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Published in: Virology Journal 1/2022

Open Access 01-12-2022 | Influenza Virus | Research

Profiles and predictive value of cytokines in children with human metapneumovirus pneumonia

Authors: Wen-qing Xiang, Lin Li, Bing-han Wang, Ahmed Faisal Ali, Wei Li

Published in: Virology Journal | Issue 1/2022

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Abstract

Background

Human metapneumovirus (HMPV) is an important cause of respiratory tract infections in young children. Early innate immune response to HMPV is focused on induction of antiviral interferons (IFNs) and other pro-inflammatory cytokines that are critical for the formation of adaptive immune responses. To evaluate the predictive value of Th1/Th2 cytokines which include IL-2, IL-4, IL-6, IL-10, INF-γ and TNF-α in pneumonia caused by HMPV.

Methods

A retrospective study was performed among 59 pneumonia pediatric patients with HMPV infection and 33 healthy children as the control cohort, which was detected by the immunofluorescence assay, and the Th1/Th2 cytokines were measured by flow cytometry. 131 children infected with Influenza virus A (IVA) and 41 children infected with influenza virus B (IVB) were detected by RT-PCR assay in throat swabs.

Results

When compared with the healthy children, children who were infected with HMPV pneumonia had a significantly lower level of IL-2 (p < 0.001) and higher levels of IL-4 (p < 0.001), IL-6 (p = 0.001), IL-10 (p < 0.001), and IFN-γ (p < 0.001). Compared with patients diagnosed with IVA or IVB infection, HMPV-positive patients had significantly higher levels of IL-4 (p < 0.001 and < 0.001), IFN-γ (p < 0.001 and < 0.001), and TNF-α (p < 0.001 and 0.016). Moreover, compared with IVA patients, HMPV-positive patients had a significantly lower level of IL-6 (p = 0.033). Finally, when comparing cytokine levels among the patients with HMPV pneumonia, IL-6 and TNF-α levels were found to be significantly higher in the severe group than the mild group (p = 0.027 and 0.049). The IL-6 and TNF-α were used to differentiate between mild symptoms and severe symptoms in children diagnosed with HMPV pneumonia with an AUC of 0.678 (95% CI 0.526–0.829) and 0.658 (95% CI 0.506–0.809), respectively.

