the molecular basis underlying many reinfections with influenza, likely occurs to some extent with hMPV, but such drift probably is not necessary for reinfection. An analysis of sequences derived from isolates over a 20-year period suggest that point mutations do occur over time; however, hMPV does not appear to sustain a linear accumulation of drift mutations that result in antigenic drift over time [26]. (See "Influenza: Epidemiology and pathogenesis".)

Immunocompromised hosts — Immunocompromised hosts appear to acquire infection at the same frequency as immunocompetent individuals. However, hMPV infections may be more severe and the course more prolonged in immunocompromised patients due to poor clearance of virus after infection has been established. The role that hMPV may play in immunocompromised hosts has been evaluated in several studies:

A cohort of 688 children and adults who underwent bronchoscopy was tested for the presence of a variety of respiratory pathogens, including hMPV, in bronchoalveolar lavage (BAL) and bronchial wash specimens [64]. HMPV was detected from six patients, four of whom were immunocompromised; the most common condition was lung transplantation. The rate of detection of hMPV was similar to that of RSV infection.

In a study of 251 episodes of upper and lower respiratory tract infection in adults with hematologic malignancies, 9 percent of episodes were associated with hMPV infection [65]. Sixteen of the 22 episodes occurred in hematopoietic cell transplant (HCT) recipients; three of nine patients with hMPV-related lower respiratory tract disease died.

In a retrospective survey of HCT recipients (most of whom were adults) who had BAL sampling performed because of respiratory illness, hMPV was isolated from 5 of 163 adult patients (3 percent) [66]. Infected patients became symptomatic within 40 days after transplantation. Initial symptoms included fever, cough, nasal congestion, and sore throat; four of five infected patients died.

In a study of 21 adults undergoing HCT, persistent nasopharyngeal hMPV infection was demonstrated in most study participants for several months, although these patients were asymptomatic [67]. These data suggest impaired clearance as documented in other immunocompromised hosts [68]. A nosocomial outbreak in an allogeneic HCT unit has been reported [69].

A large study in South Africa that included children and adults showed that the incidence of hMPV-associated hospitalization was higher in HIV-infected persons compared with HIV-uninfected persons [70].

A high burden of hMPV infections has been reported in a retrospective study of children and adults with cancer, especially those with hematologic malignancies [71].

Severe hMPV infections can occur following HCT. Progression from upper to lower respiratory tract disease occurred in up to 60 percent of pediatric and adult HCT recipients with risk factors that included systemic glucocorticoid use and low lymphocyte counts [72].

In a retrospective study of 55 immunocompromised children with hMPV infection, 16 (29 percent) presented with lower respiratory tract infection, 12 (23 percent) required intensive care unit admission and/or supplemental oxygen with ≥28 percent FiO2, and 3 (5 percent) died [73]. Those with severe disease were more likely to be neutropenic.

Lung transplant patients are susceptible to severe hMPV disease; in one study, a third of HMPV-infected lung transplant recipients developed chronic lung allograft dysfunction (CLAD) progression within one year, with lack of early lung function recovery predicting long-term CLAD progression [74].

These studies suggest that hMPV-related infection should be considered a potential cause of respiratory illness in immunocompromised patients. (See "Overview of infections following hematopoietic cell transplantation" and "Viral infections following lung transplantation".)

DIAGNOSIS — Reverse-transcriptase polymerase chain reaction (RT-PCR) is the most sensitive and commonly used method for diagnosis of hMPV infection. In the first decade after discovery, viral culture with shell vial assays and fluorescent immunoassay with or without culture were the principal techniques used, but the percentage of studies using these methods decreased from 21.4 percent in the period between 2001 to 2010 to 15.2 percent in 2011 to 2019 [75]. Serologic data suggest that hMPV has been causing clinical disease for at least 60 years, although this was only recognized in 2001 [1]. At least two factors contributed to the delay in identifying hMPV: the clinical manifestations are not unique, and the virus replicates slowly and inefficiently in culture.

In temperate areas, hMPV should be suspected in cases of acute respiratory tract illness in the late winter. Testing to achieve a specific diagnosis of hMPV in the setting of severe respiratory tract illness is helpful to avoid unnecessary use of antibiotics and to isolate patients properly in the hospital.

Reverse-transcriptase PCR — Testing for viral RNA in human respiratory secretions using reverse-transcriptase polymerase chain reaction (RT-PCR) in both conventional and real-time formats has been developed with a variety of different primers and probes [1,26,27,37,44]. As noted above, RT-PCR is the most sensitive method for diagnosis of hMPV infection, but the primers and techniques are not standardized among laboratories. RT-PCR tests for hMPV as a single target are available in research laboratories and a limited number of commercial diagnostic laboratories.

