Are Noroviruses Emerging
http://www.100md.com
《传染病的形成》
Centers for Disease Control and Prevention, Atlanta, Georgia, USA
In 1972, noroviruses (previously called "Norwalk-like viruses") were discovered as the first viruses definitively associated with acute gastroenteritis. During the next 2 decades, researchers were unable to develop simple methods to detect these common viruses or to find the etiologic agents of nonbacterial gastroenteritis outbreaks and hospitalizations. Indeed, of >2,500 foodborne outbreaks reported to the Centers for Disease Control and Prevention from 1993 to 1997, <1% were attributed to noroviruses, and 68% were of "unknown etiology" (1). As a result, noroviruses were out of sight and mind and thus relegated to a minor role as agents of gastroenteritis at a time when high-profile outbreaks of Salmonella Enteritidis (2) and Escherichia coli (3) had focused attention and budgets on preventing foodborne bacterial illnesses.
The development of reverse transcription–polymerase chain reaction in the early 1990s provided the breakthrough needed to facilitate diagnosis of norovirus infection. Today, noroviruses are recognized as the most common cause of infectious gastroenteritis among persons of all ages (4). They are responsible for ≤50% of all foodborne gastroenteritis outbreaks in the United States (5) and are a major contributor to illness in nursing homes (6) and hospitals (7). Noroviruses have been detected in 35% of persons with sporadic gastroenteritis of known cause (8) and in 14% of all children <3 years old hospitalized for gastroenteritis (9). Norovirus infection has put apparently healthy people in intensive care (10) and has been associated with chronic diarrhea among transplant patients (11). In addition, we now know of a myriad of strains of norovirus, which have been classified into 5 genogroups, distinguishable from sapoviruses, a separate genus of human caliciviruses, but also in the Caliciviridae family. This diversity represents a dramatic increase from the single calicivirus strain discovered >30 years ago. Moreover, the known host range of noroviruses has expanded: the virus is found in mice (12), cows (13), and pigs (14), and antibodies to bovine strains have been found in humans, which has stimulated speculation about zoonotic transmission (15). However, a fundamental question remains—is the increased detection of norovirus the result of better application of improved diagnostics or does evidence exist that norovirus disease is an emergent problem
Recent reports have established that norovirus strains can periodically emerge either globally or nationally, displace other strains, and increase disease incidence (16,17). In winter 2002, a new virus variant was attributed to a well-publicized surge of norovirus outbreaks on cruise ships and in nursing homes in the United States (18,19) and in healthcare facilities in Europe (20). Why these strains emerge into prominence is unclear, but they often belong to genogroup II, cluster 4 (Bristol virus). Whether these strains cause different or more severe symptoms than other noroviruses, are more transmissible, or can better evade the host immune response is not known. The periodic emergence of strains is likely to have always been a feature of noroviruses, but we do not know whether norovirus infections are more frequent now than in 1929, when Zahorsky first described "winter vomiting disease" (21). Despite a lack of consistent retrospective data to definitively answer this question, several factors suggest that norovirus disease may actually be more common today.
First, the rates of bacterial foodborne illnesses are declining, in large part because of measures such as improved refrigeration and use of Hazard Analysis and Critical Control Point systems to reduce contamination of food of animal origin (22). Most of these measures, however, will be ineffective against noroviruses, which are resistant to chlorination and freezing, persist in the environment, and require only very low inoculums to infect. Thus, the relative contribution of noroviruses to foodborne disease is likely to be increasing. Second, modern lifestyles make us more vulnerable to norovirus infection than when these viruses were discovered. Since 1972 in the United States, more elderly people live in communal settings, with the number of beds in nursing homes increasing >75% (23). In addition, we now eat more foods that have been handled by a variety of potentially infected people; 46% of household food expenditures is now spent on eating out, compared with 32% in 1972 (24). We also eat more of the foods that are likely to be contaminated with norovirus; consumption of fresh vegetables and fruit has risen >20% in the last 30 years (25), and this produce is often grown in countries where crops are still irrigated with sewage-contaminated water. Finally, more people than ever are traveling and have an increased risk for norovirus infection through exposure to hotels, airplanes, and cruise ships. From 1993 to 1998, for example, the number of cruise ship passengers in the United States increased by 50% (26). Faced with these trends, how should the public health community respond
First, research on the disease prevalence of noroviruses is only beginning. If noroviruses are an increasingly common cause of infectious gastroenteritis, with some cases resulting in diarrhea-related deaths and hospitalizations, then substantially greater investments are required in their diagnosis. Increased use of diagnostics along with improved surveillance, such as in sentinel sites, will permit identification of new strains and shifts in the epidemiology of norovirus disease. The development of easy-to-use, sensitive assays for use by clinical and public health laboratories should also have a high priority.
