- Email: [email protected]
Small round structured viruses: airborne transmission and hospital control
reducing the vulnerability of communities
to the health of disasters.5 effects Results of epidemiological research on disasters have formed the scientific basis for increasingly effective prevention and intervention strategies. For example, epidemiological studies of tornadoes have led to changes in local housing and land-use regulations regarding the danger of mobile homes, and have formed the basis of US National Weather Service safety guidelines issued to citizens in tornado-prone parts of the country.’ Epidemiological investigations have also facilitated specific interventions to prevent specific disaster-related health effects (eg, and evacuation before improved warning flash floods and tropical cyclones,8 identification of effective safety actions for occupants of buildings during earthquakes,9 and development of measures to avoid
and
medical
"clean-up" injuries following hurricanes),"
information about disaster prevention and mitigation can be disseminated to people living in even the most remote areas. We now need to explore ways in which -emergency preparedness and disaster prevention strategies can be integrated more effectively into ongoing health activities at the national, regional, and community levels. ‘3
which
Eric K
1
2
3
to measure
the effectiveness of disaster prevention and preparedness programmes, and to help local communities develop better emergency preparedness and mitigation
policies. The importance of the health sector is clearly seen in sudden-impact natural disasters. For example, in the days immediately following the recent Los Angeles earthquake, local health officials conducted a rapid health needs assessment by use of a cluster sampling method adopted in 1992 by the Centers for Disease Control and Prevention and state health authorities during the aftermath of hurricane Andrew in Florida and Louisiana." From the experience of epidemiologists in Los Angeles who conducted these assessments we have learned that this technique of data collection may have to be modified for earthquake disasters. Thus, unlike hurricanes, where damage is generally uniform over a large geographical area and therefore lends itself to a random sampling approach, earthquake-related structural damage can vary widely depending on local soil conditions, rate of groundshaking attenuation from the epicentre, and quality of building construction. Consequently, use of a random sampling approach to assess damage after an earthquake may lead health authorities to overlook seriously affected areas in their survey and thereby underestimate overall
Noji
Centers for Disease Control and Prevention, Atlanta,
4
5
6 7 8
9
10 11
12 13
Georgia,
USA
National Research Council. Confronting natural disasters: an International Decade for Natural Disaster Reduction. Washington, DC: National Academy Press, 1987: 1-67. International Federation of Red Cross and Red Crescent Societies. World disasters report. Dordrecht: Martinus Nijhoff, 1993. Centers for Disease Control. Coccidioidomycosis following the Northridge earthquake-California, 1994. MMWR 1994; 43: 194-95. United Nations. The International Decade for Natural Disaster Reduction. United Nations General Assembly Resolution 42/160. A/RES/42/169. Dec 11, 1987. New York: United Nations, 1988. Noji EK. The role of epidemiology in natural disaster reduction: an interdisciplinary approach. In: Proceedings of the 2nd US-Japan Natural Disaster Reduction Workshop, Sept 23-27, 1991, Karuizawa, Japan. Tokyo: Japan Science and Technology Agency, 1992: 327-45. Binder S, Sanderson LM. The role of the epidemiologist in natural disasters. Ann Emerg Med 1987; 16: 1081-84. Glass RI, Craven RB, Bregman DJ, et al. Injuries from the Wichita Falls tornado: implications for prevention. Science 1980; 207: 734-38. French JG, Ing R, Von Allmen S, Wood R. Mortality from flash floods: a review of National Weather Service reports, 1969-81. Publ Health Rep 1983; 98: 584-88. Armenian HK, Noji EK, Oganessian AP. Case control study of injuries due to the earthquake in Soviet Armenia. Bull WHO 1992; 70: 251-57. Centers for Disease Control. Injuries and illnesses related to hurricane Andrew—Louisiana, 1992. MMWR 1993; 42: 243-46. Centers for Disease Control. Rapid health needs assessment following hurricane Andrew-Florida and Louisiana. MMWR 1992; 41: 696-98. Frankel DH. Public health assessment after earthquake. Lancet 1994; 343: 347-48. Lechat MF. The International Decade for Natural Disaster Reduction: background and objectives. Disasters 1990; 14: 1-6.