The BioFire FilmArray Respiratory Panel assay, a multiplex PCR panel, has been cleared by the US Food and Drug Administration for simultaneous testing for the presence of hMPV and a variety of other pathogens including strains of adenovirus, coronavirus, influenza A and B, parainfluenza viruses 1 to 4, rhinovirus/enterovirus, respiratory syncytial virus, Bordetella pertussis, Chlamydia pneumoniae, and Mycoplasma pneumoniae [76,77]. This test is performed in many hospital laboratories. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Other respiratory viruses'.)

Direct fluorescent antibody — The direct fluorescent antibody (DFA) technique allows detection of virus antigen in cells present in nasopharyngeal aspirates within two to three hours. However, this technique is labor intensive and requires a high level of expertise and is generally performed only in reference laboratories.

Viral culture — Isolation of hMPV requires inoculation of nasopharyngeal specimens onto special cell lines that are used in research laboratories and requires the use of trypsin treatment [26]. Only about one-half of cultures that are positive for hMPV by RT-PCR yield cultivable virus by current techniques. Shell vial centrifugation cultures can be used for rapid diagnosis of hMPV, mostly in research settings, with detection using monoclonal antibodies. With this technique, virus can be detected as early as one to two days after inoculation, which could offer an advantage over routine culture [78].

Serology — Testing for the presence of hMPV-reactive antibodies is not used clinically on a routine basis but is used in epidemiology studies and vaccine research settings. Research-grade serologies to detect hMPV-specific antibodies are performed using enzyme-linked immunosorbent assays (ELISAs) [79] or serum virus-neutralizing antibody tests.

Seropositivity is almost universal by age 5 [1]. A definitive serologic diagnosis requires either seroconversion or at least a fourfold increase in titer on serial samples [44].

Imaging — Chest radiographic findings are not specific in the setting of hMPV infection, most commonly showing perihilar opacities, hyperinflation, atelectasis, and occasionally consolidation but not pleural effusion or pneumothorax [80].

TREATMENT — Treatment is supportive and varies with the clinical manifestations. Some drugs, such as ribavirin, may exhibit antiviral activity in vitro against hMPV [81]. However, there are no clinical data on the efficacy of ribavirin or other antivirals for hMPV infections. Therefore, antiviral therapy is not recommended for patients with hMPV infections.

The rate of secondary bacterial lung infection or bacteremia in patients with hMPV infection has not been defined but is thought to be low. As a result, the use of antibiotics is not usually indicated in the treatment of infants hospitalized with hMPV bronchiolitis or pneumonia.

PREVENTION

Infection control — It is likely that transmission of hMPV is by direct or close contact with contaminated secretions. (See 'Transmission' above.)

When hMPV infection is suspected or confirmed, infection control measures used for respiratory syncytial virus (RSV) and other acute respiratory illnesses are warranted. These include contact precautions including hand washing in all settings. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Infection control in the health care setting'.)

Contact precautions are used for hospitalized patients. Control of nosocomial spread depends upon rigorous compliance with contact precautions and is complicated by exposures to other infected patients, staff, or family members and other visitors. Patients with known hMPV infection who require hospitalization should be cared for in single rooms or placed with a cohort of hMPV-infected patients. When feasible, patients with RSV infection should be cared for in a separate area from hMPV-infected patients, since coinfection can occur and may be associated with more severe disease [54,56]. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Contact precautions'.)

Children with hMPV infection shed infectious virus for many days (and probably for weeks in some cases). Infants or children who are diagnosed with hMPV also may pose a risk of transmission of virus following discharge or as outpatients. As hMPV infection is ubiquitous in childhood, once children have resolved their acute illness, they are allowed to return to daycare or school. Immunocompromised patients of any age should avoid contact with children during acute hMPV infection and early convalescence.

Vaccine development — Live and subunit experimental vaccine candidates are in preclinical development, but none is near licensure [82,83]. Recombinant hMPV F protein constructs that stabilize the protein in the prefusion and postfusion conformations have been engineered, and X-ray crystal structures of both conformations have been determined [84,85]. For the related virus RSV, prefusion-specific antibodies dominate the protective response [86], but, for hMPV F, experimental immunization with postfusion or prefusion hMPV F induce similar antibody responses [85].

