- Email: [email protected]
Zero progress with hypochondriasis
COMMENTARY
hygiene during childhood did not find any association with ulcerative colitis.2 Are there practical implications of this line of research? In view of the low incidence rates of ulcerative colitis, appendicectomy cannot be recommended as a preventive measure, especially since, despite compelling data, observational studies cannot prove cause. The observed association between appendicectomy and ulcerative colitis may, however, prove very important, because it provides tantalising evidence about the role of the gut immune system in mediating disease.
Robert S Sandler Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA 1
Breslin NP, McDonnell C, O’Morain C. Surgical and smoking history in inflammatory bowel disease: a case-control study. Inflamm Bowel Dis 1997; 3: 1–5. 2 Duggan AE, Usmani I, Neal KR. Logan RFA. Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case-control study. Gut 1998; 43: 494–98. 3 Gent AE, Heller MD, Grace RH, Swarbrick ET, Coggon D. Inflammatory bowel disease and domestic hygiene in infancy. Lancet 1994; 343: 766–67. 4 Gilat T, Hacohen D, Lilos P, Langman MJS. Childhood factors in ulcerative colitis and Crohn’s disease: an international cooperative study. Scand J Gastroenterol 1987; 22: 1009–24. 5 Minocha A, Raczkowski CA. Role of appendectomy and tonsillectomy in pathogenesis of ulcerative colitis. Dig Dis Sci 1997; 42: 1567–69. 6 Russel MG, Dorant E, Brummer R-JM, et al. Appendectomy and the risk of developing ulcerative colitis or Crohn’s disease: results of a large case-control study. Gastroenterology 1997; 113: 377–82. 7 Rutgeerts P, D’Haens G, Hiele M, Geboes K, Van Trappen G. Appendectomy protects against ulcerative colitis. Gastroenterology 1994; 106: 1251-–53. 8 Smithson JE, Radford-Smith G, Jewell GP. Appendectomy and tonsillectomy in patients with inflammatory bowel disease. J Clin Gastroenterol 1995; 21: 283–86. 9 Wurzelmann JI, Lyles CM, Sandler RS. Childhood infections and the risk of inflammatory bowel disease. Dig Dis Sci 1994; 39: 555–60. 10 Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK. Role of appendix in the development of inflammatory bowel disease in TCR-a mutant mice. J Exp Med 1996; 184: 707–15. 11 Rath HC, Ikeda JS, Linde H-J, Schölmerich J, Wilson KH, Sartor RB. Varying cecal bacterial loads influences colitis and gastritis in HLAB27 transgenic rats. Gastroenterology (in press).
Zero progress with hypochondriasis Imagine the following scenario. A doctor is saying to one of his more difficult patients: “We both know you are very worried about the pains in your stomach and chest, and the odd sensation in your leg. I have examined you on several occasions, and performed a wide variety of tests. I am convinced there is no serious physical cause for your experiences. I know you don’t agree, but I think you are suffering from hypochondriasis. The good news is that there is a group conducting a trial of psychological treatments for this disorder, and I can refer you to them. however, you should know that there is a one in two chance that the treatment you receive will be a sham.” Such an encounter is the kind of challenge to be overcome in randomised controlled trials of psychological treat-ments for hypochondriasis. The successes, and more importantly, the failures, of a recent study1 are instructive. Patients who puzzle their doctors receive a variety of labels.2 Hypochondriasis is a conviction of disease without adequate justification. Hypochondriacal patients seek to act on that conviction. Hysteria is nowadays reserved for complaints of loss of function of a body part without physical cause. The more recent term, somatisation, is both a syndrome and a figure of speech. The syndrome refers to a long history of multisystem complaints and 1798
medical investigations and treatment, but with no physical cause being found for the symptoms. The figure of speech describes the presentation of a bodily symptom instead of a direct statement of disturbed emotions. Since the body is the medium for expression of emotion in most cultures, it might be more appropriate to describe individuals who say things such as “I am depressed” as psychologisers,3 but that is another matter. Hypochondriacal patients are distressed, and cause distress to those around them. An effective treatment would clearly be welcome. Although various therapies have been advocated,4,5 there is no convincing evidence that any treatment produces a specific effect. A group from Oxford1 tried to