Human Metapneumovirus and Respiratory Syncytial Virus in Children: A Comparative Analysis

Leah A Goldstein; Marian G Michaels; Abigail Salthouse; Ariana P Toepfer; Samar Musa; Robert W Hickey; Monika Johnson; Anna F Wang-Erickson; Geoffrey A Weinberg; Peter G Szilagyi; Elizabeth P Schlaudecker; Mary A Staat; Leila C Sahni; Julie A Boom; Eileen J Klein; Janet A Englund; Jennifer E Schuster; Rangaraj Selvarangan; Christopher J Harrison; Natasha B Halasa; Laura S Stewart; Fatimah S Dawood; Heidi L Moline; John V Williams

doi:10.1542/peds.2024-070218

. Author manuscript; available in PMC: 2026 Jan 23.

Published in final edited form as: Pediatrics. 2025 Sep 1;156(3):e2024070218. doi: 10.1542/peds.2024-070218

Human Metapneumovirus and Respiratory Syncytial Virus in Children: A Comparative Analysis

Leah A Goldstein ¹, Marian G Michaels ^2,³, Abigail Salthouse ¹, Ariana P Toepfer ¹, Samar Musa ^2,³, Robert W Hickey ^2,³, Monika Johnson ^2,³, Anna F Wang-Erickson ^2,^3,⁴, Geoffrey A Weinberg ⁵, Peter G Szilagyi ^5,⁶, Elizabeth P Schlaudecker ^7,⁸, Mary A Staat ^7,⁸, Leila C Sahni ^9,¹⁰, Julie A Boom ^9,¹⁰, Eileen J Klein ¹¹, Janet A Englund ¹¹, Jennifer E Schuster ¹², Rangaraj Selvarangan ¹³, Christopher J Harrison ¹², Natasha B Halasa ¹⁴, Laura S Stewart ¹⁴, Fatimah S Dawood ¹, Heidi L Moline ^1,^a, John V Williams ^2,^3,^a

¹US Centers for Disease Control and Prevention, Atlanta, Georgia;

²UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania;

³Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;

⁴Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania;

⁵Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York;

⁶Department of Pediatrics, University of California Los Angeles, Los Angeles, California;

⁷Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio;

⁸Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio;

⁹Texas Children’s Hospital, Houston, Texas;

¹⁰Department of Pediatrics, Baylor College of Medicine, Houston, Texas;

¹¹Seattle Children’s Research Institute, Department of Pediatrics, University of Washington, Seattle, Washington;

¹²Department of Pediatrics, Children’s Mercy Hospital, Kansas City, Missouri;

¹³Department of Pathology and Laboratory Medicine, Children’s Mercy Hospital, Kansas City, Missouri;

¹⁴Vanderbilt University Medical Center, Nashville, Tennessee

Co–senior authors

Ms Goldstein drafted the initial manuscript and led data analysis and interpretation of the data; Dr Michaels provided substantial contributions to conception and design of the study and design of data collection instruments, supervised data collection locally, and provided substantial contributions to interpretation of the data; Ms Salthouse supervised data collection nationally and conducted data replication; Ms Toepfer supervised data collection nationally; Ms Musa and Ms Johnson and Drs Schlaudecker, Wang-Erickson, and Hickey provided substantial contributions to design of data collection instruments and supervised data collection locally; Drs Harrison, Halasa, Schuster, Staat, Klein, Weinberg, Boom, Stewart, Selvarangan, Michaels, and Englund provided substantial contributions to conception and design of the study and design of data collection instruments, supervised data collection locally, and provided substantial contributions to interpretation of the data; Dr Dawood provided substantial contributions to interpretation of the data; Dr Moline provided substantial contributions to the design of the study and data collection instruments, supervised data collection nationally, and provided substantial contributions to interpretation of the data; Dr Williams supervised data collection locally and provided substantial contributions to interpretation of the data; and all authors critically reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

^✉

Address correspondence to: Leah Goldstein, MPH, Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30329. jws6@cdc.gov

PMCID: PMC12824835 NIHMSID: NIHMS2131839 PMID: 40763933

Abstract

BACKGROUND:

Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are genetically related viruses and major causes of medically attended acute respiratory illness in children. Research comparing the severity of illnesses resulting from these infections lacks consensus.

METHODS:

Children younger than 18 years with acute respiratory illness were enrolled through active, prospective surveillance from 2016 to 2020 at 7 US pediatric hospitals and emergency departments (EDs). Clinical information was obtained from parent interviews and medical records. Midturbinate nasal swabs were collected and tested for RSV and HMPV using molecular diagnostic assays at each site. We compared descriptive and clinical features of children with RSV or HMPV and calculated adjusted odds ratios (aOR) for severe outcomes comparing RSV with HMPV. Risk factors for severe outcomes were assessed in children with RSV or HMPV using logistic regression models.

RESULTS:

A total of 5329 children hospitalized with RSV (n = 4398) or HMPV (n = 931) and 3276 children with RSV-associated (n = 2371) or HMPV-associated (n = 905) ED visits were enrolled. The median age of children hospitalized with RSV was lower than that of children with HMPV (7 months vs 16 months, P < .0001). Children presenting to the ED with RSV-associated acute respiratory illness had higher odds of being hospitalized than children with HMPV (aOR, 1.68; 95% CI, 1.50–1.87), with the highest odds in infants younger than 6 months (aOR, 3.27; 95% CI, 2.53–4.23). Underlying conditions were more than twice as common among infants hospitalized with HMPV (26%) than those with RSV (11%).

CONCLUSIONS:

Children with HMPV-associated hospitalization tend to be older and more likely to have underlying medical conditions compared with children with RSV-associated hospitalization.

