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Intussusception and Rotavirus

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Intussusception and Rotavirus

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Yoshimaru Koichiro (Orcid ID: 0000-0002-8709-7313)

Title Page

Category of manuscript: Original Article

Title:

Characteristics of intussusception in the era of

arbitrary Rotavirus vaccination


Running Title: Risk of intussusception after RV.

Authors:

Mutsumi Nakamura1a, Koichiro Yoshimaru2a, Toshiharu Matsuura2* , Hiroshi Hamada1 ,

Yoshitomo Motomura3 , Makoto Hayashida1 , Shouichi Ohga3 , Tatsuro Tajiri1 , Toshiro Hara4

and Tomoaki Taguchi5

a, These authors equally contributed this work (Co-first Author).

* Correspondence Author.

Affiliation:

1. Department of Pediatric Surgery, Fukuoka Children’s Hospital, Fukuoka, Japan.

2. Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of

Medical Sciences, Kyushu University, Fukuoka, Japan.

3. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University,

Fukuoka, Japan.

4. Fukuoka Children's Hospital, Fukuoka, Japan.

5. Fukuoka College of Health Sciences, 2-15-1 Tamura, Sawara-ku, Fukuoka, 814-0193,

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:

Toshiharu Matsuura, MD, PhD*

Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of

Medical Sciences, Kyushu University, Fukuoka, Japan.

Telephone: +81-92-642-5573 Facsimile: +81-92-642-5580

E-mail: [email protected]

Number of

Text pages: 14 pages

Words: 2279 words

Reference pages: 2 pages

Tables: 1

Figures: 3

Legends to figures: 1

Author Information:

Mutsumi Nakamura, MD.

Department of Pediatric Surgery, Fukuoka Children’s Hospital, 5-1-1, Kashiiteriha, Fukuoka,

813-0017, Japan.

E-mail: [email protected]

Koichiro Yoshimaru, MD, PhD.

Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of

Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

E-mail: [email protected]
Toshiharu Matsuura, MD, PhD.

Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of

Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

E-mail: [email protected]

Hiroshi Hamada, MD.

Department of Pediatric Surgery, Fukuoka Children’s Hospital, 5-1-1, Kashiiteriha, Fukuoka,

813-0017, Japan.

E-mail: [email protected]

Yoshitomo Motomura, MD, PhD.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1,

Maidashi, Higashi-ku, Fukuoka, 812-8582, Fukuoka, Japan.

E-Mail: [email protected]

Makoto Hayashida, MD, PhD.

Department of Pediatric Surgery, Fukuoka Children’s Hospital, 5-1-1, Kashiiteriha, Fukuoka,

813-0017, Japan.

E-mail: [email protected]

Shouichi Ohga, MD, PhD.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1,

Maidashi, Higashi-ku, Fukuoka, 812-8582, Fukuoka, Japan.

E-Mail: [email protected]
Tatsuro Tajiri, MD, PhD.

Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of

Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

E-mail: [email protected] u.ac.jp

Toshiro Hara, MD, PhD

Fukuoka Children’s Hospital, 5-1-1, Kashiiteriha, Fukuoka, 813-0017, Japan.

E-mail: [email protected]

Tomoaki Taguchi, MD, PhD, FACS

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

vaccination to prevent RV-associated gastroenterocolitis. We examined the characteristics of

intussusception following RV vaccination in our two centers.

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

of intussusception were retrospectively investigated.

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

the contrast enema was 92.5±4.4 vs. 92.2±4.4 cmH2 O (p=0.97).

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

vaccination enables accurate treatment.

Key words: rotavirus, vaccine, intussusception, hydrostatic contrast enema


Introduction

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.

In Japan, arbitrary RV vaccination started in November 2011.

An association between intussusception and RV vaccination was initially identified in

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

has been reported as a severe adverse event after RV vaccination [8].

In Japan, a two-dose oral monovalent RV vaccine (RV1, Rotarix®) and a three-dose

oral pentavalent RV vaccine (RV5, RotaTeq®) were launched as voluntary vaccinations in

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

intussusception and RV vaccination and the outcome of intussusception, we investigated the

incidence and characteristics of intussusception after the introduction of arbitrary RV

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

performance of RV vaccination: patients diagnosed with intussusception in the pre-RV vaccine

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

were retrospectively investigated using clinical records.

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

without RV vaccination (Study 2).

Vaccination schedule in Japan

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

weeks old [9].

Definition of ‘early-onset intussusception’

We defined early-onset intussusception as the occurrence of intussusception before 6 months

old, as its peak incidence is at 6–18 months old [10,11].


Definition of ‘RV vaccine-related intussusception’

We defined RV vaccine-related intussusception as the intussusception which were diagnosed

within 1 month according to previous reports which suggested that this duration reflected the

short-term effect of the RV vaccine [12, 13].

The diagnosis and treatment

The management protocols of the two centers were the same. The diagnosis initially depended

on clinical suspicon. Patients with a typical presentation, including a sudden onset of

intermittent severe abdominal pain with or without hematochezia and vomiting, or

characteristic findings on radiography were directly advanced to a non-operative diagnosis and

received reduction therapy using a hydrostatic contrast enema.

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-

pressure contrast enema, which is contraindicated in patients with suspected intestina l

perforation. Surgical treatment was performed for patients in whom reduction by non-surgic a l

treatment was considered difficult or in cases with suspected intestinal perforation.

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

proceeds to surgical treatment.

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

considered to indicate a statistically significant difference.

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

Patient background characteristics and treatment

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

3.3 patients in Group A and 3.1 in Group B, showing no significant difference.


Among a total of 560 patients, 521 (93.0%) successfully underwent non-surgic a l

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.

No surgical mortality or morbidity was noted in this study population.

The incidence of the early-onset intussusception in each group

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).

To compare the characteristics of intussusception patients with and without RV vaccine

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

definition of ‘RV vaccine-related intussusception’). Then, we finally categorized 7 as the

patients with RV vaccine-related intussusception, and another 10 patients with vaccine-

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-

pressure contrast enema.

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

consecutive seasons after the introduction of RV vaccination compared to the pre-vaccinatio n

2011 RVGE epidemic season.

Intussusception has been reported as a severe adverse event following RV vaccinatio n

[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

by a skilled pediatrician, pediatric radiologist, and pediatric surgeon. Intussusception is also a

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

to surgery, with 7 cases requiring ileocecal resection; no patients died.

In the present study, in all cases of intussusception following RV vaccination, the

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

intussusception following RV vaccination enables accurate treatment. To our best of knowledge,

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

management of subsequent intussusception.

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.

In conclusion, there was no difference in age distribution of intussusception between

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

Yamazaki (Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu

University) for their excellent assistance.

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

approved the final manuscript.


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Figure Legends:

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

6 months old in Group B. RV, rotavirus.

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.

1
PED_15332_Intussuceprion_Fig.1 20220226_350.tif
PED_15332_Intussuceprion_R1_Fig.2 20220719_350.tif
PED_15332_Intussuceprion_R1_Fig.3 20220719_350.tif

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