remedy this lack with a study of a cognitive behavioural strategy for hypochondriasis. The therapy was based on challenging the patient’s hypochondriacal beliefs. Experiences with drug trials6 reinforce the importance of including a sham or placebo treatment in any study of hypochondriasis. Response to treatment in the placebo group may be very high. A sham or placebo psychological treatment would involve regular attention without other active components. D M Clark and colleagues did not attempt to devise such a treatment: instead they tried to develop a credible psychosocial treatment that excluded the critical element of a direct challenge to the patients’ beliefs. Their initial attempt was not acceptable to the patients, so they settled for a study of the comparative efficacy of two active psychological treatments—the cognitive treatment, and a more generic stress-management and relaxation approach. The inclusion of waiting-list controls, assessed and then re-examined at the end of the same time period as active treatment, showed that spontaneous remissions were rare in the group under study. Such controls cannot, however, substitute for a sham treatment in tests of treatment effect. The trial was conducted very carefully and generally described in exemplary detail. At the end of the 12month follow-up period, the outcomes from the two treatments were similar. The cognitive approach had produced more impressive results at first, but these were not sustained over the follow-up. The generic approach produced an initially smaller, but more constant, effect. Thus the result did not favour either treatment. Only 48 people were recruited to the study over a 3year period. The investigators do not state how many people were referred, although all general practitioners, psychologists, and psychiatrists in a large area were canvassed to refer participants. Thus the reader cannot tell whether the investigators planned to recruit only a small number of participants (a study of cognitive treatment had shown such a striking effect7 that a fairly small number of participants may have been deemed adequate), or had problems with recruitment. It is therefore hard to know how acceptable the basic approach was to the target population. This point and the small sample size make generalisation from this study to the overall population of hypochondriacal patients difficult. Interestingly, another Oxford group has reported great difficulty in recruiting individuals with non-cardiac chest pain to a similar study.8 Unfortunately, clinicians are left not knowing whether intensive psychological treatment programmes are acceptable to hypochondriacal patients, or whether such programmes have a therapeutic effect over and above simple attention. It was the late Michael Balint9 who put
THE LANCET • Vol 352 • December 5, 1998
COMMENTARY
forward the notion of patients needing regular access to the drug, “doctor”. There seems little alternative to practitioners continuing to monitor that drug, and to use it with discretion to help hypochondriacal patients. And it is always important to remember that even hypochondriacal patients can fall ill.
*David I Ben-Tovim, Adrian Esterman Departments of Psychiatry and Clinical Epidemiology and Health Outcomes, Flinders Medical Centre, Bedford Park, SA 5042, Australia 1
2
3 4 5 6 7
8
9
Clark DM, Salkoviskis PM, Hackmann A, et al. Two psychological treatments for hypochondriasis: a randomised controlled trial. Br J Psychiatry 1998; 173: 218–25. American Psychiatric Association. Somatization disorders. In: Diagnostic and statistical manual of mental disorders, 4th edn. Washington: American Psychiatric Association, 1994. Leff GP. Psychiatry around the global: a transcultural view, 2nd edn. London: Gaskell, 1988. Papageorgriou C, Wells A. Effects of attention training on hypochondriasis: a brief case series. Psychol Med 1998; 28: 193–200. Barsky AJ. Hypochondriasis: medical management and psychiatric treatment. Psychosomatics 1996, 37: 48–56. Fallon BA, Schneier FR, Marshall R, et al. The pharmacotherapy of hypochondriasis. Psychopharmacol Bull 1996; 32: 607–11. Warwick HM, Clark DM, Cobb AM, Salkovskis PM. A controlled trial of cognitive-behavioural treatment of hypochondriasis. Br J Psychiatry 1996; 169: 189–95. Mayou RA, Bryant BM, Sanders D, Bass C, Klimes I, Forfar C. A controlled trial of congnitive behavioural therapy for non-cardiac chest pain. Psychol Med 1997; 27: 1021–31. Balint M. The doctor, his patient, and the illness, 2nd edn. London: Pitman Medical, 1964.
