Increase in Neisseria meningitidis serogroup W invasive disease in Canada : 2009 – 2016

Background: Since 2010, there has been an increase in serogroup W Neisseria meningitidis (MenW) disease in many countries due to an emerging sequence type-11 clonal complex (ST-11 CC). In 2016, a small increase in MenW disease due to the ST-11 CC was documented in Ontario, Canada. Objective: To examine the trends in MenW disease in Canada and to assess whether there have been changes in the type of ST clonal complex causing MenW disease between 2009-2016. Methods: Invasive N. meningitidis isolates routinely submitted from across the country to the National Microbiology Laboratory were analyzed. The proportional distribution of MenW compared with other serogroups was calculated. The MenW isolates were then further characterized by serotype, serosubtype and ST clonal complex. The geographic distribution of the emerging ST-11 CC was documented and the age of patients with ST-11 CC was compared with the traditional ST-22 CC. Results: Of the 888 invasive isolates examined, 63 were MenW giving an average annual rate of 7.1%. However, the percentage of MenW varied from 2.7% in 2012 to 18.8% in 2016. From 2009 to 2013, 91% of the MenW were typed as the traditional ST-22 CC while from 2014 to 2016, 75% were typed to be the emerging ST-11 CC. ST-11 MenW CC was documented in five provinces across Canada (British Columbia, Alberta, Manitoba, Ontario and Quebec). The median age of patients infected with the emerging ST-11 MenW CC was 53.5 years, while for patients with the traditional ST-22 CC it was 23.5 years. Conclusion: MenW meningococcal disease is growing in prevalence in Canada and is associated with an increase in the emerging ST-11 CC. This emerging clonal complex has now been identified in five provinces in Canada. It appears to be more common in older patients than the traditional ST-22 CC, which occurs more often in younger patients. Affiliations 1 National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB 2 BC Public Health Microbiology and Reference Laboratory, Vancouver, BC 3 Provincial Laboratory for Public Health, Edmonton, AB 4 Saskatchewan Disease Control Laboratory, Regina, SK 5 Cadham Provincial Laboratory, Winnipeg, MB 6 Public Health Ontario, Toronto, ON 7 Faculty of Medicine, University of Toronto, Toronto, ON 8 Laboratoire de santé publique du Québec, Institut national de santé publique du Québec, Sainte-Anne-de-Bellevue, QC 9 Nova Scotia Health Authority, Halifax, NS 10 Dalhousie University, Halifax, NS 11 Communicable Disease Control Unit, Department of Health, Government of New Brunswick, Fredericton, NB 12 Department of Health, Government of Prince Edward Island, Charlottetown, PE 13 Provincial Public Health Laboratory, Eastern Health Microbiology Services, St. John’s, NL 14 Department of Laboratory Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL Correspondence: raymond. tsang@phac-aspc.gc.ca Suggested citation: Tsang RSW, Hoang L, Tyrrell GJ, Horsman G, Van Caeseele P, Jamieson F, Lefebvre B, Haldane D, Gad RR, German GJ, Zahariadis G. Increase in Neisseria meningitidis serogroup W invasive disease in Canada: 2009–2016. Can Commun Dis Rep. 2017;43(7/8):144-9.


Introduction
Invasive meningococcal disease (IMD) has been a notifiable disease in Canada since 1924 (1).It is caused by Neisseria meningitidis, which normally resides in the upper respiratory tract of healthy carriers.For reasons not completely understood, N. meningitidis may invade the blood stream and cause serious systemic infection leading to meningitis, septicemia, septic arthritis, bacteremic pneumonia and pericarditis (2).Initial clinical presentation of IMD can be nonspecific but it may progress rapidly, leading to septic shock.The disease has an average case-fatality rate of 10% (3).
The strains causing IMD have been described as "shifting sands", with unique strains emerging with the potential to spread regionally and internationally.For example, MenA of subgroup III caused epidemics in China in the 1960s and subsequently spread to Russia and then globally (6).ET-5 MenB caused an intercontinental outbreak with a wide geographic spread that lasted for over a decade (7).The ET-15 MenC clone first emerged in Canada in the mid-1980s and led to worldwide dissemination, which ultimately led to the introduction of MenC conjugate vaccine programs in many countries.Other notable MenB clones that have caused epidemics include cluster A4 and lineage 3 (5).
The first report of MenW causing a major outbreak or epidemic occurred in 2000; this outbreak started in Saudi Arabia during the Hajj and involved more than 400 cases.The strain was characterized as ST-11 clonal complex (8).With pilgrims returning to their countries in Africa, Asia, Europe, North America and South America, this strain was disseminated globally.The gradual increase in MenW disease in recent years was first reported in sub-Saharan Africa (9) and South America (10,11).Since 2010, other countries have reported an increase in IMD caused by .
In December 2016, Tsang et al. (16) reported an increase in invasive MenW strains in Ontario, Canada.This increase started in 2014 and was associated with a replacement of the traditional ST-22 clonal complex with the ST-11 clonal complex (16).There was also a small increase in the number of MenW IMD cases in that province.To determine if clonal replacement had occurred in MenW disease nationally, this study examines the trends in MenW disease and changes in clonal complex in Canada between 2009 and 2016.

