Vaccine Reports
Risk of Intussusception After Rotavirus Vaccination Meta-analysis of Postlicensure Studies Dominique Rosillon, PhD,* Hubert Buyse, MD,* Leonard R. Friedland, MD,† Su-Peing Ng, MBBS,* F. Raúl Velázquez, MD, MSc,‡ and Thomas Breuer, MD* Background: Postlicensure surveillance studies suggest a small temporal increase in the risk for intussusception with both currently available rotavirus vaccines (RV1; Rotarix, GSK and RV5; RotaTeq, Merck & Co., Inc.). This meta-analysis was undertaken to provide a single overall estimate of the relative risk of intussusception during the 7-day period after administration of RV1 and RV5. Methods: Meta-analysis based on estimates of relative risk and corresponding 95% confidence intervals from 5 postlicensure studies providing an estimate of risk of intussusception during the 7-day period after administration of dose 1 and/or dose 2 of RV1 and/or RV5, based on active and/or passive surveillance, for confirmed intussusception cases (Brighton or other method of case confirmation). For each vaccine, the relative risk of intussusception was estimated postdose 1 and postdose 2. Results were pooled using the inverse variance method using both fixed-effect and random-effect models. Results: The overall estimate of relative risk of intussusception during the 7 days postdose 1 was 5.4 (95% confidence interval: 3.9–7.4, 3 studies) for RV1 and 5.5 (3.3–9.3, 3 studies) for RV5. The overall estimate of relative risk of intussusception during the 7 days postdose 2 was 1.8 (1.3–2.5, 4 studies) for RV1 and 1.7 (1.1–2.6, 3 studies) for RV5. Conclusions: This meta-analysis showed a similar increased risk of intussusception, during the first 7 days after administration of dose 1 and, to a lesser extent, dose 2, for both currently available rotavirus vaccines. This suggests that intussusception may be a class effect of currently available oral rotavirus vaccines. Key Words: rotavirus, vaccine, intussusception (Pediatr Infect Dis J 2015;34:763–768)
R
otavirus (RV) is the major cause of acute gastroenteritis among infants and young children worldwide.1–3 Before the introduction of currently available RV vaccines, RV gastroenteritis (RVGE) accounted for approximately 2.4 million hospitalizations and half a million deaths annually among children younger than 5 years worldwide.1–4 The burden of RV disease is significant in both developing and developed countries; however, there are marked differences in the nature of this burden, with h ighest
Accepted for publication December 11, 2014. From *GlaxoSmithKline Vaccines, Wavre, Belgium; †GlaxoSmithKline, Philadelphia, PA; and ‡Medical Research Unit on Infectious Diseases, Pediatrics Hospital, National Medical Center-Century-XXI, Mexican Institute of Social Security (IMSS), Mexico City, D.F., Mexico. Su-Peing Ng, MB BS is currently at the Global Medical Affairs, Sanofi Pasteur, Lyon, France. This study was funded by GlaxoSmithKline Biologicals SA (GSK). GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of this manuscript. D.R., H.B., L.F. and T.B. are employees of the GSK group of companies. S.N. was formerly an employee of the GSK group of companies. D.R., L.F., S.N. and T.B. all declare to be in receipt of GSK stocks. R.V. has received a grant for his institution IMSS from GSK. Address for correspondence: Dominique Rosillon, PhD, GlaxoSmithKline Vaccines, Avenue Fleming, Wavre, Belgium. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3407-0763 DOI: 10.1097/INF.0000000000000715
mortality seen in low-income countries.3,4 The World Health Organization recommends that all infants are vaccinated to prevent RV disease.5,6 An oral rhesus-human reassortant RV tetravalent vaccine (RRV-TV; RotaShield, Wyeth) was licensed in the US in October 1998. However, 9 months later, the RRV-TV immunization program was suspended because of a temporal association between RV vaccination and occurrence of intussusception.7 The relative risk of intussusception during the 3–7 days after RRV-TV administration was 58.9 [95% confidence interval (CI): 31.7–109.6] postdose 1 and 11.0 (4.1–29.5) postdose 2.8 Intussusception is a rare condition. A recent systematic review of 82 studies worldwide reported a mean incidence of intussusception of 74 per 100,000 children aged less than 1 year, with considerable geographic variability noted (range: 9–328).9 Intussusception case fatality rate also varies between regions, being higher in Africa (9%) than in other regions ( case-control > cohort > observed versus expected.
Statistical Methods The meta-analysis was based on log-transformed estimates of relative risk and corresponding 95% CI from each eligible study. Undefined risk estimates (ie, risk estimate ≅ 0 or ∞) were not included in the statistical calculations. No raw data were used. Separate analyses were performed for RV1 and RV5. For each vaccine, the relative risk of intussusception was estimated postdose 1 and postdose 2. Results were pooled using both fixed and random study effect model.30 Heterogeneity between studies was tested using the Cochran Q test. The degree of the heterogeneity was assessed by the I² index, with 25%, 50% and 75% representing low, moderate and high heterogeneity, respectively.31,32 Results are presented as forest plots. We performed a sensitivity analysis for each vaccine after each dose including data from the study by Weintraub et al.29 This study was not included in the main analysis because nonconfirmed cases were included in the observed versus expected analysis. However, this is one of the few studies to provide an estimate of risk for both RV1 and RV5 in the same setting.
