- Email: [email protected]
Effectiveness of vaccination for Haemophilus influenzae type b
RESEARCH LETTERS
Contributors R M Cawthon had the idea for the basic study design, measured telomere lengths, obtained some of the survival data, and contributed to data analysis, discussion of findings, and writing of the report. K R Smith and R A Kerber contributed to study design, obtained survival and causespecific mortality data, did the data analysis, and contributed to discussion of findings, and writing of the report. E O’Brien contributed to discussion of findings and writing of the report. A Sivatchenko contributed to data analysis and interpretation.
Conflict of interest statement R M Cawthon has submitted a patent application for the method of telomere measurement by quantitative PCR. No other actual or potential conflict of interest is declared.
Acknowledgments We thank Mark Leppert for access to the Utah CEPH DNA samples; Geri Mineau, Alison Fraser, and Diana Lane for collection of survival and cause of death data; and Missy Dixon for collection of survival data. This work was supported by the AlliedSignal Award for Research on Aging; the Alliance For Ageing Research; NIH grants K01 AG00767, R29CA69421, and AG13478; the Utah Resource for Genetic and Epidemiologic Research; and the Huntsman General Clinical Research Center. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. 1
2 3
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Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413: 432–35. Saretzki G, Von Zglinicki T. Replicative aging, telomeres, and oxidative stress. Ann N Y Acad Sci 2002; 959: 24–29. White R, Leppert M, Bishop DT, et al. Construction of linkage maps with DNA markers for human chromosomes. Nature 1985; 313: 101–05. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res 2002; 30: e47. Ghali WA, Quan H, Brant R, et al. Comparison of 2 methods for calculating adjusted survival curves from proportional hazards models. JAMA 2001; 286: 1494–97.
Department of Human Genetics (R M Cawthon MD) and Department of Family and Consumer Studies (K R Smith PhD), University of Utah, Salt Lake City, UT, USA; and Department of Oncological Sciences (A Sivatchenko MD, R A Kerber PhD), Huntsman Cancer Institute (K R Smith, E O’Brien PhD, R A Kerber), University of Utah, Salt Lake City, UT Correspondence to: Dr Richard M Cawthon, Department of Human Genetics, University of Utah, 15 N 2030 E Street, Room 2100, Salt Lake City, UT 84112, USA (e-mail: [email protected])
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
Effectiveness of vaccination for Haemophilus influenzae type b David Garner, Vivienne Weston Several cases of invasive Haemophilus influenzae type b (Hib) infection have been identified in children previously vaccinated against this disease. We have reviewed all cases of Hib in Nottingham, UK, since the conjugated vaccine was introduced into the primary course of childhood immunisations in 1992. Our results show a worrying increase in the frequency of Hib in Nottingham, which is much the same as the national trends. We believe that the medical profession should be aware of the return of Hib, and that we now need to review the need for a booster vaccination for what was thought to be a disease of the past.
Lancet 2003; 361: 395–96 See Commentary page 360
Acute epiglottitis used to frequently strike fear into the hearts of general practitioners and paediatricians in the UK. On Oct 1, 1992, Haemophilus influenzae type b (Hib) conjugate vaccine became part of the primary course of childhood immunisations at 2, 3, and 4 months of age and during 1993, all children younger than 4 years were offered “catch-up” vaccinations with a single dose of vaccine. This programme greatly reduced the frequency of acute epiglottitis and invasive Hib disease throughout the UK. However, over the past 3 years the frequency of invasive Hib in the UK has more than doubled and this disorder should still be considered a cause of acute stridor. In Nottingham, from October to December, 2001, we recorded four cases of invasive Hib disease in children younger than 4 years of age who had previously been vaccinated. Thus, the microbiology consultant alerted the consultant in Paediatric Intensive Care to the presence of Hib within vaccinated children—a timely intervention. The following week a child, previously vaccinated against Hib, was referred to Paediatric Intensive Care Unit from Accident and Emergency with severe croup. The consultant in Paediatric Intensive Care was immediately alerted to the presence of Hib epiglottitis and proceeded to manage this child appropriately. The diagnosis was later confirmed by culture of Haemophilus influenzae type b from blood. Without the warning from the microbiology department, instigation of appropriate antimicrobial treatment might have been unnecessarily delayed in this child. There were 23·8 cases of invasive Hib per 100 000 children in England and Wales in 1991, the year before the childhood immunisation programme was introduced; by 1996, prevalence had dropped to 0·92 per 100 000; and in
Number of cases
vascular disease and cancer were not significantly higher in individuals with shorter telomeres (table). The mortality rate from infectious disease was eight times higher for individuals in the bottom 25% of the telomere length distribution than for individuals in the top 75% (p=0·015). Of the deaths from infectious disease, the shortest time between blood draw and death was 1.5 years. Our results lend support to the hypothesis that telomere shortening contributes to the rise in mortality rates from multiple diseases typically seen with ageing. Alternatively, telomere shortening might not affect mortality, but might be controlled by (and so serve as a useful indicator of) progression of a process of senescence that raises mortality rates by other mechanisms. Short telomeres in blood could indicate the presence of an age-related disease that has, perhaps, triggered a shift in the proportions of white-blood-cell subsets, thereby reducing average telomere lengths. This scenario, however, predicts that the strength of the association of shorter telomeres with higher mortality should decline as the number of years that individuals needed to survive after blood draw increases, and we did not see such a decline. Telomere length in age-matched people can be affected by many factors,2 including telomerase activity, rates of cell division, and amounts of oxidative stress, which in turn might be determined by genetic and environmental factors.
