Background: In September 2009, a mumps outbreak originated in New York and spread to Northeastern USA and Canada. This study compares the performance of different diagnostic testing methods used in Ontario and describes molecular characteristics of the outbreak strain. Methods: Between September 2009 and February 2010, specimens from suspect cases were submitted to Public Health Ontario Laboratory for mumps serology, culture and/or real-time reverse-transcriptase PCR (rRT-PCR) testing. rRT-PCR-positive specimens underwent genotyping at Canada’s National Microbiology Laboratory. Whole genome sequencing was performed on four outbreak and three sporadic viral culture isolates. Results: Six hundred ninety-eight patients had IgM serology testing, of which 255 (37%) had culture and rRT-PCR. Among those, 35/698 (5%) were IgM positive, 39/255 (15%) culture positive and 47/255 (18%) rRT-PCR-positive. Buccal swabs had the highest rRT-PCR positivity (21%). The outbreak isolates were identical to that in the New York outbreak occurring at the same time. Nucleotide and amino acid identity with the Jeryl Lynn vaccine strain ranged from 85.0-94.5% and 82.4-99.4%, depending on the gene and coding sequences. Homology of the HN protein, the main immunogenic mumps virus protein, was found to be 94.5 and 95.3%, when compared to Jeryl Lynn vaccine major and minor components, respectively. Conclusions: Despite higher sensitivity than serology, rRT-PCR testing is underutilized. Further work is needed to better understand the suboptimal match of the HN gene between the outbreak strain and the Jeryl Lynn vaccine strain. Keywords: Mumps, Outbreak, PCR, Serology, Viral culture, Diagnosis, Phylogeny Background infected . Meningitis, oophoritis and epididymo- Mumps virus is a single-stranded negative sense RNA orchitis represent the most common complications . virus, and a member of the Paramyxoviridae family. Symptoms and complications might vary between im- This usually self-limited disease is endemic worldwide munized and unimmunized patients. Diagnosis relies on and occurs primarily in children and adolescents. serology, viral culture, or molecular testing, such as real- Twenty-five to 30% of infections are asymptomatic . time reverse-transcription polymerase chain reaction The most frequent clinical presentation is nonsuppura- (rRT-PCR). If available, rRT-PCR is recommended on all tive parotitis, which occurs in up to 60-70% of persons patients being tested during the acute phase of illness because it has greater sensitivity than serology and, to a * Correspondence: email@example.com lesser extent, culture, as well as a faster turnaround Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, time than culture [3–6]; moreover, serology has a low Canada Public Health Ontario, 661 University Avenue, Toronto, Ontario M5G 1M1, positive predictive value in a low prevalence setting . Canada Although immunization with the live-attenuated mumps Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. L’Huillier et al. Virology Journal (2018) 15:98 Page 2 of 9 vaccine (Jeryl Lynn strain), first licenced in the United the IFA used a mumps monoclonal murine IgG1k anti- States in 1967, and in Canada in 1969, has markedly re- body made against the Enders mumps strain and targeting duced the incidence of mumps to around 0.1 cases per two different epitopes of the fusion protein (Light 100,000 persons/year, outbreaks still occur . During the Diagnostics™ Mumps IFA Kit, EMD Millipore Corporation, summer of 2009, a mumps outbreak that originated in CA, USA). Initially negative cultures were passaged after New York State subsequently spread to Northeastern 10 days, and reported negative following a further 7 days USA and Ontario, Canada [2, 9]. One hundred and thirty incubation (total incubation time 17 days). Cultured speci- four cases of mumps were identified in Ontario, which mens were only considered mumps-positive if the mumps has a population of 13 million inhabitants. The outbreak antigen was detected by IFA. The rRT-PCR was conducted continued until June 2010 . As the microbiology at PHOL