Human Metapneumovirus Circulation in the United States, 2008 to 2014 Amber K. Haynes, MPH,a Ashley L. Fowlkes, MPH, b Eileen Schneider, MD,a Jeffry D. Mutuc, MPH,a Gregory L. Armstrong, MD,c Susan I. Gerber, MDa

BACKGROUND: Human metapneumovirus (HMPV) infection causes respiratory illness, including abstract bronchiolitis and pneumonia. However, national HMPV seasonality, as it compares with respiratory syncytial virus (RSV) and influenza seasonality patterns, has not been well described. METHODS: Hospital and clinical laboratories reported weekly aggregates of specimens tested and positive detections for HMPV, RSV, and influenza to the National Respiratory and Enteric Virus Surveillance System from 2008 to 2014. A season was defined as consecutive weeks with ≥3% positivity for HMPV and ≥10% positivity for RSV and influenza during a surveillance year (June through July). For each virus, the season, onset, offset, duration, peak, and 6-season medians were calculated. RESULTS: Among consistently reporting laboratories, 33 583 (3.6%) specimens were positive for HMPV, 281 581 (15.3%) for RSV, and 401 342 (18.2%) for influenza. Annually, 6 distinct HMPV seasons occurred from 2008 to 2014, with onsets ranging from November to February and offsets from April to July. Based on the 6-season medians, RSV, influenza, and HMPV onsets occurred sequentially and season durations were similar at 21 to 22 weeks. HMPV demonstrated a unique biennial pattern of early and late seasonal onsets. RSV seasons (onset, offset, peak) were most consistent and occurred before HMPV seasons. There were no consistent patterns between HMPV and influenza circulations. CONCLUSIONS: HMPV circulation begins in winter and lasts until spring and demonstrates distinct seasons each year, with the onset beginning after that of RSV. HMPV, RSV, and influenza can circulate simultaneously during the respiratory season.

Divisions of aViral Diseases, and bInfl uenza, National Center for Immunization and Respiratory Diseases, and WHAT’S KNOWN ABOUT THIS SUBJECT: Human c Offi ce of Advanced Molecular Detection, National Center for Emerging and Zoonotic Infectious Diseases, metapneumovirus is a respiratory virus that causes Centers for Disease Control and Prevention, Atlanta, Georgia upper and lower respiratory infections. Clinical Ms Haynes helped conceptualize and design the study and drafted the initial manuscript; presentation, populations most severely impacted, Mr Mutuc carried out preliminary analyses; Mr Mutuc and Dr Armstrong reviewed the and circulation patterns are similar to those of manuscript; Ms Fowlkes served as infl uenza virus subject matter expert; Ms Fowlkes and respiratory syncytial virus; however, national human Dr Schneider helped design the study; Ms Fowlkes and Drs Schneider and Gerber critically metapneumovirus circulation has not been well reviewed the manuscript; Dr Schneider served as human metapneumovirus subject matter described. expert; Dr Armstrong conceptualized the study analysis; Drs Armstrong and Gerber revised the manuscript; Dr Gerber guided the study concept and design; and all authors approved the fi nal WHAT THIS STUDY ADDS: This study describes manuscript as submitted. national human metapneumovirus circulation The fi ndings and conclusions in this report are those of the authors and do not necessarily using laboratory detections reported to a national represent the offi cial position of the Centers for Disease Control and Prevention. surveillance system from 2008 to 2014. Defi ning periods of elevated human metapneumovirus DOI: 10.1542/peds.2015-2927 circulation may guide virus detection and clinical Accepted for publication Jan 27, 2016 management, aiding in identifying illness and Address correspondence to Amber K. Haynes, MPH, National Center for Immunization and outbreaks. Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd, NE, MS A-34, Atlanta, GA 30329. E-mail: [email protected] To cite: Haynes AK, Fowlkes AL, Schneider E, et al. Human Metapneumovirus Circulation in the United States, 2008 to 2014. Pediatrics. 2016;137(5):e20152927

