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Haemophilus influenzae type b infections are preventable everywhere
THE LANCET
COMMENTARY
COMMENTARY
Haemophilus influenzae type b infections are preventable everywhere See pages 1191, 1197 The virtual elimination by vaccine of invasive Haemophilus influenzae type b (Hib) disease in industrial countries is a modern public health triumph. Early vaccines, consisting of the Hib polysaccharide capsule, were shown to be effective in the prevention of invasive disease in older children in Finland in 1974. Conjugate Hib vaccines consisting of protein combined with polysaccharide had better immunogenicity in young infants and were shown to be highly effective. During the 1990s widespread use of conjugate Hib vaccines has virtually eliminated Hib disease from North America, northern Europe, Australia, and New Zealand.1,2 Until recently the burden of Hib disease was not well defined in many developing regions, and it was not clear whether Hib vaccines would be effective in these regions.3,4 This issue of The Lancet carries two reports on the use of Hib vaccine, each of which confirms previous data and has notable implications. The evaluation of Hib vaccine introduction in the UK confirms the previously reported high effectiveness of this vaccine. As shown in Scandinavia, these data suggest that a booster dose after the first year of life may not be necessary for effectiveness in well-immunised populations. The analyses conducted after the introduction of the vaccine provide an example of the imaginative use of surveillance data to assess vaccine effectiveness. The prospective randomised efficacy trial from The Gambia shows that an Hib conjugate vaccine has an efficacy of more than 90% against Hib meningitis in a developing-country setting, similar to reports from North America, Europe,2 and Chile.5 A secondary analysis of data from the Gambian study shows an additional substantial effect against severe radiographically proven pneumonia. Although there are wide confidence limits on the estimated effect, these data extend and confirm earlier studies on the aetiology of pneumonia, which were known to underestimate Hib disease.6 In The Gambia bacterial pneumonia is far more common than bacterial meningitis. In the fully vaccinated cohort, 11 cases of meningitis and 38 cases of radiographic pneumonia were prevented, which suggests that the overall effect on pneumonia and meningitis is 4·5-fold greater than the effect on meningitis alone. This unexpected “bonus” for regions with higher rates of bacterial pneumonia is a case for not delaying the 1186
introduction of routine Hib vaccination in developing regions as Mulholland and colleagues emphasise. Because of the high efficacy of conjugate Hib vaccines in every environment in which they have been tested, and their very low rate of adverse events, WHO and the Children’s Vaccine Initiative (CVI), are currently considering supply and delivery issues, before recommending its widespread use in Expanded Programs of Immunization (EPI). A recent meeting on Hib in Asia showed that Hib was the commonest cause of childhood bacterial meningitis in India and Thailand, but some Asian regions reported low levels of Hib disease.7 Careful studies are needed to determine whether prior antibiotic therapy or bacterial and/or human host factors may account for the apparently low rates of Hib disease reported in some Asian societies. A separate issue is how to provide a new highly effective vaccine in the existing EPI system. In common with other newly developed vaccines, (including existing hepatitis B, and hepatitis A vaccines, and imminent pneumococcal conjugate vaccines, as well as respiratory syncytial virus, shigella, and typhoid vaccines), Hib vaccines are currently more expensive to produce than those already in the EPI. WHO, CVI, and others are exploring approaches to reducing the cost of these vaccines for non-industrialised countries. A recent meeting in Bellagio outlined approaches towards improving the availability of Hib and other vaccines.8 Hib disease is not mentioned in many textbooks of tropical medicine, yet now it must be considered a preventable illness in many tropical populations. Indeed, bacterial meningitis (most of which is due to Hib, pneumococcus, and meningococcus) could be targeted as a preventable illness if vaccines against these three organisms were added to EPI programmes.9 In many regions bacterial meningitis is under appreciated and not reported. The surveillance and reporting of bacterial meningitis should be given higher priority, since this syndrome soon will be vaccine preventable. Improved surveillance for childhood bacterial meningitis might usefully be added to current programmes for enhancing the surveillance of poliomyelitis. Although the impetus for development of Hib vaccines was prevention of the devastation caused by Hib meningitis in the industrialised countries, the vaccines will have an enlarged role in less developed countries in
Vol 349 • April 26, 1997
THE LANCET
COMMENTARY preventing Hib meningitis and pneumonia. Additionally, the success of Hib vaccines can accelerate the consideration of how new and more expensive vaccines can be made available to populations with limited resources.
