Human metapneumovirus (HMPV) is an important respiratory pathogen that primarily infects young children, older adults, and immunocompromised individuals. ¹ First identified in 2001, HMPV belongs to the family Paramyxoviridae and the genus Metapneumovirus. ² Structurally, it is an enveloped, single-stranded RNA virus that has a broad host range that includes humans and various mammalian species. Although HMPV shares certain clinical features with other respiratory viruses, such as respiratory syncytial virus (RSV), it has distinct biological and pathological characteristics that distinguish it as a significant cause of respiratory illness, particularly during the cold season. ^{3, 4} In particular, the incidence of HMPV infections has increased in recent years, leading to increased attention from global health organisations concerned about the potential for widespread outbreaks. This review aims to provide a comprehensive overview of HMPV infections and identify strategies for prevention and treatment. Particular emphasis is placed on protecting vulnerable groups such as the general population, young children, the elderly, and people with weakened immune systems.

The structure of HMPV is icosahedral (a feature shared by many viruses of the Paramyxoviridae family), and its diameter is about 150 nm. ⁵ The virus has an envelope, and the envelope has surface glycoproteins that are important for attachment to and entry into the host cell, the fusion (F) and attachment (G) proteins, respectively. ^{6– 8} The F protein is responsible for viral fusion with the host cell membrane, while the G protein is the first target for viral attachment to the host cells. The viral RNA genome is packed into the envelope with nucleoproteins and several other structural proteins to form a ribonucleoprotein complex that protects the RNA and ensures replication. ^{9– 11} The RNA genome of HMPV is approximately 13.2 kb in size and contains several proteins that are essential for the replication cycle and pathogenicity of the virus. ¹²

HMPV is divided into two main subgroups, A and B, each of which is subdivided into several subtypes, mostly A1, A2, B1, and B2, by sequence variations of the G protein. ¹³ These subtypes differ in flow patterns and logarithmic progression of clinical severity. There are different epidemiological distributions of HMPV subtypes A and B, with subtype A2 predominating in some areas at certain times. ^{14– 16} These subtypes may also differ in the mechanisms of immune defence and may influence the extent of virulence in different patient populations. However, in the coastal region of Kenya, the hot season with little rainfall is not associated with HMPV infection, as shown in a study by Owor et al., which found that HMPV subgroup A2 is most prevalent during the hot season. ¹⁶ In contrast to the occurrence in the coastal region of Kenya, HMPV subgroup A2 infection occurs during the cold season in Fukui, Japan. ¹⁷ However, overlap between subtypes is frequently observed, suggesting complex epidemiological dynamics. ^{14– 18}

The virulence of HMPV also depends on the induction of a strong immune response, whereby the virus bypasses immune surveillance. The fusion protein (F), a critical virulence factor of the virus, mediates the formation of syncytia in infected cells, which is an important feature of Paramyxoviridae family members and the pathogenesis of respiratory infection. ^{19, 20} The G protein is also a surface glycoprotein involved in virus binding and immunomodulation. HMPV also induced the production of several pro-inflammatory cytokines such as IL-4, IL-6, IL-10 and IL-18, the chemokine IP-10, interferons (INF-γ) and tumour necrosis factor (TNF-α), which may contribute to the pathogenesis of a variety of respiratory diseases such as bronchiolitis, pneumonia and exacerbations of asthma and chronic obstructive pulmonary disease (COPD). ^{21– 23} Asians have an increased prevalence of disease in young children and the elderly, probably due to their immature or compromised immune status. ^{21– 24}

HMPV was first discovered in 2001 by van den Hoogen et al. in the Netherlands. ⁶ The virus was discovered by molecular techniques that revealed new viruses in the airways of patients with symptoms similar to RSV and parainfluenza viruses. HMPV was documented in a significant proportion of respiratory illnesses, particularly in children, and its clinical presentation resembled that of RSV, which in early reports included bronchiolitis, pneumonia, and croup. ^{25– 27} The first comprehensive reports of HMPV emergence were from Europe, where it was found to circulate similarly to other respiratory viruses, particularly during the winter season. ²⁸

