RSV Infection — Not for Kids Only
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《新英格兰医药杂志》
It is ironic that respiratory syncytial virus (RSV) infection in adults, though recognized for several decades, has been overlooked, at least in part, because of the importance of RSV in the pediatric population. The report by Falsey et al. in this issue of the Journal has placed the public health dimensions of RSV infection in adults in perspective.1 Though there are no immediate clinical implications of this study, it does have important repercussions for public health strategy and for the prioritization of the development of vaccines and antiviral agents.
Several important features of the study design used by Falsey et al. deserve emphasis because they contribute substantially to the report's significance. Most common respiratory viral and bacterial infections are of short duration. It is therefore no surprise that cross-sectional studies regarding these infections abound in the literature and indeed provide valuable information regarding disease presentation, management, and prognosis. Prospective longitudinal studies in this field are few because of expense and complexity, but such studies provide unique perspectives, as exemplified by this report and others.1,2 With a prospective longitudinal design, baseline characteristics of the patients before the acquisition of infection can be clearly defined. The importance of clearly defined cohorts is well illustrated by the observed differences in the effect of RSV infection on healthy and high-risk groups — a distinction that would not have been recognized if this study had been confined to acutely ill, hospitalized patients. The establishment of baseline characteristics also allows for an accurate assessment of changes in measures — for example, changes in titers of antibody to RSV.
Another goal of the study design was to conduct an investigation for influenzavirus infection simultaneously with the search for RSV infection. This structure provides a frame of reference to understand the epidemiology and clinical consequences of RSV infection. However, because vaccination prevents and attenuates a substantial proportion of influenza infections, the findings of this study apply only to populations with similarly high rates of influenza vaccination (>90 percent).3 In such populations, Falsey et al. have shown that the symptoms of RSV infection and influenza were similar and that RSV infection was twice as prevalent as influenza. In otherwise healthy elderly patients, RSV infection was a milder disease than influenza and was an uncommon cause of hospitalization or death. On the other hand, among elderly patients who had coexisting cardiac and pulmonary illnesses, the consequences of RSV infection (as measured in terms of emergency room visits, hospitalization rates, and mortality) were similar to those of influenza.
With the advent of molecular diagnostics, additional techniques that diagnose viral infections more accurately and rapidly than culture and serologic testing are now available. These techniques provide nonculture detection of viruses in respiratory secretions, either by reverse-transcriptase–polymerase chain reaction (RT-PCR) or by direct immunofluorescence staining with monoclonal antibodies.4 Falsey et al. used RT-PCR in addition to viral culture and serologic testing, to enhance the diagnostic yield and provide a more accurate picture of the epidemiology of RSV infection. However, one must be cautious in making a diagnosis of RSV infection solely on the basis of a positive RT-PCR result. Colonization with RSV in patients with stable chronic obstructive pulmonary disease as detected by RT-PCR has been reported.5,6 This raises the possibility that the higher frequency of RSV infection reported in the high-risk cohort may reflect overdiagnosis on the basis of the RT-PCR assay in such colonized patients. In the study by Falsey et al., however, only 20 percent of cases of RSV infection were diagnosed by RT-PCR alone, and 83 percent of patients with a positive RT-PCR assay had immune responses. RT-PCR assay for RSV at baseline in the prospective cohorts would have further allayed this concern.
A well-recognized phenomenon in the pathophysiology of respiratory tract infection is the viral–bacterial interaction, with simultaneous or sequential infections often occurring. The value of this study would have been enhanced if detailed diagnostic testing for bacterial infection had been included to establish what proportion of the illnesses involved a concomitant bacterial infection and what proportion represented viral processes alone.7 A more complete understanding of the epidemiology and pathogenesis of respiratory infections and consequently more appropriate treatment would be obtained if future research were to analyze for viral and bacterial infections simultaneously.
