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Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination
Vaccine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination Matthew J. Kelly a,⇑, David Foley b, Timothy K. Blackmore b,c a b c
Department of Medicine, Hutt Hospital, Hutt Valley District Health Board, High St, Lower Hutt 5010, New Zealand Wellington SCL Microbiology Laboratory, Wellington Hospital, Riddiford St, Wellington 6010, New Zealand Department of Infection Services, Wellington Hospital, Capital and Coast District Health Board, Riddiford St, Wellington 6010, New Zealand
a r t i c l e
i n f o
Article history: Received 23 August 2016 Received in revised form 16 June 2017 Accepted 5 July 2017 Available online xxxx Keywords: Rotavirus Vaccination New Zealand Hospital admission
a b s t r a c t Aim: To assess the impact of the introduction of rotavirus vaccination in New Zealand at a regional and national level, underlining the utility of a passively collected laboratory dataset. Method: Retrospective laboratory data for rotavirus testing from Wellington and Hutt Hospitals from 1 January 2010 to 31 December 2016, matched with hospital admissions data of children under 5 years of age with gastroenteritis primary and secondary coded admissions. The second part of the study examined the national dataset of primary coded hospital gastroenteritis admissions from the same period. Results: Rotavirus testing was performed in 1054 (64.1%) of the 1645 gastroenteritis admissions to Wellington and Hutt Hospitals. Four hundred and nine of these tests (38.8%) were positive. Children who were not given a primary code of gastroenteritis accounted for 5.7% of rotavirus admissions. The estimated annual rotavirus hospitalisation rate in the Hutt and Wellington regions for children under 5 years during the pre-vaccination period was 427.1 per 100,000. In the post-vaccination period (2015–2016), there was a 94.6% reduction in confirmed rotavirus gastroenteritis hospitalisations with only 8 confirmed cases. The total number of gastroenteritis admissions declined by 51.4%. On a national scale, there was a decline of 34.4% in the average annual number of gastroenteritis admissions and the number of coded rotavirus admissions was 87.1% lower than the pre-vaccination average. Conclusion: The non-restrictive continuous approach to rotavirus testing has provided a detailed description of the epidemiology of rotavirus gastroenteritis hospitalisations in the Wellington and Hutt regions. Rotavirus vaccination introduced on the crest of a peak in rotavirus cases has lead to a marked reduction in the number of admissions with gastroenteritis in New Zealand in the two years following vaccine introduction. The national figures likely underestimate the impact of the vaccine. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Rotavirus gastroenteritis has a significant burden of morbidity and mortality [1]. Prior to the introduction of the rotavirus vaccine, it was estimated that 90% of children in New Zealand would have developed rotavirus gastroenteritis by three years of age [2]. Approximately one in five children would have received medical care and one in 43 would have been admitted to hospital by five years of age [3]. In 2006, an effective vaccine began to be adopted by national immunization programs worldwide [4]. In July 2014, New Zealand introduced a live attenuated pentavalent reassortment vaccine (RotaTeq) for use in the prevention of rotavirus gas-
⇑ Corresponding author. E-mail address: [email protected] (M.J. Kelly).
troenteritis [1]. The reassortment viruses, isolated from bovine and human hosts, express a combination of outer capsid proteins and attachment proteins from their parent strains [5]. This orally administered vaccine was included as part of the routine free immunisation schedule at six weeks, three months and five months [1]. By September 2015, 79 countries including New Zealand had incorporated the vaccine into their schedules [4]. Completing the vaccination regimen has been found to be protective against 74% of rotavirus gastroenteritis of any severity, with almost complete protection against severe gastroenteritis [6]. A systematic review of published data from 9 countries reported a decline of between 49% and 89% in laboratory-confirmed rotavirus hospitalizations of children less than five years in the two years after vaccine introduction [7]. A decline was also seen in the incidence of infection in children that were not vaccinated indicating a herd effect [4].
http://dx.doi.org/10.1016/j.vaccine.2017.07.018 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
2
M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx
The aim of this study was to assess the impact of the introduction of the rotavirus vaccine in New Zealand at a regional and national level. We report on the utility of a regional continuous passively collected dataset in providing a detailed epidemiological evaluation of the impact of the introduction at a regional level. We examined the data from two neighbouring district health boards, Wellington and Hutt Hospital laboratory services. Wellington and Hutt Hospitals provide the only acute inpatient hospital services for the local population consisting of over 28,000 children under 5 years accounting for 9.2% of that population in New Zealand [8]. The only other emergency services available for children in the region are general practice clinics. Data from the period spanning pre- and post-vaccine introduction was utilised to describe the epidemiology of gastroenteritis admissions and rotavirus in the hospital setting, including hospital-acquired infections. Secondly, we evaluated the impact on the overall national admission rate for gastroenteritis and rotavirus coded hospital admissions of children under 5 years in New Zealand. 2. Methods The first part of the study employed retrospective laboratory data for rotavirus testing from Wellington and Hutt Hospitals from 1st January 2010 to 31st December 2016, matched with hospital admissions data of children under 5 years of age. It is our standard practice that all stool specimens from children under 5 years of age are tested for rotavirus, even when not specifically requested. This is the only viral test that is reflexively performed. Testing for other viruses such as adenovirus or norovirus must be specifically requested. Rotavirus tests were performed using the Coris BioConcept RotaStrip test (Wellington Hospital) or Meridian Latex agglutination test (Hutt Hospital). Duplicate tests were defined as a repeat test performed on the same date and were excluded. Children with a primary or secondary diagnostic code for acute gastroenteritis (ICD-10-AM) covering known infectious or unknown causes of gastroenteritis (A000–A090) were selected from the hospital admissions database. This includes the specific code for rotaviral enteritis (A080). An admission was classified as admission onto a paediatric ward. Children discharged from the Emergency Departments or Child Assessment Units were not included. Second admissions were excluded if occurring within 7 days. Data was matched in Microsoft Excel using the unique National Health Index (NHI). The rotavirus test was considered to be relevant to the child’s admission if the test was performed from 3 days prior to admission until 3 days after discharge. To account for potential miscoding, children with a positive rotavirus test without a gastroenteritis admission code were identified. If an admission occurred without a gastroenteritis code, the clinical notes were reviewed to determine if the admission could be attributed to rotavirus. These cases were included in the analysis. 2.1. Burden of disease To estimate the total number of rotavirus admissions, children with gastroenteritis who did not have a rotavirus test performed were assumed to have the same positivity rate as those who did undergo testing, standardising for age (six-monthly intervals), coding category (primary vs. secondary) and season (summer-autumn vs. winter-spring). Population estimates were calculated using data from Statistics New Zealand from Census 2013 [8]. Rotavirus vaccine became freely available from the start of July 2014. This corresponded with the peak season for rotavirus. The year of vaccine introduction was included as part of the pre-vaccination period due to the relatively small number of children eligible for vaccination during this time.
