Human metapneumovirus: the hidden viral menace making headlines

INTRODUCTION

Acute respiratory tract infection (ARI) is a leading cause of morbidity and mortality worldwide. Globally, ARIs were responsible for about 20% of total deaths in children less than 5 years of age in 2000 alone; moreover, about 70% of these deaths occurred in Sub-Saharan Africa and the southern regions of Asia.¹ ARIs affect children regardless of their economic status, with similar incidence rates in both developed and developing countries, but with a higher mortality rate in developing countries.² The risk of pneumonia is higher in children in developing countries (10–20%, compared to 3–4% in developed countries).³ Human metapneumovirus (HMPV) was first discovered in 2001 in the Netherlands, when the virus was isolated from a paediatric patient who had symptoms similar to those of hRSV infection.⁴ Since then, HMPV has been detected in 4–16% of patients with ARIs.⁵ Belonging to the order Mononegavirales, the Paramyxoviridae family is divided into the subfamilies Paramyxovirinae and Pneumovirinae. The Pneumovirinae subfamily is further divided into two genera, Pneumovirus and Metapneumovirus. hRSV is placed under the genus Pneumovirus, while HMPV is placed under the genus Metapneumovirus. Whole genome analysis has shown that HMPV exists as two genotypes, A and B. Based upon the sequence variability of the attachment (G) and fusion (F) surface glycoproteins, these two genotypes are further divided into subgroups A1, A2, B1 and B2. Subgroup A2 is again subdivided into A2a and A2b.⁶ The prevalence of HMPV has been documented in many countries and is considered a leading cause of ARTIs worldwide owing to the limited prevention and control measures.⁴ The clinical symptoms of HMPV infection in infants, elderly individuals and immunocompromised individuals are mainly characterized by fever, cough and gasp for breath, etc.⁷ HMPV has been widely prevalent worldwide and continuously brings a significant medical burden to the local area, as effective vaccine or antiviral drug for treating or preventing HMPV infection is not licensed.⁸ This review will explore the current understanding of human metapneumovirus, with a focus on its epidemiology, pathogenesis, clinical characteristics as well as strategies for prevention and control.

DISCOVERY OF HUMAN METAPNEUMOVIRUS

In 2001, researchers in the Netherlands first identified HMPV from stored nasopharyngeal samples from 28 children with respiratory illness by using electron microscopy and random reverse transcription-polymerase chain reaction (RT-PCR) techniques. This novel virus exhibited cytopathic effect but not hemadsorption in tertiary monkey kidney epithelial cells. The genome was most closely related to avian metapneumovirus serotype C (up to 88%homology).

However, the newly discovered virus replicated efficiently in monkeys but not in birds.⁹ Archived sera from the 1950s contained neutralizing antibodies against HMPV. Two retrospective Canadian studies detected HMPV in specimens collected from patients with respiratory illness between 1993 and 2001 and a US study detected HMPV in specimens from 1976 to 2001.^10-12 Collectively, these studies show that HMPV has been circulating undetected for many decades.

Epidemiology

Human metapneumovirus has been isolated on all continents and has a seasonal distribution. Outbreaks occur mainly in the spring and winter months – January to March in the northern hemisphere and June to July in the southern hemisphere.^13,14 Outbreaks of HMPV infection tend to peak in early spring over a 4–6 week period, slightly later than outbreaks of hRSV infection, which also are more spread out in time.¹⁵ Seroprevalence studies have shown that a high percentage (90–100%) of children have been infected by the time they are 5–10 years old, but re-infection can occur throughout adulthood.⁴

This may be due to insufficient immunity acquired during the initial infection and/or due to infection by different viral genotypes. The incubation period varies from individual to individual, but is commonly between 3 and 5 days. Two studies found that both genotypes of HMPV (A and B) co-circulated during a typical respiratory virus season and frequent re-infections with different genotypes occur.¹⁶ The annual rate of hospitalization due to hMPV infection is equal to that of influenza and parainfluenza 1, 2 and 3 combined.

