1198
The rather heavy-handed style of clinical guideline documents is not entirely the fault of their semiofficial status. Carefully selected words are an excellent way to obscure meaning-or the lack of it. The final report may misrepresent the keen debate that preceded it. The New England Journal of Medicine, in justification of its refusal to publish every consensus statement, summarised this feature when referring to "bland generalities" and "points so mild, so far from the cutting edge of progress and so well established that surely everyone must already know them".13 The Lancet can offer a simple test for such anodyne conclusions. Invert the meaning by inserting a simple negative. If no sane or competent advocate for that position can be imagined then the primary statement is not worth making. Take "effective interaction is the key to effective pain management".8 Would anyone seriously propose that "ineffective interaction is the key to effective pain management"? Consensus guidelines have another danger. If experts are in apparent agreement, there is surely no need for further investigation. The NIH Consensus Program, at least in its original intention, maintained that areas of uncertainty and research need would be defined. This requirement often seems to be forgotten in the face of a wish to give firm advice for action. The potential for stifling research and innovation has given rise to considerable unease. 12,13 Such considerations would be of purely theoretical interest if no notice were taken of consensus guidelines. In some cases the NIH consensus statement has resulted in action by funding agencies. When a statement sought to influence clinical practice, there was little evidence of efficacy.In a more formal study, a group at McMaster analysed the effects of a widely disseminated Canadian consensus statement on recommendations for caesarean section.14 Although obstetricians and hospitals said that they had been influenced, there was no objective evidence to support this claim. Thus one could conclude that the main impact of consensus statements is on policy makers and that they are largely ignored by the clinicians to whom they are directed. This is not necessarily reassuring for the clinical critics of consensus. The solution is
straightforward: consensus guidelines on guidelines are required. They should be targeted at unacceptable variations in clinical practice and not at minimising legitimate difference of opinion, and they should define clearly the areas of research need. And when that has been achieved we need more guidelines for propagating their use. 1. Shaw GB. The doctor’s dilemma. London: Constable and Company, 1911. 2. British Hyperlipidaemia Association. Strategies for reducing coronary heart disease and desirable limits for blood lipid concentrations: guidelines of the British Hyperlipidaemia Association. Br Med J 1987; 295: 1245-46. 3. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988; 148: 36-69.
4.
Joint National Commitiee on Detection, Evaluation and Treatment of High Blood Pressure. 1988 report. Arch Intern Med 1988; 148:
1023-38. 5. British Hypertension Society Working Party. Treating mild hypertension: agreement from the large trials. Br Med J 1989; 298: 694-98. 6. Perry S, Kalberer JT. The NIH Consensus-Development Program and the assessment of health-care technologies. N Engl J Med 1980; 303: 169-72. 7. Perry S. The NIH Consensus Development Program. N Engl JMed 1987; 317: 485-88. 8. Acute Pain Management Guideline Panel. Acute pain management: operative or medical procedures and trauma. Clinical practice guideline. Washington, DC: Agency for Health Care Policy and Research. Publication number 62-0032. AHCPR, Public Health Service, US Department of Health and Human Services, 1992. 9. Spencer H. First principles. London: Williams-Norgate, 1927. 10. May WE. Consensus or coercion. JAMA 1985; 254: 1077. 11. Oliver MF. Consensus or nonsensus conferences on heart disease. Lancet 1985; i: 1087-89. 12. Ahrens EH Jr. The diet-heart question in 1985: has it really been settled? Lancet 1985; i: 1085-87. 13. Rennie D. Consensus statements. N Engl J Med 1981; 304: 665-66. 14. Lomas J, Anderson GM, Domnick-Pierre K, Vayda E, Enkin MW, Hannah WJ. Do practice guidelines guide practice? The effect of a consensus statement on the practice of physicians. N Engl J Med 1989; 321: 1306-11.
