Effect of respiratory microflorae colonization on short and long-time outcomes of respiratory syncytial virus infection in children: A scoping review

Abstract

Respiratory syncytial virus (RSV) is an essential cause of lower respiratory tract infection in children under 2 years of age, especially under 6 months. In decades, studies have shown that the respiratory tract microflorae with RSV infection were related to disease severity and played a role in the development of recurrent wheezing, but the effect of respiratory microflorae on RSV infection are still underestimated. This study aims to conclude the effect of respiratory microflorae colonization on RSV infectious disease severity and recurrent wheezing and provide suggestions for future research directions from the perspective of respiratory tract florae. We conducted a scoping review. Studies were eligible if they reported on the effect of microflorae on RSV infectious diseases among children. We exacted the following information: title, publication time, first author’s country, and article type. We finally included 33 articles in this scoping review. The number of studies rapidly increased since 2013 and the highest number of hospitalizations were reported in children <2 years. More than half (69.70%) were conducted in America and most studies are original studies (57.58%). The Review highlighted that the respiratory microflorae played an important role in RSV infectious disease severity and recurrent wheezing. We found that Streptococcus pneumoniae (S. pn), Haemophilus influenza (HI), Moraxella catarrhalis (M.ca), and Staphylococcus aureus (SA) were the dominant profiles in children with RSV infection. Understanding the respective role of respiratory microflorae on RSV infection and its mechanisms would improve prevention and treatment strategies from the perspective of microflorae.

Keywords

childhood asthma / disease severity / microflorae / recurrent wheezing / respiratory syncytial virus

References

[1] de SwartRL. Location matters in RSV protection. Cell Host Microbe. 2022; 30(1):15-16.

[2] Rosas-SalazarC, ShiltsMH, TovchigrechkoA, et al. Nasopharyngeal Lactobacillus is associated with a reduced risk of childhood wheezing illnesses following acute respiratory syncytial virus infection in infancy. J Allergy Clin Immunol. 2018; 142(5):1447-1456.e9.

[3] StewartCJ, Mansbach JM, WongMC, et al. Associations of nasopharyngeal metabolome and microbiome with severity among infants with bronchiolitis. A multiomic analysis. Am J Respir Crit Care Med. 2017; 196(7):882-891.

[4] de Steenhuijsen PitersWAA, BinkowskaJ, Bogaert D. Early life microbiota and respiratory tract infections. Cell Host Microbe. 2020; 28(2):223-232.

[5] PaynterS, WareRS, LuceroMG, et al. Malnutrition: a risk factor for severe respiratory syncytial virus infection and hospitalization. Pediatr Infect Dis J. 2014; 33(3):267-271.

[6] HasegawaK, Mansbach JM, AjamiNJ, et al. Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis. Eur Respir J. 2016; 48(5):1329-1339.

[7] LiY, WangX, BlauDM, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019:a systematic analysis. Lancet. 2022; 399(10340):2047-2064.

[8] PtaschinskiC, LukacsNW. Early life respiratory syncytial virus infection and asthmatic responses. Immunol Allergy Clin. 2019; 39(3):309-319.

[9] LanaspaM, BassatQ, MedeirosMM, Muñoz-Almagro C. Respiratory microbiota and lower respiratory tract disease. Expert Rev Anti Infect Ther. 2017; 15(7):703-711.

[10] HydeER, Petrosino JF, PiedraPA, CamargoCA, Jr, Espinola JA, MansbachJM. Nasopharyngeal Proteobacteria are associated with viral etiology and acute wheezing in children with severe bronchiolitis. J Allergy Clin Immunol. 2014; 133(4):1220-1222.

[11] de Steenhuijsen PitersWAA, HeinonenS, HasratR, et al. Nasopharyngeal microbiota, host transcriptome, and disease severity in children with respiratory syncytial virus infection. Am J Respir Crit Care Med. 2016; 194(9):1104-1115.

[12] HasegawaK, Mansbach JM, AjamiNJ, et al. The relationship between nasopharyngeal CCL5 and microbiota on disease severity among infants with bronchiolitis. Allergy. 2017; 72(11):1796-1800.

[13] HasegawaK, Mansbach JM, AjamiNJ, et al. Serum cathelicidin, nasopharyngeal microbiota, and disease severity among infants hospitalized with bronchiolitis. J Allergy Clin Immunol. 2017; 139(4):1383-1386.e6.

[14] RaitaY, Pérez-Losada M, FreishtatRJ, et al. Integrated omics endotyping of infants with respiratory syncytial virus bronchiolitis and risk of childhood asthma. Nat Commun. 2021; 12(1):3601.

