Kristine M. Bisgard

Infant pertussis: who was the source?

Background: In the United States in the 1990s, the incidence of reported pertussis in adults, adolescents and infants increased; infants younger than 1 year of age had the highest reported incidence. Methods: In 4 states with Enhanced Pertussis Surveillance, we examined the epidemiology of reported pertussis cases to determine the source of pertussis among infants. A source was defined as a person with an acute cough illness who had contact with the case-infant 7-20 days before the infants onset of cough. Results: The average annual pertussis incidence per 100,000 infants younger than 1 year of age varied by state: 22.9 in Georgia; 42.1 in Illinois; 93.0 in Minnesota; and 35.8 in Massachusetts. Family members of 616 (80%) of 774 reported case-infants were interviewed; a source was identified for 264 (43%) of the 616 case-infants. Among the 264 case-infants, mothers were the source for 84 (32%) and another family member was the source for 113 (43%). Of the 219 source-persons with known age, 38 (17%) were age 0-4 years, 16 (7%) were age 5-9 years, 43 (20%) were age 10-19 years, 45 (21%) were age 20-29 years and 77 (35%) were age ≥30 years. Conclusions: The variation in reported pertussis incidence in the 4 states might have resulted from differences in awareness of pertussis among health care providers, diagnostic capacity and case classification. Among case-infants with an identifiable source, family members (at any age) were the main source of pertussis. Understanding the source of pertussis transmission to infants may provide new approaches to prevent pertussis in the most vulnerable infants.

Polymorphism in Bordetella pertussis Pertactin and Pertussis Toxin Virulence Factors in the United States, 1935–1999

To elucidate the potential role of the etiologic agent in recent increases of pertussis incidence in the United States, we studied the polymorphism in pertactin and pertussis toxin, which are Bordetella pertussis proteins important for pathogenesis and immunity. We sequenced regions of their genes (prn and ptx) in 152 B. pertussis strains isolated from 1935 through 1999 and identified 2 prn sequences: prn1 (old), observed continuously since 1935, and prn2 (new), not recognized until 1981 but seen in 97% of tested isolates in 1999. There were 3 ptx S1 subunit sequences: ptxS1D (old) was identified in 3 strains (1935 and 1939); ptxS1B (old) represented 87% of the strains recovered during 1935-1974; and ptxS1A (new) was the most prevalent during 1975-1987 and 1989-1999 (64% and 78%, respectively). Potential association between vaccination and the observed shift from old to new types requires further study. Our results provide the basis for prospectively monitoring for changes among circulating B. pertussis that might have epidemiologic relevance.

Establishment of Diagnostic Cutoff Points for Levels of Serum Antibodies to Pertussis Toxin, Filamentous Hemagglutinin, and Fimbriae in Adolescents and Adults in the United States

ABSTRACT Numerous reports have documented that serologic methods are much more sensitive than culture for the diagnosis of pertussis in adolescents and adults. However, a standardized serologic test for pertussis is not routinely available to most clinicians, and the serologic test levels or cutoff points correlated with diseases have not been determined. The goal of the present study was to examine the distribution of immunoglobulin G (IgG) levels against three Bordetella pertussis antigens (pertussis toxin [PT], filamentous hemagglutinin [FHA], and fimbria types 2 and 3 [FIM]) and to determine population-based antibody levels for the purpose of establishing such diagnostic cutoff points. Enzyme-linked immunosorbent assays (ELISAs) were performed with sera from >6,000 U.S. residents aged 6 to 49 years who participated in the Third National Health and Nutrition Examination Survey. Mixture models were developed to identify hypothesized exposure groups and establish diagnostic cutoffs. Quantifiable (>20 ELISA units/ml [EU]) anti-FHA and anti-FIM IgG antibodies were common (65 and 62% of individuals, respectively), but quantifiable anti-PT IgG antibodies were less frequent (16%). Given the distributions of antibody levels, an anti-PT IgG level of ≥94 EU was proposed as the diagnostic cutoff point. Application of this cutoff point to culture-confirmed illness in a prior study investigating cough illness yielded a high diagnostic sensitivity (80%) and specificity (93%). A standardized ELISA for anti-PT IgG with a single serum sample appears to be useful for the identification of recent B. pertussis infection in adolescents and adults with cough illness. The PT cutoff point will be further evaluated in prospective studies of confirmed B. pertussis infection.

