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Published in: BMC Infectious Diseases 1/2016

Open Access 01-12-2016 | Research article

High pneumococcal density correlates with more mucosal inflammation and reduced respiratory syncytial virus disease severity in infants

Authors: Marloes Vissers, Inge M. Ahout, Corné H. van den Kieboom, Christa E. van der Gaast de Jongh, Laszlo Groh, Amelieke J. Cremers, Ronald de Groot, Marien I. de Jonge, Gerben Ferwerda

Published in: BMC Infectious Diseases | Issue 1/2016

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Abstract

Background

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infections in infants. A small percentage of the infected infants develops a severe infection, while most of these severely ill patients were previously healthy. It remains unclear why these children develop severe RSV infections. In this study, we investigate whether pneumococcal nasopharyngeal carriage patterns correlate with mucosal inflammation and severity of disease.

Methods

In total, 105 infants hospitalized with RSV infection were included and recovery samples were taken from 42 patients. The presence and density of Streptococcus pneumoniae was determined by RT qPCR to study its relation to viral load, inflammation (MMP-9 and IL-6) and severity of RSV disease.

Results

We show that pneumococcal presence or absence in the nasopharynx does not correlate with viral load, inflammation or severity of disease. However, when pneumococcus is present in patients, a higher nasopharyngeal pneumococcal density was correlated with a higher RSV load, higher MMP-9 levels and a less severe course of disease.

