Clinical characteristics and molecular epidemiology of human metapneumovirus in children with acute lower respiratory tract infections in China, 2017 to 2019: A multicentre prospective observational study

Hongwei Zhao; Qianyu Feng; Ziheng Feng; Yun Zhu; Junhong Ai; Baoping Xu; Li Deng; Yun Sun; Changchong Li; Rong Jin; Yunxiao Shang; Xiangpeng Chen; Lili Xu; Zhengde Xie

doi:10.1016/j.virs.2022.08.007

December 2022

. doi: 10.1016/j.virs.2022.08.007

Citation: Hongwei Zhao, Qianyu Feng, Ziheng Feng, Yun Zhu, Junhong Ai, Baoping Xu, Li Deng, Yun Sun, Changchong Li, Rong Jin, Yunxiao Shang, Xiangpeng Chen, Lili Xu, Zhengde Xie. Clinical characteristics and molecular epidemiology of human metapneumovirus in children with acute lower respiratory tract infections in China, 2017 to 2019: A multicentre prospective observational study .VIROLOGICA SINICA, 2022, 37(6) : 874-882. http://dx.doi.org/10.1016/j.virs.2022.08.007

2017-2019年我国儿童偏肺病毒感染临床特征分析及多中心分子流行病学研究

赵宏伟 ^a,b ,
冯黔玉 ^a,b ,
冯梓恒 ^a,b ,
朱云 ^a,b ,
艾军红 ^a,b ,
徐保平 ^c ,
邓昱 ^d ,
孙云 ^e ,
李昌崇 ^f ,
靳蓉 ^g ,
尚云晓 ^h ,
陈祥鹏 ^a,b ,
许黎黎 ^a,b,, ,
谢正德 ^a,b

1 儿童呼吸道感染性疾病研究北京市重点实验室, 教育部儿科重大疾病研究重点实验室, 国家呼吸系统疾病临床医学研究中心, 儿科国家重点学科(首都医科大学), 北京市儿科研究所感染与病毒研究室, 北京市儿童医院, 首都医科大学, 国家儿童健康中心, 北京, 100045;
2 中国医学科学院儿童危重感染诊治创新单元, 2019RU016;
3 首都医科大学附属北京儿童医院呼吸疾病一科, 国家儿童健康中心呼吸疾病临床研究中心, 北京 100045;
4 广州市妇女儿童医学中心, 广州 510623;
5 银川市妇幼保健院, 银川, 750000;
6 温州医科大学附属第二医院、育英儿童医院, 温州, 325027;
7 贵阳妇女和儿童保健医院, 贵阳, 550003;
8 中国医科大学盛京医院, 沈阳, 110004

通讯作者： 许黎黎, justinexull26@163.com;
收稿日期： 2022-04-06
录用日期： 2022-06-21

摘要

人偏肺病毒（HMPV）是急性呼吸道疾病（ARI）儿童住院的主要原因之一。这项多中心研究的目的是分析2017年至2019年中国急性下呼吸道感染住院儿童中HMPV阳性病例的临床和分子流行病学特征。我们前瞻性地收集了2017年至2019年在6家医院住院治疗急性下呼吸道感染的儿童的呼吸道样本，进行HMPV分子检测和序列分析，并使用标准化问卷获得临床数据。在入组的2733份样本中的145份（5.3%）中检测到HMPV。大多数HMPV阳性儿童年龄在2岁以下（67.6%），中位年龄为1岁。HMPV可独立引起幼儿急性下呼吸道感染，而所有患者均表现出轻微的临床症状，主要是发热，咳嗽，咳痰和流涕。同时，在所有共感染病例中，HMPV最常与肠道病毒（EV）或鼻病毒（RhV）共同被检测到（38.0%，但EV或RhV未进一步分型），其次是呼吸道合胞病毒（RSV）（32.0%）。在中国北部和南部，3月至5月的检出率最高。在145份阳性样本中，48份可以成功分型，其中36份（75%）为A2c基因型，8份（16.7%）为B1亚型，4份（8.3%））为B2亚型。此外，16份A2c基因型在G基因中含有111个核苷酸重复。本研究共成功获得27个完整的HMPV基因组，25份（92.6%）属于A2c基因型，B1和B2亚型各一份。在25份A2c基因型的全基因组中共检测到277个突变。
- 人偏肺病毒
- , 急性下呼吸道感染
- , 临床特征
- , 分子流行病学特征
- , 多中心研究

Clinical characteristics and molecular epidemiology of human metapneumovirus in children with acute lower respiratory tract infections in China, 2017 to 2019: A multicentre prospective observational study