2.2. Hospital acquired infections Potential hospital-acquired infections (HAI) with rotavirus were defined as a positive rotavirus test 3 or more days after the date of admission or within 7 days of discharge. The clinical notes of potential cases were reviewed to determine if this was consistent with a probable HAI. Probable HAI cases were excluded from analyses of gastroenteritis hospitalisations. 2.3. National data The second part of the study examined the national data set of all coded paediatric hospital admissions from January 2010 to December 2016. This data set captures all public and private hospital discharge codes. The number of admissions of children under 5 years of age with a primary diagnostic code of acute gastroenteritis (A000-A090) and rotaviral enteritis (A080) were extracted. Only acute admissions were included in the analysis. The data was examined in yearly cohorts. 2.4. Analysis Statistical analyses were performed using Stata/IC 11.1 statistical software. Categorical variables were compared using chisquared tests. Unconditional logistic regression was performed to assess the impact of factors on testing and positive results. Results of statistical tests are presented as odds ratios with 95% confidence intervals. 2.5. Ethics This study was a surveillance activity using routinely collected clinical and laboratory data. The Hospital Research Governance Group determined that this did not require formal ethical review. The study was registered with the local Child Health Research Committee. 3. Results During the study period, 3836 rotavirus tests were performed (excluding 64 duplicates) of which 498 (13.0%) were positive. The number of children admitted with a diagnostic code for gastroenteritis during this period was 1645 which included 334 (20.3%) admissions with gastroenteritis as a secondary diagnostic code. A further 11 admissions with a positive rotavirus test which did not have a diagnostic code for gastroenteritis were identified from the laboratory data and were included in the data set. Twenty-five admissions, including 3 un-coded cases, were identified as hospital-acquired rotavirus infection and were excluded from the analysis. Rotavirus testing was performed in 1054 (64.1%) of the 1645 gastroenteritis admissions (Table 1). Four hundred and nine of these tests (38.8%) were positive. The rotavirus specific code (A080) was used in 362 (88.5%) of these confirmed rotavirus gastroenteritis admissions. Twenty-six children (7.2%) were incorrectly coded with the A080 code when they had either a negative rotavirus test or had not been tested. 3.1. Factors associated with being tested Children were more likely to be tested if they were admitted to Wellington hospital compared to Hutt Hospital (68.5% vs. 56.1%, OR 1.67, 95%CI 1.36–2.05). Testing was more likely to occur during the winter-spring seasons when rotavirus is more prevalent compared to the summer-autumn season (66.6% vs. 59.9%, OR 1.33,
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
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M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx Table 1 Characteristics of children under 5 years of age admitted with gastroenteritis to Wellington and Hutt hospitals for 2010–2016.
a
Gastroenteritis admissions n = 1645 (%)
Tested for rotavirus n = 1054 (%)
Rotavirus positive n = 409 (%)
Year 2010–2014 (pre vaccine) Yearly average 2015–2016 (post vaccine) Yearly average
1378 (83.8) 276 267 (16.2) 134
906 (85.6) 181 148 (14.0) 74
401 (98.0) 80 8 (2.0) 4
Season Winter/Spring Summer/Autumn
1032 (62.7) 613 (37.3)
687 (65.2) 367 (34.8)
344 (84.1) 65 (15.9)
Hospital Wellington Hutt
1027 (62.4) 618 (37.6)
704 (66.8) 350 (33.2)
232 (56.7) 177 (43.3)
Coding categorya Primary diagnosis Secondary diagnosis
1303 (79.2) 334 (20.3)
822 (78.0) 224 (21.3)
378 (92.4) 23 (5.6)
Gender Male Female
845 (51.4) 800 (48.6)
551 (52.3) 503 (47.7)
201 (49.1) 208 (50.9)
Age in months 0–11 12–24 24–35 36–47 48–59
679 (41.3) 500 (30.4) 236 (14.3) 137 (8.3) 93 (5.7)
480 (45.5) 343 (32.5) 128 (12.1) 66 (6.3) 37 (3.5)
106 (25.9) 174 (42.5) 78 (19.1) 35 (8.6) 16 (3.9)
Ethnicity European/other Maori Pacific
1153 (70.1) 293 (17.8) 199 (12.1)
739 (70.1) 185 (17.6) 130 (12.3)
283 (69.2) 80 (19.6) 46 (11.2)
Percentages do not add up to 100 as there were a further 8 rotavirus admissions identified from the laboratory data but not coded as gastroenteritis.
