The Burden of Human Metapneumovirus (hMPV) Disease in Older and High-Risk Adults in Developed Countries: A Systematic Literature Review.

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Key Summary Points

Introduction

Human metapneumovirus (hMPV) is a respiratory pathogen that causes infections in humans at all ages, particularly affecting young children and immunocompromised individuals [ 1 , 2 ]. hMPV is a member of the Pneumoviridae family, like respiratory syncytial virus (RSV), and spreads through respiratory droplets and contact with contaminated surfaces [ 1 , 3 ].

The clinical spectrum of hMPV infection ranges from asymptomatic cases to those with mild symptoms, such as fever, cough, and wheezing, to severe manifestations including bronchiolitis, pneumonia, and exacerbation of asthma and chronic obstructive pulmonary disease (COPD) [ 2 ]. While hMPV infections are usually mild and self-limiting, their clinical course can be complicated in frail, elderly, and immunocompromised patients [ 4 ].

The burden of hMPV in adults has been documented after the virus’s first identification in 2001 [ 1 ]. In a prospective cohort study, hMPV was identified in 5.9% of adults aged ≥ 65 years and 9.1% of high-risk adults with any respiratory symptoms from 1999 to 2003 in New York, US. Moreover, it accounted for 4–13% of acute respiratory infections requiring hospitalisation [ 4 ]. Among adult patients hospitalised with pneumonia in eight US hospitals between 2010 and 2012, hMPV was identified in 3.8% of the cases [ 5 ].

Despite the significant burden of hMPV infection, no licensed vaccines or specific antiviral treatments are currently available, and supportive care is recommended to manage the symptoms. Research toward developing a vaccine is ongoing, and promising candidates have shown efficacy in animal models [ 6 ]. Several candidates are undergoing preclinical research, including two promising mRNA and virus-like particle vaccine candidates [ 7 ].

While the overall impact of hMPV in children has been synthesised [ 8 ], limited studies have focused on hMPV burden in adults. To fill this knowledge gap, we conducted a systematic literature review (SLR) and meta-analysis of peer-reviewed literature to summarise the published evidence on hMPV burden of disease in older and high-risk adults.

Methods

The reporting of this SLR was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [ 9 ]. We prospectively registered the protocol in PROSPERO (registration number CRD42023439068).

Search Strategy

We searched Embase and MEDLINE (via PubMed) databases to identify peer-reviewed articles published between January 1, 2000, and June 12, 2023, inclusive (date of search), using predefined terms (Table S1 ).

Selection Criteria

We included original articles reporting on prevalence, incidence, mortality, and clinical presentation of hMPV infection; hMPV-related severe outcomes (including its risk factors), complications, and healthcare utilisation; coinfection with RSV or influenza; and transmission from children to adults. The hMPV clinical outcome definitions are compiled in Table S2 . We defined hMPV cases as both symptomatic and asymptomatic individuals with laboratory-confirmed infection, either by polymerase chain reaction (PCR) or serology tests, including only those who tested positive. Populations of interest were older adults aged ⩾50 years and adults aged ⩾18 years at-risk of complications of infection due to underlying conditions (high-risk). Older adults comprised the general elderly population, which may include individuals with chronic conditions and diseases, but were not selected based on any particular condition. We included studies from developed countries recognised by the United Nations [ 10 ], without language restrictions. All original articles that met these criteria were included; no studies were excluded due to small sample size. The complete inclusion criteria are defined in Table S3 .

Data Extraction, Synthesis, and Analysis

All records identified were imported into EndNote for deduplication. Two independent reviewers screened the titles, abstracts, and full texts and selected the included articles. All title-abstracts were screened in duplicate. Thirty percent of the full-text review, data extraction, and risk of bias (RoB) assessment were performed in duplicate. Disagreements were resolved by consensus among reviewers. Relevant SLRs were screened to identify additional studies of interest. The selection process was conducted in Distiller SR [ 11 ] and illustrated in a PRISMA-like diagram (Fig. S1 ). Extracted items included country, study aim, setting, period (including seasons), design and population type, age and sex, high-risk subgroup and sample size, hMPV detection method and sample type, case definition, type of respiratory infection, outcome-specific methodology, and results. If available, age-stratified data were extracted.