INTRODUCTION

Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are genetically related viruses, both members of the Pneumoviridae family¹ and major causes of acute respiratory illness (ARI) in children.^2–5 Both viruses typically cause upper respiratory symptoms, with some children experiencing lower respiratory tract illness.⁶ RSV is the leading cause of infant hospitalizations in the United States and a major cause of outpatient visits in young children.^4,7 HMPV is also a leading contributor to the burden of medically attended ARI.³ Before the COVID-19 pandemic, in the United States and other temperate settings, RSV and HMPV typically cocirculated annually with RSV peaking between November and January^8–10 and HMPV peaking in March or April.^2,9,11,12

Previous studies have found that RSV disproportionately causes severe disease in young infants whereas HMPV typically affects older babies and children.^13–15 Research comparing the severity of illnesses from RSV and HMPV infection in children lacks consensus, with some studies finding comparable symptoms and severity,^14,16,17 some observing greater severity for RSV,^2,9,15,18 and still others suggesting greater severity for HMPV.^19–21 Many of the existing comparative studies were retrospective or based on convenience samples, relying on clinician-directed testing, which is irregularly conducted and uncommon for HMPV.

In 2023, 2 novel products for the prevention of RSV-associated respiratory illness were approved by the Food and Drug Administration and recommended by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices: nirsevimab, a long-acting monoclonal antibody for infants and young children,²² and a vaccine for pregnant women.²³ Palivizumab, a monoclonal antibody for the prevention of RSV, has been available since the late 1990s but is indicated only for children at high risk for severe RSV disease, and few children are eligible.^24,25 Although there are currently no preventive therapies for HMPV, vaccines are in development for both adults and children.^26–29

HMPV and RSV are genomically related, cause similar syndromes, and have both been targeted for interventions. The introduction of new RSV prevention products has the potential to affect severity and seasonality of RSV and may indirectly change the epidemiology of HMPV. Data about the seasonality and epidemiology of both viruses are needed to establish a baseline for future analyses of the impact of RSV prevention products and guide future HMPV vaccine implementation. Using prospective, population-based surveillance data for medically attended ARI among children, we compared the seasonality, clinical presentations, and risk factors for severe respiratory disease associated with HMPV and RSV.

METHODS

New Vaccine Surveillance Network Study Design and Population

From December 2016 to March 2020, children were prospectively enrolled from 7 US pediatric medical centers as previously described.⁵ Children were eligible for enrollment if they had an illness duration of less than 14 days, were enrolled within 48 hours of admission (inpatient [IP] only), and had at least 1 qualifying ARI sign or symptom, apparent life-threatening event, or brief resolved unexplained event. Children were excluded if they had a known nonrespiratory cause for hospitalization or visit, had fever and neutropenia following chemotherapy, were admitted less than 5 days after a previous hospitalization, were transferred from another hospital after an admission of more than 48 hours, were a newborn who had never been discharged from the hospital, or had previously been enrolled in the surveillance program less than 14 days before their current visit or hospitalization.⁵ Demographic and clinical data were systematically collected through parent/guardian interviews and medical record abstraction. Race and ethnicity were reported by the child’s parent/guardian and categories were selected based on Office of Management and Budget Standards for Maintaining, Collecting, and Presenting Federal Data on Race and Ethnicity.³⁰ Infectious disease differences in race and ethnicity can be multifactorial; we aimed to establish whether racial differences for severe outcomes exist for children with RSV or HMPV, which may prompt future exploration of the causes.

Children were included in this analysis if they were younger than 18 years, had the highest level of care in the emergency department (ED) or IP setting, and tested positive for RSV or HMPV with a surveillance or clinical molecular test.⁵ Children could be enrolled in IP units 5 or more days per week and in the ED 4 or more days per week for 6 or more hours per day.⁵ Inpatient enrollment occurred year-round. Age eligibility and surveillance period for ED enrollment varied by site prior to 2020.⁵ Children with RSV and HMPV codetection were excluded from the analysis, but children with other viral codetections were included.

Laboratory Methods

Midturbinate nasal specimens or throat swabs were collected for all enrolled children and systematically tested for 8 respiratory viruses, including RSV and HMPV, by real-time reverse transcription–polymerase chain reaction.¹⁰ For patients from whom specimens could not be obtained, clinically obtained respiratory specimens were salvaged for surveillance testing.⁵ Additional molecular clinical test results were ascertained from medical records.

Statistical Analysis

Categorical variables were compared using the Pearson χ² test or Fisher exact tests when expected values were less than 5. Wilcoxon rank-sum was used for continuous variables. Observed differences of P < .05 were considered significant. Age-stratified comparisons of underlying conditions and severity outcomes were performed to account for differences in age distribution between children with medically attended RSV and HMPV. The setting of care (ED or IP) was determined by the highest level of care, identified by medical record review. All analyses were performed using SAS software (version 9.4; SAS Institute).

Seasonality was assessed using surveillance seasons defined as follows: December 1, 2016, to September 30, 2017; October 1, 2017, to September 30, 2018; October 1, 2018, to September 30, 2019; and October 1, 2019, to March 31, 2020. This period represents recent typical, pre– COVID-19 viral circulation, as irregular circulation of respiratory viruses occurred during the COVID-19 pandemic.^5,8 We calculated a 3-week moving average of percent positivity for RSV and HMPV by site and overall during the pre-pandemic study period. We identified seasonal peaks and calculated the difference in peak circulation weeks between RSV and HMPV.

Disease severity was analyzed using 3 dichotomous outcomes: hospital admission, intensive care unit (ICU) admission, and length of hospital admission 3 or more days. The latter 2 outcomes applied only to hospitalized children. These outcomes were selected as objective measures correlated with disease severity that are commonly used in other studies.^15,31,32 We calculated adjusted odds ratios (aORs) for each outcome comparing RSV with HMPV using multivariable logistic regressions models controlling for age in months and study site. We also calculated aORs for each outcome with age-stratified models, controlling for study site alone.

