Respiratory Virus Studies

M. Boeckh, W.G. Nichols, J. Englund, J. Kuypers, J. Chien, A. Peck, V. Erard

Respiratory virus infections are a major cause morbidity and mortality after HCT. RSV, Influenzavirus A and B, and parainfluenzaviruses are well established causes of morbidity and mortality.   The role of recently discovered viruses such as human metapneumovirus (hMPV) and the coronaviruses is less clear.   Areas of research include:

1. Subclinical shedding of respiratory viruses. Subclinical viral shedding may be an important means of person-to-person transmission. It may also be a predictor for clinically symptomatic infection and disease.   Patients will be longitudinally monitored with weekly nasal washes using both conventional (culture, DFA) and quantitative molecular detection methods for respiratory viruses.   Taqman-based quantitative PCR assays have been developed by Jane Kuypers, PhD, for RSV (A and B), Influenza (A and B), parainfluenzaviruses, hMPV, rhinovirus and coronaviruses.
2. Significance of recently discovered viruses. Recently developed quantitative molecular assays for hMPV and SARS-coronavirus will be used to define the role of these viruses in upper and lower respiratory tract disease.
3. Defining immunologic control of respiratory viruses (RSV, hMPV).   The role of virus-specific humoral and cell-mediated immumity in acquisition and progression from upper to lower tract disease are examined using neutralizing antibody and ELISA techniques as well as ELISPOT and intracellular cytokine techniques. This is done in part in collaboration with the University of Rochester (E.Walsh and A. Falsey).   The role cytokines in disease pathogenesis is another area of research.
4. Respiratory viruses and airflow obstruction after HCT.   A longitudinal study is ongoing to determine the impact of respiratory virus infections on the development of airflow obstruction after HCT.
5. Role of community respiratory virus infections in late airflow obstruction.   Recent data suggest that CRV infection is a risk factor for late airflow obstruction in HCT recipients.   A program has been initiated in collaboration with the Program in Pulmonology to determine the role of CRV in late airflow obstruction.   A large prospective cohort study is being designed. Subjects will be followed CRV using molecular detection techniques and results will be correlated with pulmonary function test results.
6. Outcome of RSV pneumonia.   RSV pneumonia is associated with poor outcome after HCT with reported mortality rates of approximately 40-50%.   Factors that determine outcome are unknown.   Specifically, the relative impact of antibody preparations (e.g. pooled intravenous immunoglobulin, RSV-specific immunoglobulin, RSV-specific monoclonal antibodies [palivizumab]) which are often given in combination with aerosolized ribavirin for treatment of RSV pneumonia is poorly defined.   An international multicenter survey is presently ongoing to develop a large database of RSV pneumonia cases. Since a recently started randomized trial had to be discontinued due to slow accrual, this data based will provide an opportunity to analyze the role of various treatment regimens by controlling for confounding host factors.   Please contact Dr. Michael Boeckh ( mboeckh@fhcrc.org ) if you would like to participate in this survey.  

Respiratory Viruses: Recent Publications:

Nichols, W.G., Corey, L., Gooley, T., Davis, C., Boeckh, M.   Parainfluenza infections after BMT: risk factors and the effect of antiviral therapy. Blood 98 : 573-578, 2001 .

Boeckh, M., Berrey, M.M., Bowden, R.A., Crawford, S.W., Balsley, J., Corey, L.   Phase I Evaluation of the RSV-Specific Humanized Monoclonal Antibody Palivizumab (MEDI-493) In Hematopoietic Stem Cell Transplant Recipients.   J Infect Dis 184 :350-54, 2001.

Ison, M.G., Hayden, F., Kaiser, L., Corey, L., Boeckh, M . Rhinovirus infections in recipients of hematopoietic stem cell transplantation with pneumonia. Clin. Infect. Dis. , 36 : 1139-43, 2003 .

Nichols, W.G., Erdman, D. D., Han, A., Zukerman, C., Corey, L., Boeckh, M . Prolonged Outbreak of Human Parainfluenza Virus 3 Infection in a Stem Cell Transplant Outpatient Department: Insights from Molecular Epidemiologic Analysis. Biol Blood Marrow Transplant 10 :58-64, 2004 .

Nichols, W.G., Guthrie, K.A., Corey, L., Englund, J., Boeckh, M. Influenza Infections After Hematopoietic Cell Transplantation: Risk Factors, Mortality And The Effect Of Antiviral Therapy. Clin Inf Dis 39 :1300-6, 2004 .

Abstracts

Boeckh M , Englund J, Carpenter M, Baker C, Cross A, Fernandez H, Riser L, Whitley R for the NIAID Collaborative Antiviral Study Group. Randomized Controlled Multicenter Trial of Aerosolized Ribavirin for RSV Upper Respiratory Tract in Stem Cell Transplant Recipients. RSV 2003 Symposium, Stone Mountain, GA, 11/8-11/2003.

Erard, V., Chien, J.W., Kim, H.W., Nichols, W.G. Flowers, M.E., Martin, P.J., Corey, L., Boeckh, M. Community respiratory virus infections and airflow obstruction after myeloablative allogeneic haematopoietic stem cell transplantation: impact of virus species and infection localization. 31 st   Annual Meeting of the EBMT, Prague, Czech Republic, 3/19-23, 2005 (abstract O239) [oral presentation].

Boeckh, M., Gooley, T., Englund, J., Chien, J., Crawford, S.W., Bowden, R., Corey, L. RSV infection in HCT recipients: risk factors for acquisition and lower tract disease, and impact on mortality. Blood 2004; 104 (11): 57a (abstract 187) [oral presentation].

Englund, J.A.*, Nichols, W.G., Kuypers, J, Hackman, R.C.,Morrow, R.A., Fredricks, D.N., Corey, L. Boeckh, M. Fatal Human Metapneumovirus Infection in Stem Cell Transplant Recipients. Blood 2004; 104 (11): 58a (abstract 189) [oral presentation].

Nichols WG, Gooley T, Boeckh, M.   Community-Acquired Respiratory Syncytial Virus and Parainfluenza Virus Infections After Hematopoietic Stem Cell Transplantation: The Fred Hutchinson Cancer Research Center Experience.   Biol. Blood Marrow Transplant . 7 Supp l:11S-15S, 2001.

Review Articles

Boeckh, M. Other Viruses after Hematopoietic Cell Transplantation.   In: Thomas’ Hematopoietic Cell Transplantation, 3 rd Edition. Editors: K.G. Blume, S.J. Forman, F.R. Appelbaum. Blackwell Publishing , Oxford, UK. Pages 757-768, 2004 .