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The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine
J Infect Chemother xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Original Article
The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine* Mayumi Kawase a, b, Takayuki Hoshina a, *, Toru Yoneda c, Masumi Kojiro b, Yasuhiko Takahashi c, Koichi Kusuhara a a b c
Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan Department of Pediatrics, Kitakyushu General Hospital, Kitakyushu, Japan Department of Pediatrics, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 May 2019 Received in revised form 10 July 2019 Accepted 1 September 2019 Available online xxx
Rotavirus (RV) vaccine contributed to the reduction of the hospitalization for gastroenteritis (GE)associated convulsion whereas there were few studies investigating the vaccination rate and the reduction of the disease simultaneously. The aim of this study is to investigate the alterations of the epidemiology and clinical characteristics of RVGE-associated convulsion after the introduction of RV vaccines and evaluate the reduction of the disease in the context of the vaccination rate. This retrospective study included hospitalized patients with GE and GE-associated convulsion from 2009 to 2015. The proportion of patients with RVGE and RVGE-associated convulsion and the clinical characteristics of RVGE-associated convulsion were compared between the pre- (2009e2011) and post-vaccination periods (2013e2015). The presumptive RV vaccination rate in the subject area was also investigated. During the pre- and post-vaccination periods, 47 and 49 patients with GE-associated convulsion, and 319 and 330 with GE were enrolled, respectively. Proportions of both hospitalized patients with RVGE-associated convulsion and those with RVGE during the post-vaccination period were significantly lower than those during the pre-vaccination periods (P ¼ 0.042 and P ¼ 0.003). Serum sodium level was significantly lower in hospitalized patients with RVGE-associated convulsion during the post-vaccination period (P ¼ 0.021). The presumptive RV vaccination rates were 35.9%, 45.8% and 52.6% in 2013, 2014 and 2015, respectively. The proportions of hospitalized patients with RVGE-associated convulsion as well as those with RVGE decreased after the introduction of RV vaccine. RV vaccination would be also effective for the prevention of extra-intestinal complications of the virus. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Rotavirus Vaccine Seizure Gastroenteritis Vaccination rate
1. Introduction Rotavirus (RV) is a representative virus causing gastroenteritis (GE) among children younger than 5 years of age. A previous Japanese surveillance indicated that RV was detected from
Abbreviations: Rotavirus, RV; gastroenteritis, GE; benign convulsion with mild gastroenteritis, CwG; measles-rubella, MR; vaccine effectiveness, VE; non-structural protein 4, NSP4; Norovirus, NV. * All authors meet the ICMJE authorship criteria. * Corresponding author. Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan. E-mail address: [email protected] (T. Hoshina).
approximately 40-50% of hospitalized GE patients in this age group [1]. In the developed countries, the number of patients hospitalized for RVGE decreased after the introduction of RV vaccines [2,3]. In Japan, the monovalent (Rotarix®, GlaxoSmithKline Biologicals, Rixensart, Belgium) and pentavalent (RotaTeq®, Merck and Company, Whitehouse Station, NJ., USA) RV vaccines were approved for licensure in November 2011 and July 2012, respectively, and the same tendency as other developed countries were observed [4]. Although the RV vaccination has not been included in the Japanese national routine immunization schedule, the presumptive vaccination rate of RV vaccine is around 60% [5]. RV often causes extra-intestinal complications including encephalitis and renal failure. In particular, seizure is a representative extra-intestinal complication of RV infection. The seizure induced
https://doi.org/10.1016/j.jiac.2019.09.001 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
2
M. Kawase et al. / J Infect Chemother xxx (xxxx) xxx
by RV is typically afebrile, and recurrent during short term [6]. The seizure rarely continues for a long time, and the prognosis is good. As the same seizure is also caused by other viral GE, it is collectively called benign convulsion with mild gastroenteritis (CwG). A previous study in Korea reported the contribution of RV vaccine to the reduction of hospitalization for RVGE-associated convulsion [7], but it did not refer the RV vaccination rate in the subject area. In the present study, we investigated the alteration of epidemiology and clinical characteristics of the hospitalization due to GE-associated convulsion after the introduction of RV vaccines. In addition, we also investigated the regional RV vaccination rate, and evaluated the reduction of the disease in the context of it. 2. Materials and methods 2.1. Study population Kitakyushu City is located in the west of Japan and is the northernmost city of the Kyushu region. Approximately one million live in the city and surrounding area. The number of children &59 months is 45,000 (4.7% of the overall population in Kitakyushu). Kitakyushu General Hospital and Japan Community Health Care Organization Kyushu Hospital are secondary medical facilities and the Hospital of Occupational and Environmental Health, Japan, is a tertiary medical hospital. Approximately 40% children living in this area are presumed to be admitted to these three hospitals. The present retrospective study included pediatric patients aged &59 months with GE-associated convulsion who were admitted to these three hospitals from 2009 to 2015. Based on the diagnostic criteria of CwG [6] excluding apyrexia, patients with seizures for the first time accompanied with GE, normal development, normal or mild abnormal electroencephalography and normal brain imaging studies were diagnosed as GE-associated convulsion. The clinical information on each patient was collected using a standardized case report form. Patients whose stool culture were positive for pathogenic bacteria were excluded from the present study. In Japan, the monovalent and pentavalent RV vaccines were approved for licensure in November 2011 and July 2012, respectively. In hospitalized patients with GE-associated convulsion, we compared the proportions of the patients with RVGE-associated convulsion between pre- (2009e2011) and post-vaccination periods (2013e2015). The children who were hospitalized in 2012 were excluded because of a transition year. Furthermore, the demographic characteristics and clinical findings of the patients with RVGE-associated convulsion were also compared between the 2 periods. In patients who were admitted to Kitakyushu General Hospital for GE, the total number of GE patients and the proportion of patients with RVGE were also compared between the 2 periods. Our study was approved by the Institutional Review Board of the University of Occupational and Environmental Health, Japan. 2.2. The diagnostic methods of RV infection Three rapid antigen detection tests, ImmunoCard ST Rotavirus (Fujirebio Inc., Tokyo, Japan), ImmunoCard SD Rota/Adeno (Fujirebio, Inc.) or RapidTesta ROTA-ADENO (Sekisui Medical Co., Ltd., Tokyo, Japan), were used for the diagnosis of RVGE. According to the package insert, the sensitivity and specificity of the first test were 93.1% and 95.8%, respectively, those of the second test were 100% and 99.7%, respectively, and those of the third test were 100% and 99.3%, respectively. Fecal swab or stool specimen was obtained from all hospitalized patients with GE-associated convulsion or GE (only patients hospitalized in Kitakyushu General Hospital), and was analyzed in accordance with the manufacturer's instructions.
