The Global Burden of Human Metapneumovirus in High-Risk Adults: A Systematic Literature Review and Meta-Analysis.

Background

Human metapneumovirus (hMPV), discovered in 2001, is an important seasonal respiratory virus causing substantial burden of respiratory illnesses across all ages with winter–spring peaks similar but distinct from influenza and respiratory syncytial virus (RSV) [ 1 , 2 ]. Among adults, hMPV burden has been under-recognized due to nonspecific symptoms and limited diagnostic testing. As a result, many cases were historically missed or misattributed to other respiratory pathogens [ 1 , 3 ]. High-risk adults, including those aged ≥ 60 years, with chronic cardiopulmonary disease, or the immunocompromised, are especially prone to severe hMPV illness (e.g., pneumonia or worsened underlying conditions), and may experience higher rates of hMPV-related hospitalization and intensive care unit (ICU) admission [ 4 – 10 ].

Multiple studies have indicated that hMPV accounts for approximately 3–7% of adult acute respiratory illness cases, including ~ 4–6% of hospitalizations for acute respiratory infection in older adults [ 1 , 8 , 11 ]. This percentage aligns with those observed for RSV or influenza in comparable populations [ 1 , 3 ]. Many high-risk hMPV patients experience severe outcomes: across studies of hospitalized patients, 5–15% required ICU care or mechanical ventilation, and approximately 5% of hospitalized cases resulted in death [ 10 ]. Moreover, like other respiratory viruses, hMPV infection can precipitate acute cardiac or respiratory decompensation in those with chronic heart or lung disease. These findings support that hMPV is a serious pathogen in vulnerable adults, much more than a benign “cold virus” [ 1 , 3 , 11 ].

Recent systematic reviews have synthesized growing evidence on hMPV disease in adults. A 2025 review reported hMPV causes ~ 3–5% of seasonal respiratory infections in older adults and ~ 4–5% in high-risk adults, with over half of medically-attended hMPV cases in high-risk groups requiring hospitalization [ 12 ]. Other analyses found that the incidence of hMPV-related lower respiratory infections is substantial in older adults and comparable to that of RSV [ 8 , 11 ]. However, these reviews only focused on high-income countries and combined data from diverse “high-risk” groups, potentially obscuring differences across specific subpopulations [ 12 ]. Data on community-dwelling high-risk adults (≥ 18 years old) remain sparse, and prior summaries did not stratify outcomes (e.g., ICU admission and mortality) by underlying condition. Despite increasing awareness of hMPV’s impact on adults, a more granular analysis of hMPV burden in distinct high-risk adult cohorts (e.g., chronic lung disease, transplant recipients, and immunocompromised individuals) is warranted.

To address this gap, we conducted a comprehensive systematic literature review and meta-analysis of hMPV epidemiology and clinical outcomes in high-risk adults globally. We aimed to quantify the prevalence of hMPV in adults with underlying chronic medical or immunocompromising conditions and characterize the severity of illness in these groups (e.g., rates of hospitalization, ICU admission, and case fatality). By synthesizing data across studies and settings, this review provides the latest assessment of hMPV burden in high-risk adults and underscores the need for targeted preventive and therapeutic strategies for these vulnerable populations.

Methods

Study Design and Protocol

We conducted a literature review and meta-analysis to assess the burden of hMPV in high-risk adults. This review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Literature Reviews and Meta-analyses (PRISMA) [ 13 ] and the protocol was prospectively registered on the PROSPERO database (CRD420250653806). This review also incorporated enhancements such as machine-learning–assisted screening and search for broader outcome measures (e.g., economic and quality-of-life data) compared to earlier reviews on hMPV.

Search Strategy

We searched Ovid MEDLINE and Embase for studies from 1 January 2010 through 6 February 2025. The search combined controlled vocabulary and keywords for “human metapneumovirus” (and related terms, including human parainfluenza virus, which is reported separately) with terms for disease burden outcomes (e.g., epidemiology, hospitalization, mortality). Searches were restricted to English-language publications. We also queried an AI-based literature platform (BioRelate), on 24 December 2024, to identify additional literature covering the same period (see Appendix 1 for search strategies).

Eligibility Criteria

We included observational studies (cohort, case-control, cross-sectional, or surveillance designs) and clinical trials that reported relevant baseline results before the intervention took place or in the placebo group. All included studies reported on laboratory-confirmed hMPV infections in high-risk adult populations. High-risk adults were defined as individuals aged ≥ 18 years with factors predisposing to severe respiratory illness. This included those with chronic underlying illnesses (e.g., chronic lung disease, congestive heart failure, diabetes, renal or liver disease), those with immunocompromising conditions (e.g., transplant recipients, patients with cancer or human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), or on immunosuppressive therapy), and residents of long-term care facilities, such as nursing homes. Eligible studies had to report either the frequency of hMPV infection (e.g., proportion of patients tested positive, or incidence/hospitalization rates) or clinical outcomes among hMPV-infected high-risk adults. Key outcomes of interest included hospitalization, ICU admission, use of mechanical ventilation or supplemental oxygen, length of hospital stay, mortality (case-fatality ratios), and if available, healthcare resource use (costs) or quality-of-life measures. We included studies from both community and hospital settings. We excluded articles without original data (reviews, commentaries), studies focusing only on pediatric patients, single-case reports or very small case series ( N < 5), and outbreak reports. When multiple publications used overlapping data, we included only the most comprehensive report to avoid duplication.

