Kimberly M. Shea

Changing serotypes causing childhood invasive pneumococcal disease: Massachusetts, 2001-2007.

Background: Heptavalent pneumococcal conjugate vaccine (PCV7) was licensed in the United States in February 2000 and distributed in Massachusetts, starting in July 2000 for universal administration to children <2 years of age and selected use in children 2 to 5 years of age. Statewide surveillance was begun in October 2001 to monitor incidence of invasive disease, serotypes causing disease, antimicrobial susceptibility, and risk features associated with ongoing childhood invasive pneumococcal disease (IPD). Methods: Massachusetts pediatric IPD cases were identified via enhanced passive surveillance of microbiology laboratory reports of pneumococcal isolates from sterile body sites of children <18 years. Serotyping and antimicrobial susceptibility testing were performed on isolates of Streptococcus pneumoniae from normally sterile body fluid. Demographic and clinical data, were collected via follow-up telephone interviews with primary care providers. Incidence rates were derived using Census 2000 denominators. Results: A total of 586 IP cases were reported between October 2001 and September 2007. Among 433 (74%) cases with isolates available for serotyping, 366 (85%) were caused by non-PCV7 serotypes and 67 (15%) were caused by PCV7 serotypes. 19A was the most common cause of any serotype identified episode of IPD (28%). IPD incidence was stable during the 6 study years because, although IPD cases due to PCV7-serotypes decreased, the incidence of non-PCV7 serotype IPD increased from 3.0 cases/100,000 children less than 18 years to a high of 5.3 cases/100,000 during 2005 to 06. Since 2005, ceftriaxone non-susceptible isolates comprised approximately 20% of isolates. There were 8 (1.4%) fatalities from IPD; 5 deaths occurred in children <1 year of age. Conclusions: Non-PCV7 serotype IPD, especially serotype 19A disease, increased during the 2001 to 2007 surveillance period in Massachusetts. The proportion of ceftriaxone non susceptible isolates also increased, particularly since 2005. Ongoing surveillance will be necessary to detect future increases in IPD incidence or antibiotic resistance in Massachusetts children, changes which have important implications for introduction of second generation pneumococcal conjugate vaccines and presumptive antibiotic choices in critically ill children.

Estimated Rate of Reactivation of Latent Tuberculosis Infection in the United States, Overall and by Population Subgroup

We estimated the rate of reactivation tuberculosis (TB) in the United States, overall and by population subgroup, using data on TB cases and Mycobacterium tuberculosis isolate genotyping reported to the Centers for Disease Control and Prevention during 2006-2008. The rate of reactivation TB was defined as the number of non-genotypically clustered TB cases divided by the number of person-years at risk for reactivation due to prevalent latent TB infection (LTBI). LTBI was ascertained from tuberculin skin tests given during the 1999-2000 National Health and Nutrition Examination Survey. Clustering of TB cases was determined using TB genotyping data collected by the Centers for Disease Control and Prevention and analyzed via spatial scan statistic. Of the 39,920 TB cases reported during 2006-2008, 79.7% were attributed to reactivation. The overall rate of reactivation TB among persons with LTBI was estimated as 0.084 (95% confidence interval (CI): 0.083, 0.085) cases per 100 person-years. Rates among persons with and without human immunodeficiency virus coinfection were 1.82 (95% CI: 1.74, 1.89) and 0.073 (95% CI: 0.070, 0.075) cases per 100 person-years, respectively. The rate of reactivation TB among persons with LTBI was higher among foreign-born persons (0.098 cases/100 person-years; 95% CI: 0.096, 0.10) than among persons born in the United States (0.082 cases/100 person-years; 95% CI: 0.080, 0.083). Differences in rates of TB reactivation across subgroups support current recommendations for targeted testing and treatment of LTBI.

