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Immune checkpoint inhibitors are increasingly used in the treatment of a number of malignancies and carry a known risk of immune-related adverse events (irAEs). IrAEs cover a broad range of affected organ systems and presenting symptoms. While the gastrointestinal system is a commonly affected system, isolated gastritis is an uncommon diagnosis. We present a patient with isolated ICI-related gastritis presenting with concomitant intussusception caused by the anti-programmed cell death-1 antibody, pembrolizumab.

Background: In January 2018, Afghanistan introduced the monovalent oral rotavirus vaccine (Rotarix) nationwide, administered as a 2-dose series at six and ten weeks of age. We describe characteristics of intussusception cases and assess potential intussusception risk associated with Rotarix vaccination in Afghan infants., Methods: Multi-center prospective active hospital-based surveillance for intussusception was conducted from May 2018 to March 2022 in four sentinel sites in Afghanistan. We applied the Brighton Level 1 criteria for intussusception and verified vaccination status by reviewing vaccine cards. We used the self-controlled case series (SCCS) methodology to compare intussusception incidence in the 1 to 21 days after each dose of Rotarix vaccination against non-risk periods., Results: A total of 468 intussusception cases were identified in infants under 12 months, with 264 cases aged between 28 and 245 days having confirmed vaccination status contributing to the SCCS analysis. Most case-patients (98 %) required surgery for treatment, and over half (59 %) of those who underwent surgery required intestinal resection. Nineteen (7 %) case-patients died. Eighty-six percent of case-patients received the first dose of Rotarix, and 69 % received the second dose before intussusception symptom onset. There was no increased risk of intussusception in the 1-7 days (relative incidence: 0.9, 95 % CI: 0.1, 7.5), 8-21 days (1.3, 95 % CI: 0.4, 4.2), or 1-21 days (1.1, 95 % CI: 0.4, 3.4) following receipt of the first dose or in the 1-7 days (0.2, 95 % CI: 0.3, 1.8), 8-21 days (0.7, 95 % CI: 0.3, 1.5), or 1-21 days (0.6, 95 % CI: 0.3, 1.2) following the second dose., Conclusion: Rotarix vaccination was not associated with an increased intussusception risk, supporting its continued use in Afghanistan's immunization program. However, there was a high level of death and resection due to intussusception among Afghan infants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: A low-level risk of intussusception following rotavirus vaccination has been observed in some settings and may vary by vaccine type. We examined the association between RotaTeq vaccination and intussusception in low-income settings in a pooled analysis from 5 African countries that introduced RotaTeq into their national immunization program., Methods: Active surveillance was conducted at 20 hospitals to identify intussusception cases. A standard case report form was completed for each enrolled child, and vaccination status was determined by review of the child's vaccination card. The pseudo-likelihood adaptation of self-controlled case-series method was used to assess the association between RotaTeq administration and intussusception in the 1-7, 8-21, and 1-21 day periods after each vaccine dose in infants aged 28-245 days., Results: Data from 318 infants with confirmed rotavirus vaccination status were analyzed. No clustering of cases occurred in any of the risk windows after any of the vaccine doses. Compared with the background risk of naturally occurring intussusception, no increased risk was observed after dose 1 in the 1-7 day (relative incidence = 2.71; 95% confidence interval [CI] = 0.47-8.03) or the 8-21 day window (relative incidence = 0.77; 95%CI = 0.0-2.69). Similarly, no increased risk of intussusception was observed in any risk window after dose 2 or 3., Conclusions: RotaTeq vaccination was not associated with increased risk of intussusception in this analysis from 5 African countries. This finding mirrors results from similar analyses with other rotavirus vaccines in low-income settings and highlights the need for vaccine-specific and setting-specific risk monitoring., Competing Interests: Potential conflicts of interest. N. A. reports being currently employed by Pfizer, financial support from Pfizer for travel to meetings and conferences, and Pfizer stock/stock options. E.L. reports consulting fees from the WHO, payment and honoraria from GSK (recombinant zoster vaccine) and Novartis (coronavirus disease 2019) for activities unrelated to rotavirus vaccines, and participation in the Global Influenza Advisory Board for Sanofi Pasteur and Moderna. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: The self-controlled case series (SCCS) is often used to monitor vaccine safety. The evaluation of intussusception after the rotavirus vaccine is complicated because the baseline rate varies with age. Time-varying baseline risk adjustments with data from unexposed cohorts are utilised. Self-controlled risk interval (SCRI), with a shorter observation period, can also mitigate the problem by studying a control period close to the risk period., Objective: An Indian rotavirus vaccine has previously been studied using SCCS. The risk of intussusception in the high-risk windows (21 days after vaccination) was comparable to the background risk. The aim was to re-analyse data of an existing SCCS study using alternate statistical methods to examine vaccine safety., Methods: We examined the mean age of intussusception in the vaccinated and the unvaccinated. We performed an SCRI analysis of the surveillance data from the SCCS study, limiting the observation period to 180 days. We analysed the time-to-intussusception from the last vaccination. Finally, we performed an SCCS analysis, excluding unvaccinated cases from the analysis., Results: We found that the mean age of intussusception was significantly lower in the vaccinated (205 days) compared to the unvaccinated (223 days) (p-value 0.0026). The Incident Risk Ratio (IRR) on SCRI analysis was 1.62 (95% CI 1.07-2.44). There were significantly more intussusceptions in the first 30 days after vaccination compared to the next 30-day window. (92 vs 63 p-value = 0.009). We found that excluding unvaccinated infants from the SCCS analysis demonstrated significantly increased risk for the risk period 1-21 days after the 3rd dose (IRR 2.47, 95% CI 1.70-3.59). The risks of intussusception were missed in traditional SCCS analysis using unvaccinated infants as controls., Conclusion: Traditional risk adjustments using data from unexposed cohorts in SCCS may not be appropriate for investigating the risk of intussusception where vaccination lowers the mean age of intussusception.

Some post-licensure studies have shown a potential increased risk of intussusception following vaccination with rotavirus vaccines. This is the first study that aimed to assess the incidence and risk of intussusception within 90 days after vaccination with RotaTeq in Chinese infants. A population-based birth cohort from 27th November 2018 to 30th June 2021 included all newborns in Ningbo city. The records of intussusception were identified through the ICD-10 code K56.1 or Chinese keywords "Chang Tao" from all hospital discharge records. Each episode was confirmed in line with the Brighton criteria, and only Brighton level 1 cases were included. The association of RotaTeq vaccination and intussusception was evaluated using the Poisson regression. A total of 108,405 eligible subjects from birth cohort were eligible, with 52.30% males. Among them, 26, 847 (24.77%) infants received at least one dose of RotaTeq, and 95.52% of them were fully vaccinated, with 76, 934 doses in total. After adjudication, none of the cases occurred post first, or second dose, the cumulative number of cases that occurred 1-7, 1-14, 1-21, 1-42, and 1-90 days post third dose was 0, 1, 1, 3, and 7, respectively. Adjusting for age, sex, birth year, birth season and location, the incidence rate ratio of intussusception after RotaTeq vaccination was 0.90 (90% two-sided CI: 0.46, 1.75). Increasing age and male gender were associated with higher risk of intussusception. In summary, no increased risk of IS was observed following 3 months of RotaTeq vaccination in this study.