Treatment of RSV infection in the elderly is largely supportive. Ribavirin has shown marginal efficacy in infants in some trials.8,9 However, the limited efficacy and high cost of ribavirin have limited its use to the treatment of immunocompromised patients and early treatment of severe RSV infection. Other antiviral agents are still in preclinical development. Palivizumab is a humanized monoclonal antibody against F protein that has become the standard for the prevention of RSV infection in high-risk infants; however, the agent is untested in the elderly.10 Clearly, there is a need for the development of better therapies for RSV infection.
Establishment of RSV as an important pathogen in elderly and high-risk adults underscores the need for the development of vaccines that are effective in these populations. RSV causes repeated infections throughout life, raising the question of whether it will be possible to induce protective immune responses by vaccination. Several observations from experimental challenge studies in adults, epidemiologic studies in infants, and clinical trials involving passive immunization support the feasibility of developing effective vaccines for RSV.11 The presence of secretory neutralizing antibody correlates with protection against upper respiratory tract infection by RSV, serum neutralizing antibody to RSV is protective against lower respiratory tract infection, and cell-mediated immune responses directed against internal viral proteins appear to terminate infection.11
The populations that will benefit most from an effective RSV vaccine are infants and the elderly. Various vaccines will probably be needed for these target populations. Vaccine development for RSV was considerably slowed by the occurrence of enhanced or augmented disease after natural infection by RSV in seronegative infants who received formalin-inactivated RSV vaccine in the 1960s. Infants have immature immune systems that have not been exposed to RSV. Attenuated live-virus vaccines are most promising for infants since such vaccines can elicit a pattern of a potentially protective immune response that parallels natural disease, thus avoiding the induction of an immune response associated with enhanced disease. By contrast, the elderly have aging immune systems that have been exposed to the virus and often have coexisting, age-related illnesses. Subunit vaccines are most likely to be useful for immunization of elderly people and high-risk children and adults. Clinical trials of several subunit vaccines are under way.11,12
The World Health Organization has designated RSV as a high-priority pathogen for vaccine development. However, during the past decade, the enthusiasm for developing RSV vaccines has declined substantially among vaccine-development companies.9 A combination of the inherent scientific challenges, the high-risk nature of the target populations, and the enormous cost of vaccine development probably accounts for the lower priority given to RSV vaccine programs. Compounding the problem is a general lack of public awareness of RSV infection. Perhaps adults who have lost their parents or grandparents to RSV infection will form advocacy groups.
Falsey et al. have provided us with a new understanding of the significance of RSV infection in adults, which should lead to increased vigilance for this infection on the part of the clinician. Furthermore, these observations should provide an impetus to renew research on the treatment and prevention of RSV infection — progress that is far from satisfactory at present.
Dr. Murphy reports having a licensing agreement for bacterial vaccine development with Wyeth.
Source Information
From the Department of Medicine, Veterans Affairs Western New York Healthcare System; and the Department of Medicine, University at Buffalo, State University of New York — both in Buffalo, N.Y.
References
Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:1749-1759.
Sethi S, Evans N, Grant BJB, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:465-471.
Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, Dejsomritrutai W, Charoenratanakul S. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest 2004;125:2011-2020.
Rovida F, Percivalle E, Zavattoni M, et al. Monoclonal antibodies versus reverse transcription-PCR for detection of respiratory viruses in a patient population with respiratory tract infections admitted to hospital. J Med Virol 2005;75:336-347.
Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1618-1623.
Borg I, Rohde G, Loseke S, et al. Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases. Eur Respir J 2003;21:944-951.
Madhi SA, Klugman KP. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 2004;10:811-813.
Welliver RC. Respiratory syncytial virus infection: therapy and prevention. Paediatr Respir Rev 2004;5:Suppl A:S127-S133.
Maggon K, Barik S. New drugs and treatment for respiratory syncytial virus. Rev Med Virol 2004;14:149-168.
Fenton C, Scott LJ, Plosker GL. Palivizumab: a review of its use as prophylaxis for serious respiratory syncytial virus infection. Paediatr Drugs 2004;6:177-197.
Polack FP, Karron RA. The future of respiratory syncytial virus vaccine development. Pediatr Infect Dis J 2004;23:Suppl:S65-S73.
