August 1999
ATLANTA - A possible link between rotavirus vaccine (RotaShield, Wyeth Lederle Vaccines) and intussusception has prompted federal health agencies to call for suspension of the vaccine until further notice.
The Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) recommended that physicians stop administering rotavirus vaccine to unimmunized or partially immunized children who are scheduled to receive the vaccine before November. This decision was made after a total of 20 reports of intussusception were identified through three data analyses: the Vaccine Adverse Events Reporting System (VAERS), a post-licensure study of adverse events and active case findings in one state.
"The postponement was done for two reasons," said Larry K. Pickering, MD, editor of the AAP 2000 Red Book."One, it is currently not rotavirus season, therefore, by postponing administration of rotavirus vaccine now, we are not harming children. And, two, there is an indication that an association is present, and when additional data are available, a refinement of recommendations can be made."
The current numbers are too small to draw a true conclusion of whether or not the vaccine causes intussusception. The results of an ongoing case-control study of intussusception following rotavirus vaccination are anticipated in a few months, at which time the situation will be reassessed.
"While the preliminary numbers are small, it is enough to warrant further investigation into the matter," Pickering said.
It also is unclear whether or not natural rotavirus infection is linked to intussusception. Some children with intussusception have been found to have evidence of prior rotavirus infection, but available studies do not provide information about whether rotavirus infection caused the intussusception.
In addition, the number of intussusception cases does not increase during the winter like rotavirus gastroenteritis does, which suggests that if rotavirus infection does cause intussusception, it does so infrequently and does not account for most of the cases, according to the CDC.
The manufacturer has suspended all shipments of the vaccine until further data are available. Wyeth Lederle also recommends that existing supplies in physician's offices not be used during the postponement. Supplies should be stored at temperatures between 2° and 8° C.
Intussusception is a type of bowel obstruction that occurs when the bowel folds in on itself. It is most common among young children. Some cases seem to occur in association with viral infections or structured abnormalities such as polyps, but most cases have not been linked to an identified cause. The usual site of obstruction is where the small bowel joins the large bowel, but it may occur at other sites as well. With treatment, most patients fully recover.
In most cases of intussusception, no cause is identified, but some cases have been associated with structural abnormalities such as polyps or with infection with adenoviruses.
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Of the 15 infants with intussusception reported to VAERS, 13 (87%) developed intussusception following the first dose of the three-dose rotavirus vaccine series. Twelve (80%) of the 15 infants developed symptoms within one week of receiving any dose of the vaccine. The median age of patients was 3 months (range 2-11 months) and 10 were boys. The reports included cases of intussusception from seven states.
In response to the VAERS reports, a preliminary analysis was performed of data from an ongoing post-licensure surveillance of adverse events following rotavirus immunization. Cases of intussusception diagnosed between Dec. 1, 1998, and June 10 were identified among infants 2 months to 11 months of age at Northern California Kaiser Permanente. A total of 16,627 doses of rotavirus vaccine were administered to 9,802 infants during the surveillance period, at which time three cases of intussusception among vaccinated infants were identified. These cases were reported to VAERS.
The rate of intussusception among unimmunized children at Kaiser was 45 per 100,000 infant-years, and among children who received the vaccine was 125 per 100,00 infant years (age-adjusted relative risk [RR]=1.9, 95% CI=0.5-7.7, P0.39).
Among children who received the vaccine during the previous three weeks, the rate was 219 per 100,000 infant years (age-adjusted RR=3.7, 95% CI=0.7-19, P0.12). Among children who received the vaccine during the previous week, the rate was 314 per 100,000 infant years (age-adjusted RR=5.7, 95% CI=0.7-50, P0.11).
According to the data from Minnesota, the observed rate of intussusception following rotavirus vaccine as 292 per 100,000 infant years. This is based on the five infants who developed intussusception among the 18 cases of intussusception among vaccinated (age range: 3-5 months) and unvaccinated (5-9 months) children and assumes that 85% of vaccine doses distributed in Minnesota were administered.
Intussusception occurred after dose one in two children, dose two in two children and dose three in one child.
The expected rate of intussusception, by chance alone, among infants younger than 12 months following receipt of any dose of rotavirus vaccine was estimated using hospital discharge data from New York for 1991-1997. This data indicated a rate of 51 per 100,000 infant-years in New York (95% confidence interval [CI]=48-54 per 100,000). The manufacturer distributed approximately 1.8 million doses of rotavirus vaccine as of June 1, and estimated that 1.5 million doses (83%) had been administered.