Rotavirus vaccines have substantially decreased rotavirus hospitalizations in countries where they have been implemented. In some high- and middle-income countries, a low-level of increased risk of intussusception, a type of acute bowel obstruction, has been detected following rotavirus vaccination. However, no increased risk of intussusception was found in India, South Africa, or a network of 7 other African countries. We assessed the association between a 2-dose monovalent rotavirus vaccine (Rotarix) and intussusception in 3 early-adopter low-income Asian countries -- Afghanistan, Myanmar, and Pakistan. Children <12 months of age admitted to a sentinel surveillance hospital with Brighton level 1 intussusception were eligible for enrollment. We collected information about each child's vaccination status and used the self-controlled case series method to calculate the relative incidence of intussusception 1-7 days, 8-21 days, and 1-21 days following each dose of vaccine and derived confidence intervals with bootstrapping. Of the 585 children meeting the analytic criteria, the median age at intussusception symptom onset was 24 weeks (IQR: 19-29). Overall, 494 (84 %) children received the first Rotarix dose and 398 (68 %) received the second dose. There was no increased intussusception risk during any of the risk periods following the first (1-7 days: 1.01 (95 %CI: 0.39, 2.60); 8-21 days: 1.37 (95 %CI: 0.81, 2.32); 1-21 days: 1.28 (95 %CI: 0.78, 2.11)) or second (1-7 days: 0.81 (95 %CI: 0.42, 1.54); 8-21 days: 0.77 (95 %CI: 0.53, 1.16); 1-21 days: 0.78 (95 %CI: 0.53, 1.16)) rotavirus vaccine dose. Our findings are consistent with other data showing no increased intussusception risk with rotavirus vaccination in low-income countries and add to the growing body of evidence demonstrating safety of rotavirus vaccines., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eleanor Burnett reports financial support was provided by GAVI Alliance., (Published by Elsevier Ltd.)

Although safe, rotavirus vaccines have been associated with increased intussusception risk. In Brazil, after the oral human rotavirus vaccine (OHRV) introduction in the childhood immunization, in 2006, increased intussusception risk was identified after the second OHRV dose, whereas in other countries, higher risk was associated to the first vaccine dose. It was hypothesized that the concomitant use of oral poliovirus vaccine (OPV) in Brazil might explain this difference. In 2012, the inactivated polio vaccine (IPV) was adopted in the first two doses of Brazilian childhood immunization schedule, creating an opportunity to study the subject. Our objective was analyzing the impact of polio vaccines on rotavirus-associated intussusception. We used surveillance data on intussusception in infants living in São Paulo State. Two periods were considered: an OPV-period (March 2006 to June 2012) and an IPV-period (October 2012 to December 2017). The period from June to September 2012 were considered as transition. Self-controlled case series analysis with event-dependent exposure was performed, considering two risk periods (7 and 21 days post-vaccination). We identified 325 intussusception cases in infants reported to the surveillance systems during the study period. The statistical analysis included 221 cases that occurred within 60 days after vaccination. Overall, a higher intussusception risk was observed in the first week after vaccination for both the first (Relative Incidence [RI] = 4.3, 95%CI 2.8-6.5, p < .001) and second vaccine doses (RI = 4.2, 95%CI 2.7-6.4; p < .001). There were no statistically significant differences in intussusception risk according to the rotavirus vaccine dose and the polio vaccine (OPV or IPV) administered concomitantly.

Introduction: Rotavirus (RV) is the most common cause of acute gastroenteritis in children <5 years of age worldwide, and vaccination reduces the disease burden. Evidence from postmarketing surveillance studies suggested an increased risk of intussusception (IS) in infants post-RV vaccination. An overall positive benefit-risk balance for the human RV vaccine (HRV) Rotarix (GlaxoSmithKline [GSK], Belgium) has been established and recent findings indicate an indirect effect of reduced IS over the long term., Objective: The aim of this study was to discuss spontaneous data from the GSK worldwide safety database on IS post-Rotarix administration., Methods: The database was reviewed for all spontaneous IS cases from 2004 to 2020. Additionally, an observed versus expected (O/E) analysis was done for adverse events attributed to IS. Data were reviewed as overall worldwide and stratified by region (Europe/USA/Japan) and dose., Results: A male predominance of IS patients was observed, consistent with earlier reports. The most frequently reported events in confirmed IS cases (Brighton Collaboration Working Group [BCWG] level 1) with time to onset ≤ 30 days post-vaccination were vomiting (55.8%), haematochezia (47.2%), and crying (21.1%). The observations from the IS spontaneous cases review and results of the O/E analysis are consistent with the known IS safety profile of RV vaccines: a transient increased incidence of IS post-vaccination (primarily in Europe/Japan/worldwide), mostly within 7 days postdose 1., Conclusion: Since the outcomes of early IS management are favourable over delayed management, healthcare professionals should inform parents about the importance of seeking immediate medical advice in case of unusual behaviour of the vaccinated infant. GSK continues to monitor the IS risk post-Rotarix administration through routine pharmacovigilance activities., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

BACKGROUND Intussusception is a common phenomenon in children, but it is rare in adults. In the pediatric population, the presentation is commonly primary, without a lead point. However, up to 90% of intussusception cases arise due to a secondary cause - a pathological lead point - which the most common etiology in adults being malignancy. Herein, we present a case report of adult intussusception without a known cause. CASE REPORT A 26-year-old woman presented to the hospital with severe abdominal pain. She admitted to not passing stool or gas for 2 days. The patient's social history was significant for chronic marijuana use. A computed tomography (CT) scan of the abdomen revealed a 6-cm in length intussuscepted segment of bowel in the descending colon distal to the splenic flexure with no obvious inciting mass. The patient was sent for emergent open abdominal surgery. Upon surgical exploration, the surgeons discovered that the intussusception had self-resolved. Aside from a small ball of stool, an intraoperative colonoscopy revealed no masses or polyps. CONCLUSIONS Marijuana use is known to disrupt gastrointestinal (GI) mobility through receptors in the GI tract nerve plexuses. The incidence of chronic marijuana use and adult intussusception is documented in the literature. Conservative management with bowel rest is confirmed to be a suitable treatment option with a favorable outcome. Therefore, we present this case to increase awareness of the potential adverse effects of chronic marijuana use, and to prevent invasive treatment.