Conclusions

Our results show correlations between S. pneumoniae density and viral load, inflammation and disease severity, suggesting that pneumococcal density may be an indicator for severity in paediatric RSV disease.
Appendix
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Literature
1.
go back to reference Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Arch Pediatr Adolesc Med. 1986;140(6):543.CrossRef Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Arch Pediatr Adolesc Med. 1986;140(6):543.CrossRef
2.
go back to reference Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, Auinger P, Griffin MR, Poehling KA, Erdman D. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588–98. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, Auinger P, Griffin MR, Poehling KA, Erdman D. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588–98.
3.
go back to reference Brand HK, de Groot R, Galama J, Brouwer ML, Teuwen K, Hermans PW, Melchers WJ, Warris A. Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. Pediatr Pulmonol. 2012;47(4):393–400. Brand HK, de Groot R, Galama J, Brouwer ML, Teuwen K, Hermans PW, Melchers WJ, Warris A. Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. Pediatr Pulmonol. 2012;47(4):393–400.
4.
go back to reference Simoes EA. Environmental and demographic risk factors for respiratory syncytial virus lower respiratory tract disease. J Pediatr. 2003;143(5):118–26.CrossRef Simoes EA. Environmental and demographic risk factors for respiratory syncytial virus lower respiratory tract disease. J Pediatr. 2003;143(5):118–26.CrossRef
5.
go back to reference Wang EE, Law BJ, Stephens D. Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. J Pediatr. 1995;126(2):212–9.CrossRefPubMed Wang EE, Law BJ, Stephens D. Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. J Pediatr. 1995;126(2):212–9.CrossRefPubMed
7.
8.
go back to reference Vissers M, de Groot R, Ferwerda G. Severe viral respiratory infections: are bugs bugging? Mucosal Immunol. 2014;7(2):227–38.CrossRefPubMed Vissers M, de Groot R, Ferwerda G. Severe viral respiratory infections: are bugs bugging? Mucosal Immunol. 2014;7(2):227–38.CrossRefPubMed
9.
go back to reference Avadhanula V, Wang Y, Portner A, Adderson E. Nontypeable Haemophilus influenzae and Streptococcus pneumoniae bind respiratory syncytial virus glycoprotein. J Med Microbiol. 2007;56(9):1133–7.CrossRefPubMed Avadhanula V, Wang Y, Portner A, Adderson E. Nontypeable Haemophilus influenzae and Streptococcus pneumoniae bind respiratory syncytial virus glycoprotein. J Med Microbiol. 2007;56(9):1133–7.CrossRefPubMed
10.
go back to reference Yokota S, Okabayashi T, Hirakawa S, Tsutsumi H, Himi T, Fujii N. Clarithromycin suppresses human respiratory syncytial virus infection-induced Streptococcus pneumoniae adhesion and cytokine production in a pulmonary epithelial cell line. Mediators Inflamm. 2012;2012:528568.CrossRefPubMedPubMedCentral Yokota S, Okabayashi T, Hirakawa S, Tsutsumi H, Himi T, Fujii N. Clarithromycin suppresses human respiratory syncytial virus infection-induced Streptococcus pneumoniae adhesion and cytokine production in a pulmonary epithelial cell line. Mediators Inflamm. 2012;2012:528568.CrossRefPubMedPubMedCentral
11.
go back to reference Hament JM, Kimpen JL, Fleer A, Wolfs TF. Respiratory viral infection predisposing for bacterial disease: a concise review. FEMS Immunol Med Microbiol. 1999;26(3–4):189–95.CrossRefPubMed Hament JM, Kimpen JL, Fleer A, Wolfs TF. Respiratory viral infection predisposing for bacterial disease: a concise review. FEMS Immunol Med Microbiol. 1999;26(3–4):189–95.CrossRefPubMed
12.
go back to reference Hament J-M, Aerts PC, Fleer A, van Dijk H, Harmsen T, Kimpen JL, Wolfs TF. Enhanced adherence of Streptococcus pneumoniae to human epithelial cells infected with respiratory syncytial virus. Pediatr Res. 2004;55(6):972–8. Hament J-M, Aerts PC, Fleer A, van Dijk H, Harmsen T, Kimpen JL, Wolfs TF. Enhanced adherence of Streptococcus pneumoniae to human epithelial cells infected with respiratory syncytial virus. Pediatr Res. 2004;55(6):972–8.
13.
go back to reference Smith CM, Sandrini S, Datta S, Freestone P, Shafeeq S, Radhakrishnan P, Williams G, Glenn SM, Kuipers OP, Hirst RA. Respiratory syncytial virus increases the virulence of Streptococcus pneumoniae by binding to penicillin binding protein 1a. A new paradigm in respiratory infection. Am J Respir Crit Care Med. 2014;190(2):196–207. Smith CM, Sandrini S, Datta S, Freestone P, Shafeeq S, Radhakrishnan P, Williams G, Glenn SM, Kuipers OP, Hirst RA. Respiratory syncytial virus increases the virulence of Streptococcus pneumoniae by binding to penicillin binding protein 1a. A new paradigm in respiratory infection. Am J Respir Crit Care Med. 2014;190(2):196–207.