Hepatitis A:
a
vaccine at last
The first hepatitis A vaccine has been licensed in the UK, Switzerland, Belgium, Austria, and Ireland, at a time when the incidence of the infection has been increasing in many developed countries. For example, in 1990 there were 9005 notifications of viral hepatitis in England and Wales, of which 7316 were for hepatitis A and only 435 for hepatitis B.1 This increase may reflect not only improved awareness and access to specific diagnostic investigations but also infection acquired by those who travel to hepatitis A endemic countries and cases of hepatitis A occurring endemically in densely populated urban areas. According to data presented at an international symposium on hepatitis A held in Vienna, Austria, in January, more than 30 million travellers from industrialised countries visit endemic areas annually. Although travel information is not always available for laboratory-confirmed cases, reports of studies conducted in England and Wales, Switzerland, and Scandinavia indicate that 40-50% of cases of hepatitis A are associated with recent international travep-3 A large Italian study4 showed that the risk of contracting hepatitis A varied considerably with destination: the odds ratios were 1-0 for no travel, 2-6 for travel to southern Italy, 5-9 for visits to Eastern Europe and Mediterranean countries, and 25-2 for travel to Africa, Asia, and South and Central America. Risks also relate to type of travel, being greater among back-pack travellers2 and visitors living in or working under primitive conditions. In most developing countries, infection by hepatitis A virus (HAV) is usually acquired subclinically in childhood but, as standards of hygiene and sanitation improve, children escape early infections-7 only to be infected clinically and in large numbers as young adults. In the recent epidemic in Shanghai, China, which was caused by ingestion of sewage-
1199
contaminated clams, more than 300 000 clinical cases of hepatitis A were reported, mostly in persons aged between 20 and 29.8 Before the outbreak, two-thirds of the population under 30 were susceptible. The recently licensed hepatitis A vaccine, which has been given to over 25 000 volunteers, is grown in diploid cell cultures, inactivated with formalin, and conjugated to alum.9 The accumulated data from over sixty clinical trials show that the vaccine is welltolerated and that side-effects are generally mild and usually limited to soreness and redness at the site of injection. Despite its low antigen concentration, the vaccine is highly immunogenic, inducing an immune response in 95-7% and 99-8% of individuals after one and two doses, respectively. The recommended primary course consists of two doses 2-4 weeks apart; a booster dose given 6-12 months later should afford
longer term protection. Studies of efficacy are in progress and encouraging results from a field study of children in Thailand were reported at the symposium.1O 40 000 children were randomised and given either hepatitis A vaccine or, as controls, hepatitis B vaccine. There were 29 cases of hepatitis A among controls vs 1 among vaccinees. This study is continuing, but the provisional data show a protective efficacy of 97%. A single dose of human normal immunoglobulin (HNIG) is about a quarter of the cost of one dose of vaccine. However, the antibody concentrations produced by two doses of vaccine are about 50-100 times higher than those achieved after a single dose of HNIG, and immunoglobulin provides protection for only a few months. Henceforth use of HNIG is likely to be limited to infrequent travellers who go to endemic countries for a short time or close contacts of persons with current infection. In travellers who require very rapid immunisation, HNIG may be given simultaneously with the vaccine. Although this strategy results in a slight reduction in immunogenicity of the vaccine, adequate concentrations of HAV antibody are induced.’1 To whom should this vaccine be given? Travellers should include diplomats going to endemic countries and members of the armed forces. During the Gulf War, US authorities virtually exhausted their country’s supplies of HNIG, and there were no cases of hepatitis A identified among US troops. This preparation was not given to British troops, 7 of whom acquired infection. Initially, most health departments are unlikely to recommend vaccination for persons other than those travellers and exposed occupationally-for example, sewage workers. However, the consensus view at the symposium in Vienna was that vaccination should also be considered for persons working in children’s day-care centres, staff and inmates of institutions for the mentally handicapped, other health-care workers who may be exposed to HAV, refugees, and male homosexuals and injecting drug users. Some of these groups have already been included in the manufacturer’s
datasheet. Clearly there is a need for studies to see whether the frequency of infection in some of these groups in fact justifies routine vaccination. Outstanding questions relate to the duration of immunity and the need for booster doses, for which answers will come from long-term follow-up studies, and whether vaccinees, when exposed to HAV, have reduced or absent virus excretion. This information is important with respect to use of this vaccine in food handlers, who may be a source of infection in foodborne outbreaks, and in limiting the spread of infection in extended community outbreaks. Preliminary studies in non-human primates are encouraging since vaccinated animals, when challenged with live virus, did not excrete virus whereas animals given HNIG, although protected against disease, did.12 Should vaccinees be screened? In developed countries, seroprevalence studies suggest that screening may be limited to persons over 50, those who have lived or travelled extensively abroad, or those with a history of jaundice. The new vaccine costs 13.60 ($24) per dose from the manufacturer. Both a live attenuated vaccine and a recombinant preparation should be cheaper. Low cost and long-term protection are essential if hepatitis A vaccines are to be recommended for use in developing countries. a PHLS working group. The present state of hepatitis A infection in England and Wales. PHLS Microbiol Dig 1991; 8: 122-26. 2. Steffen R. Risk of hepatitis A in travellers. Vaccine (in press). 3. Nordenfelt E. Hepatitis A in Swedish travellers. Vaccine (in press). 4. Mele A, Sagliocca L, Palumbo F, et al. Travel-associated hepatitis A: effect of place of residence and country visited. J Public Health Med
1.