SUMMARY AND RECOMMENDATIONS

Human metapneumovirus (hMPV) was discovered in 2001 but has been responsible for respiratory tract infections for at least 60 years with a worldwide distribution. HMPV is classified as a member of the family Pneumoviridae, which comprises large enveloped negative-sense RNA viruses. (See 'Introduction' above.)

It is likely that transmission of hMPV is by direct or close contact with contaminated secretions, not small particle aerosols. (See 'Transmission' above.)

HMPV can cause upper and lower respiratory tract infection in patients of all age groups, but symptomatic disease most often occurs in young children or older adults. (See 'Epidemiology' above.)

Serosurveys suggest that hMPV is usually associated with mild, self-limited infections in children and adults. The incubation period is not fully defined but is thought to be five to nine days in most cases, with a typical duration of illness of approximately one week. (See 'Incubation period' above and 'Clinical manifestations' above.)

Among patients who require hospitalization, clinical manifestations can range from bronchiolitis or asthma exacerbation to severe pneumonia and acute respiratory distress syndrome. (See 'Clinical manifestations' above.)

Reverse-transcriptase polymerase chain reaction (PCR) on nasopharyngeal specimens is the most sensitive method for diagnosis of hMPV infection, but the primers and techniques are not standardized among laboratories. The BioFire FilmArray Respiratory Panel assay, a multiplex PCR panel, has been cleared by the US Food and Drug Administration for simultaneous testing for the presence of hMPV and a variety of other pathogens; this test can be performed in hospital laboratories. HMPV grows slowly and inefficiently in culture. (See 'Diagnosis' above and 'Reverse-transcriptase PCR' above.)

Treatment is supportive and varies with the clinical manifestations. There are no clinical data on the efficacy of antiviral therapy for hMPV infections. Antiviral therapy is therefore not recommended for patients with hMPV infection. (See 'Treatment' above.)