Pertussis Vaccine Effectiveness Among Children 6 to 59 Months of Age in the United States, 1998–2001

Background. Despite the dramatic pertussis decrease since the licensure of whole-cell pertussis (diphtheria-tetanus toxoids-pertussis [DTP]) vaccines in the middle 1940s, pertussis remains endemic in the United States and can cause illness among persons at any age; >11000 pertussis cases were reported in 2003. Since July 1996, in addition to 2 DTP vaccines already in use, 5 acellular pertussis (diphtheria-tetanus toxoids-acellular pertussis [DTaP]) vaccines were licensed for use among infants; 3 DTaP vaccines were distributed widely during the study period. Because of the availability of 3 DTaP and 2 DTP vaccines and the likelihood of the vaccines being used interchangeably to vaccinate children with the recommended 5-dose schedule, measuring the effectiveness of the pertussis vaccines was a high priority. Objective. To measure the pertussis vaccine effectiveness (VE) among US children 6 to 59 months of age. Design. We conducted a case-control study in the Cincinnati, Ohio, metropolitan area, Colorado, Idaho, and Minnesota. Participants. Confirmed pertussis cases among children 6 to 59 months of age at the time of disease onset, with onset in 1998–2001, were included. For each case subject, 5 control children were matched from birth certificate records, according to the date of birth and residence. Outcome Measures. A standardized questionnaire was used to obtain vaccination data from parents and providers. Parents/guardians were asked about demographic characteristics, child care attendance, the number of household members who stayed at the same home as the enrolled child for ≥2 nights per week, and cough illness of ≥2-week duration among these household members in the month before the case patients cough onset. Pertussis vaccine doses among case children were counted as valid if they were received ≥14 days before the cough onset date (“valid period”). The age of the case patient (in days) at the end of the valid period was determined, and doses of vaccine for the matched control subjects were counted as valid if they were received by that age. Conditional logistic regression models were used to estimate the matched odds ratios (ORs) for pertussis according to the number of pertussis vaccine doses. The VE was calculated with the following formula: (1 − OR) × 100. Because the pertussis antigen components or amounts differed according to vaccine, the VE of 3 or 4 doses of DTP and/or DTaP was estimated according to the recorded vaccine manufacturer and vaccine type. Results. All enrolled children (184 case subjects and 893 control subjects) had their vaccine history verified. The proportions of children who received 0, 1 or 2, 3, and ≥4 pertussis (DTP and/or DTaP) vaccine doses among case subjects were 26%, 14%, 26%, and 34% and among control subjects were 2%, 8%, 33%, and 57%, respectively. Compared with 0 doses, the unadjusted VE estimate for 1 or 2 pertussis doses was 83.6% (95% confidence interval [CI]: 61.1–93.1%), that for 3 doses was 95.6% (95% CI: 89.7–98.0%), and for ≥4 doses was 97.7% (95% CI: 94.7–99.0%). Among children who received 4 pertussis vaccinations, the risk of pertussis was slightly higher among those who received only 1 type of vaccine (either 4 DTP doses or 4 DTaP doses), compared with those who received a combination of DTP for doses 1 to 3 and DTaP for dose 4 (OR: 2.4; 95% CI: 1.1–5.2). Among children who received 3 or 4 DTaP vaccine doses, the risk of pertussis was slightly higher among those who received a DTaP vaccine with 4 pertussis antigen components (a vaccine no longer available), compared with those who received the DTaP vaccine with 2 pertussis antigen components (OR: 2.5; 95% CI: 1.1–5.8). Among children who received 4 doses, the risk of pertussis was 2.7 times higher for children who received dose 4 early (age of ≤13 months), compared with children who received dose 4 at an older age (age of ≥14 months) (95% CI: 1.1–6.8). For children 6 to 23 months of age, features of household structure were significant risk factors for pertussis. In a multivariate model, compared with living with an older parent (≥25 years of age), not living with an “other” household member (a relative other than a parent or sibling or a nonrelated person), and not living with a sibling 6 to 11 years of age, the risk of pertussis for children 6 to 23 months of age was 6.8 times higher if they lived with a young parent (≤24 years of age) (95% CI: 3.1–15.0), 2.5 times higher if they lived with an “other” household member (95% CI: 1.2–5.4), and 2.2 times higher if they lived with a sibling 6 to 11 years of age (95% CI: 1.2–4.3). Adjusting for these risk factors did not change the VE. Compared with control children, case children were significantly more likely to live with a household member (representing all age groups and relationships) who reported a recent cough illness with duration of ≥2 weeks (87 [52%] of 168 case subjects, compared with 79 [8%] of 860 control subjects). Conclusions. Any combination of ≥3 DTP/DTaP vaccine doses for children 6 to 59 months of age was highly protective against pertussis. However, there were differences according to vaccine type (DTaP or DTP) and DTaP manufacturer. Among children who received 4 pertussis vaccine doses, a combination of 3 DTP doses followed by 1 DTaP dose had a slightly higher VE than other combinations; among children who received 3 or 4 DTaP vaccine doses, 1 DTaP vaccine performed less well. The finding that pertussis dose 4 was more effective when given to children at ≥14 months of age might be confounded if health care providers were more likely to vaccinate children at 12 months of age because of a perceived risk of undervaccination and if these same children were also at higher risk for pertussis. Household members of any age group and relationship could have been the source of pertussis, and household structure was associated with risk for pertussis for children 6 to 23 months of age. In contrast to control children in the study, 26% of case children had never been vaccinated against pertussis. Unvaccinated children are at risk for pertussis and, in a community with other unvaccinated children, can lead to community-wide pertussis outbreaks. Parents need to be educated about the morbidity and mortality risks associated with Bordetella pertussis infection, and they need to be encouraged to vaccinate their children against pertussis on time and with the recommended number of vaccine doses for optimal protection.