damage.’2
Small round structured viruses: airborne transmission and hospital control
Effective disaster response by local medical and public health communities is a key part of the immediate response to a disaster. For example, community members who have been trained in simple first aid can reduce the numbers of serious casualties and deaths that occur before outside help arrives. The ability of local health and medical systems to withstand the sudden added stress of a disaster-whether by building wind-resistant or seismicresistant hospitals, or by being equipped with emergency generators, extra supplies, equipment, and special reserve stocks of key drugs-can make a considerable difference to the outcome. An important goal during the remainder of the International Decade for Natural Disaster Reduction is to provide effective channels through which to communicate information and transfer technology. The numbers of deaths and injuries can be reduced through greater community awareness of natural hazards and improved national, regional, and local preplanning for disasters. The network of medical and public health professionals in any country constitutes an excellent channel through
Hyperemesis hiemis (winter vomiting disease), now universally recognised as epidemic non-bacterial gastroenteritis, was originally described by Zahorsky in. 1929.’40 years later an aetiological agent (Norwalk agent) was identified and subsequently other morphologically identical but antigenically distinct viruses were described. The illnesses produced by these agents have a common clinical presentation. Because of their poorly defmed taxonomic status, the agents themselves were called small round structured viruses (SRSVs).’ SRSVs cause mild self-limiting epidemic gastroenteritis, with high attack rates in semiclosed communities, and they circulate throughout the year within the community. They are also important causes of foodborne outbreaks of gastroenteritis. After a dose-dependent incubation period of 15-50 hours, patients present with explosive diarrhoea and/or vomiting without a defined prodrome. There is often substantial spread to secondary contacts (>50% attack rate), and these characteristics commonly result in closure of hospital wards.
1240
How do SRSVs spread so rapidly? Studies in volunteers have shown that the faecal/oral route is important, but this alone is not the full explanation. Other more important modes of transmission have been proposed; vomit, in which virus particles have been identified by electron microscopy, represents a major source of infection.4 Because 106 particles/mL need to be present for detection by electron microscopy, and if we assume that patients vomit a bolus of at least 30 mL, then 30000000 particles, with an infectious dose of 10-100 particles, will be distributed into the environment. This will be compounded as the number of vomiting patients increases. These observations explain the rapid spread of hand/mouth SRSVs via transmission from the contaminated environment. What other aspects of vomiting are important? Both respiratory and "airborne" inhalation routes5,6 have lately been proposed. Evidence for respiratory spread is unfounded since replication of SRSVs in respiratory mucosal cells has not been documented. By contrast, "airborne" transmission may well be important since projectile vomiting could give rise to infectious aerosols. Air currents generated by open windows or air conditioning will disperse aerosols widely. Moreover, when aerosols are generated during projectile vomiting in confined spaces, inhalation of aerosolised virus is likely. Unfortunately, studies that have so far suggested "airborne" transmission by inhalation’ have not definitely excluded hand/mouth transmission from environmental contamination. There is now compelling evidence that the projectile vomiter represents an important source of infectious virus and this poses considerable problems for control of infection procedures within hospitals. Three areas are applicable to control of SRSV spread: (a) introduction of SRSV into hospitals (b) containment at individual ward level; and (c) control of spread to other wards. Since SRSV infections lack a prodrome and circulate widely in the community, attempts to circumvent their introduction into hospitals are unrealistic. However, some fundamental guidelines are appropriate. All health care workers, including ancillary staff and food handlers, should stay away from work after an episode of gastroenteritis, however mild, until 48 hours after recovery. Notification of illness to line managers is essential to raise awareness, and education of all staff about SRSV transmission routes is essential; specific instructions should be included in control-of-infection policies. Hand washing is crucial both before and after attending to individual patients-initiation of such