The risk factors for each outcome were assessed in children with RSV or HMPV using separate multivariable logistic regression models. Models controlled for study site and age in months, determined a priori. Models assessing age group also controlled for the presence of any underlying condition. Collinearity assessments were performed and found no condition indices greater than 30 in the models.

Ethical Review and Data Reporting

This study was reviewed and approved by the institutional review boards at the CDC and each of the 7 sites (See 45 CFR part 46.114; 21 CFR part 56.114). Informed consent and assent, when applicable, were obtained from a parent or legal guardian of each eligible child prior to any study procedures. This analysis adheres to the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.

RESULTS

Overall, 8605 children with RSV or HMPV infection were enrolled, including 5329 hospitalized with RSV (n = 4398) or HMPV (n = 931) and 3276 ED patients with RSV (n = 2371) or HMPV (n = 905).

Characteristics and Clinical Course

In both IP and ED, the median age of children with RSV was lower than that of children with HMPV (IP: 7 months vs 16 months, ED: 15 months vs 22 months) (Table 1). Among hospitalized children, 29.2% of children with RSV were aged 0 to 2 months compared with 5.9% of children with HMPV (Table 1; Figure 1). Most children younger than 2 years hospitalized with RSV or HMPV were previously healthy, whereas most children aged 2 years and older hospitalized with RSV or HMPV had preexisting conditions (Table 2). However, compared with hospitalized children younger than 12 months with HMPV, a smaller proportion of hospitalized children of the same age with RSV had any underlying condition (<6 months: 7.8% vs 19.9%, P < .0001; 6–11 months: 18.2% vs 31.7%, P < .0001) (Table 2).

TABLE 1.

Comparison of Characteristics and Clinical Course of Children Younger Than 18 Years With RSV or HMPV, New Vaccine Surveillance Network, December 2016 to March 2020

	Inpatient			ED
	RSV	HMPV		RSV	HMPV
	n (%)	n (%)	P Value^a	n (%)	n (%)	P Value^a
Total enrolled	4398	931		2371	905
Age group
0–2 mo	1285 (29.2)	55 (5.9)	<.0001	201 (8.5)	33 (3.7)	<.0001
3–5 mo	737 (16.8)	106 (11.4)		288 (12.2)	96 (10.6)
6–11 mo	764 (17.4)	199 (21.4)		464 (19.6)	152 (16.8)
12–23 mo	781 (17.8)	208 (22.3)		619 (26.1)	192 (21.2)
2–4 y	625 (14.2)	217 (23.3)		678 (28.6)	323 (35.7)
5–11 y	173 (3.9)	113 (12.1)		102 (4.3)	88 (9.7)
12–17 y	33 (0.8)	33 (3.5)		19 (0.8)	21 (2.3)
Age, median (IQR), mo	7 (2–18)	16 (7–39)	<.0001	15 (7–30)	22 (9–44)	<.0001
Sex, male	2464 (56.0)	507 (53.9)	.237	1302 (54.9)	517 (57.1)	.254
Race and ethnicity
Non-Hispanic white	2117 (48.1)	378 (40.6)	.0005	636 (26.8)	194 (21.4)	.0006
Non-Hispanic Black	784 (17.8)	188 (20.2)		888 (37.5)	359 (39.7)
Hispanic	1025 (23.3)	263 (28.3)		610 (25.7)	285 (31.5)
Non-Hispanic Native Hawaiian/Other Pacific Islander	31 (0.7)	7 (0.8)		28 (1.2)	8 (0.9)
Non-Hispanic American Indian/Alaska Native	40 (0.9)	6 (0.6)		7 (0.3)	4 (0.4)
Non-Hispanic Asian	154 (3.5)	46 (4.9)		82 (3.5)	15 (1.7)
Non-Hispanic multiple race or other	222 (5.1)	38 (4.1)		102 (4.3)	32 (3.5)
Unknown	25 (0.6)	5 (0.5)		18 (0.8)	8 (0.9)
Study site
Nashville, TN	550 (12.5)	122 (13.1)	<.0001	475 (20.0)	210 (23.2)	.0009
Rochester, NY	492 (11.2)	80 (8.6)		229 (9.7)	101 (11.2)
Cincinnati, OH	467 (10.6)	84 (9.0)		270 (11.4)	86 (9.5)
Seattle, WA	408 (9.3)	86 (9.2)		337 (14.2)	113 (12.5)
Houston, TX	907 (20.6)	260 (27.9)		203 (8.6)	99 (10.9)
Kansas City, MO	399 (9.1)	77 (8.3)		372 (15.7)	158 (17.5)
Pittsburgh, PA	1175 (26.7)	222 (23.9)		485 (20.5)	138 (15.3)
Underlying medical conditions
≥1 underlying condition	1033 (23.5)	422 (45.3)	<.0001	364 (15.4)	188 (20.8)	.0002
Cardiovascular condition^b	211 (4.8)	102 (11.0)	<.0001	36 (1.5)	18 (2.0)	.344
Respiratory condition excluding asthma^c	234 (5.3)	134 (14.4)	<.0001	37 (1.6)	21 (2.3)	.14
Asthma (among children aged ≥2 y)	283/831 (34.1)	128/363 (35.3)	.687	166/799 (20.8)	94/432 (21.8)	.687
Neurological condition^d	208 (4.7)	132 (14.2)	<.0001	41 (1.7)	29 (3.2)	.009
Gastrointestinal/hepatic condition^e	205 (4.7)	99 (10.6)	<.0001	49 (2.1)	17 (1.9)	.732
Genetic/metabolic condition^f	254 (5.8)	130 (14.0)	<.0001	48 (2.0)	26 (2.9)	.144
Other condition^g	200 (4.6)	89 (9.6)	<.0001	62 (2.6)	32 (3.5)	.158
History of prematurity (among children aged <2 y)^h	733/3567 (20.6)	164/568 (28.9)	<.0001	238/1572 (15.1)	83/473 (17.6)	.206
Palivizumab receipt (any doses) (among children aged <2 y)
Yes	145/3567 (4.1)	41/568 (7.2)	.003	84/1572 (5.3)	26/473 (5.5)	.668
No	3033 (85.0)	467 (82.2)		1299 (82.6)	383 (81.0)
Unknown/missing	389 (10.9)	60 (10.6)		189 (12.0)	64 (13.5)
Maternal education level (high school or less)	2306 (52.4)	524 (56.3)	.304	1442 (60.8)	602 (66.7)	.002
Smoking in homeⁱ	1179 (26.8)	247 (26.5)	.862	653 (27.5)	271 (29.9)	.172
Never breastfed (among children aged <3 y)	860/3907 (19.6)	144/677 (15.5)	.667	494/1877 (26.3)	162/594 (27.3)	.646
Clinical course
Oxygen saturation <90%	1320 (30.0)	299 (32.1)	.205	102 (4.3)	31 (4)	.256
Supplemental oxygen	2728 (62.1)	564 (60.7)	.421	63 (2.7)	20 (2.2)	.478
Mechanical ventilation	172 (3.9)	55 (5.9)	.006	NA	NA
Intensive care	913 (20.8)	184 (19.8)	.506	NA	NA
Length of stay, median (IQR), d	2 (1–4)	2 (1–4)	.524	NA	NA
Length of stay ≥3 d	1717 (39.0)	371 (39.9)	.646	NA	NA
Presenting symptoms
Fever	3174 (72.7)	771 (83.6)	<.0001	1824 (77.5)	728 (81.0)	.03
Cough	4347 (99.0)	904 (97.2)	<.0001	2327(98.2)	890 (98.5)	.658
Retractions	3364 (76.9)	641 (69.5)	<.0001	646 (27.5)	156 (17.5)	<.0001
Dyspnea	4011 (91.8)	805 (87.3)	<.0001	1640 (69.8)	533 (59.5)	<.0001
Wheezing	3717 (84.5)	753 (80.9)	.006	1685 (71.1)	557 (61.6)	<.0001
Decreased appetite	3418 (78.6)	705 (77.4)	.408	1656 (70.3)	596 (66.0)	.017
Vomiting	1058 (24.3)	233 (25.3)	.531	461 (19.5)	206 (22.8)	.036
Discharge diagnosis^j
Pneumonia	777 (17.7)	331 (35.6)	<.0001	118 (5.0)	54 (6.0)	.256
Bronchiolitis	3371 (76.7)	422 (45.4)	<.0001	723 (30.5)	133 (14.7)	<.0001
Asthma	548 (12.5)	178 (19.1)	<.0001	194 (8.2)	85 (9.4)	.267
Acute upper respiratory tract infection	331 (7.5)	90 (9.7)	.028	568 (24.0)	262 (29.0)	.003
Fever	256 (5.8)	68 (7.3)	.085	437 (18.4)	189 (20.9)	.11
Seizure	88 (2.0)	50 (5.4)	<.0001	13 (0.6)	11 (1.2)	.045
Bacteremia/septicemia	74 (1.7)	40 (4.3)	<.0001	0 (0.0)	1 (0.1)	.276^k
Pharyngitis	15 (0.3)	9 (1.0)	.01	31 (1.3)	33 (3.7)	<.0001
Respiratory failure	917 (20.9)	222 (23.9)	.042	3 (0.1)	0 (0.0)	.566