Rates of Pneumococcal Disease in Adults With Chronic Medical Conditions

Background.  Although it is widely accepted that adults with immunocompromising conditions are at greatly increased risk of pneumococcal infection, the extent of risk among immunocompetent adults with chronic medical conditions is less certain, particularly in the current era of universal vaccination of children with pneumococcal conjugate vaccines. Methods.  We conducted a retrospective cohort study using data from 3 healthcare claims repositories (2006–2010) to compare rates of pneumococcal disease in immunocompetent adults with chronic medical conditions (“at-risk”) and immunocompromised adults (“high-risk”), with rates in adults without these conditions (“healthy”). Risk profiles and episodes of pneumococcal disease—all-cause pneumonia, pneumococcal pneumonia, and invasive pneumococcal disease (IPD)—were ascertained from diagnosis, procedure, and drug codes. Results.  Rates of all-cause pneumonia among at-risk persons aged 18–49 years, 50–64 years, and ≥65 years were 3.2 (95% confidence interval [CI], 3.1–3.2), 3.1 (95% CI, 3.1–3.1), and 3.0 (95% CI, 3.0–3.0) times the rates in age-matched healthy counterparts, respectively. We identified rheumatoid arthritis, systemic lupus erythematosus, Crohns disease, and neuromuscular or seizure disorders as additional at-risk conditions for pneumococcal disease. Among persons with at-risk conditions, the rate of all-cause pneumonia substantially increased with the accumulation of concurrent at-risk conditions (risk stacking): among persons 18–49 years, rate ratios increased from 2.5 (95% CI, 2.5–2.5) in those with 1 at-risk condition to 6.2 (95% CI, 6.1–6.3) in those with 2 conditions, and to 15.6 (95% CI, 15.3–16.0) in those with ≥3 conditions. Findings for pneumococcal pneumonia and IPD were similar. Conclusions.  Despite widespread use of pneumococcal conjugate vaccines, rates of pneumonia and IPD remain disproportionately high in adults with at-risk conditions, including those with conditions not currently included in the Advisory Committee on Immunization Practices’ guidelines for prevention and those with multiple at-risk conditions.

Risk of Pneumococcal Disease in Children With Chronic Medical Conditions in the Era of Pneumococcal Conjugate Vaccine

BACKGROUND In the current era of universal immunization of young children with pneumococcal conjugate vaccine, it is unclear whether the high risk ratios for pneumococcal disease previously attributed to specified chronic conditions have persisted. In addition, further analysis of pneumococcal disease risk may clarify whether certain chronic conditions that currently are not specified as significantly increasing the risk of pneumococcal disease should be so considered. METHODS We conducted a retrospective cohort analysis utilizing healthcare claims data from the period 2007-2010 to compare rates of pneumococcal disease among children <5 and 5-17 years of age with high-risk and at-risk conditions to rates among children without these conditions in the same age group. Risk profiles and manifestations of pneumococcal infection were ascertained from diagnosis, procedure, and drug codes. RESULTS Among at-risk children, rate ratios for invasive pneumococcal disease (vs children without at-risk/high-risk conditions) were 1.8 (95% confidence interval [CI], 1.4-2.3) in children <5 years of age and 3.3 (95% CI, 2.4-4.4) in children 5-17 years of age. Corresponding rate ratios for high-risk children were 11.2 (95% CI, 7.0-17.9) and 40.1 (95% CI, 28.8-56.0). Rate ratios increased in asthmatic children with increasing disease severity and in all at-risk children by the number of concurrent at-risk conditions. Rate ratios for pneumococcal pneumonia and all-cause pneumonia demonstrated similar patterns. CONCLUSIONS Children with high-risk and at-risk conditions continue to demonstrate an increased burden of pneumococcal disease. Pneumococcal disease rates are high among asthmatic children with moderate and severe disease and children with multiple at-risk conditions.

Modeling the decline in pneumococcal acute otitis media following the introduction of pneumococcal conjugate vaccines in the US

We hypothesized that following the introduction of PCV7, the exchange of vaccine serotypes (VST) for non-vaccine serotypes (NVST) in the nasopharynx has resulted in fewer episodes of pneumococcal acute otitis media (AOM) due to the reduced capacity for common NVST strains to cause disease. We modeled the change in the proportion of children colonized with S. pneumoniae who would develop pneumococcal AOM that would occur due to serotype replacement, and projected the future impact of PCV13. Our model is based on observed changes in the nasopharyngeal pneumococcal serotype distribution from the pre- to post-PCV7 era, and an estimated capacity of each serotype to produce pneumococcal AOM given colonization; the latter was derived by dividing serotype-specific disease prevalence by serotype-specific carriage prevalence in the same population. Our results indicate a 12% (95% CI 0.5-26) decline in the number of AOM episodes attributable to S. pneumoniae in children less than 3 years of age between 2000 and 2007 due to the combined effects of PCV7 vaccine efficacy and vaccine-induced serotype replacement, and predicts that PCV13 will further decrease pneumococcal AOM an additional 27% (95% CI 13-40) from 2007 to 2013. Evaluation of changes in VST disease revealed a 91% (95% CI 83-97) decrease in PCV7-VST AOM from 2000 to 2007, and predicted an additional 65% (95% CI 57-74) decrease in PCV13-VST AOM from 2007 to 2013. Our model indicates that following vaccination, nasopharyngeal replacement of VST by NVST has led to a decrease in the amount of pneumococcal AOM despite a consistent rate of S. pneumoniae colonization, and that pneumococcal AOM may continue to decrease as pneumococcal serotypes with greater capacity to cause disease are replaced by less locally invasive serotypes.