Mark C Steinhoff Department of International Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA 1 2
3 4 5
6
7 8 9
Ward J. H. influenzae vaccines. In: Plotkin SA, Mortimer EA Jr, eds. Vaccines, 2nd ed. Philadelphia: WB Saunders Co, 1994: 337-86. Robbins JB, Schneerson R, Anderson P, Smith DH. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. JAMA 1996; 276: 1181-85. Keusch GT. Should Haemophilus influenzae type b conjugate vaccine be introduced into EPI? Lancet 1992; 339: 802-03. Steinhoff MC. Developing and deploying pneumococcal and haemophilus vaccines. Lancet 1993; 342: 630-31. Lagos R, Horwitz I, Toro J, et al. Large scale, postlicensure, selective vaccination of Chilean infants with PRP-T conjugate vaccine: practicality and effectiveness in preventing invasive Haemophilus influenzae type b infections. Pediatr Infect Dis J 1996; 15: 216-22. Funkhouser A, Steinhoff MC, Ward J. H influenzae disease and immunization in developing countries. Rev Infect Dis 1991; 13: S542-54. Proceedings of International Seminar on Hib in Asia meeting, WHO, AMP. Indonesia, Dec 1996. Bellagio conference. Global availability of new vaccines. Rockefeller Foundation, Feb 1997. Wright PF. Approaches to prevention of acute bacterial meningitis in developing countries. Bull World Health Organ 1989; 67: 479-86.
Centralisation of paediatric intensive care to improve outcome See page 1213 In some European countries there is controversy over whether critically ill children should be admitted to paediatric intensive-care units, to adult intensive-care units, or to normal paediatric wards. Naturally, quality of care should be the deciding factor in selecting the preferred alternative. Prerequisites for high-quality care, especially in specialties looking after complex and heterogeneous patient categories, are adequate continuous staff training and maintenance of their practical experience.1 These provisions are unlikely to be obtainable in small units with few admissions and insufficient variation in case mix. Hence centralisation of paediatric intensive care into a limited number of tertiary units seems preferable to unrestricted fragmented care in adult intensive-care units or paediatric wards that lack staff specially assigned to
Vol 349 • April 26, 1997
paediatric intensive care.2 Many would consider this conclusion self evident, but others want evidence substantiating the benefits of centralisation.3 In (paediatric) intensive care a common index of performance is the standardised (ie, adjusted for severity of illness) mortality rate, derived from scoring systems such as the Pediatric Risk of Mortality (PRISM) score. With this index, a superior outcome was found in centres providing tertiary paediatric intensive care, especially in categories with higher mortality risks, in a statewide comparison of the management of children with head trauma or respiratory insufficiency in the USA.4 A similar study in the Netherlands showed that high-risk children had a substantially higher chance of dying in a non-tertiary centre (odds ratio 2·45).5 In today’s Lancet the effectiveness of paediatric intensive care in an area with fragmented care (Trent, UK) is compared with an area where it is highly centralised in a single tertiary centre (Victoria, Australia). Severity-of-illness-adjusted mortality for Trent children was significantly higher than that for Victorians (odds ratio 2·09). Several explanations can be offered for these alarming differences. The authors used a scoring system that has not yet been validated by an independent group. However, the severity-of-illness-adjusted mortality was similar to that obtained with the more established PRISM score. In addition, there are differences between Trent and Victoria, one being the larger size and less dense population of Victoria, which probably mean longer transportation times to the sole paediatric intensive-care unit and fewer children involved in motor vehicle accidents in the latter. Also, in Victoria centralised paediatric intensive care has been well established, with specially trained medical and nursing staff assigned solely to paediatric care. Therefore it is very unlikely that factors other than quality-of-care related factors would have accounted for a meaningful proportion of the difference in severity-of-illnessadjusted mortality. Hence, the findings in today’s report add to the body of evidence indicating that severity-of-illness-adjusted mortality in tertiary paediatric intensive care units is lower than that in other, non-tertiary settings. These benefits are due primarily to the availability of medical and nursing staff dedicated full time to paediatric intensive care, and probably also to larger unit sizes due to centralisation. With centralisation transport facilities must be set up. Studies have shown that retrieval of critically ill children by specialist transport teams is safe and does not increase the occurrence of adverse events despite the longer distances to centralised units.6 The use of specialist transfer teams also enables early stabilisation in the referring centre by the team. The marginal costs of longer transportation are unlikely to exceed those gained by increased