95%CI 1.09–1.64). A logistic regression model was employed to analyse testing controlling for season group (winter-spring versus summer-autumn), age at admission, gender, ethnicity and hospital location. The winter-spring period (OR 1.42, 95%CI 1.14–1.75) and Wellington hospital (OR 1.65, 95%CI 1.33–2.04) were associated with an increased rate of testing. Increasing age was associated with reduced testing (OR 0.70, 95% CI 0.64–0.76). Children were less likely to be tested during the post-vaccination period (2015– 2016) compared to the pre-vaccination period (2010–2014) (55.4% vs. 65.7%, OR 0.65, 95%CI 0.50–0.84). This effect remained significant after controlling for season group (winter-spring versus summer-autumn), age at admission, gender, ethnicity and hospital location (OR = 0.64, 95%CI 0.48–0.84). 3.2. Factors associated with testing positive for rotavirus Children tested at Wellington Hospital were less likely to be positive compared with being tested at Hutt Hospital (33.0% vs. 50.6%, OR 0.48, 95%CI 0.37–0.62). Cases with a primary code for gastroenteritis were more likely to test positive (46.0% vs. 10.3%, OR 5.52, 95%CI 3.70–8.23) as were those tested in winter-spring (50.1% vs. 17.7%, OR 4.66, 95%CI 3.43–6.33). There was no statistically significant difference in rotavirus cases based on gender or ethnicity. A logistic regression model was employed to analyse factors associated with a positive test, controlling for season group (winter-spring versus summer-autumn), age at admission, gender, ethnicity and hospital location. Again, the winter-spring period was statistically associated with a positive test result (OR 4.62, 95% CI 3.35–6.38) as was increasing age (OR 1.66, 95% CI 1.45– 1.90). Testing at Wellington hospital was associated with a reduced likelihood of a positive test result (OR 0.48, 95% CI 0.36–0.64).
during the 2014 winter-spring season (Fig. 1), although none of the confirmed cases were in the age group eligible for free vaccination. The average number of confirmed admissions per year in the prevaccination period was 80. The number of confirmed rotavirus admissions in the two year post-vaccination period declined by 94.6% with only 8 confirmed cases. The average number of gastroenteritis admissions per year declined by 51.4% from 276 down to 134. After taking into account those children who were not tested for rotavirus, the estimated number of rotavirus admissions in the pre-vaccination period was 628 (standardised for age, season and coding category). This accounted for 45.6% (628/1378) of all gastroenteritis admissions and 3.8% (628/16488) of all under 5 year old admissions to the paediatric wards during 2010–2014. The estimated annual rotavirus hospitalisation rate in the Hutt and Wellington regions for children under 5 years was 427.1 per 100,000 in the pre-vaccination period. Hospitalisation for rotavirus gastroenteritis occurred most frequently in children between 6 and 24 months of age (Fig. 2). 3.4. Hospital-acquired infections There were 25 cases of probable hospital-acquired rotavirus infection. Ten (40.0%) of these occurred during summer-autumn when there are usually low levels of rotavirus transmission in the community. Eight of the cases were in surgical patients. It was noted the HAI cases frequently occurred in clusters and in one instance there were 5 cases of HAI over the space of 10 days during one summer month. The estimated incidence of rotavirus HAI for the pre-vaccination period was 0.15 cases per 100 admissions. There were no confirmed rotavirus HAI in the postvaccination period.
3.3. Burden of severe rotavirus pre and post vaccination
3.5. National coded data
Vaccination became freely available in the middle of winter (July) in 2014. There were a large number of rotavirus admissions
During the pre-vaccination period (2010–2014), the average annual number of hospitalisations of children less than five years
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
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M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx
Fig. 1. Distribution by month and year of the number of children under 5 years of age admitted to Wellington and Hutt hospitals with gastroenteritis, tested for rotavirus, and positive for rotavirus. Rotavirus vaccination was introduced in July 2014.
Fig. 2. Number of admissions to Wellington and Hutt hospitals for 2010–2014 (prevaccine period) of children under 5 years of age with all causes of gastroenteritis and estimated number due to rotavirus according to age. Estimates were calculated standardising for age (six-monthly intervals), coding category (primary vs. secondary) and season (summer/autumn vs. winter/spring).
with a primary diagnostic code for acute gastroenteritis was 3782. The yearly average for the specific code for rotavirus was 661. In the post-vaccination period (2015–2016) the average annual number of gastroenteritis admissions was 2480, a decline of 34.4% (Fig. 3). The average annual number of hospitalisations coded as rotavirus was 86, 87.1% lower than the pre-vaccination average.
4. Discussion Our study used passive surveillance laboratory data matched with hospital admissions coding data to give an accurate description of the epidemiology of severe rotavirus infection. Our results are consistent with the findings from an earlier, more costly and labour intensive prospective study in New Zealand [9]. This demonstrates the utility of using laboratory data for monitoring purposes when it is known that coding data alone is inaccurate or incomplete. Our most striking finding was that there were only eight confirmed rotavirus admissions in the Wellington and Hutt regions
Fig. 3. Number of admissions of children in New Zealand under 5 years of age with a primary diagnostic code of acute gastroenteritis (A000-A090) and rotaviral enteritis (A080) for 2010–2016. Rotavirus vaccination was introduced in July 2014.