2.3. The presumptive vaccination rate of RV vaccine As RV vaccination rate is not disclosed in public, we calculated the presumptive RV vaccination rate in Kitakyushu city from 2013 to 2015 by using the following method. Questionnaires were preliminarily sent to clinics and hospitals in Kitakyushu City where the subject children could receive vaccines. When a child received the second dose of a measles-rubella (MR II) in the clinics or hospitals, the medical staff asked his/her parents to describe the fact into a questionnaire on his/her inoculation history of RV vaccine. The questionnaires were returned to University of Occupational and Environmental Health, Japan to calculate the presumptive RV vaccination rate. Total number of children receiving RV or MR vaccines in Kitakyushu City could not be derived from this method because all institutions did not collaborate with this survey. On the other hand, MR vaccine is included in the national routine immunization schedule and the exact vaccination rate is disclosed in public [8]. The proportion of children with inoculation of history of RV vaccine in those receiving MR II vaccine were assumed to be equal between the participants of the questionnaire survey and total pediatric population, because the institutions that cooperated with this survey provided information on most of the children receiving MR II. Thus, the presumptive RV vaccination rate was calculated using the following formula; (the number of children receiving RV vaccine)/(the number of children receiving MR II vaccine) x (vaccination rate of MR II vaccine). As MR II vaccination rate by each year in Kitakyushu City was 95.8% in 2013, 95.0% in 2014 and 93.9% in 2015, 0.958, 0.95 and 0.939 were inserted in “vaccination rate of the second dose of MR II vaccine”. 2.4. Statistical analysis The Mann-Whitney U test was used to compare the quantitative values and the chi-squared test and Fisher's exact test were used for the qualitative analyses. The Stata software program (version 15, Stata Corporation, College Station, TX) was used to perform the statistical analyses. P-values of <0.05 were considered to indicate statistical significance. 3. Results During the pre- and post-vaccination periods, 47 and 49 pediatric patients were admitted to the 3 hospitals for GE-associated convulsion, respectively (Table 1, Fig. 1). The proportion of hospitalized patients with RVGE-associated convulsion during the postvaccination period was significantly lower than that of them during the pre-vaccination periods (P ¼ 0.042). The number of patients hospitalized for RVGE-associated convulsion was declined by 36.0% after the beginning of RV vaccination (Table 1). We compared the demographic characteristics and clinical findings of hospitalized patients with RVGE-associated convulsion between the pre- and post-vaccination periods. Serum sodium level in the hospitalized patients during the post-vaccination period was significantly lower than that during the pre-vaccination period (P ¼ 0.021, Table 2). During the pre- and post-vaccination periods, 319 and 330 patients were admitted to Kitakyushu General Hospital for GE, respectively (Table 3, Fig. 2). The proportion of hospitalized patients with RVGE during the post-vaccination period was significantly lower than that during the pre-vaccination periods (P ¼ 0.003). The number of patients hospitalized for RVGE was declined by 19.0% after the beginning of RV vaccination (Table 3). The number of children receiving RV or MR vaccines was assessed from returned questionnaires. Total of 1,034, 1400 and 1987 questionnaries described receiving RV vaccine and 2,932, 3057 and 3508 ones described receiving MR vaccine were returned
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
M. Kawase et al. / J Infect Chemother xxx (xxxx) xxx
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Table 1 The comparison of the changes of the hospitalization for gastroenteritis (GE)-associated convulsion between the pre- and post-rotavirus (RV) vaccination periods. No. (%)
All-cause GE-associated convulsion hospitalization Subgroups (causative pathogen) RV Others
Change rate
Pre-vaccination
Post-vaccination
47
49
þ4.3%
25 (53.2) 22 (46.8)
16 (32.7) 33 (67.3)
36.0% þ50.0%
The pre-and post-vaccination periods indicate 2009e2011, 2013e2015, respectively.
