Nancy E. Messonnier

Bacterial Meningitis in the United States, 1998-2007

BACKGROUND The rate of bacterial meningitis declined by 55% in the United States in the early 1990s, when the Haemophilus influenzae type b (Hib) conjugate vaccine for infants was introduced. More recent prevention measures such as the pneumococcal conjugate vaccine and universal screening of pregnant women for group B streptococcus (GBS) have further changed the epidemiology of bacterial meningitis. METHODS We analyzed data on cases of bacterial meningitis reported among residents in eight surveillance areas of the Emerging Infections Programs Network, consisting of approximately 17.4 million persons, during 1998-2007. We defined bacterial meningitis as the presence of H. influenzae, Streptococcus pneumoniae, GBS, Listeria monocytogenes, or Neisseria meningitidis in cerebrospinal fluid or other normally sterile site in association with a clinical diagnosis of meningitis. RESULTS We identified 3188 patients with bacterial meningitis; of 3155 patients for whom outcome data were available, 466 (14.8%) died. The incidence of meningitis changed by -31% (95% confidence interval [CI], -33 to -29) during the surveillance period, from 2.00 cases per 100,000 population (95% CI, 1.85 to 2.15) in 1998-1999 to 1.38 cases per 100,000 population (95% CI 1.27 to 1.50) in 2006-2007. The median age of patients increased from 30.3 years in 1998-1999 to 41.9 years in 2006-2007 (P<0.001 by the Wilcoxon rank-sum test). The case fatality rate did not change significantly: it was 15.7% in 1998-1999 and 14.3% in 2006-2007 (P=0.50). Of the 1670 cases reported during 2003-2007, S. pneumoniae was the predominant infective species (58.0%), followed by GBS (18.1%), N. meningitidis (13.9%), H. influenzae (6.7%), and L. monocytogenes (3.4%). An estimated 4100 cases and 500 deaths from bacterial meningitis occurred annually in the United States during 2003-2007. CONCLUSIONS The rates of bacterial meningitis have decreased since 1998, but the disease still often results in death. With the success of pneumococcal and Hib conjugate vaccines in reducing the risk of meningitis among young children, the burden of bacterial meningitis is now borne more by older adults. (Funded by the Emerging Infections Programs, Centers for Disease Control and Prevention.).

Changes in Neisseria meningitidis Disease Epidemiology in the United States, 1998–2007: Implications for Prevention of Meningococcal Disease

BACKGROUND In January 2005, a quadrivalent (serogroups A, C , Y, and W-135) meningococcal conjugate vaccine was licensed for use in adolescents. This report describes the epidemiologic features of meningococcal disease in the United States from January 1998 through December 2007, before and during implementation of adolescent quadrivalent meningococcal conjugate vaccination. METHODS Data were collected from active surveillance for invasive Neisseria meningitidis conducted through the Active Bacterial Core surveillance (ABCs) sites during 1998-2007. Isolates from cases were serogrouped at the ABCs site and confirmed at the Centers for Disease Control and Prevention. Estimates of the incidence and number of cases in the 50 states were calculated, standardizing for race and age group. RESULTS In the period 1998-2007, a total of 2262 cases of meningococcal disease were reported from ABCs sites; 11.3% of these cases were fatal. The estimated United States average annual incidence of meningococcal disease was 0.53 cases per 100,000 population (95% confidence interval, 0.51-0.55), and an estimated 1525 (95% confidence interval, 1470-1598) cases occurred annually. The annual incidence decreased 64.1%, from 0.92 cases per 100,000 population in 1998 to 0.33 cases per 100,000 population in 2007. Infants aged <1 year have the highest incidence of meningococcal disease (5.38 cases per 100,000 population). After introduction of the quadrivalent meningococcal conjugate vaccine, no significant decrease in serogroup C or Y meningococcal disease was seen among those aged 11-19 years in 2006-2007, compared with 2004-2005. CONCLUSIONS Before the introduction of the quadrivalent meningococcal conjugate vaccine, the incidence of meningococcal disease in the United States decreased to a historic low. However, meningococcal disease still causes a substantial burden of disease among all age groups. Future vaccination strategies may include targeting infants and preventing serogroup B meningococcal disease.

