Andrew L. Baughman

Increase in deaths from pertussis among young infants in the United States in the 1990s.

Background. Severe pertussis primarily occurs among infants (<12 months of age). Despite high levels of immunization, reported pertussis cases increased in the United States in the 1990s among all age groups, including infants. Methods. To characterize fatal pertussis cases, we analyzed pertussis deaths reported to CDC in the 1990s and compared these with data on pertussis deaths reported in the 1980s. Data from national surveillance systems and from available medical records were used, including data from analyses of deaths reported in 1992 through 1995. Results. In 1980 through 1989, 77 pertussis deaths were reported; 61 deaths were among infants (1.67 deaths per million), including 49 among infants <4 months of age. In the 1990s 103 pertussis deaths were reported; 93 deaths were among infants (2.40 deaths per million), including 84 among infants <4 months of age. Of 89 infants with ethnicity data, 31 (36%) were Hispanic; the mortality rate among Hispanic infants (4.77 per million) was higher than among non-Hispanic infants (1.80 per million). Of 76 infants with reported gestational age, 40 (53%) were born at <37 weeks, including 22 (29%) who were born at <35 weeks. Severe pulmonary hypertension was a common lethal complication among infants. Conclusions. Pertussis deaths increased among infants too young to be protected by immunization. A disproportionate share of deaths were complicated by pulmonary hypertension and occurred among Hispanic infants and infants born at <37 weeks gestation. New approaches to prevent infection among infants <4 months of age and improved therapies for pertussis complications are needed.

Population Incidence of Guillain-Barré Syndrome: A Systematic Review and Meta-Analysis

Population incidence of Guillain-Barré syndrome (GBS) is required to assess changes in GBS epidemiology, but published estimates of GBS incidence vary greatly depending on case ascertainment, definitions, and sample size. We performed a meta-analysis of articles on GBS incidence by searching Medline (1966–2009), Embase (1988–2009), Cinahl (1981–2009) and CABI (1973–2009) as well as article bibliographies. We included studies from North America and Europe with at least 20 cases, and used population-based data, subject matter experts to confirm GBS diagnosis, and an accepted GBS case definition. With these data, we fitted a random-effects negative binomial regression model to estimate age-specific GBS incidence. Of 1,683 nonduplicate citations, 16 met the inclusion criteria, which produced 1,643 cases and 152.7 million person-years of follow-up. GBS incidence increased by 20% for every 10-year increase in age; the risk of GBS was higher for males than females. The regression equation for calculating the average GBS rate per 100,000 person-years as a function of age in years was exp[–12.0771 + 0.01813(age in years)] × 100,000. Our findings provide a robust estimate of background GBS incidence in Western countries. Our regression model may be used in comparable populations to estimate the background age-specific rate of GBS incidence for future studies.

Population-Based Incidence of Pertussis among Adolescents and Adults, Minnesota, 1995–1996

To estimate the incidence of pertussis, a prospective study was done among members of a managed care organization in Minneapolis/St. Paul, Minnesota. Of 212 patients 10-49 years old enrolled from January 1995 through December 1996, 8 were found to be culture positive, 10 were found to be positive by polymerase chain reaction assay, 13 had a > or =2-fold increase in IgG or IgA to pertussis toxin (PT), and 18 had IgG to PT in a single serum specimen > or =3 SD above the mean of an age-matched control group. At least 1 positive laboratory test result for pertussis infection was found in 27 (13%) patients, among whom the duration of cough illness was a median of 42 days (range, 27-66 days). On the basis of any positive laboratory result, the estimated annual incidence of pertussis was 507 cases per 100,000 person-years (95% confidence interval, 307-706 cases). Bordetella pertussis infection may be a more common cause of cough illness among adolescents and adults than was recognized previously.