The World Health Organization (WHO) recommended the worldwide use of rotavirus vaccines initially in 2007 and 2009 applying a strict age restriction criterion due to the potential for age-related association with increased risk of intussusception in infants. The restriction was relaxed in the 2013 after detailed review of robust safety data generated in post-marketing surveillance studies. We assessed the status of the implementation of the 2013 recommendation to remove age restriction in the WHO African region (AFR). Of the approximately 75% (35/47) of countries that had introduced the vaccine by 2018, only 43% (15/35) removed age restriction, exclusively from South and East sub-region (78%, 14/18). Avoiding confusion at the health facilities and financial constraints particularly resources required for re-training the health workers, use of vaccine off-label were cited as the main reasons for not implementing the 2013 WHO recommendation on age restriction removal. The 2013 WHO recommendation has not been fully implemented by African countries, suggesting the need for technical advisory bodies to further guide the countries, continue monitoring the implementation status and impact on the rotavirus vaccine coverage and intussusception in the Africa region., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: In 2006 and 2008, two live, oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), were introduced into the routine immunization program in the United States. A previous rotavirus vaccine, RotaShield, was associated with an increased risk of intussusception, with data suggesting an age-dependent variation in risk. Advisory Committee on Immunization Practices (ACIP) currently recommends that RV5 or RV1 immunization be initiated by age 14 weeks and 6 days and completed by 8 months 0 days., Methods: We searched for U.S. VAERS reports of RV5, RV1, or unknown rotavirus vaccine brand among individuals aged ≥8 months. We analyzed reports by 2 age groups (individuals aged ≥8 months-≤5 years and ≥6 years), vaccine brand name, adverse event (AE) reported, classification of seriousness (death, non-death serious, and non-serious) and mode of exposure (direct vs. indirect exposure). For serious reports we reviewed available medical records and assigned a primary diagnosis., Results: VAERS received a total of 344 U.S. reports following rotavirus vaccination among individuals ≥8 months of age, 32 (9.3%) were serious. In the younger age-group, 307 (99%) of 309 reports followed direct vaccination of the child. In contrast, in individuals aged ≥6 years, 21 (60%) of 35 reports were via potential indirect exposure to a vaccinated child. The frequently reported AEs in the younger age-group were inappropriate schedule of drug administration 104 (34%) and drug administered to patient of inappropriate age 45 (15%); in the older group these were accidental exposure 9 (26%) and eye irritation 7 (20%). No difference in the safety profile was observed between RV1 and RV5., Conclusions: We did not identify any unexpected AEs for RV vaccines among individuals aged ≥8 months. Health care providers should adhere to the ACIP recommended schedule and older individuals should apply necessary precautions to prevent potential secondary exposure from vaccinated children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: An association between rotavirus vaccination and intussusception has been documented in post-licensure studies in some countries. We evaluated the risk of intussusception associated with monovalent rotavirus vaccine (Rotavac) administered at 6, 10 and 14 weeks of age in India., Methods: Active prospective surveillance for intussusception was conducted at 22 hospitals across 16 states from April 2016 through September 2017. Data on demography, clinical features and vaccination were documented. Age-adjusted relative incidence for 1-7, 8-21, and 1-21 days after rotavirus vaccination in children aged 28-364 days at intussusception onset was estimated using the self-controlled case-series (SCCS) method. Only Brighton Collaboration level 1 cases were included., Results: Out of 670 children aged 2-23 months with intussusception, 311 (46.4%) children were aged 28-364 days with confirmed vaccination status. Out of these, 52 intussusception cases with confirmed receipt of RVV were included in the SCCS analysis. No intussusception case was observed within 21 days of dose 1. Only one case occurred during 8-21 days after the dose 2. Post-dose 3, two cases in 1-7 days and 7 cases during 8-21 days period were observed. There was no increased risk of intussusception during 1-7 days after the doses 1 and 2 (zero cases observed) or dose 3 (relative incidence [RI], 1.71 [95% confidence interval {CI} 0.0-5.11]). Similarly, no increased risk during 8-21 days after the dose 1 (zero cases observed), dose 2 (RI, 0.71 [95% CI, 0.0-3.28]) or dose 3 (RI, 2.52 [95% CI, 0.78-5.61]). The results were similar for 1-21 day periods after the doses separately or pooled., Conclusions: The risk of intussusception during the first 21 days after any dose of rotavirus vaccine (Rotavac) was not higher among the Indian infants than the background risk, based on limited SCCS analysis of 52 children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rotavirus (RV) is one of the leading causes of severe childhood gastroenteritis in children <5 years of age. Several countries have successfully implemented vaccination against RV disease; however, hesitancy to include RV vaccination in the national immunization program exists and relates, among other reasons, to the results of international post-licensure studies of RV vaccines that established an increased risk of intussusception (IS) in infants following immunization. IS is one of the major causes of bowel obstruction in infants between 4 and 10 months of age. Some studies have investigated the etiology of IS, including the role of natural RV infection and available evidence suggests that RV disease may be an independent risk factor for IS. In this regard, the benefit-risk profile of RV vaccination, which is recognized as positive, could potentially turn out to be even more favorable in preventing IS cases triggered by RV disease. However, further research is prompted to quantify the IS risk attributable to RV disease.

