- Email: [email protected]
Ecological studies, rotavirus vaccination, and intussusception
CORRESPONDENCE
resolve this impasse. Does Hall believe that the confounders adjusted for in the CDC study were so great that such a discrepancy was realistic? Does he believe that Simonsen and colleagues might have missed a vaccine-associated epidemic of intussusception? What does he think about the possibility of Simonsen’s trigger-compensatory decrease hypothesis? Is any triggering, followed by any decrease, ever acceptable? If the estimates from their study were shown to be accurate how would that alter the dialogue? Was any risk acceptable or was a totally risk-free vaccine the standard? Would a risk comparable to other infant vaccines be acceptable? If the vaccine actually protected against intussusception caused by rotavirus, as Simonsen and colleagues suggest, would this affect future discussions? An estimated 600 000–873 000 infants and young children die from rotavirus diarrhoea annually worldwide. Completely safe vaccines are the ideal, but how long will we have to wait? Albert Z Kapikian
findings. I was requested to focus on methods. I do believe that Lone Simonsen and colleagues’ study missed an increased incidence of intussusception associated with the vaccine. This increase would have occurred in the poorer strata of US society and, since the study could not assess this outcome, nor link vaccine and disease directly, nor estimate under-reporting of disease, it could well have missed such an effect. As I stated, numerical estimates from such a study design are, in my opinion, not helpful. Even well designed and analysed observational study estimates have a degree of uncertainty because confounding can never be fully controlled. I agree with the argument put forward by Susan Ellenberg1 of the US Food and Drug Administration for larger randomised trials in the assessment of vaccines, the larger size not being driven by a need to measure efficacy or effectiveness, but by the need to establish safety in the one situation where confounding is eliminated.
Epidemiology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6700 Brockledge Drive, Bethesda, MD 20892, USA
Andrew J Hall
1
1
2
3
4
5
Hall AJ. Ecological studies and debate on rotavirus vaccine and intussusception. Lancet 2001; 358: 1197–98. Simonsen L, Morens DM, Elixhauser A, Gerber M, Van Raden M, Blackwelder WC. Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception. Lancet 2001; 358: 1224–29. Murphy TM, Garguillo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001; 344: 564–72. Advisory Committee on Immunization Practices, Vol III. Verbatim transcript of the ACIP conference convening at 8:00 a.m. on Friday, October 22, 1999, at the Center for Disease Control and Prevention, 1600 Clifton Road, Auditorium B, Atlanta, Georgia. Nancy Lee and Associates, Court Reporters, 1999: 1–174. Chang H-GH, Smith PF, Ackelsberg J, Morse DL, Glass RI. Intussusception, rotavirus diarrhea, and rotavirus vaccine use among children in New York State. Pediatrics 2001; 108: 54–60.
Author’s reply Sir—I entirely agree with Albert Kapikian that the losers in the rotavirus vaccine and intussusception saga are children and parents, especially in areas of the world where mortality remains high because of inadequate health services and poverty. I and colleagues were in the midst of a trial of the vaccine in west Africa, which was curtailed by the US
1066
Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK (e-mail: [email protected]) Ellenberg SS. Safety considerations for new vaccine development. Pharmacoepidemiol Drug Saf 2001; 10: 1–5.
Sir—We wish to clarify two points raised by Andrew Hall in his commentary,1 one on comparability of our2 and the CDC study,3 and the other on linking of intussusception occurrence to vaccination status of individual patients. Comparison of our study with the CDC study may be unfair, since they used different approaches to answer different questions. The CDC study was designed to assess the presence or absence of a temporal association between intussusception and previous vaccination, not to measure its magnitude, whereas we aimed to measure its magnitude and not temporal patterns in risk. Therefore, any inference about one study contradicting the other is inappropriate. To reconcile CDC’s finding of a temporal association between intussusception and vaccination, with our finding of a decrease in intussception occurrence during the RRV-TV use period, we suggested that benefits of vaccination are seen later in infancy. We also suggested that this vaccine might have triggered early onset of intussception cases destined to occur
eventually, with a compensatory decrease in occurrence later. New data from the CDC study suggest that the strong intussusception-RRV-TV association in the immediate weeks before intussusception was preceded by a significant depression in vaccination frequency at more remote times before intussusception (adjusted odds ratio 0·3 [95% CI 0·1–0·5] >21 days before intussusception).4 This finding could be due to significant uncontrolled biases in the matching of cases and controls, but is also consistent with Rotashield triggering and compensatory protection effect. In response to Hall’s second point, in the USA, for reasons of privacy protection, several limitations are imposed on the use of hospital data for research purposes. Three notable limitations are: the central collection of state hospital discharge databases by federal government agencies does not allow access to personal identifiers; agreements between the federal government and the state data agencies that collect hospital data specifically prohibit researchers from contacting hospitals and providers to request additional information about patients; and additional restrictions are placed on linking patient-level hospital data to other data sources. We were, therefore unable to validate intussusception diagnoses further by these methods. Our case data source was not subject to sampling error or bias, since it included 100% of hospital admissions for intussusception in each state. New data gathered since completion of the original study from 20 states confirm a decrease in infant intussusception hospital admissions in states with moderate-to-high RRV-TV coverage. US recommendations for this vaccine are expected in the near future. Therefore, intensive reassessment of collected evidence is needed, including the post-publication observations in the CDC case-control study, new data from an extended phase of the CDC cohort study, and augmented data from our study. We also hope for assessment of the benefit of vaccination in infants and highrisk subpopulations at increased risk for severe outcomes of rotavirus diarrhoea, and of at what level of intussusception risk should be acceptable.5 All published studies of the RRV-TV-intussusception association, including ours, have shortcomings in their methods but we are convinced that they all contribute important pieces of information needed to form the best possible picture of what
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
resolve this impasse. Does Hall believe that the confounders adjusted for in the CDC study were so great that such a discrepancy was realistic? Does he believe that Simonsen and colleagues might have missed a vaccine-associated epidemic of intussusception? What does he think about the possibility of Simonsen’s trigger-compensatory decrease hypothesis? Is any triggering, followed by any decrease, ever acceptable? If the estimates from their study were shown to be accurate how would that alter the dialogue? Was any risk acceptable or was a totally risk-free vaccine the standard? Would a risk comparable to other infant vaccines be acceptable? If the vaccine actually protected against intussusception caused by rotavirus, as Simonsen and colleagues suggest, would this affect future discussions? An estimated 600 000–873 000 infants and young children die from rotavirus diarrhoea annually worldwide. Completely safe vaccines are the ideal, but how long will we have to wait? Albert Z Kapikian
findings. I was requested to focus on methods. I do believe that Lone Simonsen and colleagues’ study missed an increased incidence of intussusception associated with the vaccine. This increase would have occurred in the poorer strata of US society and, since the study could not assess this outcome, nor link vaccine and disease directly, nor estimate under-reporting of disease, it could well have missed such an effect. As I stated, numerical estimates from such a study design are, in my opinion, not helpful. Even well designed and analysed observational study estimates have a degree of uncertainty because confounding can never be fully controlled. I agree with the argument put forward by Susan Ellenberg1 of the US Food and Drug Administration for larger randomised trials in the assessment of vaccines, the larger size not being driven by a need to measure efficacy or effectiveness, but by the need to establish safety in the one situation where confounding is eliminated.