Second, we do not know how to stop norovirus transmission. Foods can be contaminated with norovirus either at the source (27) or at the point of service by infected food handlers. Noroviruses can spread by water, direct person-to-person contact, or airborne droplets of vomitus (28), and they can persist in the environment as a source of continuing infection despite efforts at disinfection (29). Recent advances in finding a cell culture system for noroviruses may allow for assessing the efficacy of various disinfectants (30), but only by full epidemiologic investigation of viral gastroenteritis outbreaks and by application of molecular tests will transmission routes be determined, differences in epidemiology between strains be detected, and targeted control measures implemented.
Norovirus infections are common and likely to become more so. Effective prevention strategies must now be designed and implemented.
Acknowledgments
We thank Alicia Fry for critical review of the manuscript and Claudia Chesley for editorial help.
Dr. Widdowson is a medical epidemiologist in the Respiratory and Enteric Viruses Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention. His research interests include all aspects of the epidemiology of viral gastroenteritis and its prevention.
References
Olsen SJ, MacKinnon LC, Goulding JS, Bean NH, Slutsker L. Surveillance for foodborne-disease outbreaks—United States, 1993–1997. MMWR CDC Surveill Summ. 2000;49(No.SS-1):1–64.
Lin FY, Morris JG Jr, Trump D, Tilghman D, Wood PK, Jackman N, et al. Investigation of an outbreak of Salmonella enteritidis gastroenteritis associated with consumption of eggs in a restaurant chain in Maryland. Am J Epidemiol. 1988;128:839–44.
Bell BP, Goldoft M, Griffin PM, Davis MA, Gordon DC, Tarr PI, et al. A multistate outbreak of Escherichia coli O157:H7-associated bloody diarrhea and hemolytic uremic syndrome from hamburgers. The Washington experience. JAMA. 1994;272:1349–53.
Mead PS, Slutsker L, Dietz V, McCagi LF, Bresee JS, Shapiro C, et al. Food-related illness and death in the United States. Emerg Infect Dis. 1999;5:607–25.
Widdowson M-A, Sulka A, Bulens S, Beard R, Chaves S, Hammond R, et al. Norovirus and foodborne disease, United States. Emerg Infect Dis 2005;11:95–102.
Green K, Belliot G, Taylor J, Valdesuso J, Lew J, Kapikian A, et al. A predominant role for Norwalk-like viruses as agents of epidemic gastroenteritis in Maryland nursing homes for the elderly. J Infect Dis. 2002;185:133–46.
Lopman BA, Reacher MH, Vipond IB, Sarangi J, Brown DW. Clinical manifestation of norovirus gastroenteritis in health care settings. Clin Infect Dis. 2004;39:318–24.
de Wit MA, Koopmans MP, Kortbeek LM, Wannet WJ, Vinje J, van Leusden F, et al. Sensor, a population-based cohort study on gastroenteritis in the Netherlands: incidence and etiology. Am J Epidemiol. 2001;154:666–74.
Bon F, Fascia P, Dauvergne M, Tenenbaum D, Planson H, Petion AM, et al. Prevalence of group A rotavirus, human calicivirus, astrovirus, and adenovirus type 40 and 41 infections among children with acute gastroenteritis in Dijon, France. J Clin Microbiol. 1999;37:3055–8.
Centers for Disease Control and Prevention. Outbreak of acute gastroenteritis associated with Norwalk-like viruses among British military personnel—Afghanistan, May 2002. MMWR Morb Mortal Wkly Rep. 2002;51:477–9.