using an in-house assay adapted from protocols reference laboratory for Ontario, Public Health Ontario developed by Canada’s National Microbiology laboratory Laboratory (PHOL) provides all mumps diagnostic testing (NML) and the US Centers for Disease Control (CDC), for the province, including testing of all clinical specimens which targets the fusion (F1) and small hydrophobic (SH) related to this outbreak. The aim of this study was to genes [12, 13]. Genotyping was performed at NML using compare the performance of different diagnostic tests RT-PCR and sequencing of the entire small hydrophobic among patients under investigation for mumps in a popu- gene (316 nucleotides) . Wholegenomesequencing lation with high immunization rates, review testing prac- (WGS) was performed on four outbreak and three sporadic tices of clinicians in Ontario, and describe the molecular viral culture Ontario isolates using overlapping primers characteristics of the mumps virus strain causing Ontario’s folllowed by either next-generation sequencing using the 2009/2010 outbreak. Illumina MiSeq (Illumina Inc. San Diego, California, USA) or Sanger sequencing using the ABI 3730 DNA Analyzer Methods (Applied Biosystems ™, Foster City, California, USA), as All clinical specimens from suspected mumps cases in previously described  and compared to mumps refer- the province of Ontario were sent to PHOL for testing, ence strains . which included serology, and both viral culture and Comparisons of assay’s sensitivity were performed mumps rRT-PCR on buccal, oral/oropharyngeal, nasopha- using McNemar’s or Chi-square tests using SAS statis- ryngeal, throat/pharyngeal, urine, sputum and cerebro- tical software (version 9.2). P-values < 0.05 were consid- spinal fluid (CSF) specimens. Persons under investigation ered significant. were classified using the Ontario Ministry of Health pro- vincial case definition for mumps , which was subse- Results quently updated in 2014 . Clinical specimens of Diagnostic testing patients with suspected mumps submitted to PHOL for Eight hundred and fifty-three blood specimens were re- testing between September 1, 2009 and February 22, 2010 ceived from 698 patients for IgM serology testing, of which were included in the analysis. Patients with confirmed 255 patients had 372 specimens submitted for both viral mumps based on clinical data and epidemiological link culture and rRT-PCR. Among those, 35/698 tested patients without laboratory testing were therefore not included in (5%) were IgM-positive, 39/255 tested patients (15%) were the study. Blood specimens submitted for diagnostic culture positive for mumps virus, and 47/255 tested pa- serology were tested for mumps IgG and IgM by a com- tients (18%) were rRT-PCR-positive (Table 1). The most mercial indirect enzyme-linked immunoassay (ELISA) kit frequent specimen collection site for rRT-PCR was buccal (Enzygnost Anti-Parotitis ELISA, Siemens AG, Munich, (n = 158; 42.5% of rRT-PCR specimens), followed by urine Germany). Qualitative IgG seroconversion was assessed if (n = 146; 39.3% of rRT-PCR specimens). IgM serology was more than one serial blood specimen was submitted (an positive in 5.7% (49/853) of tested specimens whereas IgG-negative specimen followed by an IgG positive speci- culture and rRT-PCR were positive in 13% (47/372) and men collected at a later date). Respiratory, urine, and CSF 17% (62/372) tested specimens, respectively. Buccal swab specimens were tested by viral culture and rRT-PCR. rRT-PCR had the highest positivity (21%) among all speci- Specimens submitted for virus culture were inoculated in men types (Table 1). Twenty-six percent (23/90) of patients rhesus monkey kidney primary cell lines and either WI-38 who had more than one serum specimen submitted dem- or MRC5 human embryonic lung fibroblast diploid cell onstrated mumps IgG seroconversion. lines (Quidel Corporation, San Diego, CA). Identification Assay comparison was conducted for all patients who of mumps virus was performed by monitoring for cyto- had more than one test done and showed that rRT-PCR pathic effect and haemadsorption