Quality assessment and RoB were assessed using the Joanna Briggs Institute checklists for prevalence studies, cohort studies, case series, and cross-sectional studies [ 12 , 13 ] (Table S4 ). The RoB assessment was documented using Distiller and summarised per type of checklist in tables.

Statistical Analysis

We analysed the extracted data and generated summary tables and forest plots using R.4.3.1 [ 14 ]. For signs and symptoms associated with hMPV, a shell table was created to display mean, minimum, and maximum percentages of patients reporting signs and symptoms from various studies.

Meta-analysis

We generated pooled estimates for outcomes reported by three or more comparable studies. Studies were classified as annual if data were collected continuously for ⩾1 year (January–December) or seasonal when referring to specific periods or several months without covering the entire year. Outbreak studies and those with subsample testing (the denominator being those positive for at least one virus) were excluded from prevalence estimates due to non-representative populations.

We stratified data by population type (community-based or medically attended) and geographic region (North America, Europe, or Western Pacific). Community-based studies involved prospective community follow-ups, while medically attended studies collected data at health service points. Data were also stratified by age when possible.

In high-risk adults' analyses, data were additionally stratified by high-risk subgroups (COPD, asthma, dementia, immunocompromised, and institutionalised older adults). Immunocompromised patients included those with human immunodeficiency virus (HIV), cancer, haematological diseases, immunosuppressive treatment, and transplant recipients. This population was further stratified by immunocompromising disease whenever possible.

The prevalence of hMPV among symptomatic and asymptomatic individuals was calculated as hMPV cases divided by study participants, illness episodes, or specimens, depending on the study design, and reported as a proportion (%). For hMPV-positive outcomes, the denominator is based on those who tested positive, not the total study participants.

A random-effects meta-analysis was used to summarise the outcomes. For individual proportions, we used the binomial exact (Clopper–Pearson) method to calculate confidence intervals (CI). Generalised linear mixed model meta-analyses with a logit link used the maximum likelihood method to pool information on proportions from various studies. Cochran’s Q -test and the I 2 statistic were employed to test and quantify between-study heterogeneity, respectively. An I 2 above 50% was considered substantial and above 75% considerable. If these occur, they are presented in the text. All I 2 outcomes are presented in the forest plots of the analyses. A sensitivity analysis was conducted by excluding studies with small sample sizes from the meta-analysis to assess their impact on effect estimates and heterogeneity.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Out of 2847 articles reviewed, 119 articles were included in the analysis, with a total of 663,361 patients (Fig. S1 , Table S5 ). Of these articles, 42 (35%) reported data on older adults, 69 (58%) on high-risk adults, and 8 (7%) on both. Characteristics of the study populations vary greatly and are listed in Table S5 . Studies were conducted in Europe ( n = 64), North America ( n = 43), and the Western Pacific ( n = 12). One single study reported on hMPV transmission from children to adults [ 15 ]. No articles were found studying risk factors for severe disease following hMPV infection. The RoB assessment results are displayed in Table S4 . Papers excluded during full-text extraction are listed in Table S6 , with the reason for exclusion.

hMPV Prevalence in Older Adults

hMPV prevalence in symptomatic older adults was reported in 30 studies, mostly from Europe ( n = 21), focusing on seasonal data ( n = 21) and medically attended populations ( n = 25).

Based on seasonal studies ( n = 21), the proportion of hMPV infection among symptomatic older adults ranged from 0.0% to 10.6%, with a pooled estimate of 4.0% (95% CI 2.9–5.3%; I 2 = 78%, p < 0.001). Pooled estimates of community and medically attended patients were nearly identical (Fig. 1 ). Based on annual studies ( n = 9), the proportion of hMPV infection ranged from 1.1% to 8.3%, with a pooled estimate of 3.4% (95% CI 2.7–4.2%; I 2 = 66%, p < 0.001) (Fig. 2 ). Due to data paucity, no annual pooled estimate for community-based studies could be calculated.