Kaufman SS, Chatterjee NK, Fuschino ME, Magid MS, Gordon RE, Morse DL, et al. Calicivirus enteritis in an intestinal transplant recipient. Am J Transplant. 2003;3:764–8.
Karst SM, Wobus CE, Lay M, Davidson J, Virgin HW IVth. STAT1-dependent innate immunity to a Norwalk-like virus. Science. 2003;299:1575–8.
van der Poel WHM, Vinje J, van der Heide R, Herrera M-I, Vivo A, Koopmans MPG. Norwalk-like calicivirus genes in farm animals. Emerg Infect Dis. 2000;6:36–41.
Sugieda M, Nagaoka H, Kakishima Y, Ohshita T, Nakamura S, Nakajima S. Detection of Norwalk-like virus genes in the caecum contents of pigs. Arch Virol. 1998;143:1215–21.
Widdowson M-A, Rockx B, Schepp R, van Duynhoven YTHP, Vinje J, van der Poel WHM, et al. Detection of serum antibodies to bovine norovirus in veterinarians and the general population in the Netherlands. J Med Virol. 2005;76:119–28.
Hale A, Mattick K, Lewis D, Estes M, Jiang X, Green J, et al. Distinct epidemiological patterns of Norwalk-like virus infection. J Med Virol 2000;62:99–103.
Noel JS, Fankhauser RL, Ando T, Monroe SS, Glass RI. Identification of a distinct common strain of "Norwalk-like viruses" having a global distribution. J Infect Dis. 1999;179:1334–44.
Widdowson M-A, Cramer E, Hadley L, Bresee J, Beard RS, Bulens S, et al. Outbreaks of acute gastroenteritis on cruise ships and on land: identification of a predominant strain of norovirus (NV), United States 2002. J Infect Dis. 2004;190:27–36.
Centers for Disease Control and Prevention. Norovirus activity—United States, 2002. MMWR Morb Mortal Wkly Rep 2003;52:41–5.
Lopman B, Vennema H, Kohli E, Pothier P, Sanchez A, Negredo A, et al. Increase in viral gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant. Lancet. 2004;363:682–8.
Zahorsky J. Hyperemesis heimis or the winter vomiting disease. Arch Pediatr. 1929;46:391.
Centers for Disease Control and Prevention. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food—selected sites, United States, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:338–43.
Centers for Disease Control and Prevention and National Center for Health Statistics. National Nursing Home Survey, selected years (1973–1999) [cited 2005 Mar 17]. Available from http://www.cdc.gov/nchs/data/nnhsd/NNHSTrends1973to1999.pdf
Economic Research Service. United States Department of Agriculture. Food cpi, prices, and expenditures: food and alcoholic beverages: total expenditures [cited 2005 Mar 17]. Available from http://www.ers.usda.gov/Briefing/CPIFoodAndExpenditures/Data/table1.htm
Economic Research Service. United States Department of Agriculture. Food consumption (per capita) data system [cited 2005 Mar 17]. Available from http://www.ers.usda.gov/Data/FoodConsumption
Cramer EH, Gu DX, Durbin RE. Diarrheal disease on cruise ships, 1990–2000. Am J Prev Med 2003;24:227–33.
Gaulin CD, Ramsay D, Cardinal P, D'Halevyn M-A. Epidemie de gastro-enterite d'origine virale associee a la consommation de framboises importees. Can J Public Health. 1999;90:37–40.
Marks PJ, Vipond IB, Regan FM, Wedgwood K, Fey RE, Caul EO. A school outbreak of Norwalk-like virus: evidence for airborne transmission. Epidemiol Infect. 2003;131:727–36.
Isakbaeva E, Widdowson MA, Bulens SN, Mullins JA, Cramer EH, Monroe SS, et al. Norovirus transmission on a cruise ship. Emerg Infect Dis. 2005;11:154–8.
