Ann Thomas

Sustained Reductions in Invasive Pneumococcal Disease in the Era of Conjugate Vaccine

BACKGROUND Changes in invasive pneumococcal disease (IPD) incidence were evaluated after 7 years of 7-valent pneumococcal conjugate vaccine (PCV7) use in US children. METHODS Laboratory-confirmed IPD cases were identified during 1998-2007 by 8 active population-based surveillance sites. We compared overall, age group-specific, syndrome-specific, and serotype group-specific IPD incidence in 2007 with that in 1998-1999 (before PCV7) and assessed potential serotype coverage of new conjugate vaccine formulations. RESULTS Overall and PCV7-type IPD incidence declined by 45% (from 24.4 to 13.5 cases per 100,000 population) and 94% (from 15.5 to 1.0 cases per 100,000 population), respectively (P< .01 all age groups). The incidence of IPD caused by serotype 19A and other non-PCV7 types increased from 0.8 to 2.7 cases per 100,000 population and from 6.1 to 7.9 cases per 100,000 population, respectively (P< .01 for all age groups). The rates of meningitis and invasive pneumonia caused by non-PCV7 types increased for all age groups (P< .05), whereas the rates of primary bacteremia caused by these serotypes did not change. In 2006-2007, PCV7 types caused 2% of IPD cases, and the 6 additional serotypes included in an investigational 13-valent conjugate vaccine caused 63% of IPD cases among children <5 years-old. CONCLUSIONS Dramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later. IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV7-type IPD.

Population Snapshot of Emergent Streptococcus pneumoniae Serotype 19A in the United States, 2005

BACKGROUND Serotype 19A invasive pneumococcal disease (IPD) increased annually in the United States after the introduction of the 7-valent conjugate vaccine (PCV7). To understand this increase, we characterized serotype 19A isolates recovered during 2005. METHODS IPD cases during 1998-2005 were identified through population-based surveillance. We performed susceptibility testing and multilocus sequence typing on 528 (95%) of 554 serotype 19A isolates reported in 2005. RESULTS The incidence of IPD due to serotype 19A increased from 0.8 to 2.5 cases per 100,000 population between 1998 and 2005 (P < .05), whereas the overall incidence of IPD decreased from 24.4 to 13.8 cases per 100,000 population (P < .05). Simultaneously, the incidence of IPD due to penicillin-resistant 19A isolates increased from 6.7% to 35% (P < .0001). Of 151 penicillin-resistant 19A isolates, 111 (73.5%) belonged to the rapidly emerging clonal complex 320, which is related to multidrug-resistant Taiwan(19F)-14. The remaining penicillin-resistant strains were highly related to other clones of PCV7 serotypes or to isolates within major 19A clonal complex 199 (CC199). In 1999, only CC199 and 3 minor clones were apparent among serotype 19A isolates. During 2005, 11 multiple-isolate clonal sets were detected, including capsular switch variants of a serotype 4 clone. CONCLUSIONS PCV7 ineffectiveness against serotype 19A, antibiotic resistance, clonal expansion and emergence, and capsular switching have contributed to the genetic diversity of 19A and to its emergence as the predominant invasive pneumococcal serotype in the United States.

Changes in Invasive Pneumococcal Disease among HIV-Infected Adults Living in the Era of Childhood Pneumococcal Immunization

