Severe Human Lower Respiratory Tract Illness Caused by Respiratory Syncytial Virus and Influenza Virus Is Characterized by the Absence of Pulmonary Cytotoxic Lymphocyte Responses

Abstract Background. Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI. Methods. We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more-severe illness. We analyzed lung tissue from infants with fatal cases of RSV and influenza virus LRTI to determine the types of inflammatory cells present. Autopsy tissues were studied for the lymphotoxin granzyme and the apoptosis marker caspase 3. Results. Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza virus, rather than RSV, infection. Lung tissues from infants with fatal RSV and influenza virus LRTI demonstrated an extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis. Conclusions. Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication, and apoptotic crisis.

[1]  A. McMichael,et al.  CELL-MEDIATED CYTOTOXIC RESPONSE TO RESPIRATORY SYNCYTIAL VIRUS IN INFANTS WITH BRONCHIOLITIS , 1987, The Lancet.

[2]  K. Carlsen,et al.  RESPIRATORY SYNCYTIAL VIRUS INFECTIONS IN OSLO 1972–1978 , 1980, Acta paediatrica Scandinavica.

[3]  R. Couch,et al.  Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  R. Garofalo,et al.  Differential response of dendritic cells to human metapneumovirus and respiratory syncytial virus. , 2006, American journal of respiratory cell and molecular biology.

[5]  C. Lam,et al.  A comparison of cytokine responses in respiratory syncytial virus and influenza A infections in infants , 2001, European Journal of Pediatrics.

[6]  Peter Cameron,et al.  A major outbreak of severe acute respiratory syndrome in Hong Kong. , 2003, The New England journal of medicine.

[7]  L. Bont,et al.  Local interferon-gamma levels during respiratory syncytial virus lower respiratory tract infection are associated with disease severity. , 2001, The Journal of infectious diseases.

[8]  D. Greenberg,et al.  Comparison of Human Metapneumovirus, Respiratory Syncytial Virus and Influenza A Virus Lower Respiratory Tract Infections in Hospitalized Young Children , 2006, The Pediatric infectious disease journal.

[9]  S. Ehl,et al.  Virus clearance and immunopathology by CD8+ T cells during infection with respiratory syncytial virus are mediated by IFN‐γ  , 2002, European journal of immunology.

[10]  C. Mandl,et al.  Reduced interferon-gamma expression in peripheral blood mononuclear cells of infants with severe respiratory syncytial virus disease. , 1999, American journal of respiratory and critical care medicine.

[11]  B. Graham,et al.  Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. , 1991, The Journal of clinical investigation.

[12]  J. Durbin,et al.  Respiratory syncytial virus-induced immunoprotection and immunopathology. , 2004, Viral immunology.

[13]  F. Chew,et al.  Seasonal variation in respiratory syncytial virus chest infection in the tropics , 2002, Pediatric pulmonology.

[14]  R. Garofalo,et al.  A comparison of epidemiologic and immunologic features of bronchiolitis caused by influenza virus and respiratory syncytial virus , 2005, Journal of medical virology.

[15]  D. Imagawa,et al.  Epidemic bronchiolitis and pneumonitis related to respiratory syncytial virus. , 1961, JAMA.

[16]  M. Fujimura,et al.  Bronchoalveolar lavage cell analysis in measles viral pneumonia. , 1993, The European respiratory journal.

[17]  H. Campbell,et al.  The magnitude of mortality from acute respiratory infections in children under 5 years in developing countries. , 1992, World health statistics quarterly. Rapport trimestriel de statistiques sanitaires mondiales.

[18]  R. Smyth,et al.  The pathogenesis of respiratory syncytial virus disease in childhood. , 2002, British medical bulletin.

[19]  T. Braciale,et al.  RSV-induced immunopathology: dynamic interplay between the virus and host immune response. , 2002, Virology.

[20]  S. Leader,et al.  Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999 , 2002, The Pediatric infectious disease journal.

[21]  J. Tregoning,et al.  Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection , 2005, Clinical Microbiology Reviews.