Hongwei Zhao ^a,b ,
Qianyu Feng ^a,b ,
Ziheng Feng ^a,b ,
Yun Zhu ^a,b ,
Junhong Ai ^a,b ,
Baoping Xu ^c ,
Li Deng ^d ,
Yun Sun ^e ,
Changchong Li ^f ,
Rong Jin ^g ,
Yunxiao Shang ^h ,
Xiangpeng Chen ^a,b ,
Lili Xu ^a,b,, ,
Zhengde Xie ^a,b

a Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China;
b Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, 2019RU016, China;
c Department of Respiratory Diseases I, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China;
d Guangzhou Women and Children's Medical Center, Guangzhou, 510623, China;
e Yinchuan Maternal and Child Health Hospital, Yinchuan, 750000, China;
f The 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China;
g Guiyang Women and Children Healthcare Hospital, Guiyang, 550003, China;
h Shengjing Hospital of China Medical University, Shenyang, 110004, China

Corresponding author: Lili Xu, justinexull26@163.com
Received Date: 06 April 2022
Accepted Date: 21 June 2022

Abstract

Human metapneumovirus (HMPV) infection is one of the leading causes of hospitalization in young children with acute respiratory illness. In this study, we prospectively collected respiratory tract samples from children who were hospitalized with acute lower respiratory tract infection in six hospitals in China from 2017 to 2019. HMPV was detected in 145 out of 2733 samples (5.3%) from the hospitalized children. The majority of HMPV-positive children were under the age of two (67.6%), with a median age of one year. HMPV can independently cause acute lower respiratory tract infection in young children, while all patients showed mild clinical symptoms. Of all the co-infected patients, HMPV was most commonly detected with enterovirus (EV) or rhinovirus (RhV) (38.0%, followed by respiratory syncytial virus (RSV) (32.0%). The highest detection rate occurred from March to May in both northern and southern China. Out of 145 HMPV positive samples, 48 were successfully typed, of which 36 strains were subgrouped into subtypes A2c (75%), eight strains were included in subtype B1 (16.7%), and four strains were included in subtype B2 (8.3%). Moreover, 16 A2c strains contained 111-nucleotide duplications in the G gene. Twenty-seven complete HMPV genomes were successfully obtained, and 25 (92.6%) strains belonged to subtype A2c, whereas one strain was included in subgroup B1 and another was included in subgroup B2. A total of 277 mutations were observed in the complete genomes of 25 A2c strains. All results presented here improve our understanding of clinical characteristics and molecular epidemiology of HMPV infection in children.
- Human metapneumovirus (HMPV)
- , Acute lower respiratory tract infection
- , Clinical characteristics
- , Molecular epidemiology
- , Multicentre prospective study