Table 3 The comparison of the changes of the hospitalization for gastroenteritis (GE) between the pre- and post-rotavirus (RV) vaccination periods. No. (%)
Change rate
Pre-vaccination All-cause GE hospitalization 319 Subgroups (causative pathogen) RV 174 (54.5) Others 145 (45.5) The pre-and respectively.
post-vaccination
periods
Post-vaccination 330
þ3.4%
141 (42.7) 189 (57.3)
19.0% þ30.3%
indicate
2009e2011,
2013e2015,
Fig. 1. The number of hospitalized patients with gastroenteritis (GE)-associated convulsion by years. The pre-vaccination period (2009e2011) indicates that before the introduction of rotavirus (RV) vaccines. The post-vaccination period (2013e2015) indicates that after the beginning of RV vaccination. The children who were hospitalized in 2012 were not assigned to either group because of a transition year. The black square indicates the number of hospitalized patients with RVGE-associated convulsion. The white square indicates the number of hospitalized patients with GE-associated convulsion caused by other pathogens.
to our institution in 2013, 2014 and 2015, respectively. Based on these results, the presumptive RV vaccination rates in Kitakyushu City were calculated to be 35.9%, 45.8% and 52.6% in 2013, 2014 and 2015, respectively. 4. Discussion The results of the present study indicated that the epidemiology of GE-associated convulsion as well as that of GE changed after the introduction of RV vaccines. Although the number of hospitalized children with GE-associated convulsion did not change, the proportion of hospitalized patients with RVGE-associated convulsion decreased significantly after the introduction of the vaccine. The unique point of the present study is that serial changes of the regional presumptive RV vaccination rate and the number of
Fig. 2. The number of hospitalized patients with gastroenteritis (GE) by years. The prevaccination period (2009e2011) indicates that before the introduction of rotavirus (RV) vaccines. The post-vaccination period (2013e2015) indicates that after the beginning of RV vaccination. The children who were hospitalized in 2012 were not assigned to either group because of a transition year. The black square indicates the number of hospitalized patients with RVGE. The white square indicates the number of the hospitalized patients with GE caused by other pathogens.
hospitalized patients with RVGE-associated convulsion were simultaneously investigated. The epidemiology of this disease will continue to change because even 50% of the vaccination rate lead to the reduction of hospitalization for RVGE-associated convulsion.
Table 2 The comparisons of the demographic characteristics and clinical findings of hospitalized patients with rotavirus gastroenteritis (GE)-associated convulsion between the preand post-vaccination periods.
Age, month Interval from the onset of GE to the development of convulsions, day Frequency of convulsions, times Fever Serum sodium level, mEq/L Serum potassium level, mEq/L Serum chloride level, mEq/L Serum glucose level, mg/dL
Pre-vaccination period (n ¼ 25)
Post-vaccination period (n ¼ 16)
P-value
21 (16e29) 3 (2e3) 2 (1e2) 17 (68.0) 137 (136e139) 4.0 (3.6e4.5) 101 (99e102) 97.0 (76.5e111.5)
21 (17e37) 3 (2.5e4) 2 (1e2) 6 (37.5) 135 (133e136) 4.1 (4.0e4.3) 100 (98e104) 78.5 (73.5e90.8)
0.482 0.079 0.061 0.747 0.021 0.776 0.726 0.085
Values are presented as median value (interquartile range) or n (%).
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
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M. Kawase et al. / J Infect Chemother xxx (xxxx) xxx
The main reason for the reduction of the number of hospitalized patients with RVGE-associated convulsion is assumed to be the reduction of the number of the patients who develop RVGE. In a previous investigation performed in Japan, the vaccine effectiveness (VE) against RVGE was calculated to be 80% [4]. In particular, RV vaccines were highly effective against severe RVGE necessitating intravenous rehydration or hospitalization (VE: 97%) [4]. In the present study, hospitalization for RVGE decreased after the introduction of RV vaccine, indicating that the reduction of the development of RVGE might contribute the reduction of the development of the convulsion which was a representative complication of RVGE. The reduction rate of hospitalized patients with RVGEassociated convulsion after the introduction of RV vaccines (36%) was larger than that of them with RVGE (19%) in the present study. This result suggested that other factors might be associated with the reduction of the number of the patients with the convulsion. The change of the genotype of RV after the introduction of RV vaccine may be another factor of the reduction of the convulsion, although the genotype was not analyzed in the present study. There was no large scale study for the relationship between RVGEassociated convulsion and the genotype whereas G3 genotype was predominantly detected from cerebrospinal fluid of diarrheic children with seizures in a small size study [9]. In Japan, the frequency of the detection of G3 genotype decreased after the introduction of RV vaccines [10]. It is important to analyze the molecular epidemiology of RVGE-associated convulsion after the introduction of RV vaccine. A previous study performed in Korea showed the change of the clinical characteristics of RVGE-associated convulsion after the introduction of RV vaccine [11]. The same tendency, including the increase of the proportion of afebrile convulsion and the elongation of the interval from the onset of GE to the development of convulsion, was observed in the present study, although the difference was not statistically significant. It was speculated that a functional change in non-structural protein 4 (NSP4), which was the RV enterotoxin and had been suggested as a causative factor of RVGE-associated convulsion [12], might have caused the change of the clinical characteristics of the disease [11]. In the present study, after the introduction of RV vaccine, serum sodium level, but not chloride or calcium level, decreased in hospitalized patients with RVGE-associated convulsion, suggested that other factors than NSP4 might be involved in this change. Further study is needed to elucidate the change of the