Since its discovery, HMPV has been found on several continents worldwide, including North America, South America, Europe, Asia and Africa. ^{16, 29– 40} The virus appears to circulate throughout the year in tropical areas, while in temperate climates seasonal peaks are observed during the cold months. ^{17, 29, 31, 35} HMPV infections are more common in young children under 5 years of age due to a lack of immunity. ^{31, 35– 37, 39, 40} In a study from China, a higher rate of HMPV infection was found in children aged < 18 months in children aged < 1 year (n = 1,693) compared to older children (n = 1,198). ⁴¹ This is supported by other reports showing that infants are at higher risk of developing respiratory disease. ^{30, 37, 39, 42} However, older and immunocompromised patients are not spared, and there are a growing number of reports of severe disease in these cohorts. ^{31, 38, 40}

Epidemiologically, HMPV is frequently underdiagnosed as the clinical symptoms overlap with other respiratory viruses such as RSV, influenza, and RV. For this reason, further progress in surveillance and reporting is needed to determine the true incidence of HMPV infections. For example, studies in the United States have shown that up to 10% of all children hospitalised with viral respiratory illnesses are infected with HMPV. ² The overall burden of HMPV is difficult to estimate accurately due to differences in diagnostic capacity, reporting systems, and overlap of symptoms with other respiratory pathogens. Recent data from the US suggest that HPMV infections are a more common cause of viral respiratory disease in children compared to RSV in areas where surveillance has been implemented. ⁴³

Transmission of HMPV most commonly occurs through respiratory droplets (e.g., when a person infected with the virus coughs, sneezes, or speaks) and is therefore highly contagious in close contact situations. ^{44, 45} Contagious agents can also spread the virus as it can survive on surfaces for short periods of time and is thus indirectly transmitted to people when they touch the surface and then touch their face, eyes, nose, or mouth. ⁴⁶

HMPV circulates mainly in winter and spring. The stability of the virus in aerosols and on surfaces may be related to environmental conditions such as lower temperatures and higher humidity, which favour transmission of the virus. ^{17, 29, 31, 35} The virus is highly contagious, with household studies showing a secondary infection rate of 12.2%. ⁴⁷ As young children, particularly those under 5 years of age, are the target reservoir for HMPV, they are frequently responsible for transmission of the virus within families and daycare centres. ^{31, 35– 37, 39, 40} Asymptomatic carriers and those with mild symptoms may also facilitate transmission of the virus, complicating prevention efforts.

HMPV can also spread in hospitals, causing outbreaks in neonatal and paediatric units where patients are more likely to contract respiratory infections. ^{48– 50} Research shows that healthcare workers can pass the virus on to vulnerable patients if they do not follow strict infection control measures. This emphasises the importance of washing hands and using personal protective equipment to limit the spread of HMPV in clinical settings. ^{51, 52} Thus, HMPV spreads from person to person through direct respiratory droplets and indirect contact. A close contact environment facilitates the spread of the virus ( Figure 1).

HMPV is primarily transmitted through direct or close contact with respiratory secretions from infected persons and through contaminated surfaces (fomites). The clinical presentation of HMPV infection is quite broad, ranging from mild upper respiratory tract symptoms to more severe lower respiratory tract involvement, such as bronchiolitis and pneumonia. Individuals with certain risk factors — including young children, older adults, and those with compromised immune systems — are more likely to develop severe forms of HMPV-related illness. ^{31, 32, 53}

Age plays an important role in determining the severity of HMPV infections. Infants, particularly those less than six months old, are particularly susceptible to severe disease, likely because their immune systems are still developing and their airways are narrower. ^{49, 54, 55} At the other end of the spectrum, older adults — especially those over 65 — are also at increased risk, likely due to age-related decline in immune function and the presence of other health problems. So, both the very young and the elderly are particularly at risk when it comes to HMPV. ^{56, 57}

Prematurity poses a particular risk, as premature babies often suffer more severe HMPV infections due to their immature lungs and underdeveloped immune systems. ^{49, 58} Similarly, people with chronic conditions such as asthma, COPD, or congenital heart disease are at higher risk of serious complications following HMPV infection. ^{24, 31, 38, 59} These underlying problems can exacerbate the respiratory problems caused by the virus itself.

