Human metapneumovirus infections

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Official reprint from UpToDate www.uptodate.com 2014 UpToDate

Human metapneumovirus infections Author James E Crowe, Jr, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2014. | This topic last updated: Nov 26, 2013. INTRODUCTION Respiratory tract infections commonly are caused by viral pathogens, especially in young children. Respiratory syncytial virus (RSV) is the most common pathogen identified in these infections, followed historically by parainfluenza virus (PIV); both of these viruses are in the Paramyxoviridae family. Other important viruses that cause respiratory tract infection include influenza and adenoviruses. However, despite improved methods for identifying viral pathogens in these infections, the etiology remains undetermined in a significant number of patients. In 2001, investigators from the Netherlands discovered a new member of the Paramyxoviridae family in the genus Metapneumovirus [1]. The first representative of this genus to cause infection in humans has been called the human metapneumovirus (hMPV). Data suggest this virus 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 "Clinical manifestations of seasonal influenza in adults" and "Parainfluenza viruses in children" and "Parainfluenza viruses in adults" and "Epidemiology and clinical manifestations of adenovirus infection".) VIROLOGY Within the Paramyxoviridae family, there are two subfamilies, Pneumovirinae and Paramyxovirinae. Genetic analysis determined that hMPV is most similar to the Pneumovirinae family, of which respiratory syncytial virus is a prominent member. 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 does lead to significant viral replication restricted to the respiratory tract with the subsequent development of upper respiratory symptoms [8]. PATHOGENESIS Viral replication has been demonstrated in the respiratory tracts of experimentally infected
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Section Editors Martin S Hirsch, MD Sheldon L Kaplan, MD