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Abbreviations: ED, emergency department; HMPV, human metapneumovirus; NA, not applicable; RSV, respiratory syncytial virus.

P values derived from Pearson chi-square or Fisher exact tests when expected values were less than 5 for categorical variables or Wilcoxon rank-sum for continuous variables.

Cardiovascular disease, heart defect, other heart disease.

Chronic lung condition, bronchopulmonary dysplasia, cystic fibrosis, airway disorders, sleep apnea, or other lung disease

Neurological/neuromuscular conditions, cerebral palsy, seizure disorder, other neurological disorders, and Guillain-Barré syndrome.

Liver diseases, chronic gastrointestinal disease, and gastroesophageal reflux disease.

Developmental disorders, genetic/metabolic conditions, Down syndrome, other genetic conditions, and other developmental disabilities.

Kidney conditions, blood disorders, liver conditions, diabetes mellitus, endocrine conditions, airway disorders, oncologic/immunosuppressive conditions, obesity, or any other condition requiring chronic treatment.

Prematurity defined as birth at less than 37 weeks’ gestation.

ⁱ

Child lives with someone who smokes tobacco products or electronic cigarettes.

Discharge diagnosis includes primary and up to 9 secondary diagnoses (International Statistical Classification of Diseases [Tenth Revision] codes): pneumonia (J12-J18), bronchiolitis (J21), asthma (J45), acute upper respiratory tract infection (J06), fever (R50), seizure (G40, R56), bacteremia/septicemia (R78.81, R65.2, P36, A40, A41), pharyngitis (J02), respiratory failure (J96).

Fisher exact test.

FIGURE 1. — Age distribution of children younger than 18 years with RSV- or HMPV-associated emergency department visits and hospitalizations, New Vaccine Surveillance Network, December 2016 to March 2020. HMPV, human metapneumovirus; RSV, respiratory syncytial virus.

TABLE 2.