Association of Childhood Pertussis With Receipt of 5 Doses of Pertussis Vaccine by Time Since Last Vaccine Dose, California, 2010

CONTEXT In 2010, California experienced its largest pertussis epidemic in more than 60 years; a substantial burden of disease was noted in the 7- to 10-year-old age group despite high diphtheria, tetanus, and acellular pertussis vaccine (DTaP) coverage, indicating the possibility of waning protection. OBJECTIVE To evaluate the association between pertussis and receipt of 5 DTaP doses by time since fifth DTaP dose. DESIGN, SETTING, AND PARTICIPANTS Case-control evaluation conducted in 15 California counties. Cases (n = 682) were all suspected, probable, and confirmed pertussis cases among children aged 4 to 10 years reported from January through December 14, 2010; controls (n = 2016) were children in the same age group who received care from the clinicians reporting the cases. Three controls were selected per case. Vaccination histories were obtained from medical records and immunization registries. MAIN OUTCOME MEASURES Primary outcomes were (1) odds ratios (ORs) for the association between pertussis and receipt of the 5-dose DTaP series and (2) ORs for the association between pertussis and time since completion (<12, 12-23, 24-35, 36-47, 48-59, or ≥60 months) of the 5-dose DTaP series. Logistic regression was used to calculate ORs, accounting for clustering by county and clinician, and vaccine effectiveness (VE) was estimated as (1 - OR) × 100%. RESULTS Among cases and controls, 53 (7.8%) and 19 (0.9%) had not received any pertussis-containing vaccines, respectively. Compared with controls, children with pertussis had a lower odds of having received all 5 doses of DTaP (OR, 0.11; 95% CI, 0.06-0.21 [estimated VE, 88.7%; 95% CI, 79.4%-93.8%]). When children were categorized by time since completion of the DTaP series, using an unvaccinated reference group, children with pertussis compared with controls were less likely to have received their fifth dose within the prior 12 months (19 [2.8%] vs 354 [17.6%], respectively; OR, 0.02; 95% CI, 0.01-0.04 [estimated VE, 98.1%; 95% CI, 96.1%-99.1%]). This association was evident with longer time since vaccination, with ORs increasing with time since the fifth dose. At 60 months or longer (n = 231 cases [33.9%] and n = 288 controls [14.3%]), the OR was 0.29 (95% CI, 0.15-0.54 [estimated VE, 71.2%; 95% CI, 45.8%-84.8%]). Accordingly, the estimated VE declined each year after receipt of the fifth dose of DTaP. CONCLUSION Among children in 15 California counties, children with pertussis, compared with controls, had lower odds of having received the 5-dose DTaP series; as time since last DTaP dose increased, the odds increased, which is consistent with a progressive decrease in estimated vaccine effectiveness each year after the final dose of pertussis vaccine.

Waning Immunity to Pertussis Following 5 Doses of DTaP

OBJECTIVE: To assess the risk of pertussis by time since vaccination in children in Minnesota and Oregon who received 5 doses of acellular pertussis vaccines (DTaP). METHODS: These cohort analyses included Minnesota and Oregon children born between 1998 and 2003 who had 5 DTaP doses recorded in state Immunization Information Systems. Immunization records and statewide pertussis surveillance data were combined. Incidence rates and risk ratios for pertussis were calculated for the 6 years after receipt of the fifth DTaP dose. RESULTS: The cohorts included 224 378 Minnesota children and 179 011 from Oregon; 458 and 89 pertussis cases were identified in Minnesota and Oregon, respectively. Pertussis incidence rates rose each year of follow-up: 15.6/100 000 (95% confidence interval [CI]: 11.1–21.4) at year 1 to 138.4/100 000 (CI: 113.3–166.9) at year 6 (Minnesota); 6.2/100 000 (CI: 3.3–10.6) in year 1 to 24.4/100 000 (CI: 15.0–37.8) in year 6 (Oregon). Risk ratios increased from 1.9 (CI: 1.3–2.9) in year 2 to 8.9 (CI: 6.0–13.0) in year 6 (Minnesota) and from 1.3 (CI: 0.6–2.8) in year 2 to 4.0 (CI: 1.9–8.4) in year 6 (Oregon). CONCLUSIONS: This evaluation reports steady increase in risk of pertussis in the years after completion of the 5-dose DTaP series. This rise is likely attributable in part to waning immunity from DTaP vaccines. Continuing to monitor disease burden and vaccine effectiveness in fully vaccinated children in coming years will be important to assess ongoing risk as additional cohorts vaccinated solely with acellular pertussis vaccines are introduced.

Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity.