using 0.6% guinea pig was superior to serology (Table 2); it also confirmed that red blood cells. Cell lines showing syncytia or a positive buccal rRT-PCR was superior to urine rRT-PCR. haemadsorption test were tested by an indirect immuno- Among the 47/255 rRT-PCR positive patients, 31 (66%) fluorescent assay (IFA) for confirmation; more specifically, had an IgM test performed, of which 13 (42%) were L’Huillier et al. Virology Journal (2018) 15:98 Page 3 of 9 Table 1 Summary of specimens tested for mumps by serology, a median duration from illness onset to collection viral culture and rRT-PCR date of 4 days (range 3-26 days). Specimens positive/tested Persons positive/tested b c (% pos) (% pos) Phylogenetic analysis IgM Serology 49/853 (6%) 35/698 (5%) Genotyping of the SH gene, performed at the Public Viral Culture 47/372 (13%) 39/255 (15%) Health Agency of Canada’s NML, confirmed that all tested outbreak and sporadic strains were genotype G; rRT-PCR 62/372 (17%) 47/255 (18%) all were > 99% identical to a predominant circulating Buccal 33/158 (21%) strain identified in Canada in 2007, with a difference of Urine 19/146 (14%) not more than two nucleotides. The four mumps Oral/Oropharyngeal 1/11 (9%) outbreak isolates which underwent WGS (GenBank ac- Throat/Pharyngeal 3/24 (13%) cession numbers: KY680537.1, KY680538.1, KY680539.1 Nasopharyngeal 0/8 (0%) and KY680540.1) had between 99.8-99.9% nucleotide identity with sequences from the New York 2009-2010 CSF 1/1 (100%) outbreak (GenBank accession numbers: JX287389.1, Sputum 0/1 (0%) JX287391.1, JX287390.1 and JX287387.1), confirming Other swab 5/23 (22%) that the same strain was circulating for the Ontario, rRT-PCR real-time reverse-transcription polymerase chain reaction, Canada and New York outbreaks (Figs. 1 and 2, Table 3). CSF cerebrospinal fluid Collection site not provided Fifteen synonymous single-nucleotide polymorphisms Serology vs culture: P < 0.0001; Serology vs rRT-PCR: P < 0.0001; Culture vs were observed within the whole genome of Ontario’sout- rRT-PCR: P = 0.12 break strains and nucleotide identity of 99.9% was obtained. Serology vs culture: P < 0.0001; Serology vs rRT-PCR: P < 0.0001; Culture vs rRT-PCR: P = 0.344 However, nucleotide identity within all seven Ontario strains (including non outbreak strains KY006856.1, positive, 14 (45%) negative, and four (13%) indetermin- KY006857.1 and KY006858.1) were calculated to be ate. Surprisingly, only 19/35 (54%) IgM positive patients 98.7-99.8%. Nucleotide and amino acid identity between hadspecimens submittedfor rRT-PCR and/or culture. the Ontario outbreak strains and the Jeryl Lynn vaccine Among the 105 patients who had both buccal and strain components varied between genes, ranging from urine specimens submitted, rRT-PCR was positive in 85.0 to 94.5% and from 82.4 to 99.4%, respectively buccal and/or urine specimen in 30 (29%). rRT-PCR was (Table 4). Homology of the HN protein, the main im- positive for buccal specimens only, urine specimens only munogenic mumps virus protein, was found to be 94.5 and both urine and buccal specimens in 13, 3 and 14 and 95.3%, when compared to Jeryl Lynn vaccine major cases, respectively; therefore, buccal swabs detected and minor components, respectively. 27/30 (90%) of rRT-PCR positive specimens, compared to 17/30 (57%) for urine (p = 0.02). Time between symptom Discussion onset and collection date was poorly reported. Only Mumps outbreaks continue to occur worldwide, including 12.4% (64/517) of patients who were IgM negative, and in populations with adequate immunization schedules and had no rRT-PCR or culture testing done, had time since coverage. In 2016, more than 6000 cases of mumps were symptom onset reported. Median duration from ill- reported in the USA, the highest in 10 years . In 2017, ness onset to collection date in this group was 4 days more than 5600 cases were reported in the USA, mostly (range 0-27 days). For IgM-positive patients, 13/35 related to an outbreak also involving Canada . The (37%) had a reported time since symptom onset, with outbreak that started in New York in 2009 