Context Routine pneumococcal conjugate vaccination for infants began in 2000. Its use markedly decreased invasive pneumococcal disease among children, but did it influence rates of disease among HIV-infected adults? Contribution Between 1998 and 2003, invasive pneumococcal disease among adults infected with HIV living in 7 surveillance areas in the United States decreased from 1127 to 919 cases per 100000 adults with AIDS. Disease caused by serotypes in the vaccine decreased 62%, whereas disease caused by nonvaccine serotypes increased 44%. Implications Indirect evidence suggests that pediatric vaccine use is associated with a decreased incidence of pneumococcal disease among HIV-infected adults. The Editors Apneumococcal conjugate vaccine containing 7 serotypes was recommended for routine use in infants in the United States beginning in 2000 (1). Widespread use of the vaccine caused steep declines in invasive pneumococcal disease among young children (2-4) and was associated with decreased disease attributable to vaccine serotypes among adults, for whom the vaccine is not licensed (3). Effects on disease among unvaccinated persons, often called herd effects, are presumably due to reduced transmission from immunized children. Because 90 pneumococcal serotypes cause human disease, there were concerns that the introduction of a conjugate vaccine containing 7 serotypes would lead to increased disease caused by nonvaccine-type organisms, a phenomenon called serotype replacement. Early postintroduction surveillance showed limited serotype replacement disease in the target age group, with no consistent trend toward increasing disease caused by nonvaccine serotypes among adults (3). To our knowledge, the effects of pediatric use of pneumococcal conjugate vaccine on immunocompromised adults, including those infected with HIV, have not previously been investigated. Persons infected with HIV are particularly susceptible to invasive pneumococcal disease, with a 50- to 100-fold higher incidence than the general U.S. population (5, 6). After the introduction of highly active antiretroviral therapy in the mid-1990s, surveillance in 3 geographic areas of the United States showed a 50% reduction in invasive pneumococcal disease among persons with AIDS (7). However, the incidence of pneumococcal disease among persons with AIDS leveled off by mid-1997 and continued to be approximately 35-fold higher in persons with AIDS than in those without HIV infection or AIDS through 2000 (7). We investigated trends in invasive pneumococcal disease among HIV-infected adults to document changes since the use of pneumococcal conjugate vaccine became widespread in children. Methods Active, laboratory-based surveillance for cases of invasive pneumococcal disease, defined as isolation of Streptococcus pneumoniae from a normally sterile site, was conducted through Active Bacterial Core surveillance of the Emerging Infections Program network (8). We included cases diagnosed between 1 January 1998 and 31 December 2003 among surveillance-area residents who were 18 to 64 years of age. We limited the analyses to 7 surveillance sites, including California (San Francisco County), Connecticut (entire state), Georgia (8-county Atlanta metropolitan area), Maryland (City of Baltimore and 5 neighboring counties), Minnesota (7-county MinneapolisSt. Paul metropolitan area), Oregon (3-county Portland metropolitan area), and Tennessee (Davidson, Hamilton, Knox, Shelby, and Williamson Counties). Information was systematically collected on the HIV status of case-patients at these sites. In 2003, the resident adult population in these 7 areas was 10.8 million (4.5% of the U.S. population between 18 and 64 years of age) (9) and included 9.5% of the estimated number of adults living with AIDS in the United States (10). Surveillance officers routinely contacted all clinical laboratories in their areas to identify cases and conducted audits of laboratory records to ensure complete ascertainment. Recurrent episodes, defined as invasive pneumococcal disease occurring more than 7 days after a previous case in a surveillance-area resident, were included in this analysis. The race and ethnicity as well as HIV status or previous AIDS diagnosis of case-patients were extracted from medical records by using standardized case report forms. Surveillance in Georgia did not prospectively collect information on HIV infection or AIDS for case-patients until 2000; for case-patients in 1999, we retrospectively reviewed medical records to collect this information. Analyses for 1998 exclude Georgia. Pneumococcal isolates were sent to reference laboratories at the Minnesota Department of Health (for case-patients from Minnesota), the Centers for Disease Control and Prevention, or the University of Texas Health Science Center at San Antonio for susceptibility testing by broth microdilution using standard protocols and quality control procedures (3, 11). Nonsusceptible