[15] Rosas-SalazarC, TangZZ, ShiltsMH, et al. Upper respiratory tract bacterial-immune interactions during respiratory syncytial virus infection in infancy. J Allergy Clin Immunol. 2022; 149(3):966-976.

[16] VissersM, AhoutIM, van den KieboomCH, et al. High pneumococcal density correlates with more mucosal inflammation and reduced respiratory syncytial virus disease severity in infants. BMC Infect Dis. 2016; 16(1):129.

[17] HoeboerSH, van der Geest PJ, NieboerD, GroeneveldABJ. The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis. Clin Microbiol Infect. 2015; 21(5):474-481.

[18] KarlssonEA, Meliopoulos VA, van de VeldeNC, et al. A perfect storm: increased colonization and failure of vaccination leads to severe secondary bacterial infection in influenza virus-infected obese mice. mBio. 2017; 8(5):e00889.-e00817.

[19] LongX, ShiPR, LuoZX, et al. Impact of Streptococcus pneumoniae colonization in upper airway on the clinical manifestations of children with respiratory syncytial virus infection. Chin J Pediatr. 2022; 60(7):694-699.

[20] BrealeyJC, Chappell KJ, GalbraithS, et al. Streptococcus pneumoniae colonization of the nasopharynx is associated with increased severity during respiratory syncytial virus infection in young children. Respirology. 2018; 23(2):220-227.

[21] EderveenTHA, Ferwerda G, AhoutIM, et al. Haemophilus is overrepresented in the nasopharynx of infants hospitalized with RSV infection and associated with increased viral load and enhanced mucosal CXCL8 responses. Microbiome. 2018; 6(1):10.

[22] MansbachJM, Hasegawa K, PiedraPA, et al. Haemophilus-dominant nasopharyngeal microbiota is associated with delayed clearance of respiratory syncytial virus in infants hospitalized for bronchiolitis. J Infect Dis. 2019; 219(11):1804-1808.

[23] SonawaneAR, TianL, ChuCY, et al. Microbiome-transcriptome interactions related to severity of respiratory syncytial virus infection. Sci Rep. 2019; 9(1):13824.

[24] StewartCJ, Mansbach JM, AjamiNJ, et al. Serum metabolome is associated with the nasopharyngeal microbiota and disease severity among infants with bronchiolitis. J Infect Dis. 2019; 219(12):2005-2014.

[25] Diaz-DiazA, BunsowE, Garcia-MaurinoC, et al. Nasopharyngeal codetection of Haemophilus influenzae and Streptococcus pneumoniae shapes respiratory syncytial virus disease outcomes in children. J Infect Dis. 2022; 225(5):912-923.

[26] ZhangX-Y, ZhangX, ZhangN, et al. Airway microbiome, host immune response and recurrent wheezing in infants with severe respiratory syncytial virus bronchiolitis. Pediatr Allergy Immunol. 2020; 31(3):281-289.

[27] MansbachJM, LunaPN, ShawCA, et al. Increased Moraxella and Streptococcus species abundance after severe bronchiolitis is associated with recurrent wheezing. J Allergy Clin Immunol. 2020; 145(2):518-527.e8.

[28] LynchJP, SikderMA, CurrenBF, et al. The influence of the microbiome on early-life severe viral lower respiratory infections and asthma-food for thought? Front Immunol. 2017; 8:156.

[29] NeumannRP, HiltyM, XuB-B, et al. Nasal microbiota and symptom persistence in acute respiratory tract infections in infants. ERJ Open Res. 2018; 4(4):00066-02018.

[30] BrandHK, de Groot R, GalamaJMD, et al. Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. Pediatr Pulmonol. 2012; 47(4):393-400.

[31] AmpofoK, BenderJ, ShengX-M, et al. Seasonal invasive pneumococcal disease in children: role of preceding respiratory viral infection. Pediatrics. 2008; 122(2):229-237.

[32] NguyenDT, LouwenR, ElberseK, et al. Streptococcus pneumoniae enhances human respiratory syncytial virus infection in vitro and in vivo. PLoS One. 2015; 10(5):e0127098.

[33] WeinbergerDM, Klugman KP, SteinerCA, SimonsenL, ViboudC. Association between respiratory syncytial virus activity and pneumococcal disease in infants: a time series analysis of US hospitalization data. PLoS Med. 2015; 12(1):e1001776.

[34] GensollenT, IyerSS, KasperDL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. 2016; 352(6285):539-544.

