Falsey, Ann R. MD
Human Metapneumovirus (hMPV) is a recently described paramyxovirus and is associated with acute respiratory tract infections in persons of all ages.1 As with all the common respiratory viruses, hMPV primary infection occurs in early childhood. Because immunity is incomplete, reinfection in adulthood is not uncommon. To date, most of the clinical data on this newly discovered pathogen is derived from studies of children; however, evidence continues to accumulate that hMPV can cause serious illness in adults as well. Similar to influenza and respiratory syncytial virus (RSV) infection with hMPV in adults is most severe in the elderly and those with chronic medical conditions.
Human metapneumovirus is a nonsegmented, single-stranded, negative sense RNA virus belonging to the Paramyxoviridae family, Pneumovirinae subfamily, and Metapneumovirus genus. The virus was first described by investigators in the Netherlands in 2001 when researchers isolated this previously unknown virus from children with bronchiolitis.1 Until this discovery, the only member of the Metapneumovirus genus was avian pneumovirus (AVP), also known as turkey rhinotracheitis virus.2 AVP causes upper respiratory tract infection of turkeys and other avian species and was first reported in the late 1970s from South Africa. The original genetic analysis of hMPV by van den Hoogen indicated greatest homology with AVP with a gene order of the 3′-N-P-M-F-M2-SH-G-L-5′. The absence of the nonstructural interferon inhibiting genes, NS1 and NS2, differs from its closest relative, RSV and other pneumoviruses.3 Given the close relationship of hMPV and AVP, it is speculated that the human virus originated from birds, however, serologic data indicating the presence of hMPV antibodies for at least 50 years suggests that the zoonotic event must have occurred in the distant past.
Studies from Europe, North America, Asia, and Australia indicate hMPV has worldwide circulation.4–7 In temperate climates, the virus circulates predominantly in winter months overlapping with other seasonal respiratory pathogens such as influenza and RSV. In the Southern Hemisphere, hMPV circulates in the summer, and in the subtropics peak activity is in the spring and early summer.5 Although comprehensive studies are lacking, preliminary data suggest hMPV intensity may exhibit yearly variation. One study of adults in the United States demonstrated a significant difference in rates of hMPV illnesses during the winters of 1999 and 2000 (1.5% versus 7%). In addition, a 3-year study of infants from Italy found marked yearly variation in the incidence of infection with 37% in 2000, 7% in 2001, and 43% in 2002.8,9 Numerous studies confirm the presence of 2 major genotypes of hMPV, which often cocirculate within the same community.10,11 The clinical significance of these different genotypes is not yet understood.
Illness in Children
Epidemiologic studies indicate that hMPV is a ubiquitous pathogen that infects almost all children by 5 years of age.1,12 Primary infection with hMPV occurs at a slightly older age than children with RSV. Among children hospitalized with respiratory illnesses rates of hMPV detection range from 5.5% to 25%.13 Although hMPV accounts for a significant proportion of respiratory illnesses in young children, the overall frequency is less than other childhood pathogens such as RSV. The clinical manifestations of hMPV infection in children are similar to RSV and range from mild upper respiratory infections (URI) to bronchiolitis and severe pneumonia requiring mechanical ventilation.13–15 The spectrum of disease seems to be dependent on the age and the health of the host. Fever and febrile seizures seem to be more common with hMPV than with RSV.5 Wheezing is another common symptom with rates ranging from 28% to 83%, whereas otitis media, conjunctivitis, pharyngitis, and laryngitis all occur with variable frequencies.10,15,16 Radiographic findings include peribronchial cuffing, patchy opacities, and hyperinflation, findings similar to those in children with RSV infection.5,15
The incidence of symptomatic infection in the general adult population is relatively low and is typically less the 5% in most studies. A 3% hMPV infection rate was reported from the Netherlands in which samples were collected from patients with symptomatic respiratory illnesses.17,18 Similarly, 2.2% of samples from patients visiting a general practitioner in the United Kingdom during the winter of 2000–2001 tested positive for hMPV. Notably, 8 of 9 subjects were over age 18 years and 4 were over age 65 years.19 In a 3-year study from Iowa, investigators found 34 of 1294 (2.6%) of respiratory specimens to be RT-PCR positive for hMPV, of whom 10 were adults and most of whom had underlying medical conditions.20 In a 2-year prospective study in Rochester, New York using RT-PCR and serology for diagnosis, symptomatic infection in young adults was relatively common with hMPV detected in 2.9–9.1% of respiratory illnesses depending on the year.9 Of note, 15% of young adults who did not report an illness during the second winter had serologic evidence of infection. It is difficult to know whether infection was truly asymptomatic or very mild and