BACKGROUND The conjugate vaccine against serogroup A Neisseria meningitidis (NmA), MenAfriVac, was first introduced in mass vaccination campaigns of 1-29-year-olds in Burkina Faso in 2010. It is not known whether MenAfriVac has an impact on NmA carriage. METHODS We conducted a repeated cross-sectional meningococcal carriage study in a representative portion of the 1-29-year-old population in 3 districts in Burkina Faso before and up to 13 months after vaccination. One district was vaccinated in September 2010, and the other 2 were vaccinated in December 2010. We analyzed 25 521 oropharyngeal samples, of which 22 093 were obtained after vaccination. RESULTS In October-November 2010, NmA carriage prevalence in the unvaccinated districts was comparable to the baseline established in 2009, but absent in the vaccinated district. Serogroup X N. meningitidis (NmX) dominated in both vaccinated and unvaccinated districts. With 4 additional sampling campaigns performed throughout 2011 in the 3 districts, overall postvaccination meningococcal carriage prevalence was 6.95%, with NmX dominating but declining for each campaign (from 8.66% to 1.97%). Compared with a baseline NmA carriage prevalence of 0.39%, no NmA was identified after vaccination. Overall vaccination coverage in the population sampled was 89.7%, declining over time in 1-year-olds (from 87.1% to 26.5%), as unvaccinated infants reached 1 year of age. NmA carriage was eliminated in both the vaccinated and unvaccinated population from 3 weeks up to 13 months after mass vaccination (P = .003). CONCLUSIONS The disappearance of NmA carriage among both vaccinated and unvaccinated populations is consistent with a vaccine-induced herd immunity effect.

Prevalence and molecular characterization of pertactin-deficient Bordetella pertussis in the United States.

ABSTRACT Pertussis has shown a striking resurgence in the United States, with a return to record numbers of reported cases as last observed in the 1950s. Bordetella pertussis isolates lacking pertactin, a key antigen component of the acellular pertussis vaccine, have been observed, suggesting that B. pertussis is losing pertactin in response to vaccine immunity. Screening of 1,300 isolates from outbreak and surveillance studies (historical isolates collected from 1935 up to 2009, isolates from the 2010 California pertussis outbreak, U.S. isolates from routine surveillance between 2010-2012, and isolates from the 2012 Washington pertussis outbreak) by conventional PCR and later by Western blotting and prn sequencing analyses ultimately identified 306 pertactin-deficient isolates. Of these pertactin-deficient strains, 276 were identified as having an IS481 in the prn gene (prnIS481 positive). The first prnIS481-positive isolate was found in 1994, and the next prnIS481-positive isolates were not detected until 2010. The prevalence of pertactin-deficient isolates increased substantially to more than 50% of collected isolates in 2012. Sequence analysis of pertactin-deficient isolates revealed various types of mutations in the prn gene, including two deletions, single nucleotide substitutions resulting in a stop codon, an inversion in the promoter, and a single nucleotide insertion resulting in a frameshift mutation. All but one mutation type were found in prn2 alleles. CDC 013 was a predominant pulsed-field gel electrophoresis (PFGE) profile in the pertactin-positive isolates (203/994) but was found in only 5% (16/306) of the pertactin-deficient isolates. Interestingly, PFGE profiles CDC 002 and CDC 237 represented 55% (167/306) of the identified pertactin-deficient isolates. These results indicate that there has been a recent dramatic increase in pertactin-deficient B. pertussis isolates throughout the United States.

Serogroup A meningococcal conjugate vaccination in Burkina Faso: analysis of national surveillance data

BACKGROUND An affordable, highly immunogenic Neisseria meningitidis serogroup A meningococcal conjugate vaccine (PsA-TT) was licensed for use in sub-Saharan Africa in 2009. In 2010, Burkina Faso became the first country to implement a national prevention campaign, vaccinating 11·4 million people aged 1-29 years. We analysed national surveillance data around PsA-TT introduction to investigate the early effect of the vaccine on meningitis incidence and epidemics. METHODS We examined national population-based meningitis surveillance data from Burkina Faso using two sources, one with cases and deaths aggregated at the district level from 1997 to 2011, and the other enhanced with results of cerebrospinal fluid examination and laboratory testing from 2007 to 2011. We compared mortality rates and incidence of suspected meningitis, probable meningococcal meningitis by age, and serogroup-specific meningococcal disease before and during the first year after PsA-TT implementation. We assessed the risk of meningitis disease and death between years. FINDINGS During the 14 year period before PsA-TT introduction, Burkina Faso had 148 603 cases of suspected meningitis with 17 965 deaths, and 174 district-level epidemics. After vaccine introduction, there was a 71% decline in risk of meningitis (hazard ratio 0·29, 95% CI 0·28-0·30, p<0·0001) and a 64% decline in risk of fatal meningitis (0·36, 0·33-0·40, p<0·0001). We identified a statistically significant decline in risk of probable meningococcal meningitis across the age group targeted for vaccination (62%, cumulative incidence ratio [CIR] 0·38, 95% CI 0·31-0·45, p<0·0001), and among children aged less than 1 year (54%, 0·46, 0·24-0·86, p=0·02) and people aged 30 years and older (55%, 0·45, 0·22-0·91, p=0·003) who were ineligible for vaccination. No cases of serogroup A meningococcal meningitis occurred among vaccinated individuals, and epidemics were eliminated. The incidence of laboratory-confirmed serogroup A N meningitidis dropped significantly to 0·01 per 100 000 individuals per year, representing a 99·8% reduction in the risk of meningococcal A meningitis (CIR 0·002, 95% CI 0·0004-0·02, p<0·0001). INTERPRETATION Early evidence suggests the conjugate vaccine has substantially reduced the rate of meningitis in people in the target age group, and in the general population because of high coverage and herd immunity. These data suggest that fully implementing the PsA-TT vaccine could end epidemic meningitis of serogroup A in sub-Saharan Africa. FUNDING None.

