Correspondence

Intussusception and an Oral Rotavirus Vaccine

N Engl J Med 2001; 344:1866-1867June 14, 2001

Article

To the Editor:

The report by Murphy et al. (Feb. 22 issue)1 is misleading in stating that vaccination with the tetravalent rhesus–human reassortant rotavirus vaccine (RRV-TV) was associated with an increased risk of intussusception. The data show only temporal clustering of cases of intussusception after vaccination, not an increased incidence over time. Although it is possible that vaccination increased the incidence of intussusception, it is equally possible that it lowered the incidence, by preventing intussusception associated with natural rotavirus infection.2 The difference is important, especially since the results of this study from the Centers for Disease Control and Prevention constituted the key evidence in the decision to remove the vaccine from use.3

Rotavirus infections cause about 1 million deaths annually worldwide.4 Many in the developing world have asked for a risk–benefit analysis of the use of the vaccine.5 Even if the most extreme interpretations of the data on vaccine-associated intussusception are true, the vaccine may still avert more deaths and prevent more severe illnesses and hospitalizations than it would cause.

Murphy et al.1 appear to agree with this possibility. Does a risk–benefit analysis of the data justify the removal of RRV-TV from use? They state that “rotavirus vaccines with an improved safety profile are urgently needed.” But other rotavirus vaccines are years away from licensing and, indeed, may never be licensed unless this controversy is resolved. A rotavirus vaccine is urgently needed in the developing world.

F. DeWolfe Miller, M.P.H., Ph.D.
University of Hawaii, Honolulu, HI 96822

5 References

1. 1

   Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344:564-572
   Full Text | Web of Science | Medline

2. 2

   Nakagomi T. Rotavirus infection and intussusception: a view from retrospect. Microbiol Immunol 2000;44:619-628
   Web of Science | Medline

3. 3

   Advisory Committee on Immunization Practices. Vol. III. ACIP Conference, Atlanta, October 22, 1999. Atlanta: Nancy Lee & Associates, 1999:1-189.
   

4. 4

   Linhares AC, Gabbay YB, Mascarenhas JDP, et al. Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Bélem, Brazil. Bull World Health Organ 1996;74:491-500
   Web of Science | Medline

5. 5

   Report of the meeting on future directions for rotavirus vaccine research in developing countries: Geneva, 9–11 February 2000. Geneva: World Health Organization, 2000. (Report no. WHO/V&B/00.23.)
   

To the Editor:

Murphy et al. report a strong association between vaccination with RRV-TV and the occurrence of intussusception. Figure 2 of the article shows that 12 percent of cases of intussusception (52 of 429) were attributable to vaccination with RRV-TV, corresponding to an increase of 14 percent above the background number of cases of 377. The authors estimated that the increase in the number of cases of intussusception would have been 28 to 57 percent if a national program of vaccination with RRV-TV had been fully implemented.

I am convinced of the causal relation between vaccination and intussusception; however, I wonder whether vaccination immediately results in an increase in the number of cases of intussusception, since any change in the overall incidence is hard to predict.1 Since rotavirus infection causes appreciable numbers of cases of intussusception,2 vaccination with RRV-TV is likely to protect children from intussusception that might otherwise have been caused by natural rotavirus infection. Vaccination may also trigger intussusception in infants in whom this type of prolapse was predisposed to develop later in life. Thus, it is important to show that there was an increase in the number of cases of intussusception only during the period of vaccine use by ensuring that the numbers of cases before vaccine use and after its use was suspended were not significantly different from the estimated background rate.

Toyoko Nakagomi, M.D.
Akita University School of Medicine, Akita 010-8543, Japan

2 References

1. 1

   Nakagomi T. Rotavirus infection and intussusception: a view from retrospect. Microbiol Immunol 2000;44:619-628
   Web of Science | Medline

2. 2

   Konno T, Suzuki H, Kutsuzawa T, et al. Human rotavirus infection in infants and young children with intussusception. J Med Virol 1978;2:265-269
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Miller and Nakagomi hypothesize that because vaccination with RRV-TV protects against rotavirus infection, the number of cases of intussusception caused by rotavirus infection will decrease with vaccination, thereby compensating for the increase caused by the vaccine itself. Nakagomi also postulates that intussusceptions caused by vaccination with RRV-TV represent premature cases in infants predisposed to intussusception, resulting in no net increase in the incidence of intussusception among vaccinated infants.