When analysing data by geographical region, we found that the seasonal hMPV prevalence was lower in the Western Pacific (1.2%, 95% CI 0.5–3.1%) compared to Europe (4.5%, 95% CI 3.3–6.0%) and North America (5.8%, 95% CI 4.4–7.6%). Heterogeneity within each region was notable (Fig. S2 ). The annual pooled estimate of hMPV prevalence in North America was 3.5% (95% CI 2.6–4.6%) (Fig. S3 ). Insufficient data were available to calculate annual pooled estimates for the Western Pacific and Europe.

Subgroup analysis by age revealed no difference in hMPV prevalence among symptomatic adults aged ≥ 50, ≥ 60, and ≥ 65 years in both seasonal and annual studies (Figs. S 4, S5 ). Age groups with non-overlapping ranges could not be compared due to data scarcity.

The incidence of symptomatic hMPV cases varied from 0 to 12 cases per 1000 persons ( n = 3) in annual and from 4.4 to 13.7 cases per 1000 persons ( n = 2) in seasonal studies (Table S7 ). Variation in study methodologies and populations across studies precluded meta-analysis.

The hMPV prevalence among asymptomatic older adults was only reported in three studies, ranging from 0.0% to 3.4% (Table S8 ).

hMPV Prevalence in High-Risk Adults

For symptomatic high-risk adults, hMPV prevalence was described in 51 studies. Most reported annual data ( n = 34), involved medically attended populations ( n = 47), and were located in Europe ( n = 27). About half of them focused on immunosuppressed patients ( n = 26), mainly transplant recipients.

Based on annual studies ( n = 34), the proportion of hMPV infection among symptomatic high-risk adults ranged from 0.0% to 21.4%, with a pooled proportion of 4.3% (95% CI 3.2–5.7%; I 2 = 68%, p < 0.001). The hMPV proportion was highest among patients with haematological malignancies (7.2%, 95% CI 5.1–10.2%) and lowest among those with HIV (1.7%, 95% CI 0.3–9.2%; Fig. 3 ). Results of high-risk groups overlapped, indicating no difference in symptomatic hMPV prevalence. A subgroup analysis of immunocompromised persons showed a pooled estimate of 4.1% (95% CI 2.7–6.2%; Fig. S6 ).

Based on seasonal studies ( n = 17), the proportion of hMPV infection among symptomatic high-risk adults ranged from 1.3% to 38.9%, and the pooled proportion was 5.1% (95% CI 3.2–7.9%; I 2 = 82%, p < 0.001). The pooled proportion of hMPV was 8.6% (95% CI 3.2–20.7%) for institutionalised older adults and 5.8% for patients with COPD (95% CI 3.1–10.4%; Fig. 4 ). Pooled estimates for other high-risk subgroups could not be calculated due to data scarcity.

Seasonal data did not show geographical differences (Fig. S7 ). However, hMPV annual prevalence was significantly higher in the Western Pacific region (9.1%, 95% CI 7.1–11.6%), compared to North America (4.0%, 95% CI 2.7–5.7%) and Europe (3.5%, 95% CI 2.2–5.7%) (Fig. S8 ). Insufficient data were available to calculate pooled estimates by age group.

hMPV incidence among symptomatic high-risk adults was only reported in outbreak studies among long-term care facility residents, varying largely from 33.7 to 170.7 per 1000 persons, despite similar study characteristics (Table S7 ).

Among asymptomatic high-risk adults, hMPV prevalence from seasonal and annual studies ranged between 0.0% and 3.5% ( n = 7, Table S8 ).

hMPV Outcomes in Older Adults

The available evidence on the proportion of hospitalisations due to hMPV in the elderly population was limited and presented small sample sizes ( n = 3, Table S 9). One study reported that one person was hospitalised among twelve hMPV cases, while the other two studies reported no hospitalisation episodes. Available evidence for intensive care unit (ICU) admission due to hMPV was also scarce ( n = 3, Table S1 0).

