Skip to main content
NCBI home page
Wiley - PMC COVID-19 Collection logoLink to Wiley - PMC COVID-19 Collection
. 2003 Aug 18;71(2):290–297. doi: 10.1002/jmv.10482

RSV‐induced bronchiolitis but not upper respiratory tract infection is accompanied by an increased nasal IL‐18 response

Inesz J van Benten 1, Cornelis M van Drunen 1,✉, Laurens P Koopman 2, Alex KleinJan 1, Barbara C van Middelkoop 1, Leon de Waal 3, Albert DME Osterhaus 3, Herman J Neijens 2, Wytske J Fokkens 1,4
PMCID: PMC7166712  PMID: 12938205

Abstract

The aim of this study was to investigate potential differences in the local nasal immune response between bronchiolitis and upper respiratory tract infection induced by respiratory syncytial virus (RSV). Nasal brush samples were obtained from 14 infants with RSV bronchiolitis and from 8 infants with RSV upper respiratory tract infection. The samples were taken during infection (acute phase) and 2–4 weeks later (convalescent phase). Cytospin preparations were stained immunohistochemically for T cells, macrophages, and eosinophils. Staining also took place for intercellular adhesion molecule‐1 (ICAM‐1), T‐helper 1 (Th1)‐like (interleukin‐12 [IL‐12], interferon‐γ [IFN‐γ]), Th2‐like (IL‐4, IL‐10), and proinflammatory cytokines (IL‐6, IL‐8, IL‐18). During both RSV‐induced bronchiolitis and upper respiratory tract infection, cellular inflammation was observed. This was characterised by an increase in the numbers of nasal macrophages, which tended to be higher in bronchiolitis than in upper respiratory tract infection. Numbers of T lymphocytes and ICAM‐1 positive cells increased during both bronchiolitis and upper respiratory tract infection. There were no differences between numbers in the groups. Interestingly, a distinct nasal proinflammatory cytokine response was observed in RSV‐induced bronchiolitis. This is characterised by an increase in the number of IL‐18 positive cells. This increase is specific for bronchiolitis, as a similar increase could not be detected in RSV‐induced upper respiratory tract infection. Numbers of IL‐6 and IL‐12 positive cells were higher in both bronchiolitis and upper respiratory tract infection, and there were no differences between the groups. By contrast, the number of IL‐8, IFN‐γ, IL‐4, and IL‐10‐positive cells remained constant. In conclusion, clear differences were found in nasal immune responses of children with RSV‐induced upper respiratory tract infection or bronchiolitis. The induction of a strong IL‐18 response was typical for bronchiolitis, as this could not be observed in RSV‐induced upper respiratory tract infection, and could explain the eosinophilia that is observed frequently during bronchiolitis. J. Med. Virol. 71:290–297, 2003. © 2003 Wiley‐Liss, Inc.