RESULTS Study Characteristics The study selection process is summarized in Figure 1. Data from a total of 5 studies met the criteria for inclusion in this metaanalysis20,23,26–28; in addition, an observed versus expected study29 including nonconfirmed cases was included in a sensitivity analysis (Table 1). For RV1, 3 studies provided information on risk of intussusception postdose 1 (all of SCCS design, 2 undertaken in Latin
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FIGURE 1. Flow chart of study selection process. America and 1 in Australia) and 4 provided information on risk of intussusception postdose 2 (3 of SCCS and 1 additional study of SCRI design undertaken in the US). One of the studies undertaken in Latin America provided separate data for the risk of intussusception after RV vaccination in 2 different countries (Mexico and Brazil)20; data for both of these countries were included separately in the meta-analysis. Three studies provided information on the risk of intussusception both postdose 1 and postdose 2 for RV5 (1 of SCCS design in Australia and 2 of SCRI design in the US). One of the studies in the US provided a risk estimate for 3–6 days after vaccination and as such did not strictly meet inclusion criterion 2.27 However, there is good evidence to suggest that the risk of intussusception within 7 days of vaccination is mainly concentrated during the 3–6 day postvaccination period; as such, this study was included in the meta-analysis.
Risk of Intussusception Postdose 1 The relative risk of intussusception during the 7-day period after the first dose of RV1 ranged from 1.1 to 6.8 among the 3 studies included in the meta-analysis (Fig. 2). Heterogeneity among studies was moderate (I² = 60.6%) and approached statistical significance (Q = 7.62, P = 0.06). This heterogeneity was primarily attributable to the data from Brazil.20 The overall estimate of relative risk of intussusception during the 7-day period after the first dose of RV1 was 5.4 (95% CI: 3.9–7.4) for the fixed-effect model and 4.7 (2.6–8.4) for the random-effect model. The relative risk of intussusception during the 7-day period after the first dose of RV5 ranged from 3.8 to 9.9 among the 3 studies included in the meta-analysis (Fig. 2). Heterogeneity among studies was low (I ² = 34.7%) and not statistically significant (Q = 3.07, P = 0.22). The overall estimate of relative risk of intussusception during the 7-day period after the first dose of RV5 was 5.5 (3.3–9.3) for the fixed-effect model and 6.1 (3.0–12.1) for the random-effect model. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Intussusception
TABLE 1. Studies Included in the Meta-analysis and Sensitivity Analysis Study Patel et al20 Velázquez et al23 Carlin et al26 Haber et al27 Yih et al28 Weintraub et al29†
Country Mexico,* Brazil* Mexico Australia US US US
Design/method
Risk period
SCCS SCCS SCCS SCRI SCRI O/E
7 days 7 days 7 days 3–6 days 7 days 7 days
Vaccine RV1 RV1 RV1, RV5 RV5 RV1, RV5 RV1, RV5
*Analysis per country. †Included in a sensitivity analysis only. SCCS indicates self-controlled case series; SCRI, self-controlled risk interval; observed versus expected.
FIGURE 2. Risk of intussusception during the 7 days after the first dose of RV1 and RV5 (bars show 95% CI).
FIGURE 3. Risk of intussusception during the 7 days after the second dose of RV1 and RV5 (bars show 95% CI).
Risk of Intussusception Postdose 2 The relative risk of intussusception during the 7-day period after the second dose of RV1 ranged from 1.3 to 3.5 among the 4 studies included in the meta-analysis (Fig. 3). Heterogeneity among studies was very low (I ² = 5.3%) and not statistically significant (Q = 4.22, P = 0.38). The overall estimate of relative risk of intussusception during the 7-day period after the second dose of RV1was 1.8 (1.3–2.5) for the fixed-effect model and 1.8 (1.3–2.6) for the random-effect model. The relative risk of intussusception during the 7-day period after the second dose of RV5 ranged from 1.4 to 2.8 among the © 2015 Wolters Kluwer Health, Inc. All rights reserved.
3 studies included in the meta-analysis (Fig. 3). No heterogeneity among studies was observed (I ² = 0%). The overall estimate of relative risk of intussusception during the 7-day period after the second dose of RV5 was 1.7 (1.1–2.6) for both fixed-effect and randomeffect models.