Given this information, 14-16 intussusception cases would be expected by chance alone during the week following receipt of any dose of rotavirus vaccine. Fourteen of 15 case-patients were vaccinated before June 1, and of those, 11 developed intussusception within one week of receiving the vaccine, according to a CDC report.
An infant-year was defined as a unit of measurement combining infants and time used as a denominator in calculating incidence. For the CDC report, an infant-year represented the sum of the individual units of time converted to years that the infants in the study population have been followed.
The reports of intussusception are not a surprise. In rotavirus vaccine prelicensure studies, five cases were reported among 10,054 children who received various formulations of rotavirus vaccine; one case occurred in 4,633 controls. It was therefore listed in the package insert as a potential adverse event.
However, an association could not be established that these cases were due to rotavirus vaccine, or whether they occurred following receipt of rotavirus vaccine by chance alone.
The prelicensure studies are almost always too small to definitely determine anything about rare events. "In reality, it would have been very difficult to be certain about this in studies of reasonable size in the prelicensure period," said Melinda Wharton, MD, chief of the Child Vaccine Preventable Disease Branch at the National Immunization Program. "It would have been very hard to do that."
To gather the necessary additional information, a case-control study is currently underway in 19 states, said Wharton. Hospital records are being reviewed to identify cases of intussusception among infants, and rotavirus vaccination histories will be obtained. Those data will be compared with vaccination history of age-matched comparison children.
| AAP Recommendations |
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Because the seasonal risk of natural rotavirus infection in the United States will be low during the next few months, the AAP made the following interim recommendations regarding use of rotavirus vaccine:
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"There has been a huge amount of work put into this by state and local health departments," she said.
Wyeth Lederle and CDC are cooperating in the case-control study, said Harold Marder, MD, senior vice president and medical director at Wyeth-Ayerst Global Pharmaceuticals.
Further data will be analyzed from the NCKP study but because they generally follow ACIP and/or CDC recommendations - which currently state that immunization should be suspended - NCKP physicians have stopped administering rotavirus vaccine. However, they will continue to follow children who already have been vaccinated and continue case finding. "It's something of an art to actually find these cases," said Wharton.
The CDC hopes to have the preliminary study data in time for the CDC's Advisory Committee on Immunization Practices (ACIP) meeting in October when the issue will be reviewed. "We are hoping to have information to help the ACIP in their discussion in October, and to help the agency make decisions about what to do," Wharton said.
If the data are not available, it is undetermined at this point whether rotavirus immunization will resume at the beginning of rotavirus season, she added.
"From our perspective, it is important to get all the right information, not just to get information by October," Marder said. "We believe there is a two-step process that is needed to make the ultimate decision about RotaShield. First is to determine whether an association exists. If an association does exist, a second process must be done. That is to determine if the increased risk of intussusception provides a greater risk to children than does natural rotavirus infection.
"Both Wyeth and the CDC are interested in ensuring that the public health of children is well protected. Therefore, all the interested parties will have to sit down together and make a decision about the risk/benefit of the vaccine," Marder said.
If a causal association is found, it could mean the vaccine would no longer be recommended for routine use, or it may be possible to use the vaccine in a way that reduces the risk of intussusception. Wharton said some have speculated that if the vaccine is given to slightly older children, the risk of intussusception may be less.
"It is premature to say that if an association is demonstrated that the vaccine would not be recommended for use," Wharton said. "The risks of what potentially may be a very rare, but potentially serious adverse event, must be weighed against real benefits in the prevention of a common disease."
Marder added that it is important to remember that "RotaShield was approved for use because rotavirus is a significant health issue."
Despite the recent events surrounding RotaShield, Marder said Wyeth Lederle has received calls from many physicians in support of the vaccine. "In the first full rotavirus infection season following the introduction of RotaShield, theses practitioners reported a dramatic reduction of rotavirus seen in their office."
The most common adverse event occurring after rotavirus vaccination is fever, usually three to five days following vaccination. This is most commonly seen following the first dose. Diarrhea has also been reported following the first dose, although this was not observed in all studies.
If a child develops intussusception or any other serious adverse event following receipt of rotavirus vaccine, whether or not it is thought to be related to the vaccine, the adverse event should be reported to VAERS (see chart for contact information).
For more information:
- CDC. Intussusception among recipients of rotavirus vaccine - United States, 1998-1999. MMWR.1999;48(27):577-581.
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