Report of
1991; 13: 256-59. KP, Lok ASF, Wong LSK, Lai C-L, Wu P-C. Current seroepidemiology of hepatitis A in Hong Kong. J Med Virol 1991; 34:
5. Chin
191-93. 6. Lim WL, Yeoh EK. Hepatitis A vaccination. Lancet 1992; i: 304. 7. Innis BL, Snitbhan R, Hoke CH, Munindhorn W, Laorakpongse T. The declining transmission of hepatitis A in Thailand. J Infect Dis 1991; 163: 989-95. 8. Mao J. Development of live, attenuated hepatitis A vaccine (H2-strain). Vaccine 1990; 8: 523-24. 9. Andre FE, Hepbum A, D’Hondt E. Inactivated candidate vaccines for hepatitis A. Prog Med Virol 1990; 37: 72-95. 10. Innis B, Snitbhan R, Kunasol P, et al. A field efficacy trial of inactivated hepatitis A vaccine among children in Thailand. Vaccine (in press). 11. Leentvaar-Kuijpers A, Coutinho RA, Brulein V, Safary A. Simultaneous passive and active immunisation against hepatitis A. Vaccine (in press). 12. Andre FE. Development of a vaccine against hepatitis A. In: Blaine Hollinger F, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Proceedings of the 1990 International Symposium on Viral Hepatitis and Liver Disease: contemporary issues and future prospects. Baltimore: Williams & Wilkins, 1990: 85-88.
Protease inhibitors for delayed cerebral ischaemia after subarachnoid haemorrhage? It is worth recalling Odysseus’ long and perilous home voyage after the Trojan war. One of many intimidating obstacles was a strait near Sicily that was guarded by a monster on either side. In steering his ship clear of the maelstrom created by Charybdis, Odysseus lost six of his crew to Scylla, a creature with six heads and twelve limbs. A similar dilemma faces
The rather heavy-handed style of clinical guideline documents is not entirely the fault of their semiofficial status. Carefully selected words are an excellent way to obscure meaning-or the lack of it. The final report may misrepresent the keen debate that preceded it. The New England Journal of Medicine, in justification of its refusal to publish every consensus statement, summarised this feature when referring to "bland generalities" and "points so mild, so far from the cutting edge of progress and so well established that surely everyone must already know them".13 The Lancet can offer a simple test for such anodyne conclusions. Invert the meaning by inserting a simple negative. If no sane or competent advocate for that position can be imagined then the primary statement is not worth making. Take "effective interaction is the key to effective pain management".8 Would anyone seriously propose that "ineffective interaction is the key to effective pain management"? Consensus guidelines have another danger. If experts are in apparent agreement, there is surely no need for further investigation. The NIH Consensus Program, at least in its original intention, maintained that areas of uncertainty and research need would be defined. This requirement often seems to be forgotten in the face of a wish to give firm advice for action. The potential for stifling research and innovation has given rise to considerable unease. 12,13 Such considerations would be of purely theoretical interest if no notice were taken of consensus guidelines. In some cases the NIH consensus statement has resulted in action by funding agencies. When a statement sought to influence clinical practice, there was little evidence of efficacy.In a more formal study, a group at McMaster analysed the effects of a widely disseminated Canadian consensus statement on recommendations for caesarean section.14 Although obstetricians and hospitals said that they had been influenced, there was no objective evidence to support this claim. Thus one could conclude that the main impact of consensus statements is on policy makers and that they are largely ignored by the clinicians to whom they are directed. This is not necessarily reassuring for the clinical critics of consensus. The solution is
straightforward: consensus guidelines on guidelines are required. They should be targeted at unacceptable variations in clinical practice and not at minimising legitimate difference of opinion, and they should define clearly the areas of research need. And when that has been achieved we need more guidelines for propagating their use. 1. Shaw GB. The doctor’s dilemma. London: Constable and Company, 1911. 2. British Hyperlipidaemia Association. Strategies for reducing coronary heart disease and desirable limits for blood lipid concentrations: guidelines of the British Hyperlipidaemia Association. Br Med J 1987; 295: 1245-46. 3. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988; 148: 36-69.