14.
go back to reference Nguyen DT, Louwen R, Elberse K, van Amerongen G, Yuksel S, Luijendijk A, Osterhaus AD, Duprex WP, de Swart RL. Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo. PLoS One. 2015;10(5):e0127098. Nguyen DT, Louwen R, Elberse K, van Amerongen G, Yuksel S, Luijendijk A, Osterhaus AD, Duprex WP, de Swart RL. Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo. PLoS One. 2015;10(5):e0127098.
15.
go back to reference Madhi SA, Klugman KP, Group TVT. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med. 2004;10(8):811–3.CrossRefPubMed Madhi SA, Klugman KP, Group TVT. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med. 2004;10(8):811–3.CrossRefPubMed
16.
go back to reference Short KR, Vissers M, de Kleijn S, Zomer A, Kedzierska K, Grant E, Reading P, Hermans P, Ferwerda G, Diavatopoulos D. Bacterial lipopolysaccharide inhibits influenza virus infection of human macrophages and the consequent induction of CD8+ T cell immunity. J Innate Immun. 2013;6(2):129–39. Short KR, Vissers M, de Kleijn S, Zomer A, Kedzierska K, Grant E, Reading P, Hermans P, Ferwerda G, Diavatopoulos D. Bacterial lipopolysaccharide inhibits influenza virus infection of human macrophages and the consequent induction of CD8+ T cell immunity. J Innate Immun. 2013;6(2):129–39.
17.
go back to reference Nguyen DT, De Witte L, Ludlow M, Yüksel S, Wiesmüller K-H, Geijtenbeek TB, Osterhaus AD, de Swart RL. The synthetic bacterial lipopeptide Pam3CSK4 modulates respiratory syncytial virus infection independent of TLR activation. PLoS Pathog. 2010;6(8):e1001049. Nguyen DT, De Witte L, Ludlow M, Yüksel S, Wiesmüller K-H, Geijtenbeek TB, Osterhaus AD, de Swart RL. The synthetic bacterial lipopeptide Pam3CSK4 modulates respiratory syncytial virus infection independent of TLR activation. PLoS Pathog. 2010;6(8):e1001049.
18.
go back to reference Wang JH, Kwon H-J, Lee B-J, Jang YJ. Staphylococcal enterotoxins A and B enhance rhinovirus replication in A549 cells. Am J Rhinol. 2007;21(6):670–4.CrossRefPubMed Wang JH, Kwon H-J, Lee B-J, Jang YJ. Staphylococcal enterotoxins A and B enhance rhinovirus replication in A549 cells. Am J Rhinol. 2007;21(6):670–4.CrossRefPubMed
19.
go back to reference Vissers M, Remijn T, Oosting M, de Jong DJ, Diavatopoulos DA, Hermans PW, Ferwerda G. Respiratory syncytial virus infection augments NOD2 signaling in an IFN‐β‐dependent manner in human primary cells. Eur J Immunol. 2012;42(10):2727–35. Vissers M, Remijn T, Oosting M, de Jong DJ, Diavatopoulos DA, Hermans PW, Ferwerda G. Respiratory syncytial virus infection augments NOD2 signaling in an IFN‐β‐dependent manner in human primary cells. Eur J Immunol. 2012;42(10):2727–35.
20.
go back to reference Sajjan US, Jia Y, Newcomb DC, Bentley JK, Lukacs NW, LiPuma JJ, Hershenson MB. H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression. FASEB J. 2006;20(12):2121–3. Sajjan US, Jia Y, Newcomb DC, Bentley JK, Lukacs NW, LiPuma JJ, Hershenson MB. H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression. FASEB J. 2006;20(12):2121–3.
21.
go back to reference Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci. 2011;108(13):5354–9. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci. 2011;108(13):5354–9.
22.
go back to reference Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012;37(1):158–70. Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012;37(1):158–70.
23.
go back to reference Kong MY, Clancy JP, Peng N, Li Y, Szul TJ, Xu X, Oster R, Sullender W, Ambalavanan N, Blalock JE. Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus. Eur Respir J. 2014;43(4):1086–96. Kong MY, Clancy JP, Peng N, Li Y, Szul TJ, Xu X, Oster R, Sullender W, Ambalavanan N, Blalock JE. Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus. Eur Respir J. 2014;43(4):1086–96.
24.
go back to reference Brand KH, Ahout IM, de Groot R, Warris A, Ferwerda G, Hermans PW. Use of MMP‐8 and MMP‐9 to assess disease severity in children with viral lower respiratory tract infections. J Med Virol. 2012;84(9):1471–80.CrossRefPubMed Brand KH, Ahout IM, de Groot R, Warris A, Ferwerda G, Hermans PW. Use of MMP‐8 and MMP‐9 to assess disease severity in children with viral lower respiratory tract infections. J Med Virol. 2012;84(9):1471–80.CrossRefPubMed
25.
go back to reference Brand HK, Ferwerda G, Preijers F, de Groot R, Neeleman C, Staal FJ, Warris A, Hermans PW. CD4+ T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection. Pediatr Res. 2012;73(2):187–93. Brand HK, Ferwerda G, Preijers F, de Groot R, Neeleman C, Staal FJ, Warris A, Hermans PW. CD4+ T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection. Pediatr Res. 2012;73(2):187–93.