  1. van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001; 7:719.
  2. Boivin G, Abed Y, Pelletier G, et al. Virological features and clinical manifestations associated with human metapneumovirus: a new paramyxovirus responsible for acute respiratory-tract infections in all age groups. J Infect Dis 2002; 186:1330.
  3. Nissen MD, Siebert DJ, Mackay IM, et al. Evidence of human metapneumovirus in Australian children. Med J Aust 2002; 176:188.
  4. Peret TC, Boivin G, Li Y, et al. Characterization of human metapneumoviruses isolated from patients in North America. J Infect Dis 2002; 185:1660.
  5. van den Hoogen BG, Bestebroer TM, Osterhaus AD, Fouchier RA. Analysis of the genomic sequence of a human metapneumovirus. Virology 2002; 295:119.
  6. Boivin G, Mackay I, Sloots TP, et al. Global genetic diversity of human metapneumovirus fusion gene. Emerg Infect Dis 2004; 10:1154.
  7. Mackay IM, Bialasiewicz S, Jacob KC, et al. Genetic diversity of human metapneumovirus over 4 consecutive years in Australia. J Infect Dis 2006; 193:1630.
  8. Kuiken T, van den Hoogen BG, van Riel DA, et al. Experimental human metapneumovirus infection of cynomolgus macaques (Macaca fascicularis) results in virus replication in ciliated epithelial cells and pneumocytes with associated lesions throughout the respiratory tract. Am J Pathol 2004; 164:1893.
  9. Lim YK, Kweon OJ, Kim HR, et al. Clinical Features, Epidemiology, and Climatic Impact of Genotype-specific Human Metapneumovirus Infections: Long-term Surveillance of Hospitalized Patients in South Korea. Clin Infect Dis 2020; 70:2683.
  10. Cseke G, Maginnis MS, Cox RG, et al. Integrin alphavbeta1 promotes infection by human metapneumovirus. Proc Natl Acad Sci U S A 2009; 106:1566.
  11. Hamelin ME, Prince GA, Gomez AM, et al. Human metapneumovirus infection induces long-term pulmonary inflammation associated with airway obstruction and hyperresponsiveness in mice. J Infect Dis 2006; 193:1634.
  12. Openshaw PJ, Dean GS, Culley FJ. Links between respiratory syncytial virus bronchiolitis and childhood asthma: clinical and research approaches. Pediatr Infect Dis J 2003; 22:S58.
  13. Peiris JS, Tang WH, Chan KH, et al. Children with respiratory disease associated with metapneumovirus in Hong Kong. Emerg Infect Dis 2003; 9:628.
  14. Kim S, Sung H, Im HJ, et al. Molecular epidemiological investigation of a nosocomial outbreak of human metapneumovirus infection in a pediatric hemato-oncology patient population. J Clin Microbiol 2009; 47:1221.
  15. Tu CC, Chen LK, Lee YS, et al. An outbreak of human metapneumovirus infection in hospitalized psychiatric adult patients in Taiwan. Scand J Infect Dis 2009; 41:363.
  16. Centers for Disease Control and Prevention (CDC). Outbreaks of human metapneumovirus in two skilled nursing facilities -West Virginia and Idaho, 2011-2012. MMWR Morb Mortal Wkly Rep 2013; 62:909.
  17. Boivin G, De Serres G, Hamelin ME, et al. An outbreak of severe respiratory tract infection due to human metapneumovirus in a long-term care facility. Clin Infect Dis 2007; 44:1152.
  18. Matsuzaki Y, Itagaki T, Ikeda T, et al. Human metapneumovirus infection among family members. Epidemiol Infect 2013; 141:827.
  19. Stockton J, Stephenson I, Fleming D, Zambon M. Human metapneumovirus as a cause of community-acquired respiratory illness. Emerg Infect Dis 2002; 8:897.
  20. Jartti T, van den Hoogen B, Garofalo RP, et al. Metapneumovirus and acute wheezing in children. Lancet 2002; 360:1393.
  21. Feikin DR, Njenga MK, Bigogo G, et al. Etiology and Incidence of viral and bacterial acute respiratory illness among older children and adults in rural western Kenya, 2007-2010. PLoS One 2012; 7:e43656.
  22. Wang Y, Chen Z, Yan YD, et al. Seasonal distribution and epidemiological characteristics of human metapneumovirus infections in pediatric inpatients in Southeast China. Arch Virol 2013; 158:417.
  23. Moe N, Stenseng IH, Krokstad S, et al. The Burden of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Hospitalized Norwegian Children. J Infect Dis 2017; 216:110.
  24. Osterhaus A, Fouchier R. Human metapneumovirus in the community. Lancet 2003; 361:890.
  25. Wang X, Li Y, Deloria-Knoll M, et al. Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study. Lancet Glob Health 2021; 9:e33.
  26. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004; 350:443.
  27. Esper F, Martinello RA, Boucher D, et al. A 1-year experience with human metapneumovirus in children aged <5 years. J Infect Dis 2004; 189:1388.
  28. Edwards KM, Zhu Y, Griffin MR, et al. Burden of human metapneumovirus infection in young children. N Engl J Med 2013; 368:633.
  29. Døllner H, Risnes K, Radtke A, Nordbø SA. Outbreak of human metapneumovirus infection in norwegian children. Pediatr Infect Dis J 2004; 23:436.
