Human metapneumovirus (hMPV) is a single negative-stranded RNA-enveloped virus classified in the Pneumovirinae subfamily of the Paramyxoviridae family. hMPV infection has clinical features that range from mild upper respiratory tract infections (URTIs) to lower respiratory tract infections (LRTIs) complicated by significant wheezing, leading to life-threatening bronchiolitis and pneumonia, in all age groups. This virus is second only to respiratory syncytial virus (RSV) as the most commonly identified cause of pediatric LRTI. See the image below.
Signs and symptoms
Infection with hMPV causes a broad spectrum of respiratory illness, from mild symptoms to severe cough, bronchiolitis, and pneumonia. The clinical symptoms are similar to those seen with RSV infection and may also include the following:
Dyspnea, tachypnea, and wheezing
COPD (chronic obstructive pulmonary disease) exacerbation
See Clinical Presentation for more detail.
Polymerase chain reaction of respiratory secretions: This is the most sensitive method for hMPV diagnosis; also useful to quantify viral load in research settings
Enzyme-linked immunoassay (ELISA): Note that seropositivity is nearly universal after early childhood, making definitive serologic diagnosis reliant on seroconversion or a 4-fold titer increase on serial samples
It is difficult to grow hMPV in cell culture; therefore, this is method is no longer a timely mode of diagnosis. Isolation is possible in a limited number of cell lines and requires trypsin supplementation.
Chest radiography is generally not helpful. Findings in patients with significant lower respiratory tract disease are indistinguishable between hMPV and other causes of viral pneumonia or bronchiolitis. Immunosuppressed persons, such as stem cell transplant or organ transplant recipients, may require CT scanning to clarify upper respiratory versus lower respiratory infection.
See Workup for more detail.
There is no specific antiviral therapy available for hMPV infection; therefore, most treatment is supportive. Hospitalization, supplemental oxygen, and mechanical ventilation may be necessary in severe hMPV infections. In severely immunosuppressed persons, oral or inhaled ribavirin can be considered. [8, 9, 50]
Human metapneumovirus (hMPV), like human respiratory syncytial virus (RSV), is classified in the Pneumovirinae subfamily of the Paramyxoviridae family. However, hMPV is most closely genetically related to avian metapneumovirus (formerly called turkey rhinotracheitis virus). These two viruses are classified in the genus Metapneumovirus, with hMPV the first in this genus to cause disease in humans. Although it is hypothesized that the human virus originated from birds, the serological evidence that hMPV has been widespread in humans since at least 1958 suggests a zoonotic divergence before this time. [8, 10]
hMPV was first described in 2001 by researchers in the Netherlands. Using polymerase chain reaction (PCR) amplification techniques, the virus was isolated from stored nasopharyngeal samples.  Since this initial report, hMPV has been identified in countries on all continents except Antarctica.
See the figure below.
Scarce data on hMPV pathophysiology based on human studies have been reported. Two prospective studies from Argentina have quantified cytokine levels in nasal washes taken from subjects with hMPV infection and compared these with cytokine levels in RSV and influenza. They found that hMPV infection produces a low level of innate and adaptive cytokine response, although with a greater bias toward a Th2 response than the comparator viruses. [12, 13]
Multiple animal models have been used to study the pathophysiology of hMPV. Chimpanzees have been the only animal to demonstrate symptomatology consistent with human disease.  However, respiratory tract viral replication of hMPV has been demonstrated in cynomolgus macaques, cotton rats, and BALB/c mice, in addition to other small rodents. [15, 16, 17, 18]
Studies of cytokine response in BALB/c mice have shown findings that are consistent with those of the human studies cited above, showing a weak innate cytokine response that corresponds with lower levels of pulmonary inflammation than with RSV infection. 