In addition, immunodeficiency — whether congenital, acquired, or as a result of medical intervention - greatly increases susceptibility to severe HMPV disease. Patients with a weakened immune response have difficulty clearing the virus efficiently, which can lead to a longer and more severe illness. ^{60, 61}

Environmental and sociodemographic factors influence the risk profile for HMPV infection. For example, crowded residential environments have been associated with higher hospitalisation rates, likely due to increased exposure and transmission in densely populated households. This association is well documented and highlights the importance of considering living conditions in risk assessment. ^{48– 50}

Interestingly, some studies have identified female sex as a possible risk factor for severe hMPV disease, although the reasons for this observation remain unclear and require further research. ⁶²

The virus characteristics themselves also play a role in the severity of the disease. Certain genotypes, particularly genotype B, have been associated with more severe courses in some studies. ⁶³ However, recent research has produced conflicting results regarding the relationship between genotype and disease severity, so the question is far from settled. ^{30, 41} In addition, coinfection with other respiratory pathogens, particularly RSV, can further worsen the clinical course of hMPV and increase morbidity. ^{30, 64}

Overall, the risk factors for severe hMPV infection are complex and multifactorial and include host-specific factors such as age, prematurity, health status and immune function as well as environmental and viral factors. A thorough understanding of these factors is essential for the identification of at-risk populations and the implementation of targeted prevention strategies to reduce the impact of hMPV infections.

Prevention strategies are crucial to contain the spread of HMPV and reduce its impact, especially among at-risk groups, as it has a significant public health impact, especially during the colder months when transmission is most common. Promoting proper hygiene, improving environmental cleanliness, immunising vulnerable groups, and, if necessary, providing supportive care and antiviral treatments are the main objectives of general prevention measures. These measures help to contain the spread of HMPV in different population groups such as young children, the elderly, and people with weakened immune systems ( Figure 1).

Accurate and rapid diagnosis of HMPV is essential for efficient patient care and the implementation of appropriate infection control measures. Various diagnostic techniques are used to identify HMPV, each with its own advantages and disadvantages.

Due to its high sensitivity and specificity, real-time reverse transcription polymerase chain reaction (RT-PCR) is the gold standard for the detection of HMPV. ^{79, 80} This technique enables the identification of HMPV even at low viral loads by amplifying viral RNA isolated from respiratory specimens. Research has shown RT-PCR to be effective in identifying HMPV in a number of patient groups, such as immunocompromised lung transplant recipients and paediatric patients being screened for pertussis. ^{79– 81}

Monoclonal antibodies are used in immunofluorescence assays (IFAs) to identify HMPV antigens in nasopharyngeal secretions. ⁸² Although IFAs provide rapid results, they are usually less sensitive than RT-PCR and may give false-negative results, especially if the virus concentration is low. ⁸³ Therefore, if clinical suspicion is still high, a confirmatory test with NAATs is recommended, and negative IFA results should be interpreted with caution.

Virus isolation is possible by cultivating HMPV in cell lines such as LLC-MK2 cells. However, this process is labour-intensive and time-consuming, and it frequently takes days to weeks for cytopathic effects to manifest. ⁸⁴ In addition, HMPV has slower replication kinetics compared to other respiratory viruses, making culture techniques less useful for standard clinical diagnostics. ⁸⁵

Retrospective evidence of infection can be provided by serological tests that identify HMPV-specific IgG and IgM antibodies. ⁸⁶ However, the usefulness of serology in acute diagnosis is limited by the delayed antibody response. In addition, serological cross-reactivity with other paramyxoviruses could make specificity less reliable.

As diagnostic technology has evolved, multiplex nucleic acid amplification tests have been developed that can detect multiple respiratory pathogens, including HMPV, simultaneously. ⁸⁷ These tests facilitate thorough investigation of respiratory infections, which is particularly helpful when coinfection is present. However, the higher cost and complexity of multiplex platforms may make them less accessible in some healthcare settings.