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 137 , number 5 , May 2016 :e 20152927 ARTICLE First identified in 2001,1 human evaluate national trends in HMPV test results. For RSV analysis, we metapneumovirus (HMPV) is a circulation. included laboratories reporting cause of both upper and lower ≥10 RSV antigen detection tests/ In the United States, surveillance respiratory tract infections, including week annually and ≥1 RSV antigen for several respiratory viruses is bronchiolitis and pneumonia, detection test for 30 of 52 weeks conducted annually through the particularly among young children of the NREVSS year; for influenza National Respiratory and Enteric (<5 years), the elderly, and analysis, we included laboratories Virus Surveillance System (NREVSS). immunocompromised patients.2–5 reporting influenza by PCR to In this study, we describe national Infection with HMPV has been the World Health Organization HMPV circulation patterns and associated with an estimated 20 000 collaborating laboratories;14 and compare with patterns of RSV and U.S. hospitalizations annually among for HMPV analysis, we included influenza activity reported to NREVSS children aged <5 years.6 However, laboratories reporting ≥1 HMPV PCR during 6 seasons from 2008 to 2014. the infrequent testing and low index or antigen detection test for 36 of 52 of suspicion associated with HMPV weeks of the NREVSS year. These are may have limited the assessment METHODS standard laboratory inclusion criteria of temporal trends in HMPV for RSV and influenza; no standard circulation. Also, many studies have NREVSS is a passive surveillance inclusion criteria exist for HMPV. demonstrated that HMPV causes a network established in 1984 that collects specimen test results respiratory tract infection clinically For each virus, we calculated the for several respiratory viruses, indistinguishable from infections weekly proportion-positive. To including HMPV, RSV, and influenza. caused by respiratory syncytial virus define the season for RSV13 and Approximately 300 clinical and (RSV) and influenza.1–5 In contrast, influenza, 14 we used the widely public health laboratories in the the specific prevention options and accepted 10% weekly proportion- United States report ≥1 specimen some populations severely affected positive threshold. Specifically, test result on average for 44 weeks vary for HMPV, RSV, and influenza.7 the RSV or influenza seasons were in a surveillance year.13 Laboratories Currently there is no vaccine for defined as the first of 2 consecutive report weekly aggregates of the HMPV. Thus, describing HMPV weeks when the proportion of number of tests performed and circulation in the United States in the positive weekly aggregates exceeded positive detections by antigen context of RSV and influenza may 10% positivity, and the season detection, polymerase chain reaction help clinicians to prioritize diagnostic offset, as the last of 2 consecutive (PCR), and viral isolation. The type of testing, identify an etiologic agent, weeks when the proportion of assay reported can vary depending manage patients clinically, and weekly aggregates exceeded 10% on the respiratory virus and year. choose appropriate prevention positivity. To define the season for For RSV, we analyzed antigen strategies. HMPV, we selected a 3% weekly detection reports; for influenza, proportion-positive threshold. We we analyzed PCR reports; and for Many studies have demonstrated a defined the HMPV season onset HMPV, we analyzed both antigen winter-to-spring circulation period as the first of 2 consecutive weeks detection and PCR reports. The for HMPV in temperate climates, 8–10 when the proportion of positive NREVSS surveillance year is defined but determination of national HMPV weekly aggregates exceeded 3% as July of the starting year through trends and comparison of HMPV positivity, and the season offset, the end of the following June to seasonality to RSV and influenza as the last of 2 consecutive weeks capture the typical national onset in multiple sites throughout the when the proportion of weekly and offset of several respiratory United States have not yet been aggregates exceeded 3% positivity. viruses. Surveillance for RSV and done. A study conducted in 3 U.S. At a threshold of 3%, 84% to 94% influenza through NREVSS is well sites identified HMPV circulation in of HMPV detections by antigen established and ongoing since 1984 winter and spring months;6 however, detection tests were captured and 1989, respectively. The first it remains unclear if this pattern each year, and 80% to 92% of HMPV diagnostic test was reported reflects trends in national HMPV HMPV detections by PCR tests to NREVSS in July 2005, but reports circulation. The increased availability were captured. For each virus, we were insufficient for robust analysis and use of molecular diagnostic calculated the onset, offset, peak, until 2008 to 2009, when test reports assays to detect respiratory viruses11 and duration (onset to offset) for to NREVSS exceeded 70 000. in recent years has highlighted each individual season and the several HMPV-associated outbreaks Laboratories included in this analysis median for the 6 seasons. A 4-season throughout the United States12 and were selected based on annual median rather than a 6-season has enhanced the opportunity to duration and volume of reported median was calculated for influenza;