  30. Haynes AK, Fowlkes AL, Schneider E, et al. Human Metapneumovirus Circulation in the United States, 2008 to 2014. Pediatrics 2016; 137.
  31. Louie JK, Schnurr DP, Pan CY, et al. A summer outbreak of human metapneumovirus infection in a long-term-care facility. J Infect Dis 2007; 196:705.
  32. Schuster JE, Cox RG, Hastings AK, et al. A broadly neutralizing human monoclonal antibody exhibits in vivo efficacy against both human metapneumovirus and respiratory syncytial virus. J Infect Dis 2015; 211:216.
  33. Corti D, Bianchi S, Vanzetta F, et al. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature 2013; 501:439.
  34. Centers for Disease Control and Prevention. The National Respiratory and Enteric Virus Surveillance System (NREVSS). Human metapneumovirus surveillance. https://www.cdc.gov/surveillance/nrevss/hmpv/index.html (Accessed on November 23, 2017).
  35. Bhattacharyya S, Gesteland PH, Korgenski K, et al. Cross-immunity between strains explains the dynamical pattern of paramyxoviruses. Proc Natl Acad Sci U S A 2015; 112:13396.
  36. Williams JV, Wang CK, Yang CF, et al. The role of human metapneumovirus in upper respiratory tract infections in children: a 20-year experience. J Infect Dis 2006; 193:387.
  37. Boivin G, De Serres G, Côté S, et al. Human metapneumovirus infections in hospitalized children. Emerg Infect Dis 2003; 9:634.
  38. Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med 2015; 372:835.
  39. Howard LM, Edwards KM, Zhu Y, et al. Clinical Features of Human Metapneumovirus-Associated Community-acquired Pneumonia Hospitalizations. Clin Infect Dis 2021; 72:108.
  40. Papenburg J, Hamelin MÈ, Ouhoummane N, et al. Comparison of risk factors for human metapneumovirus and respiratory syncytial virus disease severity in young children. J Infect Dis 2012; 206:178.
  41. Williams JV, Tollefson SJ, Heymann PW, et al. Human metapneumovirus infection in children hospitalized for wheezing. J Allergy Clin Immunol 2005; 115:1311.
  42. Pancham K, Sami I, Perez GF, et al. Human Metapneumovirus Infection is Associated with Severe Respiratory Disease in Preschool Children with History of Prematurity. Pediatr Neonatol 2016; 57:27.
  43. Midgley CM, Baber JK, Biggs HM, et al. Notes from the Field: Severe Human Metapneumovirus Infections - North Dakota, 2016. MMWR Morb Mortal Wkly Rep 2017; 66:486.
  44. Falsey AR, Erdman D, Anderson LJ, Walsh EE. Human metapneumovirus infections in young and elderly adults. J Infect Dis 2003; 187:785.
  45. Walsh EE, Peterson DR, Falsey AR. Human metapneumovirus infections in adults: another piece of the puzzle. Arch Intern Med 2008; 168:2489.
  46. Widmer K, Zhu Y, Williams JV, et al. Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults. J Infect Dis 2012; 206:56.
  47. Jain S, Self WH, Wunderink RG, et al. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med 2015; 373:415.
  48. Mullins JA, Erdman DD, Weinberg GA, et al. Human metapneumovirus infection among children hospitalized with acute respiratory illness. Emerg Infect Dis 2004; 10:700.
  49. Xepapadaki P, Psarras S, Bossios A, et al. Human Metapneumovirus as a causative agent of acute bronchiolitis in infants. J Clin Virol 2004; 30:267.
  50. Schlapbach LJ, Agyeman P, Hutter D, et al. Human metapneumovirus infection as an emerging pathogen causing acute respiratory distress syndrome. J Infect Dis 2011; 203:294.
  51. Esper F, Boucher D, Weibel C, et al. Human metapneumovirus infection in the United States: clinical manifestations associated with a newly emerging respiratory infection in children. Pediatrics 2003; 111:1407.
  52. Wolf DG, Greenberg D, Shemer-Avni Y, et al. Association of human metapneumovirus with radiologically diagnosed community-acquired alveolar pneumonia in young children. J Pediatr 2010; 156:115.
  53. Davis CR, Stockmann C, Pavia AT, et al. Incidence, Morbidity, and Costs of Human Metapneumovirus Infection in Hospitalized Children. J Pediatric Infect Dis Soc 2016; 5:303.
  54. Greensill J, McNamara PS, Dove W, et al. Human metapneumovirus in severe respiratory syncytial virus bronchiolitis. Emerg Infect Dis 2003; 9:372.
  55. Semple MG, Cowell A, Dove W, et al. Dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis. J Infect Dis 2005; 191:382.
  56. König B, König W, Arnold R, et al. Prospective study of human metapneumovirus infection in children less than 3 years of age. J Clin Microbiol 2004; 42:4632.
  57. Madhi SA, Ludewick H, Kuwanda L, et al. Pneumococcal coinfection with human metapneumovirus. J Infect Dis 2006; 193:1236.
  58. Schildgen O, Glatzel T, Geikowski T, et al. Human metapneumovirus RNA in encephalitis patient. Emerg Infect Dis 2005; 11:467.
  59. Sánchez Fernández I, Rebollo Polo M, Muñoz-Almagro C, et al. Human Metapneumovirus in the Cerebrospinal Fluid of a Patient With Acute Encephalitis. Arch Neurol 2012; 69:649.