measures after an outbreak is established will inevitably fail. Once the index case (vomiter) presents within a ward, immediate isolation of the case and the area is essential. Projectile vomiting is pathognomonic of SRSV infection, and in the absence of other causes should be enough for a presumptive diagnosis. Rapid secondary spread will often confirm the diagnosis before the laboratory provides the answer, and signals the need to introduce urgent controlof-infection measures. Enteric precautions and attention to deep environmental cleansing of hard surfaces with hypochlorite8 (including high-risk areas such as toilets), is essential to containment. Contaminated and potentially contaminated linen (adjacent beds) and removable fabrics should be rapidly dealt with and exposed consumables,
such
fruit, should be discarded. A key
containment is to "immobilise" the symptomatic patient to avoid the possibility of further spread. Antiemetics (intramuscularly) rapidly terminate vomiting, lessen dehydration, and act as a sedative, reducing patient mobility. Nursing staff will be at special risk from expelled aerosols immediately after a patient has vomited, and here the use of respiratory masks needs evaluation. Air currents should be minimised and the ward closed to new admissions once spread is established. Because outbreaks as
to
of SRSV are so common, control-of-infection policies should consider environmental decontamination as a continuous rolling programme. Carpeted areas may be aesthetically pleasing but they are difficult to decontaminate and their use within hospitals should be readdressed. Gross carpet soilage can be cleaned initially by gloved personnel and then by use of hot detergent (100°C) and heavy duty vacuum cleaning. The most achievable measure is to eliminate spread to other wards. Total restriction of all staff movements from the affected ward to other wards, particularly communal rooms, should be imposed. Unless this policy is instigated immediately the virus will spread rapidly. Patient movement must also be restricted unless it is clinically imperative. Because of the high secondary attack rate, staff with symptoms should be confined to the affected ward or, if symptoms arise outside the ward, at their place of residence. Are these stringent control-of-infection procedures excessive for a mild infection? Not when one considers that the alternative will be closure of wards, and in some cases even whole hospitals. What are the longer term prospects of reducing the effects of SRSV outbreaks in hospitals? Identification of the complete RNA sequence of one SRSV serotype9 and subsequently of Norwalk virus’O may lead to the production of effective vaccines. The recent molecular characterisation of a new subgroup of SRSVs" highlights the need to characterise all serotypes before such vaccines can be produced. Moreover, vaccines will have to address the unusual immunobiology of these viruses for which symptomatic reinfection to homologous virus challenge has been shown.2 We still have much to learn about the immunopathogenesis of SRSVs before we can contemplate vaccine-induced immunity for the population. Until then, our main defence will be effective control-of-infection measures. E Owen Caul Regional Virus Laboratory, 1 2
3
4 5
6 7
Public Health
Laboratory, Bristol, UK
Zahorsky J. Hyperemesis hiemis or the winter vomiting disease. Arch Pediatr 1929; 46: 391-95. Kapikian AZ. Norwalk and Norwalk-like viruses. In: Kapikian AZ, ed. Viral infections of the gastrointestinal tract. 2nd ed. New York: Marcel Dekker, 1994: 471-518. Caul EO. Small round faecal viruses. In: Patterson J, ed. Human parvovirus and disease. Boca Raton, Florida: CRC Press, 1988: 139-63. Greenberg HB, Wyatt RG, Kapikian AZ. Norwalk virus in vomitus. Lancet 1979; i: 55. Gellert GA, Glass RI. Airborne transmission of a small round structured virus. Lancet 1994; 343: 609. Chadwick PR, Walker M, Rees AE. Airborne transmission of a small round structured virus. Lancet 1994;; 343: 171. Sawyer LA, Murphy JJ, Kaplan JE, et al. 25 to 30 nm virus associated with a hospital outbreak of acute gastroenteritis with evidence of airborne transmission. Am J Epidemiol 1988; 127: 1261-71.
8
Caul EO. Chairman: Viral gastroenteritis sub-committee of the PHLS
1241
9
virology committee. Outbreaks of gastroenteritis associated with SRSVs. PHLS Microbiol Digest 1993; 10: 2-8. Lambden PR, Caul EO, Ashley CR, Clarke IN. Sequence and general organization of a human small round structured (Norwalk-like) virus.
Science 1993; 259: 516-18. 10 Jiang X, Wang K, Graham DY, Estes MK. Sequence and general organization of Norwalk virus. Virology 1993; 195: 51-61. 11 Green SM, Dingle KE, Lambden PR, Caul EO, Ashley CR, Clarke IN. Human enteric caliciviridae: a new prevalent SRSV group defined by RNA-dependent RNA polymerase and capsid diversity. J Gen Virol (in press).
