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Risk of Intussusception with Rotavirus Vaccines

intussuceptionRotavirus is the leading cause of severe diarrhea in infants and children worldwide, leading to more than half a million deaths each year in children under the age of 5. Before the introduction of the rotavirus vaccine, almost all children in the US were infected by the age of 5, and rotavirus infections were responsible for 400,000 doctor visits, 200,000 ER visits, 55,000-70,000 hospitalizations, and 20-60 deaths each year. The first rotavirus vaccine, RotaShield, was found to have an association with intussusception. Two newer vaccines, Rotateq and Rotarix, were thought not to carry that risk, but two new trials have shown that they do. Still, the risk is small and the benefits of the vaccines are great.

What is intussusception?

Intussusception is a “telescoping” of the intestine where one section slides inside another section. This can cut off the blood supply, block the intestine, and cause tears, infections, and death. Most cases are in young children. They have severe abdominal pain (intermittent at first), and pass blood in the stool, typically mixed with mucus and having the appearance of currant jelly. A barium enema can confirm the diagnosis and simultaneously treat it. Sometimes surgery is needed.

The baseline incidence of intussusception in children is on the order of 1-4 per 1,000. Most cases have no identified cause, but the most plausible candidate is hypertrophied lymphoid tissue resulting from viral illnesses, especially rotavirus infections.

Vaccine studies

The first rotavirus vaccine, Rotashield, was introduced in 1999. It was voluntarily withdrawn from the market within a year because post-marketing surveillance found 1-2 excess cases of intussusception per 10,000 recipients. Newer vaccines, Rotateq and Rotarix, were licensed only after testing (in over 60,000 infants each) failed to find any association with intussusception. Those trials were designed to have enough statistical power to detect a risk similar to that of RotaShield. Both new vaccines contain live, attenuated strains of virus and are given orally. Rotateq is a pentavalent (prepared from 5 strains) vaccine given in 3 doses at age 2, 4, and 6 months. Rotarix is monovalent (prepared from 1 strain) and is given in 2 doses at age 2 and 4 months. Either is recommended, but about 10 times more doses of the pentavalent vaccine have been administered.

After the new vaccines came into common use, studies in other countries pointed to a small increase in intussusception with the newer vaccines, although at a much lower rate than with Rotashield. The FDA responded by initiating a new study of both vaccines in the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program, a component of the Mini-Sentinel pilot program that was developed by the FDA to conduct active surveillance of the safety of medical products.

That study, by Yih et al., was published in the February 6, 2014 issue of The New England Journal of Medicine simultaneously with another study by Weintraub et al. that was based on data from the Vaccine Safety Datalink project, a collaborative effort between the CDC and nine large managed care organizations including Kaiser Permanente and Group Health Cooperative.

Results

The Yih study found a significant increase in the risk of intussusception after the first dose of Rotateq, with 1.5 excess cases per 100,000 vaccine recipients. They found no association with subsequent doses, but couldn’t rule that out.

For Rotarix, the findings were not significant, but a relatively small number of children got that vaccine (an order of magnitude lower), and the authors concluded that their risk estimates were imprecise and should be considered in the context of findings of increased risk in other studies.

The Weintraub study identified 6 cases of intussusception after Rotarix, compared to 0.72 cases expected from historical data. They found no association with Rotateq.

The two studies appear to have found different results, but they are based on only a handful of cases of intussusception. Small variations in case detection, confirmation of vaccine status, and chance alone could have affected the outcomes.

Their results should be considered along with other studies from the US and other countries. It is reasonable to conclude that intussusception can occur with either vaccine, but that the risk is low, on the order of 1-5 cases per 100,000 infants.