Conclusion

Our study indicated that difference in cytokine trends depending on the virus species. The levels of IL-4, TNF-α and IFN-γ were significantly distinguished in children infected with HMPV versus IVA and IVB. IL-6 and TNF-α may be helpful in assessing the severity and prognosis of HMPV infection.
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Literature
1.
go back to reference van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, Osterhaus AD. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7(6):719–24.CrossRef van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, Osterhaus AD. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7(6):719–24.CrossRef
2.
go back to reference Panda S, Mohakud NK, Pena L, Kumar S. Human metapneumovirus: review of an important respiratory pathogen. Int J Infect Dis. 2014;25:45–52.CrossRef Panda S, Mohakud NK, Pena L, Kumar S. Human metapneumovirus: review of an important respiratory pathogen. Int J Infect Dis. 2014;25:45–52.CrossRef
3.
go back to reference de Zwart AES, Riezebos-Brilman A, Alffenaar JC, van den Heuvel ER, Gan CT, van der Bij W, Kerstjens HAM, Verschuuren EAM. Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients. Am J Transplant. 2020;20(12):3529–37.CrossRef de Zwart AES, Riezebos-Brilman A, Alffenaar JC, van den Heuvel ER, Gan CT, van der Bij W, Kerstjens HAM, Verschuuren EAM. Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients. Am J Transplant. 2020;20(12):3529–37.CrossRef
4.
go back to reference Broor S, Bharaj P, Chahar HS. Human metapneumovirus: a new respiratory pathogen. J Biosci. 2008;33(4):483–93.CrossRef Broor S, Bharaj P, Chahar HS. Human metapneumovirus: a new respiratory pathogen. J Biosci. 2008;33(4):483–93.CrossRef
5.
go back to reference Holzemer NF, Hasvold JJ, Pohl KJ, Ashbrook MJ, Meert KL, Quasney MW. Human metapneumovirus infection in hospitalized children. Respir Care. 2020;65(5):650–7.CrossRef Holzemer NF, Hasvold JJ, Pohl KJ, Ashbrook MJ, Meert KL, Quasney MW. Human metapneumovirus infection in hospitalized children. Respir Care. 2020;65(5):650–7.CrossRef
6.
go back to reference van den Hoogen BG, Osterhaus DM, Fouchier RA. Clinical impact and diagnosis of human metapneumovirus infection. Pediatr Infect Dis J. 2004;23(Suppl 1):25–32.CrossRef van den Hoogen BG, Osterhaus DM, Fouchier RA. Clinical impact and diagnosis of human metapneumovirus infection. Pediatr Infect Dis J. 2004;23(Suppl 1):25–32.CrossRef
7.
go back to reference Wang X, Li Y, Deloria-Knoll M, Madhi SA, Cohen C, Ali A, Basnet S, Bassat Q, Brooks WA, Chittaganpitch M, et al. Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study. Lancet Glob Health. 2021;9(1):e33–43.CrossRef Wang X, Li Y, Deloria-Knoll M, Madhi SA, Cohen C, Ali A, Basnet S, Bassat Q, Brooks WA, Chittaganpitch M, et al. Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study. Lancet Glob Health. 2021;9(1):e33–43.CrossRef
8.
go back to reference Døllner H, Risnes K, Radtke A, Nordbø SA. Outbreak of human metapneumovirus infection in norwegian children. Pediatr Infect Dis J. 2004;23(5):436–40.CrossRef Døllner H, Risnes K, Radtke A, Nordbø SA. Outbreak of human metapneumovirus infection in norwegian children. Pediatr Infect Dis J. 2004;23(5):436–40.CrossRef
9.
go back to reference Singleton RJ, Bulkow LR, Miernyk K, DeByle C, Pruitt L, Hummel KB, Bruden D, Englund JA, Anderson LJ, Lucher L, et al. Viral respiratory infections in hospitalized and community control children in Alaska. J Med Virol. 2010;82(7):1282–90.CrossRef Singleton RJ, Bulkow LR, Miernyk K, DeByle C, Pruitt L, Hummel KB, Bruden D, Englund JA, Anderson LJ, Lucher L, et al. Viral respiratory infections in hospitalized and community control children in Alaska. J Med Virol. 2010;82(7):1282–90.CrossRef
10.