Background: Since 2006, two rotavirus vaccines have been licensed in Taiwan, either as a 2- (RV1) or 3-dose (RV5) schedule administered at ages 2, 4, and 6 months. This study assessed the risk of intussusception and Kawasaki disease (KD) associated with rotavirus vaccines among infants., Methods: Cases of intussusception and KD in infants aged less than 365 days were identified from the National Health Insurance databases, from 1 January 2007 through 31 December 2014, using the first-ever ICD-9-CM diagnosis codes. Histories of rotavirus vaccination were obtained from the National Immunization Information System. The modified self-controlled case series design included vaccinated cases, and compared incidence rate ratios (IRRs) between the risk period (postvaccination days 1-21 [intussusception] or days 1-28 [KD]) and control period (ages 0-364 days outside the -14 to +21 [intussusception] or +28 [KD] days of vaccination) by each type and dose of vaccine. Conditional Poisson regression models were adjusted for age using age-in-week (7-day) categorization., Results: Overall 2064 intussusception cases and 2079 KD cases were diagnosed in 567,726 recipients (5313 [0.9%] received both RV5 and RV1). An increase in intussusception risk was observed in the 1-7 days (IRR 12.59, 95% confidence interval [CI] 8.07-19.66) and 8-21 days (IRR 1.78, 95% CI 1.00-3.16) post dose 1 of RV1, but not RV5. Risk of KD was higher during the third week post dose 2 of RV5 (IRR 2.33, 95% CI 1.35-4.00), and fourth week post dose 1 of RV1 (IRR 1.98, 95% CI 1.16-3.40)., Conclusion: Our finding of an increased risk of intussusception associated with RV1 in the first week after dose 1 is consistent with results of previous postlicensure studies. Further research should verify a potentially delayed risk of KD after rotavirus vaccination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: An increased risk of intussusception has been reported following rotavirus vaccination. We sought to determine whether introduction of rotavirus vaccination in England in July 2013 was associated with a change in the burden of total and age group-specific childhood hospital admissions for intussusception., Methods: We identified all children aged 0-36 months admitted to hospitals in England with intussusception using the Hospital Episode Statistics dataset. We performed a retrospective ecological analysis comparing hospital admission rates for intussusception during the periods before (2008/2009-2012/2013) and after (2014/2015-2017/2018) introduction of rotavirus vaccination using modified Poisson regression and interrupted time series analysis. Length of hospital stay and clinical outcomes were also examined., Results: The mean annual admission rate for intussusception in infants over the ten-year study period was 31.5 per 100,000 person-years. An increase in the admission rate in the 8-16 weeks age group (RR 1.46, 95% CI 1.12-1.91), those receiving vaccination, was compensated for by decreases in the 17-24 weeks (RR 0.77, 0.63-0.94), 25-32 weeks (RR 0.71, 0.59-0.86) and 41-52 weeks (RR 0.80, 0.66-0.98) age groups. Using interrupted time series analysis, we observed a significant decrease in incidence in the 0-12 months age group (RR 0.80, 0.67-0.96), but not in the overall 0-36 months age group (RR 1.09, 0.98-1.20). There was no significant change in the proportion of children requiring surgical intervention or with major complications of intussusception. Length of hospital stay decreased among infants receiving surgery for intussusception., Conclusions: Our results suggest that introduction of rotavirus vaccination in England has resulted in a downward shift in the age at which intussusception occurs in infants, with no overall increase in hospital admission rate or disease severity. These findings support the view that the benefits of rotavirus vaccination outweigh the small increased risk of intussusception in the early post-vaccination period., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Pre-licensure trials of ROTAVAC® were not adequately powered to assess risk of intussusception, a rare adverse event associated with other rotavirus vaccines in some settings. We examined the risk of intussusception after ROTAVAC® vaccination among Indian infants during pilot rollout of the vaccine in the public health system in three states - Himachal Pradesh, Maharashtra and Tamil Nadu., Methods: Passive surveillance for intussusception was set up in 35 sentinel health facilities covering 26.3 million population in the three states under monitoring of an Interministerial-Interagency Steering Committee. Clinical and immunization data were collected by independent teams. An expert committee blinded to vaccination status, classified intussusception cases using Brighton criteria. The self-controlled case-series method was used to estimate risk of intussusception (Brighton Level 1) after ROTAVAC® vaccination., Results: 151 intussusception cases were included in the analysis. The relative incidence (incidence during the risk period compared to the control period) 1-21 days after doses 1 and 2 combined was 1.56 (95% CI, 0.0-5.28) and that for three doses combined was 1.88 (95% CI, 0.76-4.30). Attributable risk 1-21 days after doses 1 and 2 combined was 0.11 (95% CI, 0.0-0.25) and that for 3 doses combined was 0.42 (95% CI, 0.0-0.70) per 100,000 doses., Conclusions: No increased risk of intussusception within 21 days of receipt of the first two doses combined or all 3 doses combined of ROTAVAC® was detected., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Postlicensure studies have shown an association between rotavirus vaccination and intussusception. We assessed the risk of intussusception associated with Rotarix (RV1) administration, at 6 and 14 weeks of age, in an upper-middle-income country, South Africa., Methods: Active prospective surveillance for intussusception was conducted in 8 hospitals from September 2013 through December 2017. Retrospective case enrollment was done at 1 hospital from July 2012 through August 2013. Demographic characteristics, symptom onset, and rotavirus vaccine status were ascertained. Using the self-controlled case-series method, we estimated age-adjusted incidence rate ratios within 1-7, 8-21, and 1-21 days of rotavirus vaccination in children aged 28-275 days at onset of symptoms. In addition, age-matched controls were enrolled for a subset of cases (n = 169), and a secondary analysis was performed., Results: Three hundred forty-six cases were included in the case-series analysis. Post-dose 1, there were zero intussusception cases within 1-7 days, and 5 cases within 8-21 days of vaccination. Post-dose 2, 15 cases occurred within 1-7 days, and 18 cases within 8-21 days of vaccination. There was no increased risk of intussusception 1-7 days after dose 1 (no cases observed) or dose 2 (relative incidence [RI], 1.71 [95% confidence interval {CI} .83-3.01]). Similarly, there was no increased risk 8-21 days after the first (RI, 4.01 [95% CI, .87-10.56]) or second dose (RI, .96 [95% CI, .52-1.60]). Results were similar for the case-control analysis., Conclusions: The risk of intussusception in the 21 days after the first or second dose of RV1 was not higher than the background risk among South Africa infants., Clinical Trials Registration: South African National Clinical Trial Register (DOH-27-0913-4183)., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose-effect on AEs., Methods: A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception., Results: Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose-effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported., Conclusions: IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

Objective: The objective of the present study was to investigate the risk factors for intussusception (IS) among infants, including vaccination against rotavirus., Methods: Case-control study with systematic inclusion of all infants aged <1 year with suspected IS admitted to emergency departments in the eastern region of France between 1 April 2008 and 31 March 2012. All cases classed level 1 according to the Brighton classification were matched to 4 hospital controls. Two exposure windows were examined; exposure to the first dose of rotavirus vaccine in the 7 and in the 14 days prior to the occurrence of IS., Results: A total of 115 cases were matched with 457 controls. The average vaccination coverage rate over the 4 years of study was 8.6%. Rotavirus vaccine was not found to be significantly associated with the occurrence of IS in the 7 days (odds ratio (OR) not calculated; p = 0.99) and in the 14 days after administration of one dose vaccine (OR 1.33, 95% confidence interval (CI) 0.14-12.82). Infant formula alone or combined with breastfeeding was associated with an excess risk of IS (OR 2.74, 95% CI 1.10-6.79). A history of gastroenteritis within 2 weeks prior to hospitalisation was also associated with an increased risk (OR 2.24, 95% CI 1.07-4.67)., Conclusion: Our study indicates that infant formula alone or combined with breastfeeding is a risk factor for IS. A small, non-significant increase in the risk of IS was observed after rotavirus vaccination, although the low vaccine coverage rate likely precluded detection of a significant increase in risk., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

As part of a regulatory commitment for post-licensure safety monitoring of live, oral human rotavirus vaccine (RV1), this study compared the incidence rates (IR) of intussusception, acute lower respiratory tract infection (LRTI) hospitalization, Kawasaki disease, convulsion, and mortality in RV1 recipients versus inactivated poliovirus vaccine (IPV) recipients in concurrent (cIPV) and recent historical (hIPV) comparison cohorts. Vaccine recipients were identified in 2 claims databases from August 2008 - June 2013 (RV1 and cIPV) and January 2004 - July 2008 (hIPV). Outcomes were identified in the 0-59 days following the first 2 vaccine doses. Intussusception, Kawasaki disease, and convulsion were confirmed via medical record review. Outcome IRs were estimated. Incidence rate ratios (IRRs) were obtained from Poisson regression models. A post-hoc self-controlled case series (SCCS) analysis compared convulsion IRs in a 0-7 day post-vaccination period to a 15-30 day post-vaccination period. We identified 57,931 RV1, 173,384 cIPV, and 159,344 hIPV recipients. No increased risks for intussusception, LRTI, Kawasaki disease, or mortality were observed. The convulsion IRRs were elevated following RV1 Dose 1 (cIPV: 2.07, 95% confidence interval [CI]: 1.27 - 3.38; hIPV: 2.05, 95% CI: 1.24 - 3.38), a finding which is inconclusive as it was observed in only one of the claims databases. The IRR following RV1 Dose 1 in the SCCS analysis lacked precision (2.40, 95% CI: 0.73 - 7.86). No increased convulsion risk was observed following RV1 Dose 2. Overall, this study supports the favorable safety profile of RV1. Continued monitoring for safety signals through routine surveillance is needed to ensure vaccine safety.