[35] JenneweinMF, Abu-Raya B, JiangY-W, AlterG, Marchant A. Transfer of maternal immunity and programming of the newborn immune system. Semin Immunopathol. 2017; 39(6):605-613.

[36] FølsgaardNV, Schjørring S, ChawesBL, et al. Pathogenic bacteria colonizing the airways in asymptomatic neonates stimulates topical inflammatory mediator release. Am J Respir Crit Care Med. 2013; 187(6):589-595.

[37] TeoSM, MokD, PhamK, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015; 17(5):704-715.

[38] TeoSM, TangHHF, MokD, et al. Airway microbiota dynamics uncover a critical window for interplay of pathogenic bacteria and allergy in childhood respiratory disease. Cell Host Microbe. 2018; 24(3):341-352.e5.

[39] KongM, ZhangWW, SewellK, et al. Azithromycin treatment vs placebo in children with respiratory syncytial virus-induced respiratory failure: a phase 2 randomized clinical trial. JAMA Netw Open. 2020; 3(4):e203482.

[40] SrinivasanM, Bacharier LB, GossCW, et al. The azithromycin to prevent wheezing following severe RSV bronchiolitis-II clinical trial: rationale, study design, methods, and characteristics of study population. Contemp Clin Trials Commun. 2021; 22:100798.

[41] FonsecaW, Malinczak CA, FujimuraK, et al. Maternal gut microbiome regulates immunity to RSV infection in offspring. J Exp Med. 2021; 218(11):e20210235.

[42] AlbaC, Aparicio M, González-Martínez F, et al. Nasal and fecal microbiota and immunoprofiling of infants with and without RSV bronchiolitis. Front Microbiol. 2021; 12:667832.

[43] LeyerGJ, LiS-G, MubasherME, Reifer C, OuwehandAC. Probiotic effects on cold and influenza-like symptom incidence and duration in children. Pediatrics. 2009; 124(2): e172-e179.

[44] HardingJN, Siefker D, VuL, et al. Altered gut microbiota in infants is associated with respiratory syncytial virus disease severity. BMC Microbiol. 2020; 20(1):140.

[45] FujimuraKE, LynchSV. Microbiota in allergy and asthma and the emerging relationship with the gut microbiome. Cell Host Microbe. 2015; 17(5):592-602.

[46] HasegawaK, Linnemann RW, MansbachJM, et al. The fecal microbiota profile and bronchiolitis in infants. Pediatrics. 2016; 138(1):e20160218.

[47] KanchongkittiphonW, Zhou Y-J, VellaR, et al. Characterization of gut microbiome in infants with severe respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol. 2019; 143(2):AB3.

[48] LangleyR, Griffin S, BastenH, BoxallJ, Templeton K, UngerS. Viruses in the gut of children with bronchiolitis and viral induced wheeze – further insight into the gut-lung-axis. Eur Res J. 2019; 54: PA1002.

[49] SencioV, Machado MG, TrotteinF. The lung-gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes. Mucosal Immunol. 2021; 14(2):296-304.

[50] GrayJ, OehrleK, WorthenG, Alenghat T, WhitsettJ, DeshmukhH. Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection. Sci Transl Med. 2017; 9(376):eaaf9412.

[51] ReymanM, van Houten MA, van BaarleD, et al. Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life. Nat Commun. 2019; 10(1):4997.

[52] HeimisdottirLH, LinBM, ChoH, et al. Metabolomics insights in early childhood caries. J Dent Res. 2021; 100(6):615-622.

[53] RajagopalaSV, Bakhoum NG, PakalaSB, et al. Metatranscriptomics to characterize respiratory virome, microbiome, and host response directly from clinical samples. Cell Rep Methods. 2021; 1(6):100091.

[54] RaitaY, Camargo CAJ, BochkovYA, et al. Integrated-omics endotyping of infants with rhinovirus bronchiolitis and risk of childhood asthma. J Allergy Clin Immunol. 2021; 147(6):2108-2117.

[55] BakkerOB, Aguirre-Gamboa R, SannaS, et al. Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses. Nat Immunol. 2018; 19(7):776-786.

[56] LangelierC, Kalantar KL, MoazedF, et al. Integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults. Proc Natl Acad Sci USA. 2018; 115(52): E12353-E12362.

[57] AnsariI, Raddatz G, GutekunstJ, et al. The microbiota programs DNA methylation to control intestinal homeostasis and inflammation. Nat Microbiol. 2020; 5(4):610-619.

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2024 The Author(s). Pediatric Discovery published by John Wiley & Sons Australia, Ltd on behalf of Children’s Hospital of Chongqing Medical University.