clinical characteristics of RVGEassociated convulsion after the introduction of RV vaccine. In the present study, the presumptive RV vaccination rate gradually increased after the introduction of the vaccines, and it reached more than 50% in 2015. This rate in our city was slightly lower than that in all over Japan [5]. The reduction rate of the number of hospitalized patients with RVGE was also lower in the present study than in a nationwide survey [13]. The number of hospitalized patients with RVGE markedly decreased in other Japanese city where the official financial support for the vaccination was implemented and the vaccination rate reached approximately 90% in 2015 [14]. There is no study evaluating the reduction of the number of the patients with RVGE-associated convulsion in the context of the vaccination rate. The larger scale study is desired to analyze this issue. After the introduction of RV vaccine, norovirus (NV) replaced RV as the leading cause of GE in children in USA [15]. In addition, NVassociated convulsion has been also increasing recently in Korea [7]. Previous study speculated that the shift of main viral etiology from RV to NV in GE-associated convulsion might depend on a decrease of RV infection with a benefit of the vaccination and abrupt increase of NV activity in 2012 with the outbreak of a new
GII.4 variant among pediatric population with GE [16]. In the present study, the number of hospitalized children with GE-associated convulsion did not change despite the reduction of the number of hospitalized patients with RVGE-associated convulsion after the introduction of the vaccine, and it was suggested that NV might have replaced RV as the leading cause of GE-associated convulsion even in Japan. The present study has some limitations. First, as the epidemic of the viral infection often fluctuates, the investigation period may not be long enough. Second, the presumptive RV vaccination rate may be differ from the actual one, because it was calculated by the ratio between the number of children receiving RV vaccine and MR vaccine based on the number of returned questionnaires. Finally, study population was relatively small; this could have affected the precision of the statistical analysis. In conclusion, hospitalization for RVGE-associated convulsion decreased after the introduction of RV vaccine. RV vaccination may be effective for the prevention of extra-intestinal complications of the virus. The more elevation of RV vaccination rate would be important for the reduction of severe complications of RVGE. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors. Conflicts of interest None. References [1] Kamiya H, Nakano T, Kamiya H, Yui A, Taniguchi K, Parashar U. Rotavirusassociated acute gastroenteritis hospitalizations among Japanese children aged <5 years: active rotavirus surveillance in Mie Prefecture, Japan. Jpn J Infect Dis 2011;64:482e7. [2] Baker JM, Tate JE, Steiner CA, Haber MJ, Parashar UD, Lopman BA. Longer-term direct and indirect effects of infant rotavirus vaccination across all ages in the US; 2000 - 2013: analysis of a large hospital discharge dataset. Clin Infect Dis 2019;68:976e83. mara M, Vivancos R, [3] Hungerford D, Smith K, Tucker A, Iturriza-Go McLeonard C, et al. Population effectiveness of the pentavalent and monovalent rotavirus vaccines: a systematic review and meta-analysis of observational studies. BMC Infect Dis 2017;17:569. [4] Araki K, Hara M, Tsugawa T, Shimanoe C, Nishida Y, Matsuo M, et al. Effectiveness of monovalent and pentavalent rotavirus vaccines in Japanese children. Vaccine 2018;36:5187e93. [5] The 4th meeting of subcommittee on vaccine evaluation, division of basic policy on immunization, sectional committee on immunization and vaccine, Health Sciences Council. document 1-3: evaluation analysis on rotavirus vaccine, 2015; 2015. http://www.mhlw.go.jp/file/05-Shingikai-10601000Daijinkanboukouseikagakuka-Kouseikagakuka/0000128401.pdf. [Accessed 17 January 2015]. [6] Uemura N, Okumura A, Negoro T, Watanabe K. Clinical features of benign convulsions with mild gastroenteritis. Brain Dev 2002;24:745e9. [7] Park SH, Kim YO, Kim HK, Kim HS, Kim BY, Cheon KR, et al. Incidence of benign convulsions with mild gastroenteritis after introduction of rotavirus vaccine. Brain Dev 2015;37:625e30. [8] Ministry of Health, Labour and Welfare. Vaccination coverage for the second dose of the measles-rubella combined vaccine by municipalities. https:// www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou21/hashika.html [accessed 19.07.10]. [9] Liu B, Fujita Y, Arakawa C, Kohira R, Fuchigami T, Mugishima H, et al. Detection of rotavirus RNA and antigens in serum and cerebrospinal fluid samples from diarrheic children with seizures. Jpn J Infect Dis 2009;62:279e83. [10] Tanaka T, Kamiya H, Asada K, Suga S, Ido M, Umemoto M, et al. Changes in rotavirus genotypes before and after vaccine introduction: a multicenter, prospective observational study in three areas of Japan. Jpn J Infect Dis 2017;70:448e52. [11] Yeom JS, Kim YS, Kim RB, Park JS, Seo JH, Park E, et al. Impact of rotavirus vaccine introduction on rotavirus-associated seizures and a related possible mechanism. J Child Neurol 2015;30:729e34. [12] Yeom JS, Kim YS, Jun JS, Do HJ, Park JS, Seo JH, et al. NSP4 antibody levels in rotavirus gastroenteritis patients with seizures. Eur J Paediatr Neurol 2017;21: 367e73.
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
M. Kawase et al. / J Infect Chemother xxx (xxxx) xxx [13] Kobayashi M, Adachi N, Miyazaki M, Tatsumi M. Decline of rotavirus-coded hospitalizations in children under 5 years: a report from Japan where rotavirus vaccines are self-financed. Vaccine 2018;36:2727e32. [14] Yoshikawa T, Matsuki T, Sato K, Mizuno M, Shibata M, Hasegawa S, et al. Impact of rotavirus vaccination on the burden of acute gastroenteritis in Nagoya city, Japan. Vaccine 2018;36:527e34.
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J, Szilagyi PG, Edwards KM, Staat MA, Weinberg GA, et al. [15] Payne DC, Vinje Norovirus and medically attended gastroenteritis in U.S. children. N Engl J Med 2013;368:1121e30. [16] Ramani S, Atmar RL, Estes MK. Epidemiology of human noroviruses and updates on vaccine development. Curr Opin Gastroenterol 2014;30: 25e33.