Rubella gene sequencing as a clinician’s tool The rubivirus genus of the Togaviridae family has only one known member, the rubella virus, for which human beings seem to be the only host. Most rubella infections are symptomless or cause only mild symptoms, but if infection occurs in a pregnant woman, the fetus is damaged in up to 80% of first-trimester and up to 30% of Congenital rubella second-trimester infections.1 syndrome (CRS) varies from a multiorgan disease to isolated ocular, cardiac, sensorineural, psychomotor, or mental disorders. Late manifestations of CRS include diabetes, thyroid disease, and progressive rubella panencephalitis. The incidence of CRS in a susceptible population used to be unknown largely because many women with proven infection undergo termination of pregnancy. An opportunity to find out emerged during an epidemic in an Amish population in the USA. The annual CRS rate was astonishingly high: 2130 cases per 100 000 livebirths2 (about 2%). The incidence in other epidemics had been fewer than 10 cases per 100 000 livebirths per year.3 Whether various musculoskeletal disorders, especially chronic arthropathy in adult women, are due to rubella (or to rubella vaccination) outside of pregnancy is However, the possible adverse controversial.4 consequences of rubella infection in pregnancy were thought to justify repatriation of a woman for her own protection from a Bosnia-Herzegovina peacekeeping force undergoing a rubella outbreak.5 With the range and severity of disorders associated with rubella virus, research that sheds light on the epidemiology, pathogenesis, prevention, and treatment of rubella is well justified. Some relevant data have been derived from the gene sequencing of 63 strains collected over 30 years in North America, Europe, and Asia.3 The genome of the single-stranded RNA rubella virus
THE LANCET • Vol 352 • December 5, 1998
consists of about 10 000 nucleotides enclosed in an icosahedral nucleocapsid. The virion is surrounded by a host-cell-derived lipid envelope in which two glycoproteins, E1 and E2, are embedded. Humoral responses (antibody production) are directed mostly against E1, because it is more exposed than E2. The reason for sequence variation in nucleotides of both RNA and DNA viruses is, supposedly, that genomic variation enables viruses to adapt to the changes in the environment and in conditions of replication. Nucleotide variation may lead to changes in the aminoacid composition of the virion, which is commonly reflected as antigenic variation. However, in most cases there is no structural change. Instead, the sequence variation helps the virus to optimise its replication. Another point is that rubella virus does not seem to be prone to variation in the major antigenic sites, whereas strains from patients with chronic arthritis have shown some variation.3 Genomic heterogeneity has two implications for clinicians. First, precise identification of the agent enables the tracking of chains of transmission of infection and sometimes the tracing of the origin of infection.6–8 Second, characterisation of a new strain can disclose the presence of an epidemiogenic virus potentially capable of spread among an immunised population.9 There are technical limitations to the analysis of genomic variation in rubella strains. Sequence data used for classification are derived from viruses grown in laboratory cell cultures, a practice that may cause selection bias and distortion of the epidemiological picture. For data on genomic variation to indicate whether strains causing CRS or chronic arthritis differ from those causing the primary infection, they have to be derived from infected individuals. RA 27/3, the strain most commonly used in rubella vaccines, differs so clearly from all other viruses that it can be recognised by nucleotide sequencing.3 A good example of the value of gene sequencing is the case of a child born to a woman vaccinated inadvertently with RA 27/3 during pregnancy; the same strain was isolated from a throat swab from the child, who was healthy.3 The finding proved that a rubella vaccine virus may persist through gestation, be shed at birth, and still leave the offspring unharmed. This finding is very good news for vaccine manufacturers—and for all those working towards the total elimination of CRS and other rubella syndromes.10
*Heikki Peltola, Pauli Leinikki *Helsinki University Central Hospital, Hospital for Children and Adolescents, FIN-00290, Helsinki, Finland; and National Public Health Institute, Helsinki 1
2
3
4
5 6
Zgorniak-Nowosielska I, Zawilinska B, Szostek S. Rubella infection during pregnancy in the 1985–86 epidemic: follow-up after seven years. Eur J Epidemiol 1996; 12: 303–08. Mellinger AK, Cragan JD, Atkinson WL, et al. High incidence of congenital rubella syndrome after a rubella outbreak. Pediatr Infect Dis J 1995; 14: 573–78. Frey TK, Abernathy ES, Bosma TJ, et al. Molecular analysis of rubella virus epidemiology across three continents, north America, Europe, and Asia, 1961–1997. J Infect Dis 1998; 178: 642–50. Frenkel LM, Nielsen K, Garakian A, Jin R, Wolinsky JS, Cherry JD. A search for persistent rubella virus infection in persons with chronic symptoms after rubella and rubella immunization and in patients with juvenile rheumatoid arthritis. Clin Infect Dis 1996; 22: 287–94. Adams MS, Croft AM, Winfeld DA, Richards PR. An outbreak of rubella in British troops in Bosnia. Epidemiol Infect 1997; 118: 253–57. Pöyry T, Kinnunen L, Kapenberg J, Kew O, Hovi T. Type 3
1799
hygiene during childhood did not find any association with ulcerative colitis.2 Are there practical implications of this line of research? In view of the low incidence rates of ulcerative colitis, appendicectomy cannot be recommended as a preventive measure, especially since, despite compelling data, observational studies cannot prove cause. The observed association between appendicectomy and ulcerative colitis may, however, prove very important, because it provides tantalising evidence about the role of the gut immune system in mediating disease.
