Respiratory viruses are now recognized as causes of pneumonia and late airflow obstruction after HCT. Although major progress has been made in understanding disease associations and in the development of diagnostic tests, major gaps remain. One such gap is the availability of a sensitive, specific, and inexpensive multiplex diagnostic platform that detects all relevant respiratory viruses, and optimally, important bacterial pathogens, as well. Fortunately, the development of such testing methods are advancing. Once these methods are established, it will allow for the study of disease associations, and will also be essential for the development of more therapeutic options, not only in the immunosuppressed, but also in immunocompetent subjects. One key reason for the slow progress in drug development is the absence of widespread office-based testing (Nichols, et al 2008
). A systematic and comprehensive evaluation of the disease burden of these infections is also needed. Historically, only pneumonia and death were reported, however, data on airflow obstruction, health care utilization including duration of hospitalization, intensive care, and mechanical ventilation are important as well.
Another area of need is that of disease pathogenesis. Although several studies point towards lymphopenia as an important risk factor for severe manifestations of disease, the exact host defense mechanisms that lead to the devastating consequences of respiratory virus infections in HCT recipients are virtually unknown. Studies of the importance of virus load, T cell and humoral immunity, as well as cytokine and chemokine expression, and genetics, are needed. To date, most studies focus on the early period after transplantation. More information is needed on the risk of progression and outcome, late after HCT (i.e. after the first 3 months), when lymphopenia is rare. There may be a birectional relationship between respiratory viruses and lung function late after transplantion; viral infections may lead to prolonged airflow obstruction, and preexisting airflow obstruction may predispose individuals to progression of lower tract disease and poor outcome.
There is also very limited knowledge of what determines the risk of virus acquisition. Studies are ongoing to determine whether there are genetic predispositions. Furthermore, major progress is needed in regards to treatment options for respiratory viruses.
With the exception of treatment for influenza virus, there are no potent and easy to administer drug treatments. The development of novel treatment and prevention options for RSV has the highest priority. Existing options (ribavirin, palivizumab, polyclonal antibody preparations) are of only moderate efficacy, complicated to give, and often prohibitively expensive--especially when given to adult patients. Several lead compounds are currently being evaluated (Nichols, et al 2008
), and a recently established volunteer infection model could speed up drug and vaccine development (Devincenzo, et al 2007
). In the past, it has been difficult to conduct randomized clinical trials for RSV in HCT recipients (Boeckh, et al 2007
). However, the failure to complete these trials was directly linked to the level of complexity required to give aerosolized ribavirin (Boeckh, et al 2007
). With novel antiviral compounds that are easy to administer, do not require hospitalization, and lack serious side effects it should be highly feasible to conduct clinical trials in the HCT setting.
Another unmet medical need is a treatment option for parainfluenzavirus, the most prevalent of the respiratory viruses with known disease associations (Nichols, et al 2008
). Also, well designed prospective observational studies are needed to define the disease burden of recently discovered respiratory viruses such as novel coronaviruses, human bocavirus, and polymaviruses. Finally, even today we see symptomatic patients in whom we are unable to make a virologic diagnosis despite multiplex PCR testing. Thus, we will probably see additional, yet to be discovered, respiratory viruses in the future.