Deputy Editor Anna R Thorner, MD

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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 [9]. In a mouse model, viral RNA and significant airway inflammation were prolonged [10]. Infection was also associated with mucus hyperproduction and hyperplasia of the respiratory epithelium, with resultant airway obstruction and hyperresponsiveness after methacholine challenge. These data are consistent with that 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 [11]. TRANSMISSION Formal transmission studies have not been reported, but it is likely that transmission is by direct or close contact with contaminated secretions, which may involve large particle aerosols, droplets, or fomites. Nosocomial infections have been reported in hospitalized children [12], including in a pediatric hematology-oncology ward [13], and in hospitalized adults [14]. Transmission to family members appears to be very efficient when an index case becomes ill, with an estimated five-day interval between the onset of symptoms in an index patient and the onset of symptoms in contacts [15]. EPIDEMIOLOGY Based upon reports from the Netherlands [1], the United Kingdom [16], Finland [17], Australia [3], Canada [2,4], Kenya [18], China [19], and many other countries, the virus is ubiquitous and has been associated with infection for at least 60 years [1,20]. 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 five and 46 percent in adults above the age of 65 [2]. Many infected children are under the age of one year [21-23]. HMPV appears to have a seasonal variation: late winter and early spring the United States, the Netherlands, the United Kingdom, Norway, and Finland, and late spring and summer in Hong Kong [1,12,21,24]. However, one summer outbreak of respiratory HMPV illnesses was described in 26 residents and 13 staff member in a US-based long-term care facility [25]. Children Seroprevalence data suggest that most children are infected by the age of five [1]. The frequency of hMPV infection in children can be illustrated by the following observations: ! In one report, nasal wash specimens were tested for the presence of hMPV in 463 otherwise healthy infants and children who presented with an acute respiratory illness [21]. Twelve percent of lower respiratory tract illnesses were associated with hMPV infection, while hMPV was also detected in 15 percent of samples from 261 patients with upper respiratory tract infection. The mean age of onset was also similar to RSV (11.6 versus 13.0 months). ! In a second series, respiratory specimens were obtained from 668 children less than five years of age who had negative test results for RSV, influenza, adenovirus, and parainfluenza viruses [22]. Upon subsequent testing with polymerase chain reaction (PCR), the proportion of cases due to hMPV was 8.1 percent overall, and 18 and 25 percent in the peak months of March and April. Sixty percent of the children with hMPV infection were less than one year of age. ! In a prospective population-based surveillance study in which children less than five years of age who presented with an acute respiratory illness or fever were tested for hMPV using real-time reverse transcriptase PCR, hMPV was detected in 200 of 3490 hospitalized children (6 percent), 222 of 3257 children in outpatient clinics (7 percent), 224 of 3001 children in the emergency department (7 percent), and 10 of 770 asymptomatic controls (1 percent) [23]. Overall annual rates of hospitalization associated with hMPV infection were 1 per 1000 children less than 5 years of age, 3 per 1000 infants less than 6 months of age, and 2 per 1000 children six to 11 months of age. In a retrospective analysis of 1532 infants and children with upper respiratory infections, hMPV RNA was detected in 5 percent of 2384 specimens; acute otitis media was detected in 50 percent of the patients harboring hMPV RNA [26].
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A similar proportion of hMPV infection (4 to 9 percent) has been described in children who required hospitalization for an acute respiratory illness [27-29]. The following distribution of causes was noted in a report of 208 such children in whom the diagnosis was made by real-time PCR and other conventional diagnostic methods: RSV in 57 percent; influenza in 24 percent; and hMPV in 6 percent [27]. In children less than three years of age who were hospitalized or 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 [29]. Among children who were hospitalized, factors independently associated with severe disease were female sex, prematurity, and genotype B infection. 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 [23]. 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. Adults HMPV infection in adults has been described less well but its frequency as a cause of an acute respiratory illness appears to be lower than in children. In a report that prospectively evaluated 984 respiratory illnesses in younger and older adults during two winter seasons, hMPV infection was identified in 4.5 percent of 984 respiratory illnesses (defined as at least a fourfold increase in anti-hMPV antibodies or more than a twofold increase in antibody titer plus a positive PCR for hMPV), 4.1 percent of asymptomatic subjects, and, in one season, 11 percent of patients with respiratory infections who required hospitalization [30]. A lower frequency was noted in a national virologic survey of patients of all ages (more than 70 percent adults) with influenza-like illnesses among sentinel general practices in the winter of 2000 to 2001 in the United Kingdom [16]. HMPV was identified in 9 of 408 specimens (2.2 percent) negative for influenza or RSV, with a higher frequency (4 of 37 [11 percent]) in adults more than 65 years of age. In a study of 1386 adults hospitalized for acute cardiorespiratory illness (pneumonia, acute bronchitis, acute exacerbations of chronic obstructive pulmonary disease or congestive heart failure, upper respiratory tract illness, viral or influenza syndrome, asthma, or respiratory failure) during four consecutive winters in the United States, hMPV was identified in 8.5 percent (range, 4.4 to 13.2 percent) by reverse-transcriptase polymerase chain reaction and/or serologic testing, depending on the year [31]. One prospective study evaluated the disease burden of respiratory virus infections among adults in a single Tennessee county. Among 508 individuals "50 years of age requiring hospitalization during the winter with an acute respiratory illness, hMPV was detected in 23 patients (4.5 percent) [32]. Over three years, the average rate of hospitalization for hMPV infection was 9.8 per 10,000 residents, which was similar to the rate for influenza (11.8 per 10,000 residents). In summary, hMPV is a common infection in adults that is often asymptomatic but can result in serious infection that requires hospitalization. CLINICAL MANIFESTATIONS Serosurveys suggest that hMPV is usually associated with mild, self-limited infections in children and adults [16,21,22,24,30]. The incubation period is not fully defined, but is thought to be five to six days in most cases [33]. 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,