Study Selection Process

Titles and abstracts were screened for relevance by one reviewer, aided by a machine-learning tool [DistillerSR, Evidence Partners [ 14 ] that prioritized citations likely to meet inclusion criteria. The tool reprioritized the list as screening progressed and identified references with very low inclusion probability (< 0.199), which were set aside after confirming via random sampling (3%) that none met criteria. All remaining citations proceeded to full-text review. For full-text screening, two reviewers independently assessed approximately 30% of articles in duplicate to ensure consistent application of criteria; disagreements were resolved by discussion or by a third reviewer. The remaining full-text articles were screened by one reviewer, with consultation from a second reviewer for any uncertain cases. Reasons for exclusion at the full-text stage were documented. A PRISMA flow diagram (Fig. 1 ) illustrates the study selection process.

Fig. 1 PRISMA flow diagram of study selection for the systematic review

Data Extraction

One reviewer extracted data from each included study using a standardized form, and a second reviewer cross-checked a subset (40%) for accuracy. Extracted information included study characteristics (publication year, country, design, setting, timeframe), population details (age range, high-risk criteria, number of cases by setting), and outcome data (including number of cases by setting). We recorded the number tested for hMPV and the number and proportion positive. For mortality, we extracted the number of patients who died and the total number of followed patients, from which the Case Fatality Ratio (CFR) was calculated. To harmonize data across studies, we grouped similar clinical presentations into broader categories of respiratory illness. For the purpose of analysis, respiratory illnesses were categorized into four groups based on the description of the clinical presentation: respiratory illnesses, lower respiratory tract infections (LRTI), acute exacerbations of chronic obstructive pulmonary disease (AECOPD) or acute exacerbations of asthma, and undefined respiratory illness. Any ambiguities in data extraction were resolved by returning to the source publication and team discussion.

Immunocompromised populations were grouped into five categories based on the underlying cause of immunosuppression: transplant-related (solid organ transplant and hematopoietic stem cell transplantation [HSCT] recipients); cancer-related (solid tumors and hematologic malignancies -including acute myeloid leukemia, multiple myeloma and non-Hodgkin lymphoma); HIV/AIDS; immunocompromised (any cause), as reported in the original study; and mixed immunocompromised conditions. The mixed immunocompromised category included individuals with more than one immunocompromising condition, such as cancer or transplant recipients combined with HIV/AIDS, corticosteroid use, chemotherapy, or other immunosuppressive therapies. Congestive heart failure and cardiovascular disease were grouped into the cardiovascular disease category.

Quality Assessment

We assessed the quality of each study using an adapted questionnaire based on the Joanna Briggs Institute critical appraisal checklist [ 15 ]. Each study was evaluated on key criteria relevant to our study objectives (e.g., appropriateness of the sample frame, sampling strategy and sample size, clarity of study subjects and setting descriptions, and the validity and reliability of methods used to identify and measure the condition of interest). One reviewer conducted the risk-of-bias assessment for all studies, and a second reviewer independently evaluated about one-third of the studies to ensure consistency. Differences in assessments were resolved by consensus. No study was excluded solely due to quality considerations.

Data Synthesis and Statistical Analysis

We synthesized data qualitatively and quantitatively. For outcomes reported by three or more studies, we performed random-effects meta-analyses to calculate pooled estimates. Proportions (such as hMPV positivity among those tested or hospitalization among those infected) were pooled using a binomial random-effects model (generalized linear mixed model) to compute summary percentages and 95% confidence intervals (CIs). Continuous outcomes (e.g., length of hospital stay) were pooled using random-effects inverse-variance models. If a study reported median values with ranges or interquartile ranges, we converted these to approximate means and standard deviations using established methods [ 16 ] to include them in the meta-analysis. We first assessed clinical heterogeneity by examining differences in study populations and case definitions. In addition, we evaluated statistical heterogeneity using the I² statistic [ 17 ], considering values greater than 50% as indicative of substantial heterogeneity. Potential sources of both clinical and statistical heterogeneity were further explored through subgroup analyses, such as comparing results by type of high-risk population or by clinical syndrome category, and these analyses were presented when deemed appropriate. Studies that contributed multiple data points to an analysis were counted as a single study while presenting the meta-analysis results. In the primary analyses, studies with small sample sizes (< 20 or < 50 participants, depending on the outcome and availability of studies for pooling) were excluded to reduce the role of chance and the potential disproportionate influence of sparse data. Sensitivity analyses including all studies to test the consistency of our findings were conducted and are presented in the supplementary material (Appendix 2 ). All statistical analyses were conducted using R (v4.3.1).

Ethical Considerations

This study synthesized data from previously published studies and did not involve any human subjects; therefore, institutional ethics approval was not required.