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Original Article
The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine* Mayumi Kawase a, b, Takayuki Hoshina a, *, Toru Yoneda c, Masumi Kojiro b, Yasuhiko Takahashi c, Koichi Kusuhara a a b c
Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan Department of Pediatrics, Kitakyushu General Hospital, Kitakyushu, Japan Department of Pediatrics, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 May 2019 Received in revised form 10 July 2019 Accepted 1 September 2019 Available online xxx
Rotavirus (RV) vaccine contributed to the reduction of the hospitalization for gastroenteritis (GE)associated convulsion whereas there were few studies investigating the vaccination rate and the reduction of the disease simultaneously. The aim of this study is to investigate the alterations of the epidemiology and clinical characteristics of RVGE-associated convulsion after the introduction of RV vaccines and evaluate the reduction of the disease in the context of the vaccination rate. This retrospective study included hospitalized patients with GE and GE-associated convulsion from 2009 to 2015. The proportion of patients with RVGE and RVGE-associated convulsion and the clinical characteristics of RVGE-associated convulsion were compared between the pre- (2009e2011) and post-vaccination periods (2013e2015). The presumptive RV vaccination rate in the subject area was also investigated. During the pre- and post-vaccination periods, 47 and 49 patients with GE-associated convulsion, and 319 and 330 with GE were enrolled, respectively. Proportions of both hospitalized patients with RVGE-associated convulsion and those with RVGE during the post-vaccination period were significantly lower than those during the pre-vaccination periods (P ¼ 0.042 and P ¼ 0.003). Serum sodium level was significantly lower in hospitalized patients with RVGE-associated convulsion during the post-vaccination period (P ¼ 0.021). The presumptive RV vaccination rates were 35.9%, 45.8% and 52.6% in 2013, 2014 and 2015, respectively. The proportions of hospitalized patients with RVGE-associated convulsion as well as those with RVGE decreased after the introduction of RV vaccine. RV vaccination would be also effective for the prevention of extra-intestinal complications of the virus. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Rotavirus Vaccine Seizure Gastroenteritis Vaccination rate
1. Introduction Rotavirus (RV) is a representative virus causing gastroenteritis (GE) among children younger than 5 years of age. A previous Japanese surveillance indicated that RV was detected from
Abbreviations: Rotavirus, RV; gastroenteritis, GE; benign convulsion with mild gastroenteritis, CwG; measles-rubella, MR; vaccine effectiveness, VE; non-structural protein 4, NSP4; Norovirus, NV. * All authors meet the ICMJE authorship criteria. * Corresponding author. Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan. E-mail address: [email protected] (T. Hoshina).
approximately 40-50% of hospitalized GE patients in this age group [1]. In the developed countries, the number of patients hospitalized for RVGE decreased after the introduction of RV vaccines [2,3]. In Japan, the monovalent (Rotarix®, GlaxoSmithKline Biologicals, Rixensart, Belgium) and pentavalent (RotaTeq®, Merck and Company, Whitehouse Station, NJ., USA) RV vaccines were approved for licensure in November 2011 and July 2012, respectively, and the same tendency as other developed countries were observed [4]. Although the RV vaccination has not been included in the Japanese national routine immunization schedule, the presumptive vaccination rate of RV vaccine is around 60% [5]. RV often causes extra-intestinal complications including encephalitis and renal failure. In particular, seizure is a representative extra-intestinal complication of RV infection. The seizure induced
https://doi.org/10.1016/j.jiac.2019.09.001 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
2
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by RV is typically afebrile, and recurrent during short term [6]. The seizure rarely continues for a long time, and the prognosis is good. As the same seizure is also caused by other viral GE, it is collectively called benign convulsion with mild gastroenteritis (CwG). A previous study in Korea reported the contribution of RV vaccine to the reduction of hospitalization for RVGE-associated convulsion [7], but it did not refer the RV vaccination rate in the subject area. In the present study, we investigated the alteration of epidemiology and clinical characteristics of the hospitalization due to GE-associated convulsion after the introduction of RV vaccines. In addition, we also investigated the regional RV vaccination rate, and evaluated the reduction of the disease in the context of it. 2. Materials and methods 2.1. Study population Kitakyushu City is located in the west of Japan and is the northernmost city of the Kyushu region. Approximately one million live in the city and surrounding area. The number of children &59 months is 45,000 (4.7% of the overall population in Kitakyushu). Kitakyushu General Hospital and Japan Community Health Care Organization Kyushu Hospital are secondary medical facilities and the Hospital of Occupational and Environmental Health, Japan, is a tertiary medical hospital. Approximately 40% children living in this area are presumed to be admitted to these three hospitals. The present retrospective study included pediatric patients aged &59 months with GE-associated convulsion who were admitted to these three hospitals from 2009 to 2015. Based on the diagnostic criteria of CwG [6] excluding apyrexia, patients with seizures for the first time accompanied with GE, normal development, normal or mild abnormal electroencephalography and normal brain imaging studies were diagnosed as GE-associated convulsion. The clinical information on each patient was collected using a standardized case report form. Patients whose stool culture were positive for pathogenic bacteria were excluded from the present study. In Japan, the monovalent and pentavalent RV vaccines were approved for licensure in November 2011 and July 2012, respectively. In hospitalized patients with GE-associated convulsion, we compared the proportions of the patients with RVGE-associated convulsion between pre- (2009e2011) and post-vaccination periods (2013e2015). The children who were hospitalized in 2012 were excluded because of a transition year. Furthermore, the demographic characteristics and clinical findings of the patients with RVGE-associated convulsion were also compared between the 2 periods. In patients who were admitted to Kitakyushu General Hospital for GE, the total number of GE patients and the proportion of patients with RVGE were also compared between the 2 periods. Our study was approved by the Institutional Review Board of the University of Occupational and Environmental Health, Japan. 2.2. The diagnostic methods of RV infection Three rapid antigen detection tests, ImmunoCard ST Rotavirus (Fujirebio Inc., Tokyo, Japan), ImmunoCard SD Rota/Adeno (Fujirebio, Inc.) or RapidTesta ROTA-ADENO (Sekisui Medical Co., Ltd., Tokyo, Japan), were used for the diagnosis of RVGE. According to the package insert, the sensitivity and specificity of the first test were 93.1% and 95.8%, respectively, those of the second test were 100% and 99.7%, respectively, and those of the third test were 100% and 99.3%, respectively. Fecal swab or stool specimen was obtained from all hospitalized patients with GE-associated convulsion or GE (only patients hospitalized in Kitakyushu General Hospital), and was analyzed in accordance with the manufacturer's instructions.