in the two years following introduction of the vaccine. The high rate of rotavirus infection in the community during the year of vaccine introduction is likely to have increased population immunity. This factor combined with rapid vaccine uptake is the likely explanation for the dramatic reduction in rotavirus hospitalisations. The national, Hutt region and Wellington region coverage for rotavirus vaccine was 89%, 89% and 88% respectively for children reaching the eight month milestone between 1st January 2015 and 31st March 2016 [10]. Vaccine introduction coinciding with an outbreak may have encouraged vaccine acceptance, timeliness and adherence [11]. Further peaks in rotavirus cases may occur in New Zealand although total burden is expected to be significantly reduced. These outbreaks may not affect the same age profile or occur in the expected winter-spring season [4]. The national data is consistent with our local findings of a marked reduction in hospitalisations following vaccine introduction although the effect is not as pronounced. Prior to the vaccine introduction, almost one in six of the national yearly average of 3782 coded gastroenteritis admissions for children less than 5 years was attributed to rotavirus infection. It is contended that this coding data is an under representation of both the total gas-
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx
troenteritis admissions and the rotavirus proportion and therefore underestimates the impact of vaccination. Unlike the approach adopted in the Wellington and Hutt region, most hospitals in New Zealand do not routinely test for rotavirus. Based on the assumption of a similar positive rate to the Hutt-Wellington region, the pre-vaccination burden nationally was more likely to be 1724 admissions per year, more than double the incidence reported in the national figures. Furthermore, the national data was retrieved using primary diagnostic codes. Our study found that 16.2% of gastroenteritis admissions were identified with a secondary diagnostic code and these cases accounted for 5.7% of confirmed rotavirus gastroenteritis admissions. The estimated incidence of rotavirus hospital-acquired infections in the pre-vaccination period was 0.15 cases per 100. This rate is similar to a previous reported rate of 0.7 (95% CI: 0.0–1.8) for children under 5 years of age [12]. Akin to other reports, our cases occurred in clusters. Interestingly, our cases occurred in lower incidence seasons. The increased frequency of HAI cases during this period suggested decreased vigilance during times of lower disease burden. There were no confirmed cases of HAI in the postvaccination period. Rotavirus HAI is anticipated to become an uncommon problem due to the reduced number of rotavirus admissions as well as greater immunity of children admitted to hospital. 4.1. Limitations The main limitation of this study is the retrospective observational design which risks confounding from known and unknown factors. The disparity in the rate of testing and the proportion of positive results between Wellington and Hutt Hospitals may represent more selective testing at Hutt Hospital. It has been previously suggested that rotavirus can be recognised by nursing staff by odour [13]. This selective testing may influence overall results, inflating the reported incidence. The two centres also used different tests and both tests are acknowledged as not being as accurate as PCR. As the incidence of rotavirus declines there would be an expected increase in the proportion of false positive test results. To account for this, all positive samples are now being submitted for PCR confirmation and viral typing as part of a national surveillance programme through the Institute of Environmental Science and Research (ESR). It is possible that the management of paediatric gastroenteritis at the two hospitals changed during the study period. This may have lead to a decline in admissions although it is unlikely that any change in practice could entirely explain such a sudden and marked reduction in admissions as occurred following vaccine introduction. Rates of testing were also lower during the postvaccination period. This may have caused an overestimation of the impact of the vaccine, however the rate of testing was still relatively high (55.4%) and active case finding is engaged as part of infection control policies in both units.
5
5. Conclusion Rotavirus vaccine introduced on the crest of a peak in rotavirus cases has had an immediate and significant impact on the number of gastroenteritis admissions in New Zealand. The non-restrictive continuous approach to rotavirus testing has provided a detailed description of the epidemiology of rotavirus gastroenteritis hospitalisations in the Wellington and Hutt regions. This data, which may not be able to be calculated elsewhere due to inconsistent testing practices, offers further characterisation of the national dataset for rotavirus admissions. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgements This study did not receive any funding support. We wish to thank Sharon Morse and Nicole O’Connor for their assistance with data extraction. We also wish to thank Tricia Martin, Sagni Prasad and all staff on the paediatric wards at Wellington and Hutt Hospitals. References [1] Immunisation Handbook 2014. 6th ed. Wellington: Ministry of Health: Ministry of Health; 2014. [2] Rotavirus. Diseases and illnesses. Ministry of Health website: Ministry of Health; 2014. [3] Milne RJ, Grimwood K. Budget impact and cost-effectiveness of including a pentavalent rotavirus vaccine in the New Zealand childhood immunization schedule. Value Health: J Int Soc Pharmacoecon Outcomes Res 2009;12:888–98. [4] Parashar UD, Johnson H, Steele AD, Tate JE. Health impact of rotavirus vaccination in developing countries: progress and way forward. Clin Infect Diseases: An Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S91–5. [5] Dohme M. RotaTeq Package insert. In: Administration FaD, editor. Online. Food and Drug Administration Website; 2013. [6] Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. New Engl J Med 2006;354:23–33. [7] Patel MM, Glass R, Desai R, Tate JE, Parashar UD. Fulfilling the promise of rotavirus vaccines: how far have we come since licensure? Lancet Infect Dis 2012;12:561–70. [8] Zealand SN. 2013 Census tables about a place. Census Data New Zealand. Online: Statistics New Zealand; 2016. [9] Grimwood K, Huang QS, Cohet C, Gosling IA, Hook SM, Teele DW, et al. Rotavirus hospitalisation in New Zealand children under 3 years of age. J Paediatr Child Health 2006;42:196–203. [10] Tuohy P. Official information act request to the Ministry of Health. In: Foley DD, editor; 2016. [11] Hull BP, Menzies R, Macartney K, McIntyre PB. Impact of the introduction of rotavirus vaccine on the timeliness of other scheduled vaccines: the Australian experience. Vaccine 2013;31:1964–9. [12] Bruijning-Verhagen P, Quach C, Bonten M. Nosocomial rotavirus infections: a meta-analysis. Pediatrics 2012;129:e1011–9. [13] Poulton J, Tarlow MJ. Diagnosis of rotavirus gastroenteritis by smell. Arch Dis Childhood 1987;62:851–2.