Allelic variation and the vitamin D
receptor Osteoporosis research is directed not only towards design of successful treatments but also towards characterisation of the basic determinants of bone density with a view to prevention. Consequently, great interest has been generated by a recent report from Morrison et al,’ who claim that a natural allelic variation or polymorphism within the vitamin D3receptor (VDR) gene is responsible for as much as 75% of the total genetic effect on bone density and that genotyping can be used to predict a predisposition to osteoporosis. The presence of a site within the gene which is sensitive to the enzyme Bsm I and designated b2 correlated strongly and positively with bone density; absence of this site in the homozygote genotype BB is associated with the greatest risk of osteoporosis. How might this polymorphism exert such a profound effect on bone density? One approach is to study regulation of VDR gene expression in these genotypes. Regulation of protein synthesis is often mediated through the 3’-untranslated region of mRNA. For example, the intrinsic properties of the sequence affect mRNA stability either through the presence of multiple copies of the AUUUA motif, which are highly sensitive to RNAses,4 or through changes in the length of the poly(A) tract.5 In preliminary experiments, Morrison et al focused on the 3’-untranslated region of the mRNA which is especially long in the VDR gene.3 Sequences of the 3’untranslated region of the two most common genotypes with respect to the Bsm I polymorphism and two other polymorphisms (Apa I and Taq I)-BBAAtt and bbaaTT-were linked to reporter genes that are used to monitor any effects the sequences in question may have on gene expression. After transfection into cells, the "minigene" representing BBAAtt increased reporter gene activity; this result suggests that, in this genotype, VDR mRNA and protein concentrations are higher. However, there are many differences in the sequences used-from point mutations to insertions and deletions-and any one or more of these variations could affect mRNA concentrations in vitro. If we were to accept that a polymorphism alters VDR gene expression in vitro, how might this effect be manifested in vivo?
1242
a
The balance between bone formation and resorption is result of a complex network of factors including
parathyroid hormone, oestrogen, and 1,25-dihydroxyvitamin D 3. Regulation of VDR gene expression in most cells is largely via extracellular factors. When a major change in one or more of these factors occurs--eg, at the menopause-VDR number and function might become more dependent on the inherent properties of the gene itself. Consequently, any subtle differences due to polymorphisms in, for example, mRNA stability, might assume greater significance and become more apparent. In view of the ubiquity of VDR and the multiplicity of effects of 1,25-dihydroxyvitamin D33 on calcium homoeostasis and the immune system, it is surprising that a polymorphism within the gene which ostensibly has such a great influence on bone density has not produced more widespread disturbances of the vitamin D endocrine system as a whole. However, cell-specific factors are also important in the regulation of gene expression. Thus, the half-life of any mRNA may vary from one cell type to another and this difference in stability is one mechanism whereby cell-specific expression of some proteins (eg, the insulin receptor) is regulated.6 In addition, there may be cell-specific interactions with other proteins that regulate gene expression. As a result, the effects of the polymorphism in the VDR may be dependent on cell type and only realised in bone cells. So, is allelic variation in the VDR gene responsible for most of the genetic effect on bone density? The case remains unproven. It is still possible that the polymorphism exhibits close linkage with another unidentified gene on the same chromosome. Meanwhile, these observations of VDR genotype have made us realise that subtle polymorphic differences in genes can have major effects on physiology, and that expression of these differences is likely to depend on cell-specific factors. Sheelagh
Farrow
Department
of Medicine,
University College London Medical School,
London, UK
density from
1
Morrison NA, Qi JC, Tokita A, et al. Prediction of bone vitamin D alleles. Nature 1994; 367: 284-87.
2
Morrison NA, Yeoman R, Kelly PJ, Eisman J. Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA 1992; 89: 6665-69.
3
Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 1988; 85: 3294-98.
4
Shaw G, Kamen R. A conserved AU sequence from the 3’-untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 1986; 46: 659-67.