Emergence of ciprofloxacin-resistant Neisseria meningitidis in North America.

We report on three cases of meningococcal disease caused by ciprofloxacin-resistant Neisseria meningitidis, one in North Dakota and two in Minnesota. The cases were caused by the same serogroup B strain. To assess local carriage of resistant N. meningitidis, we conducted a pharyngeal-carriage survey and isolated the resistant strain from one asymptomatic carrier. Sequencing of the gene encoding subunit A of DNA gyrase (gyrA) revealed a mutation associated with fluoroquinolone resistance and suggests that the resistance was acquired by means of horizontal gene transfer with the commensal N. lactamica. In susceptibility testing of invasive N. meningitidis isolates from the Active Bacterial Core surveillance system between January 2007 and January 2008, an additional ciprofloxacin-resistant isolate was found, in this case from California. Ciprofloxacin-resistant N. meningitidis has emerged in North America.

Current Epidemiology and Trends in Invasive Haemophilus influenzae Disease—United States, 1989–2008

BACKGROUND With the introduction of Haemophilus influenzae serotype b (Hib) conjugate vaccines, there has been a dramatic reduction of Hib disease in young children and the epidemiological trends of invasive H. influenzae have shifted. METHODS Data were collected from active surveillance for invasive H. influenzae disease conducted through Active Bacterial Core surveillance sites during 1989-2008. RESULTS During 1999-2008, the estimated mean annual incidence of H. influenzae infection was 1.62 cases per 100 000 population; 15.3% of cases were fatal. Incidence was higher among adults aged ≥65 years, compared with other age groups. The largest burden of disease among children aged <5 years was in infants aged <1 year; many of these cases occurred during the first month of life in preterm or low-birth weight infants. An estimated 10% of the total burden of disease among children aged <5 years occurred in American Indian and Alaska Native children. During 1989-2008, 7559 cases of H. influenzae disease were reported from Active Bacterial Core surveillance sites. Small increases in the incidence of serotypes a, e, and f were observed during 1989-2008. The largest of these increases was in serotype f and was primarily among adults aged ≥18 years. CONCLUSIONS Since the introduction of Hib conjugate vaccines, the incidence of invasive disease caused by H. influenzae in the United States has decreased dramatically; however, a considerable burden of non-Hib disease is still present in the oldest and youngest age groups. There is no evidence of substantial replacement disease with non-b serotypes in young children in the United States.

Clinical Validation of Multiplex Real-Time PCR Assays for Detection of Bacterial Meningitis Pathogens

ABSTRACT Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae are important causes of meningitis and other infections, and rapid, sensitive, and specific laboratory assays are critical for effective public health interventions. Singleplex real-time PCR assays have been developed to detect N. meningitidis ctrA, H. influenzae hpd, and S. pneumoniae lytA and serogroup-specific genes in the cap locus for N. meningitidis serogroups A, B, C, W135, X, and Y. However, the assay sensitivity for serogroups B, W135, and Y is low. We aimed to improve assay sensitivity and develop multiplex assays to reduce time and cost. New singleplex real-time PCR assays for serogroup B synD, W135 synG, and Y synF showed 100% specificity for detecting N. meningitidis species, with high sensitivity (serogroup B synD, 99% [75/76]; W135 synG, 97% [38/39]; and Y synF, 100% [66/66]). The lower limits of detection (LLD) were 9, 43, and 10 copies/reaction for serogroup B synD, W135 synG, and Y synF assays, respectively, a significant improvement compared to results for the previous singleplex assays. We developed three multiplex real-time PCR assays for detection of (i) N. meningitidis ctrA, H. influenzae hpd, and S. pneumoniae lytA (NHS assay); (ii) N. meningitidis serogroups A, W135, and X (AWX assay); and (iii) N. meningitidis serogroups B, C, and Y (BCY assay). Each multiplex assay was 100% specific for detecting its target organisms or serogroups, and the LLD was similar to that for the singleplex assay. Pairwise comparison of real-time PCR between multiplex and singleplex assays showed that cycle threshold values of the multiplex assay were similar to those for the singleplex assay. There were no substantial differences in sensitivity and specificity between these multiplex and singleplex real-time PCR assays.