Keywords: cytokines, infant, bronchiolitis, RSV

REFERENCES

  1. Abu‐Harb M, Bell F, Finn A, Rao WH, Nixon L, Shale D, Everard ML. 1999. IL‐8 and neutrophil elastase levels in the respiratory tract of infants with RSV bronchiolitis. Eur Respir J 14: 139–143. [DOI] [PubMed] [Google Scholar]
  2. Alaaeddine N, Olee T, Hashimoto S, Creighton‐Achermann L, Lotz M. 2001. Production of the chemokine RANTES by articular chondrocytes and role in cartilage degradation. Arthritis Rheum 44: 1633–1643. [DOI] [PubMed] [Google Scholar]
  3. Arnold R, Humbert B, Werchau H, Gallati H, Konig W. 1994. Interleukin‐8, interleukin‐6, and soluble tumour necrosis factor receptor type I release from a human pulmonary epithelial cell line (A549) exposed to respiratory syncytial virus. Immunology 82: 126–133. [PMC free article] [PubMed] [Google Scholar]
  4. Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F, Draaisma JT, Geelen SM, van Vught HJ, Kimpen JL. 1999. Peripheral blood cytokine responses and disease severity in respiratory syncytial virus bronchiolitis. Eur Respir J 14: 144–149. [DOI] [PubMed] [Google Scholar]
  5. Brandenburg AH, Kleinjan A, van Het Land B, Moll HA, Timmerman HH, de Swart RL, Neijens HJ, Fokkens W, Osterhaus AD. 2000. Type 1‐like immune response is found in children with respiratory syncytial virus infection regardless of clinical severity. J Med Virol 62: 267–277. [PubMed] [Google Scholar]
  6. Buck RH, Cordle CT, Thomas DJ, Winship TR, Schaller JP, Dugle JE. 2002. Longitudinal study of intracellular T cell cytokine production in infants compared to adults. Clin Exp Immunol 128: 490–497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Campbell E, Kunkel SL, Strieter RM, Lukacs NW. 2000. Differential roles of IL‐18 in allergic airway disease: induction of eotaxin by resident cell populations exacerbates eosinophil accumulation. J Immunol 164: 1096–1102. [DOI] [PubMed] [Google Scholar]
  8. Chalmers IM, Janossy G, Contreras M, Navarrete C. 1998. Intracellular cytokine profile of cord and adult blood lymphocytes. Blood 92: 11–18. [PubMed] [Google Scholar]
  9. De Weerd W, Twilhaar WN, Kimpen JL. 1998. T cell subset analysis in peripheral blood of children with RSV bronchiolitis. Scand J Infect Dis 30: 77–80. [DOI] [PubMed] [Google Scholar]
  10. Dinarello CA. 1999. IL‐18: A Th1‐inducing, proinflammatory cytokine and new member of the IL‐1 family. J Allergy Clin Immunol 103: 11–24. [DOI] [PubMed] [Google Scholar]
  11. Ehlenfield DR, Cameron K, Welliver RC. 2000. Eosinophilia at the time of respiratory syncytial virus bronchiolitis predicts childhood reactive airway disease. Pediatrics 105: 79–83. [DOI] [PubMed] [Google Scholar]
  12. Fisher RG, Gruber WC, Edwards KM, Reed GW, Tollefson SJ, Thompson JM, Wright PF. 1997. Twenty years of outpatient respiratory syncytial virus infection: a framework for vaccine efficacy trials. Pediatrics 99: E7. [DOI] [PubMed] [Google Scholar]
  13. Fujishima H, Saito I, Okamoto Y, Takeuchi T, Tsubota K. 1998. Respiratory syncytial virus‐induced interleukin‐4 production by human conjunctival epithelial cells contributes to allergy: preliminary study. Curr Eye Res 17: 656–662. [PubMed] [Google Scholar]
  14. Garofalo R, Dorris A, Ahlstedt S, Welliver RC. 1994. Peripheral blood eosinophil counts and eosinophil cationic protein content of respiratory secretions in bronchiolitis: relationship to severity of disease. Pediatr Allergy Immunol 5: 111–117. [DOI] [PubMed] [Google Scholar]
  15. Garofalo RP, Patti J, Hintz KA, Hill V, Ogra PL, Welliver RC. 2001. Macrophage inflammatory protein‐1alpha (not T helper type 2 cytokines) is associated with severe forms of respiratory syncytial virus bronchiolitis. J Infect Dis 184: 393–399. [DOI] [PubMed] [Google Scholar]
  16. Godthelp T, Holm AF, Fokkens WJ, Doornenbal P, Mulder PG, Hoefsmit EC, Kleinjan A, Prens EP, Rijntjes E. 1996. Dynamics of nasal eosinophils in response to a nonnatural allergen challenge in patients with allergic rhinitis and control subjects: a biopsy and brush study. J Allergy Clin Immunol 97: 800–811. [DOI] [PubMed] [Google Scholar]