Underlying Conditions, Prematurity, and Clinical Course Among Hospitalized Children Younger Than 18 Years With HMPV or RSV, by Age Group, New Vaccine Surveillance Network, December 2016 to March 2020

	<6 Months			6–11 Months			12–23 Months			2–4 Years			≥5 Years
	RSV	HMPV		RSV	HMPV		RSV	HMPV		RSV	HMPV		RSV	HMPV
	n (%)	n (%)	P Value^a	n (%)	n (%)	P Value^a	n (%)	n (%)	P Value^a	n (%)	n (%)	P Value^a	n (%)	n (%)	P Value^a
Total enrolled	2022	161		764	199		781	208		625	217		206	146
≥1 underlying condition	158 (7.8)	32 (19.9)	<.0001	139 (18.2)	63 (31.7)	<.0001	234 (30.0)	68 (32.7)	.447	334 (53.4)	135 (62.2)	.025	167 (81.1)	124 (84.9)	.345
Cardiovascular condition^b	51 (2.5)	12 (7.5)	.002^c	34 (4.5)	18 (9.1)	.011	45 (5.8)	17 (8.2)	.202	56 (9.0)	35 (16.1)	.003	25 (12.1)	20 (13.7)	.665
Respiratory condition excluding asthma^d	18 (0.9)	6 (3.7)	.007^c	33 (4.3)	29 (14.6)	<.0001	51 (6.5)	20 (9.6)	.126	79 (12.6)	43 (19.8)	.01	53 (25.7)	26 (24.7)	.82
Asthma (among children aged ≥2 y)	NA	NA		NA	NA		NA	NA		172 (27.5)	67 (30.9)	.345	111 (53.9)	61 (41.8)	.025
Neurological condition^e	11 (0.5)	7 (4.4)	.0002^c	18 (2.4)	14 (7.0)	.001	59 (7.6)	18 (8.7)	.599	70 (11.2)	39 (18.10)	.011	50 (24.3)	54 (37.0)	.01
Gastro/hepatic condition^f	52 (2.6)	9 (5.6)	.041^c	33 (4.3)	15 (7.5)	.063	36 (4.6)	15 (7.2)	.132	47 (7.5)	30 (13.8)	.006	37 (18.0)	30 (20.6)	.543
Genetic/metabolic condition^g	17 (0.8)	8 (5.0)	.0003	29 (3.8)	18 (9.1)	.002	53 (6.8)	21 (10.1)	.107	101 (16.2)	34 (15.7)	.865	54 (26.2)	49 (33.6)	.136
Other condition^h	29 (1.4)	4 (2.5)	.293	33 (4.3)	13 (6.5)	.192	43 (5.5)	10 (4.8)	.691	62 (9.9)	33 (15.2)	.034	33 (16.0)	29 (19.9)	.351
History of prematurity (among children aged <2 y)ⁱ	356 (17.7)	42 (26.1)	.008	179 (23.7)	65 (33.2)	.007	198 (25.6)	57 (27.4)	.595	NA	NA		NA	NA
Oxygen saturation <90%	566 (28.0)	30 (18.6)	.010	215 (28.1)	58 (29.2)	.780	256 (32.8)	74 (35.6)	.447	219 (35.0)	83 (32.3)	.396	64 (31.1)	54 (37.0)	.247
Supplemental oxygen	1266 (62.6)	82 (51.3)	.004	462 (60.6)	124 (62.3)	.650	476 (61.0)	129 (62.0)	.794	397 (63.5)	142 (65.4)	.612	127 (61.7)	87 (59.6)	.696
Mechanical ventilation	108 (5.3)	16 (9.9)	.015	29 (3.8)	7 (3.5)	.854	18 (2.3)	10 (4.8)	.053	9 (1.4)	9 (4.2)	.018	8 (3.9)	13 (8.9)	.050
Intensive care	509 (25.2)	35 (21.9)	.348	127 (16.6)	38 (19.1)	.410	132 (16.9)	36 (17.3)	.890	99 (15.9)	43 (19.9)	.172	46 (22.3)	32 (21.9)	.927
Length of stay ≥3 d	864 (42.7)	64 (39.8)	.462	296 (38.7)	79 (39.7)	.806	282 (36.1)	69 (33.2)	.432	200 (32.0)	95 (43.8)	.002	75 (36.4)	64 (43.8)	.160

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Abbreviations: HMPV, human metapneumovirus; NA, not applicable; RSV, respiratory syncytial virus.

P values derived from Pearson chi-square or Fisher exact tests when expected values were less than 5.

Cardiovascular disease, heart defect, other heart disease.

Fisher exact.

Chronic lung condition, bronchopulmonary dysplasia, cystic fibrosis, airway disorders, sleep apnea, or other lung disease.

Neurological/neuromuscular conditions, cerebral palsy, seizure disorder, other neurological disorders, and Guillain-Barré syndrome.

Liver diseases, chronic gastrointestinal disease, and gastroesophageal reflux disease.

Developmental disorders, genetic/metabolic conditions, Down syndrome, other genetic conditions, and other developmental disabilities.

ⁱ

Prematurity defined as birth at less than 37 weeks’ gestation.

Among hospitalized children with RSV or HMPV, similar proportions required supplemental oxygen (62.1% vs 60.7%, P = .421) or ICU-level care (20.8% vs 19.8%, P = .506) and median length of hospitalization was the same (2 vs 2 days, P = .524). Children hospitalized with RSV were less likely to require mechanical ventilation than children hospitalized with HMPV (3.9% vs 5.9%, P = .006) (Table 1), a trend consistent across most age groups (Table 2). Some differences in discharge diagnoses were observed: patients hospitalized with HMPV were more likely to be discharged with diagnoses of pneumonia (35.6% vs 17.7%, P < .0001) and bacteremia/septicemia (4.3% vs 2.01.7%, P < .0001) (Table 1). Although the number of children who received palivizumab was small (<5% of children aged <2 years), a greater percentage of children hospitalized with RSV received it compared with those with HMPV (7.2% vs 4.1%, P = .003). No differences were seen in the ED (Table 1).

The clinical course for children infected with RSV or HMPV alone compared with children with a viral coinfection was generally similar, although children hospitalized with either virus with coinfections were less likely to have oxygen saturation less than 90% than those with single infections, and children with RSV coinfections were more likely to require mechanical ventilation than children with RSV alone (3.6% vs 5.1%, P < .025) (Supplemental Table 1).