IntroductionTwo vaccines available for protection against rotavirus gastroenteritis (RVGE), Rotarix and RotaTeq, have contributed to a large decrease in the incidence of paediatric diarrhoea in countries where they have been used. However, they have also led to a small increase in the risk of intussusception. Methods: We compare the number of prevented hospitalisations for RVGE to the number of vaccine-induced hospitalised intussusceptions in France. Results: With 9.5% coverage (French 2015 estimation), vaccination was estimated to prevent, annually, a median of 1,074 hospitalisations (2.5th and 97.5th percentiles (2.5th-97.5th): 810-1,378) and 1.4 deaths (2.5th-97.5th: 1.2-1.6) from RVGE. It was also estimated to cause, annually, 5.0 hospitalisations (2.5th-97.5th: 3.2-7.7) and 0.005 deaths (2.5th-97.5th: 0.001-0.015) from intussusception. The benefit-risk ratio is therefore 214 (2.5th-97.5th: 128-362) for hospitalisations and 273 (2.5th-97.5th: 89-1,228) for deaths. Under a hypothetical 92% coverage, rotavirus vaccination with Rotarix would avoid 10,459 (2.5th-97.5th: 7,702-13,498) hospitalisations for RVGE and induce 47.0 (2.5th-97.5th: 25.1-81.4) hospitalisations for intussusception annually, thereby preventing 13.7 (2.5th-97.5th: 11.1-15.2) deaths and inducing 0.05 (2.5th-97.5th: 0.01-0.15) deaths. Conclusion: The benefit-risk ratio in France is similar to that of other European countries.

A 48-year-old man noticed nausea and took health examination. After chest X-ray and gastrointestinal barium study was underwent, he was referred to our hospital because of abnormal shadow in the chest X-ray. CT scan revealed about 4 cm tumor in the hilum of left lung and target sign in the small intestine. He was diagnosed with intussusception and emergency operation was performed. During the laparotomy, we found 2 intussusceptions in the small intestine and we performed manual reduction using Hutchinson's maneuver. We confirmed the mass in oral side of the intussusception site but we did not confirmed any tumor in anal of the intussusception. This suggests the intussusception was caused by barium. Finally 3 small intestine tumor was observed and we resected and reconstructed each of the tumor. Histopathological examination showed small intestinal metastasis from pleomorphic carcinoma of the lung.

The 9th African rotavirus symposium was held in Maputo, Mozambique from the 8th to 10th of December 2015, including a total of 101 delegates from 17 countries, 15 of which were African countries. This forum brought together participants with various expertise including scientists, clinicians, immunization program managers, public health officials and policymakers. By the time of the symposium, 29/47 (61%) of countries in the World Health Organization (WHO) African Region had introduced rotavirus vaccine into their routine immunization program. Countries that had started monitoring impact and effectiveness of the rotavirus vaccines as well as potential adverse events following immunization (AEFI) including intussusception) also participated. Seven Rotarix® vaccine-using countries and another four countries that are using the Rotateq® vaccine are conducting systematic surveillance on intussusception and report data to the WHO and partners. The symposium concluded that the regional rotavirus surveillance network has played a crucial role in pre-vaccine data through documenting burden and epidemiology of rotavirus diarrhea in Africa, seasonal trends and identifying common rotavirus genotypes. The sentinel surveillance platform is now being used to assess the impact of the vaccines and monitoring adverse events with a focus on intussusception., (Copyright © 2017.)

Background: Intussusception has been identified as a rare adverse event following rotavirus immunization. We sought to determine the incidence of intussusception among infants in Canada both before and after introduction of rotavirus immunization programs., Methods: We used Canadian Institute for Health Information (CIHI) Discharge Abstract Database (DAD) to identify infants under 1 y of age who were admitted to a Canadian hospital, which the exception of Quebec, which does not submit data to CIHI, with a diagnosis of intussusception (ICD-10 code K56.1, and ICD-9 code 560) between January 1st, 2003 and December 31, 2013. We compared rates of intussusception hospitalization before and after rotavirus vaccine program introduction. Rates were adjusted for calendar year, age (in months), sex and region using Poisson regression models. Denominator data for infants under 1 year, stratified by age in months, were obtained from Statistics Canada., Results: Annual intussusception hospitalization rates ranged from 20-30 per 100,000 infants over the study period, with no evidence of a trend over time. Intussusception hospitalization rates were highest in infants 4 to <8 months and lowest in those under 2 months or between 10 and <12 months. Males had higher rates than females both overall and within each age group. The rate of intussusception hospitalization after rotavirus vaccine program introduction was 22.4 (95% CI: 18.3, 27.4) compared to 23.4 (95% CI: 21.5, 25.4) per 100,000 before program introduction., Conclusions: We have described baseline intussusception hospitalization rates for infants in Canada and have found no evidence of a change in rate after implementation of routine rotavirus immunization programs.

Objective: To study the case series for intussusception associated with the vaccination of rotavirus vaccine in children., Methods: The study of spontaneous adverse event monitoring such as intussusception due to rotavirus vaccine was carried out from the year 2011 through 2015. The individual case safety reports (ICSRs) of this event were collated, assessed and recorded as per the requirement of Suspected Adverse Drug Reactions Reporting form of Pharmacovigilance Programme of India (PvPI)., Results: In the present study, 10 ICSRs of intussussception due to rotavirus vaccine were reported to PvPI. Of which 3 ICSRs were found to be causal relationship with rotavirus vaccine, as evidenced by the adequate information provided in ICSRs., Conclusions: Since intussusception, the emerging safety as one of the important safety concern, healthcare professionals are advised to monitor and report to the concerned authority for appropriate action.

Rotavirus vaccines have demonstrated significant impact in reducing the burden of morbidity and mortality from childhood diarrhoea in countries that have implemented routine vaccination to date. Despite this success, in many countries, rotavirus vaccine coverage remains lower than that of other routine childhood vaccines. Several issues may potentially affect vaccine uptake, namely safety concerns related to intussusception with consequent age restrictions on rotavirus vaccination, contamination with porcine circovirus, vaccine-derived reassortant strains and hospitalization in newborn nurseries at time of administration of live oral rotavirus vaccine. In addition to these safety concerns, other factors may also affect uptake, including lower vaccine efficacy in the developing world, potential emergence of strains escaping from vaccine protection resulting in lower overall impact of a vaccination programme and sustainable vaccine financing. Although further work is needed to address some of these concerns, global policy bodies have reaffirmed that the benefits of rotavirus vaccination outweigh the risks, and vaccine use is recommended globally., (Published by Elsevier Ltd.)

In May 2016 we published in the journal Human Vaccines and Immunotherapy. 1 79 80 the case-report "Post-rotavirus vaccine intussusception in identical twins: a case report." We received a reply letter from "Sicilian Public Health Authorities" that placed attention to some points of our work. We would like to do some clarifications.

As a results of the case report "Post-rotavirus vaccine intussusception in identical twins: a case report" recently published on Human Vaccines & Immunotherapy by La Rosa et al., the principal Sicilian Public Health Authorities decided to specify several points and underline some important details omitted by the authors. In particular, aims to underline the remarkable benefit for Sicilian Regional Health service after the introduction of the rotavirus vaccination. Universal mass vaccination against rotavirus is properly managed by the Regional Health Authorities and is contributing to a consistent increase of public health in the Sicilian pediatric population; any modification of such a program should be based on robust scientific evidences. Finally, a single case report should not be considered as a basis to recommend a change in the clinical practice but instead a possible point of start for discussion and research.