Pneumococcal Disease in the Era of Pneumococcal Conjugate Vaccine

Universal immunization of infants and toddlers with pneumococcal conjugate vaccines over the last 15 years has dramatically altered the landscape of pneumococcal disease. Decreases in invasive pneumococcal disease, all-cause pneumonia, empyema, mastoiditis, acute otitis media, and complicated otitis media have been reported from multiple countries in which universal immunization has been implemented. Children with comorbid conditions have higher rates of pneumococcal disease and increased case fatality rates compared with otherwise healthy children, and protection for the most vulnerable pediatric patients will require new strategies to address the underlying host susceptibility and the expanded spectrum of serotypes observed.

Underlying conditions in children with invasive pneumococcal disease in the conjugate vaccine era.

We analyzed characteristics of invasive pneumococcal disease cases occurring in Massachusetts after the introduction and use of conjugate vaccine by underlying risk. Among 578 cases with sufficient information, 16% had high-risk or presumed high-risk conditions (HR/PHR), 3% had asthma, and 80% had no known risk (NKR). The most common HR/PHR conditions were disorders associated with immunosuppression. HR/PHR cases tended to be older and were more likely to be hospitalized than were children with NKR. Children with asthma presented with pneumonia more often than children with NKR.

Vaccination, Underlying Comorbidities, and Risk of Invasive Pneumococcal Disease

OBJECTIVES: Children with underlying conditions remain at increased risk for invasive pneumococcal diseases (IPD). This study describes the epidemiology, serotype distribution, clinical presentations, and outcomes of IPD in children with and without comorbidity. METHODS: Cases of childhood IPD in Massachusetts were identified via enhanced surveillance from 2002 through 2014. Demographic and clinical data were collected via follow-up telephone interviews with parents and/or primary care providers. Underlying conditions were classified according to the 2012 Report of the Committee on Infectious Diseases and 2013 recommendations by the Advisory Committee on Immunization Practices. RESULTS: Among 1052 IPD cases in Massachusetts children <18 years old, 22.1% had at least 1 comorbidity. Immunocompromising conditions (32.7%) and chronic respiratory diseases (22.4%) were most common. Children with comorbidities were older at the time of IPD diagnosis (median 54 vs 23 months, P < .001), had higher hospitalization (odds ratio 2.5; 95% confidence interval 1.7–3.6) and case-fatality rates (odds ratio 3.7; 95% confidence interval 1.5–8.9) compared with children without known underlying conditions after adjusting for age, gender, year of diagnosis, and pneumococcal vaccination status. During the last 2 years of the study, IPD among children with comorbidities was caused by non–pneumococcal conjugate vaccine 13 serotypes in 23-valent polysaccharide pneumococcal vaccine (6/12, 50%) or serotypes that are not included in any of the vaccines (6/12; 50%). CONCLUSIONS: In children with comorbidity, IPD results in higher mortality, and a large proportion of disease is due to serotypes not included in current conjugate vaccines. Further research is needed, specifically to develop and evaluate additional strategies for prevention of IPD in the most vulnerable children.

Rethinking Risk for Pneumococcal Disease in Adults: The Role of Risk Stacking

Using data from 3 private healthcare claims repositories, we evaluated the incidence of pneumococcal disease among adults with US Advisory Committee on Immunization Practices (ACIP) defined at-risk conditions or rheumatoid arthritis, lupus, Crohns disease, and neuromuscular disorder/seizures and those with traditional high-risk conditions. We observed that adults with ≥2 concurrent comorbid conditions had pneumococcal disease incidence rates that were as high as or higher than rates observed in those with traditional high-risk conditions.

Randomized clinical trials to identify optimal antibiotic treatment duration

BackgroundAntibiotic resistance is a major barrier to the continued success of antibiotic treatment. Such resistance is often generated by overly long durations of antibiotic treatment. A barrier to identifying the shortest effective treatment duration is the cost of the sequence of clinical trials needed to determine shortest optimal duration. We propose a new method to identify the optimal treatment duration of an antibiotic treatment regimen.MethodsSubjects are randomized to varying treatment durations and the cure proportions of these durations are linked using a logistic regression model, making effective use of information across all treatment duration groups. In this paper, Monte Carlo simulation is used to evaluate performance of such a model.ResultsUsing a hypothetical dataset, the logistic regression model is seen to provide increased precision in defining the point estimate and confidence interval (CI) of the cure proportion at each treatment duration. When applied to the determination of non-inferiority, the regression model allows identification of the shortest duration meeting the predefined non-inferiority margin.ConclusionsThis analytic strategy represents a practical way to develop shortened regimens for tuberculosis and other infectious diseases. Application of this strategy to clinical trials of antibiotic therapy could facilitate decreased antibiotic usage, reduce cost, minimize toxicity, and decrease the emergence of antibiotic resistance.