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Profile of serogroup Y meningococcal infections in Canada : implications for vaccine selection Le Saux, Nicole; Bettinger, Julie A.; Wootton, Susan; Halperin, Scott A.; Vaudry, Wendy; Scheifele, David W.; Tsang, Raymond 2009

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Can J Infect Dis Med Microbiol Vol 20 No 4 Winter 2009e130Profile of serogroup Y meningococcal infections in Canada: Implications for vaccine selectionNicole Le Saux MD1, Julie A Bettinger PhD MPH2, Susan Wootton MD3, Scott A Halperin MD4,  Wendy Vaudry MD5, David W Scheifele MD2, Raymond Tsang PhD6, for the members of the Canadian Immunization Monitoring Program, Active (IMPACT)1Children’s Hospital of Eastern Ontario Research Institute and the University of Ottawa, Ottawa, Ontario; 2Vaccine Evaluation Center, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia; 3University of Texas Health Science Center, Houston, Texas, USA; 4Clinical Trials Research Center, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia; 5Stollery Children’s Hospital and University of Alberta, Edmonton, Alberta; 6National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, ManitobaCorrespondence: Dr Nicole Le Saux, Children’s Hospital of Eastern Ontario, Division of Infectious Diseases, Ottawa, Ontario K1H 8L1. Telephone 613-737-7600 ext 2651, e-mail lesaux@cheo.on.caCanada is a leader in establishing routine infant immuniza-tion programs against meningococcal C disease. Currently, all provinces have routine programs to provide meningococcal C conjugate (MenC) vaccines to infants and children. The motivation for these programs included the cyclical occurrence of serogroup C epidemics, unpredictable hyperendemic disease in some areas, the circulation of a hypervirulent serogroup C strain and relatively high disease incidence in infants and young children (1-6) The result of the existing programs has been a decrease in serogroup C incidence (7). The second most common vaccine-preventable serogroup in Canada is serogroup Y, the incidence of which has been stable (7,8).The availability of a quadrivalent conjugate vaccine against serogroups A, C, Y and W135 focuses attention on sero-group Y disease as it becomes relatively more prominent as a cause of vaccine-preventable invasive meningococcal disease. This vaccine was licensed in November 2006 but is not rou-tinely used except in Nunavut, New Brunswick and Prince Edward Island. To allow a better understanding of the ‘value added’ by a serogroup Y-containing vaccine, it is necessary to have a contemporary profile of serogroup Y disease in Canada. We have summarized recent surveillance data on invasive meningococcal disease across Canada.MethodsFrom 2002 to 2007, active, metropolitan area surveillance for adult and pediatric hospital admissions related to infection with Neisseria meningitidis was conducted by the 12 centres of the Canadian Immunization Monitoring Program, Active (IMPACT), in collaboration with local public health officials. IMPACT is a national surveillance initiative with centres located in pediatric tertiary care centres in Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Saskatchewan, Alberta and British Columbia. All local and referred cases seen at an IMPACT hospital were reported. In addition to cases admitted to IMPACT centres, each IMPACT centre identified a geographic area with a defined population base and captured all hospitalized cases occurring in children and adults residing orIgInal artICle©2009 Pulsus Group Inc. All rights reservedN Le saux, JA Bettinger, susan Wootton, et al; for the members of the Canadian Immunization Monitoring Program, Active (IMPACt). Profile of serogroup Y meningococcal infections in Canada: Implications for vaccine selection. Can J Infect dis Med Microbiol 2009;19(4):e130-e134.Canada is a leader in establishing routine infant immunization pro-grams against meningococcal C disease. Currently, all