Vaccine benefits

As always, risks must be weighed against benefits, and the benefits of these vaccines are indisputable. An accompanying editorial in the NEJM estimated that each year in the US the vaccines have prevented 53,000 hospitalizations and 170,000 ER visits at the cost of 45 to 213 cases of intussusception. The ACIP estimates that 14 infant deaths are prevented each year in the US, and in Mexico deaths from diarrhea decreased by 40% after the vaccine program was implemented. Even the unvaccinated may benefit as they are exposed to fewer rotavirus infections in the community. The greatest benefits will be seen in Third World countries, but there is greater risk there too. If intussusception is promptly diagnosed and treated, it is relatively benign and has no lasting consequences; but adequate medical care may not be readily available in Third World countries. Another consideration: it’s possible that some infants may be protected from intussusceptions caused by the rotavirus itself.

Recommendations

A rotavirus vaccine (either one) is recommended by the CDC, the American Pediatric Association, and other professional groups as part of the routine immunization schedule in the US. Parents should be informed of the signs of intussusception and should monitor their infants especially in the first 7 days after vaccination; and since intussusception can recur, caution is advised in children who have a history of intussusception.

Science-based medicine in action

This is a success story. Pretty much everything about the rotavirus vaccines was done right. A serious potentially preventable health problem was identified, and the responsible strains of virus were pinpointed. An effective vaccine was developed and extensively tested. The first vaccine was voluntarily withdrawn by the manufacturer within a year because of a problem recognized during post-marketing surveillance. Government programs provided even more effective post-marketing surveillance for the newer vaccines. A possible side effect was recognized. Two (not one) new studies were funded by government agencies, not by Big Pharma. Even VAERS (the Vaccine Adverse Event Reporting System) was used appropriately, not to blame vaccines for random events following vaccination, but to compare the numbers of spontaneously reported cases at different time periods following vaccination and to give researchers a clue that the first dose of vaccine might be implicated, aiding them in designing appropriate studies. Vaccines work, and the scientific process generally works pretty well in spite of the flawed humans who carry it out.

Posted in: Vaccines

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12 thoughts on “Risk of Intussusception with Rotavirus Vaccines

  1. Björn Geir says:

    Thank you Harriet for another excellent contribution.

    I feel a bit thick in the head this morning so I hope I manage to comprehensibly present this thought I have after reading this.
    Excess risk of intussusception in vaccinated cases is estimated in relation to a known baseline incidence. So when saying for example that there are 1.5 excess cases per 100 000, this would be relative to a historical incidence of intussusception in the same area(?) rather than in randomly unvaccinated toddlers at the time of the trial, right?
    I assume this historical incidence was not corrected for the rate of Rotavirus infections. So differences in the incidence of vaccine-associated cases of intussusception between the studies may be due to differences in Rotavirus exposure in the historical references used?? One might suspect that if the rate of Rotavirus infections in the reference populations was known and corrected for, the excess incidence in the vaccinated population may even prove to be lower than a baseline population with an average (for an unvaccinated population) incidence of Rotavirus induced intussusceptions?
    Or do I just have to go and take my morning shower and clear my head :)

    1. Harriet Hall says:

      That’s a good point. And as I mentioned, rotavirus infection may itself be a cause of intussusception, so it is conceivable that the vaccine might reduce the overall incidence.

      1. Andrey Pavlov says:

        Indeed. I think it would be difficult to suss out those exact differences, especially since the data seems to indicate (though is not 100% confirmed) that the mechanism of intussusception in these cases is (as Dr. Hall mentioned) inflamed Peyer’s patches providing a focus of traction by which the proximal gut and fixate and telescope inwards from normal peristaltic action. If that is the case, then actually having the infection should be able to do it, though it is possible that the rest of the disease state might mitigate some of that (i.e. mildly inflamed Peyer’s in an otherwise healthy gut can be traction points, but in an actual rotavirus infection the altered physiology and state of the gut can make that moot).

        Either way, I would see it as an academic point rather than a practical one. The known harms of rotavirus infection vastly outweigh the known harms of vaccination. So even if we assumed that nobody with infection gets intussusception whilst the vaccine induces it at the levels noted, that does not change the risk:benefit calculus in any appreciable manner.

  2. goodnightirene says:

    Oh my goodness, I never heard of this vaccine. My youngest is 27, and I have no idea if he got this! I presume my grandchildren have it–the younger ones anyway.