5
Murphy D, Pardy K, Seah V, Carter D. Posttranscriptional regulation of rat growth hormone gene expression: increased message stability and nuclear polyadenylation accompany thyroid hormone depletion. Mol Cell Biol 1992; 12: 2624-32. Tewari M, Tewari DS, Taub R. Posttranscriptional mechanisms account for differences in steady state levels of insulin receptor
6
messenger RNA in different cells. Mol Endocrinol
1991; 5: 653-60.
to the health of disasters.5 effects Results of epidemiological research on disasters have formed the scientific basis for increasingly effective prevention and intervention strategies. For example, epidemiological studies of tornadoes have led to changes in local housing and land-use regulations regarding the danger of mobile homes, and have formed the basis of US National Weather Service safety guidelines issued to citizens in tornado-prone parts of the country.’ Epidemiological investigations have also facilitated specific interventions to prevent specific disaster-related health effects (eg, and evacuation before improved warning flash floods and tropical cyclones,8 identification of effective safety actions for occupants of buildings during earthquakes,9 and development of measures to avoid
and
medical
"clean-up" injuries following hurricanes),"
information about disaster prevention and mitigation can be disseminated to people living in even the most remote areas. We now need to explore ways in which -emergency preparedness and disaster prevention strategies can be integrated more effectively into ongoing health activities at the national, regional, and community levels. ‘3
which
Eric K
1
2
3
to measure
the effectiveness of disaster prevention and preparedness programmes, and to help local communities develop better emergency preparedness and mitigation
policies. The importance of the health sector is clearly seen in sudden-impact natural disasters. For example, in the days immediately following the recent Los Angeles earthquake, local health officials conducted a rapid health needs assessment by use of a cluster sampling method adopted in 1992 by the Centers for Disease Control and Prevention and state health authorities during the aftermath of hurricane Andrew in Florida and Louisiana." From the experience of epidemiologists in Los Angeles who conducted these assessments we have learned that this technique of data collection may have to be modified for earthquake disasters. Thus, unlike hurricanes, where damage is generally uniform over a large geographical area and therefore lends itself to a random sampling approach, earthquake-related structural damage can vary widely depending on local soil conditions, rate of groundshaking attenuation from the epicentre, and quality of building construction. Consequently, use of a random sampling approach to assess damage after an earthquake may lead health authorities to overlook seriously affected areas in their survey and thereby underestimate overall
Noji
Centers for Disease Control and Prevention, Atlanta,
4
5
6 7 8
9
10 11
12 13
Georgia,
USA
National Research Council. Confronting natural disasters: an International Decade for Natural Disaster Reduction. Washington, DC: National Academy Press, 1987: 1-67. International Federation of Red Cross and Red Crescent Societies. World disasters report. Dordrecht: Martinus Nijhoff, 1993. Centers for Disease Control. Coccidioidomycosis following the Northridge earthquake-California, 1994. MMWR 1994; 43: 194-95. United Nations. The International Decade for Natural Disaster Reduction. United Nations General Assembly Resolution 42/160. A/RES/42/169. Dec 11, 1987. New York: United Nations, 1988. Noji EK. The role of epidemiology in natural disaster reduction: an interdisciplinary approach. In: Proceedings of the 2nd US-Japan Natural Disaster Reduction Workshop, Sept 23-27, 1991, Karuizawa, Japan. Tokyo: Japan Science and Technology Agency, 1992: 327-45. Binder S, Sanderson LM. The role of the epidemiologist in natural disasters. Ann Emerg Med 1987; 16: 1081-84. Glass RI, Craven RB, Bregman DJ, et al. Injuries from the Wichita Falls tornado: implications for prevention. Science 1980; 207: 734-38. French JG, Ing R, Von Allmen S, Wood R. Mortality from flash floods: a review of National Weather Service reports, 1969-81. Publ Health Rep 1983; 98: 584-88. Armenian HK, Noji EK, Oganessian AP. Case control study of injuries due to the earthquake in Soviet Armenia. Bull WHO 1992; 70: 251-57. Centers for Disease Control. Injuries and illnesses related to hurricane Andrew—Louisiana, 1992. MMWR 1993; 42: 243-46. Centers for Disease Control. Rapid health needs assessment following hurricane Andrew-Florida and Louisiana. MMWR 1992; 41: 696-98. Frankel DH. Public health assessment after earthquake. Lancet 1994; 343: 347-48. Lechat MF. The International Decade for Natural Disaster Reduction: background and objectives. Disasters 1990; 14: 1-6.