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Year Cases of invasive Haemophilus influenzae type B (Hib) in Nottingham Public Health Laboratory 1992–2001
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For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
2001, prevalence had slowly increased to 1·88 per 100 000, with the highest prevalence of 2·81 per 100 000 in 2002 in those aged 1–4 years (M Ramsay, personal communication). In Nottingham, the number of cases has risen from none in 1996 to seven in 2001, with 17 cases in total since 1999 (figure). In 2001, six cases were in children, from a population of 750 000, giving a rate of 0·8 per 100 000. However this value includes only those in whom we could culture Hib from a normally sterile site, and does not include those who had Hib antigen tests or Hib serology consistent with invasive Hib disease as used by the British Paediatric Surveillance Unit. Thus, our value is probably an underestimate of the true prevalence. We have also witnessed the increase in disease within the 1–4 year old group with five of seven cases in 2001. The change in pattern of invasive Hib disease could have been the result of a normal fluctuation in background incidence of Hib1 or because of use of the catch-up immunisation, which resulted in a high degree of immunity in preschool children and might have produced a low carriage rate. Protection against carriage probably does not persist, and thus, higher carriage rates in older children could be contributing to the increased disease rates today. The change in pattern could also have been due to the more widespread use since January, 2000, dictated by the interruption of supply of a combination vaccine including an acellular pertussis component as opposed to wholecell pertussis. This has been shown to have a less immunogenic effect than its whole-cell alternative,2 though the clinical significance of this is uncertain since the changes in incidence began before this use became widespread. From 1999, in Nottingham we recorded seven true vaccine failures, six since January, 2001, as defined by the British Paediatric Surveillance Unit. There was no link between cases in terms of batch of vaccine used. From September, 1992, to March, 2001, surveillance of vaccine failures in children by the British Paediatric Surveillance Unit identified 202 children who had received three doses of vaccine within the first year of life. 56% of these were older than 2 years.3 Results of studies have shown that about 44% of true vaccine failures have a risk factor (prematurity, immunoglobulin deficiency, or another clinical factor).4 Previously vaccinated children, who have antiHib immunoglobulin below a protective level in the convalescent phase of invasive Hib disease, which is less immunogenic than the vaccine, have been shown to produce a protective level when given a booster dose of vaccine, with one study showing a response in 23 of 24 children.4 Thus, we have offered our cases of true vaccine failure a further dose of vaccine. It is clear from our experience in Nottingham and nationally that, despite the large initial fall in incidence, invasive Hib disease has not gone away since the vaccination programme was introduced. Although invasive Hib has now been dropped from the British Paediatric Surveillance Unit reporting scheme, continued surveillance is essential to investigate recent trends in incidence of Hib. It might also be time to consider the need for booster vaccination in the UK. Contributors D Garner wrote the report. V Weston edited the report and reviewed data.
Conflict of interest statement None declared.
Acknowledgments No funding was sought or allocated to the research for or production of this letter.
396
1
2
3
4
Public Health Laboratory Service. Surveillance of invasive Haemophilus influenzae infections in children. CDR weekly Jan 24; 2002: 3–4. Eskola J, Ward J, Dagan R, Goldblatt D, Zepp F, Siegrist S-A. Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet 1999; 354: 2063–68. McVernon J, Heath P, Booy R. Invasive Haemophilus influenzae infection. British Paediatric Surveillance Unit 15th Annual Report 2000–01: 23–25. Heath PT, Booy R, Griffiths H, et al. Clinical and immunological risk factors associated with Haemophilus influenzae type b conjugate vaccine failure in childhood. Clin Infect Dis 2000; 31: 973–80.