and Table 2 Comparison of test performance in mumps positive patients tested by more than one testing modality Positive mumps test (denominator) Comparator test positivity (numerator) Buccal rRT-PCR Urine rRT-PCR Any rRT-PCR Any virus culture IgM IgG seroconversion Buccal rRT-PCR positive 14/27 (51.9%) 33/33 (100%) 29/33 (87.9%) 8/24 (33.3%) 4/23 (17.4%) Urine rRT-PCR positive 14/17 (82.4%) 19/19 (100%) 15/18 (83.3%) 8/14 (57.1%) 3/25 (12.0%) Any rRT-PCR positive 33/40 (82.5%) 19/36 (52.8%) 37/45 (82.2%) 13/31 (41.9%) 6/30 (20.0%) Any virus culture positive 29/33 (87.9%) 15/29 (51.7%) 37/39 (94.9%) 9/27 (33.3%) 4/30 (13.3%) IgM positive 8/16 (50.0%) 8/14 (57.1%) 13/19 (68.4%) 9/17 (52.9%) 10/90 (11.1%) IgG seroconversion 4/8 (50.0%) 3/10 (30.0%) 6/10 (60%) 4/9 (44.4%) 10/23 (43.5%) rRT-PCR real-time reverse-transcription polymerase chain reaction L’Huillier et al. Virology Journal (2018) 15:98 Page 4 of 9 Fig. 1 Whole genome sequencing (WGS) phylogenetic tree. The WGS phylogenetic tree was constructed using the nearly complete genomes (15,264 nucleotides) of four genotype G mumps outbreak isolates from Ontario (GenBank accession numbers: KY680537.1, KY680538.1, KY680539.1 and KY680540.1), three sporadic Ontario isolates (GenBank accession numbers: KY006856.1, KY006857.1 and KY006858.1) and representatives of other genotypes available in NCBI’s GenBank sequence database. The phylogenetic tree containing 37 strains was reconstructed using the Neighbor-Joining method and Maximum Composite Likelihood was used to compute the evolutionary distances. The statistical significance of the phylogenies constructed was estimated by bootstrap analysis of 1000 pseudo-replicate data sets (bootstrap values of > 70% are given at each node). The horizontal length of the bar denotes the nucleotide changes per site (MEGA version 6.06 software package). Outbreak and non-outbreaks isolates identified at Public Health Ontario Laboratory in 2010 are labelled with red and blue circles respectively subsequently reached Ontario is one of the biggest re- New York outbreak was a child who recently returned ported outbreaks since universal immunization, with more from the United Kingdom where a large outbreak was than 3500 reported cases in the USA alone . Phylogen- happening . etic analyses confirmed that the strain responsible for the The outbreak in Ontario occurred in a population outbreak in Ontario was similar to the one causing the where 14% of cases were unimmunized, whereas 55 and outbreak in New York . Moreover, WGS confirmed that 28% of cases had previously received 1 and 2 doses, re- outbreak isolates were > 98.7% similar to sporadic iso- spectively . Therefore, the outbreak occured in a con- lates, suggesting that the outbreak strain has been pre- text of suboptimal immunization as well as possible viously circulating. The presumed index case of the waning of immunity. The relatively low percentage of L’Huillier et al. Virology Journal (2018) 15:98 Page 5 of 9 Fig. 2 Small hydrophobic (SH) gene sequencing phylogenetic tree. The SH phylogenetic tree was constructed based on the 316 nucleotides of the entire SH gene of four genotype G mumps outbreak isolates from Ontario (GenBank accession numbers: KY680537.1, KY680538.1, KY680539.1 and KY680540.1), three sporadic Ontario isolates (GenBank accession numbers: KY006856.1, KY006857.1 and KY006858.1) and representatives of other genotypes available in NCBI’s GenBank sequence database. The phylogenetic tree containing 37 strains was reconstructed using the Neighbor-Joining method and Maximum Composite Likelihood was used to compute the evolutionary distances. The statistical significance of the phylogenies constructed was estimated by bootstrap analysis of 1000 pseudo-replicate data sets (bootstrap values of > 70% are given at each node). The horizontal length of the bar denotes the nucleotide changes per site (MEGA version 6.06 software package). Outbreak and non-outbreaks isolates identified at Public Health Ontario Laboratory in 2010 are labelled with red and blue circles respectively sequence homology between our strain