Sensitivity Analysis Despite the fact that the study by Weintraub et al29 suggested a relative risk of intussusception within 7 days of RV1 compared with RV5 of 9.4 (1.4–103.8), the sensitivity analysis gave similar relative risk estimates for both vaccines after each dose. www.pidj.com | 765
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Rosillon et al
For RV1, the overall estimate of relative risk of intussusception postdose 1 was 5.5 (4.0–7.5) for the fixed-effect model and 5.0 (3.0–8.4) for the random-effect model. For RV5, the overall estimate of relative risk of intussusception postdose 1 was 4.9 (3.0– 7.8) for the fixed-effect model and 5.1 (2.8–9.3) for the randomeffect model. The overall estimate of relative risk of intussusception postdose 2 of RV1 was 2.0 (1.5–2.8) for the fixed-effect model and 2.4 (1.5–3.9) for the random-effect model. Sensitivity analysis for RV5 could not be performed postdose 2 because the risk estimate was undefined (relative risk = 0) in the study by Weintraub et al.29
DISCUSSION Intussusception is a rare form of intestinal obstruction in which a segment of the bowel prolapses into a more distal portion; mean incidence is reported to range from 9 to 328 per 100,000 children aged less than 1 year.9 Intussusception constitutes the most frequent cause of acute intestinal obstruction among young children independent of exposure to RV vaccines. Most cases occur in infants aged less than 1 year, with peak incidence between 4 and 7 months of age.9 Intussusception had been observed in prelicensure trials of the first RV vaccine, RRV-TV, but the risk was not fully appreciated until about a million doses of the licensed vaccine had been administered in the US and about 100 cases had been reported. The risk of intussusception appeared greatest 3–7 days after administration of the first vaccine dose.8 Postlicensure surveillance studies with current RV vaccines have been undertaken in several countries.20–29 These studies have varied in terms of geographic location, design, statistical methodology and results. Of particular note, studies of intussusception risk associated with RV1 have been undertaken in both developing and developed countries (Mexico, Brazil, Australia and the US), whereas studies of RV5 were exclusively performed in developed countries (Australia and the US). The present meta-analysis was undertaken to provide an overall estimate of the risk of intussusception after vaccination with RV1 and RV5. Despite the differences in study design, m ethods and geographical location, the degree of heterogeneity between the included studies was found to be low. Because of the general low heterogeneity, the fixed model estimate is, therefore, considered a good estimate of risk for the general vaccinated population. The overall estimate of relative risk of intussusception during the 7 days after vaccination with RV1 was 5.4 postdose 1 and 1.8 postdose 2. The overall estimate of relative risk of intussusception during the 7 days after vaccination with RV5 was 5.5 postdose 1 and 1.7 postdose 2. The relative risk estimates obtained are very similar for both currently available RV vaccines and are approximately 10-fold lower than those reported for RRV-TV.8 This is the first study to report an overall estimate of the relative risk of intussusception postdose 1 and postdose 2 with the 2 commercially available RV vaccines, and this study appears to indicate a class effect. We used relative risk and not attributable risk as the main parameter because of the large variation in the background incidence of intussusception worldwide.9 Moreover, attributable risk was not provided for all included studies. However, good homogeneity of relative risk estimates among the studies indicates that the overall estimate of relative risk obtained is a valuable parameter that can be used to estimate the attributable risk in a specific setting (attributable risk = relative risk multiplied by the number of expected cases in the given setting/country). A key strength of this meta-analysis is the strict inclusion criteria used. Only postmarketing studies were included because the objective was to assess the risk of intussusception in real clinical practice. Furthermore, only data from studies that reported
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confirmed cases of intussusception were included. This increases the robustness of our analysis and the findings; in particular, conferring a high specificity of the endpoint to reduce a possible bias to the null hypothesis (no risk), which can occur with a lack of specificity. In addition, risk was estimated for each dose separately because all studies showed a risk difference between the 2 doses. The risk of intussusception beyond the 7-day p ostvaccination period was not assessed in this study because of lack of homogeneity in the definition of these other risk periods among the various studies. All included studies provided an estimate of risk for the 7-day postvaccination period. Most studies also provided risk estimates for other time periods; however, these other risk periods varied among studies (1–7, 1–14, 1–21, 1–30, 8–14, 15–21 and 8–21 days). Furthermore, most studies20,21,23,25 did not show evidence of increased risk after the 7-day postvaccination period; one study in Mexico20 showed a small elevated risk (~2) during the 8–21 day period postdose 2 of RV1 and another study in Australia26 showed an elevated risk during the 8–21 day period postdose 1 for both RV1 (~3) and RV5 (~6). Another limitation could be the limited number of studies included in the present meta-analysis (3 or 4 depending on the vaccine and the dose). However, strict inclusion criteria were used to have a very specific endpoint and to avoid bias to the null hypothesis of absence of risk. Although methodology differed between studies, all controlled for age effect either by age-adjustment analysis (SCCS and SCRI studies) or by using age-specific expected number (observed vs. expected study). In addition, a sensitivity analysis, which included the study by Weintraub et al,29 yielded very similar relative risk estimates for both vaccines postdose 1 and for RV1 postdose 2. This shows the risk estimates derived by this meta-analysis to be robust. During preparation of this article, 2 other studies of the risk of intussusception after RV vaccination have been published.33,34 The first study reported risk of intussusception after vaccination