2.3. The presumptive vaccination rate of RV vaccine As RV vaccination rate is not disclosed in public, we calculated the presumptive RV vaccination rate in Kitakyushu city from 2013 to 2015 by using the following method. Questionnaires were preliminarily sent to clinics and hospitals in Kitakyushu City where the subject children could receive vaccines. When a child received the second dose of a measles-rubella (MR II) in the clinics or hospitals, the medical staff asked his/her parents to describe the fact into a questionnaire on his/her inoculation history of RV vaccine. The questionnaires were returned to University of Occupational and Environmental Health, Japan to calculate the presumptive RV vaccination rate. Total number of children receiving RV or MR vaccines in Kitakyushu City could not be derived from this method because all institutions did not collaborate with this survey. On the other hand, MR vaccine is included in the national routine immunization schedule and the exact vaccination rate is disclosed in public [8]. The proportion of children with inoculation of history of RV vaccine in those receiving MR II vaccine were assumed to be equal between the participants of the questionnaire survey and total pediatric population, because the institutions that cooperated with this survey provided information on most of the children receiving MR II. Thus, the presumptive RV vaccination rate was calculated using the following formula; (the number of children receiving RV vaccine)/(the number of children receiving MR II vaccine) x (vaccination rate of MR II vaccine). As MR II vaccination rate by each year in Kitakyushu City was 95.8% in 2013, 95.0% in 2014 and 93.9% in 2015, 0.958, 0.95 and 0.939 were inserted in “vaccination rate of the second dose of MR II vaccine”. 2.4. Statistical analysis The Mann-Whitney U test was used to compare the quantitative values and the chi-squared test and Fisher's exact test were used for the qualitative analyses. The Stata software program (version 15, Stata Corporation, College Station, TX) was used to perform the statistical analyses. P-values of <0.05 were considered to indicate statistical significance. 3. Results During the pre- and post-vaccination periods, 47 and 49 pediatric patients were admitted to the 3 hospitals for GE-associated convulsion, respectively (Table 1, Fig. 1). The proportion of hospitalized patients with RVGE-associated convulsion during the postvaccination period was significantly lower than that of them during the pre-vaccination periods (P ¼ 0.042). The number of patients hospitalized for RVGE-associated convulsion was declined by 36.0% after the beginning of RV vaccination (Table 1). We compared the demographic characteristics and clinical findings of hospitalized patients with RVGE-associated convulsion between the pre- and post-vaccination periods. Serum sodium level in the hospitalized patients during the post-vaccination period was significantly lower than that during the pre-vaccination period (P ¼ 0.021, Table 2). During the pre- and post-vaccination periods, 319 and 330 patients were admitted to Kitakyushu General Hospital for GE, respectively (Table 3, Fig. 2). The proportion of hospitalized patients with RVGE during the post-vaccination period was significantly lower than that during the pre-vaccination periods (P ¼ 0.003). The number of patients hospitalized for RVGE was declined by 19.0% after the beginning of RV vaccination (Table 3). The number of children receiving RV or MR vaccines was assessed from returned questionnaires. Total of 1,034, 1400 and 1987 questionnaries described receiving RV vaccine and 2,932, 3057 and 3508 ones described receiving MR vaccine were returned
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
M. Kawase et al. / J Infect Chemother xxx (xxxx) xxx
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Table 1 The comparison of the changes of the hospitalization for gastroenteritis (GE)-associated convulsion between the pre- and post-rotavirus (RV) vaccination periods. No. (%)
All-cause GE-associated convulsion hospitalization Subgroups (causative pathogen) RV Others
Change rate
Pre-vaccination
Post-vaccination
47
49
þ4.3%
25 (53.2) 22 (46.8)
16 (32.7) 33 (67.3)
36.0% þ50.0%
The pre-and post-vaccination periods indicate 2009e2011, 2013e2015, respectively.