provinces have routine programs to provide meningococcal C conjugate vaccines to infants and children. The result of the existing programs has been a decrease in serogroup C incidence. The second most common vaccine-preventable serogroup in Canada is serogroup Y, the incidence of which has been stable. The availability of a quadrivalent conjugate vaccine against serogroups A, C, Y and W135 focuses attention on serogroup Y disease as it becomes relatively more prominent as a cause of vaccine-preventable invasive meningococcal disease. This vaccine was licensed in November 2006 but is not routinely used except in Nunavut, New Brunswick and Prince Edward Island. To allow a better understanding of the ‘value added’ by a serogroup Y-containing vac-cine, it is necessary to have a contemporary profile of Y disease in Canada. In the present paper, recent surveillance data on invasive meningococcal disease across Canada are summarized.Key Words: Invasive meningococcal disease; Meningococcal vaccine; Morbidity; Mortality; Neisseria meningitides; Serogroups A, C, Y, W135Le profil des infections à méningocoque de sérogroupe Y au Canada : Les conséquences sur la sélection des vaccinsLe Canada est un chef de file dans la mise en œuvre de programmes systématiques de vaccination des enfants contre la maladie à méningocoque de sérogroupe C. Toutes les provinces sont dotées de programmes systématiques pour administrer le vaccin conjugué contre le méningocoque de sérogroupe C aux nourrissons et aux enfants. Grâce à ces programmes, l’incidence du sérogroupe C a diminué. Le deuxième sérogroupe évitable par un vaccin en importance au Canada est le sérogroupe Y, dont l’incidence est stable. La disponibilité d’un vaccin conjugué quadrivalent contre les sérogroupes A, C, Y et W135 fixe l’attention sur la maladie à sérogroupe Y, qui devient relativement plus dominante comme cause de maladie à méningocoque envahissante évitable par un vaccin. Ce vaccin a été homologué en novembre 2006, mais il n’est pas utilisé systématiquement, sauf au Nunavut, au Nouveau-Brunswick et à l’Île-du-Prince-Édouard. Afin de mieux comprendre la « valeur ajoutée » d’un vaccin contenant le sérogroupe Y, il est nécessaire de disposer d’un profil contemporain de la maladie à sérogroupe Y au Canada. Dans le présent article, on résume les récentes données de surveillance sur la maladie à méningocoque envahissante au Canada.Profile of serogroup Y meningococcal infections in CanadaCan J Infect Dis Med Microbiol Vol 20 No 4 Winter 2009 e131within this defined area. Surveillance included over 16 mil-lion Canadians, or just over 50% of the Canadian population. Ethics approval was obtained at all hospitals.All centres used the same case finding strategies, case defin-ition and report form to abstract information from the patient’s chart. Patients were not directly contacted. Information on the case report form included the patient’s age, sex, prior health, including any pre-existing medical conditions, presenting manifestations, the clinical presentation of the current menin-gococcal infection, the sources of positive cultures, level of care required, outcome and complications or sequelae. Presenting manifestations included signs of bacteremia (with and without diagnosed septic shock), meningitis, pneumonia, pericarditis, arthritis, endophthalmitis, seizure, petechial rash, ecchymosis and skin necrosis. Charts were reviewed after hospital dis-charge to capture data on sequelae at discharge. Sequelae included amputation, scarring, renal dysfunction, deafness, seizures requiring anticonvulsants on discharge and other neurological deficits. Meningitis as a presenting manifestation was defined as having either a positive culture from cerebro-spinal fluid (CSF); detection of nucleic acid from N meningitidis by polymerase chain reaction (PCR) from CSF; or positive blood culture with CSF pleocytosis (white blood cell count greater than 10×106/L). Inclusion