The hospitalisation rate in older adults varied from 1.8 to 59.3 per 10,000 persons and increased with age (Table S1 1). Data on hospital length of stay (LoS) (Table S1 2), outpatient and emergency visits (Table S1 3) were limited. Reported complications of hMPV infection included pneumonia and the need for mechanical ventilation (Table S1 4).

Five small studies reported case fatality rate (CFR) among hMPV-infected older adults in long-term care facilities and inpatients (Table S1 5). In two studies with fewer than 20 cases each [ 16 , 17 ], no deaths were reported. The other three studies reported a CFR between 0.0% and 8.7% [ 4 , 18 , 19 ]. Insufficient data precluded the calculation of pooled CFRs by region and age group.

hMPV Outcomes in High-Risk Adults

Eighteen studies reporting the hospitalisation of high-risk adults with severe respiratory symptoms/illness due to hMPV, such as severe influenza-like illness or acute respiratory infection (ARI), were included. Most studies presented small sample sizes; only four reported > 20 hMPV cases. The overall pooled proportion of hMPV cases was 51.4% (95% CI 33.2–69.3%, n = 18, Fig. 5 ). This estimate was largely driven by data from haematopoietic transplant recipients (59.8%, 95% CI 35.3–80.3%) and solid organ transplant recipients (41.4%, 95% CI 29.7–54.2%). Subgroup analysis by region revealed no geographical differences (Fig. S9 ). A sensitivity analysis excluding studies with a denominator of 1 resulted in similar estimates but higher heterogeneity (data not shown).

Nine studies reported on the proportion of hMPV cases among high-risk adults admitted to the ICU with severe respiratory illness or symptoms. Six studies reported < 10 hMPV cases. The overall rate of ICU admissions was estimated at 6.6% (95% CI 4.8–9.1%, n = 9) and at 4.6% (95% CI 1.7–11.6%) for haematopoietic transplant recipients (Fig. S1 0).

Eight studies reported LoS among hMPV cases in high-risk adults. The median LoS ranged from 4 to 17 days, and the mean LoS ranged from 10 to 25 days across different risk groups (Table S1 6). The available evidence regarding outpatient and emergency visits was limited (Table S1 3).

A large number of studies ( n = 32) reported the CFR among cases of hMPV in high-risk adults. Studies had a relatively small sample size; seven studies had > 20 hMPV cases. The CFR was estimated at 9.3% (95% CI 4.6–18.0%; I 2 = 0%; p = 0.504; Fig. 6 ). Subgroup analysis by high-risk category revealed overlapping results, with a pooled CFR of 30.0% (95% CI 16.4–48.3%) for institutionalised older adults, 22.8% (95% CI 13.4–36.0%) for haematological malignancy patients, and 14.5% (95% CI 5.2–34.1%) for haematological transplant recipients. Among solid transplant recipients (all lung transplant recipients), no hMPV cases resulted in death during the study period. CFR did not differ among geographic regions (Fig. S1 1). A sensitivity analysis excluding studies with very low sample sizes (denominator ≤ 3) resulted in similar estimates but higher heterogeneity (data not shown).

The need for mechanical ventilation among hMPV cases in high-risk adults was estimated at 7.8% (95% CI 2.2–24.0%, I 2 = 24%, p = 0.207) (Fig. S1 2). For haematopoietic transplant patients, this proportion was 6.8% (95% CI 1.4–26.4%). We found insufficient data to calculate pooled estimates for other high-risk groups. Six studies reported pneumonia as a complication with a pooled estimate of 18.4% (95% CI 3.3–60.1%) (Fig. S1 3). Other severe complications associated with hMPV infection included acute rejection (in up to 33.3% of transplant recipients, n = 6), chronic rejection (in up to 63.2%, n = 7), and acute respiratory distress syndrome (in up to 28.5% of high-risk patients, n = 2) (Table S1 7).