Robert S Sandler Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA 1
Breslin NP, McDonnell C, O’Morain C. Surgical and smoking history in inflammatory bowel disease: a case-control study. Inflamm Bowel Dis 1997; 3: 1–5. 2 Duggan AE, Usmani I, Neal KR. Logan RFA. Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case-control study. Gut 1998; 43: 494–98. 3 Gent AE, Heller MD, Grace RH, Swarbrick ET, Coggon D. Inflammatory bowel disease and domestic hygiene in infancy. Lancet 1994; 343: 766–67. 4 Gilat T, Hacohen D, Lilos P, Langman MJS. Childhood factors in ulcerative colitis and Crohn’s disease: an international cooperative study. Scand J Gastroenterol 1987; 22: 1009–24. 5 Minocha A, Raczkowski CA. Role of appendectomy and tonsillectomy in pathogenesis of ulcerative colitis. Dig Dis Sci 1997; 42: 1567–69. 6 Russel MG, Dorant E, Brummer R-JM, et al. Appendectomy and the risk of developing ulcerative colitis or Crohn’s disease: results of a large case-control study. Gastroenterology 1997; 113: 377–82. 7 Rutgeerts P, D’Haens G, Hiele M, Geboes K, Van Trappen G. Appendectomy protects against ulcerative colitis. Gastroenterology 1994; 106: 1251-–53. 8 Smithson JE, Radford-Smith G, Jewell GP. Appendectomy and tonsillectomy in patients with inflammatory bowel disease. J Clin Gastroenterol 1995; 21: 283–86. 9 Wurzelmann JI, Lyles CM, Sandler RS. Childhood infections and the risk of inflammatory bowel disease. Dig Dis Sci 1994; 39: 555–60. 10 Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK. Role of appendix in the development of inflammatory bowel disease in TCR-a mutant mice. J Exp Med 1996; 184: 707–15. 11 Rath HC, Ikeda JS, Linde H-J, Schölmerich J, Wilson KH, Sartor RB. Varying cecal bacterial loads influences colitis and gastritis in HLAB27 transgenic rats. Gastroenterology (in press).
Zero progress with hypochondriasis Imagine the following scenario. A doctor is saying to one of his more difficult patients: “We both know you are very worried about the pains in your stomach and chest, and the odd sensation in your leg. I have examined you on several occasions, and performed a wide variety of tests. I am convinced there is no serious physical cause for your experiences. I know you don’t agree, but I think you are suffering from hypochondriasis. The good news is that there is a group conducting a trial of psychological treatments for this disorder, and I can refer you to them. however, you should know that there is a one in two chance that the treatment you receive will be a sham.” Such an encounter is the kind of challenge to be overcome in randomised controlled trials of psychological treat-ments for hypochondriasis. The successes, and more importantly, the failures, of a recent study1 are instructive. Patients who puzzle their doctors receive a variety of labels.2 Hypochondriasis is a conviction of disease without adequate justification. Hypochondriacal patients seek to act on that conviction. Hysteria is nowadays reserved for complaints of loss of function of a body part without physical cause. The more recent term, somatisation, is both a syndrome and a figure of speech. The syndrome refers to a long history of multisystem complaints and 1798
medical investigations and treatment, but with no physical cause being found for the symptoms. The figure of speech describes the presentation of a bodily symptom instead of a direct statement of disturbed emotions. Since the body is the medium for expression of emotion in most cultures, it might be more appropriate to describe individuals who say things such as “I am depressed” as psychologisers,3 but that is another matter. Hypochondriacal patients are distressed, and cause distress to those around them. An effective treatment would clearly be welcome. Although various therapies have been advocated,4,5 there is no convincing evidence that any treatment produces a specific effect. A group from Oxford1 tried to remedy this lack with a study of a cognitive behavioural strategy for hypochondriasis. The therapy was based on challenging the patient’s hypochondriacal beliefs. Experiences with drug trials6 reinforce the importance of including a sham or placebo treatment in any study of hypochondriasis. Response to treatment