isolates were defined as those with minimum inhibitory concentrations classified as intermediate or resistant for the antibiotic tested, according to the 2002 definitions of the National Committee for Clinical Laboratory Standards (12). Serotyping by the Quellung reaction was done at the Centers for Disease Control and Prevention or the Minnesota Department of Health (Minnesota cases only). The study personnel are listed in the Appendix. AIDS Surveillance Data For aggregated counties in each of the 7 surveillance areas, we obtained the estimated number of persons 18 to 64 years of age living with AIDS (as outlined in the 1993 Centers for Disease Control and Prevention case definition) (13), according to race and ethnicity and sex, on 30 June of each year. We obtained this number from the Centers for Disease Control and Prevention with permission from state AIDS surveillance coordinators. These estimates are derived from case report data by using a maximum likelihood method to account for delays in reporting new AIDS diagnoses and deaths among persons with AIDS (10), 14. Estimates of the number of persons living with HIV infection, not AIDS, were unavailable from 5 sites (California, Connecticut, Georgia, Maryland, and Oregon) that accounted for more than 80% of adults living with AIDS in the surveillance areas. Statistical Analysis For each surveillance area, we calculated the annual incidence rates of invasive pneumococcal disease among persons with AIDS as follows. We divided the number of cases of pneumococcal disease diagnosed during the calendar year among patients documented as having AIDS by the estimated number of persons 18 to 64 years of age living with AIDS. To calculate incidence among adults not infected with HIV, we used cases of pneumococcal disease in persons without documented HIV infection or AIDS in the numerator. For the denominator, we subtracted the number of adults living with AIDS from the total population of persons 18 to 64 years of age who lived in the surveillance areas; this number was obtained from the U.S. Census Bureau (9). As a proxy for the incidence rates among HIV-infected adults, we calculated a ratio of cases of pneumococcal disease among adults with HIV infection or AIDS to the estimated adult population living with AIDS, multiplied by 100000. Ratios for specific race and ethnicity categories were adjusted, assuming that the distribution of race and ethnicity for case-patients missing these data (3% of cases of pneumococcal disease) was the same as the sex-specific distribution of case-patients within each surveillance area for which race and ethnicity data were available. We adjusted data for selected serotypes (that is, conjugate vaccine or nonvaccine serotypes) or antibiotic-resistant pneumococci on the basis of the percentage of cases with isolates available for testing, assuming the distribution of cases missing serotype (9%) or antibiotic susceptibility data (7%) was the same as that of cases with isolates tested across all sites. We calculated 95% CIs for these ratios by using the standard error of the proportion of cases with isolates tested. To assess changes in the ratio of the number of cases of pneumococcal disease among HIV-infected adults to the number of adults living with AIDS before and after the introduction of the pneumococcal conjugate vaccine for children, we calculated percentage change and exact 95% CIs by comparing the average ratio during 1998 and 1999, called the baseline period, with that during 2002 or 2003. For differences or linear trends in proportions of cases or pneumococcal isolates, we calculated P values using chi-square tests; P values less than 0.05 indicated statistical significance. Statistical analyses were conducted with SAS, version 9.0 for Windows (SAS Institute, Inc., Cary, North Carolina), and EpiInfo, version 6.0 (Centers for Disease Control and Prevention, Atlanta, Georgia). Role of the Funding Source The funding source had no role in the design, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results From 1998 through 2003, 8582 cases of invasive pneumococcal disease occurred in surveillance-area residents who were 18 to 64 years of age. Of these, 2013 cases occurred in persons with HIV infection or AIDS (Figure 1). When the latter group was excluded, the annual incidence rate in persons who were 18 to 64 years of age during the 1998 to 1999 baseline period averaged 13 cases per 100000 adults without AIDS. By 2003, this rate decreased to 9 cases per 100000, a decrease of 30% (95% CI, 25% to 35%; P< 0.001). Of the 2013 cases of pneumococcal disease among HIV-infected adults, 759 (38%) occurred among adults documented as having AIDS. Based on estimates of the number of adults living with AIDS in the surveillance areas, the incidence of invasive pneumococcal disease among persons with AIDS during the baseline period was 441 cases per 100000 adults. In 2002, the rate was 360 cases per 10000