Results

Study Selection

We identified 8,962 records through database searches (see PRISMA flow diagram, Fig. 1 ). After removing 808 duplicates, 8,154 unique records remained. We screened titles and abstracts, excluding 6,048 that were clearly irrelevant (including 3,959 via AI-assisted screening). We sought 2,106 full-text articles for review (10 could not be obtained) and assessed 2,096 full-texts against eligibility criteria. Of these, 2,024 were excluded for various reasons (e.g., wrong population or outcomes), and 27 additional records identified through citation searching were also excluded. Ultimately, 72 studies met the inclusion criteria and were included in this systematic review. The full references of these articles are provided in Supplementary Table S1 .

Study characteristics

Of the 72 included studies in this literature review, 59 were conducted in high-income countries (14 in the United States). Most studies were observational (70/72, including 32 prospective). Two were randomized trials (excluded from meta-analysis because their study design differed from those of the other included studies). Inpatient hospital settings predominated (53 studies), with 12 using mixed inpatient/outpatient settings and 6 in outpatient settings. Most studies included adults aged ≥ 18 years (35/69 reporting age criteria), and 4 studies focused only on adults aged ≥ 60 years. Enrollment criteria varied: 37 cohorts included patients based on broad respiratory illness symptoms (general respiratory symptoms, respiratory illness, upper respiratory tract infection [URTI], LRTI, acute respiratory infection [ARI], or influenza-like illness [ILI]), 14 cohorts specifically targeted chronic obstructive pulmonary disease (COPD) or asthma exacerbations, and 11 studies included only laboratory-confirmed hMPV cases (See Appendix 3 , Supplementary Tables S1 – 8 for detailed study characteristics and outcomes). More information on which patients were tested for hMPV and used case definitions per study can be found in Supplementary Table S9 . The risk of bias assessment showed that study subjects and settings were generally described in sufficient detail to address our study objectives. Approximately 40% of the studies had limited sample sizes, and 5.5% had unclear measurement or follow-up, which may affect the generalizability of the results (Appendix 4).

Hospitalization in High-Risk Outpatients with hMPV

Six studies reported the proportion of patients with laboratory-confirmed hMPV infection (identified as outpatients or in emergency care) who required hospitalization (Supplementary Table S3 ). Notably, all six studies involved immunocompromised patients (e.g., hematopoietic stem cell transplant recipients, solid organ transplant patients, cancer patients on chemotherapy, or patients on long-term steroids). We found no studies assessing hospitalization after an outpatient visit for other high-risk groups (such as nursing home residents or persons with chronic lung or heart disease), indicating a gap in the literature.

Across the immunocompromised cohorts, hospitalization occurred in 22.6% to 71.1% of hMPV-infected outpatients. Our meta-analysis of four studies [excluding two very small cohorts [ 18 , 19 ] ] yielded a pooled hospitalization rate of 55.2% (95% CI, 42.0–67.7%); i.e., about half of immunocompromised adults who contracted hMPV as outpatients required hospital admission. Between-study variability was moderate (I 2 = 80%; Fig. 2 ).

Fig. 2 Proportion of immunocompromised adult hMPV patients (outpatient/ED setting) who were hospitalized. Pooled estimate from meta-analysis of 4 studies (patients with solid organ or stem cell transplants, cancer, or other immunosuppressive conditions). Studies with sample sizes below 20 were excluded from analysis but are included in sensitivity analysis in supplemental materials. Including the small studies (N<20) did not substantially change the estimate (pooled estimate 56.2%, 95% CI, 43.0–68.5%) (Appendix 2 ; Supplementary Fig. S1 ). All six studies (including the two with small sample sizes) focused on immunocompromised conditions, and none addressed other high-risk categories in outpatient settings.

hMPV Positivity in Hospitalized High-Risk Patients

A total of 61 studies reported the proportion of adults with high-risk conditions hospitalized with respiratory illness (Supplementary Table S2 ) and were tested hMPV-positive. Given the high heterogeneity, we performed subgroup meta-analyses by high-risk group: immunocompromised patients, exacerbations of COPD and asthma, and patients with cardiovascular disease.

Immunocompromised inpatients (by respiratory clinical presentation)

Eighteen data points from fourteen studies, which used different case definitions for respiratory symptoms, focused on immunocompromised adults hospitalized with respiratory illnesses (Fig. 3 ). In thirteen studies (fourteen data points) of immunocompromised inpatients with respiratory illnesses excluding patients with only LRTIs, hMPV positivity ranged from 0.6% to 44.4%. The pooled hMPV positivity was 5.4% (95% CI, 2.7–10.8%). In four cohorts of immunocompromised inpatients with pneumonia or other LRTI, hMPV positivity ranged from 0.3% to 39.0%, with a pooled prevalence of 3.2% (95% CI, 0.3–24.0%). Between-study heterogeneity was very high for both respiratory illness and LRTI groups (I 2 = 97% and 95%, respectively), reflecting the diverse settings and case definitions. Three outlier studies reported notably high hMPV rates: two included patients positive for respiratory viruses only [ 20 , 21 ], while a small study of severely ill HIV-positive patients reported a 39% hMPV positivity for unclear reasons [ 22 ].