with RV1 using worldwide spontaneous reports33; however, because there was no case ascertainment, this study does not meet the inclusion criteria of our meta-analysis. The second study reported observed versus expected standardized morbidity ratio for RV1 and RV5.34 This study used confirmed cases of spontaneously reported intussusception in Germany from 2006 to 2010 and met the inclusion criteria for our meta-analysis. Despite the low number of observed cases of intussusception (7 for RV1 and 8 for RV5), the risk estimates obtained are consistent with the overall risk estimates of our meta-analysis. The findings of this meta-analysis for RV1 and RV5, and the previous experience with RRV-TV, provide an indication that the slight increase in the risk of intussusception postvaccination may be a class effect of oral RV vaccines, albeit with different risk levels for RRV-TV and the currently licensed RV1 and RV5 vaccines. This meta-analysis shows that RV1 and RV5 have virtually identical risk estimates for intussusception after each vaccine dose, and that this risk is slightly higher in postdose 1 than in postdose 2. The availability of a single global estimate for relative risk of intussusception after administration of currently licensed RV vaccines will support healthcare decision-making and enables benefit–risk assessments to be made, especially in countries with limited local intussusception surveillance infrastructure. Any new RV vaccine licensed in the future will have to undergo an extensive period of postlicensure evaluation for intussusception with appropriate study designs to ascertain the risk associated with the individual product. Even though the risk of intussusception with RV vaccines appears to be a class effect, the risk of intussusception can vary substantially as the experience with RRV-TV and the 2 currently licensed vaccines (RV1 and RV5) has shown, with © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
implications for overall benefit–risk depending on the setting in which the vaccine will be used. It remains to be fully determined whether the short-term increased risk of intussusception immediately after vaccination translates into an overall population-level increase in intussusception incidence during the first year of life and beyond, or whether there is a compensatory effect in the more distant postvaccination periods as suggested by some data for the RRV-TV vaccine.35 The studies included in this meta-analysis concentrated on a specific period of observation (7 days postvaccination) and did not attempt to define the possible impact of RV vaccination on the overall incidence of intussusception. However, there has been no evidence of sustained population level changes in intussusception rates in the United States before and after RV vaccine introduction.36 Similarly, a recent German study also found no overall increase in intussusception rate after the introduction of RV vaccination.37 Available data confirm that the documented benefits of the currently available RV vaccines by far outweigh the small temporal increase in risk for intussusception immediately after vaccination.20,38–43 Accordingly, public health agencies worldwide continue to strongly endorse routine RV vaccination of infants.40,41,43,44 The etiology of intussusception remains poorly understood, and better understanding of the biological mechanism of intussusception and the overall risk of intussusception in vaccinated children is needed. Previous epidemiological studies have failed to demonstrate an association between natural RV infection and intussusception.45–47 Apparent clustering of intussusception in the first 7 days after RV vaccination coincides with the peak period of vaccinevirus viral replication48,49; viral shedding has been detected with all RV vaccines after each vaccine dose and is highest postdose 1.50,51 However, whether there is any causal association between occurrence of viral replication in the gastrointestinal tract of vaccinated infants and the development of intussusception remains unknown. The small increase in risk of intussusception after vaccination is already reflected in the prescribing information for both RV1 and RV5 and acknowledged by regulatory authorities worldwide. This risk should be taken into context with the overall benefit–risk evaluation of RV vaccination. Early diagnosis and treatment of intussusception is essential to prevent injury to the intestine and associated sequelae. Accordingly, healthcare professionals should follow-up on any symptoms possibly indicative of intussusception (severe abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/or high fever), and parents/ guardians should be advised to promptly report such symptoms to their healthcare provider. In summary, results of this meta-analysis show a similar increase in the overall estimate of relative risk of intussusception mostly during the first 7 days after administration of dose 1 and, to a lesser extent, dose 2, for both currently available RV vaccines, RV1 and RV5. This suggests that intussusception may be a class effect of currently available oral RV vaccines.
ACKNOWLEDGMENTS The authors thank Nicolas Praet (GSK epidemiologist) for his assistance with the retrospective literature review, Jean-Yves Pirçon (GSK statistician) for his contribution to the statistical calculations and Laurence Baril (GSK epidemiologist) for her assistance with data interpretation and manuscript review. The authors also thank Jennifer Coward (independent medical writer on behalf of GSK) for her help with preparing the manuscript and Uta Gomes (independent publication manager ginkgosolutions Ltd. on behalf of GSK) for editing and publication coordination. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intussusception