thus, not recalled during the subsequent spring evaluation. In contrast to serologic evidence of asymptomatic infection, the detection of hMPV by RT-PCR seems to be relatively uncommon in persons without respiratory symptoms. In a Dutch study only 2 of 1282 (0.2%) of respiratory samples from subjects without respiratory illness were RT-PCR positive.18 In addition, investigators in New York found 5 of 146 (3.4%) of adults presenting to the doctor with respiratory illness to be hMPV positive by RT-PCR compared with 0 of 158 controls without illness.21 In composite, these studies suggest that hMPV infection in young healthy adults is relatively common and that illness is often mild. Although infection rates in older adults seem to be lower than in young adults, asymptomatic serologic responses are less common. In the Rochester study symptomatic infection occurred in 1.7% of healthy elderly and 2.9% of adults with cardiopulmonary disease with equivalent rates of asymptomatic serologic responses.9 Other investigators have found variable rates of hMPV infection in older adults but confirm that serious sequelae can occur in the elderly. In a study from Northern Ireland hMPV was identified by RT-PCR in 6/741 (0.81%) of samples from adults. The mean age of patients was 72 years and 2 patients with underlying rheumatologic diseases on immunosuppressive therapy died.22 A Canadian surveillance study from the public health laboratories encompassing 4 provinces identified hMPV in 66/445 (14.8%) of specimens. Thirty-six were in persons over age 21 and hospitalization rates were highest in those under the age of 5 or over age 50.23
Long Term Care Facilities
Shortly after the virus was identified, investigators in Canada isolated hMPV from archived specimens from 37 patients of whom 7 were residents of a long-term care facility.24 Other common respiratory viruses such as influenza RSV and parainfluenza can spread efficiently in closed populations and have been documented to cause outbreaks of illness in nursing homes. Although reports are limited, it seems that hMPV is also capable of causing outbreaks in long-term care facilities. Honda et al25 described an outbreak in a Japanese hospital for the elderly in which 8 of 23 residents became ill during a 2-week period in January. All 8 were RT-PCR positive and 75% demonstrated a ≥4-fold rise in HMPV specific antibody. Although 5 had symptoms of lower respiratory tract involvement and 3 had radiographic evidence of pneumonia all recovered. More recently, an outbreak of severe respiratory illness in long term care facility in Quebec, Canada, was reported by Boivin et al26 Among the 6 RT-PCR confirmed cases, 100% had fever, 33% had breathing difficulties, 17% had pneumonia, and 50% died. An elderly woman with extensive right middle and lower lobe pneumonia died and autopsy material confirmed the presence of virus in the lower airways by immunohistochemical staining.
Chronic Obstructive Pulmonary Disease
Respiratory viral infections are a well-established cause of acute exacerbations of chronic obstructive pulmonary disease (AE-COPD).27 Several studies utilizing RT-PCR have examined the role of hMPV as a factor in AE-COPD and detection rates have ranged from 0% to 6%.28–31 Differences in rates likely reflect the fact that some studies were restricted to winter months and other included a 12-month period. During a winter study from Connecticut, hMPV was documented in 6% of patients hospitalized with AE-COPD as compared with 4% from RSV and 2% secondary to influenza A.31 Concerns have been raised about viral persistence in COPD patients with RSV, however, chronic hMPV has not been documented. Rhode et al28 found hMPV RNA in 2.3% of patients hospitalized with AE-COPD but none in patients with stable COPD or symptomatic smokers.
Similar to other common respiratory viruses such as RSV, influenza, and parainfluenza, severe illness and pneumonitis have been associated with hMPV infection in immunocompromised patients.32,33 Most fatalities described to date have involved patients with neoplasia. A number of case reports describe patients with fatal progressive pneumonia in which hMPV has been the only pathogen isolated. HMPV was detected in the respiratory secretions of a bone marrow transplant recipient who became ill with a URI and died of progressive respiratory failure.33 Englund et al32 recently described a series of hMPV infection in hematopoietic stem cell transplants recipients (HSCT). Five of 163 broncho-alveolar lavage specimens were positive for hMPV. All patients were less than 40 days from transplant and all developed severe pneumonia characterized by nasal congestion, fever, cough, and pulmonary hemorrhage. Four patients and died and lung biopsy showed diffuse alveolar damage. HMPV infection was felt to be a cause of “idiopathic pneumonia” among HSCT patients. In contrast to the report by Englund, a study of adult HSCT patients in Italy described detection of hMPV by RT-PCT in 18 of 21 HSCT patients in who were either asymptomatic or had very mild URI symptoms.34 There were no seasonal differences in detection rates and RNA could be detected for as many as 94 days. At present the reason for these discrepant results remains unexplained.