Clinical Presentation of hMPV Infection

Few included studies described the clinical presentation of upper and lower respiratory tract infections (URTI: 1 study/LRTI: 3 studies) among hMPV-infected older adults. Only one study reported on the proportion of hMPV patients presenting with bronchitis (Table S1 8).

For high-risk adults, the estimated pooled proportion of URTI and LRTI in hMPV cases was 61.7% (95% CI 43.5–77.1, n = 14) and 34.7% (95% CI 26.2–44.3, n = 23), respectively, with substantial heterogeneity ( I 2 = 56%; p < 0.005 and I 2 = 57%; p < 0.001, respectively) (Figs. S1 4, S1 5). The proportion of URTI among hMPV cases in haematological transplant recipients was estimated at 73.4% (95% CI 61.2–82.9%), which was significantly higher than that among solid organ transplant (lung transplant) patients (46.3%, 95% CI 34.8–58.2%). Subgroup analyses showed no variation between high-risk groups for LRTI and no geographical differences for URTI and LRTI (Figs. S1 6, S1 7). Sensitivity analyses for URTI and LRTI resulted in similar estimates without improving the heterogeneity (data not shown).

Among the self-reported hMPV symptoms in older adults, cough was the most frequent (median of 93.4%), followed by dyspnoea (87.0%), wheezing (73.1%), congested nose (70.9%), and fever (52.2%) (Table S1 9). Wheezing was the most frequently found sign on examination (78.3%) (Table S2 0). In high-risk adults, self-reported symptoms were only documented among immunocompromised and institutionalised patients, with cough being the most common symptom (82.6% and 66.7%, respectively). Immunocompromised patients also reported dyspnoea (75.7%), fatigue (73.3%), constitutional symptoms (70.6%), congested nose (64.6%), and new or worsening sputum (60.9%) (Table S1 9). Signs on examination were reported for institutionalised, immunocompromised, COPD, and asthma patients. Fever was observed in all four groups, with rates of 100%, 75%, 66.7%, and 57.1%, respectively. Other signs on examination were only reported among immunocompromised patients, with rhinorrhoea (64.7%) and desaturation (75%) being most frequent (Table S2 0).

Coinfections

The proportion of hMPV cases in older adults coinfected with influenza virus ranged from 0.0% to 22.2%, with a pooled estimate of 0.6% (95% CI 0.0–8.3%; I 2 = 42%, p = 0.114, n = 6; Fig. S1 8). Similar results were found for coinfection with RSV ( n = 6, Fig. S1 9).

In high-risk populations, the proportion of hMPV coinfection with influenza virus ranged from 0.0% to 16.7%, with a pooled estimate of 5.2% (95% CI 2.7–9.7%) and no heterogeneity observed between studies ( n = 23, Fig. S20 ). Subgroup analyses by high-risk group and region revealed no significant differences. The proportion of hMPV cases in high-risk adults coinfected with RSV ranged from 0.0% to 18.2%, with a pooled estimate of 0.9% (95% CI 0.0–14.1%) and no heterogeneity observed between studies ( n = 19, Fig. S21 ).

Discussion

This SLR and meta-analysis synthesised the available evidence on the burden of hMPV disease among older adults (aged ⩾50 years) and high-risk adults in developed countries. Our analysis included 119 articles, mostly covering high-risk and medically attended populations, with which pooled estimates were generated, primarily representing these patient cohorts rather than community populations. The compiled evidence underscores the importance of hMPV as a substantial cause of illness in adults, particularly those with underlying diseases.

We estimated that hMPV accounts for 3.4–4.0% of symptomatic respiratory infections in older adults and for 4.3–5.1% in high-risk adults. Furthermore, for high-risk adults, 51.4% of hMPV-positive outpatients required hospitalisation, 6.6% of hospitalised hMPV patients required ICU admission, and 9.3% of hMPV-positive cases resulted in mortality, with cases being medically attended and occurring in long-term care facilities. For older adults, the evidence on hospitalisation due to hMPV was limited and comprised studies with small sample sizes. The hospitalisation rates varied widely, and ICU admission rate was reported at 13.2% in the largest study on medically attended patients aged ≥ 65 years. Reported complications included pneumonia and the need for mechanical ventilation, with CFRs ranging from 0.0% to 8.7%, occurring in hospital settings or long-term care facilities.