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Risk of Intussusception After Rotavirus Vaccination Meta-analysis of Postlicensure Studies Dominique Rosillon, PhD,* Hubert Buyse, MD,* Leonard R. Friedland, MD,† Su-Peing Ng, MBBS,* F. Raúl Velázquez, MD, MSc,‡ and Thomas Breuer, MD* Background: Postlicensure surveillance studies suggest a small temporal increase in the risk for intussusception with both currently available rotavirus vaccines (RV1; Rotarix, GSK and RV5; RotaTeq, Merck & Co., Inc.). This meta-analysis was undertaken to provide a single overall estimate of the relative risk of intussusception during the 7-day period after administration of RV1 and RV5. Methods: Meta-analysis based on estimates of relative risk and corresponding 95% confidence intervals from 5 postlicensure studies providing an estimate of risk of intussusception during the 7-day period after administration of dose 1 and/or dose 2 of RV1 and/or RV5, based on active and/or passive surveillance, for confirmed intussusception cases (Brighton or other method of case confirmation). For each vaccine, the relative risk of intussusception was estimated postdose 1 and postdose 2. Results were pooled using the inverse variance method using both fixed-effect and random-effect models. Results: The overall estimate of relative risk of intussusception during the 7 days postdose 1 was 5.4 (95% confidence interval: 3.9–7.4, 3 studies) for RV1 and 5.5 (3.3–9.3, 3 studies) for RV5. The overall estimate of relative risk of intussusception during the 7 days postdose 2 was 1.8 (1.3–2.5, 4 studies) for RV1 and 1.7 (1.1–2.6, 3 studies) for RV5. Conclusions: This meta-analysis showed a similar increased risk of intussusception, during the first 7 days after administration of dose 1 and, to a lesser extent, dose 2, for both currently available rotavirus vaccines. This suggests that intussusception may be a class effect of currently available oral rotavirus vaccines. Key Words: rotavirus, vaccine, intussusception (Pediatr Infect Dis J 2015;34:763–768)
R
otavirus (RV) is the major cause of acute gastroenteritis among infants and young children worldwide.1–3 Before the introduction of currently available RV vaccines, RV gastroenteritis (RVGE) accounted for approximately 2.4 million hospitalizations and half a million deaths annually among children younger than 5 years worldwide.1–4 The burden of RV disease is significant in both developing and developed countries; however, there are marked differences in the nature of this burden, with h ighest
Accepted for publication December 11, 2014. From *GlaxoSmithKline Vaccines, Wavre, Belgium; †GlaxoSmithKline, Philadelphia, PA; and ‡Medical Research Unit on Infectious Diseases, Pediatrics Hospital, National Medical Center-Century-XXI, Mexican Institute of Social Security (IMSS), Mexico City, D.F., Mexico. Su-Peing Ng, MB BS is currently at the Global Medical Affairs, Sanofi Pasteur, Lyon, France. This study was funded by GlaxoSmithKline Biologicals SA (GSK). GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of this manuscript. D.R., H.B., L.F. and T.B. are employees of the GSK group of companies. S.N. was formerly an employee of the GSK group of companies. D.R., L.F., S.N. and T.B. all declare to be in receipt of GSK stocks. R.V. has received a grant for his institution IMSS from GSK. Address for correspondence: Dominique Rosillon, PhD, GlaxoSmithKline Vaccines, Avenue Fleming, Wavre, Belgium. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3407-0763 DOI: 10.1097/INF.0000000000000715
mortality seen in low-income countries.3,4 The World Health Organization recommends that all infants are vaccinated to prevent RV disease.5,6 An oral rhesus-human reassortant RV tetravalent vaccine (RRV-TV; RotaShield, Wyeth) was licensed in the US in October 1998. However, 9 months later, the RRV-TV immunization program was suspended because of a temporal association between RV vaccination and occurrence of intussusception.7 The relative risk of intussusception during the 3–7 days after RRV-TV administration was 58.9 [95% confidence interval (CI): 31.7–109.6] postdose 1 and 11.0 (4.1–29.5) postdose 2.8 Intussusception is a rare condition. A recent systematic review of 82 studies worldwide reported a mean incidence of intussusception of 74 per 100,000 children aged less than 1 year, with considerable geographic variability noted (range: 9–328).9 Intussusception case fatality rate also varies between regions, being higher in Africa (9%) than in other regions ( case-control > cohort > observed versus expected.
Statistical Methods The meta-analysis was based on log-transformed estimates of relative risk and corresponding 95% CI from each eligible study. Undefined risk estimates (ie, risk estimate ≅ 0 or ∞) were not included in the statistical calculations. No raw data were used. Separate analyses were performed for RV1 and RV5. For each vaccine, the relative risk of intussusception was estimated postdose 1 and postdose 2. Results were pooled using both fixed and random study effect model.30 Heterogeneity between studies was tested using the Cochran Q test. The degree of the heterogeneity was assessed by the I² index, with 25%, 50% and 75% representing low, moderate and high heterogeneity, respectively.31,32 Results are presented as forest plots. We performed a sensitivity analysis for each vaccine after each dose including data from the study by Weintraub et al.29 This study was not included in the main analysis because nonconfirmed cases were included in the observed versus expected analysis. However, this is one of the few studies to provide an estimate of risk for both RV1 and RV5 in the same setting.
RESULTS Study Characteristics The study selection process is summarized in Figure 1. Data from a total of 5 studies met the criteria for inclusion in this metaanalysis20,23,26–28; in addition, an observed versus expected study29 including nonconfirmed cases was included in a sensitivity analysis (Table 1). For RV1, 3 studies provided information on risk of intussusception postdose 1 (all of SCCS design, 2 undertaken in Latin
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FIGURE 1. Flow chart of study selection process. America and 1 in Australia) and 4 provided information on risk of intussusception postdose 2 (3 of SCCS and 1 additional study of SCRI design undertaken in the US). One of the studies undertaken in Latin America provided separate data for the risk of intussusception after RV vaccination in 2 different countries (Mexico and Brazil)20; data for both of these countries were included separately in the meta-analysis. Three studies provided information on the risk of intussusception both postdose 1 and postdose 2 for RV5 (1 of SCCS design in Australia and 2 of SCRI design in the US). One of the studies in the US provided a risk estimate for 3–6 days after vaccination and as such did not strictly meet inclusion criterion 2.27 However, there is good evidence to suggest that the risk of intussusception within 7 days of vaccination is mainly concentrated during the 3–6 day postvaccination period; as such, this study was included in the meta-analysis.