as a case of invasive meningococcal disease required isolation of N meningitidis from a sterile site (eg, blood, CSF, joint, pleural, peritoneal or pericardial fluid), or a positive PCR test from blood or CSF. Isolates were forwarded to the National Microbiology Laboratory in Winnipeg, Manitoba, for further characterization and confirmation of serogroup. The latter data were used when available; otherwise, locally determined serogroup data were used. For the present analysis the focus was on vaccine-preventable cases caused by sero-groups C and Y. Cases caused by serogroup A and W135 were few and are briefly described. Cases caused by serogroup B or other serogroups were excluded because these are not currently preventable by licensed vaccines in Canada. Three separate multivariate logistic regression models were used to determine differences between serogroups C and Y, and predictors for morbidity and mortality among all four vaccine-preventable serogroups (A, C, Y and W135). Characteristics examined in univariate regression were age, sex, pre-existing underlying health condition, manifestations (bacteremia, meningitis or both), septic shock, intensive care unit stay, sequelae and death. Characteristics with a P≤0.05 were considered signifi-cant and included in the final model. SAS version 9.1.3 (SAS Institute, USA) was used for all analyses.ResuLtsIn total, 227 meningococcal cases caused by vaccine-preventable serogroups A, C, Y and W135 were identified during six years of active surveillance. Two hundred seventy-two serogroup B cases, one nonencapsulated mutant (9), 11 cases identified by PCR without serogrouping, and three isolates that were not available for serogrouping were excluded from the analysis. Two serogroup A cases occurred in adults with recent travel history to India and Pakistan, respectively, and appear to be imported cases. Characteristics of the cases caused by sero-groups C, Y and W135 are shown in Table 1. The median age of cases was 18.5 years with a range of zero to 95 years. The most common presenting manifestations included signs of bacteremia (51%), signs and symptoms of meningitis (18%), or signs of both bacteremia and meningitis (26%). Additional laboratory features by age for cases with serogroups C and Y are shown in Table 2. For the W135 cases (not shown in Table 2), diagnosis was made entirely by positive culture of blood (15 of 20) or CSF (seven of 20); seven of 20 (35%) had associated thrombocytopenia and one had leukopenia.differences between serogroup Y and CSerogroup Y was significantly more likely to occur in adults 60 years of age and older (odds ratio [OR] 3.82, 95% CI 1.83 to 8.01) and in cases with underlying medical conditions (OR 3.38, 95% CI 1.88 to 6.1) when compared with serogroup C. After adjusting for age and underlying health conditions, cases with serogroup Y infection were significantly less likely to have septic shock (OR 0.20, 95% CI 0.08 to 0.48), less likely to require intensive care (OR 0.50, 95% CI 0.14 to 1.0), less likely to die (OR 0.11, 95% CI 0.02 to 0.52) and less likely to suffer significant sequelae (OR 0.28, 95% CI 0.11 to 0.69) than those with serogroup C. Finally, as shown in Table 2, the clinical manifestations and laboratory features of serogroup Y were less severe than those of serogroup C. Predictors for deathOf the 20 deaths, two occurred in children two to five years of age, two in adolescents 18 to 19 years of age and 16 in adults 20 years of age and older (eight in adults 20 to 49 years of age). In adults, 13 deaths (81%) were caused by serogroup C, two by Table 1Characteristics of cases of serogroup C, Y and W135 infection, 2002 to 2007CharacteristicsSerogroupC, n=122Y, n=83W135,  n=20Total, n=227*Age group, years   <2 4 (3) 7 (8) 7 (35) 18 (8)   2–19 33 (27) 28 (34) 7 (35) 68 (30)   20–59 72 (59) 22 (27) 4 (20) 99 (44)   ≥60† 13 (11) 26 (31) 2 (10) 42 (19)Male 66 (54) 39 (47) 10 (50) 116 (51)Underlying health