Epidemiology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6700 Brockledge Drive, Bethesda, MD 20892, USA
Andrew J Hall
1
1
2
3
4
5
Hall AJ. Ecological studies and debate on rotavirus vaccine and intussusception. Lancet 2001; 358: 1197–98. Simonsen L, Morens DM, Elixhauser A, Gerber M, Van Raden M, Blackwelder WC. Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception. Lancet 2001; 358: 1224–29. Murphy TM, Garguillo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001; 344: 564–72. Advisory Committee on Immunization Practices, Vol III. Verbatim transcript of the ACIP conference convening at 8:00 a.m. on Friday, October 22, 1999, at the Center for Disease Control and Prevention, 1600 Clifton Road, Auditorium B, Atlanta, Georgia. Nancy Lee and Associates, Court Reporters, 1999: 1–174. Chang H-GH, Smith PF, Ackelsberg J, Morse DL, Glass RI. Intussusception, rotavirus diarrhea, and rotavirus vaccine use among children in New York State. Pediatrics 2001; 108: 54–60.
Author’s reply Sir—I entirely agree with Albert Kapikian that the losers in the rotavirus vaccine and intussusception saga are children and parents, especially in areas of the world where mortality remains high because of inadequate health services and poverty. I and colleagues were in the midst of a trial of the vaccine in west Africa, which was curtailed by the US
1066
Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK (e-mail: [email protected]) Ellenberg SS. Safety considerations for new vaccine development. Pharmacoepidemiol Drug Saf 2001; 10: 1–5.
Sir—We wish to clarify two points raised by Andrew Hall in his commentary,1 one on comparability of our2 and the CDC study,3 and the other on linking of intussusception occurrence to vaccination status of individual patients. Comparison of our study with the CDC study may be unfair, since they used different approaches to answer different questions. The CDC study was designed to assess the presence or absence of a temporal association between intussusception and previous vaccination, not to measure its magnitude, whereas we aimed to measure its magnitude and not temporal patterns in risk. Therefore, any inference about one study contradicting the other is inappropriate. To reconcile CDC’s finding of a temporal association between intussusception and vaccination, with our finding of a decrease in intussception occurrence during the RRV-TV use period, we suggested that benefits of vaccination are seen later in infancy. We also suggested that this vaccine might have triggered early onset of intussception cases destined to occur
eventually, with a compensatory decrease in occurrence later. New data from the CDC study suggest that the strong intussusception-RRV-TV association in the immediate weeks before intussusception was preceded by a significant depression in vaccination frequency at more remote times before intussusception (adjusted odds ratio 0·3 [95% CI 0·1–0·5] >21 days before intussusception).4 This finding could be due to significant uncontrolled biases in the matching of cases and controls, but is also consistent with Rotashield triggering and compensatory protection effect. In response to Hall’s second point, in the USA, for reasons of privacy protection, several limitations are imposed on the use of hospital data for research purposes. Three notable limitations are: the central collection of state hospital discharge databases by federal government agencies does not allow access to personal identifiers; agreements between the federal government and the state data agencies that collect hospital data specifically prohibit researchers from contacting hospitals and providers to request additional information about patients; and additional restrictions are placed on linking patient-level hospital data to other data sources. We were, therefore unable to validate intussusception diagnoses further by these methods. Our case data source was not subject to sampling error or bias, since it included 100% of hospital admissions for intussusception in each state. New data gathered since completion of the original study from 20 states confirm a decrease in infant intussusception hospital admissions in states with moderate-to-high RRV-TV coverage. US recommendations for this vaccine are expected in the near future. Therefore, intensive reassessment of collected evidence is needed, including the post-publication observations in the CDC case-control study, new data from an extended phase of the CDC cohort study, and augmented data from our study. We also hope for assessment of the benefit of vaccination in infants and highrisk subpopulations at increased risk for severe outcomes of rotavirus diarrhoea, and of at what level of intussusception risk should be acceptable.5 All published studies of the RRV-TV-intussusception association, including ours, have shortcomings in their methods but we are convinced that they all contribute important pieces of information needed to form the best possible picture of what
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.