Intussusception and Rotavirus
Intussusception and Rotavirus
Title Page
Title:
Authors:
Yoshitomo Motomura3 , Makoto Hayashida1 , Shouichi Ohga3 , Tatsuro Tajiri1 , Toshiro Hara4
* Correspondence Author.
Affiliation:
Fukuoka, Japan.
Japan.
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/ped.15332
This article is protected by copyright. All rights reserved.
Address for Correspondence:
E-mail: [email protected]
Number of
Tables: 1
Figures: 3
Legends to figures: 1
Author Information:
813-0017, Japan.
E-mail: [email protected]
Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
E-mail: [email protected]
Toshiharu Matsuura, MD, PhD.
Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
E-mail: [email protected]
813-0017, Japan.
E-mail: [email protected]
E-Mail: [email protected]
813-0017, Japan.
E-mail: [email protected]
E-Mail: [email protected]
Tatsuro Tajiri, MD, PhD.
Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
E-mail: [email protected]
Fukuoka College of Health Sciences, 2-15-1 Tamura, Sawara-ku, Fukuoka, 814-0193, Japan
E-mail: [email protected]
Disclosure:
The authors declare no conflicts of interest in association with the present study.
Abstract:
Background: In November 2011, rotavirus (RV) vaccine was launched in Japan as a voluntar y
Methods: We investigated intussusception patients <16 years old from January 2006 to
September 2020. Patients were categorized according to the era (before [Group A] or after the
introduction of arbitrary RV vaccination [Group B]). The patient characteristics and treatment
Results: During the study period, 560 patients (group A, n=233; group B, n=327) were
identified. The distribution of patients 0–6 months old was not significantly different between
the groups (group A, n=12 [5.2%]; group B, n=18 [5.5%]). Among these 18 patients in Group
B, 7 were associated with RV vaccination, and 10 were not associated. One patient was
excluded due to unsatisfied data. On comparing these patients with and without RV vaccinatio n,
the mean age at the onset of intussusception was 3.3±0.4 vs. 4.0±0.3 months (p=0.19), the
mean interval from the onset to treatment was 7.5±2.4 vs. 16.0±2.2 h (p=0.03), the time of the
contrast enema for treatment was 9.1±3.3 vs. 7.7±2.8 min (p=0.76), and the final pressure of
Conclusions: Arbitrary RV vaccination did not influence the age distribution of intussusceptio n,
and the interval from the onset to treatment was significantly shorter in the patients with RV
vaccination than in those without it. Recognizing the presence of intussusception following RV
Rotavirus (RV) is generally known to be a major cause of viral gastroenteritis in children [1],
and encephalitis with severe dehydration is a challenging problem, as a fatal condition may
develop [2]. In 2008, the World Health Organization (WHO) reported that approximate ly
453,000 children died due to RV-associated gastroenterocolitis and/or encephalitis (RVGE) [2].
Almost all children under 5 years old are initially infected with RVGE, and many recover with
only mild symptoms [3]. However, approximately 600,000 children die annually from RV
infection, mainly in developing countries [4]. In Japan, 10–20 children per year died due to
severe RVGE before the introduction of RV vaccination [5]. Since RV vaccination helps
prevent severe RV infection (mortality in children <5 years old in 2015 was reduced by two-
thirds from the level in 1990) [1], the WHO has consistently recommended routine vaccinatio n.
1998, and RotaShield (Wyeth-Lederle Vaccines) was withdrawn because it was associated with
an increased risk of intussusception [6,7]. Since the publication of that report, intussuscep tio n
November 2011 and July 2012, respectively, and Rotavirus (RV) vaccine coverage in Japan
increased from 30.0% in 2012 to 78.4% in 2019 [9]. To assess the potential association between
vaccination.