Fig. 3 Pooled hMPV positivity among hospitalized immunocompromised adults, stratified by clinical presentation (respiratory illness vs. pneumonia/LRTI). Meta-analysis of 15 studies in immunocompromised inpatients (including transplant recipients, patients with cancer, HIV, or other immunosuppressive conditions) presenting with respiratory illnesses or pneumonia/LRTI. Studies with sample sizes below 50 were excluded from analysis but are included in sensitivity analysis in supplemental materials. Abbreviations: hMPV, human metapneumovirus; LRTI, lower respiratory tract infection; CI, confidence interval; Walker, 2014: reason for respiratory testing not described in the article

In a sensitivity analysis (Appendix 2 ; Supplementary Fig. S2 ) including smaller studies (sample < 50), the overall combined hMPV positivity in immunocompromised inpatients changed to 6.6% (95% CI, 3.8–11.2%) (with stratified estimates 7.4% for respiratory illnesses and 3.2% for LRTI, similar to the main analysis), indicating that ~ 3–7% of immunocompromised patients hospitalized with a respiratory illness have hMPV.

Inpatients with Cardiovascular Disease

Five studies evaluated hMPV in adults with underlying cardiovascular disease (CVD) who were hospitalized for respiratory illness (e.g., heart failure patients with ARI/ILI) (Fig. 4 ). hMPV positivity in this group ranged from 5.1% to 15.9%. The pooled proportion of CVD patients testing hMPV-positive was 11.4% (95% CI, 8.0–16.1%), with substantial heterogeneity (I 2 = 83%). This suggests that about 1 in 10 hospitalized patients with cardiopulmonary conditions or CVD and respiratory illness had hMPV infection in these studies.

Fig. 4 Pooled hMPV positivity among hospitalized patients with underlying cardiovascular disease and respiratory illness. Meta-analysis of 5 studies. Abbreviations: hMPV, human metapneumovirus; ARI, acute respiratory infection; ILI, influenza-like illness; CI, confidence interval; Walker, 2014: reason for respiratory testing not described in the article

Inpatients with COPD

Nine studies examined hMPV in adults hospitalized for acute exacerbations of COPD (Fig. 5 ). The hMPV positivity in these hospitalized COPD cohorts ranged from 0.9% to 8.1%. The pooled prevalence of hMPV across these studies was 3.4% (95% CI, 2.4–5.0%), with moderate heterogeneity (I 2 = 45%), indicating on average that ~ 1 in 30 hospitalized COPD exacerbation patients had an hMPV infection.

Fig. 5 Pooled hMPV positivity among patients hospitalized with acute COPD exacerbation. Meta-analysis of 9 studies. Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; hMPV, human metapneumovirus; CI, confidence interval

Inpatients with Asthma

Seven studies reported hMPV detection in adults hospitalized for acute asthma exacerbations (Fig. 6 ). The proportion of hospitalized asthma patients who tested hMPV-positive ranged from 1.9% to 16.7%. The pooled positivity was 7.6% (95% CI, 2.5–20.5%), although heterogeneity was high (I 2 = 90%).

Fig. 6 Pooled hMPV positivity among patients hospitalized with acute asthma exacerbation. Meta-analysis of 3 studies. Studies with sample sizes below 50 were excluded from analysis but are included in sensitivity analysis in supplemental materials. Abbreviations: hMPV, human metapneumovirus; ARI, acute respiratory infection; CI, confidence interval

Including four smaller studies in a sensitivity analysis (Appendix 2 ; Supplementary Fig. S3 ) yielded a similar pooled estimate (8.2%). These results suggest that about 8% of adults hospitalized with asthma exacerbations may have underlying hMPV infection, although results varied widely between studies.

ICU Admissions in High-Risk, Hospitalized hMPV Patients

Six studies reported the frequency of ICU admission among high-risk adults hospitalized with hMPV infection (Supplementary Table S4 ). Across individual studies, ICU admission rates ranged widely from as low as 4.5% to 39.5% of patients. The highest ICU percentages were observed in a study (excluded from meta-analysis) that included high-risk patients with chronic conditions: 39.5% of congestive heart failure patients, 34.0% of COPD patients, and 31.3% of asthma patients required ICU care in that study [ 6 ]. In contrast, studies focusing on immunocompromised patients tended to report lower ICU rates ranging from 4.5% to 18%.

We performed a meta-analysis of three studies (presenting five populations) that included only immunocompromised high-risk patients. In these patients, 13.0% (95% CI, 8.8–18.9%) of those hospitalized with hMPV required ICU admission (i.e., ~ 1 in 8 immunocompromised inpatients had illness severe enough for ICU care) (Fig. 7 and Supplementary Table S4 ). Heterogeneity among these studies was low (I 2 = 40%).