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination Matthew J. Kelly a,⇑, David Foley b, Timothy K. Blackmore b,c a b c
Department of Medicine, Hutt Hospital, Hutt Valley District Health Board, High St, Lower Hutt 5010, New Zealand Wellington SCL Microbiology Laboratory, Wellington Hospital, Riddiford St, Wellington 6010, New Zealand Department of Infection Services, Wellington Hospital, Capital and Coast District Health Board, Riddiford St, Wellington 6010, New Zealand
a r t i c l e
i n f o
Article history: Received 23 August 2016 Received in revised form 16 June 2017 Accepted 5 July 2017 Available online xxxx Keywords: Rotavirus Vaccination New Zealand Hospital admission
a b s t r a c t Aim: To assess the impact of the introduction of rotavirus vaccination in New Zealand at a regional and national level, underlining the utility of a passively collected laboratory dataset. Method: Retrospective laboratory data for rotavirus testing from Wellington and Hutt Hospitals from 1 January 2010 to 31 December 2016, matched with hospital admissions data of children under 5 years of age with gastroenteritis primary and secondary coded admissions. The second part of the study examined the national dataset of primary coded hospital gastroenteritis admissions from the same period. Results: Rotavirus testing was performed in 1054 (64.1%) of the 1645 gastroenteritis admissions to Wellington and Hutt Hospitals. Four hundred and nine of these tests (38.8%) were positive. Children who were not given a primary code of gastroenteritis accounted for 5.7% of rotavirus admissions. The estimated annual rotavirus hospitalisation rate in the Hutt and Wellington regions for children under 5 years during the pre-vaccination period was 427.1 per 100,000. In the post-vaccination period (2015–2016), there was a 94.6% reduction in confirmed rotavirus gastroenteritis hospitalisations with only 8 confirmed cases. The total number of gastroenteritis admissions declined by 51.4%. On a national scale, there was a decline of 34.4% in the average annual number of gastroenteritis admissions and the number of coded rotavirus admissions was 87.1% lower than the pre-vaccination average. Conclusion: The non-restrictive continuous approach to rotavirus testing has provided a detailed description of the epidemiology of rotavirus gastroenteritis hospitalisations in the Wellington and Hutt regions. Rotavirus vaccination introduced on the crest of a peak in rotavirus cases has lead to a marked reduction in the number of admissions with gastroenteritis in New Zealand in the two years following vaccine introduction. The national figures likely underestimate the impact of the vaccine. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Rotavirus gastroenteritis has a significant burden of morbidity and mortality [1]. Prior to the introduction of the rotavirus vaccine, it was estimated that 90% of children in New Zealand would have developed rotavirus gastroenteritis by three years of age [2]. Approximately one in five children would have received medical care and one in 43 would have been admitted to hospital by five years of age [3]. In 2006, an effective vaccine began to be adopted by national immunization programs worldwide [4]. In July 2014, New Zealand introduced a live attenuated pentavalent reassortment vaccine (RotaTeq) for use in the prevention of rotavirus gas-
⇑ Corresponding author. E-mail address: [email protected] (M.J. Kelly).
troenteritis [1]. The reassortment viruses, isolated from bovine and human hosts, express a combination of outer capsid proteins and attachment proteins from their parent strains [5]. This orally administered vaccine was included as part of the routine free immunisation schedule at six weeks, three months and five months [1]. By September 2015, 79 countries including New Zealand had incorporated the vaccine into their schedules [4]. Completing the vaccination regimen has been found to be protective against 74% of rotavirus gastroenteritis of any severity, with almost complete protection against severe gastroenteritis [6]. A systematic review of published data from 9 countries reported a decline of between 49% and 89% in laboratory-confirmed rotavirus hospitalizations of children less than five years in the two years after vaccine introduction [7]. A decline was also seen in the incidence of infection in children that were not vaccinated indicating a herd effect [4].
http://dx.doi.org/10.1016/j.vaccine.2017.07.018 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
2
M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx
The aim of this study was to assess the impact of the introduction of the rotavirus vaccine in New Zealand at a regional and national level. We report on the utility of a regional continuous passively collected dataset in providing a detailed epidemiological evaluation of the impact of the introduction at a regional level. We examined the data from two neighbouring district health boards, Wellington and Hutt Hospital laboratory services. Wellington and Hutt Hospitals provide the only acute inpatient hospital services for the local population consisting of over 28,000 children under 5 years accounting for 9.2% of that population in New Zealand [8]. The only other emergency services available for children in the region are general practice clinics. Data from the period spanning pre- and post-vaccine introduction was utilised to describe the epidemiology of gastroenteritis admissions and rotavirus in the hospital setting, including hospital-acquired infections. Secondly, we evaluated the impact on the overall national admission rate for gastroenteritis and rotavirus coded hospital admissions of children under 5 years in New Zealand. 2. Methods The first part of the study employed retrospective laboratory data for rotavirus testing from Wellington and Hutt Hospitals from 1st January 2010 to 31st December 2016, matched with hospital admissions data of children under 5 years of age. It is our standard practice that all stool specimens from children under 5 years of age are tested for rotavirus, even when not specifically requested. This is the only viral test that is reflexively performed. Testing for other viruses such as adenovirus or norovirus must be specifically requested. Rotavirus tests were performed using the Coris BioConcept RotaStrip test (Wellington Hospital) or Meridian Latex agglutination test (Hutt Hospital). Duplicate tests were defined as a repeat test performed on the same date and were excluded. Children with a primary or secondary diagnostic code for acute gastroenteritis (ICD-10-AM) covering known infectious or unknown causes of gastroenteritis (A000–A090) were selected from the hospital admissions database. This includes the specific code for rotaviral enteritis (A080). An admission was classified as admission onto a paediatric ward. Children discharged from the Emergency Departments or Child Assessment Units were not included. Second admissions were excluded if occurring within 7 days. Data was matched in Microsoft Excel using the unique National Health Index (NHI). The rotavirus test was considered to be relevant to the child’s admission if the test was performed from 3 days prior to admission until 3 days after discharge. To account for potential miscoding, children with a positive rotavirus test without a gastroenteritis admission code were identified. If an admission occurred without a gastroenteritis code, the clinical notes were reviewed to determine if the admission could be attributed to rotavirus. These cases were included in the analysis. 2.1. Burden of disease To estimate the total number of rotavirus admissions, children with gastroenteritis who did not have a rotavirus test performed were assumed to have the same positivity rate as those who did undergo testing, standardising for age (six-monthly intervals), coding category (primary vs. secondary) and season (summer-autumn vs. winter-spring). Population estimates were calculated using data from Statistics New Zealand from Census 2013 [8]. Rotavirus vaccine became freely available from the start of July 2014. This corresponded with the peak season for rotavirus. The year of vaccine introduction was included as part of the pre-vaccination period due to the relatively small number of children eligible for vaccination during this time.