Department of Microbiology and Public Health Laboratory, Queens Medical Centre, University Hospital, Nottingham NG7 2UH, UK (D Garner MRCPCH, V Weston MRCPATH) Correspondence to: Dr David Garner (e-mail: [email protected])
Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E 2/3/4 genotype Bernard Keavney, Sarah Parish, Alison Palmer, Sarah Clark, Linda Youngman, John Danesh, Colin McKenzie, Marc Delépine, Mark Lathrop, Richard Peto, Rory Collins, for the International Studies of Infarct Survival (ISIS) Collaborators* Results from two small studies, involving a total of only 174 cases, have suggested that the increased risk of coronary heart disease conferred by cigarette smoking is substantially affected by genotype at the apolipoprotein E (APOE) 2/3/4 polymorphism. We have established APOE genotypes in 4484 patients with acute myocardial infarction diagnosed before the age of 55 years for male and 65 years for female patients, and in 5757 controls with no history of cardiovascular disease. On average, the hazard ratio for myocardial infarction was 1·17 (95% CI 1·09–1·25; p<0·00001) per stepwise change from 3/2 to 3/3 to 3/4 genotype. Among individuals in this study with known cigarette smoking status, the hazard ratio for myocardial infarction in smokers versus non-smokers was 4·6 (4·2–5·1). There was, however, no significant difference between the smoker/non-smoker hazard ratios for those with different APOE genotypes (22=0·69; p=0·7). When differences in risk between different genotypes are not extreme (as with this APOE polymorphism), reliable assessment of hypothesised gene-environment interactions will often require the study of many thousands of disease cases.
Lancet 2003: 361: 396–98 *For information on collaborators and participating centres see reference 5
Genetic and environmental factors affect the risk of coronary heart disease. Cigarette smoking is an important environmental risk factor,1 and certain genotypes at the apolipoprotein E (APOE) 2/3/4 polymorphism have been associated with moderately increased risks of coronary disease.2 Results from two recent studies have suggested that the effect of smoking on coronary disease risk is strongly affected by APOE 2/3/4 genotype, but both studies had only small numbers of cases. In one of them, involving 59 cases of coronary disease, a more extreme
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Contributors R M Cawthon had the idea for the basic study design, measured telomere lengths, obtained some of the survival data, and contributed to data analysis, discussion of findings, and writing of the report. K R Smith and R A Kerber contributed to study design, obtained survival and causespecific mortality data, did the data analysis, and contributed to discussion of findings, and writing of the report. E O’Brien contributed to discussion of findings and writing of the report. A Sivatchenko contributed to data analysis and interpretation.
Conflict of interest statement R M Cawthon has submitted a patent application for the method of telomere measurement by quantitative PCR. No other actual or potential conflict of interest is declared.
Acknowledgments We thank Mark Leppert for access to the Utah CEPH DNA samples; Geri Mineau, Alison Fraser, and Diana Lane for collection of survival and cause of death data; and Missy Dixon for collection of survival data. This work was supported by the AlliedSignal Award for Research on Aging; the Alliance For Ageing Research; NIH grants K01 AG00767, R29CA69421, and AG13478; the Utah Resource for Genetic and Epidemiologic Research; and the Huntsman General Clinical Research Center. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. 1
2 3
4 5
Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413: 432–35. Saretzki G, Von Zglinicki T. Replicative aging, telomeres, and oxidative stress. Ann N Y Acad Sci 2002; 959: 24–29. White R, Leppert M, Bishop DT, et al. Construction of linkage maps with DNA markers for human chromosomes. Nature 1985; 313: 101–05. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res 2002; 30: e47. Ghali WA, Quan H, Brant R, et al. Comparison of 2 methods for calculating adjusted survival curves from proportional hazards models. JAMA 2001; 286: 1494–97.
Department of Human Genetics (R M Cawthon MD) and Department of Family and Consumer Studies (K R Smith PhD), University of Utah, Salt Lake City, UT, USA; and Department of Oncological Sciences (A Sivatchenko MD, R A Kerber PhD), Huntsman Cancer Institute (K R Smith, E O’Brien PhD, R A Kerber), University of Utah, Salt Lake City, UT Correspondence to: Dr Richard M Cawthon, Department of Human Genetics, University of Utah, 15 N 2030 E Street, Room 2100, Salt Lake City, UT 84112, USA (e-mail: [email protected])
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
Effectiveness of vaccination for Haemophilus influenzae type b David Garner, Vivienne Weston Several cases of invasive Haemophilus influenzae type b (Hib) infection have been identified in children previously vaccinated against this disease. We have reviewed all cases of Hib in Nottingham, UK, since the conjugated vaccine was introduced into the primary course of childhood immunisations in 1992. Our results show a worrying increase in the frequency of Hib in Nottingham, which is much the same as the national trends. We believe that the medical profession should be aware of the return of Hib, and that we now need to review the need for a booster vaccination for what was thought to be a disease of the past.