Seasonality

Overall, RSV detections typically peaked in December, with peaks varying from November to January across sites and years. HMPV detections most often peaked in March and were less pronounced and more variable than for RSV, with site-specific peaks ranging from October to June across the 4 years (Figure 2). Peaks in RSV and HMPV occurred an average of 14 weeks apart (range 11–19 weeks) overall, but the interval between peaks varied considerably by site from an average of 3.3 weeks (Kansas City) to 20 weeks (Houston).

FIGURE 2. — Percentage of viral polymerase chain reaction tests positive^a for RSV and HMPV among children younger than 18 years with acute respiratory illness–associated emergency department visits and hospitalizations, overall and by site, New Vaccine Surveillance Network, December 2016 to March 2020.

^a3-week moving average.

HMPV, human metapneumovirus; RSV, respiratory syncytial virus.

Risk of Severe Disease

Children presenting to the ED with RSV-associated ARI had higher odds of being hospitalized (aOR, 1.68; 95% CI, 1.50–1.87) than children with HMPV, after adjusting for site and age. This difference was most pronounced among children younger than 6 months, where the odds of hospitalization with RSV were 3.3 times higher than the odds of hospitalization with HMPV (Table 3). Once hospitalized, however, children with RSV had similar odds of being admitted to the ICU (aOR, 1.10; 95% CI, 0.92–1.33) or having a length of stay of 3 or more days (aOR, 0.99; 95% CI, 0.85–1.15) compared with those with HMPV.

TABLE 3.

Adjusted Odds of Severe Outcomes Among Children Younger Than 18 Years With RSV Compared With Children With HMPV, by Age Group, New Vaccine Surveillance Network, December 2016 to March 2020

	Adjusted OR, RSV vs HMPV (95% CI)
	All Ages^a	<6 Months^b	6–11 Months^b	12–23 Months^b	2–4 Years^c	≥5 Years^b
Hospitalization vs ED visit	1.68^c (1.50–1.87)	3.27^c (2.53–4.23)	1.21 (0.94–1.55)	1.28^d (1.01–1.61)	1.51 (1.22–1.87)	1.12 (0.76–1.67)
ICU admission^e	1.10 (0.92–1.33)	1.31 (0.88–1.94)	0.84 (0.56–1.26)	1.03 (0.68–1.55)	0.85 (0.57–1.28)	1.21 (0.71–2.06)
Length of stay ≥3 d^e	0.99 (0.85–1.15)	1.16 (0.83–1.62)	0.98 (0.71–1.35)	1.22 (0.87–1.70)	0.64^d (0.46–0.89)	0.82 (0.52–1.29)

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Abbreviations: HMPV, human metapneumovirus; ICU, intensive care unit; OR, odds ratio; RSV, respiratory syncytial virus.

Adjusted for study site and age in months.

Adjusted for study site.

P < .0001.

P < .05.

Among those hospitalized.

Children younger than 6 months with RSV had significantly greater odds of hospitalization vs ED visit and severe in-hospital outcomes compared with all older age groups. In contrast, there was no difference in odds of hospitalization for children aged 6 to 11 or 12 to 23 months with HMPV compared with children younger than 6 months and no difference in odds of being admitted to the ICU for any age group. Children with HMPV aged 12 to 23 months and 5 years and older had significantly lower odds of length of a hospital stay of 3 or more days compared with children younger than 6 months, but those aged 6 to 11 months and 2 to 4 years did not (Figure 3).

FIGURE 3. — Risk factors for hospitalization, ICU admission, and length of stay of 3 or more days among children younger than 18 years with RSV or HMPV, New Vaccine Surveillance Network, December 2016 to March 2020.

^aUnique multivariable logistic regression models were used for each outcome OR. All models adjusted for study site and age in months. Age group analysis also adjusted for any underlying condition.

^bCompared with younger than 6 months.

^cCompared with non-Hispanic white.

^dCardiovascular disease, heart defect, other heart disease.

^eChronic lung condition, bronchopulmonary dysplasia, cystic fibrosis, airway disorders, sleep apnea, or other lung disease.

^fDevelopmental disorders, genetic/metabolic conditions, Down syndrome, other genetic conditions, and other developmental disabilities.

^gLiver diseases, chronic gastrointestinal disease, and gastroesophageal reflux disease.

^hDevelopmental disorders, genetic/metabolic conditions, Down syndrome, other genetic conditions, and other developmental disabilities.

ⁱPrematurity defined as birth at less than 37 weeks’ gestation.

^jHigh school or less.

^kChild lives with someone who smokes tobacco products or electronic cigarettes.

aOR, adjusted odds ratio; HMPV, human metapneumovirus; ICU, intensive care unit; OR, odds ratio; RSV, respiratory syncytial virus.

Compared with previously healthy children with RSV or HMPV, children with an underlying medical condition had higher odds of being hospitalized (RSV: aOR, 2.53; 95% CI, 2.18–2.97; HMPV: aOR, 3.43; 95% CI, 2.71–4.33) (Figure 3). Similarly, children younger than 2 years with a history of prematurity infected with either virus had higher odds of being hospitalized compared with children without a history of prematurity (RSV: aOR, 1.62; 95% CI, 1.37–1.92; HMPV: aOR, 1.92; 95% CI, 1.41–2.62). Children with RSV or HMPV with a history of prematurity or one of the following conditions: cardiovascular, lung excluding asthma, neurological, gastrointestinal/hepatic, or genetic/metabolic had higher odds of length of stay ≥3 days and ICU admission compared to those without (Figure 3).

After adjusting for site and age, non-Hispanic white race was associated with greater odds of hospitalization vs ED visit with RSV and HMPV but was not significantly associated with length of stay or ICU admission (Figure 3). For both RSV and HMPV, the odds of hospitalization for non-Hispanic Black children were approximately one-fourth those of non-Hispanic white children (RSV: aOR, 0.26; 95% CI, 0.20–0.34; HMPV: aOR, 0.26; 95% CI, 0.22–0.30). This association was persistent, even when adjusting for insurance status or presence of underlying medical conditions (data not shown).