and the Jeryl Our study demonstrated that rRT-PCR was the most sen- Lynn vaccine strain is related to the fact that they belong sitive assay for mumps detection. Viral culture was slightly to genotypes G and A, respectively, which has been sug- less sensitive, and this difference did not reach statistical gested as a potential cause of suboptimal vaccine effect- significance. However, IgM serology was significantly less iveness [19, 20]. However, additional studies have shown sensitive than both rRT-PCR and viral culture. Our ob- that vaccine-induced antibody effectively neutralizes served order of assay sensitivity is consistent with large wild-type virus [19, 21, 22]. Consequently, the patho- studies with > 80 laboratory confirmed cases [3, 5, 23, 24]. physiology of mumps vaccine failure is still unclear. In addition, a number of studies have shown a better L’Huillier et al. Virology Journal (2018) 15:98 Page 6 of 9 Table 3 Percentage of whole genome sequence identity between mumps sequences Outbreak and non-outbreaks isolates identified at Public Health Ontario Laboratory in 2010 are labelled in red and blue respectively sensitivity of rRT-PCR compared to IgM serology [4, 25– whereas IgM is more likely to be positive if collected ≥ 3 32] and, to a lesser extent, culture [12, 25, 26]. However, days after symptom onset . Among the same population, inconsistent findings in smaller studies has been observed Rota et al. showed that sensitivity of rRT-PCR was higher where IgM yielded similar or better sensitivity than cul- than serology from day 0 to day 2 after symptom onset, ture [25, 26, 33] or RT-PCR . More than 3500 cases whereas the sensitivity of serology was higher than were confirmed in the USA during the 2009-2010 out- rRT-PCR from day 3 onwards . The fact that rRT-PCR break that reached Ontario . Among the 1648 tested yield was highest during day one to three after parotitis on- patients in the USA, 831 (50%) were positive by at least set and decreased afterwards was confirmed in two other one assay. In this large sample, rRT-PCR was the most studies, using rRT-PCR and RT-PCR , respectively. sensitive assay with 68% positivity (373/550) among cases Additional testing showed that rRT-PCR and IgM sen- who had rRT-PCR testing, compared to 64% (283/443) sitivity varied significantly using different assays [6, 35]. and 35% (550/1563) of cases who underwent cell culture In the Ontario outbreak, negative IgM tests in our con- and IgM testing, respectively. The discrepant sensitivity of firmed cases could not be explained by early collection RT-PCR, culture and serology between the above- of specimens, as we observed a median duration of 4 mentioned studies could be a result of confounding by the days from symptom onset to blood collection, which different vaccination status and different time between should have been ample time for IgM to develop. The symptom onset and specimen collection among the low sensitivity of IgM serology may also be confounded studied populations. Indeed, previously immunized pa- by immunization status. It has been suggested that tients are less likely to develop an IgM response when sub- immunized individuals have modified B cell responses sequently exposed to mumps [2, 6]. Moreover, rRT-PCR that allow for the rapid generation of IgG antibodies and andculture aremorelikelytobepositiveifspecimens were a blunted, or absent IgM response, when exposed to collected in the first 2 days after parotitis onset [2, 6], mumps virus . This phenomenon could also result in Table 4 Identity between Jeryl Lynn vaccine mumps strain and Ontario mumps whole genome sequences Gene JL Major % identity JL Minor % identity Nucleotide (%) Amino acid (%) Nucleotide (%) Amino acid (%) Nucleocapsid Protein (NP) 94.4 98.3 94.5 98.3 Phosphoprotein (P) 92.7–92.8 89.6–89.9 91.9–92.0 87.5–87.8 Matrix (M) 93.2–93.3 99.2 92.9–93.1 99.4 Fusion (F) 92.9–93.1 94.7–95.1 94.3–94.5 96.0–96.4 Small Hydrophobic (SH) 87.3 85.9 85.0 82.4 Hemagglutinin–Neuraminidase (HN) 91.0 94.5 91.9 95.3 Large Protein (L) 94.0 98.8–98.9 94.2–94.3 98.7–98.8 JL Jeryl Lynn L’Huillier