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 HAYNES et al TABLE 1 HMPV Diagnostic Tests Reported to NREVSS by Test Type and Year, United States, 2008 to 2014 NREVSS Year Antigen Detection PCR Totala Laboratories States Tests, n (%) Laboratories States Tests, n (%) Laboratories States Reporting, n Represented, n Reporting, n Represented, n Reporting, n Represented, n 2008 to 2009 15 14 69 698 (77) 9 8 20 353 (23) 21 16 2009 to 2010 20 17 83 033 (52) 20 12 77 342 (48) 33 21 2010 to 2011 21 17 76 710 (48) 32 17 83 155 (52) 46 25 2011 to 2012 25 19 59 935 (42) 35 18 83 241 (58) 53 28 2012 to 2013 24 18 60 573 (30) 43 21 141 709 (70) 62 31 2013 to 2014 20 15 28 881 (15) 49 28 161 206 (85) 60 30 A total of 945 836 test results were reported for HMPV (antigen detection, 378 830 [40%]; PCR, 567 006 [60%]). a Total includes those qualifying laboratories reporting HMPV test results by antigen detection, PCR, or both diagnostic test methods.

2 seasons (2008 to 2009, 2009 to 2010) were excluded because of the unprecedented occurrence of the H1N1 pandemic. An early season was defined as a season with an earlier onset than the 6-season median and higher peak proportion-positive than the 6-season median, and a late season was defined as a later onset than the 6-season median and lower peak proportion-positive than the FIGURE 1 6-season median. Geographic distribution of states with laboratories consistently reporting HMPV diagnostic test results by test type, United States, 2008 to 2014. n = number of states with qualifying laboratories consistently reporting HMPV test results for the specifi ed NREVSS Year. Laboratories reporting HMPV test results by antigen detection, PCR, or both diagnostic methods. RESULTS increased from 21 laboratories increased from 3 in 2008 to 2009 to 9 Among all laboratories reporting in 2013 to 2014. HMPV tests results to NREVSS from representing 16 states in 2008 to 2009 to 60 laboratories representing July 2008 to June 2014, 1 065 742 The weekly proportion of specimens HMPV test results were reported 30 states in 2013 to 2014 (Table 1, Fig 1). The number of HMPV tests positive by antigen detection or PCR and 38 160 (3.6%) were positive methods for HMPV show definitive (25 409 [3.9%] by PCR; 12 751 remained relatively constant over the 6 surveillance years, but the seasonal patterns each year (Fig 2A). [3.0%] by antigen detection). Among The weekly proportion of positive most prevalent diagnostic method consistently reporting laboratories HMPV tests ranged from a low of reported fluctuated from year to included in our analysis, 945 836 <1% between July and November to year. In 2008 to 2009 and 2009 to tests were reported from July 2008 a maximum of 6% to 16% between 2010, 77% and 52%, respectively, to June 2014, and 33 583 (3.6%) March and April. We observed a of HMPV diagnostic tests reported were positive (21 972 [3.9%] by PCR, slight biennial pattern with early were antigen detection; however, 11 611 [3.1%] by antigen detection) and late seasons for HMPV based on from 4 seasons that spanned 2010 to for HMPV, 1 839 877 tests were the median weekly proportion-PCR 2014, 52% to 85% of diagnostic tests reported and 281 581 (15.3%) were positive tests with early (NREVSS reported were PCR. Similarly, the positive for RSV, and 2 206 654 tests surveillance years: 2009 to 2010, number of laboratories consistently were reported (including specimens 2011 to 2012, and 2013 to 2014) reporting HMPV by antigen detection from the H1N1 influenza pandemic) and late (NREVSS surveillance years: decreased from the 2008 to 2009 to and 401 342 (18.2%) were positive 2008 to 2009, 2010 to 2011, and 2013 to 2014 season (median 21, for influenza. During the study 2012 to 2013) seasons (Fig 2B). period, laboratories consistently range 15 to 25), and the number reporting HMPV comprised general of laboratories reporting by PCR Nationally, the HMPV 6-season hospitals (60.3%), children’s increased from the 2008 to 2009 to median onset occurred in early hospitals/facilities (28.9%), public the 2013 to 2014 season (median 34, January (week 1), and individual health facilities (9.6%), and reference range 9 to 49) (Table 1). Reporting season onsets occurred from late laboratories (1.2%). The number of both test methods for HMPV by November to late February within laboratories reporting HMPV tests laboratories was infrequent but 5 weeks of the 6-season median