  17. Grigg J, Riedler J, Robertson CF. 1999. Bronchoalveolar lavage fluid cellularity and soluble intercellular adhesion molecule‐1 in children with colds. Pediatr Pulmonol 28: 109–116. [DOI] [PubMed] [Google Scholar]
  18. Makela MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, Kimpimaki M, Blomqvist S, Hyypia T, Arstila P. 1998. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 36: 539–542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. 2001. Interleukin‐18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev 12: 53–72. [DOI] [PubMed] [Google Scholar]
  20. Nicholson KG, Kent J, Ireland DC. 1993. Respiratory viruses and exacerbations of asthma in adults. BMJ 307: 982–986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Noah TL, Henderson FW, Wortman IA, Devlin RB, Handy J, Koren HS, Becker S. 1995. Nasal cytokine production in viral acute upper respiratory infection of childhood. J Infect Dis 171: 584–592. [DOI] [PubMed] [Google Scholar]
  22. Pit DS, Polderman AM, Schulz‐Key H, Soboslay PT. 2000. Prenatal immune priming with helminth infections: parasite‐specific cellular reactivity and Th1 and Th2 cytokine responses in neonates. Allergy 55: 732–739. [DOI] [PubMed] [Google Scholar]
  23. Roman M, Calhoun WJ, Hinton KL, Avendano LF, Simon V, Escobar AM, Gaggero A, Diaz PV. 1997. Respiratory syncytial virus infection in infants is associated with predominant Th‐2‐like response. Am J Respir Crit Care Med 156: 190–195. [DOI] [PubMed] [Google Scholar]
  24. Rothbarth PH, Habova JJ, Masurel N. 1988. Rapid diagnosis of infections caused by respiratory syncytial virus. Infection 16: 252. [DOI] [PubMed] [Google Scholar]
  25. Sung RY, Hui SH, Wong CK, Lam CW, Yin J. 2001. A comparison of cytokine responses in respiratory syncytial virus and influenza A infections in infants. Eur J Pediatr 160: 117–122. [DOI] [PubMed] [Google Scholar]
  26. Tanaka H, Miyazaki N, Oashi K, Teramoto S, Shiratori M, Hashimoto M, Ohmichi M, Abe S. 2001. IL‐18 might reflect disease activity in mild and moderate asthma exacerbation. J Allergy Clin Immunol 107: 331–336. [DOI] [PubMed] [Google Scholar]
  27. Tripp RA, Moore D, Barskey At, Jones L, Moscatiello C, Keyserling H, Anderson LJ. 2002. Peripheral blood mononuclear cells from infants hospitalized because of respiratory syncytial virus infection express T helper‐1 and T helper‐2 cytokines and CC chemokine messenger RNA. J Infect Dis 185: 1388–1394. [DOI] [PubMed] [Google Scholar]
  28. van Schaik SM, Tristram DA, Nagpal IS, Hintz KM, Welliver RC II, Welliver RC. 1999. Increased production of IFN‐gamma and cysteinyl leukotrienes in virus‐induced wheezing. J Allergy Clin Immunol 103: 630–636. [DOI] [PubMed] [Google Scholar]
  29. Wang SZ, Hallsworth PG, Dowling KD, Alpers JH, Bowden JJ, Forsyth KD. 2000. Adhesion molecule expression on epithelial cells infected with respiratory syncytial virus. Eur Respir J 15: 358–366. [DOI] [PubMed] [Google Scholar]
  30. Wang W, Tanaka T, Okamura H, Sugita M, Higa S, Kishimoto T, Suemura M. 2001. Interleukin‐18 enhances the production of interleukin‐8 by eosinophils. Eur J Immunol 31: 1010–1016. [DOI] [PubMed] [Google Scholar]
  31. Welliver RC, Duffy L. 1993. The relationship of RSV‐specific immunoglobulin E antibody responses in infancy, recurrent wheezing, and pulmonary function at age 7–8 years. Pediatr Pulmonol 15: 19–27. [DOI] [PubMed] [Google Scholar]
  32. Yamada G, Shijubo N, Shigehara K, Okamura H, Kurimoto M, Abe S. 2000. Increased levels of circulating interleukin‐18 in patients with advanced tuberculosis. Am J Respir Crit Care Med 161: 1786–1789. [DOI] [PubMed] [Google Scholar]
  33. Yoshida A, Takahashi HK, Nishibori M, Iwagaki H, Yoshino T, Morichika T, Yokoyama M, Kondo E, Akagi T, Tanaka N. 2001. IL‐18‐induced expression of intercellular adhesion molecule‐1 in human monocytes: involvement in IL‐12 and IFN‐gamma production in PBMC. Cell Immunol 210: 106–115. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Virology are provided here courtesy of Wiley

RESOURCES