References
1. Arnott, A., Vong, S., Sek, M., Naughtin, M., Beaute, J., Rith, S., Guillard, B., Deubel, V., Buchy, P., 2013. Genetic variability of human metapneumovirus amongst an all ages population in Cambodia between 2007 and 2009. Infect. Genet. Evol. 15, 43–52.
2. Bosis, S., Esposito, S., Osterhaus, A.D., Tremolati, E., Begliatti, E., Tagliabue, C., Corti, F., Principi, N., Niesters, H.G., 2008. Association between high nasopharyngeal viral load and disease severity in children with human metapneumovirus infection. J. Clin. Virol. 42, 286–290.
3. Burstein, R., Henry, N.J., Collison, M.L., Marczak, L.B., Sligar, A., Watson, S., Marquez, N., Abbasalizad-Farhangi, M., Abbasi, M., Abd-Allah, F., et al., 2019. Mapping 123 million neonatal, infant and child deaths between 2000 and 2017. Nature 574, 353–358.
4. Choe, Y.J., Park, S., Michelow, I.C., 2020. Co-seasonality and co-detection of respiratory viruses and bacteraemia in children: a retrospective analysis. Clin. Microbiol. Infect. 26, 1690 e1695-1690 e1698.
5. Choi, S.H., Hong, S.B., Huh, J.W., Jung, J., Kim, M.J., Chong, Y.P., Kim, S.H., Sung, H., Koo, H.J., Do, K.H., Lee, S.O., Lim, C.M., Kim, Y.S., Woo, J.H., Koh, Y., 2019. Outcomes of severe human metapneumovirus-associated community-acquired pneumonia in adults. J. Clin. Virol. 117, 1–4.
6. Cui, A., Xie, Z., Yu, P., Zhu, R., Ma, Y., Xiang, X., Zhang, L., Zhu, Y., Wu, J., Gao, Z., Zhang, R., Han, G., Xu, W., Zhang, Y., 2021. Viral infection and epidemiological characteristics of human metapneumovirus in febrile respiratory syndrome cases in nine provinces in China from 2009 to 2021. Chin. J. Appl. Clin. Pediatr. 36, 1861–1865 (in Chinese).
7. Divarathna, M.V.M., Rafeek, R.a.M., Noordeen, F., 2020. A review on epidemiology and impact of human metapneumovirus infections in children using TIAB search strategy on PubMed and PubMed Central articles. Rev. Med. Virol. 30, e2090.
8. Edwards, K.M., Zhu, Y., Griffin, M.R., Weinberg, G.A., Hall, C.B., Szilagyi, P.G., Staat, M.A., Iwane, M., Prill, M.M., Williams, J.V., New Vaccine Surveillance, N., 2013. Burden of human metapneumovirus infection in young children. N. Engl. J. Med. 368, 633–643.
9. Gray, G.C., Capuano, A.W., Setterquist, S.F., Erdman, D.D., Nobbs, N.D., Abed, Y., Doern, G.V., Starks, S.E., Boivin, G., 2006. Multi-year study of human metapneumovirus infection at a large US Midwestern Medical Referral Center. J. Clin. Virol. 37, 269–276.
10. Haas, L.E., Thijsen, S.F., Van Elden, L., Heemstra, K.A., 2013. Human metapneumovirus in adults. Viruses 5, 87–110.
11. Kong, W., Wang, Y., Zhu, H., Lin, X., Yu, B., Hu, Q., Yang, X., Guo, D., Peng, J., Zhou, D., 2016. Circulation of human metapneumovirus among children with influenza-like illness in Wuhan, China. J. Med. Virol. 88, 774–781.
12. Lefebvre, A., Manoha, C., Bour, J.B., Abbas, R., Fournel, I., Tiv, M., Pothier, P., Astruc, K., Aho-Glele, L.S., 2016. Human metapneumovirus in patients hospitalized with acute respiratory infections: a meta-analysis. J. Clin. Virol. 81, 68–77.
13. Legrand, L., Vabret, A., Dina, J., Petitjean-Lecherbonnier, J., Stephanie, G., Cuvillon, D., Tripey, V., Brouard, J., Freymuth, F., 2011. Epidemiological and phylogenic study of human metapneumovirus infections during three consecutive outbreaks in Normandy, France. J. Med. Virol. 83, 517–524.
14. Li, J., Wang, Z., Gonzalez, R., Xiao, Y., Zhou, H., Zhang, J., Paranhos-Baccala, G., Vernet, G., Jin, Q., Wang, J., Hung, T., 2012. Prevalence of human metapneumovirus in adults with acute respiratory tract infection in Beijing, China. J. Infect. 64, 96–103.
15. Nao, N., Saikusa, M., Sato, K., Sekizuka, T., Usuku, S., Tanaka, N., Nishimura, H., Takeda, M., 2020. Recent molecular evolution of human metapneumovirus (HMPV):subdivision of HMPV A2b strains. Microorganisms 8.
16. Nao, N., Sato, K., Yamagishi, J., Tahara, M., Nakatsu, Y., Seki, F., Katoh, H., Ohnuma, A., Shirogane, Y., Hayashi, M., Suzuki, T., Kikuta, H., Nishimura, H., Takeda, M., 2019. Consensus and variations in cell line specificity among human metapneumovirus strains. PLoS One 14, e0215822.
17. Nidaira, M., Taira, K., Hamabata, H., Kawaki, T., Gushi, K., Mahoe, Y., Maeshiro, N., Azama, Y., Okano, S., Kyan, H., Kudaka, J., Tsukagoshi, H., Noda, M., Kimura, H., 2012. Molecular epidemiology of human metapneumovirus from 2009 to 2011 in Okinawa, Japan. Jpn. J. Infect. Dis. 65, 337–340.