Risk of Intussusception Postdose 1 The relative risk of intussusception during the 7-day period after the first dose of RV1 ranged from 1.1 to 6.8 among the 3 studies included in the meta-analysis (Fig. 2). Heterogeneity among studies was moderate (I² = 60.6%) and approached statistical significance (Q = 7.62, P = 0.06). This heterogeneity was primarily attributable to the data from Brazil.20 The overall estimate of relative risk of intussusception during the 7-day period after the first dose of RV1 was 5.4 (95% CI: 3.9–7.4) for the fixed-effect model and 4.7 (2.6–8.4) for the random-effect model. The relative risk of intussusception during the 7-day period after the first dose of RV5 ranged from 3.8 to 9.9 among the 3 studies included in the meta-analysis (Fig. 2). Heterogeneity among studies was low (I ² = 34.7%) and not statistically significant (Q = 3.07, P = 0.22). The overall estimate of relative risk of intussusception during the 7-day period after the first dose of RV5 was 5.5 (3.3–9.3) for the fixed-effect model and 6.1 (3.0–12.1) for the random-effect model. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Intussusception
TABLE 1. Studies Included in the Meta-analysis and Sensitivity Analysis Study Patel et al20 Velázquez et al23 Carlin et al26 Haber et al27 Yih et al28 Weintraub et al29†
Country Mexico,* Brazil* Mexico Australia US US US
Design/method
Risk period
SCCS SCCS SCCS SCRI SCRI O/E
7 days 7 days 7 days 3–6 days 7 days 7 days
Vaccine RV1 RV1 RV1, RV5 RV5 RV1, RV5 RV1, RV5
*Analysis per country. †Included in a sensitivity analysis only. SCCS indicates self-controlled case series; SCRI, self-controlled risk interval; observed versus expected.
FIGURE 2. Risk of intussusception during the 7 days after the first dose of RV1 and RV5 (bars show 95% CI).
FIGURE 3. Risk of intussusception during the 7 days after the second dose of RV1 and RV5 (bars show 95% CI).
Risk of Intussusception Postdose 2 The relative risk of intussusception during the 7-day period after the second dose of RV1 ranged from 1.3 to 3.5 among the 4 studies included in the meta-analysis (Fig. 3). Heterogeneity among studies was very low (I ² = 5.3%) and not statistically significant (Q = 4.22, P = 0.38). The overall estimate of relative risk of intussusception during the 7-day period after the second dose of RV1was 1.8 (1.3–2.5) for the fixed-effect model and 1.8 (1.3–2.6) for the random-effect model. The relative risk of intussusception during the 7-day period after the second dose of RV5 ranged from 1.4 to 2.8 among the © 2015 Wolters Kluwer Health, Inc. All rights reserved.
3 studies included in the meta-analysis (Fig. 3). No heterogeneity among studies was observed (I ² = 0%). The overall estimate of relative risk of intussusception during the 7-day period after the second dose of RV5 was 1.7 (1.1–2.6) for both fixed-effect and randomeffect models.
Sensitivity Analysis Despite the fact that the study by Weintraub et al29 suggested a relative risk of intussusception within 7 days of RV1 compared with RV5 of 9.4 (1.4–103.8), the sensitivity analysis gave similar relative risk estimates for both vaccines after each dose. www.pidj.com | 765
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Rosillon et al
For RV1, the overall estimate of relative risk of intussusception postdose 1 was 5.5 (4.0–7.5) for the fixed-effect model and 5.0 (3.0–8.4) for the random-effect model. For RV5, the overall estimate of relative risk of intussusception postdose 1 was 4.9 (3.0– 7.8) for the fixed-effect model and 5.1 (2.8–9.3) for the randomeffect model. The overall estimate of relative risk of intussusception postdose 2 of RV1 was 2.0 (1.5–2.8) for the fixed-effect model and 2.4 (1.5–3.9) for the random-effect model. Sensitivity analysis for RV5 could not be performed postdose 2 because the risk estimate was undefined (relative risk = 0) in the study by Weintraub et al.29
DISCUSSION Intussusception is a rare form of intestinal obstruction in which a segment of the bowel prolapses into a more distal portion; mean incidence is reported to range from 9 to 328 per 100,000 children aged less than 1 year.9 Intussusception constitutes the most frequent cause of acute intestinal obstruction among young children independent of exposure to RV vaccines. Most cases occur in infants aged less than 1 year, with peak incidence between 4 and 7 months of age.9 Intussusception had been observed in prelicensure trials of the first RV vaccine, RRV-TV, but the risk was not fully appreciated until about a million doses of the licensed vaccine had been administered in the US and about 100 cases had been reported. The risk of intussusception appeared greatest 3–7 days after administration of the first vaccine dose.8 Postlicensure surveillance studies with current RV vaccines have been undertaken in several countries.20–29 These studies have varied in terms of geographic location, design, statistical methodology and results. Of particular note, studies of intussusception risk associated with RV1 have been undertaken in both developing and developed countries (Mexico, Brazil, Australia and the US), whereas studies of RV5 were exclusively performed in developed countries (Australia and the US). The present meta-analysis was undertaken to provide an overall estimate of the risk of intussusception after vaccination with RV1 and RV5. Despite the differences in study design, m ethods and geographical location, the degree of heterogeneity between the included studies was found to be low. Because of the general low heterogeneity, the fixed model estimate is, therefore, considered a good estimate of risk for the general vaccinated population. The overall estimate of relative risk of intussusception during the 7 days after vaccination with RV1 was 5.4 postdose 1 and 1.8 postdose 2. The overall estimate of relative risk of intussusception during the 7 days after vaccination with RV5 was 