Multistate surveillance for laboratory-confirmed, influenza-associated hospitalizations in children: 2003-2004.

Background: Increasing use of rapid influenza diagnostics facilitates laboratory confirmation of influenza infections. We describe laboratory-confirmed, influenza-associated hospitalizations in a population representing almost 6% of children in the United States. Methods: We conducted population-based surveillance for influenza-associated hospitalizations between October 1, 2003, and March 31, 2004, in 54 counties in 9 states (4.2 million children) participating in the Emerging Infections Program Network. Clinical characteristics, predictors of intensive care unit admission and geographic and age-specific incidence were evaluated. Results: Surveillance identified 1,308 case-patients; 80% were <5 years and 27% were <6 months of age. Half of the patients and 4 of 5 pediatric deaths did not have a medical indication for influenza vaccination and were outside the 6- to 23-month age group. Twenty-eight percent of case-patients had radiographic evidence of a pulmonary infiltrate, 11% were admitted to intensive care and 3% received mechanical ventilation. The median length of hospital stay was 2 days. Community-acquired invasive bacterial coinfections (1% of patients) were associated with intensive care admission (adjusted odds ratio, 16.9; 95% confidence interval, 5.0–56.8). Thirty-five percent of patients ≥6 months old had received at least one influenza vaccine dose that season. The overall incidence of influenza-associated hospitalizations was 36 per 100,000 children (range per state, 10 per 100,000 to 86 per 100,000). Conclusions: Influenza was an important cause of hospitalizations in children during 2003–2004. Hospitalizations were particularly common among children <6 months of age, a group for whom influenza vaccine is not licensed. Continued surveillance for laboratory-confirmed influenza could inform prevention strategies.

A Community-Based Outbreak of Severe Respiratory Illness Caused by Human Adenovirus Serotype 14

BACKGROUND Human adenoviruses (Ads) typically cause mild illnesses in otherwise healthy hosts. We investigated a community-based outbreak that had substantial morbidity caused primarily by Ad14, an uncommon serotype. METHODS We retrospectively reviewed the medical records of all patients with confirmed cases of Ad infection from 1 November 2006 through 31 July 2007 in Oregon. Isolates were typed by sequencing. We analyzed clinical and laboratory variables to identify risk factors for severe Ad14 disease. RESULTS Ad14 first emerged in Oregon in 2005. Of 67 cases of Ad infection detected during the study period, 40 (60%) involved Ad14. Most of the 38 Ad14-infected patients who had medical records available for review presented with fever and cough; 29 (76%) required hospitalization, 23 (61%) required supplemental oxygen, 18 (47%) required critical care, 9 (24%) required vasopressors, and 7 (18%) died. Lobar infiltrates on chest radiographs suggestive of bacterial pneumonia were common among those needing hospitalization. Older age, chronic underlying condition, low absolute lymphocyte counts, and elevated creatinine levels were associated with severe illness. Except for 1 case of possible hospital transmission, we identified no epidemiological links among patients. CONCLUSION Ad14 emerged in Oregon in 2005 and became the predominant circulating type by 2007. Infection with this uncommon virus was primarily associated with a community-acquired pneumonia syndrome and caused substantial morbidity and mortality.