Wobus CE, Karst SM, Thackray LB, Chang KO, Sosnovtsev SV, Belliot G, et al. Replication of Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol 2004;2:e432.(Marc-Alain Widdowson, Ste)
In 1972, noroviruses (previously called "Norwalk-like viruses") were discovered as the first viruses definitively associated with acute gastroenteritis. During the next 2 decades, researchers were unable to develop simple methods to detect these common viruses or to find the etiologic agents of nonbacterial gastroenteritis outbreaks and hospitalizations. Indeed, of >2,500 foodborne outbreaks reported to the Centers for Disease Control and Prevention from 1993 to 1997, <1% were attributed to noroviruses, and 68% were of "unknown etiology" (1). As a result, noroviruses were out of sight and mind and thus relegated to a minor role as agents of gastroenteritis at a time when high-profile outbreaks of Salmonella Enteritidis (2) and Escherichia coli (3) had focused attention and budgets on preventing foodborne bacterial illnesses.
The development of reverse transcription–polymerase chain reaction in the early 1990s provided the breakthrough needed to facilitate diagnosis of norovirus infection. Today, noroviruses are recognized as the most common cause of infectious gastroenteritis among persons of all ages (4). They are responsible for ≤50% of all foodborne gastroenteritis outbreaks in the United States (5) and are a major contributor to illness in nursing homes (6) and hospitals (7). Noroviruses have been detected in 35% of persons with sporadic gastroenteritis of known cause (8) and in 14% of all children <3 years old hospitalized for gastroenteritis (9). Norovirus infection has put apparently healthy people in intensive care (10) and has been associated with chronic diarrhea among transplant patients (11). In addition, we now know of a myriad of strains of norovirus, which have been classified into 5 genogroups, distinguishable from sapoviruses, a separate genus of human caliciviruses, but also in the Caliciviridae family. This diversity represents a dramatic increase from the single calicivirus strain discovered >30 years ago. Moreover, the known host range of noroviruses has expanded: the virus is found in mice (12), cows (13), and pigs (14), and antibodies to bovine strains have been found in humans, which has stimulated speculation about zoonotic transmission (15). However, a fundamental question remains—is the increased detection of norovirus the result of better application of improved diagnostics or does evidence exist that norovirus disease is an emergent problem
Recent reports have established that norovirus strains can periodically emerge either globally or nationally, displace other strains, and increase disease incidence (16,17). In winter 2002, a new virus variant was attributed to a well-publicized surge of norovirus outbreaks on cruise ships and in nursing homes in the United States (18,19) and in healthcare facilities in Europe (20). Why these strains emerge into prominence is unclear, but they often belong to genogroup II, cluster 4 (Bristol virus). Whether these strains cause different or more severe symptoms than other noroviruses, are more transmissible, or can better evade the host immune response is not known. The periodic emergence of strains is likely to have always been a feature of noroviruses, but we do not know whether norovirus infections are more frequent now than in 1929, when Zahorsky first described "winter vomiting disease" (21). Despite a lack of consistent retrospective data to definitively answer this question, several factors suggest that norovirus disease may actually be more common today.
First, the rates of bacterial foodborne illnesses are declining, in large part because of measures such as improved refrigeration and use of Hazard Analysis and Critical Control Point systems to reduce contamination of food of animal origin (22). Most of these measures, however, will be ineffective against noroviruses, which are resistant to chlorination and freezing, persist in the environment, and require only very low inoculums to infect. Thus, the relative contribution of noroviruses to foodborne disease is likely to be increasing. Second, modern lifestyles make us more vulnerable to norovirus infection than when these viruses were discovered. Since 1972 in the United States, more elderly people live in communal settings, with the number of beds in nursing homes increasing >75% (23). In addition, we now eat more foods that have been handled by a variety of potentially infected people; 46% of household food expenditures is now spent on eating out, compared with 32% in 1972 (24). We also eat more of the foods that are likely to be contaminated with norovirus; consumption of fresh vegetables and fruit has risen >20% in the last 30 years (25), and this produce is often grown in countries where crops are still irrigated with sewage-contaminated water. Finally, more people than ever are traveling and have an increased risk for norovirus infection through exposure to hotels, airplanes, and cruise ships. From 1993 to 1998, for example, the number of cruise ship passengers in the United States increased by 50% (26). Faced with these trends, how should the public health community respond
First, research on the disease prevalence of noroviruses is only beginning. If noroviruses are an increasingly common cause of infectious gastroenteritis, with some cases resulting in diarrhea-related deaths and hospitalizations, then substantially greater investments are required in their diagnosis. Increased use of diagnostics along with improved surveillance, such as in sentinel sites, will permit identification of new strains and shifts in the epidemiology of norovirus disease. The development of easy-to-use, sensitive assays for use by clinical and public health laboratories should also have a high priority.