Fig. 7 Proportion of hospitalized high-risk adult hMPV patients requiring ICU admission (pooled estimate for immunocompromised patients). Meta-analysis of 3 studies of immunocompromised patients (primarily transplant recipients and hematologic malignancy patients). Studies with sample sizes below 20 were excluded from analysis but are included in sensitivity analysis in supplemental materials. Abbreviations: ICU, intensive care unit; hMPV, human metapneumovirus; CI, confidence interval; IC, immunocompromised

Including two very small studies (with < 20 patients) [ 18 , 23 ] did not change the pooled ICU estimate (12.9% [95% CI, 8.9–18.3%]; I 2 = 12%), indicating consistent findings (Appendix 2 ; Supplementary Fig. S4 ).

Other Severe Outcomes in Hospitalized High-Risk Patients

We also assessed respiratory support needs and length of stay among high-risk patients with hMPV (with any respiratory clinical presentation).

Use of Supplemental Oxygen

Three studies (two in transplant patients and one in HIV-positive patients) reported on the need for supplemental oxygen among hospitalized hMPV-infected patients (Fig. 8 ). In these studies, between 34.4% and 85.7% of patients required oxygen support. The pooled estimate was 43.6% (95% CI, 34.9–52.7%), with moderate heterogeneity (I 2 = 54%), and included one very small study ( N = 7). In summary, ~ 2 in 5 hospitalized high-risk patients needed supplemental oxygen therapy during their hMPV illness (all patients in these studies were in hospital, as outpatient oxygen use was not reported). We did not perform a sensitivity analysis due to the small number of studies.

Fig. 8 Proportion of hospitalized hMPV-positive high-risk adults who required supplemental oxygen. Meta-analysis of 3 studies of immunocompromised patients (transplant recipients and others) needing oxygen therapy. Abbreviations: hMPV, human metapneumovirus; CI, confidence interval

Mechanical Ventilation

Five studies reported the proportion of patients who required mechanical ventilation (MV) during their hMPV-associated hospitalization. Two studies (in lung transplant recipients and in hematopoietic cell transplant [HCT] recipients) observed no cases requiring MV (0%) [ 23 , 24 ]. In the other three studies (mixed immunocompromised populations), between 6.0% and 30.4% of patients needed MV support, a broad range [ 18 , 25 , 26 ]. We pooled the three larger studies (each with > 20 patients); 7.3% (95% CI, 1.2–33.8%) of hospitalized immunocompromised hMPV patients required MV (Fig. 9 ). This pooled MV rate of roughly 7% had substantial between-study heterogeneity (I 2 = 70%), reflecting the disparate results.

Fig. 9 Proportion of hospitalized immunocompromised hMPV patients who required mechanical ventilation. Meta-analysis of 3 studies (with n > 20 each); two smaller studies reported 0% MV and were excluded from primary analysis but are included in sensitivity analysis in supplemental materials. Abbreviations: hMPV, human metapneumovirus; MV, mechanical ventilation; CI, confidence interval; IC, immunocompromised

Including the two very small studies in a sensitivity analysis yielded a similar combined estimate (7.0% required MV), with reduced heterogeneity (I 2 = 41%) (Appendix 2 ; Supplementary Fig. S5 ). Thus, on average, about 1 in 15 patients hospitalized with hMPV needed critical ventilatory support, although certain subgroups experienced much higher rates. All patients who needed MV were, by definition, already hospitalized (typically in ICU settings).

Length of Hospital Stay

Data on hospital length of stay (LOS) for immunocompromised hMPV cases were available from only three studies (Fig. 10 ). One study provided LOS for multiple subgroups (solid organ transplant, HCT, solid tumor, hematologic cancer), while the other two reported overall LOS for immunocompromised patients (one focused on mixed immunocompromise, one on HIV-positive patients). The pooled mean LOS was 10.4 days (95% CI, 3.4–17.4 days). However, variability was high (I 2 = 92%), indicating LOS differed greatly by patient group. For instance, median hospital stays in some chemotherapy patients were reportedly shorter, whereas one cohort (hematopoietic cell transplant) had prolonged mean LOS over 20 days. Despite the heterogeneity, these results suggest hMPV often leads to multi-week hospitalizations in high-risk groups (Fig. 10 ).

Fig. 10 Length of hospital stay (mean days) among immunocompromised adults hospitalized with hMPV infection. Meta-analysis of 3 studies. Abbreviations: LOS, length of stay; CI, confidence interval; IQR, interquartile range

Case Fatality Ratios in Hospitalized High-Risk Patients with hMPV

Reported mortality among high-risk adults hospitalized with hMPV infection varied widely across the 21 studies that documented this outcome. Studies measured mortality at different time intervals, e.g., 30 days, 60 days, or 90 days, (For definitions, see Supplementary Table S5 ). In a total of 37 distinct high-risk patient populations (some studies reported number of deaths for multiple subgroups), 14 cohorts had 0% mortality (no deaths) during the observed period. At the other extreme, 12 cohorts experienced proportions above 10%, with estimates ranging from 12% up to 73%. The highest observed proportion (73%) came from a small South Korean study of 11 severely immunodeficient patients, which tracked mortality over 90 days post-hospitalization [ 27 ]. A longer follow-up can capture delayed deaths, inflating the CFR, as seen in that study. Most studies reported mortality during hospitalization or 30-day mortality, which collected mortality data during a shorter period and were generally lower.