Issues Associated with and Recommendations for Using PCR To Detect Outbreaks of Pertussis

ABSTRACT Two outbreaks of respiratory tract illness associated with prolonged cough occurring in 1998 and 1999 in New York State were investigated. A PCR test for Bordetella pertussis was primarily used by a private laboratory to confirm 680 pertussis cases. Several clinical specimens had positive culture results for B. pertussis during both outbreaks, which confirmed that B. pertussis was circulating during the outbreaks. However, testing by the New York State Department of Health reference laboratory suggested that some of the PCR results may have been falsely positive. In addition, features of the outbreak that suggested that B. pertussis may not have been the primary agent of infection included a low attack rate among incompletely vaccinated children and a significant amount of illness among patients testing PCR negative for B. pertussis. These investigations highlight the importance of appropriate clinical laboratory quality assurance programs, of the limitations of the PCR test, and of interpreting laboratory results in context of clinical disease.

Changes in Predominance and Diversity of Genomic Subtypes of Bordetella pertussis Isolated in the United States, 1935 to 1999

Pulsed-field gel electrophoresis (PFGE) of Bordetella pertussis chromosomal DNA fragments generated by XbaI restriction has been used to subtype isolates for epidemiologic studies. To better understand the natural history of pertussis, we determined the PFGE profiles of 1,333 strains isolated in the United States from 1935 to 1999. Results showed a shift in prevalent profiles from the earliest to the latest study periods. In addition, genetic diversity decreased over time, and prevalent profiles were more highly related to each other than to less common profiles. These results provide the foundation for investigating the impact of prevention strategies, including the use of the acellular vaccines, on the currently circulating B. pertussis population.

Pertussis outbreak in an elementary school with high vaccination coverage.

BACKGROUND An outbreak of pertussis in a US elementary school with high vaccination coverage was investigated to evaluate vaccine effectiveness and to identify potential contributing factors. METHODS Survey and cohort study of all 215 students of an elementary school (including 36 case patients) and 16 secondary cases among contacts. RESULTS Fifty-two pertussis cases were identified (attack rate among students, 17%). Receipt of <3 doses of pertussis-containing-vaccine compared with receipt of complete vaccination series was a significant risk factor for pertussis [relative risk, 5.1; 95% confidence interval (CI), 3 to 8.6]. The effectiveness of the complete vaccination series was 80% (95% CI 66 to 88). No evidence of waning immunity among students was found. The following contributing factors for the outbreak were identified: multiple introductions of pertussis from the community; delays in identification and treatment of early cases; and high contact rates among students. Antimicrobial treatment initiated >14 days after cough onset was associated with increased risk of further transmission of pertussis (relative risk, 10.1; 95% CI 1.5 to 70.3) compared with treatment within 14 days of onset. CONCLUSIONS This investigation demonstrated the potential for pertussis outbreaks to occur in well-vaccinated elementary school populations. Aggressive efforts to identify cases and contacts and timely antimicrobial treatment can limit spread of pertussis in similar settings. High vaccination coverage should be maintained, because vaccination significantly reduces the risk of the disease throughout the elementary school years, and to ensure timely diagnosis and treatment health care providers should maintain a high index of suspicion for pertussis among elementary school age children.