Our results were comparable to those of other studies addressing hMPV burden in specific high-risk groups. Previous SLRs estimated a hMPV prevalence of 7% for both haematopoietic cell transplant recipients and patients with haematologic malignancies [ 20 ] and of 2.8% for patients with exacerbations in COPD [ 21 ]. Another SLR focusing on RSV, parainfluenza virus, and hMPV infection in lung transplant patients reported estimates of CFR and risk of chronic lung allograft dysfunction (2% and 12–32%, respectively) consistent with our findings [ 22 ]. These findings support the need for vigilant viral infection monitoring in high-risk populations, with a continued focus on long-term complications.

The incidence of hMPV among older adults in our SLR ranged from 0.005 to 2.1 and from 4.4 and 13.7 cases per 1000 persons for annual and seasonal data, respectively. By comparison, studies report an incidence of medically attended hMPV of approximately 10 cases per 1000 among those aged 65 + during 2018/2019 flu season [ 23 ]. For the high-risk groups, incidences reported in outbreak studies highlight hMPV's impact on long-term care facility residents. Similarly, Checovich et al. showed hMPV has the potential to be one of the most prevalent causes of ARI among long-term care facility residents during non-outbreak influenza seasons. Across three consecutive influenza seasons (2016/2017, 2017/2018, and 2018/2019), hMPV accounted for 20.9% of ARI cases with confirmed viral aetiology [ 24 ].

Overall, hMPV represents a considerable disease burden for adults. hMPV was identified among the main causes of ARI in an SLR and meta-analysis of case–control studies, being almost ten times more common among ARI/pneumonia cases compared to healthy/asymptomatic older adults, with an attributable fraction of 90% among those exposed to hMPV [ 25 ]. Moreover, a recent SLR [ 26 ] estimated 473,000 (95% CI 396,000–777,000) hMPV-associated hospitalisations globally among adults aged ≥ 65 years in 2019.

Some studies have identified hMPV alongside influenza virus and RSV, which are widely recognised for their substantial disease burden and their role as etiological agents of respiratory infections in older adults. For example, in a study conducted from 2011 to 2016, the prevalence of influenza, RSV, and hMPV was 9.5%, 5.4%, and 3.1%, respectively, in the Paris area [ 27 ]. Other studies comparing the prevalence of these viruses among symptomatic cases during influenza seasons found similar results [ 28 – 30 ]. A recent meta-analysis by Nguyen-Van-Tam et al. estimated a prevalence of RSV among symptomatic respiratory infections from 4.7% to 7.8% for older adults; the CFR observed among RSV-infected adults (9.9%) was similar to that of high-risk adults (9.3%) estimated in our study [ 31 ]. These trends were consistent with those reported in a US study among hospitalised adults aged ⩾50 years. Although with small sample sizes, ICU admission rates were 13.0% for hMPV, 9.7% for RSV, and 6.1% for influenza [ 19 ]; mechanical ventilation was needed in 4.4% of hMPV cases, 3.2% of RSV cases, and 0.0% of influenza patients; and in-hospital mortality occurred in 8.7% of hMPV patients, 6.5% of RSV patients, and no deaths were reported among influenza patients. When comparing the burden of hMPV to that of other respiratory viruses, the need for prevention strategies is evident.

While Nguyen-Van-Tam et al. [ 31 ] meta-analysis followed a similar methodology to our SLR, the direct comparison of the results was limited by differences in the populations included. They defined older adults as those aged ⩾60 years (compared to ⩾50 years in our study) and high-risk population as those patients with diabetes and chronic kidney disease. The differences in study design and population definitions among studies should be closely considered when interpreting the findings.