Durbin AP, Karron RA. Progress in the development of respiratory syncytial virus and parainfluenza virus vaccines. Clin Infect Dis 2003;37:1668-1677.(Sanjay Sethi, M.D., and T)
Several important features of the study design used by Falsey et al. deserve emphasis because they contribute substantially to the report's significance. Most common respiratory viral and bacterial infections are of short duration. It is therefore no surprise that cross-sectional studies regarding these infections abound in the literature and indeed provide valuable information regarding disease presentation, management, and prognosis. Prospective longitudinal studies in this field are few because of expense and complexity, but such studies provide unique perspectives, as exemplified by this report and others.1,2 With a prospective longitudinal design, baseline characteristics of the patients before the acquisition of infection can be clearly defined. The importance of clearly defined cohorts is well illustrated by the observed differences in the effect of RSV infection on healthy and high-risk groups — a distinction that would not have been recognized if this study had been confined to acutely ill, hospitalized patients. The establishment of baseline characteristics also allows for an accurate assessment of changes in measures — for example, changes in titers of antibody to RSV.
Another goal of the study design was to conduct an investigation for influenzavirus infection simultaneously with the search for RSV infection. This structure provides a frame of reference to understand the epidemiology and clinical consequences of RSV infection. However, because vaccination prevents and attenuates a substantial proportion of influenza infections, the findings of this study apply only to populations with similarly high rates of influenza vaccination (>90 percent).3 In such populations, Falsey et al. have shown that the symptoms of RSV infection and influenza were similar and that RSV infection was twice as prevalent as influenza. In otherwise healthy elderly patients, RSV infection was a milder disease than influenza and was an uncommon cause of hospitalization or death. On the other hand, among elderly patients who had coexisting cardiac and pulmonary illnesses, the consequences of RSV infection (as measured in terms of emergency room visits, hospitalization rates, and mortality) were similar to those of influenza.
With the advent of molecular diagnostics, additional techniques that diagnose viral infections more accurately and rapidly than culture and serologic testing are now available. These techniques provide nonculture detection of viruses in respiratory secretions, either by reverse-transcriptase–polymerase chain reaction (RT-PCR) or by direct immunofluorescence staining with monoclonal antibodies.4 Falsey et al. used RT-PCR in addition to viral culture and serologic testing, to enhance the diagnostic yield and provide a more accurate picture of the epidemiology of RSV infection. However, one must be cautious in making a diagnosis of RSV infection solely on the basis of a positive RT-PCR result. Colonization with RSV in patients with stable chronic obstructive pulmonary disease as detected by RT-PCR has been reported.5,6 This raises the possibility that the higher frequency of RSV infection reported in the high-risk cohort may reflect overdiagnosis on the basis of the RT-PCR assay in such colonized patients. In the study by Falsey et al., however, only 20 percent of cases of RSV infection were diagnosed by RT-PCR alone, and 83 percent of patients with a positive RT-PCR assay had immune responses. RT-PCR assay for RSV at baseline in the prospective cohorts would have further allayed this concern.
A well-recognized phenomenon in the pathophysiology of respiratory tract infection is the viral–bacterial interaction, with simultaneous or sequential infections often occurring. The value of this study would have been enhanced if detailed diagnostic testing for bacterial infection had been included to establish what proportion of the illnesses involved a concomitant bacterial infection and what proportion represented viral processes alone.7 A more complete understanding of the epidemiology and pathogenesis of respiratory infections and consequently more appropriate treatment would be obtained if future research were to analyze for viral and bacterial infections simultaneously.
Treatment of RSV infection in the elderly is largely supportive. Ribavirin has shown marginal efficacy in infants in some trials.8,9 However, the limited efficacy and high cost of ribavirin have limited its use to the treatment of immunocompromised patients and early treatment of severe RSV infection. Other antiviral agents are still in preclinical development. Palivizumab is a humanized monoclonal antibody against F protein that has become the standard for the prevention of RSV infection in high-risk infants; however, the agent is untested in the elderly.10 Clearly, there is a need for the development of better therapies for RSV infection.