The available evidence does not suggest that rotavirus infection is a major cause of intussusception. None of the three studies reporting rotavirus infection among infants with intussusception had a comparison group of infants without intussusception. Most retrospective examinations have found no increase in the incidence of intussusception during epidemic rotavirus activity.1 Recent analyses of rotavirus disease and intussusception in a large managed-care organization also found no association (Chang EJ, UCLA Center for Vaccine Research: personal communication). Thus, the proportion of cases of intussusception that could be prevented by vaccination is unknown. We believe it is unlikely to be large.

Similarly, no evidence to date suggests that the marked temporal clustering of cases of intussusception after vaccination with RRV-TV represents a change in the timing of intussusception in infants in whom intussusception would have developed later. In an ongoing cohort study, more than 450,000 infants are being followed to estimate the long-term changes in the risk of intussusception after vaccination with RRV-TV.2 However, uncertainty may persist because of the low incidence of intussusception. To demonstrate that no net increase in the incidence of intussusception occurs after vaccination, one might examine large hospital-discharge data bases for the nine months in which RRV-TV was available and during subsequent periods. It will remain difficult to make reliable inferences with the use of this approach, given the low rates of vaccination and the low and variable background rates of intussusception.

Current evidence does not confirm the hypothesis that rotavirus infection induces large numbers of cases of intussusception or that vaccination with RRV-TV prematurely initiates intussusception and thus could compensate for the estimated increase of 28 to 57 percent in the number of cases over base-line levels that would be caused by vaccination. The concern expressed by Miller and Nakagomi may be most applicable to areas in which mortality from rotavirus infection is high, rather than to the United States, where mortality from rotavirus infection is low. We agree with Miller's call for a risk–benefit analysis of the use of RRV-TV in the developing world, where both the risks and the benefits differ from those in the United States.

Trudy V. Murphy, M.D.
Paul M. Gargiullo, Ph.D.
John R. Livengood, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333

2 References

1. 1

   Rennels MB, Parashar UD, Holman RC, Le CT, Chang HG, Glass RI. Lack of an apparent association between intussusception and wild or vaccine rotavirus infection. Pediatr Infect Dis J 1998;17:924-925
   CrossRef | Web of Science | Medline

2. 2

   Kramarz P, France EK, Destefano F, et al. Population-based study of rotavirus vaccination and intussusception. Pediatr Infect Dis J 2001;20:410-416
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Anissa Chouikha, Imene Fodha, Kaies Maazoun, Mohamed Ben Brahim, Saida Hidouri, Abdellattif Nouri, Abdelhalim Trabelsi, Andrew Duncan Steele. (2009) Rotavirus infection and intussusception in Tunisian children: implications for use of attenuated rotavirus vaccines. Journal of Pediatric Surgery 44:11, 2133-2138
   CrossRef

2. 2

   Albert Z. Kapikian, Lone Simonsen, Timo Vesikari, Yasutaka Hoshino, David M. Morens, Robert M. Chanock, John R. La Montagne, Brian R. Murphy. (2005) A Hexavalent Human Rotavirus–Bovine Rotavirus (UK) Reassortant Vaccine Designed for Use in Developing Countries and Delivered in a Schedule with the Potential to Eliminate the Risk of Intussusception. The Journal of Infectious Diseases 192:s1, S22-S29
   CrossRef

3. 3

   Nigel A Cunliffe, Osamu Nakagomi. (2005) A critical time for rotavirus vaccines: a review. Expert Review of Vaccines 4:4, 521-532
   CrossRef

4. 4

   EMILY J. CHANG, KENNETH M. ZANGWILL, HANG LEE, JOEL I. WARD. (2002) Lack of association between rotavirus infection and intussusception: implications for use of attenuated rotavirus vaccines. The Pediatric Infectious Disease Journal 21:2, 97-102
   CrossRef

5. 5

   &NA;. (2001) Oral rotavirus vaccine and intussusception: is there a link?. Reactions Weekly &NA;:857, 2
   CrossRef

6. 6

   &NA;. (2001) Oral rotavirus vaccine and intussusception: is there a link?. Inpharma Weekly &NA;:1293, 17
   CrossRef