in the placebo group may be very high. A sham or placebo psychological treatment would involve regular attention without other active components. D M Clark and colleagues did not attempt to devise such a treatment: instead they tried to develop a credible psychosocial treatment that excluded the critical element of a direct challenge to the patients’ beliefs. Their initial attempt was not acceptable to the patients, so they settled for a study of the comparative efficacy of two active psychological treatments—the cognitive treatment, and a more generic stress-management and relaxation approach. The inclusion of waiting-list controls, assessed and then re-examined at the end of the same time period as active treatment, showed that spontaneous remissions were rare in the group under study. Such controls cannot, however, substitute for a sham treatment in tests of treatment effect. The trial was conducted very carefully and generally described in exemplary detail. At the end of the 12month follow-up period, the outcomes from the two treatments were similar. The cognitive approach had produced more impressive results at first, but these were not sustained over the follow-up. The generic approach produced an initially smaller, but more constant, effect. Thus the result did not favour either treatment. Only 48 people were recruited to the study over a 3year period. The investigators do not state how many people were referred, although all general practitioners, psychologists, and psychiatrists in a large area were canvassed to refer participants. Thus the reader cannot tell whether the investigators planned to recruit only a small number of participants (a study of cognitive treatment had shown such a striking effect7 that a fairly small number of participants may have been deemed adequate), or had problems with recruitment. It is therefore hard to know how acceptable the basic approach was to the target population. This point and the small sample size make generalisation from this study to the overall population of hypochondriacal patients difficult. Interestingly, another Oxford group has reported great difficulty in recruiting individuals with non-cardiac chest pain to a similar study.8 Unfortunately, clinicians are left not knowing whether intensive psychological treatment programmes are acceptable to hypochondriacal patients, or whether such programmes have a therapeutic effect over and above simple attention. It was the late Michael Balint9 who put
THE LANCET • Vol 352 • December 5, 1998
COMMENTARY
forward the notion of patients needing regular access to the drug, “doctor”. There seems little alternative to practitioners continuing to monitor that drug, and to use it with discretion to help hypochondriacal patients. And it is always important to remember that even hypochondriacal patients can fall ill.
*David I Ben-Tovim, Adrian Esterman Departments of Psychiatry and Clinical Epidemiology and Health Outcomes, Flinders Medical Centre, Bedford Park, SA 5042, Australia 1
2
3 4 5 6 7
8
9
Clark DM, Salkoviskis PM, Hackmann A, et al. Two psychological treatments for hypochondriasis: a randomised controlled trial. Br J Psychiatry 1998; 173: 218–25. American Psychiatric Association. Somatization disorders. In: Diagnostic and statistical manual of mental disorders, 4th edn. Washington: American Psychiatric Association, 1994. Leff GP. Psychiatry around the global: a transcultural view, 2nd edn. London: Gaskell, 1988. Papageorgriou C, Wells A. Effects of attention training on hypochondriasis: a brief case series. Psychol Med 1998; 28: 193–200. Barsky AJ. Hypochondriasis: medical management and psychiatric treatment. Psychosomatics 1996, 37: 48–56. Fallon BA, Schneier FR, Marshall R, et al. The pharmacotherapy of hypochondriasis. Psychopharmacol Bull 1996; 32: 607–11. Warwick HM, Clark DM, Cobb AM, Salkovskis PM. A controlled trial of cognitive-behavioural treatment of hypochondriasis. Br J Psychiatry 1996; 169: 189–95. Mayou RA, Bryant BM, Sanders D, Bass C, Klimes I, Forfar C. A controlled trial of congnitive behavioural therapy for non-cardiac chest pain. Psychol Med 1997; 27: 1021–31. Balint M. The doctor, his patient, and the illness, 2nd edn. London: Pitman Medical, 1964.