For a quantitative summary, we conducted a meta-analysis of four larger studies among hospitalized immunocompromised populations (Fig. 11 ). In two of these, no deaths occurred; in the other two, CFRs were 4.6% and 39.1%. The pooled CFR was 2.4% (95% CI, 0.1–35.1%), suggesting that, on average, roughly 1 in 40 high-risk patients hospitalized with hMPV died, although there was a very wide CI and an I 2 of 80%, indicating considerable uncertainty and heterogeneity.

Fig. 11 Inpatient case fatality ratios among immunocompromised adults hospitalized with hMPV infection. Meta-analysis of 4 studies reporting short-term mortality; many studies had zero fatalities. Studies with sample sizes below 20 were excluded from analysis but are included in sensitivity analysis in supplemental materials. Abbreviations: CFR, case fatality ratio; CI, confidence interval; IC, immunocompromised

A sensitivity analysis (Appendix 2 ; Supplementary Fig. S6 ) incorporating several additional small studies (including those with zero deaths and some with very high proportions of patients dying) raised the pooled fatality estimate to about 7.0% (95% CI, 1.4–28.9%).

Additional Findings and Knowledge Gaps

In addition to the main outcomes above, some studies provided data on other high-risk conditions.

Other Underlying Conditions

The hMPV burden extended to patients with chronic non-respiratory illnesses. For example, among patients with diabetes hospitalized for respiratory illnesses, hMPV positivity ranged from 10.4% to 20.0% in two studies [ 21 , 28 ]. In those with renal disease (chronic kidney disease or renal failure) hospitalized for respiratory illnesses, hMPV positivity ranged from 14% to 20% [ 28 , 29 ]. One study reported an hMPV positivity of 13.9% in chronic kidney disease patients [ 21 ] and another study reported 7.9% in chronic liver disease patients [ 30 ].

Nursing Home Residents

Only one study explicitly examined long-term care facility residents [ 31 ]. In that study of older adults living in nursing homes, the hMPV case fatality rate among residents with an outbreak-associated ARI was 2.9%, which is in line with the lower end of estimates reported for hospital cohorts. Data on nursing home outbreaks or outcomes were otherwise sparse.

Economic and Quality-of-Life Outcomes

We found no studies that reported on the healthcare costs, economic burden, or quality-of-life impacts associated with hMPV in high-risk adults. This represents an important knowledge gap. No included study provided utility scores, cost analyses, or long-term functional outcomes for high-risk patients recovering from hMPV infection.

Discussion

This systematic review shows that hMPV is a substantial cause of severe respiratory illness in high-risk adults. Across studies of adults hospitalized with respiratory illness, hMPV was detected in approximately 3% of COPD exacerbations, ~ 8% of asthma exacerbations, and 10% of hospitalizations among adults with cardiovascular disease. The proportion of respiratory disease that is positive for hMPV is often lower than for influenza and RSV; nevertheless, when it is present hMPV clinical severity is comparable to other viral pathogens [ 32 ]. Across immunocompromised populations with hMPV, approximately half progressed to hospitalization, and among hospitalized immunocompromised hMPV-positive patients, around one in eight required ICU care and ~ 7% required MV. Reported mortality associated with hMPV varied across studies, with some immunocompromised subgroups experiencing high mortality.

Our results align with and extend emerging evidence that hMPV’s impact on high-risk adults rivals that of other major respiratory viruses. Rising hMPV cases have been reported in China and several Asian countries in a recent study, with hMPV accounting for 6% of respiratory illnesses and 5% of hospitalizations in recent outbreaks [ 33 ]. Previous studies have shown that outcomes for hMPV are similar to those for RSV or influenza in older adult cohorts. For example, a retrospective U.S. study from 2017 to 2019 found hMPV accounted for 8.1% of detected respiratory viruses in hospitalized adults ≥ 18 and had an ICU admission rate (16.5%) comparable to RSV and higher than influenza, with a 3.9% in-hospital mortality. Similarly, published short-term mortality rates for hospitalized high-risk adults are in the same range for hMPV (~ 2–9%), RSV (~ 3–10%), and influenza (~ 2–11%) [ 29 , 34 – 38 ].