[22]  W. Gruber,et al.  Illness severity, viral shedding, and antibody responses in infants hospitalized with bronchiolitis caused by respiratory syncytial virus. , 2002, The Journal of infectious diseases.

[23]  E. Yunis,et al.  Demonstration of respiratory syncytial virus in an autopsy series. , 1990, Pediatric pathology.

[24]  R. Chanock,et al.  Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. , 1969, American journal of epidemiology.

[25]  W. Hall,et al.  Clinical and physiological manifestations of bronchiolitis and pneumonia. Outcome of respiratory syncytial virus. , 1979, American journal of diseases of children.

[26]  S. Furukawa,et al.  ACTIVATION OF PERIPHERAL BLOOD CD8+ T CELLS IN ADENOVIRUS INFECTION , 2000, The Pediatric infectious disease journal.

[27]  T. Braciale,et al.  Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and peripheral CD8+ T-cell memory in the respiratory tract , 2002, Nature Medicine.

[28]  Pk Smith,et al.  Leucocyte populations in respiratory syncytial virus‐induced bronchiolitis , 2001, Journal of paediatrics and child health.

[29]  A. Milner,et al.  Analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection. , 1994, Archives of disease in childhood.

[30]  R. Garofalo,et al.  Macrophage Inflammatory Protein-1α (Not T Helper Type 2 Cytokines) Is Associated with Severe Forms of Respiratory Syncytial Virus Bronchiolitis , 2001 .

[31]  W. P. Glezen,et al.  HLA-restricted CD8+ cytotoxic T lymphocyte, interferon-gamma, and interleukin-4 responses to respiratory syncytial virus infection in infants and children. , 2001, The Journal of infectious diseases.

[32]  S. J. Hoffman,et al.  Differential production of inflammatory cytokines in primary infection with human metapneumovirus and with other common respiratory viruses of infancy. , 2004, The Journal of infectious diseases.

[33]  J. Renauld,et al.  Alpha and Lambda Interferon Together Mediate Suppression of CD4 T Cells Induced by Respiratory Syncytial Virus , 2006, Journal of Virology.

[34]  Li Lin,et al.  [Pathogenesis of respiratory syncytial virus infection]. , 2006, Zhonghua er ke za zhi = Chinese journal of pediatrics.

[35]  A. Bush,et al.  Respiratory syncytial virus load predicts disease severity in previously healthy infants. , 2005, The Journal of infectious diseases.

[36]  R. Tasker,et al.  Lymphocyte apoptosis in acute respiratory syncytial virus bronchiolitis , 2004, Clinical and experimental immunology.

[37]  N. Hussain,et al.  Neutrophil apoptosis during the development and resolution of oleic acid-induced acute lung injury in the rat. , 1998, American journal of respiratory cell and molecular biology.

[38]  R. Couch,et al.  Respiratory syncytial virus pneumonia in hospitalized adult patients with leukemia. , 1995, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[39]  R. Pinto,et al.  T Helper 1/T Helper 2 Cytokine Imbalance in Respiratory Syncytial Virus Infection Is Associated With Increased Endogenous Plasma Cortisol , 2006, Pediatrics.

[40]  B. Graham,et al.  Respiratory syncytial virus immunobiology and pathogenesis. , 2002, Virology.

[41]  R. Chanock,et al.  Cell-mediated Immunity to Respiratory Syncytial Virus Induced by Inactivated Vaccine or by Infection , 1976, Pediatric Research.

[42]  H. Whittle,et al.  The clinical spectrum of respiratory syncytial virus disease in The Gambia. , 1998, The Pediatric infectious disease journal.

[43]  Y. Koh,et al.  Bronchoalveolar lavage cellular composition in acute asthma and acute bronchiolitis. , 2000, The Journal of pediatrics.

[44]  R. Truitt,et al.  Characterization of human proliferative T cell responses to adenovirus. , 1995, The Journal of infectious diseases.

[45]  C B Hall,et al.  R ESPIRATORY S YNCYTIAL V IRUS AND P ARAINFLUENZA V IRUS , 2001 .

[46]  M. Perkins,et al.  Primary respiratory syncytial virus infection in mice , 1988, Journal of medical virology.