As of January 2016, 80 countries have introduced rotavirus vaccines into their national immunization programs. Many have documented significant declines in rotavirus-specific and all-cause diarrheal illnesses following vaccine introduction. Two globally licensed rotavirus vaccines have been associated with a low risk of intussusception in several studies. In July 2014, the Rotavirus Organization of Technical Allies Council convened a meeting of research and advocacy organizations, public health experts, funders, and vaccine manufacturers to discuss post-marketing intussusception surveillance and rotavirus vaccine impact data. Meeting objectives were to evaluate updated data, identify and prioritize research gaps, discuss best practices for intussusception monitoring in lower-income settings and risk communication, and provide insight to country-level stakeholders on best practices for intussusception monitoring and communication. Meeting participants agreed with statements from expert bodies that the benefits of vaccination with currently available rotavirus vaccines outweigh the low risk of vaccination-associated intussusception. However, further research is needed to better understand the relationship of intussusception to wild-type rotavirus and rotavirus vaccines and delineate potential etiologies and mechanisms of intussusception. Additionally, evidence from research and post-licensure evaluations should be presented with evidence of the benefits of vaccination to best inform policymakers deciding on vaccine introduction or vaccination program sustainability.

The intussusception is one of the most frequent causes of occlusive syndrome in infants and in children. (1) The mesenteric lymphadenopathy, wich is very rare post rotavirus vaccination, can cause intussusception, (2-5) especially in genetically predisposed individuals. (6) There is an association between intussusception and some classes of genotype. (7-9) Two infants aged 3 months, vaccinated against rotavirus. After about a week, one of the 2 identical infants presented inconsolable crying, vomiting, loose stools mixed with blood, and was diagnosed with bowel obstruction with intussusception. He was operated in urgency. After a few hours, his brother presented vomiting, and was admitted to our Hospital for suspected intussusception. The controls carried out have confirmed the presence of intussusception that was treated early, before the onset of severe symptoms. The incidence of post rotavirus vaccine intussusception is very low. The determining factor hypothetically might be linked to the presence of a genotype that exposes infants to a greater risk of developing mesenteric lymphadenitis and intussusception. In our case, the diagnosis of intussusception occurred in a twin, which allowed us to recognize early symptoms which accused the brother and schedule the surgery with less urgency. Our experience may want to sensitize families and pediatricians to report cases of intussusception given a theoretical familiar association. The study of the genotype could be decisive for or not to exclude the presence of a risk of invagination, thus avoiding vaccination.

Objective: To assess feasibility of monitoring intussusception by hospitals participating in the National Rotavirus Surveillance Network., Methods: Questionnaire-based survey in 28 hospitals. One hospital with electronic records selected for detailed data analysis., Results: There was 75% response to the questionnaire. Few network hospitals were suitable for monitoring intussusception in addition to ongoing activities, but there was at least one potential sentinel hospital in each region. The hospital selected for detailed data analysis of cases of intussusception reported an incidence rate of 112 per 100,000 child years in infants. Over 90% of intussusceptions were managed without surgery., Conclusions: Selection of sentinel hospitals for intussusception surveillance is feasible and necessary, but will require training, increased awareness and referral.

Objectives: To assess the quality of national Hospital Episode Statistics (HES) data for intussusception, and evaluate this routinely collected database for rotavirus vaccine safety surveillance by estimating pre-vaccination trends in intussusception hospitalisation., Methods: Data linkage was performed between HES and prospective intussusception data from the British Paediatric Surveillance Unit (BPSU), followed by capture-recapture analysis to verify HES data quality. Inclusion criteria were infants aged less than 12 months and admitted for intussusception to National Health Service (NHS) hospitals in England from March 2008 to March 2009. To estimate pre-vaccination incidence rates of intussusception, we performed a retrospective analysis of HES data. Infants aged less than 12 months and admitted for intussusception to NHS hospitals in England between 1995 and 2009 were included., Results: Data linkage between 254 cases of intussusception identified in HES data and 190 cases reported via the BPSU resulted in 163 cases common to both data sources. Of remaining 91 cases in HES, 37 had confirmed intussusception. HES data accuracy was 78.7% (200 confirmed/254 cases) and completeness for intussusception was 86% (163 matched/190 BPSU cases) compared to 81.5% (163 matched/200 HES cases) for BPSU. A total of 233 (95% CI: 227.4 to 238.8) intussusception cases were estimated for the infant population (2008 to 2009). For retrospective analysis, of 6462 intussusception admissions in HES data (1995 to 2009), 1594 (24.7%) were duplicate admissions. A declining trend in intussusception incidence was observed in the infant population, from 86/100,000 in 1997 to 34/100,000 in 2009 (60% reduction, P<0.001). Cosinor modelling showed an excess of cases among infants in winter and spring (P<0.001, n=4957, 1995 to 2009)., Conclusion: National hospital data capture the majority of admissions for intussusception and should be considered for the post-implementation surveillance of rotavirus vaccine safety in England., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In 1999, the first rhesus-human reassortant rotavirus vaccine licensed in the U.S. was withdrawn within a year of its introduction after it was linked with intussusception at a rate of ~1 excess case per 10,000 vaccinated infants. While clinical trials of 60,000-70,000 infants of each of the two current live oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), did not find an association with intussusception, post-licensure studies have documented a risk in several high and middle income countries, at a rate of ~1-6 excess cases per 100,000 vaccinated infants. However, considering this low risk against the large health benefits of vaccination that have been observed in many countries, including in countries with a documented vaccine-associated intussusception risk, policy makers and health organizations around the world continue to support the routine use of RV1 and RV5 in national infant immunization programs. Because the risk and benefit data from affluent settings may not be directly applicable to developing countries, further characterization of any associated intussusception risk following rotavirus vaccination as well as the health benefits of vaccination is desirable for low income settings., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In 2006 and 2008, two new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States. US data on intussusception have been mostly related to RV5, with limited data on RV1., Methods: We assessed intussusception events following RV1 reported to the Vaccine Adverse Event Reporting System (VAERS), a US national passive surveillance system, during February 2008-December 2014. We conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception after the first 2 doses of RV1 comparing average daily reports 3-6 versus 0-2 days after vaccination. We calculated the excess risk of intussusception per 100,000 vaccinations based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates., Results: VAERS received 108 confirmed insusceptible reports after RV1. A significant clustering was observed on days 3-8 after does1 (p=0.001) and days 2-7 after dose 2 (p=0.001). The DRR comparing the 3-6 day and the 0-2 day periods after RV1 dose 1 was 7.5 (95% CI=2.3, 24.6), translating to an excess risk of 1.6 (95% CI=0.3, 5.8) per 100,000 vaccinations. The DRR was elevated but not significant after dose 2 (2.4 [95% CI=0.8,7.5]). The excess risk ranged from 1.2 to 2.8 per 100,000 in sensitivity analysis., Conclusions: We observed a significant increased risk of intussusception 3-6 days after dose 1 of RV1. The estimated small number of intussusception cases attributable to RV1 is outweighed by the benefits of rotavirus vaccination., (Published by Elsevier Ltd.)