4.
Joint National Commitiee on Detection, Evaluation and Treatment of High Blood Pressure. 1988 report. Arch Intern Med 1988; 148:
1023-38. 5. British Hypertension Society Working Party. Treating mild hypertension: agreement from the large trials. Br Med J 1989; 298: 694-98. 6. Perry S, Kalberer JT. The NIH Consensus-Development Program and the assessment of health-care technologies. N Engl J Med 1980; 303: 169-72. 7. Perry S. The NIH Consensus Development Program. N Engl JMed 1987; 317: 485-88. 8. Acute Pain Management Guideline Panel. Acute pain management: operative or medical procedures and trauma. Clinical practice guideline. Washington, DC: Agency for Health Care Policy and Research. Publication number 62-0032. AHCPR, Public Health Service, US Department of Health and Human Services, 1992. 9. Spencer H. First principles. London: Williams-Norgate, 1927. 10. May WE. Consensus or coercion. JAMA 1985; 254: 1077. 11. Oliver MF. Consensus or nonsensus conferences on heart disease. Lancet 1985; i: 1087-89. 12. Ahrens EH Jr. The diet-heart question in 1985: has it really been settled? Lancet 1985; i: 1085-87. 13. Rennie D. Consensus statements. N Engl J Med 1981; 304: 665-66. 14. Lomas J, Anderson GM, Domnick-Pierre K, Vayda E, Enkin MW, Hannah WJ. Do practice guidelines guide practice? The effect of a consensus statement on the practice of physicians. N Engl J Med 1989; 321: 1306-11.
Hepatitis A:
a
vaccine at last
The first hepatitis A vaccine has been licensed in the UK, Switzerland, Belgium, Austria, and Ireland, at a time when the incidence of the infection has been increasing in many developed countries. For example, in 1990 there were 9005 notifications of viral hepatitis in England and Wales, of which 7316 were for hepatitis A and only 435 for hepatitis B.1 This increase may reflect not only improved awareness and access to specific diagnostic investigations but also infection acquired by those who travel to hepatitis A endemic countries and cases of hepatitis A occurring endemically in densely populated urban areas. According to data presented at an international symposium on hepatitis A held in Vienna, Austria, in January, more than 30 million travellers from industrialised countries visit endemic areas annually. Although travel information is not always available for laboratory-confirmed cases, reports of studies conducted in England and Wales, Switzerland, and Scandinavia indicate that 40-50% of cases of hepatitis A are associated with recent international travep-3 A large Italian study4 showed that the risk of contracting hepatitis A varied considerably with destination: the odds ratios were 1-0 for no travel, 2-6 for travel to southern Italy, 5-9 for visits to Eastern Europe and Mediterranean countries, and 25-2 for travel to Africa, Asia, and South and Central America. Risks also relate to type of travel, being greater among back-pack travellers2 and visitors living in or working under primitive conditions. In most developing countries, infection by hepatitis A virus (HAV) is usually acquired subclinically in childhood but, as standards of hygiene and sanitation improve, children escape early infections-7 only to be infected clinically and in large numbers as young adults. In the recent epidemic in Shanghai, China, which was caused by ingestion of sewage-
1199
contaminated clams, more than 300 000 clinical cases of hepatitis A were reported, mostly in persons aged between 20 and 29.8 Before the outbreak, two-thirds of the population under 30 were susceptible. The recently licensed hepatitis A vaccine, which has been given to over 25 000 volunteers, is grown in diploid cell cultures, inactivated with formalin, and conjugated to alum.9 The accumulated data from over sixty clinical trials show that the vaccine is welltolerated and that side-effects are generally mild and usually limited to soreness and redness at the site of injection. Despite its low antigen concentration, the vaccine is highly immunogenic, inducing an immune response in 95-7% and 99-8% of individuals after one and two doses, respectively. The recommended primary course consists of two doses 2-4 weeks apart; a booster dose given 6-12 months later should afford