condition†34 (28) 47 (57) 9 (45) 90 (40)Immunocompromised 5 (4) 8 (10) 1 (5) 14 (6)Presenting manifestation   Bacteremia 53 (43) 55 (66) 7 (35) 116 (51)   Meningitis 23 (18.9) 12 (15) 5 (25) 40 (18)   Bacteremia/meningitis† 43 (35) 9 (11) 5 (25) 58 (26)   Other manifestation 3 (3) 7 (8) 3 (15) 13 (6)Septic shock† 59 (48) 10 (12) 3 (15) 73 (32)Mean days in hospital (range)14.4  (1–272)10.7 (1–91)10.0 (1–53)12.6 (1–272)ICU care† 87 (71) 30 (36) 7 (35) 126 (56)Days in ICU, mean (range)5.8 (1–36) 4.3 (1–11) 4.0 (1–18) 5.4 (1–36)Death from infection† 16 (13) 2 (2.4) 1 (5) 20 (8.8)Sequelae† 28 (23) 7 (8) 2 (10) 37 (16)Data presented as n (%) unless otherwise specified. *Total includes two sero-group A cases; †Significant difference (P≤0.05) in univariate regression between serogroup C and serogroup Y. ICU Intensive care unitle Saux et alCan J Infect Dis Med Microbiol Vol 20 No 4 Winter 2009e132serogroup Y and one by serogroup A. In children and adoles-cents, three deaths were caused by serogroup C and one by serogroup W135. Adults were more likely to die from meningo-coccal infection than children (OR 1.59, 95% CI 1.05 to 2.40), regardless of serogroup. Cases infected with sero-group C were more likely to die, regardless of age (OR 4.5, 95% CI 1.4 to 14.5) when compared with serogroups A, Y and W135. Seventeen (7.5%) cases had a history of receipt of anti-biotics not related to treatment of meningococcal infection before admission, and all survived. sequelaeA total of 37 (16.3%) patients suffered sequelae related to their infection, described in Table 3. The two W135 cases with sequelae (not shown in the table) occurred in children younger than two years of age: one suffered severe unilateral deafness and one had central hypotonia, visual loss and pituitary insuffi-ciency. Of the serogroup C and Y cases with renal dysfunc-tion, four serogroup C cases (three adults and one child) were dialysis dependent, while no serogroup Y case was. Serogroup C caused severe, bilateral deafness in three cases and mild bilateral deafness in three cases, while serogroup Y caused mild, bilateral deafness in one case. Severe central nervous system sequelae caused by serogroup C occurred in six cases, includ-ing hydrocephalus (two cases), focal cerebral ischemia (two cases), visual loss (one case) and a third cranial nerve palsy (one case). Three other patients had other persistent signifi-cant neurological sequelae manifesting as extremity numb-ness, tremors and significant weakness. No such sequelae followed serogroup Y infections. Among the eight serogroup C patients with neurological sequelae, no differences were found in presenting manifestations (two with bacteremia, three with meningitis and three with both bacteremia and meningitis) or the occurrence of septic shock (four of eight). Predictors for sequelaeMultivariate logistic regression showed children younger than two years of age were significantly more likely to suffer from sequelae than older children and adults (OR 7.2, 95% CI 2.0 to 25.5) regardless of causative serogroup. Children ages two to 19 years of age were more likely than adults to suffer from sequelae (OR 2.0, 95% CI 0.87 to 4.4). Cases infected with serogroup C who survived were also significantly more likely to have sequelae, regardless of age (OR 4.8, 95% CI 1.9 to 11.8). Table 2Selected clinical and laboratory features for invasive disease due to serogroups C and Y by age Serogroup and agePositive blood culture Positive CSF culture PCR positiveOther sterile site culture*CSF pleocytosis† abnormal INR‡abnormal platelets WbC <5×109/lSerogroup C, n=122 (%) 92 (75) 37 (30) 20 (16) 3 (3) 60/75 (80) 82/108 (76) 75 (62) 13 (11)Age, years   <2, n=4 3 (75) 1 (25) 0 0 3/3 (100) 3/3 (100) 2 (50) 1 (25)   2–19, n=33 25 (76) 10 (30) 6 (18) 0 18/24 (75) 23/31 (74) 18 (55) 3 (9)   20–59, n=72 53 (74) 24 (33) 14 (19) 2 (3) 34/42 (81) 47/63 (75) 47 (65) 9 (11)   ≥60, n=13 11 (85) 2 (15) 0 1 (8) 5/6 (83) 9/11 (82) 