Influenza — Interpandemic as Well as Pandemic Disease
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《新英格兰医药杂志》
Influenza occurs in both pandemic and interpandemic forms. Fortunately, pandemics, defined as worldwide outbreaks of severe disease, occur infrequently. Interpandemic influenza, although less extensive in its impact, occurs virtually every year. Widespread avian infection with influenza A (H5N1) and associated clusters of human disease have aroused concern about the threat of a pandemic, and attention has been appropriately focused on control measures to deal with such an event. However, interpandemic influenza has a substantial effect, both cumulatively and in individual outbreaks, and has much to teach us about transmission, pathogenesis, and potentially effective control measures.
Since the H1N1 pandemic of 1977, interpandemic disease has occurred annually in outbreaks of varying extent and severity. From 1979 through 2001, an average of 226,000 hospitalizations related to influenza occurred each year in the United States.1 From 1990 through 1999, approximately 325,000 patients died of influenza-related pulmonary and circulatory causes in the United States alone.2 The majority of these hospitalizations and deaths occurred in persons who were 65 years of age or older or in patients with pulmonary or cardiovascular disorders or certain other chronic diseases, characterized as high-risk conditions. More recently, it has been recognized that the impact of influenza on pediatric populations is also substantial. This effect appears to be greatest among children under the age of two years, who, although otherwise healthy, have rates of hospitalization for influenza-related disease similar to or higher than those of older children with high-risk conditions. These data have led to current recommendations from the Advisory Committee on Immunization Practices (ACIP) for annual influenza vaccination for all children between the ages of 6 months and 23 months.3 The article by Bhat and colleagues in this issue of the Journal (pages 2559–2567) describes 153 influenza-associated deaths among children in the United States during the 2003–2004 influenza season. Of these deaths, 63 percent occurred in children under the age of five years, and the highest rates were in infants under the age of six months. Although one third of the deaths occurred in children who had ACIP-defined high-risk conditions, nearly half of the deaths occurred in children without documented medical disorders.
(Figure)
Estimated Rates of Hospitalization for a Primary Diagnosis of Influenza or Pneumonia.
Rates are based on weighted monthly data. Data are from Thompson et al.1
The pathogenesis of fatal illness associated with influenza infection is not well understood, particularly in fulminant cases that occur in apparently healthy persons. Whether such cases reflect features of intrinsic viral pathogenicity, host immunity, other host responses, concomitant infections with other pathogens, or a combination of these factors is not clear. Differences in virulence appear to exist among various influenza viruses and perhaps are present more broadly among various subtypes. The subtype associated with the pediatric deaths in the 2003–2004 influenza season was H3N2, which appears to be involved in severe disease more frequently than does H1N1. Concomitant bacterial infections were detected in only 24 percent of the pediatric cases cited in the study. Studies of influenza in experimental models and, to a lesser extent, in humans have associated certain systemic manifestations of illness with the induction of proinflammatory cytokines — particularly type I interferons, tumor necrosis factor , interleukin-6, and interleukin-8 — in human disease. Studies are very much needed to better define the pathogenesis of severe cases and to determine whether therapy that is directed against specific host responses would be of benefit.
Antiviral therapy is available against influenza A viruses in the form of amantadine and rimantadine (although isolates of H5N1 appear to be resistant to this class of drugs) and against both influenza A and B viruses through the use of the neuraminidase inhibitors, oseltamivir and zanamivir. These drugs have a moderate but well-established effect in uncomplicated, self-limited cases of influenza. However, it is not clear whether these drugs are of benefit in the treatment or prevention of life-threatening disease. A recent meta-analysis of studies of therapy with oseltamivir reported reductions in antibiotic use and hospitalization rates among subjects who received the drug.4 Amantadine and oseltamivir are approved for therapy in children as young as one year of age and zanamivir in children as young as seven years of age. Thus, there is no approved antiviral therapy for influenza in children under the age of one year, which includes the age group with the highest mortality, as noted above. Studies of the use of antiviral drugs in this age group are also much needed.
In addition to having severe effects from influenza, young children play a central role in the transmission of the disease. Outbreaks among young children are often the sentinel events in epidemics. A study of the 2000–2004 influenza seasons in Massachusetts5 demonstrated that increases in the number of respiratory illnesses were consistently manifested first in children and that patients between the ages of three and four years were the group in which the earliest cases of pneumonia and influenza were noted. As reported in the study by Bhat et al., an age of under five years was also most strongly associated with mortality.