2.2. Hospital acquired infections Potential hospital-acquired infections (HAI) with rotavirus were defined as a positive rotavirus test 3 or more days after the date of admission or within 7 days of discharge. The clinical notes of potential cases were reviewed to determine if this was consistent with a probable HAI. Probable HAI cases were excluded from analyses of gastroenteritis hospitalisations. 2.3. National data The second part of the study examined the national data set of all coded paediatric hospital admissions from January 2010 to December 2016. This data set captures all public and private hospital discharge codes. The number of admissions of children under 5 years of age with a primary diagnostic code of acute gastroenteritis (A000-A090) and rotaviral enteritis (A080) were extracted. Only acute admissions were included in the analysis. The data was examined in yearly cohorts. 2.4. Analysis Statistical analyses were performed using Stata/IC 11.1 statistical software. Categorical variables were compared using chisquared tests. Unconditional logistic regression was performed to assess the impact of factors on testing and positive results. Results of statistical tests are presented as odds ratios with 95% confidence intervals. 2.5. Ethics This study was a surveillance activity using routinely collected clinical and laboratory data. The Hospital Research Governance Group determined that this did not require formal ethical review. The study was registered with the local Child Health Research Committee. 3. Results During the study period, 3836 rotavirus tests were performed (excluding 64 duplicates) of which 498 (13.0%) were positive. The number of children admitted with a diagnostic code for gastroenteritis during this period was 1645 which included 334 (20.3%) admissions with gastroenteritis as a secondary diagnostic code. A further 11 admissions with a positive rotavirus test which did not have a diagnostic code for gastroenteritis were identified from the laboratory data and were included in the data set. Twenty-five admissions, including 3 un-coded cases, were identified as hospital-acquired rotavirus infection and were excluded from the analysis. Rotavirus testing was performed in 1054 (64.1%) of the 1645 gastroenteritis admissions (Table 1). Four hundred and nine of these tests (38.8%) were positive. The rotavirus specific code (A080) was used in 362 (88.5%) of these confirmed rotavirus gastroenteritis admissions. Twenty-six children (7.2%) were incorrectly coded with the A080 code when they had either a negative rotavirus test or had not been tested. 3.1. Factors associated with being tested Children were more likely to be tested if they were admitted to Wellington hospital compared to Hutt Hospital (68.5% vs. 56.1%, OR 1.67, 95%CI 1.36–2.05). Testing was more likely to occur during the winter-spring seasons when rotavirus is more prevalent compared to the summer-autumn season (66.6% vs. 59.9%, OR 1.33,
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
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M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx Table 1 Characteristics of children under 5 years of age admitted with gastroenteritis to Wellington and Hutt hospitals for 2010–2016.
a
Gastroenteritis admissions n = 1645 (%)
Tested for rotavirus n = 1054 (%)
Rotavirus positive n = 409 (%)
Year 2010–2014 (pre vaccine) Yearly average 2015–2016 (post vaccine) Yearly average
1378 (83.8) 276 267 (16.2) 134
906 (85.6) 181 148 (14.0) 74
401 (98.0) 80 8 (2.0) 4
Season Winter/Spring Summer/Autumn
1032 (62.7) 613 (37.3)
687 (65.2) 367 (34.8)
344 (84.1) 65 (15.9)
Hospital Wellington Hutt
1027 (62.4) 618 (37.6)
704 (66.8) 350 (33.2)
232 (56.7) 177 (43.3)
Coding categorya Primary diagnosis Secondary diagnosis
1303 (79.2) 334 (20.3)
822 (78.0) 224 (21.3)
378 (92.4) 23 (5.6)
Gender Male Female
845 (51.4) 800 (48.6)
551 (52.3) 503 (47.7)
201 (49.1) 208 (50.9)
Age in months 0–11 12–24 24–35 36–47 48–59
679 (41.3) 500 (30.4) 236 (14.3) 137 (8.3) 93 (5.7)
480 (45.5) 343 (32.5) 128 (12.1) 66 (6.3) 37 (3.5)
106 (25.9) 174 (42.5) 78 (19.1) 35 (8.6) 16 (3.9)
Ethnicity European/other Maori Pacific
1153 (70.1) 293 (17.8) 199 (12.1)
739 (70.1) 185 (17.6) 130 (12.3)
283 (69.2) 80 (19.6) 46 (11.2)
Percentages do not add up to 100 as there were a further 8 rotavirus admissions identified from the laboratory data but not coded as gastroenteritis.