et al. Virology Journal (2018) 15:98 Page 7 of 9 a lack of IgG seroconversion being observed following guidelines recommend to perform serology as well as mumps infection in previously immunized patients, due rRT-PCR or culture, but emphasize the lower yield of to an IgG boost occurring prior to clinical presentation. urine compared to buccal specimens . On the other Studies performed in the USA during the 2009-2010 hand, the Public Health Agency of Canada recommends outbreak showed that IgM serology was less likely to be to perform serology as well as buccal and urine rRT-PCR positive among immunized (26%) than unimmunized pa- but no longer recommends culture in the current tients (76%, P < 0.05), whereas immunization status had guidelines . Clinician education is needed to increase no influence on rRT-PCR and culture results [2, 6]. This awareness of the availability, better sensitivity and test per- low yield of IgM in immunized patients during an out- formance of rRT-PCR compared to serology. break has been reported in other studies [24, 36]. Compared to rRT-PCR, IgM serology has lower sensitiv- Our study also confirmed that rRT-PCR sensitivity ity and may be highly influenced by immunization status. varied with specimen type and was higher for buccal As such, rRT-PCR should be considered as the gold stand- than oropharyngeal swabs or urine. This is consistent ard for mumps detection because of its high sensitivity with previous studies showing that saliva swabs per- and its quick turnaround time. However, it is not uncom- formed better than pharyngeal swabs, whereas test sensi- mon that patients with negative rRT-PCR [27, 29, 32]or tivity was lowest for urine [4, 23, 37]. Similarly, Hindiyeh RT-PCR , have positive IgM. As a consequence, these et al. showed that RT-PCR sensitivity was higher with two assays are somewhat complementary, as IgM yield pharyngeal or parotid fluid than urine . increases with time following symptom onset, when The main limitation of the study is the relative lack of RT-PCR yield decreases. However, clinicians should keep clinical data about the studied population, such as symp- in mind the poor positive predictive value of IgM when toms at disease onset. This is related to the fact that cli- used in a low prevalence setting such as North America, nicians in the community forward specimens to our for example in the absence of an outbreak . Due to the laboratory for mumps testing, often without providing impact of time since symptom onset and the relative sen- significant clinical data. As a consequence, it was not sitivity of rRT-PCR and serology, we therefore emphasize possible to know precisely the immunization status of the need to continue educating healthcare providers of the the tested patients which would have allowed compari- importance of submitting both buccal swab and urine son of diagnostic methods between immunized and un- specimens for rRT-PCR, in addition to a specimen for immunized patients; however, the immunization status IgM/IgG serology when mumps is suspected, in accord- of the same population at this time was reported in an- ance with current guidelines. other publication, showing that 86% of the population had received at least one dose and more than 55% two Conclusions doses . Similarly, the time between symptom onset This study confirms that rRT-PCR has higher sensitivity and specimen collection was provided for a minority of than serology, and is still underutilized for the diagnosis patients only. As these data might influence serology of mumps. This work also confirms the superiority of and RT-PCR sensitivity, it would have provided import- buccal rRT-PCR compared to urine rRT-PCR. Phylogen- ant additional information in this setting. As it has been etic analysis confirmed the discrepancies in nucleotide shown that a rRT-PCR targeting the nucleoprotein gene and amino acid homology between outbreak and vaccine was more sensitive than a rRT-PCR targeting the SH strains. Further work is needed to better understand the gene , the fact that our assay targeted the F1 and SH suboptimal match of