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 Hospitalizations Among Infants in the United States, 1993 to 2004

OBJECTIVE. We sought to describe the rates of pertussis hospitalization among infants by using databases that do not rely on passive reporting and compare with results obtained from the passive national surveillance system. METHODS. The incidence of infant pertussis hospitalization in 1993 to 2004 was determined by using 2 national hospitalization discharge databases (Nationwide Inpatient Sample and Kids’ Inpatient Database) and the National Notifiable Disease Surveillance System/Supplemental Pertussis Surveillance System. Rates were determined for separate age groups among infants <1 year of age. Pertussis complications and procedures were examined by using the Kids’ Inpatient Database. RESULTS. In 1993 to 2004, the pertussis hospitalization rates for infants ≤2 months of age were generally stable, by the discharge databases. The incidence of infant pertussis hospitalization obtained from the Nationwide Inpatient Sample and Kids’ Inpatient Database was ∼2 times greater than that obtained from the passive reporting system. Infants 1 to 2 months of age had the highest incidence (239 hospitalizations per 100000 live births in the 2003 Kids’ Inpatient Database). An annual average of 2678 hospitalizations occurred in 2000 and 2003; 86% occurred in infants ≤3 months of age. Among those with ages provided, 95% of infants who required mechanical ventilation and all of those who died were ≤3 months of age. CONCLUSIONS. Pertussis hospitalization incidence rates among the youngest infants were generally stable in 1993 to 2004 and were highest for infants 1 to 2 months of age. The impact of the new adolescent and adult tetanus-diphtheria-acellular pertussis vaccines on infant pertussis should be monitored through such discharge databases. Additional vaccination strategies should be evaluated to protect infants as early in life as possible.

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.

Comparison of Laboratory Diagnostic Procedures for Detection of Mycoplasma pneumoniae in Community Outbreaks

BACKGROUND Mycoplasma pneumoniae continues to be a significant cause of community-acquired pneumonia (CAP). A more definitive methodology for reliable detection of M. pneumoniae is needed to identify outbreaks and to prevent potentially fatal extrapulmonary complications. METHODS We analyzed 2 outbreaks of CAP due to M. pneumoniae. Nasopharyngeal and/or oropharyngeal swab specimens and serum samples were obtained from persons with clinically defined cases, household contacts, and asymptomatic individuals. Real-time polymerase chain reaction (PCR) for M. pneumoniae was performed on all swab specimens, and the diagnostic utility was compared with that of 2 commercially available serologic test kits. RESULTS For cases, 21% yielded positive results with real-time PCR, whereas 81% and 54% yielded positive results with the immunoglobulin M and immunoglobulin G/immunoglobulin M serologic tests, respectively. For noncases, 1.8% yielded positive results with real-time PCR, whereas 63% and 79% yielded serologically positive results with the immunoglobulin M and immunoglobulin G/immunoglobulin M kits, respectively. The sensitivity of real-time PCR decreased as the duration between symptom onset and sample collection increased, with a peak sensitivity of 48% at 0-21 days. A specificity of 43% for the immunoglobulin M antibody detection assay was observed for persons aged 10-18 years, but the sensitivity increased to 82% for persons aged 19 years. DISCUSSION Thorough data analysis indicated that no single available test was reliable for the identification of an outbreak of CAP due to M. pneumoniae. A combination of testing methodologies proved to be the most reliable approach for identification of outbreaks of CAP due to M. pneumoniae, especially in the absence of other suspected respiratory pathogens.

The safety of immunizing with tetanus-diphtheria-acellular pertussis vaccine (Tdap) less than 2 years following previous tetanus vaccination: experience during a mass vaccination campaign of healthcare personnel during a respiratory illness outbreak.