95%CI 1.09–1.64). A logistic regression model was employed to analyse testing controlling for season group (winter-spring versus summer-autumn), age at admission, gender, ethnicity and hospital location. The winter-spring period (OR 1.42, 95%CI 1.14–1.75) and Wellington hospital (OR 1.65, 95%CI 1.33–2.04) were associated with an increased rate of testing. Increasing age was associated with reduced testing (OR 0.70, 95% CI 0.64–0.76). Children were less likely to be tested during the post-vaccination period (2015– 2016) compared to the pre-vaccination period (2010–2014) (55.4% vs. 65.7%, OR 0.65, 95%CI 0.50–0.84). This effect remained significant after controlling for season group (winter-spring versus summer-autumn), age at admission, gender, ethnicity and hospital location (OR = 0.64, 95%CI 0.48–0.84). 3.2. Factors associated with testing positive for rotavirus Children tested at Wellington Hospital were less likely to be positive compared with being tested at Hutt Hospital (33.0% vs. 50.6%, OR 0.48, 95%CI 0.37–0.62). Cases with a primary code for gastroenteritis were more likely to test positive (46.0% vs. 10.3%, OR 5.52, 95%CI 3.70–8.23) as were those tested in winter-spring (50.1% vs. 17.7%, OR 4.66, 95%CI 3.43–6.33). There was no statistically significant difference in rotavirus cases based on gender or ethnicity. A logistic regression model was employed to analyse factors associated with a positive test, controlling for season group (winter-spring versus summer-autumn), age at admission, gender, ethnicity and hospital location. Again, the winter-spring period was statistically associated with a positive test result (OR 4.62, 95% CI 3.35–6.38) as was increasing age (OR 1.66, 95% CI 1.45– 1.90). Testing at Wellington hospital was associated with a reduced likelihood of a positive test result (OR 0.48, 95% CI 0.36–0.64).
during the 2014 winter-spring season (Fig. 1), although none of the confirmed cases were in the age group eligible for free vaccination. The average number of confirmed admissions per year in the prevaccination period was 80. The number of confirmed rotavirus admissions in the two year post-vaccination period declined by 94.6% with only 8 confirmed cases. The average number of gastroenteritis admissions per year declined by 51.4% from 276 down to 134. After taking into account those children who were not tested for rotavirus, the estimated number of rotavirus admissions in the pre-vaccination period was 628 (standardised for age, season and coding category). This accounted for 45.6% (628/1378) of all gastroenteritis admissions and 3.8% (628/16488) of all under 5 year old admissions to the paediatric wards during 2010–2014. The estimated annual rotavirus hospitalisation rate in the Hutt and Wellington regions for children under 5 years was 427.1 per 100,000 in the pre-vaccination period. Hospitalisation for rotavirus gastroenteritis occurred most frequently in children between 6 and 24 months of age (Fig. 2). 3.4. Hospital-acquired infections There were 25 cases of probable hospital-acquired rotavirus infection. Ten (40.0%) of these occurred during summer-autumn when there are usually low levels of rotavirus transmission in the community. Eight of the cases were in surgical patients. It was noted the HAI cases frequently occurred in clusters and in one instance there were 5 cases of HAI over the space of 10 days during one summer month. The estimated incidence of rotavirus HAI for the pre-vaccination period was 0.15 cases per 100 admissions. There were no confirmed rotavirus HAI in the postvaccination period.
3.3. Burden of severe rotavirus pre and post vaccination
3.5. National coded data
Vaccination became freely available in the middle of winter (July) in 2014. There were a large number of rotavirus admissions
During the pre-vaccination period (2010–2014), the average annual number of hospitalisations of children less than five years
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
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M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx
Fig. 1. Distribution by month and year of the number of children under 5 years of age admitted to Wellington and Hutt hospitals with gastroenteritis, tested for rotavirus, and positive for rotavirus. Rotavirus vaccination was introduced in July 2014.
Fig. 2. Number of admissions to Wellington and Hutt hospitals for 2010–2014 (prevaccine period) of children under 5 years of age with all causes of gastroenteritis and estimated number due to rotavirus according to age. Estimates were calculated standardising for age (six-monthly intervals), coding category (primary vs. secondary) and season (summer/autumn vs. winter/spring).
with a primary diagnostic code for acute gastroenteritis was 3782. The yearly average for the specific code for rotavirus was 661. In the post-vaccination period (2015–2016) the average annual number of gastroenteritis admissions was 2480, a decline of 34.4% (Fig. 3). The average annual number of hospitalisations coded as rotavirus was 86, 87.1% lower than the pre-vaccination average.
4. Discussion Our study used passive surveillance laboratory data matched with hospital admissions coding data to give an accurate description of the epidemiology of severe rotavirus infection. Our results are consistent with the findings from an earlier, more costly and labour intensive prospective study in New Zealand [9]. This demonstrates the utility of using laboratory data for monitoring purposes when it is known that coding data alone is inaccurate or incomplete. Our most striking finding was that there were only eight confirmed rotavirus admissions in the Wellington and Hutt regions
Fig. 3. Number of admissions of children in New Zealand under 5 years of age with a primary diagnostic code of acute gastroenteritis (A000-A090) and rotaviral enteritis (A080) for 2010–2016. Rotavirus vaccination was introduced in July 2014.