Methods
Provincial public health laboratories receive case isolates from hospitals and clinical diagnostic laboratories for identification and serogroup typing.As part of the enhanced surveillance program on IMD, all provinces and territories in Canada routinely submit all their invasive N. meningitidis isolates from culture-confirmed cases to the National Microbiology Laboratory (NML) for serogroup confirmation and additional strain characterization (17).This study included all N. meningitidis isolates obtained from culture-confirmed IMD cases submitted to the NML between 2009 and 2016.

Typing of meningococci
At the NML, serogrouping is done by slide agglutination using rabbit anti-grouping antisera produced in-house and/or polymerase chain reaction (PCR) (18).Serotyping and serosubtyping is done by whole-cell enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies (19).PorA genotyping and multilocus sequence typing were conducted according to previously described standard methods (20,21).

Geographic distribution, source and patient characteristics
Based on the requisition information provided by the provincial public health laboratories, the NML collects and analyzes information on the geographic origin of the specimens, the source (e.g.blood, cerebral spinal, pericardial or intra-articular fluid) and the age and sex of patients from whom the specimens were drawn.

Trends in MenW meningococcal disease
In Canada, between 2009 and 2016, a total of 888 N. meningitidis isolates were recovered from individual IMD cases and sent to the NML.Of these, 63 were grouped as MenW.The percentage of MenW isolates varied by year from a low of 2.7% in 2012 to a high of 18.8% in 2016 (Table 1), for an average percentage of 7.1%.

Changes in clonal complex
The increase in the number of MenW isolates from IMD cases coincided with the identification of the ST-11 (ET-37) CC (Figure 1).From 2009 to 2013, 91% (32 out of 35) MenW isolates were typed as the traditional ST-22 clonal complexes whereas from 2014 to 2016, only 25% (7 out of 28) MenW isolates belonged to this clonal complex.Over this same period, the emerging ST-11 clonal complex increased from 3% (1 out of 35 isolates) to 75% (21 out of 28 isolates).

SURVEILLANCE
The first major ST-11 CC MenW outbreak occurred during the Hajj pilgrimage in 2000.The pilgrims returning to their countries initiated the global dissemination of this clone (26).In England and Wales, the increase in the ST-11 MenW clone first became apparent in 2009/2010 (27) and its prevalence increased yearly until 2015 when a targeted vaccination program was introduced (28).A similar increase in MenW disease as a result of the same clone has been seen in Australia since 2013 (29), also leading to the introduction of a targeted vaccination program (30).The ST-11 CC MenW has now been documented in a number of other countries around the world (9)(10)(11)(12)(13)(14)(15).
The Canadian ST-11 CC MenW isolates have serotype antigen 2a and serosubtype antigen P1.5,2, typical of isolates of this clonal complex (31).They also differ antigenically from meningococci of the ST-22 CC.Currently there is no evidence to suggest that these ST-11 MenW arose by capsule switching from MenC ST-11 strain.Investigations into the MenB ST-11 that arose from MenC ST-11 by capsule switching suggest that these capsule-switched strains may not be stable for endemic spread (32).Rather, the increase in MenW ST-11 isolates in Canada and elsewhere is likely due to clonal expansion of an endemic strain (25,26).
This study has two limitations.First, it included only bacteriologic culture-confirmed cases and not those confirmed using PCR.

Table 2 :
Demographic characteristics and specimen source for invasive Neisseria meningitidis serogroup W (MenW) cases according to clonal complex inCanada,  2009Canada,   -2016 (26)ver, only about 10% of the IMD cases confirmed in Canada between 2006 and 2011 were diagnosed by PCR(17)and there is no evidence to suggest that PCR-diagnosed cases differ from culture-confirmed cases.Second, this study does not include data on the meningococcal vaccination history of patients with MenW.The quadrivalent meningococcal A, C, W and Y conjugate vaccine has protective immunity against MenW, but determining if any of the patients had been vaccinated prior to their illness was not possible.It is important to note that IMD due to MenW ST-11 CC may have an atypical clinical presentation.In England, for example, a review of MenW cases in teenagers (aged 15 to 19 years) found that 7 out of 15 patients initially presented with acute gastrointestinal symptoms of nausea, vomiting and diarrhea; four were sent home from hospital, delaying the diagnosis(34).In another study of 129 MenW cases in England and Wales from 2010 to 2013, half of which were diagnosed in patients aged 45 years or above, 23% were with atypical clinical presentations of pneumonia (12%), septic arthritis (7%) and epiglottitis or supraglottitis (4%)(26).The unusual initial clinical symptoms may have implications in the early diagnosis of the disease.Timely diagnosis of IMD is important for patient treatment, contact tracing and public health control of the disease.Ongoing surveillance of these trends is indicated.ConclusionIn summary, the traditional endemic MenW ST-22 CC has been replaced by an abrupt emergence of MenW ST-11 CC in five provinces in Canada.Although the overall number of MenW cases in Canada remains small, MenW is responsible for 19% of all IMD cases.Of note for clinicians and public health professionals, this ST-11 MenW clone has the potential to cause outbreaks, has occurred in an older age group in Canada and may have an atypical clinical presentation.The NML will continue its surveillance program on this disease including laboratory characterization of strains.