Further limitations in this SLR include small sample sizes and the number of studies, which impact the certainty of the overall evidence and contribute to high heterogeneity and wide CIs. The inclusion of small sample sizes or few number of studies in some analyses hinders the possibility of providing strong conclusions. Several pooled estimates showed substantial variability, so caution is warranted in the interpretation of our findings. Differences in the methodology, definitions, or populations among studies may be related to the observed variability. Additionally, the global variations on hMPV and RSV seasonal patterns mean some studies may not have captured a full season's data, affecting generalisability.

It is important to note that the elderly populations included in our study likely reflect the general older adult population, which typically includes individuals with chronic conditions. We categorised individuals as older adults (⩾50 years) when the original studies did not explicitly define them as being in a high-risk group based on underlying comorbidities, whereas our high-risk groups were defined as such in the original studies. However, our categorisation reflects the way the data were originally reported to maintain consistency across sources. We acknowledge that the presence of comorbidities in older adults could have contributed to an overestimation of the healthcare burden attributed to hMPV in this age group.

Regarding the testing methods, this SLR considered studies reporting laboratory-confirmed hMPV cases using diverse PCR or serology tests. The heterogeneity of testing methods may affect comparability and can also drive the variability in our results. Furthermore, identification of hMPV cases is limited by the availability of testing methods, as hMPV is not a routinely tested pathogen and is not commonly included in respiratory panels in many countries, including high-income settings. Consequently, our analysis is limited to studies that explicitly tested for hMPV, potentially underestimating its true burden. These findings underscore the need to expand and standardise diagnostic testing to include a broader panel of respiratory viruses. Improving routine detection of hMPV would support more robust disease models and more accurate burden estimates, which are essential for guiding public health interventions.

Considering the limitations on hMPV testing and evidence in community settings, the hMPV disease burden is likely underestimated. In addition, the clinical presentations and disease outcomes are mostly representative of patients seeking medical care, which may limit the inclusion of milder forms of the disease. This gap was also observed in a recent SLR on hMPV burden in older adults [ 26 ]. Further research is needed on community settings to obtain the true burden of hMPV disease in the adult population.

Finally, since our search strategy incorporated a search string specifically for hMPV, any studies containing hMPV results, but without reference to hMPV in their title, abstract, or index terms, would not be identified by our search. This may have happened, for example, in studies implementing multiplex PCR testing of a wide variety of respiratory viruses. Despite the possibility of overlooking some studies, we did not anticipate this affecting the overall conclusions of this meta-analysis, although a literature search that includes direct screening of full text would be useful for gaining a more complete understanding of evidence gaps.

Regardless of these limitations, our findings offer valuable insights and the best available evidence. Our study strengths include strict inclusion criteria, RoB assessment, and sensitivity analyses. In the meta-analysis, studies with a small sample size were attributed to less weight than larger studies. The observed consistency of hMPV prevalence across studies with varying sample sizes reinforces the robustness and validity of the reported data. However, our results suggest that larger sample sizes would be needed to estimate more accurately hMPV infection outcomes such as hospitalisation, ICU admission, and CFR.

When interpreting the hospitalisation, ICU admission, and CFR data for hMPV-positive older adults and high-risk populations, it is important to note that the denominators for these outcomes included only patients confirmed as hMPV-positive. The hospitalisation data were derived from initially outpatient cases, while the ICU admission data included only those already hospitalised. Similarly, the CFR reflected outcomes among confirmed positive cases. Consequently, the sample sizes for these outcomes were smaller compared to those for symptomatic and asymptomatic proportions, which were based on the entire study populations. This distinction should be considered to avoid direct comparison and potential misinterpretation, as the data sets reflected different clinical contexts and studies. Finally, the true burden of hMPV in this SLR might be underestimated due to the inclusion of only laboratory-confirmed cases and the limited data from community settings compared to medical settings.