Lancet 2003; 361: 395–96 See Commentary page 360
Acute epiglottitis used to frequently strike fear into the hearts of general practitioners and paediatricians in the UK. On Oct 1, 1992, Haemophilus influenzae type b (Hib) conjugate vaccine became part of the primary course of childhood immunisations at 2, 3, and 4 months of age and during 1993, all children younger than 4 years were offered “catch-up” vaccinations with a single dose of vaccine. This programme greatly reduced the frequency of acute epiglottitis and invasive Hib disease throughout the UK. However, over the past 3 years the frequency of invasive Hib in the UK has more than doubled and this disorder should still be considered a cause of acute stridor. In Nottingham, from October to December, 2001, we recorded four cases of invasive Hib disease in children younger than 4 years of age who had previously been vaccinated. Thus, the microbiology consultant alerted the consultant in Paediatric Intensive Care to the presence of Hib within vaccinated children—a timely intervention. The following week a child, previously vaccinated against Hib, was referred to Paediatric Intensive Care Unit from Accident and Emergency with severe croup. The consultant in Paediatric Intensive Care was immediately alerted to the presence of Hib epiglottitis and proceeded to manage this child appropriately. The diagnosis was later confirmed by culture of Haemophilus influenzae type b from blood. Without the warning from the microbiology department, instigation of appropriate antimicrobial treatment might have been unnecessarily delayed in this child. There were 23·8 cases of invasive Hib per 100 000 children in England and Wales in 1991, the year before the childhood immunisation programme was introduced; by 1996, prevalence had dropped to 0·92 per 100 000; and in
Number of cases
vascular disease and cancer were not significantly higher in individuals with shorter telomeres (table). The mortality rate from infectious disease was eight times higher for individuals in the bottom 25% of the telomere length distribution than for individuals in the top 75% (p=0·015). Of the deaths from infectious disease, the shortest time between blood draw and death was 1.5 years. Our results lend support to the hypothesis that telomere shortening contributes to the rise in mortality rates from multiple diseases typically seen with ageing. Alternatively, telomere shortening might not affect mortality, but might be controlled by (and so serve as a useful indicator of) progression of a process of senescence that raises mortality rates by other mechanisms. Short telomeres in blood could indicate the presence of an age-related disease that has, perhaps, triggered a shift in the proportions of white-blood-cell subsets, thereby reducing average telomere lengths. This scenario, however, predicts that the strength of the association of shorter telomeres with higher mortality should decline as the number of years that individuals needed to survive after blood draw increases, and we did not see such a decline. Telomere length in age-matched people can be affected by many factors,2 including telomerase activity, rates of cell division, and amounts of oxidative stress, which in turn might be determined by genetic and environmental factors.