8 (62) 0Serogroup Y n=83 (%) 68 (82) 16 (19) 4 (5) 4 (5) 20/31 (65) 25/42 (60) 27 (33) 7 (8)Age, years   <2, n=7 5 (71) 4 (57) 1 (14) 0 5/7 (71) 1/1 (100) 4 (57) 1 (17)   2–19, n=28 20 (71) 6 (21) 3 (11) 2 (7) 9/12 (75) 12/14 (86) 9 (32) 4 (14)   20–59, n=22 18 (82) 4 (18) 0 2 (4) 4/6 (67) 6/13 (46) 6 (27) 1 (5)   ≥60, n=26 25 (96) 2 (8) 0 0 2/6 (33) 6/14 (43) 8 (31) 1 (4)Percentage is calculated based on number in each age group within each serogroup, unless otherwise stated. *Other sterile sites include joint fluid (n=6), skin biopsy (n=1) and vitreous fluid (n=1); †Cerebrospinal fluid (CSF) examined for n=106 (52%) and abnormal white blood cells (WBC) for n=80 (number abnormal/total number done); ‡International normalized ratio (INR) examined in n=150 (73%) (number abnormal/total number done). PCR Polymerase chain reactionTable 3Type of sequelae due to serogroups C and Y by ageSerogroup and age amputation Skin scarring Renal dysfunction Deafness Seizures* Neurological sequelaeSerogroup C, n=28 (%) 9 (32) 9 (31) 8 (28) 6 (21) 4 (14) 8 (29)Age, years   <2, n=3 1 (33) 1 (33) 1 (33) 1 (33) 1 (33) 1 (33)   2–19, n=9 5 (56) 4 (44) 2 (22) 2 (22) 0 2 (22)   20–59, n=12 3 (19) 3 (25) 4 (33) 2 (17) 2 (17) 5 (31)   ≥60, n=4 0 1 (25) 1 (25) 1 (25) 1 (25) 0Serogroup Y, n=7 (%) 1 (14) 2 (29) 2 (29) 1 (14) 0 0Age, years   <2, n=1 0 0 0 1 (100) 0 0   2-19, n=4 1 (25) 2 (50) 1 (25) 0 0 0   20-59, n=2† 0 0 1 (50) 0 0 0   ≥60, n=0 0 0 0 0 0 0*Seizures requiring anticonvulsants on discharge; †One patient had a cataract resulting from serogroup Y infectionProfile of serogroup Y meningococcal infections in CanadaCan J Infect Dis Med Microbiol Vol 20 No 4 Winter 2009 e133dIsCussIoNThe strengths of the IMPACT meningococcal surveillance data are its contemporary nature (current through 2007), national scope, active, population-based case finding, and linked clin-ical and microbiological data. Moreover, it provides a detailed picture of serogroup A, Y and W135 disease that is unmodified by quadrivalent conjugate vaccine use. An assessment of mor-bidity and mortality caused by these vaccine-preventable inva-sive meningococcal serogroups is therefore timely, especially for immunization program planners and health economists.Significant epidemiological and clinical differences exist between serogroup Y and C disease. Although serogroup C incidence has shown a significant decrease over the past five years in Canada, serogroup Y incidence has remained relatively constant with an average annual incidence per 100,000 of 0.14 (95% CI 0.09 to 0.20) in children younger than 20 years of age and 0.09 (95% CI 0.06 to 0.11) in adults and has not thus far exhibited signs of serogroup replacement (7). Stable serogroup Y incidence has also been shown in the United Kingdom, which started routine infant conjugate C immunization pro-grams in 2000 (10). Whereas in the United States, serogroup Y incidence increased significantly in the 1990’s, before conju-gated vaccines for meningococcal disease were available, as a result of the sequential emergence of two clonal groups attrib-utable to antigenic shifts (11-15). In the present series, serogroup Y disease was significantly more likely to occur in adults older than 60 years of age. This is consistent with previous Canadian data from 1999 to 2003, which indicated that the highest percentage of serogroup Y isolates were from adults older than 60 years of age (16). Two large case series of serogroup Y disease from the United States in the period 1992 to 1994 also noted that patients were older compared with non-serogroup Y disease (11,17) This contrasts with recent reports from Colombia that show an increased burden of disease for serogroup Y in children with just 7.5% of the cases in patients 60 years of age and older (18). We found that disease due to serogroup Y was generally milder than serogroup C disease. Specifically, patients with disease due to serogroup Y were less likely to present