This SLR highlights some critical knowledge gaps that require attention in future research. First, several studies did not stratify outcomes by age or comorbidity, limiting the ability to assess differential risk among vulnerable populations. Second, the limited number of studies or studies with small sample sizes reporting specific clinical outcomes constrained our ability to conduct meta-analyses across multiple domains. Third, while paediatric populations are relatively well-represented in the literature, data on adults and older adults—who may also experience significant morbidity—remain insufficient. Fourth, while our review focused on studies conducted in high-income countries, data on hMPV are particularly scarce in low- and middle-income settings, where surveillance infrastructure is often limited. Furthermore, many studies included cases of viral coinfection, and clinical outcomes related to disease severity were often not analysed separately for single hMPV infections. This lack of disaggregated data makes it difficult to specifically attribute outcomes to hMPV, further limiting the accuracy of burden estimates. Future studies should address these limitations by implementing standardised diagnostic protocols that routinely include hMPV, ensuring the systematic collection of age- and risk-group-specific data, and expanding research to underrepresented geographic regions. Improving data quality and consistency across these dimensions will facilitate the development of more accurate disease models and support informed public health decision-making.

Conclusions

This SLR and meta-analysis identified a significant burden of hMPV among older and high-risk adults, both in terms of morbidity and mortality. These findings underscore the need for tailored prevention and treatment strategies for hMPV and suggest significant potential for mitigation through vaccination or antiviral treatment. Further research, particularly prospective studies conducted in community settings, is needed to inform the development of targeted prevention and treatment strategies.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 7095 KB)

Acknowledgments

Medical Writing, Editorial, and Other Assistance

The authors would like to acknowledge Pimnara Peerawaranun and Juan Luis Ramirez Agudelo (P95 Clinical & Epidemiology Services, Leuven, Belgium) for statistical analysis support. The authors would like to acknowledge Elvira Carrió, Marc Baay, and Laura Sarabia (P95 Clinical & Epidemiology Services, Leuven, Belgium) for manuscript writing and submission support. This support was funded by Icosavax, a member of the AstraZeneca Group.

Author Contributions

Ajoke Sobanjo-ter Meulen: conceptualisation, formal analysis, writing—review and editing, funding. Aura Victoria Gutierrez: methodology, investigation, data curation, formal analysis, writing—original draft, writing—review and editing, visualisation. Hilde Vroling: methodology, investigation, data curation, formal analysis, writing—original draft, writing—review and editing, supervision. Jennifer Eeuwijk: methodology, investigation, data curation, formal analysis, writing—original draft, writing—review and editing, supervision. Niranjan Kanesa-thasan: conceptualisation, formal analysis, writing—review and editing, funding. Ornella Ruiz: methodology, investigation, data curation, formal analysis, writing—original draft, writing—review and editing, visualisation.

Funding

This study and the journal's Rapid Service Fee were funded by Icosavax, a member of the AstraZeneca Group.

Data Availability

The study protocol is available at PROSPERO (CRD42023439068). Tables with characteristics of all included studies and a list of excluded articles with reasons are available in the appendix. Additional information is available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Aura V. Gutierrez, Ornella Ruiz, Jennifer Eeuwijk, and Hilde Vroling were all under the employ of P95 Clinical & Epidemiology Services when they carried out the literature review, a project which was financially supported by Icosavax, a member of the AstraZeneca group. During the completion of the manuscript, Aura V. Gutierrez became affiliated with Odds Epidemiology, Bogota, Colombia, while Hilde Vroling joined the Health Council of the Netherlands, Den Haag, the Netherlands. Ajoke Sobanjo-ter Meulen and Niranjan Kanesa-thasan are employees and stockholders of Icosavax, a member of the AstraZeneca group.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Footnotes

Prior Presentation: This manuscript is not based on work previously published. However, some findings were presented in a poster for the 8th ReSViNET Conference, 13–16 February 2024, Mumbai, India.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Supplementary Materials

Supplementary file1 (PDF 7095 KB)

Data Availability Statement

The study protocol is available at PROSPERO (CRD42023439068). Tables with characteristics of all included studies and a list of excluded articles with reasons are available in the appendix. Additional information is available from the corresponding author on reasonable request.