When choosing a diagnostic technique for HMPV in clinical practise, the patient’s age, immunological status, clinical presentation, and availability of laboratory resources should be considered. The inclusion of rapid antigen detection tests may be beneficial in situations requiring immediate results, although RT-PCR remains the recommended diagnostic method due to its exceptional sensitivity and specificity. To improve patient outcomes and guide public health interventions, ongoing research into innovative diagnostic technologies aims to improve the speed, accuracy, and accessibility of HMPV detection.

Most HMPV infections typically resolve on their own within two to five days, unless the individual is dealing with a concurrent infection. ⁸⁸ As there is no specific antiviral treatment currently approved for HMPV, the primary approach to management involves supportive care tailored to the patient’s clinical condition and overall health status.

In the general population, the most frequent symptoms of HMPV affecting the upper respiratory tract include fever, a cough, and nasal congestion. To manage these symptoms, individuals can take antipyretics to reduce fever, ensure they stay well-hydrated, and use analgesics to alleviate pain. ⁸⁹ Over-the-counter antihistamines may help relieve nasal congestion. Most individuals recover independently without needing medical intervention. However, if symptoms persist or worsen, it is advisable to consult a healthcare professional, as this may suggest the condition has progressed to involve the lower respiratory tract.

Severe infections caused by HMPV can lead to pneumonia or bronchiolitis in young children, particularly infants. Managing these cases involves vigilant monitoring for signs of respiratory distress, such as low oxygen levels, retractions, or rapid breathing. Supportive measures, including oxygen therapy to maintain adequate oxygen levels and intravenous fluids to ensure hydration, especially if oral intake is insufficient, may require hospitalization. ⁸⁹ In critical cases, mechanical ventilation might be necessary. ⁹⁰ Some patients also need bronchodilators and corticosteroids to manage wheezing and asthma exacerbations. ⁹¹ Antibiotics are administered only when a bacterial co-infection is suspected or confirmed. ⁹² Educating parents in this group is crucial for recognizing early signs of respiratory distress and ensuring timely medical assessment.

In older adults, the decline in immune function due to age and the presence of other health conditions often leads to more severe cases of HMPV. Management strategies include personalized supportive care and vigilant monitoring of respiratory health. Hospitalization might be necessary for those experiencing severe community-acquired pneumonia, exacerbations of COPD, or significant respiratory distress. ^{93, 94} Oxygen therapy is commonly administered to address hypoxemia, and careful fluid management is crucial to prevent fluid overload, particularly in patients with kidney issues or heart failure. ⁸⁹ Although ribavirin, an antiviral drug, is typically reserved for severe HMPV cases, research has shown that its use does not significantly enhance outcomes. ⁹⁴ Preventive measures, such as vaccinations against other respiratory pathogens like influenza and pneumococcus, can help reduce the overall burden of respiratory illnesses in this demographic. ^{74, 75}

Individuals with compromised immune systems, such as those undergoing chemotherapy, organ transplants, or living with HIV/AIDS, face a heightened risk of severe and prolonged HMPV infections. ^{95– 97} These patients often have complex medical issues that require a multidisciplinary approach to care. While supportive care remains the primary treatment, these patients often need to be hospitalized for close observation due to the potential for rapid clinical decline. ^{98– 100} Several studies have shown positive outcomes when ribavirin, intravenous immunoglobulin, or both are combined with short-term steroid therapy for immunocompromised patients. ^{100– 102}

The lack of targeted antiviral treatments and vaccines for HMPV emphasises the need for further research. Novel antiviral drugs and immunomodulatory therapies are among the experimental treatments being investigated. In addition, efforts are being made to develop vaccines that provide long-term protection, especially for high-risk groups. With a focus on preventative measures to curb transmission and reduce the incidence of severe disease, treatment of HMPV will remain supportive until such progress is made.

To summarise, patient demographics and underlying medical conditions influence the treatment of HMPV infection. The cornerstone of treatment for all populations remains supportive care, with particular attention to monitoring and treating problems in vulnerable populations such as young children, the elderly, and immunocompromised patients. To improve outcomes for those affected by this common respiratory pathogen, further research is needed to develop targeted therapies and vaccines.

This study is a literature review and does not involve human participants; therefore, no ethical approval is required.

As this research is based on a literature review, consent to participate is not applicable.