Human Metapneumovirus and Its Association With Otorhinolaryngological Manifestations: A Systematic Review With Descriptive Synthesis

Abstract

Human metapneumovirus (HMPV) is a respiratory virus that predominantly affects the pediatric population. Its role as an infective agent in ear, nose, and throat (ENT) diseases is not yet well understood. To systematically review the available literature on the association between HMPV and ENT manifestations, following PRISMA guidelines, a detailed search was conducted on PubMed/Medline from January 1, 2000 to May 25, 2025. Studies reporting ENT conditions associated with laboratory confirmed HMPV infection were included. Data were synthesized descriptively due to heterogeneity in study designs, populations, diagnostic methods, and reported outcomes, which precluded formal meta‐analysis. Twelve studies were included in the final analysis out of 1345 initially identified records. All percentages represent study‐level proportions unless otherwise specified. Quality assessment was performed using the Joanna Briggs Institute checklist and Newcastle‐Ottawa Scale. Twelve studies including a total of 2302 patients were identified, the majority of whom were pediatric (88.3%). The USA contributed half of the studies. Acute otitis media was reported in 50.0% of included studies, followed by upper respiratory tract infections in 25.0%. The most frequently used test to confirm infection was RT‐PCR (41.67% of studies). Antibiotic use was reported in all included studies (100.0% of studies), regardless of confirmed bacterial infection. Outcomes were inconsistently reported with 33.3% of studies lacking follow‐up data. This systematic review highlights a possible association between HMPV and ENT manifestations; however, due to limited and heterogeneous evidence, no causal relationship can be established, and further well‐designed studies are required.

Graphical abstract

Keywords

acute otitis media / ENT infections / human metapneumovirus / pediatric otolaryngology / sinusitis

1 Introduction

Human metapneumovirus (HMPV), first discovered in 2001, is a respiratory virus classified under the Paramyxoviridae family, subfamily Pneumovirinae [1]. HMPV is primarily associated with upper and lower respiratory tract infections in young children, elderly subjects, and immunocompromised patients [1, 2]. Emerging evidence suggests a potential association between HMPV and various otorhinolaryngological (ENT) conditions, including rhinosinusitis, tonsillitis, pharyngitis, laryngitis/laryngotracheitis, and otitis [3, 4]. However, its causal role remains unclear. HMPV has been increasingly recognized in both acute and chronic conditions. It has been detected in patients with adenotonsillar hypertrophy and chronic tonsillar disease. This may contribute to increased rates of adenotonsillectomy and healthcare burden [5, 6]. In a prospective cohort study conducted from September to May between 2004 and 2008, among 648 infants with acute upper respiratory illness or bronchiolitis, HMPV was identified in 3% of bronchiolitis cases, indicating a relatively low yet noteworthy role in the disease's etiology [7]. HMPV has been detected in patients with chronic rhinosinusitis (CRS), with respiratory viruses detected in 54% of CRS patients, suggesting a possible association. HMPV was the most frequently identified virus, found in 25% of patients, alongside human rhinovirus (HRV), highlighting a significant viral presence in chronic upper airway inflammation [8]. However, viral detection alone does not establish etiology. Most acute otitis media (AOM) cases arise as complications of viral upper respiratory tract infections (URTIs) with HMPV, which enhance bacterial growth and inflammation in the nasopharynx and Eustachian tube, facilitating bacterial entry into the middle ear [9, 10]. Seasonal respiratory syncytial virus (RSV), HMPV, and influenza activity were temporally associated with increased diagnoses of AOM among children. These data show that HMPV is associated with a proportion of AOM and thus has additional morbidity and healthcare impact related to these illnesses [3, 11]. This systematic review aims to utilize available evidence on the ENT manifestations associated with HMPV infection, focusing on clinical presentations such as AOM, rhinosinusitis, and other upper airway complications. By combining current knowledge, this review seeks to establish the association between the ENT manifestations of HMPV and highlight areas requiring further research.

2 Methodology

This detailed systematic review with descriptive analysis was conducted to evaluate updated evidence on the detection and clinical relevance of HMPV in ENT patients. The review implemented the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines to ensure transparency in methodology.

A detailed and systematic search of databases, including PubMed/Medline, was conducted between January 1, 2000 and May 25, 2025, using predefined keywords and according to Boolean operators (AND/OR). The search strategy was developed using a combination of Medical Subject Headings (MeSH) terms and keywords related to HMPV and ENT diseases. The core search terms included: (“Human metapneumovirus” OR “HMPV”) AND (“ENT diseases” OR “otitis media” OR “rhinosinusitis” OR “tonsillitis” OR “pharyngitis”). Search terms were refined to include only HMPV‐related keywords, excluding avian pneumovirus terms to avoid irrelevant results. The complete reproducible search strategy used for PubMed/Medline is provided in Supporting Information S1: Appendix 1.