Pathogenesis

Humans and animals mount neutralizing antibody responses to HMPV. In mice, neutralizing antibodies are first detected five to seven days after infection, peaking between four and six weeks after infection. In mouse models, initial infection with HMPV protects against re-infection and antibodies alone can protect in small animal models.^17,18 In contrast, when macaques were exposed to a challenge 12 weeks after their initial HMPV infection, virus replication was observed despite the presence of serum antibodies and no protection was evident when the challenge occurred 8 months after the primary infection.¹⁹

These findings indicate that in primates and humans, antibody levels diminish over time, allowing for re-infection. A prospective study in humans observed that older adults who later became infected had lower baseline HMPV antibody levels compared to those who remained uninfected, suggesting that antibodies provide a protective effect.²⁰

Clinical manifestations

Human metapneumovirus patients are generally diagnosed with bronchiolitis, bronchitis and pneumonia. They show common symptoms like fever, cough, hypoxia, upper respiratory tract infection, lower respiratory tract infection and wheezing.²¹ However, the most common causes of hospitalization are bronchiolitis and pneumonia. The average duration of fever in HMPV-positive cases is about 10 days, with a peak during the course of the illness.²² Young adults with HMPV re-infection show mild cold and flu-like symptoms, with fever in a small proportion of infected cases.

However, in the case of elderly patients, re-infection can lead to severe symptoms (such as pneumonitis) and even to death. A study reported that HMPV infection was found in about 8% of children who came to the hospital with wheezing.²³ Wheezing is a common clinical symptom observed in multiple studies of children with HMPV-associated lower respiratory tract infections. It can lead to asthma exacerbations in small children and adults. HMPV was detected by real-time RT-PCR in asymptomatic children, but they had significantly lower viral loads that those found in symptomatic children.²⁴ Higher HMPV viral loads were significantly correlated with the course of illness and disease severity, irrespective of genotype.²⁵

Laboratory examination may show lymphopenia, neutropenia and elevated transaminases. Studies on imaging with chest X-ray and computed tomotography (CT) show initially signs of acute interstitial pneumonia (ground glass opacity and air-space consolidation) turning into signs of bronchiolitis/bronchitis (bronchial(ar) wall thickening or impaction).^26,27 Compared to RSV and influenza, similar rates of intensive care unit (ICU) admission, mechanical ventilation, length of stay for hospitalization and length of stay in ICU were seen for HMPV infection in adults.²⁸

Diagnosis

HMPV growth in cell culture is fastidious; this may be one reason for its late identification. Most studies have reported reliable cytopathic effects only in tertiary monkey kidney or LLC-MK2 cells.¹¹ The cytopathic effect is variable, with some strains inducing hRSV-like syncytia formation and others inducing focal rounding and cell destruction.

Typically, the cytopathic effect is displayed more than 10–14 days after inoculation. Confirmation of HMPV cytopathic effect relies on RT-PCR testing of infected supernatants, particularly in the absence of commercially available antibodies.

A recent study demonstrated that HMPV can replicate more effectively in human laryngeal carcinoma (HEp-2) cells, even without exhibiting a cytopathic effect.²⁹ In such cases, the presence of HMPV was verified by directly testing HEp-2 cell culture supernatants using RT-PCR or by passaging the virus onto LLC-MK2 cells to observe cytopathic effects. However, many clinical laboratories do not at present have the capability to perform routine diagnostic RT-PCR for HMPV detection.