5.5 postdose 1 and 1.7 postdose 2. The relative risk estimates obtained are very similar for both currently available RV vaccines and are approximately 10-fold lower than those reported for RRV-TV.8 This is the first study to report an overall estimate of the relative risk of intussusception postdose 1 and postdose 2 with the 2 commercially available RV vaccines, and this study appears to indicate a class effect. We used relative risk and not attributable risk as the main parameter because of the large variation in the background incidence of intussusception worldwide.9 Moreover, attributable risk was not provided for all included studies. However, good homogeneity of relative risk estimates among the studies indicates that the overall estimate of relative risk obtained is a valuable parameter that can be used to estimate the attributable risk in a specific setting (attributable risk = relative risk multiplied by the number of expected cases in the given setting/country). A key strength of this meta-analysis is the strict inclusion criteria used. Only postmarketing studies were included because the objective was to assess the risk of intussusception in real clinical practice. Furthermore, only data from studies that reported
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confirmed cases of intussusception were included. This increases the robustness of our analysis and the findings; in particular, conferring a high specificity of the endpoint to reduce a possible bias to the null hypothesis (no risk), which can occur with a lack of specificity. In addition, risk was estimated for each dose separately because all studies showed a risk difference between the 2 doses. The risk of intussusception beyond the 7-day p ostvaccination period was not assessed in this study because of lack of homogeneity in the definition of these other risk periods among the various studies. All included studies provided an estimate of risk for the 7-day postvaccination period. Most studies also provided risk estimates for other time periods; however, these other risk periods varied among studies (1–7, 1–14, 1–21, 1–30, 8–14, 15–21 and 8–21 days). Furthermore, most studies20,21,23,25 did not show evidence of increased risk after the 7-day postvaccination period; one study in Mexico20 showed a small elevated risk (~2) during the 8–21 day period postdose 2 of RV1 and another study in Australia26 showed an elevated risk during the 8–21 day period postdose 1 for both RV1 (~3) and RV5 (~6). Another limitation could be the limited number of studies included in the present meta-analysis (3 or 4 depending on the vaccine and the dose). However, strict inclusion criteria were used to have a very specific endpoint and to avoid bias to the null hypothesis of absence of risk. Although methodology differed between studies, all controlled for age effect either by age-adjustment analysis (SCCS and SCRI studies) or by using age-specific expected number (observed vs. expected study). In addition, a sensitivity analysis, which included the study by Weintraub et al,29 yielded very similar relative risk estimates for both vaccines postdose 1 and for RV1 postdose 2. This shows the risk estimates derived by this meta-analysis to be robust. During preparation of this article, 2 other studies of the risk of intussusception after RV vaccination have been published.33,34 The first study reported risk of intussusception after vaccination with RV1 using worldwide spontaneous reports33; however, because there was no case ascertainment, this study does not meet the inclusion criteria of our meta-analysis. The second study reported observed versus expected standardized morbidity ratio for RV1 and RV5.34 This study used confirmed cases of spontaneously reported intussusception in Germany from 2006 to 2010 and met the inclusion criteria for our meta-analysis. Despite the low number of observed cases of intussusception (7 for RV1 and 8 for RV5), the risk estimates obtained are consistent with the overall risk estimates of our meta-analysis. The findings of this meta-analysis for RV1 and RV5, and the previous experience with RRV-TV, provide an indication that the slight increase in the risk of intussusception postvaccination may be a class effect of oral RV vaccines, albeit with different risk levels for RRV-TV and the currently licensed RV1 and RV5 vaccines. This meta-analysis shows that RV1 and RV5 have virtually identical risk estimates for intussusception after each vaccine dose, and that this risk is slightly higher in postdose 1 than in postdose 2. The availability of a single global estimate for relative risk of intussusception after administration of currently licensed RV vaccines will support healthcare decision-making and enables benefit–risk assessments to be made, especially in countries with limited local intussusception surveillance infrastructure. Any new RV vaccine licensed in the future will have to undergo an extensive period of postlicensure evaluation for intussusception with appropriate study designs to ascertain the risk associated with the individual product. Even though the risk of intussusception with RV vaccines appears to be a class effect, the risk of intussusception can vary substantially as the experience with RRV-TV and the 2 currently licensed vaccines (RV1 and RV5) has shown, with © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