DISCUSSION

In this multiyear, multisite study comparing more than 8000 children with RSV- or HMPV-associated ED visits and hospitalizations, the in-hospital severity and course of illness associated with these viruses were similar, with no difference in median length of stay or proportion requiring supplemental oxygen or ICU care. We did observe some differences, however: the overall odds of hospitalization vs ED visit were 1.7 times higher among children with RSV-associated illness, after adjusting for site and age. Although the number of children requiring mechanical ventilation was small, children hospitalized with HMPV had a greater likelihood of requiring mechanical ventilation across nearly all age groups. This difference may be partially attributed to the finding that pneumonia diagnoses were twice as frequent among children hospitalized with HMPV than among those with RSV. Although numerous studies have compared epidemiology and disease severity for children infected with these related viruses,^2,9,14–21 this is the first prospective, multicenter, longitudinal study to examine these questions.

Despite the many similarities, there are clear differences in the populations most affected by these viruses. Specifically, compared with children with RSV-associated hospitalization, those with HMPV-associated hospitalizations tend to be older and are more likely to have underlying medical conditions. We found that after the first 2 years of life, most children hospitalized with either RSV or HMPV have underlying medical conditions. However, in the first year of life, underlying conditions were more than twice as common among infants hospitalized with HMPV (26%) than among those with RSV (11%), suggesting that previously healthy infants infected with RSV are at greater risk of developing severe illness than those with HMPV.

This analysis supports existing literature suggesting that young infants are at highest risk for severe disease with RSV, whereas HMPV typically affects children later in childhood.^{3,4,9,13–15,33} In this study, nearly half of all RSV-associated hospitalizations occurred in children younger than 6 months, compared with approximately 1 in 6 HMPV-associated hospitalizations. Young age was a persistent risk factor for severe outcomes among children with RSV but was inconsistent for those with HMPV. Unlike children with RSV, infants younger than 6 months with HMPV had no difference in the odds of hospitalization compared with children aged 6 to 11 or 12 to 23 months. Age younger than 6 months was a significant risk factor for RSV-associated ICU admission, but not so for HMPV.

Because infants are not at the highest risk of severe HMPV-associated disease in the first months of life, prevention efforts aimed at this group such as maternal and newborn immunization may have less impact than for RSV. Rather, the presence of underlying conditions and prematurity appear to be more robust risk factors for severe HMPV-associated disease, and immunization strategies that prioritize these children may be most effective. We also found that HMPV generally has less well-defined seasonality and peak circulation than RSV,^3,8 suggesting that the timing and durability of immunization administration may need to differ from current RSV recommendations^22,23 to achieve optimal impact.

In our analysis, the odds of hospitalization vs ED visit for non-Hispanic white children with RSV or HMPV were significantly higher than those for non-Hispanic Black and Hispanic children. Non-Hispanic white children with RSV or HMPV were approximately 4 times more likely to be hospitalized rather than have an ED visit than non-Hispanic Black children and approximately 3 times more likely than Hispanic children. However, we observed no significant association between race and ethnicity and ICU admission or length of stay once children were hospitalized. Other studies have noted similar associations between non-Hispanic white race and hospital admission among children with RSV,³⁴ and our study extends these findings to HMPV. As there was no difference in severity of disease by race and ethnicity once hospitalized, observed differences may be related to differences in access to primary care that influence ED usage patterns, biases in admission practices, or other health differences. Further exploration is needed to elucidate these trends.

Strengths of this analysis are its prospective design and the use of multisite, population-based surveillance with systematic viral testing over multiple seasons among a geographically and demographically diverse population. This study is also subject to several limitations. Enrollment at surveillance sites may have varied by age group and site throughout the study period. Although patients are systematically enrolled prior to viral testing, it is possible enrolled children may not reflect the full spectrum of illness among nonenrolled children. In addition, this study is restricted to the most severely ill children seen in the ED or hospitalized, and there may be demographic or clinical differences for children with milder disease. New Vaccine Surveillance Network sites are academic pediatric health systems with catchment areas and hospitalization acuity that may not be nationally representative. Additionally, these data are from prior to the COVID-19 pandemic to establish a reliable baseline for comparison with future seasons and may not represent recent trends. Seasons following 2020 were not included in this analysis due to atypical circulation and epidemiology of these viruses during the COVID-19 pandemic, which have been progressively shifting back to pre-pandemic trends.⁸ Lastly, as palivizumab administration is limited to infants at high risk of severe RSV, the observed lower frequency of underlying conditions among infants hospitalized with RSV may be partially due to its protective effect. However, less than 4% of children younger than 1 year in the study received palivizumab, and we believe this influence to be minimal.

CONCLUSION

RSV and HMPV are leading causes of severe respiratory illness in children. Although the clinical presentation and severity of illness may be similar, these viruses impact different populations and age groups and exhibit different seasonal trends. As new RSV and HMPV prevention products become available, continued monitoring of the epidemiology of these viruses will be necessary.

Supplementary Material

Supplement

NIHMS2131839-supplement-Supplement.pdf^{(262.3KB, pdf)}

WHAT’S KNOWN ON THIS SUBJECT:

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are genetically related viruses and major causes of acute respiratory illness in children. Children hospitalized with RSV tend to be younger than those with HMPV. RSV circulation typically precedes HMPV circulation.

WHAT THIS STUDY ADDS:

We compare characteristics and clinical outcomes among children in the emergency department or hospitalized with RSV or HMPV. We describe the seasonality of these viruses and compare risk factors for severe disease, identifying populations at highest risk.