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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 airways 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 [27,28,30,34,35]. Children A number of studies have described the clinical manifestations of hMPV infection in children [21,22,24,34,36,37]. The range and frequency of symptoms and signs was illustrated in three series that included approximately 150 children with hMPV infection [21,22]: ! 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 [21,24]. 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) [21]. An association with wheezing and exacerbation of asthma has been noted in other studies [17,22,24,37]: ! A Finnish study, which assessed 132 consecutive admissions for wheezing in children who had not taken corticosteroids in the preceding four weeks, found hMPV by PCR in 10 cases (9 percent) [17]. ! Younger age may be associated with hMPV disease. The prevalence of HMPV was significantly higher in children less than three years of age who were hospitalized for wheezing compared to controls (8.9 versus 1.3 percent); however hMPV did not play a significant role in symptomatic respiratory disease in children older than three years of age [38]. The most common reasons for hospitalization in hMPV-infected children are acute bronchiolitis and pneumonia [27,34]. Disease severity may be increased when there is coinfection with RSV. Among RSV-infected children less than two years of age, coinfection with hMPV has been associated with severe RSV bronchiolitis [39,40], the need for admission to the intensive care unit [41], and a 10-fold increase in the need for mechanical ventilation [40]. Other studies however, have not identified a high rate of coinfections in hospitalized subjects, 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 [38]. (See "Approach to wheezing in children".) Immunization of HIV-infected children with pneumococcal vaccine reduces the prevalence of hMPV-associated lower respiratory tract illnesses, suggesting an interaction of bacteria and the virus in severe disease [42]. Encephalitis has been reported rarely in children with upper respiratory tract hMPV disease [43,44]. In one report of fatal encephalitis in a 14-month-old boy, reverse-transcriptase polymerase chain reaction (PCR) tests of both brain and lung tissue during the post-mortem were positive for hMPV [43]. 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 [44]. Magnetic resonance imaging of both patients demonstrated multifocal cortical and subcortical lesions. 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
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above, the following frequency of symptoms was noted [30]: ! 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 elderly patients, while hoarseness was more common in young adults. HMPV infection has been associated with acute exacerbation of asthma in adults [45]. In addition, hMPV has been associated with outbreaks of severe lower respiratory tract infection in residents of long-term care facilities, with attack rates of 34 to 72 percent [33,46]. Possible role in COPD exacerbations The role of hMPV in exacerbations of chronic obstructive pulmonary disease is controversial. One group identified the agent to be associated with exacerbations in about five percent of cases, whereas another series could not identify a single patient with hMPV in this context [47,48]. 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 [49]. 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 [21]. (See "Epidemiology of influenza", section on 'Antigenic drifts'.) 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 patients who underwent bronchoscopy was tested for the presence of a variety of respiratory pathogens, including hMPV, in bronchoalveolar lavage (BAL) and bronchial wash specimens [50]. Seventy-two percent were immunocompromised; the most common condition was lung transplantation. The cohort included 210 patients without acute illness who underwent routine bronchoscopy for surveillance after lung transplantation or follow-up of rejection. Six cases of hMPV infection were identified using real-time polymerase chain reaction, four of which occurred in immunocompromised patients. Histopathology of lung tissue showed diffuse alveolar damage, hyaline membranes, and smudge cell formation in all five patients who underwent biopsy. All patients with hMPV presented with fever, cough, dyspnea, and wheezing; no cases were identified in asymptomatic individuals. The rate of detection of hMPV was similar to RSV infection. ! In a study of 251 episodes of upper and lower respiratory tract infection in patients with hematologic malignancies, 9 percent of episodes were associated with hMPV infection [51]. Sixteen of the 22 episodes occurred in
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hematopoietic cell transplant recipients; three of nine patients with hMPV-related lower respiratory tract disease died. ! In a retrospective survey of hematopoietic cell transplant recipients who had bronchoalveolar lavage sampling performed because of respiratory illness, hMPV was isolated from 5 of 163 patients (3 percent) [52]. 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 small study of 21 patients undergoing hematopoietic cell transplantation, persistent nasopharyngeal hMPV infection was demonstrated in most study participants for several months, although these patients were asymptomatic from a respiratory standpoint [53]. These data suggest impaired clearance, as documented in other immunosuppressed hosts [54]. 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 "Bacterial infections following lung transplantation".) DIAGNOSIS Although serologic data suggests that hMPV has been causing clinical disease for at least 60 years, it was only recognized in 2001 [1]. At least two factors contributed to the delay in identifying this agent: the clinical manifestations are not unique and hMPV grows slowly and inefficiently in culture. Reverse transcriptase (RT)-PCR is the most sensitive method for diagnosis of hMPV infection, but the primers and techniques are not standardized among laboratories. (See 'Reverse transcriptase PCR' below.) 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 [21]. Only about one-half of cultures that are positive for hMPV by reverse transcriptase (RT)-PCR yield cultivable virus by current techniques. Serology Standardized viral antigens are needed for serologic surveys. An enzyme-linked immunosorbent assay (ELISA) has been developed using the nucleoprotein (N) as antigen, which has been tested in adults and children [55]. Serum virus neutralizing antibody tests are also available in some research laboratories. Seropositivity is almost universal by age five [1]. A definitive serologic diagnosis requires either seroconversion or at least a fourfold increase in titer on serial samples [30]. Reverse transcriptase PCR Testing for viral RNA in human respiratory secretions based upon reverse transcriptase (RT)-PCR in both conventional and real-time formats has been developed with a variety of different primers and probes [1,21,22,27,30]. 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. Currently, RT-PCR is available in research laboratories and a limited number of commercial diagnostic laboratories. Shell vial cultures Shell vial centrifugation cultures are commonly used for rapid diagnosis, but require sensitive and specific monoclonal antibodies. A mouse monoclonal antibody has been developed designated MAb-8 that targets the hMPV matrix protein and is both broadly reactive with hMPV isolates and nonreactive with other common respiratory viruses, such as RSV and influenza. Three cell lines inoculated with laboratory-passaged virus or clinical specimens demonstrated that virus could be identified as early as one to two days after inoculation, which could offer an advantage over routine culture [56]. TREATMENT Treatment is supportive and varies with the clinical manifestations. There are no clinical data on the susceptibility of hMPV to antiviral therapy. Ribavirin, which has activity against respiratory syncytial virus (RSV), is also active against hMPV in vitro [57] and reduces viral replication in experimentally infected mice [58]. The safety and efficacy of ribavirin in humans with hMPV infection are unknown.