in septic shock, have thrombocytopenia or require intensive care. We observed 2.4% mortality among those infected with serogroup Y versus 13% mortality with serogroup C, with mortality most often occurring in adults in both groups. This is consistent with data from others where the case fatality rate for sporadic serogroup C disease was between 11% and 23% whereas the case fatality rate for serogroup Y or W135 has been reported as being between 5% and 9% (11,14,17,19,20).Although cases infected with serogroup Y were typically older or had underlying medical conditions, they suffered fewer sequelae and in particular, fewer neurological sequelae com-pared to those infected with serogroup C. Apart from one case of deafness, none of the patients with disease due to serogroup Y had seizures or neurological sequelae. This may be a reflec-tion of less frequent central nervous infection in adults with serogroup Y compared with serogroup C infections (Table 2). Others have noted sequelae rates of 2% to 15% for invasive meningococcal disease, but these rates were not serogroup specific (21-23).While serogroup Y disease may justify efforts to prevent it through routine vaccination, it is clearly less of a threat than serogroup C disease. The incidence of serogroup Y disease recently in Canada was one-third (35%) of the baseline rate of serogroup C disease (7,8). This fact, along with the milder nature of serogroup Y disease, means that it will be less cost-effective from a public health perspective to prevent such cases through vaccination than was the case for serogroup C disease. However, the cost-benefit ratio will improve if vaccination costs decrease, disease incidence due to serogroups A, Y or W135 increases or virulent clones of these serogroups emerge. The cost-benefit ratio for a quadrivalent vaccine is favourable from an individual perspective, especially for persons at higher risk or those wishing to reduce their risk of invasive meningococcal dis-ease to a minimum. Continued surveillance particularly aimed at monitoring for capsule replacement is essential to understand the effect of vaccination programs on the evolution of meningococcal disease in Canada. IMPACt MeMBeRs ANd Co-INvestIgAtoRs INCLude the foLLoWINg: St John’s R Morris, J Hutchinson, F Stratton Halifax S Halperin, A Coombs, S McNeil Quebec City P Déry, G De Serres, P de Wals Montreal M Lebel, D Moore Ottawa N Le Saux, V Roth, G Dunkley Toronto D Tran, E Chan, C D’Cunha, K Green,   F Jamieson, H Kassam, I Kitai, C Kawa, R Kyle,   A McGeer, D McKeown, B Nosal, G Pasut,   S Richardson, A Simor, J Tollkin, L Van Horne,   B Yaffe Winnipeg  J Embree, R Tsang Saskatoon  B Tan  Edmonton  W Vaudry, G Taylor Calgary T Jadavji, D Gregson, J Kellner, J MacDonald Vancouver  D Scheifele, J Bettinger, P Daly, R Guasparini,   G StiverACKNoWLedgeMeNts: We gratefully acknowledge the expert assistance provided by the Monitor Liaison (Heather Samson), the IMPACT nurse monitors and staff of the data centre (Kim Marty, Wenli Zhang, Shu Yu Fan and Debbe Heayn) and the National Microbiology Laboratory (Averil Henderson). We thank the Directors and staff of the provincial and territorial public health laboratories for providing the isolates for this study. fuNdINg: This surveillance activity is conducted by the IMPACT network of pediatric investigators and managed by the Canadian Paediatric Society (CPS). CPS receives ongo-ing funding from the Public Health Agency of Canada’s Centre for Immunization and Respiratory Infectious Diseases for the Canadian Immunization Monitoring Program Active, a national surveillance initiative. Funding for the meningococcal surveil-lance project was provided by Sanofi Pasteur.RefeReNCes1. Tsang RS, Law DK, Henderson AM, Blake ML, Stoltz J. Increase in serogroup C meningococcal disease in Canada is associated with antigenic changes in the protein antigens of the ET-15 clone of Neisseria meningitidis. J Infect Dis 