Other studies have shown that vaccination of school-aged children has been associated with a reduction in the transmission of influenza, and the above data suggest that immunization of preschool-aged children (especially those between the ages of three and four years) might have a particularly salutary effect on transmission. In the fatal cases reported by Bhat et al., only 26 percent of children with high-risk conditions and 19 percent of those between the ages of 6 and 23 months had received influenza immunization as currently recommended. Unfortunately, no influenza vaccines are approved for infants under the age of six months, the most vulnerable group in terms of serious disease. Influenza immunization is now recommended for women who are pregnant during the influenza season because of the increased risk of influenza-related complications during pregnancy.3 Such immunization may also provide the additional benefit of protection to the newborn during the first six months of life. This might be considered an additional reason to advocate influenza immunization of pregnant women, as well as immunization of household contacts and caregivers of children under the age of six months.
The development of a live attenuated influenza vaccine offers an important opportunity to consider more widespread use of influenza immunization. Currently, this vaccine is recommended as an option for healthy persons between the ages of 5 and 49 years who wish to avoid contracting influenza.3 Administering live attenuated influenza vaccine appears to be a particularly attractive approach to the immunization of young children because of its ease of administration (by intranasal spray rather than by injection), as well as because of its ability to induce broad mucosal and systemic responses. During the 2004–2005 influenza season, a large-scale study of more than 8000 children between the ages of 6 and 36 months compared the results of the administration of refrigerator-stable live attenuated influenza vaccine with that of inactivated influenza vaccine. Analysis of this study should provide important safety and efficacy data for the use of live attenuated influenza vaccine in children in this age group.
Children constitute both a population that is highly vulnerable to influenza infection and one of the most important links in its transmission. Control measures for interpandemic and pandemic influenza, such as vaccines and antiviral drugs, need to be effective and applicable to the youngest among us.
Source Information
Dr. Dolin is a professor of medicine (microbiology and molecular genetics) and dean for academic and clinical programs at Harvard Medical School and is a senior attending physician at Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Boston.
References
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004;292:1333-1340.
Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-186.
Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54:1-40.
Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003;326:1235-1235.
Brownstein JS, Kleinman KP, Mandl KD. Identifying pediatric age groups for influenza vaccination using a real-time regional surveillance system. Am J Epidemiol 2005;162:686-693.(Raphael Dolin, M.D.)
Since the H1N1 pandemic of 1977, interpandemic disease has occurred annually in outbreaks of varying extent and severity. From 1979 through 2001, an average of 226,000 hospitalizations related to influenza occurred each year in the United States.1 From 1990 through 1999, approximately 325,000 patients died of influenza-related pulmonary and circulatory causes in the United States alone.2 The majority of these hospitalizations and deaths occurred in persons who were 65 years of age or older or in patients with pulmonary or cardiovascular disorders or certain other chronic diseases, characterized as high-risk conditions. More recently, it has been recognized that the impact of influenza on pediatric populations is also substantial. This effect appears to be greatest among children under the age of two years, who, although otherwise healthy, have rates of hospitalization for influenza-related disease similar to or higher than those of older children with high-risk conditions. These data have led to current recommendations from the Advisory Committee on Immunization Practices (ACIP) for annual influenza vaccination for all children between the ages of 6 months and 23 months.3 The article by Bhat and colleagues in this issue of the Journal (pages 2559–2567) describes 153 influenza-associated deaths among children in the United States during the 2003–2004 influenza season. Of these deaths, 63 percent occurred in children under the age of five years, and the highest rates were in infants under the age of six months. Although one third of the deaths occurred in children who had ACIP-defined high-risk conditions, nearly half of the deaths occurred in children without documented medical disorders.
(Figure)
Estimated Rates of Hospitalization for a Primary Diagnosis of Influenza or Pneumonia.