CONFLICT OF INTEREST DISCLOSURES:

Dr Halasa receives research support from Merck and has consulted for CSL-Seqirus; Dr Schuster’s institution receives research funding from Merck for a study on which she is an investigator; Dr Staat’s institution receives funding from Cepheid and has consulted for Merck; Dr Schlaudecker’s institution received funding from Pfizer and has received honorarium from Sanofi Pasteur; Dr Weinberg received honoraria from Merck and Co. for the writing and revision of chapters in the Merck Manual and has consulted for Inhalon, Biopharma, and ReViral; Dr Selvarangan received research funds from Hologic, BioFire, Becton Dickinson, Luminex, and Cepheid and serves on an advisory board for GlaxoSmithKline; Dr Englund’s institution received research finding from AstraZeneca, GlaxoSmithKline, Merck, Pfizer, and Moderna, has consulted for Abbvie, AstraZeneca, GlaxoSmithKline, Meissa Vaccines, Moderna, Pfizer, and Sanofi Pasteur, and has received payment for presentation from Pfizer; and the other authors have indicated that they have no conflicts of interest relevant to this article to disclose.

FUNDING:

This article is supported by the US Centers for Disease Control and Prevention (cooperative agreements RFA-IP-16-004). Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Dr Wang-Erickson was supported in part by a National Center for Advancing Translational Sciences (NCATS) National Institutes of Health (NIH) grant (KL2TR001856). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

ABBREVIATIONS

aOR: adjusted odds ratio
ARI: acute respiratory illness
CDC: Centers for Disease Control and Prevention
ED: emergency department
HMPV: human metapneumovirus
ICU: intensive care unit
IP: inpatient
RSV: respiratory syncytial virus

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Associated Data

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Supplementary Materials

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[R1] 1.van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7(6):719–724. doi: 10.1038/89098 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] 2.Boivin G, De Serres G, Côté S, et al. Human metapneumovirus infections in hospitalized children. Emerg Infect Dis. 2003;9(6): 634–640. doi: 10.3201/eid0906.030017 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Edwards KM, Zhu Y, Griffin MR, et al. ; New Vaccine Surveillance Network. Burden of human metapneumovirus infection in young children. N Engl J Med. 2013;368(7):633–643. doi: 10.1056/NEJMoa1204630 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] 4.Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009; 360(6):588–598. doi: 10.1056/NEJMoa0804877 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Perez A, Lively JY, Curns A, et al. ; New Vaccine Surveillance Network Collaborators. Respiratory virus surveillance among children with acute respiratory illnesses - New Vaccine Surveillance Network, United States, 2016–2021. MMWR Morb Mortal Wkly Rep. 2022;71(40):1253–1259. doi: 10.15585/mmwr.mm7140a1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] 6.Kimberlin DW, Barnett E, Lynfield R, Sawyer MH, eds. Red Book 2021: Report of the Committee on Infectious Diseases. American Academy of Pediatrics; 2021. doi: 10.1542/9781610025225 [DOI] [Google Scholar]

[R7] 7.Suh M, Movva N, Jiang X, et al. Respiratory syncytial virus is the leading cause of United States infant hospitalizations, 2009–2019: a study of the national (nationwide) inpatient sample. J Infect Dis. 2022;226(suppl 2):S154–S163. doi: 10.1093/infdis/jiac120 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] 8.Hamid S, Winn A, Parikh R, et al. Seasonality of respiratory syncytial virus - United States, 2017–2023. MMWR Morb Mortal Wkly Rep. 2023;72(14):355–361. doi: 10.15585/mmwr.mm7214a1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] 9.Illan Montero J, Berger A, Levy J, Busson L, Hainaut M, Goetghebuer T. Retrospective comparison of respiratory syncytial virus and metapneumovirus clinical presentation in hospitalized children. Pediatr Pulmonol. 2023;58(1):222–229. doi: 10.1002/ppul.26188 [DOI] [PubMed] [Google Scholar]

[R10] 10.Toepfer AP, Amarin JZ, Spieker AJ, et al. Seasonality, clinical characteristics, and outcomes of respiratory syncytial virus disease by subtype among children aged <5 years: New Vaccine Surveillance Network, United States, 2016–2020. Clin Infect Dis. 2024;78(5):1352–1359. doi: 10.1093/cid/ciae085 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Human Metapneumovirus and Respiratory Syncytial Virus in Children: A Comparative Analysis

Leah A Goldstein, MPH

Marian G Michaels, MD, MPH

Abigail Salthouse, MPH

Ariana P Toepfer, MPH

Samar Musa, MPH

Robert W Hickey, MD FAAP, FAHA

Monika Johnson

Anna F Wang-Erickson, PhD

Geoffrey A Weinberg, MD

Peter G Szilagyi, MD, MPH

Elizabeth P Schlaudecker, MD, MPH

Mary A Staat, MD, MPH

Leila C Sahni, PhD, MPH

Julie A Boom, MD

Eileen J Klein, MD, MPH

Janet A Englund, MD

Jennifer E Schuster, MD

Rangaraj Selvarangan, BVSc, PhD

Christopher J Harrison, MD

Natasha B Halasa, MD, MPH

Laura S Stewart, PhD

Fatimah S Dawood, MD

Heidi L Moline, MD

John V Williams, MD

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSIONS:

INTRODUCTION

METHODS

New Vaccine Surveillance Network Study Design and Population

Laboratory Methods

Statistical Analysis

Ethical Review and Data Reporting

RESULTS

Characteristics and Clinical Course

TABLE 1.

FIGURE 1.

TABLE 2.

Seasonality

FIGURE 2.

Risk of Severe Disease

TABLE 3.

FIGURE 3.

DISCUSSION

CONCLUSION

Supplementary Material

WHAT’S KNOWN ON THIS SUBJECT:

WHAT THIS STUDY ADDS:

CONFLICT OF INTEREST DISCLOSURES:

FUNDING:

ABBREVIATIONS

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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