2006;194:1791-2.2. De Wals P. Immunization strategies for the control of serogroup C meningococcal disease in developed countries. Expert Rev Vaccines 2006;5:269-75.3. De Wals P, Deceuninck G, Boulianne N, De SG. Effectiveness of a mass immunization campaign using serogroup C meningococcal conjugate vaccine. JAMA 2004;292:2491-4.le Saux et alCan J Infect Dis Med Microbiol Vol 20 No 4 Winter 2009e1344. Tyrrell GJ, Chui L, Johnson M, Chang N, Rennie RP, Talbot JA. Outbreak of Neisseria meningitidis, Edmonton, Alberta, Canada. Emerg Infect Dis 2002;8:519-21.5. Squires SG, Deeks SL, Tsang RS. Enhanced surveillance of invasive meningococcal disease in Canada: 1 January, 1999, through 31 December, 2001. Can Commun Dis Rep 2004;30:17-28.6. Patrick DM, Champagne S, Goh SH, et al. Neisseria meningitidis carriage during an outbreak of serogroup C disease. Clin Infect Dis. 2003;37:1183-8.7.  Bettinger JA, Scheifele DW, Le Saux N, Halperin SA, Vaudry W, Tsang R; the members of the Canadian Immunization Monitoring Program, Active (IMPACT). The impact of childhood meningococcal serogroup C conjugate vaccine programs in Canada. Pediatr Infect Dis J 2009;28:220-4.8. Enhanced surveillance of invasive meningococcal disease in Canada: 1 January, 2004, through 31 December, 2005. Can Commun Dis Rep 2007;33:1-15.9. Hoang LM, Thomas E, Tyler S, et al. Rapid and fatal meningococcal disease due to a strain of Neisseria meningitidis containing the capsule null locus. Clin Infect Dis  2005;40:e38-e42.10. Balmer P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccine in the UK. J Med Microbiol 2002;51:717-22.11. Rosenstein NE, Perkins BA, Stephens DS, et al. The changing epidemiology of meningococcal disease in the United States, 1992-1996. J Infect Dis 1999;180:1894-901.12. Harrison LH, Jolley KA, Shutt KA, et al. Antigenic shift and increased incidence of meningococcal disease. J Infect Dis 2006;193:1266-74.13. McEllistrem MC, Kolano JA, Pass MA, et al. Correlating epidemiologic trends with the genotypes causing meningococcal disease, Maryland. Emerg Infect Dis 2004;10:451-6.14. Gray SJ, Trotter CL, Ramsay ME, et al. Epidemiology of meningococcal disease in England and Wales 1993/94 to 2003/04: Contribution and experiences of the Meningococcal Reference Unit. J Med Microbiol 2006;55:887-96.15. Trotter CL, Ramsay ME, Gray S, Fox A, Kaczmarski E. No evidence for capsule replacement following mass immunisation with meningococcal serogroup C conjugate vaccines in England and Wales. Lancet Infect Dis 2006;6:616-7.16. Tsang RS, Henderson AM, Cameron ML et al. Genetic and antigenic analysis of invasive serogroup Y Neisseria meningitidis isolates collected from 1999 to 2003 in Canada. J Clin Microbiol 2007;45:1753-8.17. Racoosin JA, Whitney CG, Conover CS, Diaz PS. Serogroup Y meningococcal disease in Chicago, 1991-1997. JAMA 1998;280:2094-8.18. Agudelo CI, Sanabria OM, Ovalle MV. Serogroup Y meningococcal disease, Columbia. Emerg Infect Dis 2008;14:990-1.19. Jensen ES, Schonheyder HC, Lind I, Berthelsen L, Norgard B, Sorensen HT. Neisseria meningitidis phenotypic markers and septicaemia, disease progress and case-fatality rate of meningococcal disease: A 20-year population-based historical follow-up study in a Danish county. J Med Microbiol  2003;52:173-9.20. Erickson L, De Wals P. Complications and sequelae of meningococcal disease in Quebec, Canada, 1990-1994. Clin Infect Dis 1998;26:1159-64.21. Barquet N, Domingo P, Cayla JA, et al. Meningococcal disease in a large urban population (Barcelona, 1987-1992): Predictors of dismal prognosis. Barcelona Meningococcal Disease Surveillance Group. Arch Intern Med 1999;159:2329-40.22. Booy R, Habibi P, Nadel S, et al. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child 2001;85:386-90.23. Kaplan SL, Schutze GE, Leake JA, et al. Multicenter surveillance of invasive meningococcal infections in children. Pediatrics 2006;118:e979-e984.

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