in the two years following introduction of the vaccine. The high rate of rotavirus infection in the community during the year of vaccine introduction is likely to have increased population immunity. This factor combined with rapid vaccine uptake is the likely explanation for the dramatic reduction in rotavirus hospitalisations. The national, Hutt region and Wellington region coverage for rotavirus vaccine was 89%, 89% and 88% respectively for children reaching the eight month milestone between 1st January 2015 and 31st March 2016 [10]. Vaccine introduction coinciding with an outbreak may have encouraged vaccine acceptance, timeliness and adherence [11]. Further peaks in rotavirus cases may occur in New Zealand although total burden is expected to be significantly reduced. These outbreaks may not affect the same age profile or occur in the expected winter-spring season [4]. The national data is consistent with our local findings of a marked reduction in hospitalisations following vaccine introduction although the effect is not as pronounced. Prior to the vaccine introduction, almost one in six of the national yearly average of 3782 coded gastroenteritis admissions for children less than 5 years was attributed to rotavirus infection. It is contended that this coding data is an under representation of both the total gas-
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018
M.J. Kelly et al. / Vaccine xxx (2017) xxx–xxx
troenteritis admissions and the rotavirus proportion and therefore underestimates the impact of vaccination. Unlike the approach adopted in the Wellington and Hutt region, most hospitals in New Zealand do not routinely test for rotavirus. Based on the assumption of a similar positive rate to the Hutt-Wellington region, the pre-vaccination burden nationally was more likely to be 1724 admissions per year, more than double the incidence reported in the national figures. Furthermore, the national data was retrieved using primary diagnostic codes. Our study found that 16.2% of gastroenteritis admissions were identified with a secondary diagnostic code and these cases accounted for 5.7% of confirmed rotavirus gastroenteritis admissions. The estimated incidence of rotavirus hospital-acquired infections in the pre-vaccination period was 0.15 cases per 100. This rate is similar to a previous reported rate of 0.7 (95% CI: 0.0–1.8) for children under 5 years of age [12]. Akin to other reports, our cases occurred in clusters. Interestingly, our cases occurred in lower incidence seasons. The increased frequency of HAI cases during this period suggested decreased vigilance during times of lower disease burden. There were no confirmed cases of HAI in the postvaccination period. Rotavirus HAI is anticipated to become an uncommon problem due to the reduced number of rotavirus admissions as well as greater immunity of children admitted to hospital. 4.1. Limitations The main limitation of this study is the retrospective observational design which risks confounding from known and unknown factors. The disparity in the rate of testing and the proportion of positive results between Wellington and Hutt Hospitals may represent more selective testing at Hutt Hospital. It has been previously suggested that rotavirus can be recognised by nursing staff by odour [13]. This selective testing may influence overall results, inflating the reported incidence. The two centres also used different tests and both tests are acknowledged as not being as accurate as PCR. As the incidence of rotavirus declines there would be an expected increase in the proportion of false positive test results. To account for this, all positive samples are now being submitted for PCR confirmation and viral typing as part of a national surveillance programme through the Institute of Environmental Science and Research (ESR). It is possible that the management of paediatric gastroenteritis at the two hospitals changed during the study period. This may have lead to a decline in admissions although it is unlikely that any change in practice could entirely explain such a sudden and marked reduction in admissions as occurred following vaccine introduction. Rates of testing were also lower during the postvaccination period. This may have caused an overestimation of the impact of the vaccine, however the rate of testing was still relatively high (55.4%) and active case finding is engaged as part of infection control policies in both units.
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5. Conclusion Rotavirus vaccine introduced on the crest of a peak in rotavirus cases has had an immediate and significant impact on the number of gastroenteritis admissions in New Zealand. The non-restrictive continuous approach to rotavirus testing has provided a detailed description of the epidemiology of rotavirus gastroenteritis hospitalisations in the Wellington and Hutt regions. This data, which may not be able to be calculated elsewhere due to inconsistent testing practices, offers further characterisation of the national dataset for rotavirus admissions. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgements This study did not receive any funding support. We wish to thank Sharon Morse and Nicole O’Connor for their assistance with data extraction. We also wish to thank Tricia Martin, Sagni Prasad and all staff on the paediatric wards at Wellington and Hutt Hospitals. References [1] Immunisation Handbook 2014. 6th ed. Wellington: Ministry of Health: Ministry of Health; 2014. [2] Rotavirus. Diseases and illnesses. Ministry of Health website: Ministry of Health; 2014. [3] Milne RJ, Grimwood K. Budget impact and cost-effectiveness of including a pentavalent rotavirus vaccine in the New Zealand childhood immunization schedule. Value Health: J Int Soc Pharmacoecon Outcomes Res 2009;12:888–98. [4] Parashar UD, Johnson H, Steele AD, Tate JE. Health impact of rotavirus vaccination in developing countries: progress and way forward. Clin Infect Diseases: An Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S91–5. [5] Dohme M. RotaTeq Package insert. In: Administration FaD, editor. Online. Food and Drug Administration Website; 2013. [6] Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. New Engl J Med 2006;354:23–33. [7] Patel MM, Glass R, Desai R, Tate JE, Parashar UD. Fulfilling the promise of rotavirus vaccines: how far have we come since licensure? Lancet Infect Dis 2012;12:561–70. [8] Zealand SN. 2013 Census tables about a place. Census Data New Zealand. Online: Statistics New Zealand; 2016. [9] Grimwood K, Huang QS, Cohet C, Gosling IA, Hook SM, Teele DW, et al. Rotavirus hospitalisation in New Zealand children under 3 years of age. J Paediatr Child Health 2006;42:196–203. [10] Tuohy P. Official information act request to the Ministry of Health. In: Foley DD, editor; 2016. [11] Hull BP, Menzies R, Macartney K, McIntyre PB. Impact of the introduction of rotavirus vaccine on the timeliness of other scheduled vaccines: the Australian experience. Vaccine 2013;31:1964–9. [12] Bruijning-Verhagen P, Quach C, Bonten M. Nosocomial rotavirus infections: a meta-analysis. Pediatrics 2012;129:e1011–9. [13] Poulton J, Tarlow MJ. Diagnosis of rotavirus gastroenteritis by smell. Arch Dis Childhood 1987;62:851–2.
Please cite this article in press as: Kelly MJ et al. Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.018