1187
COMMENTARY
COMMENTARY
Haemophilus influenzae type b infections are preventable everywhere See pages 1191, 1197 The virtual elimination by vaccine of invasive Haemophilus influenzae type b (Hib) disease in industrial countries is a modern public health triumph. Early vaccines, consisting of the Hib polysaccharide capsule, were shown to be effective in the prevention of invasive disease in older children in Finland in 1974. Conjugate Hib vaccines consisting of protein combined with polysaccharide had better immunogenicity in young infants and were shown to be highly effective. During the 1990s widespread use of conjugate Hib vaccines has virtually eliminated Hib disease from North America, northern Europe, Australia, and New Zealand.1,2 Until recently the burden of Hib disease was not well defined in many developing regions, and it was not clear whether Hib vaccines would be effective in these regions.3,4 This issue of The Lancet carries two reports on the use of Hib vaccine, each of which confirms previous data and has notable implications. The evaluation of Hib vaccine introduction in the UK confirms the previously reported high effectiveness of this vaccine. As shown in Scandinavia, these data suggest that a booster dose after the first year of life may not be necessary for effectiveness in well-immunised populations. The analyses conducted after the introduction of the vaccine provide an example of the imaginative use of surveillance data to assess vaccine effectiveness. The prospective randomised efficacy trial from The Gambia shows that an Hib conjugate vaccine has an efficacy of more than 90% against Hib meningitis in a developing-country setting, similar to reports from North America, Europe,2 and Chile.5 A secondary analysis of data from the Gambian study shows an additional substantial effect against severe radiographically proven pneumonia. Although there are wide confidence limits on the estimated effect, these data extend and confirm earlier studies on the aetiology of pneumonia, which were known to underestimate Hib disease.6 In The Gambia bacterial pneumonia is far more common than bacterial meningitis. In the fully vaccinated cohort, 11 cases of meningitis and 38 cases of radiographic pneumonia were prevented, which suggests that the overall effect on pneumonia and meningitis is 4·5-fold greater than the effect on meningitis alone. This unexpected “bonus” for regions with higher rates of bacterial pneumonia is a case for not delaying the 1186
introduction of routine Hib vaccination in developing regions as Mulholland and colleagues emphasise. Because of the high efficacy of conjugate Hib vaccines in every environment in which they have been tested, and their very low rate of adverse events, WHO and the Children’s Vaccine Initiative (CVI), are currently considering supply and delivery issues, before recommending its widespread use in Expanded Programs of Immunization (EPI). A recent meeting on Hib in Asia showed that Hib was the commonest cause of childhood bacterial meningitis in India and Thailand, but some Asian regions reported low levels of Hib disease.7 Careful studies are needed to determine whether prior antibiotic therapy or bacterial and/or human host factors may account for the apparently low rates of Hib disease reported in some Asian societies. A separate issue is how to provide a new highly effective vaccine in the existing EPI system. In common with other newly developed vaccines, (including existing hepatitis B, and hepatitis A vaccines, and imminent pneumococcal conjugate vaccines, as well as respiratory syncytial virus, shigella, and typhoid vaccines), Hib vaccines are currently more expensive to produce than those already in the EPI. WHO, CVI, and others are exploring approaches to reducing the cost of these vaccines for non-industrialised countries. A recent meeting in Bellagio outlined approaches towards improving the availability of Hib and other vaccines.8 Hib disease is not mentioned in many textbooks of tropical medicine, yet now it must be considered a preventable illness in many tropical populations. Indeed, bacterial meningitis (most of which is due to Hib, pneumococcus, and meningococcus) could be targeted as a preventable illness if vaccines against these three organisms were added to EPI programmes.9 In many regions bacterial meningitis is under appreciated and not reported. The surveillance and reporting of bacterial meningitis should be given higher priority, since this syndrome soon will be vaccine preventable. Improved surveillance for childhood bacterial meningitis might usefully be added to current programmes for enhancing the surveillance of poliomyelitis. Although the impetus for development of Hib vaccines was prevention of the devastation caused by Hib meningitis in the industrialised countries, the vaccines will have an enlarged role in less developed countries in
Vol 349 • April 26, 1997
THE LANCET
COMMENTARY preventing Hib meningitis and pneumonia. Additionally, the success of Hib vaccines can accelerate the consideration of how new and more expensive vaccines can be made available to populations with limited resources.