damage.’2
Small round structured viruses: airborne transmission and hospital control
Effective disaster response by local medical and public health communities is a key part of the immediate response to a disaster. For example, community members who have been trained in simple first aid can reduce the numbers of serious casualties and deaths that occur before outside help arrives. The ability of local health and medical systems to withstand the sudden added stress of a disaster-whether by building wind-resistant or seismicresistant hospitals, or by being equipped with emergency generators, extra supplies, equipment, and special reserve stocks of key drugs-can make a considerable difference to the outcome. An important goal during the remainder of the International Decade for Natural Disaster Reduction is to provide effective channels through which to communicate information and transfer technology. The numbers of deaths and injuries can be reduced through greater community awareness of natural hazards and improved national, regional, and local preplanning for disasters. The network of medical and public health professionals in any country constitutes an excellent channel through
Hyperemesis hiemis (winter vomiting disease), now universally recognised as epidemic non-bacterial gastroenteritis, was originally described by Zahorsky in. 1929.’40 years later an aetiological agent (Norwalk agent) was identified and subsequently other morphologically identical but antigenically distinct viruses were described. The illnesses produced by these agents have a common clinical presentation. Because of their poorly defmed taxonomic status, the agents themselves were called small round structured viruses (SRSVs).’ SRSVs cause mild self-limiting epidemic gastroenteritis, with high attack rates in semiclosed communities, and they circulate throughout the year within the community. They are also important causes of foodborne outbreaks of gastroenteritis. After a dose-dependent incubation period of 15-50 hours, patients present with explosive diarrhoea and/or vomiting without a defined prodrome. There is often substantial spread to secondary contacts (>50% attack rate), and these characteristics commonly result in closure of hospital wards.
1240
How do SRSVs spread so rapidly? Studies in volunteers have shown that the faecal/oral route is important, but this alone is not the full explanation. Other more important modes of transmission have been proposed; vomit, in which virus particles have been identified by electron microscopy, represents a major source of infection.4 Because 106 particles/mL need to be present for detection by electron microscopy, and if we assume that patients vomit a bolus of at least 30 mL, then 30000000 particles, with an infectious dose of 10-100 particles, will be distributed into the environment. This will be compounded as the number of vomiting patients increases. These observations explain the rapid spread of hand/mouth SRSVs via transmission from the contaminated environment. What other aspects of vomiting are important? Both respiratory and "airborne" inhalation routes5,6 have lately been proposed. Evidence for respiratory spread is unfounded since replication of SRSVs in respiratory mucosal cells has not been documented. By contrast, "airborne" transmission may well be important since projectile vomiting could give rise to infectious aerosols. Air currents generated by open windows or air conditioning will disperse aerosols widely. Moreover, when aerosols are generated during projectile vomiting in confined spaces, inhalation of aerosolised virus is likely. Unfortunately, studies that have so far suggested "airborne" transmission by inhalation’ have not definitely excluded hand/mouth transmission from environmental contamination. There is now compelling evidence that the projectile vomiter represents an important source of infectious virus and this poses considerable problems for control of infection procedures within hospitals. Three areas are applicable to control of SRSV spread: (a) introduction of SRSV into hospitals (b) containment at individual ward level; and (c) control of spread to other wards. Since SRSV infections lack a prodrome and circulate widely in the community, attempts to circumvent their introduction into hospitals are unrealistic. However, some fundamental guidelines are appropriate. All health care workers, including ancillary staff and food handlers, should stay away from work after an episode of gastroenteritis, however mild, until 48 hours after recovery. Notification of illness to line managers is essential to raise awareness, and education of all staff about SRSV transmission routes is essential; specific instructions should be included in control-of-infection policies. Hand washing is crucial both before and after attending to individual patients-initiation of such