longer term protection. Studies of efficacy are in progress and encouraging results from a field study of children in Thailand were reported at the symposium.1O 40 000 children were randomised and given either hepatitis A vaccine or, as controls, hepatitis B vaccine. There were 29 cases of hepatitis A among controls vs 1 among vaccinees. This study is continuing, but the provisional data show a protective efficacy of 97%. A single dose of human normal immunoglobulin (HNIG) is about a quarter of the cost of one dose of vaccine. However, the antibody concentrations produced by two doses of vaccine are about 50-100 times higher than those achieved after a single dose of HNIG, and immunoglobulin provides protection for only a few months. Henceforth use of HNIG is likely to be limited to infrequent travellers who go to endemic countries for a short time or close contacts of persons with current infection. In travellers who require very rapid immunisation, HNIG may be given simultaneously with the vaccine. Although this strategy results in a slight reduction in immunogenicity of the vaccine, adequate concentrations of HAV antibody are induced.’1 To whom should this vaccine be given? Travellers should include diplomats going to endemic countries and members of the armed forces. During the Gulf War, US authorities virtually exhausted their country’s supplies of HNIG, and there were no cases of hepatitis A identified among US troops. This preparation was not given to British troops, 7 of whom acquired infection. Initially, most health departments are unlikely to recommend vaccination for persons other than those travellers and exposed occupationally-for example, sewage workers. However, the consensus view at the symposium in Vienna was that vaccination should also be considered for persons working in children’s day-care centres, staff and inmates of institutions for the mentally handicapped, other health-care workers who may be exposed to HAV, refugees, and male homosexuals and injecting drug users. Some of these groups have already been included in the manufacturer’s
datasheet. Clearly there is a need for studies to see whether the frequency of infection in some of these groups in fact justifies routine vaccination. Outstanding questions relate to the duration of immunity and the need for booster doses, for which answers will come from long-term follow-up studies, and whether vaccinees, when exposed to HAV, have reduced or absent virus excretion. This information is important with respect to use of this vaccine in food handlers, who may be a source of infection in foodborne outbreaks, and in limiting the spread of infection in extended community outbreaks. Preliminary studies in non-human primates are encouraging since vaccinated animals, when challenged with live virus, did not excrete virus whereas animals given HNIG, although protected against disease, did.12 Should vaccinees be screened? In developed countries, seroprevalence studies suggest that screening may be limited to persons over 50, those who have lived or travelled extensively abroad, or those with a history of jaundice. The new vaccine costs 13.60 ($24) per dose from the manufacturer. Both a live attenuated vaccine and a recombinant preparation should be cheaper. Low cost and long-term protection are essential if hepatitis A vaccines are to be recommended for use in developing countries. a PHLS working group. The present state of hepatitis A infection in England and Wales. PHLS Microbiol Dig 1991; 8: 122-26. 2. Steffen R. Risk of hepatitis A in travellers. Vaccine (in press). 3. Nordenfelt E. Hepatitis A in Swedish travellers. Vaccine (in press). 4. Mele A, Sagliocca L, Palumbo F, et al. Travel-associated hepatitis A: effect of place of residence and country visited. J Public Health Med
1.
Report of
1991; 13: 256-59. KP, Lok ASF, Wong LSK, Lai C-L, Wu P-C. Current seroepidemiology of hepatitis A in Hong Kong. J Med Virol 1991; 34:
5. Chin
191-93. 6. Lim WL, Yeoh EK. Hepatitis A vaccination. Lancet 1992; i: 304. 7. Innis BL, Snitbhan R, Hoke CH, Munindhorn W, Laorakpongse T. The declining transmission of hepatitis A in Thailand. J Infect Dis 1991; 163: 989-95. 8. Mao J. Development of live, attenuated hepatitis A vaccine (H2-strain). Vaccine 1990; 8: 523-24. 9. Andre FE, Hepbum A, D’Hondt E. Inactivated candidate vaccines for hepatitis A. Prog Med Virol 1990; 37: 72-95. 10. Innis B, Snitbhan R, Kunasol P, et al. A field efficacy trial of inactivated hepatitis A vaccine among children in Thailand. Vaccine (in press). 11. Leentvaar-Kuijpers A, Coutinho RA, Brulein V, Safary A. Simultaneous passive and active immunisation against hepatitis A. Vaccine (in press). 12. Andre FE. Development of a vaccine against hepatitis A. In: Blaine Hollinger F, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Proceedings of the 1990 International Symposium on Viral Hepatitis and Liver Disease: contemporary issues and future prospects. Baltimore: Williams & Wilkins, 1990: 85-88.
Protease inhibitors for delayed cerebral ischaemia after subarachnoid haemorrhage? It is worth recalling Odysseus’ long and perilous home voyage after the Trojan war. One of many intimidating obstacles was a strait near Sicily that was guarded by a monster on either side. In steering his ship clear of the maelstrom created by Charybdis, Odysseus lost six of his crew to Scylla, a creature with six heads and twelve limbs. A similar dilemma faces