For rapid and accurate diagnosis of HMPV infections, a combination of immunofluorescence assays and direct fluorescent antibody methods is used as the first-line of diagnosis, followed by RT-PCR on the negative samples.³⁰

Immunofluorescent staining of shell vial centrifugation culture (SVCC) has been used successfully for a more rapid detection of respiratory viruses. SVCC allows detection of viral antigen after a culture time of just 2 days. A monoclonal antibody (MAb-8) specific to HMPV is not useful for immunofluorescence assay (IFA) directly on patient specimens, but it can be used to detect HMPV when used with SVCC with several cell lines.³¹ A home-brew ELISA method has also been developed using cell lysates of HMPV.²⁰ Clearly, simpler ELISA tests using viral proteins possibly derived from the 2 main groups are needed to conduct large serological surveys in many parts of the world.

Differential diagnosis

The clinical presentation of HMPV, encompassing both upper and lower respiratory tract infections (URTI and LRTI), closely resembles that of RSV. The differential diagnosis for HMPV includes other respiratory viruses such as influenza A and B, RSV, parainfluenza viruses, rhinoviruses and coronaviruses.

Bacterial causes of community-acquired pneumonia should also be considered. In patients with underlying asthma or COPD, acute HMPV infection may present similarly to exacerbations of these conditions.

Treatment

Currently, the treatments available for HMPV infection are primarily supportive. But a few reports have raised the possibility of using ribavirin, immunoglobulin, fusion inhibitors and small interfering ribonucleic acids for the treatment and control of HMPV infection.^32,33 Ribavirin is a nucleoside with broad spectrum inhibitory activity against a variety of RNA and DNA viruses, including HMPV.

Ribavirin has demonstrated in vitro inhibition of Tumor Necrosis Factor-alfa, interferon-gamma and interleukin (IL)-10, suggesting a down regulation in Th1 and Th2 cytokine production and an increase of IL-2 production by peripheral blood mononuclear cells.^34,35 Ribavirin may terminate T-cell immune-mediated damage caused by viral infections. It limits viral transcription and showed to have immunomodulatory effects. The in vitro results are confirmed by an in vivo study in BALB/c mouse.³²

NMSO3, a sulfated sialyl lipid known to inhibit RSV replication in cell culture and in the cotton rat model, has also been shown to inhibit HMPV replication, syncytia formation and cell-to-cell virus spread in culture.³⁶ None of these compounds have been systematically tested in humans for the treatment of HMPV infection, although a case report describes apparently successful treatment with ribavirin of a patient who had undergone lung transplant and had severe HMPV infection.³⁷

Prevention and control

Preventing HMPV infection is similar to preventing other respiratory illnesses which includes frequent handwashing with soap and water or using alcohol-based hand sanitizers, covering the mouth and nose while coughing or sneezing and wearing masks in crowded or poorly ventilated areas. In healthcare settings, infection control remains a priority, with measures such as isolating infected patients, using personal protective equipment (PPE) like gloves, gowns and masks and thoroughly disinfecting high-touch surfaces. Environmental cleaning with appropriate agents, such as diluted bleach solutions, is also encouraged. Despite ongoing research, there are currently no vaccines or antiviral treatments specifically approved for HMPV. Clinical management focuses on supportive care, including hydration, oxygen supplementation for severe cases and over-the-counter medications for symptom relief.

Public health initiatives also play a critical role, including active surveillance to monitor HMPV outbreaks, educating the public on preventive measures and encouraging those with symptoms to stay home to prevent further spread. The World Health Organization (WHO) and other health agencies highlight the need for continued research into effective vaccines and treatments, with several vaccine candidates currently under development.³⁸

CONCLUSION

Human metapneumovirus (HMPV) remains a significant cause of acute respiratory infections, particularly in vulnerable populations such as children, the elderly and immunocompromised individuals. Despite extensive research, no licensed vaccines or specific antiviral therapies are available, leaving prevention dependent on hygiene measures, infection control and supportive care. Enhanced diagnostic tools for early and precise detection, along with an integrated approach combining vaccine development, antiviral treatments and robust public health strategies, will be essential to alleviating the medical and economic impact of HMPV. Sustained investment in research and global action protocol rooted in collaboration will be the key to advancing efforts against this pervasive respiratory pathogen.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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