Predefined inclusion and exclusion criteria were applied to identify eligible studies. All case reports, case series, and original articles containing complete and confirmed cases of ENT infections that were diagnosed with HMPV were included. Studies with only English‐language and accessible full text with complete information were included, which may add to the selection bias. Whereas editorial, pictorial essays, letters to editors, and short communications were excluded. All animals, cadaveric or non‐human studies were also excluded.

Three reviewers (Abdul Rehman Shahid Khan, Muhammad Ahmad Farooq, and Habban Ghani) independently screened articles based on titles and abstracts first, followed by full‐text screening of the articles. The discrepancies were resolved by a fourth reviewer, Ali Gohar. A total of 1345 articles were identified through database searching. After removal of 25 duplicates, 1320 records remained for title and abstract screening. Of these, 1297 were excluded based on irrelevance to the study objectives.

A total of 23 full‐text articles were assessed for eligibility. Among these, 11 articles were excluded due to insufficient clinical data, non‐ENT focus, or irrelevant outcomes.

Finally, 12 studies were included in the systematic review. The detailed study selection process is illustrated in the PRISMA flow diagram (Figure 1).

Data were extracted using a standardized Excel sheet form that included key study characteristics such as sample size, age group, diagnosis, diagnostic method, treatment, outcomes, year of publication, and participant demographics. All extracted data was imported into the Statistical Package for Social Sciences software (SPSS) for statistical analysis. Quality assessment was conducted using study design‐specific tools. The Joanna Briggs Institute (JBI) checklist was applied to case reports and case series, while the Newcastle‐Ottawa Scale (NOS) was used for observational studies. This approach ensured that each study type was evaluated using an appropriate and validated assessment tool.

Data were analyzed descriptively. Confidence intervals were not calculated due to study‐level aggregation and it would not provide meaningful inference due to heterogeneity and small number of studies.

A quantitative meta‐analysis was not performed due to substantial heterogeneity in study characteristics, including variations in study design, diagnostic methods, outcome definitions, and reporting. All percentages represent study‐level proportions (n = 12) unless otherwise stated.

Tables were generated to illustrate the key findings of the review.

3 Results

All percentages reported in this review represent study‐level proportions (n = 12) and should not be interpreted as patient‐level prevalence. The total number of studies included was 12. Most studies (25.00%) were published in 2015, which was followed by 2005, 2013, and 2014 (each having 16.67%) as shown in Table 1. The majority (50.00%) originated from the USA, with contributions from Australia (16.67%), Brazil (16.67%), Japan (8.33%), and Ireland (8.33%) as shown in Table 2. A total of 2302 individuals participated in the study. Out of these 1174 (60.0%) were male, 862 (37.4%) were female, and 266 (11.6%) did not specify their gender. The majority of the population 88.3% (2033) were children whereas 11.7% (269) were adults. RT‐PCR was the most commonly used diagnostic modality (41.67%), followed by other PCR‐based techniques. Some studies used multiple diagnostic modalities; therefore, percentages may exceed 100% (Table 3). The most common specimen site was the nasopharyngeal secretions (41.7%), followed by Bronchoalveolar lavage specimen (16.7%). In 33.3% of studies, the site was not specified, and one study used adenoids and tonsils (8.3%) as shown in Table 4. ENT manifestations that were reported included AOM reported in 50.0% of included studies (6/12), upper respiratory tract infections in 25.0% of studies (3/12), recurrent rhinosinusitis with unilateral choanal atresia, CRS, and chronic tonsillitis with adenotonsillar hypertrophy (8.3% each) as shown in Table 5. In 50.0% of included studies, treatment was symptomatic, surgical in 33.3% (4/12 studies); while in 16.7%, it was not specified as shown in Table 6. Antibiotic use was reported in all included studies (12/12), irrespective of confirmed bacterial co‐infection, while methylprednisolone was used in one case (8.3%) as shown in Table 7. Post‐treatment recovery was reported in 50.0% of included studies (6/12), static condition in 16.7%, while 33.3% (4/12 studies) did not mention outcomes as depicted in Table 8. Overall, the findings demonstrate that AOM was the most frequently reported ENT manifestation, diagnostic approaches were heterogeneous, and treatment strategies lacked standardization, with frequent use of antibiotics despite viral etiology.

Summary of characteristics of included studies is shown in Table 9. The quality assessment results are summarized in Table 10. Overall, most studies demonstrated moderate methodological quality. Common limitations included small sample sizes, lack of control groups, incomplete outcome reporting, and limited follow‐up duration.