Utility of Composite Reference Standards and Latent Class Analysis in Evaluating the Clinical Accuracy of Diagnostic Tests for Pertussis

ABSTRACT Numerous evaluations of the clinical sensitivity and specificity of PCR and serologic assays for Bordetella pertussis have been hampered by the low sensitivity of culture, the gold standard test, which leads to biased accuracy estimates. The bias can be reduced by using statistical approaches such as the composite reference standard (CRS) (e.g., positive if culture or serology positive; negative otherwise) or latent class analysis (LCA), an internal reference standard based on a statistical model. We illustrated the benefits of the CRS and LCA approaches by reanalyzing data from a 1995 to 1996 study of cough illness among 212 patients. The accuracy of PCR in this study was evaluated using three reference standards: culture, CRS, and LCA. Using specimens obtained 0 to 34 days after cough onset, estimates of the sensitivity of PCR obtained using CRS (47%) and LCA (34%) were lower than the culture-based estimate (62%). The CRS and LCA approaches, which utilized more than one diagnostic marker of pertussis, likely produced more accurate reference standards than culture alone. In general, the CRS approach is simple, with a well-defined disease status. LCA requires statistical modeling but incorporates more indicators of disease than CRS. When three or more indicators of pertussis are available, these approaches should be used in evaluations of pertussis diagnostic tests.

Molecular epidemiology of Bordetella pertussis by pulsed-field gel electrophoresis profile : Cincinnati, 1989-1996

Reported cases of pertussis have increased in the United States, with peaks occurring every few years. Bordetella pertussis isolates collected in Cincinnati from 1989 to 1996 were analyzed with pulsed-field gel electrophoresis (PFGE), to evaluate trends. Among 496 isolates, 30 PFGE profiles were identified; 32% were CYXXI-010, the profile that predominated each year. Eighteen profiles (198 strains) were identified in 1989-1992, 20 profiles (197 strains) were identified during the 1993 epidemic, and 11 profiles (101 strains) were identified in 1994-1996. From 1989 to 1996, among 42 patients, isolates from household members in 17 (89%) of 19 households had concordant PFGE profiles. There was no association between PFGE profile and seasonality, age, and hospitalization or pneumonia in infants <1 year old. The 1993 epidemic was associated primarily with an increased prevalence of PFGE profiles that circulated before and after 1993, which suggests that the epidemic was due to factors other than the emergence of a novel B. pertussis strain.

Surveillance for transmission and antibiotic adverse events among neonates and adults exposed to a healthcare worker with pertussis.

BACKGROUND During a hospital obstetric rotation, a medical student demonstrated classic symptoms of pertussis. The diagnosis was confirmed by isolation of Bordetella pertussis. Because this exposure occurred in a high-risk hospital setting, control measures were undertaken to prevent transmission and illness. OBJECTIVES To identify secondary cases of pertussis, to determine compliance with chemoprophylaxis recommendations, and to monitor for adverse events associated with chemoprophylaxis following a hospital exposure to pertussis. PATIENTS More than 500 individuals were potentially exposed, including 168 neonates; antimicrobial chemoprophylaxis was administered to 281 individuals. Fifty-eight neonates and 194 adults began azithromycin chemoprophylaxis; 18 neonates and 2 adults began erythromycin chemoprophylaxis. METHODS Active surveillance was instituted for (1) secondary cases of pertussis among healthcare coworkers, obstetric patients, their neonates, and labor companions and (2) antibiotic compliance and tolerance. RESULTS No secondary cases of pertussis were confirmed by laboratory tests; however, 26 suspected cases and 5 clinically compatible cases were identified. Antibiotic courses were completed by 95% of the individuals who initiated therapy. Neonates taking azithromycin had statistically significantly less gastrointestinal distress compared with neonates taking erythromycin (12% vs 50%; P = .002); there were no cases of infantile hypertrophic pyloric stenosis. CONCLUSIONS Although it was not possible to assess the effectiveness of the antibiotic regimens, the lack of laboratory-confirmed secondary cases suggests control measures were successful. Data from the 58 neonates who received azithromycin suggest it may be well tolerated in this age group.