go back to reference Moe N, Krokstad S, Stenseng IH, Christensen A, Skanke LH, Risnes KR, Nordbø SA, Døllner H. Comparing human metapneumovirus and RSV: viral co-detections, genotypes and risk factors for severe disease. PLoS ONE. 2017;12(1):e0170200.CrossRef Moe N, Krokstad S, Stenseng IH, Christensen A, Skanke LH, Risnes KR, Nordbø SA, Døllner H. Comparing human metapneumovirus and RSV: viral co-detections, genotypes and risk factors for severe disease. PLoS ONE. 2017;12(1):e0170200.CrossRef
11.
go back to reference Biacchesi S, Skiadopoulos MH, Boivin G, Hanson CT, Murphy BR, Collins PL, Buchholz UJ. Genetic diversity between human metapneumovirus subgroups. Virology. 2003;315(1):1–9.CrossRef Biacchesi S, Skiadopoulos MH, Boivin G, Hanson CT, Murphy BR, Collins PL, Buchholz UJ. Genetic diversity between human metapneumovirus subgroups. Virology. 2003;315(1):1–9.CrossRef
12.
go back to reference Huck B, Scharf G, Neumann-Haefelin D, Puppe W, Weigl J, Falcone V. Novel human metapneumovirus sublineage. Emerg Infect Dis. 2006;12(1):147–50.CrossRef Huck B, Scharf G, Neumann-Haefelin D, Puppe W, Weigl J, Falcone V. Novel human metapneumovirus sublineage. Emerg Infect Dis. 2006;12(1):147–50.CrossRef
13.
go back to reference Nao N, Saikusa M, Sato K, Sekizuka T, Usuku S, Tanaka N, Nishimura H, Takeda M. Recent molecular evolution of human Metapneumovirus HMPV: subdivision of HMPV A2b strains. Microorganisms. 2020;8(9):1280.CrossRef Nao N, Saikusa M, Sato K, Sekizuka T, Usuku S, Tanaka N, Nishimura H, Takeda M. Recent molecular evolution of human Metapneumovirus HMPV: subdivision of HMPV A2b strains. Microorganisms. 2020;8(9):1280.CrossRef
14.
go back to reference Principi N, Bosis S, Esposito S. Human metapneumovirus in paediatric patients. Clin Microbiol Infect. 2006;12(4):301–8.CrossRef Principi N, Bosis S, Esposito S. Human metapneumovirus in paediatric patients. Clin Microbiol Infect. 2006;12(4):301–8.CrossRef
15.
go back to reference Butt SA, Maceira VP, McCallen ME, Stellrecht KA. Comparison of three commercial RT-PCR systems for the detection of respiratory viruses. J Clin Virol. 2014;61(3):406–10.CrossRef Butt SA, Maceira VP, McCallen ME, Stellrecht KA. Comparison of three commercial RT-PCR systems for the detection of respiratory viruses. J Clin Virol. 2014;61(3):406–10.CrossRef
16.
go back to reference Lin CY, Hwang D, Chiu NC, Weng LC, Liu HF, Mu JJ, Liu CP, Chi H. Increased detection of viruses in children with respiratory tract infection using PCR. Int J Environ Res Public Health. 2020;17(2):564.CrossRef Lin CY, Hwang D, Chiu NC, Weng LC, Liu HF, Mu JJ, Liu CP, Chi H. Increased detection of viruses in children with respiratory tract infection using PCR. Int J Environ Res Public Health. 2020;17(2):564.CrossRef
17.
go back to reference Emanuels A, Hawes SE, Newman KL, Martin ET, Englund JA, Tielsch JM, Kuypers J, Khatry SK, LeClerq SC, Katz J, Chu HY. Respiratory viral coinfection in a birth cohort of infants in rural Nepal. Influenza Other Respir Viruses. 2020;14(6):739–46.CrossRef Emanuels A, Hawes SE, Newman KL, Martin ET, Englund JA, Tielsch JM, Kuypers J, Khatry SK, LeClerq SC, Katz J, Chu HY. Respiratory viral coinfection in a birth cohort of infants in rural Nepal. Influenza Other Respir Viruses. 2020;14(6):739–46.CrossRef
18.
go back to reference Rodriguez PE, Frutos MC, Adamo MP, Cuffini C, Cámara JA, Paglini MG, Moreno L, Cámara A. Human metapneumovirus: epidemiology and genotype diversity in children and adult patients with respiratory infection in Córdoba, Argentina. PLoS ONE. 2020;15(12):e0244093.CrossRef Rodriguez PE, Frutos MC, Adamo MP, Cuffini C, Cámara JA, Paglini MG, Moreno L, Cámara A. Human metapneumovirus: epidemiology and genotype diversity in children and adult patients with respiratory infection in Córdoba, Argentina. PLoS ONE. 2020;15(12):e0244093.CrossRef
19.