  60. Vicente D, Montes M, Cilla G, Pérez-Trallero E. Human metapneumovirus and chronic obstructive pulmonary disease. Emerg Infect Dis 2004; 10:1338.
  61. Beckham JD, Cadena A, Lin J, et al. Respiratory viral infections in patients with chronic, obstructive pulmonary disease. J Infect 2005; 50:322.
  62. Williams JV, Crowe JE Jr, Enriquez R, et al. Human metapneumovirus infection plays an etiologic role in acute asthma exacerbations requiring hospitalization in adults. J Infect Dis 2005; 192:1149.
  63. Pelletier G, Déry P, Abed Y, Boivin G. Respiratory tract reinfections by the new human Metapneumovirus in an immunocompromised child. Emerg Infect Dis 2002; 8:976.
  64. Sumino KC, Agapov E, Pierce RA, et al. Detection of severe human metapneumovirus infection by real-time polymerase chain reaction and histopathological assessment. J Infect Dis 2005; 192:1052.
  65. Williams JV, Martino R, Rabella N, et al. A prospective study comparing human metapneumovirus with other respiratory viruses in adults with hematologic malignancies and respiratory tract infections. J Infect Dis 2005; 192:1061.
  66. Englund JA, Boeckh M, Kuypers J, et al. Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Intern Med 2006; 144:344.
  67. Debiaggi M, Canducci F, Sampaolo M, et al. Persistent symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients. J Infect Dis 2006; 194:474.
  68. Larcher C, Geltner C, Fischer H, et al. Human metapneumovirus infection in lung transplant recipients: clinical presentation and epidemiology. J Heart Lung Transplant 2005; 24:1891.
  69. Hoellein A, Hecker J, Hoffmann D, et al. Serious outbreak of human metapneumovirus in patients with hematologic malignancies. Leuk Lymphoma 2016; 57:623.
  70. Groome MJ, Moyes J, Cohen C, et al. Human metapneumovirus-associated severe acute respiratory illness hospitalisation in HIV-infected and HIV-uninfected South African children and adults. J Clin Virol 2015; 69:125.
  71. El Chaer F, Shah DP, Kmeid J, et al. Burden of human metapneumovirus infections in patients with cancer: Risk factors and outcomes. Cancer 2017; 123:2329.
  72. Seo S, Gooley TA, Kuypers JM, et al. Human Metapneumovirus Infections Following Hematopoietic Cell Transplantation: Factors Associated With Disease Progression. Clin Infect Dis 2016; 63:178.
  73. Chu HY, Renaud C, Ficken E, et al. Respiratory Tract Infections Due to Human Metapneumovirus in Immunocompromised Children. J Pediatric Infect Dis Soc 2014; 3:286.
  74. Permpalung N, Sait AS, Bazemore K, et al. Human Metapneumovirus and Parainfluenza Virus Infections in Lung Transplant Recipients: The Effects on Lung Allograft and Clinical Outcomes. Transplantation 2021; 105:2625.
  75. Jeong S, Park MJ, Song W, Kim HS. Advances in laboratory assays for detecting human metapneumovirus. Ann Transl Med 2020; 8:608.
  76. Poritz MA, Blaschke AJ, Byington CL, et al. FilmArray, an automated nested multiplex PCR system for multi-pathogen detection: development and application to respiratory tract infection. PLoS One 2011; 6:e26047.
  77. BioFire Diagnostics. FilmArray Respiratory Panel. http://www.biofiredx.com/pdfs/FilmArray/InfoSheet,%20FilmArray%20Respiratory%20Panel-0229.pdf (Accessed on October 21, 2014).
  78. Landry ML, Ferguson D, Cohen S, et al. Detection of human metapneumovirus in clinical samples by immunofluorescence staining of shell vial centrifugation cultures prepared from three different cell lines. J Clin Microbiol 2005; 43:1950.
  79. Hamelin ME, Boivin G. Development and validation of an enzyme-linked immunosorbent assay for human metapneumovirus serology based on a recombinant viral protein. Clin Diagn Lab Immunol 2005; 12:249.
  80. Hilmes MA, Daniel Dunnavant F, Singh SP, et al. Chest radiographic features of human metapneumovirus infection in pediatric patients. Pediatr Radiol 2017; 47:1745.
  81. Wyde PR, Chetty SN, Jewell AM, et al. Comparison of the inhibition of human metapneumovirus and respiratory syncytial virus by ribavirin and immune serum globulin in vitro. Antiviral Res 2003; 60:51.
  82. Buchholz UJ, Nagashima K, Murphy BR, Collins PL. Live vaccines for human metapneumovirus designed by reverse genetics. Expert Rev Vaccines 2006; 5:695.
  83. Cseke G, Wright DW, Tollefson SJ, et al. Human metapneumovirus fusion protein vaccines that are immunogenic and protective in cotton rats. J Virol 2007; 81:698.
  84. Battles MB, Más V, Olmedillas E, et al. Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein. Nat Commun 2017; 8:1528.
  85. Más V, Rodriguez L, Olmedillas E, et al. Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation. PLoS Pathog 2016; 12:e1005859.
  86. Ngwuta JO, Chen M, Modjarrad K, et al. Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med 2015; 7:309ra162.
Topic 8311 Version 25.0

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