By January 2015, rotavirus vaccination had been implemented in national vaccination programmes in 75 countries worldwide. Two live oral rotavirus vaccines are internationally available: human, monovalent vaccine and human-bovine pentavalent reassortant vaccine. Since January 2014, another live, oral human-bovine monovalent vaccine has been available in India. After implementation of rotavirus vaccines in childhood immunization programmes, there has been an over 90% reduction of rotavirus hospitalizations in industrialized and resource-deprived countries. Additionally, in Latin America, significant reduction of rotavirus-associated deaths has been recorded. Still, numerous countries do not recommend rotavirus mass vaccination because of assumed lack of cost-effectiveness and potential risk of intussusception, which is estimated at 1 per 50 000-70 000 doses of rotavirus vaccines. Cost-effectiveness of vaccination is affected in some countries by high price. Inclusion of herd protection and indirect costs in calculations for cost-effectiveness results in clear benefit: costs saved by health systems due to reduced rotavirus gastroenteritis hospitalizations far exceed the costs for implementation of rotavirus vaccination. There have been objections that high rotavirus vaccination coverage could put selective pressure on certain rotavirus strains against which protection after vaccination is less distinct. However, data now strongly suggest that even if there might be a relative increase of some specific genotypes after the use of rotavirus vaccines, this is not an absolute increase in incidence from certain genotypes and does not affect the overall effectiveness of rotavirus mass vaccination, which resulted in a major decrease of severe cases of rotavirus gastroenteritis in both industrialized and resource deprived countries., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

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.

Purpose: Rotarix(TM) was launched in November 2011 in Japan to prevent rotavirus gastroenteritis. Some studies suggest that Rotarix(TM) may have a temporal association with a risk of intussusception (IS). We assessed a possible association between IS and Rotarix(TM) vaccination in Japan., Methods: All IS cases spontaneously reported post-vaccination (Brighton collaboration levels 1, 2, and 3) were extracted from the GlaxoSmithKline spontaneous report database on the 11th of January 2013. Expected numbers of IS cases were estimated using the number of vaccine doses distributed and the Japanese incidence rate of IS stratified by month of age. The observed versus expected analysis considered the IS cases for each risk period (7 and 30 days post-vaccination) and for each vaccine dose (two doses)., Results: Before January 2013, approximately 601 000 Rotarix(TM) doses were distributed in Japan. For a risk period of 7 days post-dose 1 and post-dose 2, 10 and five IS cases were observed, whereas 3.4 and 7.6 were expected, providing an observed-to-expected ratio of 2.96 (95% confidence interval [CI]: 1.42; 5.45) and 0.66 (95% CI: 0.21; 1.53), respectively. For a risk period of 30 days post-dose 1 and post-dose 2, 14 and eight cases were observed, whereas 14.5 and 32.7 were expected, providing an observed-to-expected ratio of 0.97 (95% CI: 0.53; 1.62) and 0.24 (95% CI: 0.11; 0.48), respectively., Conclusion: A statistically significant excess of IS cases was observed within 7 days post-dose 1, but not post-dose 2. These results are consistent with previous observations in large post-marketing safety studies in other world regions., (© 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.)

Background: The new rotavirus vaccines RV5 and RV1 have been associated with small increase in intussusception risk in active vaccine surveillance studies. It is unclear what the impact might be on the overall trends of intussusception hospitalizations at a large population basis., Methods: We conducted an ecological study of hospital discharges of infants with intussusception discharge diagnosis using the California Office of Statewide Health Planning and Development database (1985-2010). We measured incidence rates (IR) of intussusception hospitalizations per 100,000 births within 3 periods (1985-1997; 2000-2005; 2006-2010) related to past, pre-introduction and post-introduction of the new rotavirus vaccines. We estimated slopes of yearly IRs within each period, changes in slopes between periods and IR ratios (IRR) of the mean IRs between periods. We did subgroup analyses for 5 age-subgroups. We also analyzed intussusception hospitalizations of infants who also had a surgical repair and/or radiologic reduction procedure code (restricted cohort)., Results: We identified 6241 intussusception hospitalizations; 4696 also had pertinent procedure codes. There was an upward trend in yearly IRs during 2006-2010 (+2 excess cases per 100,000 births per year; P = 0.023); the change in slopes between 2006-2010 and 2000-2005 was +3.2 excess cases per 100,000 births per year (P = 0.052), and the IR in 2006-2010 was 10% higher than in 2000-2005 (IRR: 1.10; 95% confidence intervals: 1.01-1.19). The IRR in 2006-2010 versus 2000-2005 for the 6-14 weeks age-subgroup was 1.90 (95% confidence intervals: 1.33-2.74). In the restricted cohort, trends were similar, though not nominally significant., Conclusions: We documented at a population-level a small increased risk in intussusception hospitalizations post-introduction of the new rotavirus vaccines.

The first evidence-based recommendations for rotavirus (RV) vaccination in Europe were prepared at the time of licensure of 2 live oral RV vaccines (Rotarix, GlaxoSmithKline Biologicals, and RotaTeq, Sanofi Pasteur MSD) in 2006 and published in 2008. Since then several countries in Europe and more globally have adopted universal RV vaccination of all healthy infants as part of their national immunization programs (NIPs). The experience from these NIPs has produced a wealth of post-introduction effectiveness data that, together with the evidence from prelicensure efficacy trials presented in the 2008 Recommendations, support the case of RV vaccination in Europe. The prelicensure safety trials of Rotarix and RotaTeq, each in populations of more than 60,000 infants, did not reveal risk of intussusception (IS), but postvaccination surveillance in several countries, particularly Australia and Mexico, has established that the risk of IS for both vaccines after the first dose might be between 1:50,000 and 1:80,000. Although it may be argued that the risk is acceptable vis-à-vis the great benefits of RV vaccination, this argument alone may not suffice, and every effort should be made to reduce the risk of IS. Considerable evidence, including postvaccination surveillance data from Germany, suggests that the risk of IS can be reduced by early administration of the first dose of oral RV vaccine. The previous European Society for Paediatric Infectious Diseases/European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommendations held that the first dose of oral RV vaccine should be given between 6 and 12 weeks of age; this recommendation is sustained but with an emphasis toward the lower range of the recommended age, that is, preferably between 6 and 8 weeks of age. At the time of the earlier recommendations, experience of RV vaccination in premature infants and other special target groups was limited. It is now recommended with greater confidence than before that prematurely born infants should be vaccinated according to their calendar age as recommended for full-term infants. It is now strongly recommended that all HIV-infected or HIV-exposed infants should be vaccinated with oral RV vaccine. Although specific information on many immunodeficiencies is lacking, infants with known severe combined immunodeficiency should not receive live RV vaccine.

Objectives: This study aimed to assess the association between the appearance of intussusception in children and medication intake in the immediately preceding period (2-15 days)., Methods: A case-crossover design was used. We selected cases of children admitted with a diagnosis of intussusception (International Classification of Diseases, Ninth Revision, 860) to the major hospitals in the city of Valencia, Spain, from 2006 to 2009. We then estimated the association between the episode of intussusception and the intake of prescription medication during the preceding 2, 7, and 15 days (case period) and for the same time window 1, 2, 3, and 4 months prior (control period). Data on previous drug administration were obtained from the Pharmaceutical Service Manager System., Results: A total of 95 cases (65.3% boys and 34.7% girls) were selected; 76.6% were younger than the age of 2 years. The association between intussusception and prior drug use varied depending on the exposure window: 15-day odds ratio (OR), 1.45 (95% confidence interval [95% CI], 0.86-2.43); 7-day OR, 1.46 (95% CI, 0.80-2.67); and 2-day OR, 2.26 (95% CI, 1.10-4.64). These associations were greater for children aged younger than 2 years and were usually due to the recent administration (preceding 2 days) of antibiotics (OR, 8.00; 95% CI, 1.47-43.7)., Conclusions: Intussusception was more common among boys aged younger than 2 years. A positive and significant association was observed when drugs were administered 2 to 7 days before the onset of symptoms in children younger than the age of 2 years.