Table 3 The comparison of the changes of the hospitalization for gastroenteritis (GE) between the pre- and post-rotavirus (RV) vaccination periods. No. (%)
Change rate
Pre-vaccination All-cause GE hospitalization 319 Subgroups (causative pathogen) RV 174 (54.5) Others 145 (45.5) The pre-and respectively.
post-vaccination
periods
Post-vaccination 330
þ3.4%
141 (42.7) 189 (57.3)
19.0% þ30.3%
indicate
2009e2011,
2013e2015,
Fig. 1. The number of hospitalized patients with gastroenteritis (GE)-associated convulsion by years. The pre-vaccination period (2009e2011) indicates that before the introduction of rotavirus (RV) vaccines. The post-vaccination period (2013e2015) indicates that after the beginning of RV vaccination. The children who were hospitalized in 2012 were not assigned to either group because of a transition year. The black square indicates the number of hospitalized patients with RVGE-associated convulsion. The white square indicates the number of hospitalized patients with GE-associated convulsion caused by other pathogens.
to our institution in 2013, 2014 and 2015, respectively. Based on these results, the presumptive RV vaccination rates in Kitakyushu City were calculated to be 35.9%, 45.8% and 52.6% in 2013, 2014 and 2015, respectively. 4. Discussion The results of the present study indicated that the epidemiology of GE-associated convulsion as well as that of GE changed after the introduction of RV vaccines. Although the number of hospitalized children with GE-associated convulsion did not change, the proportion of hospitalized patients with RVGE-associated convulsion decreased significantly after the introduction of the vaccine. The unique point of the present study is that serial changes of the regional presumptive RV vaccination rate and the number of
Fig. 2. The number of hospitalized patients with gastroenteritis (GE) by years. The prevaccination period (2009e2011) indicates that before the introduction of rotavirus (RV) vaccines. The post-vaccination period (2013e2015) indicates that after the beginning of RV vaccination. The children who were hospitalized in 2012 were not assigned to either group because of a transition year. The black square indicates the number of hospitalized patients with RVGE. The white square indicates the number of the hospitalized patients with GE caused by other pathogens.
hospitalized patients with RVGE-associated convulsion were simultaneously investigated. The epidemiology of this disease will continue to change because even 50% of the vaccination rate lead to the reduction of hospitalization for RVGE-associated convulsion.
Table 2 The comparisons of the demographic characteristics and clinical findings of hospitalized patients with rotavirus gastroenteritis (GE)-associated convulsion between the preand post-vaccination periods.
Age, month Interval from the onset of GE to the development of convulsions, day Frequency of convulsions, times Fever Serum sodium level, mEq/L Serum potassium level, mEq/L Serum chloride level, mEq/L Serum glucose level, mg/dL
Pre-vaccination period (n ¼ 25)
Post-vaccination period (n ¼ 16)
P-value
21 (16e29) 3 (2e3) 2 (1e2) 17 (68.0) 137 (136e139) 4.0 (3.6e4.5) 101 (99e102) 97.0 (76.5e111.5)
21 (17e37) 3 (2.5e4) 2 (1e2) 6 (37.5) 135 (133e136) 4.1 (4.0e4.3) 100 (98e104) 78.5 (73.5e90.8)
0.482 0.079 0.061 0.747 0.021 0.776 0.726 0.085
Values are presented as median value (interquartile range) or n (%).
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
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M. Kawase et al. / J Infect Chemother xxx (xxxx) xxx
The main reason for the reduction of the number of hospitalized patients with RVGE-associated convulsion is assumed to be the reduction of the number of the patients who develop RVGE. In a previous investigation performed in Japan, the vaccine effectiveness (VE) against RVGE was calculated to be 80% [4]. In particular, RV vaccines were highly effective against severe RVGE necessitating intravenous rehydration or hospitalization (VE: 97%) [4]. In the present study, hospitalization for RVGE decreased after the introduction of RV vaccine, indicating that the reduction of the development of RVGE might contribute the reduction of the development of the convulsion which was a representative complication of RVGE. The reduction rate of hospitalized patients with RVGEassociated convulsion after the introduction of RV vaccines (36%) was larger than that of them with RVGE (19%) in the present study. This result suggested that other factors might be associated with the reduction of the number of the patients with the convulsion. The change of the genotype of RV after the introduction of RV vaccine may be another factor of the reduction of the convulsion, although the genotype was not analyzed in the present study. There was no large scale study for the relationship between RVGEassociated convulsion and the genotype whereas G3 genotype was predominantly detected from cerebrospinal fluid of diarrheic children with seizures in a small size study [9]. In Japan, the frequency of the detection of G3 genotype decreased after the introduction of RV vaccines [10]. It is important to analyze the molecular epidemiology of RVGE-associated convulsion after the introduction of RV vaccine. A previous study performed in Korea showed the change of the clinical characteristics of RVGE-associated convulsion after the introduction of RV vaccine [11]. The same tendency, including the increase of the proportion of afebrile convulsion and the elongation of the interval from the onset of GE to the development of convulsion, was observed in the present study, although the difference was not statistically significant. It was speculated that a functional change in non-structural protein 4 (NSP4), which was the RV enterotoxin and had been suggested as a causative factor of RVGE-associated convulsion [12], might have caused the change of the clinical characteristics of the disease [11]. In the present study, after the introduction of RV vaccine, serum sodium level, but not chloride or calcium level, decreased in hospitalized patients with RVGE-associated convulsion, suggested that other factors than NSP4 might be involved in this change. Further study is needed to elucidate the change of the clinical characteristics of RVGEassociated convulsion after the introduction of RV vaccine. In the present study, the presumptive RV