26.
go back to reference Vissers M, Hartman Y, Groh L, de Jong DJ, de Jonge MI, Ferwerda G. Recognition of Streptococcus pneumoniae and Muramyl Dipeptide by NOD2 Results in Potent Induction of MMP-9, Which Can Be Controlled by Lipopolysaccharide Stimulation. Infect Immun. 2014;82(12):4952–8.CrossRefPubMedPubMedCentral Vissers M, Hartman Y, Groh L, de Jong DJ, de Jonge MI, Ferwerda G. Recognition of Streptococcus pneumoniae and Muramyl Dipeptide by NOD2 Results in Potent Induction of MMP-9, Which Can Be Controlled by Lipopolysaccharide Stimulation. Infect Immun. 2014;82(12):4952–8.CrossRefPubMedPubMedCentral
27.
go back to reference Hong J-S, Greenlee KJ, Pitchumani R, Lee S-H, Song L-z, Shan M, Chang SH, Park PW, Dong C, Werb Z. Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J Immunol. 2011;186(11):6427–36. Hong J-S, Greenlee KJ, Pitchumani R, Lee S-H, Song L-z, Shan M, Chang SH, Park PW, Dong C, Werb Z. Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J Immunol. 2011;186(11):6427–36.
28.
go back to reference van der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis. 1997;176(2):439–44.CrossRefPubMed van der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis. 1997;176(2):439–44.CrossRefPubMed
29.
go back to reference Templeton KE, Scheltinga SA, Beersma MF, Kroes AC, Claas EC. Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza A and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4. J Clin Microbiol. 2004;42(4):1564–9.CrossRefPubMedPubMedCentral Templeton KE, Scheltinga SA, Beersma MF, Kroes AC, Claas EC. Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza A and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4. J Clin Microbiol. 2004;42(4):1564–9.CrossRefPubMedPubMedCentral
30.
go back to reference Shak JR, Cremers AJ, Gritzfeld JF, de Jonge MI, Hermans PW, Vidal JE, Klugman KP, Gordon SB. Impact of Experimental Human Pneumococcal Carriage on Nasopharyngeal Bacterial Densities in Healthy Adults. PLoS One. 2014;9(6):e98829. Shak JR, Cremers AJ, Gritzfeld JF, de Jonge MI, Hermans PW, Vidal JE, Klugman KP, Gordon SB. Impact of Experimental Human Pneumococcal Carriage on Nasopharyngeal Bacterial Densities in Healthy Adults. PLoS One. 2014;9(6):e98829.
31.
go back to reference Tettelin H, Nelson KE, Paulsen IT, Eisen JA, Read TD, Peterson S, Heidelberg J, DeBoy RT, Haft DH, Dodson RJ. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science. 2001;293(5529):498–506. Tettelin H, Nelson KE, Paulsen IT, Eisen JA, Read TD, Peterson S, Heidelberg J, DeBoy RT, Haft DH, Dodson RJ. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science. 2001;293(5529):498–506.
32.
go back to reference Nizet V, Colina KF, Almquist JR, Rubens CE, Smith AL. A virulent nonencapsulated Haemophilus influenzae. J Infect Dis. 1996;173(1):180–6.CrossRefPubMed Nizet V, Colina KF, Almquist JR, Rubens CE, Smith AL. A virulent nonencapsulated Haemophilus influenzae. J Infect Dis. 1996;173(1):180–6.CrossRefPubMed
33.
go back to reference Gritzfeld JF, Gordon SB, Cremers A. Detection limits in pneumococcal carriage. Pediatr Infect Dis J. 2013;32(4):425–6.CrossRefPubMed Gritzfeld JF, Gordon SB, Cremers A. Detection limits in pneumococcal carriage. Pediatr Infect Dis J. 2013;32(4):425–6.CrossRefPubMed
34.
go back to reference Gritzfeld J, Cremers A, Ferwerda G, Ferreira DM, Kadioglu A, Hermans PW, Gordon SB. Density and duration of experimental human pneumococcal carriage. Clin Microbiol Infect. 2014;20(12):O1145–51.CrossRefPubMedPubMedCentral Gritzfeld J, Cremers A, Ferwerda G, Ferreira DM, Kadioglu A, Hermans PW, Gordon SB. Density and duration of experimental human pneumococcal carriage. Clin Microbiol Infect. 2014;20(12):O1145–51.CrossRefPubMedPubMedCentral
35.
go back to reference Chien Y-W, Vidal JE, Grijalva CG, Bozio C, Edwards KM, Williams JV, Griffin MR, Verastegui H, Hartinger SM, Gil AI. Density interactions between Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus in the nasopharynx of young Peruvian children. Pediatr Infect Dis J. 2013;32(1):72. Chien Y-W, Vidal JE, Grijalva CG, Bozio C, Edwards KM, Williams JV, Griffin MR, Verastegui H, Hartinger SM, Gil AI. Density interactions between Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus in the nasopharynx of young Peruvian children. Pediatr Infect Dis J. 2013;32(1):72.
36.