the HN gene between the outbreak genes might also be a potential limitation of the study. strain and the Jeryl Lynn vaccine strain, in order to bet- Despite the abundance of previous data showing that ter protect vaccinated individuals. RT-PCR, and to a lesser extent viral culture, are the most sensitive detection methods, most patients in our Abbreviations study had serology testing during the acute illness with- CPE: Cytopathic effect; CSF: Cerebrospinal fluid; F1: Fusion gene; PHOL: Public out any rRT-PCR or culture testing. This testing pattern Health Ontario Laboratory; rRT-PCR: Real-time reverse-transcriptase PCR; was also observed in the US outbreak and may reflect SH: Small hydrophobic gene; WGS: Whole genome sequencing the current practice in North America. During the same outbreak in the USA, IgM serology was used in 95% Funding This work was supported by Public Health Ontario. The funding source had (n = 1563) of the 1648 tested patients, whereas rRT-PCR no involvement in study design, data collection, analysis or interpretation, as and viral culture were used in only 33% (n = 550) and 27% well as manuscript writing and decision to submit the manuscript. (n = 443), respectively . This testing practice is in con- trast to a 2009 Australian study that showed that RT-PCR Availability of data and materials was the most frequently used diagnostic method during a All data generated or analysed during this study are included in this mumps outbreak in that country . The current CDC published article. L’Huillier et al. Virology Journal (2018) 15:98 Page 8 of 9 Depositories 10. The Ontario Ministry of Health and Long-Term Care. Mumps. Can Commun The GenBank accession numbers for the four outbreak and the three sporadic Dis Rep. 2009;35(S2):73–4. isolates sequenced in this study are KY680537.1/KY680538.1/KY680539.1/ 11. The Ontario Ministry of Health and Long-Term Care. Infectious Diseases KY680540.1 and KY006856.1/KY006857.1/KY006858.1 respectively. Protocol. Mumps. Appendix B: Provincial Cases Definitions for Reportable Diseases. Revised January 2014. 2014. Available from: http://www.health.gov. Authors’ contributions on.ca/en/pro/programs/publichealth/oph_standards/docs/mumps_cd.pdf. CR, DA, JG, and TM designed the study. AE, CR, KO, EL, RH, EK and JM Accessed 23 Jan 2018. performed the laboratory analyses. AL, AR, CR, DA, EK, JM, JG, and TM 12. Uchida K, Shinohara M, Shimada S, Segawa Y, Doi R, Gotoh A, et al. Rapid analysed the data. AL, AE, KO, EL, RH, JG, and TM wrote the manuscript. and sensitive detection of mumps virus RNA directly from clinical samples All authors read and approved the final manuscript. by real-time PCR. J Med Virol. 2005;75:470–4. https://doi.org/10.1002/ jmv.20291. Ethics approval and consent to participate 13. Boddicker JD, Rota PA, Kreman T, Wangeman A, Lowe L, Hummel KB, et al. These data are also used for routine laboratory surveillance, which is a Real-time reverse transcription-PCR assay for detection of mumps virus RNA mandate of PHOL. Therefore, consultation with our organization’s privacy in clinical specimens. J Clin Microbiol. 2007;45:2902–8. https://doi.org/10. office or ethics committee was not required. To protect patient privacy and 1128/JCM.00614-07. confidentiality, data are reported in an aggregated anonymized format. 14. Mumps virus nomenclature update: 2012. Wkly Epidemiol Rec. 2012;87(22): 217–24. Competing interests 15. Ma SLJ, Shi H, Wang L, Wang J, Liu L, Li Q. Complete nucleotide sequence JB Gubbay has received research grants from GlaxoSmithKline Inc. and of a mumps virus SP strain isolated in China. Virol Sin. 2009;24:28–36. Hoffman-La Roche Ltd. to study antiviral resistance in influenza, and from https://doi.org/10.1007/s12250-009-2984-9. Pfizer Inc. to conduct microbiological surveillance of Streptococcus pneumoniae. 16. Jin L, Orvell C, Myers R, Rota PA, Nakayama T, Forcic D, et al. Genomic The authors declare that they have no competing interests. diversity of mumps virus and global distribution of the 12 genotypes. 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Published: Jun 5, 2018