Patients and Methods
Patients
Patients <16 years old who were diagnosed with intussusception between January 2006 and
September 2020 were identified from the clinical records of Kyushu University Hospital and
Fukuoka Children’s Hospital. These patients were categorized into two groups according to the
period were classified into Group A (January 2006 to October 2011), while those diagnosed in
the era of arbitrary RV vaccination were classified into Group B (November 2011 to October
2020). The incidence, history of RV vaccination, and type and treatment of intussuscep tio n
First, we evaluated the characteristics of all the intussusception cases treated at two
centers in present study (Study 1). Next, we evaluated the patients aged less than 6 months old
in the era of arbitrary vaccination to compare the characteristics of patients related with and
A two-dose oral monovalent RV vaccine (RV1, Rotarix®) and a three-dose oral pentavale nt
RV vaccine (RV5, RotaTeq®) were available. In Japan, the first RV vaccine should be
administered at 6–15 weeks old to reduce the risk of intussusception, and there should be an
interval of at least 4 weeks between doses, with the whole vaccine course completed by 24
within 1 month according to previous reports which suggested that this duration reflected the
The management protocols of the two centers were the same. The diagnosis initially depended
Intussusception was ultimately diagnosed based on the identification of the crab hand
appearance on hydrostatic contrast enema and the target sign and pseudo-kidney sign on
ultrasonography, which indicate intestinal invagination. The first step of treatment is a high-
perforation. Surgical treatment was performed for patients in whom reduction by non-surgic a l
Our therapeutic procedure was described previously [14]. Briefly, fluoroscopy is used
to monitor the whole procedure. we use 6-fold diluted gastrografin (iso-osmotic) in order to
ensure safety in case of perforation. The technique begins with insertion of a Foley catheter in
to the rectum. Then, we set the initial height as 80 to 100 cm, and instill the contrast medium
gently until the intussusception is shown. We are careful not to exceed 120 cm of a height.
Reflux of contrast medium into the terminal ileum and the disappearance of the mass at the
ileocecal valve usually indicated the successful reduction. If the procedure is unsuccessful after
three 3-minute sessions, it is considered a failure of non-surgical treatment, and the patient
Statistical analyses
All continuous data are reported as the mean ±standard error (SE). The chi-squared test was
used to evaluate significant differences. The JMP Pro 15.1.0 software program was used to
perform the statistical analyses (SAS Institute Inc., Cary, NC, USA). P values of <0.05 were
Ethical concerns
This retrospective study was performed according to the Ethical Guidelines for Clinic a l
Research published by the Ministry of Health, Labour and Welfare of Japan on July 30, 2003
(revised in 2008) and complied with the Declaration of Helsinki (revised in 2008). This study
was approved by the ethics committee for clinical research of Kyushu University Hospital (29-
652).
Results
As Study 1, we evaluated all of the intussusception cases treated at two centers (See Fig. 1). A
total of 560 patients (male, n=370; female, n=190) were identified in the present study. Groups
A and B included 233 and 327 patients, respectively. The age distribution of each group is
shown in Fig. 2. Most patients were 6–11 months old, and children from 6 months to 3 years
old accounted for 86% of the study population. The age distribution did not differ significa ntly
between the two groups. The monthly incidence of intussusception in the two institutions was
treatment (high-pressure contrast enema), while 39 (7.0%) required surgical treatment. Among
the surgically treated patients, 28 (72%) were successfully reduced with Hutchinso n's
maneuver. Ileocecal resection was performed for the 8 other patients (21%) with intestina l
necrosis. Exploratory laparotomy was performed in 3 patients (7%) with spontaneous reduction.