Studies on viral time course in these models demonstrates a peak of viral load at 4-5 days after infection. While most models show clearance of the virus by postinfection day 10-14, viable hMPV virus has been recovered in BALB/c mice up to 2 months following infection. The significance of this viral persistence in relation to human disease is unknown. [18, 20]
Two recent studies have examined the significance of hMPV viral load, as assessed by real-time PCR, on illness parameters. One study showed that increased viral loads correlated with lower respiratory tract illness and hospitalization.  The second found that an increasing viral load was associated with increased fever, increased bronchodilator use, and increased length of hospitalizations, independent of age and underlying chronic illness. This study also evaluated viral loads in RSV illness and did not find this same correlation with disease severity, again suggesting a different pathology mechanism between these two related viruses. 
hMPV is considered ubiquitous. This belief is based on the widespread detection of infection, as well as high prevalence of antibodies against the virus in all age groups. In their initial 2001 report, van den Hoogen et al demonstrated 100% seropositivity by age 10 years in 28 young children in the Netherlands. Similar studies worldwide have confirmed this high rate of seroprevalence in early childhood. [8, 23, 24]
The largest study of hMPV epidemiology is an examination of nasal washes collected prospectively during acute respiratory illnesses in an outpatient cohort of children over a 20-year period. Consistent with other studies, hMPV was detected throughout the year, with a peak incidence from late winter to early spring, later than the seasonal peak of RSV and influenza during the entire period studied. In the northern hemisphere, the hMPV peak tends to be from January to March; in the southern hemisphere, the peak is from June to July.  Over a 20-year period, hMPV was detected in 1%-5% of pediatric upper respiratory infections, with variation from year to year.  A similar study by the same group found a 12% incidence of hMPV in lower respiratory tract infections. Additionally, this study isolated hMPV from only 1% of asymptomatic children, further establishing disease causality.  The incubation period may vary but averages between 3 and 5 days from exposure. 
These studies and many others indicate that hMPV is the second most commonly identified cause of pediatric lower respiratory illness, behind only RSV. While there are geographical differences in seasonality and incidence of hMPV infection, this virus undoubtedly plays a significant role in respiratory illnesses in the pediatric population.
Little research has been done to determine the incidence of hMPV in adult populations, although hMPV infection has been well established in high-risk adult populations, including those with chronic obstructive pulmonary disease (COPD), elderly patients, and immunocompromised patients. [1, 2, 3] Multiple outbreaks in healthcare facilities have been detailed in the literature, not only from infected residents but also from asymptomatic shedding of the virus in nonresidents. 
hMPV has been documented as a significant cause of illness in transplant recipients. Studies have linked hMPV with idiopathic pneumonia, fulminant respiratory failure, and high mortality rates in stem cell transplant recipients. [27, 28] Additionally, in one study, hMPV was found in 10% of lung transplant recipients with acute respiratory tract infections, similar to the rate of RSV detection.  Thus, transplant patients appear to be at significant risk for severe hMPV illness.
In temperate climates, the seasonality of hMPV infection mimics that in the United States, with most infections occurring in the winter and spring.  Peak viral activity in tropical regions occurs during the spring and summer months, as demonstrated in studies from Hong Kong.  Strains have also circulated in Latin America,  Italy,  and India. 
hMPV is the second-leading identifiable cause of lower respiratory tract disease in children and is known to cause disease in all age groups. hMPV infection likely accounts for up to 10% of hospitalizations for pediatric respiratory illnesses.
Risk factors for severe hMPV disease appear to be similar to those for severe RSV disease and include prematurity, heart disease, pulmonary disease, immunocompromise, and organ or stem cell transplantation. [27, 28, 4, 35] hMPV infection in lung transplant recipients can lead to permanent lung graft dysfunction and increased morbidity. 
Little is known about the sequelae of hMPV illness. However, a small study of premature infants infected with hMPV did show increased airway resistance at follow-up. 
hMPV infection has no reported sexual predilection, with attack rates similar in males and females.
Initial hMPV infection occurs early in childhood, with most individuals seroconverting by age 5 years. The seropositivity rate approaches 100% by age 10 years in multiple populations studied. [8, 23, 24] However, reinfection is possible, and hMPV disease has been documented in adult patients.