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Year Cases of invasive Haemophilus influenzae type B (Hib) in Nottingham Public Health Laboratory 1992–2001
395
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
2001, prevalence had slowly increased to 1·88 per 100 000, with the highest prevalence of 2·81 per 100 000 in 2002 in those aged 1–4 years (M Ramsay, personal communication). In Nottingham, the number of cases has risen from none in 1996 to seven in 2001, with 17 cases in total since 1999 (figure). In 2001, six cases were in children, from a population of 750 000, giving a rate of 0·8 per 100 000. However this value includes only those in whom we could culture Hib from a normally sterile site, and does not include those who had Hib antigen tests or Hib serology consistent with invasive Hib disease as used by the British Paediatric Surveillance Unit. Thus, our value is probably an underestimate of the true prevalence. We have also witnessed the increase in disease within the 1–4 year old group with five of seven cases in 2001. The change in pattern of invasive Hib disease could have been the result of a normal fluctuation in background incidence of Hib1 or because of use of the catch-up immunisation, which resulted in a high degree of immunity in preschool children and might have produced a low carriage rate. Protection against carriage probably does not persist, and thus, higher carriage rates in older children could be contributing to the increased disease rates today. The change in pattern could also have been due to the more widespread use since January, 2000, dictated by the interruption of supply of a combination vaccine including an acellular pertussis component as opposed to wholecell pertussis. This has been shown to have a less immunogenic effect than its whole-cell alternative,2 though the clinical significance of this is uncertain since the changes in incidence began before this use became widespread. From 1999, in Nottingham we recorded seven true vaccine failures, six since January, 2001, as defined by the British Paediatric Surveillance Unit. There was no link between cases in terms of batch of vaccine used. From September, 1992, to March, 2001, surveillance of vaccine failures in children by the British Paediatric Surveillance Unit identified 202 children who had received three doses of vaccine within the first year of life. 56% of these were older than 2 years.3 Results of studies have shown that about 44% of true vaccine failures have a risk factor (prematurity, immunoglobulin deficiency, or another clinical factor).4 Previously vaccinated children, who have antiHib immunoglobulin below a protective level in the convalescent phase of invasive Hib disease, which is less immunogenic than the vaccine, have been shown to produce a protective level when given a booster dose of vaccine, with one study showing a response in 23 of 24 children.4 Thus, we have offered our cases of true vaccine failure a further dose of vaccine. It is clear from our experience in Nottingham and nationally that, despite the large initial fall in incidence, invasive Hib disease has not gone away since the vaccination programme was introduced. Although invasive Hib has now been dropped from the British Paediatric Surveillance Unit reporting scheme, continued surveillance is essential to investigate recent trends in incidence of Hib. It might also be time to consider the need for booster vaccination in the UK. Contributors D Garner wrote the report. V Weston edited the report and reviewed data.
Conflict of interest statement None declared.
Acknowledgments No funding was sought or allocated to the research for or production of this letter.
396
1
2
3
4
Public Health Laboratory Service. Surveillance of invasive Haemophilus influenzae infections in children. CDR weekly Jan 24; 2002: 3–4. Eskola J, Ward J, Dagan R, Goldblatt D, Zepp F, Siegrist S-A. Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet 1999; 354: 2063–68. McVernon J, Heath P, Booy R. Invasive Haemophilus influenzae infection. British Paediatric Surveillance Unit 15th Annual Report 2000–01: 23–25. Heath PT, Booy R, Griffiths H, et al. Clinical and immunological risk factors associated with Haemophilus influenzae type b conjugate vaccine failure in childhood. Clin Infect Dis 2000; 31: 973–80.
Department of Microbiology and Public Health Laboratory, Queens Medical Centre, University Hospital, Nottingham NG7 2UH, UK (D Garner MRCPCH, V Weston MRCPATH) Correspondence to: Dr David Garner (e-mail: [email protected])
Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E 2/3/4 genotype Bernard Keavney, Sarah Parish, Alison Palmer, Sarah Clark, Linda Youngman, John Danesh, Colin McKenzie, Marc Delépine, Mark Lathrop, Richard Peto, Rory Collins, for the International Studies of Infarct Survival (ISIS) Collaborators* Results from two small studies, involving a total of only 174 cases, have suggested that the increased risk of coronary heart disease conferred by cigarette smoking is substantially affected by genotype at the apolipoprotein E (APOE) 2/3/4 polymorphism. We have established APOE genotypes in 4484 patients with acute myocardial infarction diagnosed before the age of 55 years for male and 65 years for female patients, and in 5757 controls with no history of cardiovascular disease. On average, the hazard ratio for myocardial infarction was 1·17 (95% CI 1·09–1·25; p<0·00001) per stepwise change from 3/2 to 3/3 to 3/4 genotype. Among individuals in this study with known cigarette smoking status, the hazard ratio for myocardial infarction in smokers versus non-smokers was 4·6 (4·2–5·1). There was, however, no significant difference between the smoker/non-smoker hazard ratios for those with different APOE genotypes (22=0·69; p=0·7). When differences in risk between different genotypes are not extreme (as with this APOE polymorphism), reliable assessment of hypothesised gene-environment interactions will often require the study of many thousands of disease cases.
Lancet 2003: 361: 396–98 *For information on collaborators and participating centres see reference 5
Genetic and environmental factors affect the risk of coronary heart disease. Cigarette smoking is an important environmental risk factor,1 and certain genotypes at the apolipoprotein E (APOE) 2/3/4 polymorphism have been associated with moderately increased risks of coronary disease.2 Results from two recent studies have suggested that the effect of smoking on coronary disease risk is strongly affected by APOE 2/3/4 genotype, but both studies had only small numbers of cases. In one of them, involving 59 cases of coronary disease, a more extreme
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.