Rubella gene sequencing as a clinician’s tool The rubivirus genus of the Togaviridae family has only one known member, the rubella virus, for which human beings seem to be the only host. Most rubella infections are symptomless or cause only mild symptoms, but if infection occurs in a pregnant woman, the fetus is damaged in up to 80% of first-trimester and up to 30% of Congenital rubella second-trimester infections.1 syndrome (CRS) varies from a multiorgan disease to isolated ocular, cardiac, sensorineural, psychomotor, or mental disorders. Late manifestations of CRS include diabetes, thyroid disease, and progressive rubella panencephalitis. The incidence of CRS in a susceptible population used to be unknown largely because many women with proven infection undergo termination of pregnancy. An opportunity to find out emerged during an epidemic in an Amish population in the USA. The annual CRS rate was astonishingly high: 2130 cases per 100 000 livebirths2 (about 2%). The incidence in other epidemics had been fewer than 10 cases per 100 000 livebirths per year.3 Whether various musculoskeletal disorders, especially chronic arthropathy in adult women, are due to rubella (or to rubella vaccination) outside of pregnancy is However, the possible adverse controversial.4 consequences of rubella infection in pregnancy were thought to justify repatriation of a woman for her own protection from a Bosnia-Herzegovina peacekeeping force undergoing a rubella outbreak.5 With the range and severity of disorders associated with rubella virus, research that sheds light on the epidemiology, pathogenesis, prevention, and treatment of rubella is well justified. Some relevant data have been derived from the gene sequencing of 63 strains collected over 30 years in North America, Europe, and Asia.3 The genome of the single-stranded RNA rubella virus
THE LANCET • Vol 352 • December 5, 1998
consists of about 10 000 nucleotides enclosed in an icosahedral nucleocapsid. The virion is surrounded by a host-cell-derived lipid envelope in which two glycoproteins, E1 and E2, are embedded. Humoral responses (antibody production) are directed mostly against E1, because it is more exposed than E2. The reason for sequence variation in nucleotides of both RNA and DNA viruses is, supposedly, that genomic variation enables viruses to adapt to the changes in the environment and in conditions of replication. Nucleotide variation may lead to changes in the aminoacid composition of the virion, which is commonly reflected as antigenic variation. However, in most cases there is no structural change. Instead, the sequence variation helps the virus to optimise its replication. Another point is that rubella virus does not seem to be prone to variation in the major antigenic sites, whereas strains from patients with chronic arthritis have shown some variation.3 Genomic heterogeneity has two implications for clinicians. First, precise identification of the agent enables the tracking of chains of transmission of infection and sometimes the tracing of the origin of infection.6–8 Second, characterisation of a new strain can disclose the presence of an epidemiogenic virus potentially capable of spread among an immunised population.9 There are technical limitations to the analysis of genomic variation in rubella strains. Sequence data used for classification are derived from viruses grown in laboratory cell cultures, a practice that may cause selection bias and distortion of the epidemiological picture. For data on genomic variation to indicate whether strains causing CRS or chronic arthritis differ from those causing the primary infection, they have to be derived from infected individuals. RA 27/3, the strain most commonly used in rubella vaccines, differs so clearly from all other viruses that it can be recognised by nucleotide sequencing.3 A good example of the value of gene sequencing is the case of a child born to a woman vaccinated inadvertently with RA 27/3 during pregnancy; the same strain was isolated from a throat swab from the child, who was healthy.3 The finding proved that a rubella vaccine virus may persist through gestation, be shed at birth, and still leave the offspring unharmed. This finding is very good news for vaccine manufacturers—and for all those working towards the total elimination of CRS and other rubella syndromes.10
*Heikki Peltola, Pauli Leinikki *Helsinki University Central Hospital, Hospital for Children and Adolescents, FIN-00290, Helsinki, Finland; and National Public Health Institute, Helsinki 1
2
3
4
5 6
Zgorniak-Nowosielska I, Zawilinska B, Szostek S. Rubella infection during pregnancy in the 1985–86 epidemic: follow-up after seven years. Eur J Epidemiol 1996; 12: 303–08. Mellinger AK, Cragan JD, Atkinson WL, et al. High incidence of congenital rubella syndrome after a rubella outbreak. Pediatr Infect Dis J 1995; 14: 573–78. Frey TK, Abernathy ES, Bosma TJ, et al. Molecular analysis of rubella virus epidemiology across three continents, north America, Europe, and Asia, 1961–1997. J Infect Dis 1998; 178: 642–50. Frenkel LM, Nielsen K, Garakian A, Jin R, Wolinsky JS, Cherry JD. A search for persistent rubella virus infection in persons with chronic symptoms after rubella and rubella immunization and in patients with juvenile rheumatoid arthritis. Clin Infect Dis 1996; 22: 287–94. Adams MS, Croft AM, Winfeld DA, Richards PR. An outbreak of rubella in British troops in Bosnia. Epidemiol Infect 1997; 118: 253–57. Pöyry T, Kinnunen L, Kapenberg J, Kew O, Hovi T. Type 3
1799