ICU utilization appears to be on par as well; a global analysis reported no significant differences in ICU admission or MV rates between adults hospitalized with hMPV, RSV, or influenza [ 39 ] (65). Evidence also suggests that hMPV cases can incur equal or greater healthcare resource use than influenza [ 32 , 40 ]. The multi-country HARTI study (2017–2019) found that hMPV-positive patients had similar hospital lengths of stay as influenza patients, but their 90-days readmission rate was higher; 33% for hMPV compared with 20.4% for influenza patients [ 41 ]. These comparisons emphasize that hMPV infection does not lead to milder disease than other viral causes of respiratory illness in high-risk groups. Our review provides context to the growing recognition of hMPV in adults, similar to how RSV’s substantial burden in older adults was long under-appreciated until recently, hMPV appears to be an under-recognized contributor to serious respiratory illness in this demographic [ 42 ]. Notably, while pediatric hMPV disease has been well documented for years, our synthesis confirms that adult patients with high-risk conditions are also disproportionately affected, supporting the inclusion of hMPV in routine surveillance and research alongside influenza and RSV. Despite the large number of studies ( n = 72) synthesized in this review, several knowledge gaps and limitations restrict our understanding of hMPV burden. Heterogeneity among studies was substantial. Study populations varied (e.g., transplant recipients vs. general older adults), as did case definitions and testing protocols, making pooled estimates imprecise for most outcomes. We attempted to mitigate this by stratifying analyses (by patient subgroup and clinical syndrome) and conducting sensitivity analyses, but notable inconsistencies persisted (reflected in wide CIs and high I² statistics). This heterogeneity highlights that “high-risk adults” are not a uniform group, and the risk from hMPV can vary by condition and context. Another limitation is that most evidence came from high-income country hospitals, potentially limiting generalizability to community settings or low-resource countries/settings. Most included studies were hospital-based; thus, the burden of hMPV in outpatient settings or long-term care facilities is underrepresented. Moreover, hMPV displays distinct but shifting seasonal peaks that vary by year, and testing in adults is often concentrated during typical respiratory virus seasons, potentially missing infections occurring outside these windows. These variations in circulation and testing likely influence case ascertainment and contribute to variability in reported burdens across studies [ 43 ].

We also found critical data gaps. Notably, no studies reported the incidence of hMPV hospitalizations in high-risk groups (e.g., per population at risk), and we found no studies matching our inclusion criteria on economic outcomes or quality of life. Two studies reporting on economic burden were excluded from the final analysis due to limitations regarding the study populations. Ison et al. (2019) calculated healthcare costs in allo-HSCT patients and found that those with an hMPV infection had higher yearly costs than those without ($561,960 versus $353,878, respectively) [ 44 ]. Furthermore, Gaunt et al. used the Disability-Adjusted Life Year (DALY) model to estimate the burden of hMPV in hospitalized immunocompromised patients [ 45 ]. The authors estimated a loss of 2.8 DALYs per 1,000 hospitalized patients. In the same study, DALY scores were estimated at 3.5 for influenza A and 1.4 for influenza B.

Additionally, there were no studies quantifying hospitalization risk for many high-risk conditions beyond immunocompromised patients. We lack data on what fraction of hMPV-infected nursing home residents or chronic heart/lung disease patients in the community end up hospitalized. Another major issue is the potential under-ascertainment of hMPV cases. Many studies relied on a single nasopharyngeal swab PCR for diagnosis, which in adults can miss infections if sampling is late in illness, since the virus may often no longer be detected in upper respiratory tract specimens. By analogy, a recent multi-specimen study for RSV in adults showed that testing only a nasopharyngeal swab captured barely half of the true cases, whereas adding sputum and serology nearly doubled the detection rate [ 46 ]. Similar findings have been seen for SARS-CoV-2 [ 47 , 48 ] and influenza [ 49 ], so it is reasonable to assume that similar under-detection could affect hMPV case finding. While multi-specimen approaches enhance case ascertainment and improve burden estimation in research and surveillance, they are not standard of care for clinical management, particularly in the absence of virus-specific therapies.

Another potential source of underestimation may arise in studies that measured outcomes only during the traditional influenza season. In a systematic literature review performed prior to the COVID-19 pandemic, hMPV epidemics were shown to occur in late winter and spring in most temperate regions, while the timing was more variable in tropical settings [ 50 ]. In settings where hMPV peaks after the influenza period, studies restricted to the flu season may miss a proportion of hMPV cases and associated hospitalizations. However, seasonal dynamics were not an objective of our review, and we are not able to make further substantiated statements on this aspect. Therefore, the burden we report might be an underestimate of the true burden. Finally, because these data are observational, there is uncertainty in attributing outcomes purely to hMPV. Patients often had multiple co-infections or comorbidities, so in some cases, hMPV may have been an incidental finding rather than the primary cause of illness. However, the consistency of severe outcomes in hMPV-positive patients and biological plausibility (hMPV is known to cause pneumonia and exacerbate chronic conditions) suggests a major contributory role. Overall, while these limitations may constrain the precision of quantitative estimates, they highlight the consistent evidence indicating that hMPV is a substantial cause of severe disease in high-risk adult populations. Future studies should address these gaps with more standardized methods and broader outcome collection.

This review underscores the need to increase awareness of and response to hMPV within clinical practice, surveillance systems, vaccine development, and public health planning. Clinicians should routinely consider hMPV in high-risk adults presenting with respiratory symptoms, as delayed diagnosis may compromise infection control and care. Hospitals should apply RSV- and influenza-level precautions for hMPV-positive patients, particularly in transplant units and long-term care settings where outbreaks have been documented [ 51 – 53 ]. Surveillance systems and epidemiologic studies should adopt more sensitive diagnostics like multiplex PCR and multi-specimen testing, to better capture hMPV burden, especially in atypical or co-infected cases [ 54 ]. Given the high documented ICU utilization and mortality, hMPV warrants prioritization alongside RSV, influenza, and SARS-CoV-2 [ 55 ]. Public health agencies should integrate hMPV into respiratory virus surveillance and evaluate preventive strategies, while manufacturers might consider the value of hMPV therapy and vaccines.