HMPV and Respiratory Failure
The role of HMPV in severe respiratory illness has been investigated in several studies of patients requiring intensive care or mechanical ventilation. Carrat et al35 detected HMPV in 1.6% of patients with respiratory failure in comparison to 6.6% with influenza and 4.9% with RSV. An Australian study of COPD patients requiring ventilatory support yielded similar results with an incidence of hMPV of 2.8%, influenza 13.1%, and RSV 6.5%.36
As with children, the clinical manifestations of hMPV infection in adults seem to depend on age and health status. Middle aged and healthy older adults present with influenza-like illness and common cold syndromes. Clinical symptoms in young adults are not distinctive from other respiratory viral illnesses although in 1 study hoarseness was more common among hMPV infected patients than in those with RSV.9 (Table 1) As previously noted the impact of hMPV infection in adults is greatest in elderly and high risk subjects. When elderly outpatients were compared with young adults, the elderly experienced wheezing and dyspnea more often than did young adults. In addition, adults with chronic cardiopulmonary conditions were ill twice as long as healthy young adults (17 versus 9 days) and more frequently sought medical attention. Patients are hospitalized with hMPV primarily elderly and 85% have chronic heart or lung conditions. Clinical manifestations are indistinguishable from influenza or RSV infection. Chest radiograph reveal patchy infiltrates with a predilection for the lower lobes in 25% of patients. In studies of hospitalized subjects, small numbers of patients have required intensive care and mechanical ventilation and deaths have been reported. The most common diagnoses associated with adult hospitalization are exacerbations of COPD, bronchitis, and pneumonia.
Isolation of hMPV with standard cell culture techniques is difficult and likely explains why the virus likely remained unidentified for many years. HMPV replicates very slowly, does not grow efficiently in continuous cell lines traditionally used for viral isolation, does not display hemagglutinating activity and seems to be relatively trypsin dependent. Currently, 3 methods of diagnosis are used; viral culture, serology and RT-PCR.
Isolation of hMPV requires inoculation of sample on tertiary cynomolgus monkey kidney cells (tMK) or rhesus monkey kidney cells (LLC-MK2) cell lines containing trypsin. Cultures should be observed for cytopathic effect (CPE) for approximately 3 weeks.6,13,18 The characteristic CPE in LLC-MK2 cells consists of small, granular cells without large syncytia. Confirmation of hMPV infection requires either immunofluorescent assays (IFA) with hMPV specific antibodies or RT-PCR of the cell supernatant.
Because infection is nearly universal by age 5, a definitive serologic diagnosis in adults requires a 4-fold rise in antibody titer or seroconversion. Serologic diagnosis is most often accomplished by enzyme immunoassay using whole virus lysates as antigen or IFA using hMPV-infected cells fixed to slides.9,37 In adults, serologic response to the A and B strains are sufficiently cross reactive so that 1 strain may used as antigen for the detection of both strains.
Because of the difficulty of isolating hMPV in cell culture most investigators have relied on molecular techniques for diagnosis. The conserved regions of several genes including those of the F, N, M, and L proteins have been used successfully in both nested and single round PCR.1,6,37 A comparison of real time-PCR using different primer sets from the N, L, M, P, and F genes demonstrated the greatest sensitivity with the N and L gene primers.38 The analytic sensitivity of the N gene RT-PCR was 100 copies of viral RNA and the sensitivity was ascribed to amplifying a more conserved gene. Modifications made by Maertzdorf et al39 have improved the sensitivity of hMPV RT-PCR and allow the detection of previously difficult to amplify group B viruses.
Rapid diagnosis of hMPV by direct immunofluorescence (DIF) staining of cells from nasopharyngeal secretions offers advantages for some laboratories. Recent studies have indicated that the sensitivity of DIF using hMPV-specific monoclonal antibodies is in the same range of RT-PCR.40,41
The newly described hMPV is a ubiquitous pathogen, which infects persons of all ages. Primary hMPV occurs during early childhood and reinfections occur throughout adult life. Infection in healthy young adults usually results in a mild URI and may be asymptomatic. Because the period of peak activity is during the winter months and the clinical features are not distinctive, infection caused by hMPV is difficult to distinguish from influenza and RSV. The primary methods of diagnosis are serology and RT-PCR because detection of hMPV in traditional cell culture is difficult. The full spectrum of hMPV disease in adults is yet to be fully defined in comprehensive prospective studies but current data indicate that similar to other respiratory viruses, infection in the frail elderly and persons with underlying disease can be severe.
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