vaccination rate gradually increased after the introduction of the vaccines, and it reached more than 50% in 2015. This rate in our city was slightly lower than that in all over Japan [5]. The reduction rate of the number of hospitalized patients with RVGE was also lower in the present study than in a nationwide survey [13]. The number of hospitalized patients with RVGE markedly decreased in other Japanese city where the official financial support for the vaccination was implemented and the vaccination rate reached approximately 90% in 2015 [14]. There is no study evaluating the reduction of the number of the patients with RVGE-associated convulsion in the context of the vaccination rate. The larger scale study is desired to analyze this issue. After the introduction of RV vaccine, norovirus (NV) replaced RV as the leading cause of GE in children in USA [15]. In addition, NVassociated convulsion has been also increasing recently in Korea [7]. Previous study speculated that the shift of main viral etiology from RV to NV in GE-associated convulsion might depend on a decrease of RV infection with a benefit of the vaccination and abrupt increase of NV activity in 2012 with the outbreak of a new
GII.4 variant among pediatric population with GE [16]. In the present study, the number of hospitalized children with GE-associated convulsion did not change despite the reduction of the number of hospitalized patients with RVGE-associated convulsion after the introduction of the vaccine, and it was suggested that NV might have replaced RV as the leading cause of GE-associated convulsion even in Japan. The present study has some limitations. First, as the epidemic of the viral infection often fluctuates, the investigation period may not be long enough. Second, the presumptive RV vaccination rate may be differ from the actual one, because it was calculated by the ratio between the number of children receiving RV vaccine and MR vaccine based on the number of returned questionnaires. Finally, study population was relatively small; this could have affected the precision of the statistical analysis. In conclusion, hospitalization for RVGE-associated convulsion decreased after the introduction of RV vaccine. RV vaccination may be effective for the prevention of extra-intestinal complications of the virus. The more elevation of RV vaccination rate would be important for the reduction of severe complications of RVGE. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors. Conflicts of interest None. References [1] Kamiya H, Nakano T, Kamiya H, Yui A, Taniguchi K, Parashar U. Rotavirusassociated acute gastroenteritis hospitalizations among Japanese children aged <5 years: active rotavirus surveillance in Mie Prefecture, Japan. Jpn J Infect Dis 2011;64:482e7. [2] Baker JM, Tate JE, Steiner CA, Haber MJ, Parashar UD, Lopman BA. Longer-term direct and indirect effects of infant rotavirus vaccination across all ages in the US; 2000 - 2013: analysis of a large hospital discharge dataset. Clin Infect Dis 2019;68:976e83. mara M, Vivancos R, [3] Hungerford D, Smith K, Tucker A, Iturriza-Go McLeonard C, et al. Population effectiveness of the pentavalent and monovalent rotavirus vaccines: a systematic review and meta-analysis of observational studies. BMC Infect Dis 2017;17:569. [4] Araki K, Hara M, Tsugawa T, Shimanoe C, Nishida Y, Matsuo M, et al. Effectiveness of monovalent and pentavalent rotavirus vaccines in Japanese children. Vaccine 2018;36:5187e93. [5] The 4th meeting of subcommittee on vaccine evaluation, division of basic policy on immunization, sectional committee on immunization and vaccine, Health Sciences Council. document 1-3: evaluation analysis on rotavirus vaccine, 2015; 2015. http://www.mhlw.go.jp/file/05-Shingikai-10601000Daijinkanboukouseikagakuka-Kouseikagakuka/0000128401.pdf. [Accessed 17 January 2015]. [6] Uemura N, Okumura A, Negoro T, Watanabe K. Clinical features of benign convulsions with mild gastroenteritis. Brain Dev 2002;24:745e9. [7] Park SH, Kim YO, Kim HK, Kim HS, Kim BY, Cheon KR, et al. Incidence of benign convulsions with mild gastroenteritis after introduction of rotavirus vaccine. Brain Dev 2015;37:625e30. [8] Ministry of Health, Labour and Welfare. Vaccination coverage for the second dose of the measles-rubella combined vaccine by municipalities. https:// www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou21/hashika.html [accessed 19.07.10]. [9] Liu B, Fujita Y, Arakawa C, Kohira R, Fuchigami T, Mugishima H, et al. Detection of rotavirus RNA and antigens in serum and cerebrospinal fluid samples from diarrheic children with seizures. Jpn J Infect Dis 2009;62:279e83. [10] Tanaka T, Kamiya H, Asada K, Suga S, Ido M, Umemoto M, et al. Changes in rotavirus genotypes before and after vaccine introduction: a multicenter, prospective observational study in three areas of Japan. Jpn J Infect Dis 2017;70:448e52. [11] Yeom JS, Kim YS, Kim RB, Park JS, Seo JH, Park E, et al. Impact of rotavirus vaccine introduction on rotavirus-associated seizures and a related possible mechanism. J Child Neurol 2015;30:729e34. [12] Yeom JS, Kim YS, Jun JS, Do HJ, Park JS, Seo JH, et al. NSP4 antibody levels in rotavirus gastroenteritis patients with seizures. Eur J Paediatr Neurol 2017;21: 367e73.
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001
M. Kawase et al. / J Infect Chemother xxx (xxxx) xxx [13] Kobayashi M, Adachi N, Miyazaki M, Tatsumi M. Decline of rotavirus-coded hospitalizations in children under 5 years: a report from Japan where rotavirus vaccines are self-financed. Vaccine 2018;36:2727e32. [14] Yoshikawa T, Matsuki T, Sato K, Mizuno M, Shibata M, Hasegawa S, et al. Impact of rotavirus vaccination on the burden of acute gastroenteritis in Nagoya city, Japan. Vaccine 2018;36:527e34.
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J, Szilagyi PG, Edwards KM, Staat MA, Weinberg GA, et al. [15] Payne DC, Vinje Norovirus and medically attended gastroenteritis in U.S. children. N Engl J Med 2013;368:1121e30. [16] Ramani S, Atmar RL, Estes MK. Epidemiology of human noroviruses and updates on vaccine development. Curr Opin Gastroenterol 2014;30: 25e33.
Please cite this article as: Kawase M et al., The changes of the epidemiology and clinical characteristics of rotavirus gastroenteritis-associated convulsion after the introduction of rotavirus vaccine, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.09.001