Establishment of RSV as an important pathogen in elderly and high-risk adults underscores the need for the development of vaccines that are effective in these populations. RSV causes repeated infections throughout life, raising the question of whether it will be possible to induce protective immune responses by vaccination. Several observations from experimental challenge studies in adults, epidemiologic studies in infants, and clinical trials involving passive immunization support the feasibility of developing effective vaccines for RSV.11 The presence of secretory neutralizing antibody correlates with protection against upper respiratory tract infection by RSV, serum neutralizing antibody to RSV is protective against lower respiratory tract infection, and cell-mediated immune responses directed against internal viral proteins appear to terminate infection.11
The populations that will benefit most from an effective RSV vaccine are infants and the elderly. Various vaccines will probably be needed for these target populations. Vaccine development for RSV was considerably slowed by the occurrence of enhanced or augmented disease after natural infection by RSV in seronegative infants who received formalin-inactivated RSV vaccine in the 1960s. Infants have immature immune systems that have not been exposed to RSV. Attenuated live-virus vaccines are most promising for infants since such vaccines can elicit a pattern of a potentially protective immune response that parallels natural disease, thus avoiding the induction of an immune response associated with enhanced disease. By contrast, the elderly have aging immune systems that have been exposed to the virus and often have coexisting, age-related illnesses. Subunit vaccines are most likely to be useful for immunization of elderly people and high-risk children and adults. Clinical trials of several subunit vaccines are under way.11,12
The World Health Organization has designated RSV as a high-priority pathogen for vaccine development. However, during the past decade, the enthusiasm for developing RSV vaccines has declined substantially among vaccine-development companies.9 A combination of the inherent scientific challenges, the high-risk nature of the target populations, and the enormous cost of vaccine development probably accounts for the lower priority given to RSV vaccine programs. Compounding the problem is a general lack of public awareness of RSV infection. Perhaps adults who have lost their parents or grandparents to RSV infection will form advocacy groups.
Falsey et al. have provided us with a new understanding of the significance of RSV infection in adults, which should lead to increased vigilance for this infection on the part of the clinician. Furthermore, these observations should provide an impetus to renew research on the treatment and prevention of RSV infection — progress that is far from satisfactory at present.
Dr. Murphy reports having a licensing agreement for bacterial vaccine development with Wyeth.
Source Information
From the Department of Medicine, Veterans Affairs Western New York Healthcare System; and the Department of Medicine, University at Buffalo, State University of New York — both in Buffalo, N.Y.
References
Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:1749-1759.
Sethi S, Evans N, Grant BJB, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:465-471.
Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, Dejsomritrutai W, Charoenratanakul S. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest 2004;125:2011-2020.
Rovida F, Percivalle E, Zavattoni M, et al. Monoclonal antibodies versus reverse transcription-PCR for detection of respiratory viruses in a patient population with respiratory tract infections admitted to hospital. J Med Virol 2005;75:336-347.
Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1618-1623.
Borg I, Rohde G, Loseke S, et al. Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases. Eur Respir J 2003;21:944-951.
Madhi SA, Klugman KP. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 2004;10:811-813.
Welliver RC. Respiratory syncytial virus infection: therapy and prevention. Paediatr Respir Rev 2004;5:Suppl A:S127-S133.
Maggon K, Barik S. New drugs and treatment for respiratory syncytial virus. Rev Med Virol 2004;14:149-168.
Fenton C, Scott LJ, Plosker GL. Palivizumab: a review of its use as prophylaxis for serious respiratory syncytial virus infection. Paediatr Drugs 2004;6:177-197.
Polack FP, Karron RA. The future of respiratory syncytial virus vaccine development. Pediatr Infect Dis J 2004;23:Suppl:S65-S73.
Durbin AP, Karron RA. Progress in the development of respiratory syncytial virus and parainfluenza virus vaccines. Clin Infect Dis 2003;37:1668-1677.(Sanjay Sethi, M.D., and T)