In 1999, the first rotavirus vaccine licensed in the USA was withdrawn 9 months after introduction due to an association with intussusception that was detected in post-licensure surveillance. This association prompted large clinical trials designed to ensure the safety of two current live oral rotavirus vaccines, RotaTeq and Rotarix, which have since been recommended for use worldwide. Following their introduction, post-licensure studies have focused not only on the effectiveness and impact of these vaccines, but also on continued surveillance for intussusception. Most recent evidence from several countries shows a small increased risk of intussusception following vaccination with Rotarix and RotaTeq within the context of their demonstrated benefits. This review summarizes the available data on the safety of rotavirus vaccines with regards to intussusception.

Background: Although rotavirus (RV) vaccination was licensed in 2006, it was not included into the officially recommended German childhood vaccination schedule until 2013. Local differences in health policies in the past led to large differences in vaccination coverage rate among the federal states of Germany. This enables an ecologic study of RV vaccine effectiveness., Methods: We performed a population-based retrospective analysis of RV vaccination use, RV notification and hospitalization among 0 to 5-year-old children in Germany during 2006 to 2011/2012. We compared effectiveness of the 2 RV vaccines, Rotateq and Rotarix, in an ambulatory setting and analyzed potential side effects., Results: We observed a significant reduction in RV notifications since introduction of RV vaccination. In areas attaining vaccine coverage of 64%, RV-related hospital admissions of 0 and 1-year-old children decreased by 60% compared with 19% reduction in the low vaccination coverage area. Decrease in RV-related hospitalizations of 0 and 1-year-old children was specific and significantly associated with vaccination coverage of the individual federal state (P < 0.0001, r = -0.68). There was no overall increase in intussusception rate or Kawasaki disease-related hospital admissions since introduction of RV vaccination. The 2 licensed RV vaccines had similar effectiveness in the ambulatory setting., Conclusions: Postmarketing data suggest that RV vaccination is efficient in reducing RV-related hospitalizations. There is no apparent difference in effectiveness for Rotarix and Rotateq.

Unlabelled: Rotavirus gastroenteritis is one of the leading causes of diarrhea in Indian children less than 2 years of age. The 116E rotavirus strain was developed as part of the Indo-US Vaccine Action Program and has undergone efficacy trials. This paper reports the efficacy and additional safety data in children up to 2 years of age. In a double-blind placebo controlled multicenter trial, 6799 infants aged 6-7 weeks were randomized to receive three doses of an oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6, 10, and 14 weeks. The primary outcome was severe (≥11 on the Vesikari scale) rotavirus gastroenteritis. Efficacy outcomes and adverse events were ascertained through active surveillance. We randomly assigned 4532 and 2267 subjects to receive vaccine and placebo, respectively, with over 96% subjects receiving all three doses of the vaccine or placebo. The per protocol analyses included 4354 subjects in the vaccine and 2187 subjects in the placebo group. The overall incidence of severe RVGE per 100 person years was 1.3 in the vaccine group and 2.9 in the placebo recipients. Vaccine efficacy against severe rotavirus gastroenteritis in children up to 2 years of age was 55.1% (95% CI 39.9 to 66.4; p<0.0001); vaccine efficacy in the second year of life of 48.9% (95% CI 17.4 to 68.4; p=0.0056) was only marginally less than in the first year of life [56.3% (95% CI 36.7 to 69.9; p<0.0001)]. The number of infants needed to be immunized to prevent one episode of severe RVGE in the first 2 years of life was 40 (95% CI 28.0 to 63.0) and for RVGE of any severity, it was 21 (95% CI 16.0 to 32.0). Serious adverse events were observed at the same rates in the two groups. None of the eight intussusception events occurred within 30 days of a vaccine dose and all were reported only after the third dose. The sustained efficacy of the 116E in the second year of life is reassuring., Clinical Trial Registry: The trial is registered with Clinical Trial Registry-India (# CTRI/2010/091/000102) and Clinicaltrials.gov (# NCT01305109)., (Copyright © 2014. Published by Elsevier Ltd.)

Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca(2+) analog MnCl2. At 6 or 2 h after administration of LPS or MnCl2, respectively, mice underwent image analysis to assess intestinal contraction rate or laparotomy to identify ISS. LPS-induced ISS (LPS-ISS) was observed in BALB/c mice, but not in C57BL/6 mice or any BALB/c mice with disruptions of TLR4 signaling. LPS-induced serum TNF-α, IL-6, and nitric oxide (NO) and intestinal NO levels were similar in BALB/c and C57BL/6 mice. The rate of LPS-ISS was significantly reduced in phagocyte-depleted, but not lymphocyte-deficient, mice. Intestinal contraction rates were reduced in LPS-ISS-susceptible BALB/c mice, but not in LPS-ISS-resistant C57BL/6 or TLR4 mutant mice, suggesting a role for reduced intestinal contraction rate in LPS-ISS susceptibility. This was tested with MnCl2, a Ca(2+) antagonist that reduced intestinal contraction rates and induced ISS, irrespective of mouse strain. Therefore, LPS-ISS is initiated by innate immune signaling that requires TLR4 and phagocytes but may be independent of TNF-α, IL-6, and NO levels. Furthermore, alteration of intestinal motility, specifically, reduced intestinal contraction rate, is a key factor in the development of ISS.

Background: Intussusception, a rare adverse event associated with rotavirus vaccines in some settings, is a common cause of intestinal obstruction in infants and toddlers globally with a peak age of 4-6 months. This age group may overlap with the extended age of administering rotavirus vaccine., Methods: A retrospective (January 2007 to June 2009) and prospective (July 2009 to June 2012) survey was conducted in 9 Zambian hospitals. Children between 0 and 24 months who were operated on for intestinal obstruction/intussusception were identified in theatre log books. In the latter part of the survey, patients were recruited prospectively. Demographic, clinical and surgical data from hospital files were collected for each patient., Results: One-hundred and five children were identified to have undergone surgery for intussusceptions. Many were boys 57.6% (57/99). Of those with complete data, intussusception was common in infants 86.9% (86/99) and many children (68.0%) were between 3 and 8 months of age with a peak age of 5-6 months. Lusaka had the highest number of children with intussusception with an estimated annual incidence rate of 12/100,000 in children <2 years of age. The overall case fatality rate was very high 33.7% (31/92)., Conclusion: Intussusception was common in infants with a peak age of 5-6 months, and of particular concern is the group of 2-4 months the age of rotavirus vaccination. The estimated incidence rate of 12/100,000 is an underestimate as many cases may not present for care. The high case fatality rate of 33.7% is due to both delayed presentation and diagnosis in hospital.