4 Discussion

This systematic review synthesized data from 12 studies involving 2302 individuals. The majority of the study population consisted of children (88.3%), aligning with existing knowledge that HMPV is most prevalent in the pediatric population [12]. Half of the studies (50.00%) were conducted in the USA, followed by Australia (16.67%), Brazil (16.67%), Japan (8.33%), and Ireland (8.33%). The regional distribution suggested a bias in available data and indicated that the true global burden of HMPV‐associated ENT conditions may be underestimated. Most studies (25.00%) were published in 2015, which was followed by 2005, 2013, and 2014 (each having 16.67%). This suggests that there is a lack of recent research on HMPV. This gap may reflect underreporting or reduced research focus on HMPV‐related ENT manifestations rather than true absence of disease burden.

4.1 Comparison to Other Studies

The diagnostic methodology used was diverse. There was a lack of standardization for diagnosing HMPV infection across studies. RT‐PCR was the most frequently utilized technique (41.67%). This was consistent with its status as the gold standard for HMPV detection due to high sensitivity and specificity [11, 13]. Other modalities, such as conventional PCR (16.67%), multiplex RT‐PCR, qPCR variants, and immunofluorescence (DFA), were also used.

Specimen collection sites were inconsistently reported. While nasopharyngeal secretions were the most sampled (41.7%), 33.3% of the studies did not specify the site of sampling. One study used adenoids and tonsils (8.3%) for sample collection [6].

AOM was the most frequently reported ENT condition, found in 50.0% of the studies. This was consistent with prior findings that linked HMPV to AOM following URIs [7, 11, 13]. Detection of HMPV RNA in tissue samples does not establish causality and may represent transient infection, colonization, or co‐infection with other pathogens.

Although they were less common, chronic ENT disorders such as adenotonsillar hypertrophy and rhinosinusitis were clinically significant. HMPV RNA was discovered in tonsillar and sinonasal tissues by Lima et al. (2015) and Proença‐Modena et al. (2014) [6, 8]. This may suggest a potential association of HMPV with chronic inflammatory processes, although causality cannot be established. Choanal atresia was linked to recurrent rhinosinusitis in one study [14]. This highlights the range of clinical manifestations linked to HMPV infection. Additionally, it demonstrated the necessity of taking HMPV into account when dealing with recurrent ENT symptoms, particularly in children with underlying structural abnormalities. The inclusion of both case reports and observational studies introduces methodological heterogeneity, which limits direct comparability across studies. Although appropriate quality assessment tools were applied for each study design, the overall strength of evidence remains limited due to the predominance of small, descriptive studies.

4.2 Clinical Applicability and Generalizability

These findings should be interpreted cautiously, as study‐level proportions do not reflect true patient‐level prevalence and may overestimate or underestimate the actual clinical burden.

In all studies (100.0%), antibiotics were used irrespective of whether or not bacterial superinfection had been confirmed. This likely reflects prescribing practices rather than confirmed bacterial necessity and should not be interpreted as evidence of clinical indication. The injudicious use of antibiotics for a viral infection like HMPV is a cause of concern [15]. Monotherapy with corticosteroid was only noted in a single study [14]. Surgical treatment was noted by other studies (33.3%), and treatment status was not specified by 16.7% of studies. This suggests a critical deficiency of standardized treatment regimens for HMPV‐induced ENT infections.

Half of the reviewed studies (50.0%) described patient recovery. A third of them did not provide outcomes whatsoever. This failure to document follow‐up and recovery prevents conclusions about HMPV infection's long‐term effect. This incomplete reporting introduces potential reporting bias and limits the reliability of conclusions regarding treatment outcomes and prognosis. In studies where outcomes were tracked, improvement was observed with supportive care. This aligned with the self‐limiting nature of viral infections. Nanda et al., emphasized the potential role of HMPV in recurrent otitis media, warranting further investigation into prognosis and sequelae [14].

4.3 Limitations

This review has limitations. The search was restricted to PubMed/Medline and English‐language, open‐access studies, which may have introduced selection bias and limited the comprehensiveness of the review. Additionally, the exclusion of other databases such as Embase, Scopus and Cochrane may have resulted in omission of relevant studies. The number of included studies was small and predominantly observational, limiting the strength of evidence and generalizability. Significant heterogeneity in study design, populations, diagnostic approaches, and outcome reporting precluded quantitative meta‐analysis and limited the ability to generate pooled estimates. Additionally, the lack of recent studies reduces current applicability. Finally, detection of HMPV does not establish definitive causality, and findings should be interpreted with caution.

5 Conclusion

This review suggests a possible association between HMPV and ENT manifestations, particularly in the pediatric population. However, due to heterogeneity and limited quality of evidence, no causal relationship can be established. Further well‐designed, prospective studies are required to clarify the clinical role of HMPV in ENT diseases.

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