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 137 , number 5 , May 2016 3 b 19 25 20 24 21 21 21 a, b 22 Season Duration, Weeks b Mar (12) 21 a May (20) Jan (3) Jan (3) a

FIGURE 2 Human metapneumovirus reporting by diagnostic test type (A) and early and late seasons (B), United States, 2008 to 2014. *Three-week moving average (average of the previous, current, and following week proportion of positive tests for each testing method) of the median weekly proportion-PCR positive tests and antigen positive tests. †Early seasons: 2009 to 2010, 2011 to 2012, 2013 to 2014; late seasons: 2008 to 2009, 2010 to 2011, 2012 to 2013. and HMPV for Individual Seasons the 6-Season Median, United States, 2008 to 2014 a onset (Table 2). The HMPV 6-season in onset, offset, and peak, unlike

uenza, median offset occurred in mid-May HMPV and influenza (Fig 3). The

Jan (01) Mar (13) May (18) (week 20) ranging from late April HMPV season onset, offset, and to early July within 7 weeks of peak occurred after RSV for all 6

a the individual season offsets. The seasons. Year-to-year patterns in 6-season median peak occurred in

uenza HMPV RSV uenza Infl HMPV RSV uenza Infl HMPV RSV uenza Infl HMPV the sequential occurrence of offset late March (week 12) and ranged and peak were similar among RSV from late February (week 7) to early and HMPV, but not influenza (Table May (week 17) for individual season 2). The 6-season median onset for peaks. The HMPV 6-season duration RSV Infl

Month Onset Occurred (MMWR Week) Month Offset Occurred (MMWR Week) Month Peak Occurred (MMWR Week) RSV, influenza, and HMPV occurred Oct (43) Nov (45) Feb (07) Mar (13) Apr (15) Jul (27) Jan (1) Dec (52) Apr (14) 23 23 Nov (44) Jan (02) Jan (02) Mar (11) Apr (14) May (20) Jan (3) Feb (6) Mar (12) 20 13 Nov (45) Apr (17) Dec (52) Mar (12) Dec (48) May (19) Jan (3) Jun (24) Feb (9) 20 32 Nov (46) Nov (47) Jan (04) Apr (14) Apr (14) Jul (27) Feb (5) Feb (5) May (17) 21 20 Nov (46) Feb (05) Dec (48) Apr (14) Jun (24) Apr (16) Jan (4) Mar (10) Feb (7) 21 20 Nov (45) Dec (48) Nov (48) Mar (13) May (20) May (20) Dec (52) Dec (52) Mar (12) 21 25 Nov (45) Dec (48) was 21 weeks (individual season in sequential order (Table 2). The duration range 19 to 25 weeks). Only first respiratory virus season median minor variations in the occurrence onset to occur was RSV, which had of the HMPV season onset, peak, and a a 6-season median onset in early offset were observed between PCR November (individual season onset and antigen detection methods. Season Onset, Offset, Peak, and Duration for RSV, Infl Season Onset, Offset, Peak, and Duration for RSV, range late October to late November). The RSV seasons were most The influenza 4-season median The 6-season median for season duration is based on the median of the season duration for the 6 seasons (4 seasons for infl uenza) and not the difference of 6-season median for onset offset. The 6-season median for season duration is based on the of 6 seasons (4 infl Infl uenza 6-season medians exclude the 2008 to 2009 and 2010 seasons because of H1N1 pandemic. Infl 2008 to 2009 2009 to 2010 2010 to 2011 2011 to 2012 2012 to 2013 2013 to 2014 6-Season Median TABLE 2 NREVSS Year a b consistent, with very little change onset occurred in early December,