Second, we do not know how to stop norovirus transmission. Foods can be contaminated with norovirus either at the source (27) or at the point of service by infected food handlers. Noroviruses can spread by water, direct person-to-person contact, or airborne droplets of vomitus (28), and they can persist in the environment as a source of continuing infection despite efforts at disinfection (29). Recent advances in finding a cell culture system for noroviruses may allow for assessing the efficacy of various disinfectants (30), but only by full epidemiologic investigation of viral gastroenteritis outbreaks and by application of molecular tests will transmission routes be determined, differences in epidemiology between strains be detected, and targeted control measures implemented.
Norovirus infections are common and likely to become more so. Effective prevention strategies must now be designed and implemented.
Acknowledgments
We thank Alicia Fry for critical review of the manuscript and Claudia Chesley for editorial help.
Dr. Widdowson is a medical epidemiologist in the Respiratory and Enteric Viruses Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention. His research interests include all aspects of the epidemiology of viral gastroenteritis and its prevention.
References
Olsen SJ, MacKinnon LC, Goulding JS, Bean NH, Slutsker L. Surveillance for foodborne-disease outbreaks—United States, 1993–1997. MMWR CDC Surveill Summ. 2000;49(No.SS-1):1–64.
Lin FY, Morris JG Jr, Trump D, Tilghman D, Wood PK, Jackman N, et al. Investigation of an outbreak of Salmonella enteritidis gastroenteritis associated with consumption of eggs in a restaurant chain in Maryland. Am J Epidemiol. 1988;128:839–44.
Bell BP, Goldoft M, Griffin PM, Davis MA, Gordon DC, Tarr PI, et al. A multistate outbreak of Escherichia coli O157:H7-associated bloody diarrhea and hemolytic uremic syndrome from hamburgers. The Washington experience. JAMA. 1994;272:1349–53.
Mead PS, Slutsker L, Dietz V, McCagi LF, Bresee JS, Shapiro C, et al. Food-related illness and death in the United States. Emerg Infect Dis. 1999;5:607–25.
Widdowson M-A, Sulka A, Bulens S, Beard R, Chaves S, Hammond R, et al. Norovirus and foodborne disease, United States. Emerg Infect Dis 2005;11:95–102.
Green K, Belliot G, Taylor J, Valdesuso J, Lew J, Kapikian A, et al. A predominant role for Norwalk-like viruses as agents of epidemic gastroenteritis in Maryland nursing homes for the elderly. J Infect Dis. 2002;185:133–46.
Lopman BA, Reacher MH, Vipond IB, Sarangi J, Brown DW. Clinical manifestation of norovirus gastroenteritis in health care settings. Clin Infect Dis. 2004;39:318–24.
de Wit MA, Koopmans MP, Kortbeek LM, Wannet WJ, Vinje J, van Leusden F, et al. Sensor, a population-based cohort study on gastroenteritis in the Netherlands: incidence and etiology. Am J Epidemiol. 2001;154:666–74.
Bon F, Fascia P, Dauvergne M, Tenenbaum D, Planson H, Petion AM, et al. Prevalence of group A rotavirus, human calicivirus, astrovirus, and adenovirus type 40 and 41 infections among children with acute gastroenteritis in Dijon, France. J Clin Microbiol. 1999;37:3055–8.
Centers for Disease Control and Prevention. Outbreak of acute gastroenteritis associated with Norwalk-like viruses among British military personnel—Afghanistan, May 2002. MMWR Morb Mortal Wkly Rep. 2002;51:477–9.