The incidence of early-onset intussusception in the two groups did not differ significa ntly
(Group A vs. Group B: n=12 [5.2%] vs. n=18 [5.5%], p=0.97) (Fig. 2).
relation, we next conducted Study 2 (Fig. 3). A summary of these 18 patients is shown in Table
1. Excluding the patient whose interval between RV vaccination to intussusception onset was
unclear (case 18), 17 were evaluated. In the aspect of the duration from the RV to the onset, we
divided these 17 patients into two groups focused on their relation to vaccination (see the
unrelated intussusception. For those with and without vaccine relation, the mean age at the
onset of intussusception was 3.3±0.4 vs. 4.0±0.3 months old (p=0.19) (Fig. 3a), the male-to-
female ratio was 3:4 and 5:5 (p=0.77), the duration from the RV vaccination to the onset was
9.83±3.53 days (n=6), the mean interval from the onset to treatment was 7.5±2.4 vs. 16.0±2.2
hours (p=0.03) (Fig. 3b), the time of the contrast enema for treatment was 9.1±3.3 vs. 7.7±2.8
min (p=0.76) (Fig. 3c), and the final pressure of the contrast enema was 92.5±4.4 vs. 92.2±4.4
cmH2 O (p=0.97) (Fig. 3d), respectively. Except for the patient, who was not associated with
RV vaccination, and whose interval from the onset to the treatment was 31 hrs, the intestina l
invagination was successfully reduced without any complications using a hydrostatic high-
Discussion
RV is recognized as a cause of diarrhea-related illness and death among infants and young
children worldwide [1]. Vaccination is thought to be the most effective approach to reducing
the incidence of RVGE, and the WHO has recommended the development of a safe and
effective vaccine [1]. In the US, a 50% decrease in RV-positive laboratory tests was found after
the routine use of RV vaccination was recommended in 2006, with the seasonal onset of RV in
2007-2008 showing a 2- to 4-month delay [15]. In Austria, the number of patients <6 years old
who were hospitalized due to RVGE decreased following the introduction of RV vaccinatio n
[16]. In Japan, arbitrary RV vaccination started from November 2011. The number of Japanese
infants who receive RV vaccination is increasing year by year (July 2013 vs. May 2014:
approximately 32% vs. approximately 60%) [17]. Oishi et al. [18,19] reported that a
significantly lower incidence of severe RVGE in children <3 years old was observed for three
[8]. Intussusception is a pediatric surgical emergency that requires a timely diagnosis and
management. The majority of patients can avoid the operation and fully recover when managed
major causative disease of bowel obstruction in patients without a history of laparotomy [20].
Adequate management resulted in a good outcome without any complications. In the US, the
risk of intussusception increased to 1.12 per 100,000 within 7 days after RV5 vaccination and
1.54 per 100,000 within 21 days after vaccination [8]. However, Yanagida et al. [21] conversely
reported that the proportion of patients with intussusception onset was 4.74 per 10,000 infants
(0.05%) after RV vaccination, and this percentage was not significantly increased compared to
the baseline incidence of intussusception. In Japan, the baseline incidence of intussuscep tio n
was higher than that observed in other countries prior to the introduction of second-generatio n
RV vaccines (143.5 per 100,000 infants [22]). Therefore, the incidence of intussusception in
Japan may not have significantly increased in comparison to other countries. Oishi et al. [18,19]
reported that cases of intussusception treated non-surgically did not decrease after the
introduction RV vaccination (before vs. after: 90.9% vs. 91.2%), and cases of intussuscep tio n
that required surgical treatment did not markedly increase (pre-vaccine vs. post-vaccine: 5.0%
vs. 6.0%). Higashio et al. [23] reported that approximately 4,950,000 RV vaccines were
administered between November 2011 and February 2016, and there were 172 intussuscep tio n
cases (including 2 recurrent cases) after RV vaccination. There were 27 cases (15.7%) leading
interval from the onset to treatment was significantly shorter in the patients with RV
vaccination than in those without it (Fig. 3b), and the reduction was non-complicated ly
possible with non-surgical intervention (Fig. 3c, 3d). Recognizing the presence of
there is no report describing the duration between the onset of intussusception and the treatment
in RV-related intussusception, however we believe the reason why it was significa ntly
shortened in present study is that the attending pediatrician was well aware of the condition.
There were nine cases of intussusception after RV vaccination in the present study.
However, arbitrary RV vaccination did not influence the age distribution of intussusceptio n.