measures after an outbreak is established will inevitably fail. Once the index case (vomiter) presents within a ward, immediate isolation of the case and the area is essential. Projectile vomiting is pathognomonic of SRSV infection, and in the absence of other causes should be enough for a presumptive diagnosis. Rapid secondary spread will often confirm the diagnosis before the laboratory provides the answer, and signals the need to introduce urgent controlof-infection measures. Enteric precautions and attention to deep environmental cleansing of hard surfaces with hypochlorite8 (including high-risk areas such as toilets), is essential to containment. Contaminated and potentially contaminated linen (adjacent beds) and removable fabrics should be rapidly dealt with and exposed consumables,
such
fruit, should be discarded. A key
containment is to "immobilise" the symptomatic patient to avoid the possibility of further spread. Antiemetics (intramuscularly) rapidly terminate vomiting, lessen dehydration, and act as a sedative, reducing patient mobility. Nursing staff will be at special risk from expelled aerosols immediately after a patient has vomited, and here the use of respiratory masks needs evaluation. Air currents should be minimised and the ward closed to new admissions once spread is established. Because outbreaks as
to
of SRSV are so common, control-of-infection policies should consider environmental decontamination as a continuous rolling programme. Carpeted areas may be aesthetically pleasing but they are difficult to decontaminate and their use within hospitals should be readdressed. Gross carpet soilage can be cleaned initially by gloved personnel and then by use of hot detergent (100°C) and heavy duty vacuum cleaning. The most achievable measure is to eliminate spread to other wards. Total restriction of all staff movements from the affected ward to other wards, particularly communal rooms, should be imposed. Unless this policy is instigated immediately the virus will spread rapidly. Patient movement must also be restricted unless it is clinically imperative. Because of the high secondary attack rate, staff with symptoms should be confined to the affected ward or, if symptoms arise outside the ward, at their place of residence. Are these stringent control-of-infection procedures excessive for a mild infection? Not when one considers that the alternative will be closure of wards, and in some cases even whole hospitals. What are the longer term prospects of reducing the effects of SRSV outbreaks in hospitals? Identification of the complete RNA sequence of one SRSV serotype9 and subsequently of Norwalk virus’O may lead to the production of effective vaccines. The recent molecular characterisation of a new subgroup of SRSVs" highlights the need to characterise all serotypes before such vaccines can be produced. Moreover, vaccines will have to address the unusual immunobiology of these viruses for which symptomatic reinfection to homologous virus challenge has been shown.2 We still have much to learn about the immunopathogenesis of SRSVs before we can contemplate vaccine-induced immunity for the population. Until then, our main defence will be effective control-of-infection measures. E Owen Caul Regional Virus Laboratory, 1 2
3
4 5
6 7
Public Health
Laboratory, Bristol, UK
Zahorsky J. Hyperemesis hiemis or the winter vomiting disease. Arch Pediatr 1929; 46: 391-95. Kapikian AZ. Norwalk and Norwalk-like viruses. In: Kapikian AZ, ed. Viral infections of the gastrointestinal tract. 2nd ed. New York: Marcel Dekker, 1994: 471-518. Caul EO. Small round faecal viruses. In: Patterson J, ed. Human parvovirus and disease. Boca Raton, Florida: CRC Press, 1988: 139-63. Greenberg HB, Wyatt RG, Kapikian AZ. Norwalk virus in vomitus. Lancet 1979; i: 55. Gellert GA, Glass RI. Airborne transmission of a small round structured virus. Lancet 1994; 343: 609. Chadwick PR, Walker M, Rees AE. Airborne transmission of a small round structured virus. Lancet 1994;; 343: 171. Sawyer LA, Murphy JJ, Kaplan JE, et al. 25 to 30 nm virus associated with a hospital outbreak of acute gastroenteritis with evidence of airborne transmission. Am J Epidemiol 1988; 127: 1261-71.
8
Caul EO. Chairman: Viral gastroenteritis sub-committee of the PHLS
1241
9
virology committee. Outbreaks of gastroenteritis associated with SRSVs. PHLS Microbiol Digest 1993; 10: 2-8. Lambden PR, Caul EO, Ashley CR, Clarke IN. Sequence and general organization of a human small round structured (Norwalk-like) virus.
Science 1993; 259: 516-18. 10 Jiang X, Wang K, Graham DY, Estes MK. Sequence and general organization of Norwalk virus. Virology 1993; 195: 51-61. 11 Green SM, Dingle KE, Lambden PR, Caul EO, Ashley CR, Clarke IN. Human enteric caliciviridae: a new prevalent SRSV group defined by RNA-dependent RNA polymerase and capsid diversity. J Gen Virol (in press).