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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. Control measures It is likely that transmission of hMPV is by direct or close contact with contaminated secretions. (See 'Transmission' above.) Although the diagnosis of hMPV infection is not established definitively in most patients, control measures used for RSV and other acute respiratory illnesses are warranted. These include contact precautions including hand washing in all settings and avoidance of cigarette smoke. (See "Respiratory syncytial virus infection: Prevention".) During the peak of the hMPV season, which is late winter and early spring in the United States and Europe and late spring and summer in Hong Kong [1,12,21,24], a significant proportion of infants and young children hospitalized with respiratory symptoms will be infected with hMPV [27,28]. Control of nosocomial spread depends upon 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 [39,41]. (See "General principles of infection control", section on 'Contact precautions'.) Live and subunit experimental vaccine candidates are in preclinical development, but none is near licensure [59,60]. SUMMARY AND RECOMMENDATIONS ! Human metapneumovirus is a paramyxovirus that was discovered in 2001, but has been responsible for respiratory tract infections for at least 60 years with a worldwide distribution. (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 six days in most cases, with a typical duration of illness of approximately one week. (See '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 (RT)-PCR on nasopharyngeal specimens is the most sensitive method for diagnosis of hMPV infection, but the primers and techniques are not standardized among laboratories. HMPV grows slowly and inefficiently in culture. (See 'Diagnosis' above.) ! Treatment is supportive and varies with the clinical manifestations. There are no clinical data on the susceptibility of hMPV to antiviral therapy. Ribavirin, which has activity against respiratory syncytial virus (RSV), is also active against hMPV in vitro and reduces viral replication in experimentally infected mice. The safety and efficacy of ribavirin in humans with hMPV infection is unknown. (See 'Treatment' above.) Use of UpToDate is subject to the Subscription and License Agreement.

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