Furthermore, Ledent et al. [24] previously concluded that the numbers of RVGE
hospitalizations and deaths prevented by vaccination were greater than those potentially caused
by intussusception, as RV vaccine-associated intussusception is very rare and can be adequately
managed. Given these findings, we believe that RV vaccination is suitable with the adequate
As a limitation of the present study, we were unable to elucidate the exact incidence of
intussusception in these two eras because our study included only intussusception cases.
the pre-vaccination era and arbitrary RV vaccination era, and the interval from the onset of
symptom to treatment was significantly shorter in the patients with RV vaccination than in
those without it. Recognizing the presence of intussusception following RV vaccination enables
accurate treatment.
Acknowledgements:
The authors thank Brian Quinn (Japan Medical Communications) for his assistance in reading
and editing the English language of the manuscript. The authors would also like to express their
gratitude to Drs. Yoshiaki Takahashi, Keiko Irie, Yuki Kawano, Yasuyuki Uchida, Keisuke
Kajihara, Yukihiro Toriigahara, and Takeshi Shirai (Department of Pediatric Surgery, Graduate
School of Medical Sciences, Kyushu University), Drs. Sayaka Okuzono, Shunichi Adachi
(Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University), Ms. Rie
Funatsu, Yukiko Nobe, Fumi Shinagawa, Yukiko Katagiri, Misa Matsuse, and Tomoko
Disclosure:
The authors declare no conflicts of interest in association with the present study.
Author contributions:
MN, KY, and TM designed the study, collected and analyzed data, wrote the manuscript. HH,
MH, and YM contributed to collect and analyze the data. SO, TTaj, TH, and TTag critica lly
reviewed the manuscript and supervised the whole study process. All authors read and
Fig. 1 | Flowchart describing the patients in this study. In study 1, an analysis of the
characteristics of 560 intussusception cases encountered at 2 centers in the whole period was
conducted. In study 2, the findings related to RV vaccination were analyzed in 17 patients under
Fig. 2 | Age distribution of each era. There were no significant differences between the two
groups. Group A, Patients were diagnosed with intussusception in the pre-RV vaccine period.
Group B, Patients were diagnosed with intussusception in the arbitrary RV vaccine period. RV,
rotavirus.
Fig. 3 | The clinical feature of 17 patients under 6 months old in the arbitrary RV
vaccination period. Study 2 included patients associated with RV vaccination (n=7) and those
not associated with RV vaccination (n=10). (a) The age of the onset of intussusception. (b) The
interval from the onset to the treatment. (c) The time required for hydrostatic contrast enema.
(d) The final pressure of the hydrostatic contrast enema. *p<0.05. RV, rotavirus.
Table 1. The summary of the patients less than 6 months of age in the era of arbitrary RV.
RV The duration from The duration from
Age Treatment time Required Pressure
case Sex vaccination the RV to the onset the onset to the Treatment
(month) (min) (cmH2O)
history (days) treatment (hours)
1 2 M Yes 2 5 contrast enema 3 90
2 3 F Yes 4 3 contrast enema 6 90
3 3 M Yes 7 5 contrast enema 6 100
4 3 F Yes 15 13.5 contrast enema 10 85
5 3 F Yes 25 11 contrast enema 28 n.a.
6 4 M Yes Within 1 month* 4.5 contrast enema 7.5 110
7 5 F Yes 6 11 contrast enema 3 80
8 2 M No - 20 contrast enema 14 95
9 3 M No - 7 contrast enema 2 100
10 3 F No - 12 contrast enema 3 90
11 4 F No - 29 contrast enema 8 80
12 5 F No - 10 contrast enema 27 120
13 5 F No - 14.5 contrast enema 0.5 100
14 5 M No - 8 contrast enema 1 85
15 5 M No - 11 contrast enema 6 80
16 5 M Yes 58 17 contrast enema 8 80
17 3 F No - 31 Hutchinson - -
18 4 F Yes unknown 5 contrast enema 3 80
Abbreviations: F, female; M, male; RV, rota virus; n.a., not available. * The detail data was not available.
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