go back to reference Suarez-Arrabal MC, Mella C, Lopez SM, Brown NV, Hall MW, Hammond S, Shiels W, Groner J, Marcon M, Ramilo O, et al. Nasopharyngeal bacterial burden and antibiotics: Influence on inflammatory markers and disease severity in infants with respiratory syncytial virus bronchiolitis. J Infect. 2015;71(4):458–69. Suarez-Arrabal MC, Mella C, Lopez SM, Brown NV, Hall MW, Hammond S, Shiels W, Groner J, Marcon M, Ramilo O, et al. Nasopharyngeal bacterial burden and antibiotics: Influence on inflammatory markers and disease severity in infants with respiratory syncytial virus bronchiolitis. J Infect. 2015;71(4):458–69.
37.
go back to reference Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis J. 2001;20(10):951–8.CrossRefPubMed Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis J. 2001;20(10):951–8.CrossRefPubMed
38.
go back to reference Chappell K, Brealey J, Mackay I, Bletchly C, Hugenholtz P. Respiratory syncytial virus infection is associated with increased bacterial load in the upper respiratory tract in young children. J Med Microbiol Diagnosis S. 2013;1:2161–0703. Chappell K, Brealey J, Mackay I, Bletchly C, Hugenholtz P. Respiratory syncytial virus infection is associated with increased bacterial load in the upper respiratory tract in young children. J Med Microbiol Diagnosis S. 2013;1:2161–0703.
39.
go back to reference Delclaux C, Delacourt C, d’Ortho M-P, Boyer V, Lafuma C, Harf A. Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane. Am J Respir Cell Mol Biol. 1996;14(3):288–95.CrossRefPubMed Delclaux C, Delacourt C, d’Ortho M-P, Boyer V, Lafuma C, Harf A. Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane. Am J Respir Cell Mol Biol. 1996;14(3):288–95.CrossRefPubMed
40.
go back to reference Yeo S-J, Yun Y-J, Lyu M-A, Woo S-Y, Woo E-R, Kim S-J, Lee H-J, Park H-K, Kook Y-H. Respiratory syncytial virus infection induces matrix metalloproteinase-9 expression in epithelial cells. Arch Virol. 2002;147(2):229–42. Yeo S-J, Yun Y-J, Lyu M-A, Woo S-Y, Woo E-R, Kim S-J, Lee H-J, Park H-K, Kook Y-H. Respiratory syncytial virus infection induces matrix metalloproteinase-9 expression in epithelial cells. Arch Virol. 2002;147(2):229–42.
41.
go back to reference DeVincenzo JP, El Saleeby CM, Bush AJ. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis. 2005;191(11):1861–8.CrossRefPubMed DeVincenzo JP, El Saleeby CM, Bush AJ. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis. 2005;191(11):1861–8.CrossRefPubMed
42.
go back to reference Fodha I, Vabret A, Ghedira L, Seboui H, Chouchane S, Dewar J, Gueddiche N, Trabelsi A, Boujaafar N, Freymuth F. Respiratory syncytial virus infections in hospitalized infants: association between viral load, virus subgroup, and disease severity. J Med Virol. 2007;79(12):1951–8. Fodha I, Vabret A, Ghedira L, Seboui H, Chouchane S, Dewar J, Gueddiche N, Trabelsi A, Boujaafar N, Freymuth F. Respiratory syncytial virus infections in hospitalized infants: association between viral load, virus subgroup, and disease severity. J Med Virol. 2007;79(12):1951–8.
43.
go back to reference Wright PF, Gruber WC, Peters M, Reed G, Zhu Y, Robinson F, Coleman-Dockery S, Graham BS. Illness severity, viral shedding, and antibody responses in infants hospitalized with bronchiolitis caused by respiratory syncytial virus. J Infect Dis. 2002;185(8):1011–8. Wright PF, Gruber WC, Peters M, Reed G, Zhu Y, Robinson F, Coleman-Dockery S, Graham BS. Illness severity, viral shedding, and antibody responses in infants hospitalized with bronchiolitis caused by respiratory syncytial virus. J Infect Dis. 2002;185(8):1011–8.
44.
go back to reference DeVincenzo JP, Buckingham SC. Relationship between respiratory syncytial virus load and illness severity in children. J Infect Dis. 2002;186(9):1376–7.CrossRefPubMed DeVincenzo JP, Buckingham SC. Relationship between respiratory syncytial virus load and illness severity in children. J Infect Dis. 2002;186(9):1376–7.CrossRefPubMed
45.
go back to reference McConnochie KM, Roghmann KJ. Parental smoking, presence of older siblings, and family history of asthma increase risk of bronchiolitis. Am J Dis Child. 1986;140(8):806–12.PubMed McConnochie KM, Roghmann KJ. Parental smoking, presence of older siblings, and family history of asthma increase risk of bronchiolitis. Am J Dis Child. 1986;140(8):806–12.PubMed
Metadata
Title
High pneumococcal density correlates with more mucosal inflammation and reduced respiratory syncytial virus disease severity in infants
Authors
Marloes Vissers
Inge M. Ahout
Corné H. van den Kieboom
Christa E. van der Gaast de Jongh
Laszlo Groh
Amelieke J. Cremers
Ronald de Groot
Marien I. de Jonge
Gerben Ferwerda
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2016
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-016-1454-x

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