    Thanks for the great example of science in action, however. Now I will go and try to find that shot record for the youngest. :-)

    1. Windriven says:

      My middle daughter nearly died of rotavirus when she was one. Spent a month in the hospital. So mark me down as a strong supporter of the vaccine.

    2. Harriet Hall says:

      Your son didn’t get the vaccine. He was past the age for vaccination by the time it came on the market. He has probably been exposed to the virus and developed some antibodies on his own.

    3. Chris says:

      “Oh my goodness, I never heard of this vaccine. My youngest is 27, and I have no idea if he got this! I presume my grandchildren have it–the younger ones anyway”

      It came out about fifteen years ago. It is an oral vaccine.

      My son got the disease over 25 years ago as a toddler, and it was horrible. He became dehydrated, which caused a grand mal seizure… and a trip to the hospital.

  3. Kiiri says:

    I am glad that my Little Man (2 and a half) got his three doses of vaccine. The risk of intussusception is small and the risk of getting rotavirus and being very ill large. The babies actually enjoy this vaccine, its a squirt of semi-sweet liquid in their mouths and they swallow it right down. He also does cry a bit after his shots, mostly from being held in place. Once let free of confinement and a bit of soothing and he is all smiles and giggles for the nurses. Fully vaccinated and proud! Excellent posts on relative risks Dr. Hall!

    1. LovleAnjel says:

      No all babies. My dear daughter made a face and pushed it out with her tongue. She rejects pretty much any medical goo, we have to mix her zantac into formula.

  4. pmoran says:

    This google search — “incidence rotavirus infection in intussusception” — yields some evidence that intussusception is not associated with natural rotavirus infection, or at least not strongly enough be a serious challenge to the associations now seen in several studies.

  5. 14012783 says:

    In order for the medical field to advance and fulfil its purpose of helping people either rid themselves of disease and illness or maintaining their good health, the medical field must frequently test and correct its methods and treatments processes. The above mentioned Rotavirus vaccines are an excellent example of the medical field’s efforts to try and eliminate harmful treatments such as Rotashield vaccinations and advance more benefitting treatments such as Rotateq and Rotarix vaccines.
    Vaccines were developed in the early 1900’s and is still supported by many that these miracle shots will eradicate a number of diseases. However with the development of the vaccine many criticisms developed as well about the effectivity of immunization.
    Scepticism and negative comments are still seen and heard today. We have to ask ourselves why so many people believe that vaccinations are bad for their health if benefits such as decrease in number of deaths are seen.
    Many vaccination critics claim that advances in sanitation and increases in water supply and sewage control throughout the ages are in actuality the real causes of the reduction of the number if diseases in the past 100 years (Livestrong 2011).
    However the biggest criticisms come from parents that do not approve of childhood vaccinations. The significant number of immunizations and mild side effects, are possible reasons why parents do not want to vaccinate their children. Immunization is seen as a process of iatrogenesis, where harm is caused on purpose by doctors (Barry et al. 2012:34). Many parents try natural remedies in order to boost their child’s immune system, and refuse to comply with the regulations of childhood vaccinations.
    I believe that such scepticism and negative remarks towards vaccinations are made due to a lack of information about vaccinations. Comments on this blog lead me to believe that not everyone is informed about certain types of vaccinations against certain diseases.
    The medical field, with its advancements, should not neglect spreading information about the improvement of vaccinations and the decrease in the chances of getting certain side effects. The benefits outweigh the side effects of some of these childhood vaccinations. Not even taking into account the benefits seen in the economy due to a healthier society that has a less of a chance in contracting diseases due to immunization.
    I support the comment that vaccinations work and that the scientific process is put into action trying to advance medicine and therefore adhere to its purpose.

    Barry.A, Y., 2012. Challenging Medical Dominance. In:Medical power and knowledge. Singapore: Sage Productions, pp.34.
    Livestrong, 2011. Vaccine Side Effects in Infants. [Online] Available : http://www.livestrong.com/article/27047-vaccine-side-effects-infants/ [Accessed 20 April 2014].

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