Even the high burden we report here likely represents a large underestimate, given the often low sensitivity of diagnostic tests [ 46 ], failure to comprehensively test all enrolled subjects, and failure to consider some outcomes, such as exacerbation of cardiac disease. The success of RSV vaccines in older adults [ 56 ] and historical vaccine probe studies for Haemophilus influenzae type b and pneumococcal conjugate vaccines [ 57 – 60 ] demonstrate that burden often is only known following vaccine use, either in licensing trials or post-licensure studies, and through evaluating all-cause outcomes such as LRI or CV disease hospitalization. Such data are critical for making the public health case for the overall value proposition of any novel vaccine and likely will be necessary for hMPV as well.

Future research should prioritize prospective cohort studies to refine incidence estimates, assess long-term outcomes, and explore links between hMPV and chronic disease exacerbations. Studies should also evaluate outcomes beyond acute hospitalization, such as 90-day mortality, rehabilitation needs, and impacts on chronic disease trajectories. As emphasized by a recent global review [ 42 ], hMPV should be treated as a priority pathogen in adult respiratory disease research and pandemic preparedness.

Conclusions

In conclusion, hMPV is a substantial and under-recognized contributor to severe respiratory illness in high-risk adults. Its burden parallels that of RSV and influenza, indicating potential implications for clinical care, surveillance, and prevention. Addressing hMPV will require improved detection, expanded research, and development of targeted vaccines and other interventions to ensure comprehensive protection for vulnerable populations.

Electronic Supplementary Material

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Supplementary Material 1

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Acknowledgements

Editorial support was provided by Dr. Somsuvro Basu of P95 Clinical and Epidemiology Services and was funded by Pfizer Inc.

Author contributions

Kashmira Date, Evangelia Antoniou, Aleksandra Polkowska-Kramek, Philip Zachariah, Anna Dorste, Jennifer Granda Acaro, Lauren Mason, Laura Mora, Bradford D. Gessner, Harish Nair, and Elizabeth Begier contributed to the study conception and design. Literature search and data analysis were performed by Anna Dorste and Pimnara Peerawararun, respectively. The manuscript was written by Kashmira Date, Evangelia Antoniou, Aleksandra Polkowska-Kramek, Lauren Mason, Laura Mora, and Jennifer Eeuwijk, with Kyla Hayford, Bradford D. Gessner, Harish Nair, and Elizabeth Begier providing critical feedback and revisions. All authors reviewed and approved the final version of the manuscript.

Funding

This study was sponsored by Pfizer Inc.

Data Availability

All data generated or analyzed in this study are presented in this published article or provided as supplementary information.

Declarations

Ethical approval

This study synthesized data from previously published studies and did not involve any human subjects; therefore, institutional ethics approval was not required.

Consent for Publication

Not applicable.

Competing interests

Kashmira Date, Philip Zachariah, Anna Dorste, Jennifer Granda Acaro, Kyla Hayford, Bradford D. Gessner, and Elizabeth Begier are employees of Pfizer Inc. and may own Pfizer stock. Evangelia Antoniou is a contractor for P95 and which received funding from Pfizer in connection with the development of this manuscript and study; she is also the owner of MetaAnalyses.com, which has held contracts with Pfizer (via Labcorp), BASF, 3 M, ISOPA, and CEFIC. Aleksandra Polkowska-Kramek, Lauren Mason, Laura Mora, Jennifer Eeuwijk, and Pimnara Peerawaranun are employees of P95 Clinical and Epidemiology Services, which received funding from Pfizer in connection with the development of this manuscript and study. Harish Nair reports grants from the Innovative Medicines Initiative related to the submitted work; grants from WHO, the National Institute for Health Research, Pfizer, and Icosavax; and personal fees from the Gates Foundation, Pfizer, ReViral, GSK, Merck, Icosavax, Sanofi, Novavax, and AbbVie, outside the submitted work.

Abbreviation

Acute exacerbations of chronic obstructive pulmonary disease

Acute respiratory infection

Case Fatality Ratio

Confidence interval

Chronic obstructive pulmonary disease

Cardiovascular disease

Disability-Adjusted Life Year

Hospitalized Acute Respiratory Tract Infection

Human immunodeficiency virus/acquired immunodeficiency syndrome

Hematopoietic cell transplant

Human metapneumovirus

Hematopoietic stem cell transplantation

Intensive care unit

Influenza-like illness

Length of stay

Lower respiratory tract infections

Mechanical ventilation

Preferred Reporting Items for Systematic Literature Reviews and Meta-analyses

Risk of bias

Respiratory syncytial virus

Test negative design

Upper respiratory tract infection

Vaccine effectiveness

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