Kaufman SS, Chatterjee NK, Fuschino ME, Magid MS, Gordon RE, Morse DL, et al. Calicivirus enteritis in an intestinal transplant recipient. Am J Transplant. 2003;3:764–8.
Karst SM, Wobus CE, Lay M, Davidson J, Virgin HW IVth. STAT1-dependent innate immunity to a Norwalk-like virus. Science. 2003;299:1575–8.
van der Poel WHM, Vinje J, van der Heide R, Herrera M-I, Vivo A, Koopmans MPG. Norwalk-like calicivirus genes in farm animals. Emerg Infect Dis. 2000;6:36–41.
Sugieda M, Nagaoka H, Kakishima Y, Ohshita T, Nakamura S, Nakajima S. Detection of Norwalk-like virus genes in the caecum contents of pigs. Arch Virol. 1998;143:1215–21.
Widdowson M-A, Rockx B, Schepp R, van Duynhoven YTHP, Vinje J, van der Poel WHM, et al. Detection of serum antibodies to bovine norovirus in veterinarians and the general population in the Netherlands. J Med Virol. 2005;76:119–28.
Hale A, Mattick K, Lewis D, Estes M, Jiang X, Green J, et al. Distinct epidemiological patterns of Norwalk-like virus infection. J Med Virol 2000;62:99–103.
Noel JS, Fankhauser RL, Ando T, Monroe SS, Glass RI. Identification of a distinct common strain of "Norwalk-like viruses" having a global distribution. J Infect Dis. 1999;179:1334–44.
Widdowson M-A, Cramer E, Hadley L, Bresee J, Beard RS, Bulens S, et al. Outbreaks of acute gastroenteritis on cruise ships and on land: identification of a predominant strain of norovirus (NV), United States 2002. J Infect Dis. 2004;190:27–36.
Centers for Disease Control and Prevention. Norovirus activity—United States, 2002. MMWR Morb Mortal Wkly Rep 2003;52:41–5.
Lopman B, Vennema H, Kohli E, Pothier P, Sanchez A, Negredo A, et al. Increase in viral gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant. Lancet. 2004;363:682–8.
Zahorsky J. Hyperemesis heimis or the winter vomiting disease. Arch Pediatr. 1929;46:391.
Centers for Disease Control and Prevention. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food—selected sites, United States, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:338–43.
Centers for Disease Control and Prevention and National Center for Health Statistics. National Nursing Home Survey, selected years (1973–1999) [cited 2005 Mar 17]. Available from http://www.cdc.gov/nchs/data/nnhsd/NNHSTrends1973to1999.pdf
Economic Research Service. United States Department of Agriculture. Food cpi, prices, and expenditures: food and alcoholic beverages: total expenditures [cited 2005 Mar 17]. Available from http://www.ers.usda.gov/Briefing/CPIFoodAndExpenditures/Data/table1.htm
Economic Research Service. United States Department of Agriculture. Food consumption (per capita) data system [cited 2005 Mar 17]. Available from http://www.ers.usda.gov/Data/FoodConsumption
Cramer EH, Gu DX, Durbin RE. Diarrheal disease on cruise ships, 1990–2000. Am J Prev Med 2003;24:227–33.
Gaulin CD, Ramsay D, Cardinal P, D'Halevyn M-A. Epidemie de gastro-enterite d'origine virale associee a la consommation de framboises importees. Can J Public Health. 1999;90:37–40.
Marks PJ, Vipond IB, Regan FM, Wedgwood K, Fey RE, Caul EO. A school outbreak of Norwalk-like virus: evidence for airborne transmission. Epidemiol Infect. 2003;131:727–36.
Isakbaeva E, Widdowson MA, Bulens SN, Mullins JA, Cramer EH, Monroe SS, et al. Norovirus transmission on a cruise ship. Emerg Infect Dis. 2005;11:154–8.
Wobus CE, Karst SM, Thackray LB, Chang KO, Sosnovtsev SV, Belliot G, et al. Replication of Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol 2004;2:e432.(Marc-Alain Widdowson, Ste)