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 HAYNES et al (individual season onset range late November to early February). The HMPV 6-season median onset occurred in early January (individual season onset range late November to late February). The first respiratory virus season offset to occur was RSV. The 6-season median offset for RSV occurred in late March (individual season offset range mid-March to early April), followed by influenza in early May (individual season offset range early April to early June) and HMPV in mid-May (individual season offset range late April to early July). FIGURE 3 The 6-season median peak occurred Onset, offset, peak, and duration by season and 6-season median for HMPV, RSV, and infl uenza, United in the following sequential order: States, 2008 to 2014. 2008 to 2009 and 2009 to 2010 infl uenza seasons not included in the 4-season RSV (late January, week 3), influenza median because of H1N1 pandemic. (late January, week 3), and HMPV (late March, week 12). The 6-season HMPV season durations occurred circulations. However, as in other median onset and peak for HMPV between November and July studies, we determined that a smaller occurred 8 and 9 weeks, respectively, (6-season median 21 weeks). Weekly proportion of diagnostic tests were after RSV and 5 and 9 weeks after HMPV positivity fluctuated between positive for HMPV compared with influenza, respectively (Table 2). The nearly zero and ≥6% every 12 other respiratory pathogens.18–21 6-season median duration for all 3 months, showing a distinguishable The data analyzed were not robust viruses were very similar at 21 to 22 seasonal pattern. Similar to RSV enough to assess regional trends in weeks. and influenza, HMPV seasons HMPV circulation. occurred during winter and spring, as previously described.8–10 The The cocirculation analysis suggest weekly HMPV percent-positivity that HMPV, RSV, and influenza DISCUSSION in this analysis never reached zero cocirculate, as previously described 15 over the 6 years of surveillance, by Esper et al. Although the This is the first published summary confirming previous reports of low circulations of influenza, RSV, and of HMPV national data from NREVSS but continuous HMPV circulation HMPV overlap, the populations and demonstrates several unique beyond winter and spring.15 We also susceptible to severe infection and features. From 2008 to 2014, the observed a biennial pattern for HMPV the management of these infections 22–24 national HMPV data suggest that of alternating early and late season differ. HMPV seasons occur later than RSV from 2008 to 2014, which was not Therefore, clinicians can use seasons, and based on the 6-season 16, 17 seen for RSV or influenza. surveillance data, such as NREVSS, median onset, the RSV season to help identify HMPV seasonality occurred first, followed by influenza The most prevalent HMPV diagnostic and help prioritize HMPV testing in and then HMPV. The unprecedented method reported shifted from patients with respiratory symptoms. H1N1 influenza pandemic that antigen detection to PCR during 2008 As laboratory recruitment into affected the 2008 to 2009 and 2009 to 2014. The shift toward increased NREVSS and PCR use continue to to 2010 seasons made comparison reporting of PCR tests likely reflects increase throughout the United States, during these seasons difficult changes in conventional diagnostic future NREVSS data should be able to to interpret. In addition, HMPV testing among participating NREVSS more reliably allow for more detailed demonstrated a biennial pattern of laboratories. Within any given season analyses, including regional HMPV early and late seasons. There were during this time period, a 3% weekly trends and outbreak occurrence, no distinct differences in HMPV ≥ positivity measure captured 80% similar to those for RSV and influenza. seasonality determined by antigen of PCR HMPV detections reported detection and PCR, and PCR was the by qualifying institutions. The 3% Our study had several limitations. most prevalent diagnostic method weekly proportion is comparatively Our findings are based on NREVSS, used to identify HMPV in the last 4 lower than the 10% positivity used to which is a passive and voluntary years of analysis. indicate elevated influenza and RSV surveillance system in which (1)

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 137 , number 5 , May 2016 5 participating laboratories can differ virus, health professionals may not season, followed by influenza and from season to season and may routinely consider or test for HMPV. then HMPV. To distinguish HMPV report different respiratory viruses; Finally, we selected a low positivity from other cocirculating viruses, (2) HMPV test reporting is relatively threshold to define HMPV seasonality health professionals should consider new and does not garner the same because fewer detections were HMPV testing during the respiratory test reporting volume or regional positive for HMPV compared with season, especially when HMPV is the representation as more established other respiratory viruses monitored predominant virus circulating. respiratory viruses, such as RSV; (3) by NREVSS. patient age and specific specimen information are not collected; and ABBREVIATIONS (4) duplication is a possibility if CONCLUSIONS HMPV: human metapneumovirus antigen detection and PCR testing In the Unites States, HMPV circulates NREVSS: National Respiratory are performed and reported on the in distinct annual seasons with and Enteric Virus same specimen or if >1 specimen is biennial patterns of early and late Surveillance System reported from a patient during the seasons. Our findings suggest that PCR: polymerase chain reaction same illness episode. Because HMPV RSV onset occurs the earliest during RSV: respiratory syncytial virus is a recently recognized respiratory the fall/winter respiratory virus

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2016 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: Supported by the Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, Division of Viral Diseases and Infl uenza. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

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