go back to reference Malmo J, Moe N, Krokstad S, Ryan L, Loevenich S, Johnsen IB, Espevik T, Nordbø SA, Døllner H, Anthonsen MW. Cytokine profiles in human metapneumovirus infected children: identification of genes involved in the antiviral response and pathogenesis. PLoS ONE. 2016;11(5):e0155484.CrossRef Malmo J, Moe N, Krokstad S, Ryan L, Loevenich S, Johnsen IB, Espevik T, Nordbø SA, Døllner H, Anthonsen MW. Cytokine profiles in human metapneumovirus infected children: identification of genes involved in the antiviral response and pathogenesis. PLoS ONE. 2016;11(5):e0155484.CrossRef
20.
go back to reference Ye Q, Shao WX, Shang SQ, Pan YX, Shen HQ, Chen XJ. Epidemiological characteristics and immune status of children with RSV. J Med Virol. 2015;2:323–9.CrossRef Ye Q, Shao WX, Shang SQ, Pan YX, Shen HQ, Chen XJ. Epidemiological characteristics and immune status of children with RSV. J Med Virol. 2015;2:323–9.CrossRef
21.
go back to reference Xu XJ, Tang YM, Liao C, Song H, Yang SL, Xu WQ, Shi SW, Zhao N. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med. 2013;39(2):319–26.CrossRef Xu XJ, Tang YM, Liao C, Song H, Yang SL, Xu WQ, Shi SW, Zhao N. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med. 2013;39(2):319–26.CrossRef
22.
go back to reference Ye Q, Shao WX, Xu XJ, Yang YZ. The clinical application value of cytokines in treating infectious diseases. PLoS ONE. 2014;9(6):e98745.CrossRef Ye Q, Shao WX, Xu XJ, Yang YZ. The clinical application value of cytokines in treating infectious diseases. PLoS ONE. 2014;9(6):e98745.CrossRef
23.
go back to reference Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, Thomson A, British Thoracic Society Standards of Care Committee. British thoracic society guidelines for the management of community acquiredpneumonia in children: Update 2011. Thorax. 2011;66:ii1–23.CrossRef Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, Thomson A, British Thoracic Society Standards of Care Committee. British thoracic society guidelines for the management of community acquiredpneumonia in children: Update 2011. Thorax. 2011;66:ii1–23.CrossRef
24.
go back to reference Respiratory Group Pediatrics Society of Chinese Medical Association. Editorial Board of Chinese Journal of Pediatrics. Guidelines for the management of community-acquired pneumonia in children 2013 revision. Chin J Pediatr. 2013;5110:856–62. Respiratory Group Pediatrics Society of Chinese Medical Association. Editorial Board of Chinese Journal of Pediatrics. Guidelines for the management of community-acquired pneumonia in children 2013 revision. Chin J Pediatr. 2013;5110:856–62.
25.
go back to reference Geiser J, Boivin G, Huang S, Constant S, Kaiser L, Tapparel C, Essaidi-Laziosi M. RSV and HMPV infections in 3D tissue cultures: mechanisms involved in virus-host and virus-virus interactions. Viruses. 2021;13(1):139.CrossRef Geiser J, Boivin G, Huang S, Constant S, Kaiser L, Tapparel C, Essaidi-Laziosi M. RSV and HMPV infections in 3D tissue cultures: mechanisms involved in virus-host and virus-virus interactions. Viruses. 2021;13(1):139.CrossRef
26.
go back to reference Yu H, Hu W, Song X, Zhao Y. Immune modulation of platelet-derived mitochondria on memory CD4 + T cells in humans. Int J Mol Sci. 2020;21(17):6295.CrossRef Yu H, Hu W, Song X, Zhao Y. Immune modulation of platelet-derived mitochondria on memory CD4 + T cells in humans. Int J Mol Sci. 2020;21(17):6295.CrossRef
27.
go back to reference Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–9.CrossRef Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–9.CrossRef
28.
go back to reference Alvarez R, Tripp RA. The immune response to human metapneumovirus is associated with aberrant immunity and impaired virus clearance in BALB/c mice. J Virol. 2005;79(10):5971–8.CrossRef Alvarez R, Tripp RA. The immune response to human metapneumovirus is associated with aberrant immunity and impaired virus clearance in BALB/c mice. J Virol. 2005;79(10):5971–8.CrossRef
29.