implications for overall benefit–risk depending on the setting in which the vaccine will be used. It remains to be fully determined whether the short-term increased risk of intussusception immediately after vaccination translates into an overall population-level increase in intussusception incidence during the first year of life and beyond, or whether there is a compensatory effect in the more distant postvaccination periods as suggested by some data for the RRV-TV vaccine.35 The studies included in this meta-analysis concentrated on a specific period of observation (7 days postvaccination) and did not attempt to define the possible impact of RV vaccination on the overall incidence of intussusception. However, there has been no evidence of sustained population level changes in intussusception rates in the United States before and after RV vaccine introduction.36 Similarly, a recent German study also found no overall increase in intussusception rate after the introduction of RV vaccination.37 Available data confirm that the documented benefits of the currently available RV vaccines by far outweigh the small temporal increase in risk for intussusception immediately after vaccination.20,38–43 Accordingly, public health agencies worldwide continue to strongly endorse routine RV vaccination of infants.40,41,43,44 The etiology of intussusception remains poorly understood, and better understanding of the biological mechanism of intussusception and the overall risk of intussusception in vaccinated children is needed. Previous epidemiological studies have failed to demonstrate an association between natural RV infection and intussusception.45–47 Apparent clustering of intussusception in the first 7 days after RV vaccination coincides with the peak period of vaccinevirus viral replication48,49; viral shedding has been detected with all RV vaccines after each vaccine dose and is highest postdose 1.50,51 However, whether there is any causal association between occurrence of viral replication in the gastrointestinal tract of vaccinated infants and the development of intussusception remains unknown. The small increase in risk of intussusception after vaccination is already reflected in the prescribing information for both RV1 and RV5 and acknowledged by regulatory authorities worldwide. This risk should be taken into context with the overall benefit–risk evaluation of RV vaccination. Early diagnosis and treatment of intussusception is essential to prevent injury to the intestine and associated sequelae. Accordingly, healthcare professionals should follow-up on any symptoms possibly indicative of intussusception (severe abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/or high fever), and parents/ guardians should be advised to promptly report such symptoms to their healthcare provider. In summary, results of this meta-analysis show a similar increase in the overall estimate of relative risk of intussusception mostly during the first 7 days after administration of dose 1 and, to a lesser extent, dose 2, for both currently available RV vaccines, RV1 and RV5. This suggests that intussusception may be a class effect of currently available oral RV vaccines.
ACKNOWLEDGMENTS The authors thank Nicolas Praet (GSK epidemiologist) for his assistance with the retrospective literature review, Jean-Yves Pirçon (GSK statistician) for his contribution to the statistical calculations and Laurence Baril (GSK epidemiologist) for her assistance with data interpretation and manuscript review. The authors also thank Jennifer Coward (independent medical writer on behalf of GSK) for her help with preparing the manuscript and Uta Gomes (independent publication manager ginkgosolutions Ltd. on behalf of GSK) for editing and publication coordination. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intussusception
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39. Desai R, Cortese MM, Meltzer MI, et al. Potential intussusception risk versus benefits of rotavirus vaccination in the United States. Pediatr Infect Dis J. 2013;32:1–7. 40. Cortese MM. Summary of intussusception risk and benefits of rotavirus vaccination in the United States. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices, 20 June 2013. Available at: http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-jun-2013/ 06-Rotavirus-Cortese.pdf. Accessed 20 May, 2014. 41. Buttery JP, Standish J, Bines JE. Intussusception and rotavirus vaccines: consensus on benefits outweighing recognized risk. Pediatr Infect Dis J. 2014;33:772–773. 42. Rha B, Tate JE, Weintraub E, et al. Intussusception following rotavirus vaccination: an updated review of the available evidence. Expert Rev Vaccines. 2014;13:1339–1348. 43. Australian Government Department of Health Therapeutic Goods Administration. Rotavirus vaccination and the risk of intussusception, 28 August 2013. Available at: http://www.tga.gov.au/safety/alerts-medicinerotavirus-130828.htm. Accessed May 20, 2014. 44. World Health Organization. Rotavirus vaccines. WHO position paper― January 2013. Wkly Epidemiol Rec. 2013;88:49–64. 45. Chang EJ, Zangwill KM, Lee H, et al. Lack of association between rotavirus infection and intussusception: implications for use of attenuated rotavirus vaccines. Pediatr Infect Dis J. 2002;21:97–102. 46. Velázquez FR, Luna G, Cedillo R, et al. Natural rotavirus infection is not associated to intussusception in Mexican children. Pediatr Infect Dis J. 2004;23 (10 Suppl):S173–S178. 47. Bines JE, Liem NT, Justice FA, et al; Intussusception Study Group. Risk factors for intussusception in infants in Vietnam and Australia: adenovirus implicated, but not rotavirus. J Pediatr. 2006;149:452–460. 48. Rivera L, Peña LM, Stainier I, et al. Horizontal transmission of a human rotavirus vaccine strain–a randomized, placebo-controlled study in twins. Vaccine 2011;29:9508–9513. 49. Yen C, Jakob K, Esona MD, et al. Detection of fecal shedding of rotavirus vaccine in infants following their first dose of pentavalent vaccine. Vaccine 2011;29:4151–4155. 50. Ward RL, Dinsmore AM, Goldberg G, et al. Shedding of rotavirus after administration of the tetravalent rhesus rotavirus vaccine. Pediatr Infect Dis J. 1998;17:386–390. 51. Bines JE, Patel M, Parashar U. Assessment of postlicensure safety of rotavirus vaccines, with emphasis on intussusception. J Infect Dis. 2009;200 (Suppl 1):S282–S290.
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