Rates are based on weighted monthly data. Data are from Thompson et al.1
The pathogenesis of fatal illness associated with influenza infection is not well understood, particularly in fulminant cases that occur in apparently healthy persons. Whether such cases reflect features of intrinsic viral pathogenicity, host immunity, other host responses, concomitant infections with other pathogens, or a combination of these factors is not clear. Differences in virulence appear to exist among various influenza viruses and perhaps are present more broadly among various subtypes. The subtype associated with the pediatric deaths in the 2003–2004 influenza season was H3N2, which appears to be involved in severe disease more frequently than does H1N1. Concomitant bacterial infections were detected in only 24 percent of the pediatric cases cited in the study. Studies of influenza in experimental models and, to a lesser extent, in humans have associated certain systemic manifestations of illness with the induction of proinflammatory cytokines — particularly type I interferons, tumor necrosis factor , interleukin-6, and interleukin-8 — in human disease. Studies are very much needed to better define the pathogenesis of severe cases and to determine whether therapy that is directed against specific host responses would be of benefit.
Antiviral therapy is available against influenza A viruses in the form of amantadine and rimantadine (although isolates of H5N1 appear to be resistant to this class of drugs) and against both influenza A and B viruses through the use of the neuraminidase inhibitors, oseltamivir and zanamivir. These drugs have a moderate but well-established effect in uncomplicated, self-limited cases of influenza. However, it is not clear whether these drugs are of benefit in the treatment or prevention of life-threatening disease. A recent meta-analysis of studies of therapy with oseltamivir reported reductions in antibiotic use and hospitalization rates among subjects who received the drug.4 Amantadine and oseltamivir are approved for therapy in children as young as one year of age and zanamivir in children as young as seven years of age. Thus, there is no approved antiviral therapy for influenza in children under the age of one year, which includes the age group with the highest mortality, as noted above. Studies of the use of antiviral drugs in this age group are also much needed.
In addition to having severe effects from influenza, young children play a central role in the transmission of the disease. Outbreaks among young children are often the sentinel events in epidemics. A study of the 2000–2004 influenza seasons in Massachusetts5 demonstrated that increases in the number of respiratory illnesses were consistently manifested first in children and that patients between the ages of three and four years were the group in which the earliest cases of pneumonia and influenza were noted. As reported in the study by Bhat et al., an age of under five years was also most strongly associated with mortality.
Other studies have shown that vaccination of school-aged children has been associated with a reduction in the transmission of influenza, and the above data suggest that immunization of preschool-aged children (especially those between the ages of three and four years) might have a particularly salutary effect on transmission. In the fatal cases reported by Bhat et al., only 26 percent of children with high-risk conditions and 19 percent of those between the ages of 6 and 23 months had received influenza immunization as currently recommended. Unfortunately, no influenza vaccines are approved for infants under the age of six months, the most vulnerable group in terms of serious disease. Influenza immunization is now recommended for women who are pregnant during the influenza season because of the increased risk of influenza-related complications during pregnancy.3 Such immunization may also provide the additional benefit of protection to the newborn during the first six months of life. This might be considered an additional reason to advocate influenza immunization of pregnant women, as well as immunization of household contacts and caregivers of children under the age of six months.
The development of a live attenuated influenza vaccine offers an important opportunity to consider more widespread use of influenza immunization. Currently, this vaccine is recommended as an option for healthy persons between the ages of 5 and 49 years who wish to avoid contracting influenza.3 Administering live attenuated influenza vaccine appears to be a particularly attractive approach to the immunization of young children because of its ease of administration (by intranasal spray rather than by injection), as well as because of its ability to induce broad mucosal and systemic responses. During the 2004–2005 influenza season, a large-scale study of more than 8000 children between the ages of 6 and 36 months compared the results of the administration of refrigerator-stable live attenuated influenza vaccine with that of inactivated influenza vaccine. Analysis of this study should provide important safety and efficacy data for the use of live attenuated influenza vaccine in children in this age group.
Children constitute both a population that is highly vulnerable to influenza infection and one of the most important links in its transmission. Control measures for interpandemic and pandemic influenza, such as vaccines and antiviral drugs, need to be effective and applicable to the youngest among us.
Source Information
Dr. Dolin is a professor of medicine (microbiology and molecular genetics) and dean for academic and clinical programs at Harvard Medical School and is a senior attending physician at Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Boston.
References
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004;292:1333-1340.
Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-186.
Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54:1-40.
Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003;326:1235-1235.
Brownstein JS, Kleinman KP, Mandl KD. Identifying pediatric age groups for influenza vaccination using a real-time regional surveillance system. Am J Epidemiol 2005;162:686-693.(Raphael Dolin, M.D.)