Allelic variation and the vitamin D
receptor Osteoporosis research is directed not only towards design of successful treatments but also towards characterisation of the basic determinants of bone density with a view to prevention. Consequently, great interest has been generated by a recent report from Morrison et al,’ who claim that a natural allelic variation or polymorphism within the vitamin D3receptor (VDR) gene is responsible for as much as 75% of the total genetic effect on bone density and that genotyping can be used to predict a predisposition to osteoporosis. The presence of a site within the gene which is sensitive to the enzyme Bsm I and designated b2 correlated strongly and positively with bone density; absence of this site in the homozygote genotype BB is associated with the greatest risk of osteoporosis. How might this polymorphism exert such a profound effect on bone density? One approach is to study regulation of VDR gene expression in these genotypes. Regulation of protein synthesis is often mediated through the 3’-untranslated region of mRNA. For example, the intrinsic properties of the sequence affect mRNA stability either through the presence of multiple copies of the AUUUA motif, which are highly sensitive to RNAses,4 or through changes in the length of the poly(A) tract.5 In preliminary experiments, Morrison et al focused on the 3’-untranslated region of the mRNA which is especially long in the VDR gene.3 Sequences of the 3’untranslated region of the two most common genotypes with respect to the Bsm I polymorphism and two other polymorphisms (Apa I and Taq I)-BBAAtt and bbaaTT-were linked to reporter genes that are used to monitor any effects the sequences in question may have on gene expression. After transfection into cells, the "minigene" representing BBAAtt increased reporter gene activity; this result suggests that, in this genotype, VDR mRNA and protein concentrations are higher. However, there are many differences in the sequences used-from point mutations to insertions and deletions-and any one or more of these variations could affect mRNA concentrations in vitro. If we were to accept that a polymorphism alters VDR gene expression in vitro, how might this effect be manifested in vivo?
1242
a
The balance between bone formation and resorption is result of a complex network of factors including
parathyroid hormone, oestrogen, and 1,25-dihydroxyvitamin D 3. Regulation of VDR gene expression in most cells is largely via extracellular factors. When a major change in one or more of these factors occurs--eg, at the menopause-VDR number and function might become more dependent on the inherent properties of the gene itself. Consequently, any subtle differences due to polymorphisms in, for example, mRNA stability, might assume greater significance and become more apparent. In view of the ubiquity of VDR and the multiplicity of effects of 1,25-dihydroxyvitamin D33 on calcium homoeostasis and the immune system, it is surprising that a polymorphism within the gene which ostensibly has such a great influence on bone density has not produced more widespread disturbances of the vitamin D endocrine system as a whole. However, cell-specific factors are also important in the regulation of gene expression. Thus, the half-life of any mRNA may vary from one cell type to another and this difference in stability is one mechanism whereby cell-specific expression of some proteins (eg, the insulin receptor) is regulated.6 In addition, there may be cell-specific interactions with other proteins that regulate gene expression. As a result, the effects of the polymorphism in the VDR may be dependent on cell type and only realised in bone cells. So, is allelic variation in the VDR gene responsible for most of the genetic effect on bone density? The case remains unproven. It is still possible that the polymorphism exhibits close linkage with another unidentified gene on the same chromosome. Meanwhile, these observations of VDR genotype have made us realise that subtle polymorphic differences in genes can have major effects on physiology, and that expression of these differences is likely to depend on cell-specific factors. Sheelagh
Farrow
Department
of Medicine,
University College London Medical School,
London, UK
density from
1
Morrison NA, Qi JC, Tokita A, et al. Prediction of bone vitamin D alleles. Nature 1994; 367: 284-87.
2
Morrison NA, Yeoman R, Kelly PJ, Eisman J. Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA 1992; 89: 6665-69.
3
Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 1988; 85: 3294-98.
4
Shaw G, Kamen R. A conserved AU sequence from the 3’-untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 1986; 46: 659-67.
5
Murphy D, Pardy K, Seah V, Carter D. Posttranscriptional regulation of rat growth hormone gene expression: increased message stability and nuclear polyadenylation accompany thyroid hormone depletion. Mol Cell Biol 1992; 12: 2624-32. Tewari M, Tewari DS, Taub R. Posttranscriptional mechanisms account for differences in steady state levels of insulin receptor
6
messenger RNA in different cells. Mol Endocrinol
1991; 5: 653-60.