BACKGROUND Tdap is recommended for health care personnel (HCP) aged <65 years who received tetanus diphtheria or tetanus toxoid immunization (Td/TT) ≥2 years earlier. During a medical center Tdap vaccination campaign, we assessed the safety of use of a Td/TT to Tdap interval <2 years in HCP. We also describe reactogenicity in HCP who were aged ≥65 years or pregnant. METHODS HCP vaccinated with Tdap were surveyed to assess time since last Td/TT (≥2 years vs. <2 years), age, pregnancy status, and injection site adverse events (AEs) during the 2 weeks after Tdap. AE rates were calculated and compared by non-inferiority analysis using a predetermined margin of 10%. We searched clinic logbooks to assess for clinically important adverse events during the 2 months after Tdap. RESULTS Of the 4524 vaccinated HCP, 2221 (49.1%) completed a safety survey which met criteria for analysis. Non-inferiority analysis found that rates of moderate and/or severe injection site AEs were not significantly greater in those vaccinated <2 years than in those vaccinated ≥2 years after previous Td/TT. Three serious adverse events were reported during the 2 months after vaccination, none in persons who were ≥65 years, pregnant or received Td/TT <2 years before. CONCLUSIONS Our findings add to the body of evidence that a short interval between Td/TT and a single dose of Tdap is safe.

Guillain-Barré Syndrome During the 2009–2010 H1N1 Influenza Vaccination Campaign: Population-based Surveillance Among 45 Million Americans

Because of widespread distribution of the influenza A (H1N1) 2009 monovalent vaccine (pH1N1 vaccine) and the prior association between Guillain-Barré syndrome (GBS) and the 1976 H1N1 influenza vaccine, enhanced surveillance was implemented to estimate the magnitude of any increased GBS risk following administration of pH1N1 vaccine. The authors conducted active, population-based surveillance for incident cases of GBS among 45 million persons residing at 10 Emerging Infections Program sites during October 2009-May 2010; GBS was defined according to published criteria. The authors determined medical and vaccine history for GBS cases through medical record review and patient interviews. The authors used vaccine coverage data to estimate person-time exposed and unexposed to pH1N1 vaccine and calculated age- and sex-adjusted rate ratios comparing GBS incidence in these groups, as well as age- and sex-adjusted numbers of excess GBS cases. The authors received 411 reports of confirmed or probable GBS. The rate of GBS immediately following pH1N1 vaccination was 57% higher than in person-time unexposed to vaccine (adjusted rate ratio = 1.57, 95% confidence interval: 1.02, 2.21), corresponding to 0.74 excess GBS cases per million pH1N1 vaccine doses (95% confidence interval: 0.04, 1.56). This excess risk was much smaller than that observed during the 1976 vaccine campaign and was comparable to some previous seasonal influenza vaccine risk assessments.

Evaluation of Laboratory Methods for Diagnosis of Varicella

BACKGROUND The incidence of varicella disease is declining as a result of vaccination, making clinical diagnosis more challenging, particularly for vaccine-modified cases. We conducted a comprehensive evaluation of laboratory tests and specimen types to assess diagnostic performance and determine what role testing can play after skin lesions have resolved. METHODS We enrolled patients with suspected varicella disease in 2 communities. Enrollees were visited at the time of rash onset and 2 weeks later. Multiple skin lesion, oral, urine, and blood or serum specimens were requested at each visit and tested for varicella zoster virus (VZV) immunoglobulin (Ig) G, IgM, and IgA antibody by enzyme-linked immunoassay; for VZV antigen by direct fluorescent antibody; and/or for VZV DNA by polymerase chain reaction (PCR). Clinical certainty of the diagnosis of varicella disease was scored. PCR results from first-visit vesicles or scab specimens served as the gold standard in assessing test performance. RESULTS Of 93 enrollees, 53 were confirmed to have varicella disease. Among 20 unmodified cases, PCR testing was 95%-100% sensitive for macular and/or papular lesions and for oral specimens collected at the first visit; most specimens from the second visit yielded negative results. Among 27 vaccine-modified cases, macular and/or papular lesions collected at the first visit were also 100% sensitive; yields from other specimens were poorer, and few specimens from the second visit tested positive. Clinical diagnosis was 100% and 85% sensitive for diagnosing unmodified and vaccine-modified varicella cases, respectively. CONCLUSIONS PCR testing of skin lesion specimens remains convenient and accurate for diagnosing varicella disease in vaccinated and unvaccinated persons. PCR of oral specimens can sometimes aid in diagnosis of varicella disease, even after rash resolves.