Mark C Steinhoff Department of International Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA 1 2
3 4 5
6
7 8 9
Ward J. H. influenzae vaccines. In: Plotkin SA, Mortimer EA Jr, eds. Vaccines, 2nd ed. Philadelphia: WB Saunders Co, 1994: 337-86. Robbins JB, Schneerson R, Anderson P, Smith DH. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. JAMA 1996; 276: 1181-85. Keusch GT. Should Haemophilus influenzae type b conjugate vaccine be introduced into EPI? Lancet 1992; 339: 802-03. Steinhoff MC. Developing and deploying pneumococcal and haemophilus vaccines. Lancet 1993; 342: 630-31. Lagos R, Horwitz I, Toro J, et al. Large scale, postlicensure, selective vaccination of Chilean infants with PRP-T conjugate vaccine: practicality and effectiveness in preventing invasive Haemophilus influenzae type b infections. Pediatr Infect Dis J 1996; 15: 216-22. Funkhouser A, Steinhoff MC, Ward J. H influenzae disease and immunization in developing countries. Rev Infect Dis 1991; 13: S542-54. Proceedings of International Seminar on Hib in Asia meeting, WHO, AMP. Indonesia, Dec 1996. Bellagio conference. Global availability of new vaccines. Rockefeller Foundation, Feb 1997. Wright PF. Approaches to prevention of acute bacterial meningitis in developing countries. Bull World Health Organ 1989; 67: 479-86.
Centralisation of paediatric intensive care to improve outcome See page 1213 In some European countries there is controversy over whether critically ill children should be admitted to paediatric intensive-care units, to adult intensive-care units, or to normal paediatric wards. Naturally, quality of care should be the deciding factor in selecting the preferred alternative. Prerequisites for high-quality care, especially in specialties looking after complex and heterogeneous patient categories, are adequate continuous staff training and maintenance of their practical experience.1 These provisions are unlikely to be obtainable in small units with few admissions and insufficient variation in case mix. Hence centralisation of paediatric intensive care into a limited number of tertiary units seems preferable to unrestricted fragmented care in adult intensive-care units or paediatric wards that lack staff specially assigned to
Vol 349 • April 26, 1997
paediatric intensive care.2 Many would consider this conclusion self evident, but others want evidence substantiating the benefits of centralisation.3 In (paediatric) intensive care a common index of performance is the standardised (ie, adjusted for severity of illness) mortality rate, derived from scoring systems such as the Pediatric Risk of Mortality (PRISM) score. With this index, a superior outcome was found in centres providing tertiary paediatric intensive care, especially in categories with higher mortality risks, in a statewide comparison of the management of children with head trauma or respiratory insufficiency in the USA.4 A similar study in the Netherlands showed that high-risk children had a substantially higher chance of dying in a non-tertiary centre (odds ratio 2·45).5 In today’s Lancet the effectiveness of paediatric intensive care in an area with fragmented care (Trent, UK) is compared with an area where it is highly centralised in a single tertiary centre (Victoria, Australia). Severity-of-illness-adjusted mortality for Trent children was significantly higher than that for Victorians (odds ratio 2·09). Several explanations can be offered for these alarming differences. The authors used a scoring system that has not yet been validated by an independent group. However, the severity-of-illness-adjusted mortality was similar to that obtained with the more established PRISM score. In addition, there are differences between Trent and Victoria, one being the larger size and less dense population of Victoria, which probably mean longer transportation times to the sole paediatric intensive-care unit and fewer children involved in motor vehicle accidents in the latter. Also, in Victoria centralised paediatric intensive care has been well established, with specially trained medical and nursing staff assigned solely to paediatric care. Therefore it is very unlikely that factors other than quality-of-care related factors would have accounted for a meaningful proportion of the difference in severity-of-illnessadjusted mortality. Hence, the findings in today’s report add to the body of evidence indicating that severity-of-illness-adjusted mortality in tertiary paediatric intensive care units is lower than that in other, non-tertiary settings. These benefits are due primarily to the availability of medical and nursing staff dedicated full time to paediatric intensive care, and probably also to larger unit sizes due to centralisation. With centralisation transport facilities must be set up. Studies have shown that retrieval of critically ill children by specialist transport teams is safe and does not increase the occurrence of adverse events despite the longer distances to centralised units.6 The use of specialist transfer teams also enables early stabilisation in the referring centre by the team. The marginal costs of longer transportation are unlikely to exceed those gained by increased
1187