18. Papenburg, J., Carbonneau, J., Isabel, S., Bergeron, M.G., Williams, J.V., De Serres, G., Hamelin, M.E., Boivin, G., 2013. Genetic diversity and molecular evolution of the major human metapneumovirus surface glycoproteins over a decade. J. Clin. Virol. 58, 541–547.
19. Pinana, M., Vila, J., Gimferrer, L., Valls, M., Andres, C., Codina, M.G., Ramon, J., Martin, M.C., Fuentes, F., Saiz, R., Alcubilla, P., Rodrigo, C., Pumarola, T., Anton, A., 2017. Novel human metapneumovirus with a 180-nucleotide duplication in the G gene. Future Microbiol. 12, 565–571.
20. Regev, L., Hindiyeh, M., Shulman, L.M., Barak, A., Levy, V., Azar, R., Shalev, Y., Grossman, Z., Mendelson, E., 2006. Characterization of human metapneumovirus infections in Israel. J. Clin. Microbiol. 44, 1484–1489.
21. Saikusa, M., Kawakami, C., Nao, N., Takeda, M., Usuku, S., Sasao, T., Nishimoto, K., Toyozawa, T., 2017. 180-Nucleotide duplication in the G gene of human metapneumovirus A2b subgroup strains circulating in Yokohama city, Japan, since 2014. Front. Microbiol. 8, 402.
22. Saikusa, M., Nao, N., Kawakami, C., Usuku, S., Tanaka, N., Tahara, M., Takeda, M., Okubo, I., 2019. Predominant detection of the subgroup A2b human metapneumovirus strain with a 111-nucleotide duplication in the G gene in Yokohama city, Japan in 2018. Jpn. J. Infect. Dis. 72, 350–352.
23. Schuster, J.E., Williams, J.V., 2014. Human Metapneumovirus. Microbiol. Spectr. 2.
24. Sloots, T.P., Mackay, I.M., Bialasiewicz, S., Jacob, K.C., Mcqueen, E., Harnett, G.B., Siebert, D.J., Masters, I.B., Young, P.R., Nissen, M.D., 2006. Human metapneumovirus, Australia, 2001–2004. Emerg. Infect. Dis. 12, 1263–1266.
25. Song, J., Wang, H., Shi, J., Cui, A., Huang, Y., Sun, L., Xiang, X., Ma, C., Yu, P., Yang, Z., Li, Q., Ng, T.I., Zhang, Y., Zhang, R., Xu, W., 2017a. Emergence of BA9 genotype of human respiratory syncytial virus subgroup B in China from 2006 to 2014. Sci. Rep. 7, 16765.
26. Song, J., Zhang, Y., Wang, H., Shi, J., Sun, L., Zhang, X., Yang, Z., Guan, W., Zhang, H., Yu, P., Xie, Z., Cui, A., Ng, T.I., Xu, W., 2017b. Emergence of ON1 genotype of human respiratory syncytial virus subgroup A in China between 2011 and 2015. Sci. Rep. 7, 5501.
27. Tsukagoshi, H., Ishioka, T., Noda, M., Kozawa, K., Kimura, H., 2013. Molecular epidemiology of respiratory viruses in virus-induced asthma. Front. Microbiol. 4, 278.
28. Tulloch, R.L., Kok, J., Carter, I., Dwyer, D.E., Eden, J.S., 2021. An amplicon-based approach for the whole-genome sequencing of human metapneumovirus. Viruses 13.
29. Van Den Hoogen, B.G., De Jong, J.C., Groen, J., Kuiken, T., De Groot, R., Fouchier, R.A., Osterhaus, A.D., 2001. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat. Med. 7, 719–724.
30. Vicente, D., Montes, M., Cilla, G., Perez-Yarza, E.G., Perez-Trallero, E., 2006. Differences in clinical severity between genotype A and genotype B human metapneumovirus infection in children. Clin. Infect. Dis. 42, e111–113.
31. Wang, C., Wei, T., Ma, F., Wang, H., Guo, J., Chen, A., Huang, Y., Xie, Z., Zheng, L., 2021. Epidemiology and genotypic diversity of human metapneumovirus in paediatric patients with acute respiratory infection in Beijing, China. Virol. J. 18, 40.
32. Xie, Z., Xu, J., Ren, Y., Cui, A., Wang, H., Song, J., Zhang, Q., Hu, M., Xu, W., Zhang, Y., 2021a. Emerging human metapneumovirus gene duplication variants in patients with severe acute respiratory infection, China, 2017-2019. Emerg. Infect. Dis. 27, 275–277.
33. Xie, Z.B., Xu, J., Ren, Y.H., Cui, A.L., Wang, H.L., Song, J.H., Zhang, Q., Hu, M.L., Xu, W.B., Zhang, Y., 2021b. Emerging human metapneumovirus gene duplication variants in patients with severe acute respiratory infection, China, 2017-2019. Emerg. Infect. Dis. 27, 275–277.
34. Yi, L., Zou, L., Peng, J., Yu, J., Song, Y., Liang, L., Guo, Q., Kang, M., Ke, C., Song, T., Lu, J., Wu, J., 2019. Epidemiology, evolution and transmission of human metapneumovirus in Guangzhou China, 2013-2017. Sci. Rep. 9, 14022.
35. Zhu, Y., Xu, B., Li, C., Chen, Z., Cao, L., Fu, Z., Shang, Y., Chen, A., Deng, L., Bao, Y., Sun, Y., Ning, L., Yu, S., Gu, F., Liu, C., Yin, J., Shen, A., Xie, Z., Shen, K., 2021. A multicenter study of viral aetiology of community-acquired pneumonia in hospitalized children in Chinese mainland. Virol. Sin. 36, 1543–1553.
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