go back to reference Welliver RC Sr. The immune response to respiratory syncytial virus infection: friend or foe? Clin Rev Allergy Immunol. 2008;34(2):163–73.CrossRef Welliver RC Sr. The immune response to respiratory syncytial virus infection: friend or foe? Clin Rev Allergy Immunol. 2008;34(2):163–73.CrossRef
30.
go back to reference Huck B, Neumann-Haefelin D, Schmitt-Graeff A, Weckmann M, Mattes J, Ehl S, Falcone V. Human metapneumovirus induces more severe disease and stronger innate immune response in BALB/c mice as compared with respiratory syncytial virus. Respir Res. 2007;8(1):6.CrossRef Huck B, Neumann-Haefelin D, Schmitt-Graeff A, Weckmann M, Mattes J, Ehl S, Falcone V. Human metapneumovirus induces more severe disease and stronger innate immune response in BALB/c mice as compared with respiratory syncytial virus. Respir Res. 2007;8(1):6.CrossRef
31.
go back to reference Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, Zhang P, Liu X, Gao G, Liu F, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123–30.CrossRef Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, Zhang P, Liu X, Gao G, Liu F, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123–30.CrossRef
32.
go back to reference Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, Foster PS, Yang M. TNF-α and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease. J Immunol. 2016;196(9):3547–58.CrossRef Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, Foster PS, Yang M. TNF-α and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease. J Immunol. 2016;196(9):3547–58.CrossRef
33.
go back to reference Pandey P, Karupiah G. Targeting tumour necrosis factor to ameliorate viral pneumonia. FEBS J. 2022;289(4):883–900.CrossRef Pandey P, Karupiah G. Targeting tumour necrosis factor to ameliorate viral pneumonia. FEBS J. 2022;289(4):883–900.CrossRef
34.
go back to reference Cui AH, Zhao J, Liu SX, Hao YS. Associations of IL-4, IL-6, and IL-12 levels in peripheral blood with lung function, cellular immune function, and quality of life in children with moderate-to-severe asthma. Med Baltim. 2017;96(12):e6265.CrossRef Cui AH, Zhao J, Liu SX, Hao YS. Associations of IL-4, IL-6, and IL-12 levels in peripheral blood with lung function, cellular immune function, and quality of life in children with moderate-to-severe asthma. Med Baltim. 2017;96(12):e6265.CrossRef
35.
go back to reference Palavecino CE, Céspedes PF, Gómez RS, Kalergis AM, Bueno SM. Immunization with a recombinant bacillus Calmette–Guerin strain confers protective Th1 immunity against the human metapneumovirus. J Immunol. 2014;192(1):214–23.CrossRef Palavecino CE, Céspedes PF, Gómez RS, Kalergis AM, Bueno SM. Immunization with a recombinant bacillus Calmette–Guerin strain confers protective Th1 immunity against the human metapneumovirus. J Immunol. 2014;192(1):214–23.CrossRef
36.
go back to reference Gu Y, Zuo X, Zhang S, Ouyang Z, Jiang S, Wang F, Wang G. The mechanism behind influenza virus cytokine storm. Viruses. 2021;13(7):1362.CrossRef Gu Y, Zuo X, Zhang S, Ouyang Z, Jiang S, Wang F, Wang G. The mechanism behind influenza virus cytokine storm. Viruses. 2021;13(7):1362.CrossRef
37.
go back to reference Wang S, Le TQ, Kurihara N, Chida J, Cisse Y, Yano M, Kido H. Influenza virus- cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza. J Infect Dis. 2010;202(7):991–1001.CrossRef Wang S, Le TQ, Kurihara N, Chida J, Cisse Y, Yano M, Kido H. Influenza virus- cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza. J Infect Dis. 2010;202(7):991–1001.CrossRef
Metadata
Title
Profiles and predictive value of cytokines in children with human metapneumovirus pneumonia
Authors
Wen-qing Xiang
Lin Li
Bing-han Wang
Ahmed Faisal Ali
Wei Li
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2022
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-022-01949-1

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