Association Between Use of Statins and Mortality Among Patients Hospitalized With Laboratory-Confirmed Influenza Virus Infections: A Multistate Study

BACKGROUND Statins may have anti-inflammatory and immunomodulatory effects that could reduce the risk of mortality from influenza virus infections. METHODS The Centers for Disease Control and Preventions Emerging Infections Program conducts active surveillance for persons hospitalized with laboratory-confirmed influenza in 59 counties in 10 states. We analyzed data for hospitalized adults during the 2007-2008 influenza season to evaluate the association between receiving statins and influenza-related death. RESULTS We identified 3043 patients hospitalized with laboratory-confirmed influenza, of whom 1013 (33.3%) received statins and 151 (5.0%) died within 30 days of their influenza test. Patients who received statins were more likely to be older, male, and white; to suffer from cardiovascular, metabolic, renal, and chronic lung disease; and to have been vaccinated against influenza that season. In a multivariable logistic regression model, administration of statins prior to or during hospitalization was associated with a protective odds of death (adjusted odds ratio, 0.59 [95% confidence interval, .38-.92]) when adjusting for age; race; cardiovascular, lung, and renal disease; influenza vaccination; and antiviral administration. CONCLUSIONS Statin use may be associated with reduced mortality in patients hospitalized with influenza.

Burden of seasonal influenza hospitalization in children, United States, 2003 to 2008.

OBJECTIVES To estimate the rates of hospitalization with seasonal influenza in children aged <18 years from a large, diverse surveillance area during 2003 to 2008. STUDY DESIGN Through the Emerging Infections Program Network, population-based surveillance for laboratory-confirmed influenza was conducted in 10 states, including 5.3 million children. Hospitalized children were identified retrospectively; clinicians made influenza testing decisions. Data collected from the hospital record included demographics, medical history, and clinical course. Incidence rates were calculated with census data. RESULTS The highest hospitalization rates occurred in children aged <6 months (seasonal range, 9-30/10 000 children), and the lowest rates occurred in children aged 5 to 17 years (0.3-0.8/10 000). Overall, 4015 children were hospitalized, 58% of whom were identified with rapid diagnostic tests alone. Forty percent of the children who were hospitalized had underlying medical conditions; asthma (18%), prematurity (15% of children aged <2 years), and developmental delay (7%) were the most common. Severe outcomes included intensive care unit admission (12%), respiratory failure (5%), bacterial coinfection (2%), and death (0.5%). CONCLUSIONS Influenza-associated hospitalization rates varied by season and age and likely underestimate true rates because many hospitalized children are not tested for influenza. The proportion of children with severe outcomes was substantial across seasons. Quantifying incidence of influenza hospitalization and severe outcomes is critical to defining disease burden.

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.

Adult Hospitalizations for Laboratory-Positive Influenza during the 2005–2006 through 2007–2008 Seasons in the United States

BACKGROUND Rates of influenza-associated hospitalizations in the United States have been estimated using modeling techniques with data from pneumonia and influenza hospitalization discharge diagnoses, but they have not been directly estimated from laboratory-positive cases. METHODS We calculated overall, age-specific, and site-specific rates of laboratory-positive, influenza-associated hospitalization among adults and compared demographic and clinical characteristics and outcomes of hospitalized cases by season with use of data collected by the Emerging Infections Program Network during the 2005-2006 through 2007-2008 influenza seasons. RESULTS Overall rates of adult influenza-associated hospitalization per 100,000 persons were 9.9 during the 2005-2006 season, 4.8 during the 2006-2007 season, and 18.7 during the 2007-2008 season. Rates of hospitalization varied by Emerging Infections Program site and increased with increasing age. Higher overall and age-specific rates of hospitalization were observed during influenza A (H3) predominant seasons and during periods of increased circulation of influenza B. More than 80% of hospitalized persons each season had > or =1 underlying medical condition, including chronic cardiovascular and metabolic diseases. CONCLUSIONS Rates varied by season, age, geographic location, and type/subtype of circulating influenza viruses. Influenza-associated hospitalization surveillance is essential for assessing the relative severity of influenza seasons over time and the burden of influenza-associated complications.

Prevention of invasive pneumococcal disease among HIV-infected adults in the era of childhood pneumococcal immunization.

Objective:Human immunodeficiency virus (HIV) infection and AIDS increase the risk of invasive pneumococcal disease (IPD). We evaluated IPD among HIV-infected adults over a 10-year period in the US to identify opportunities for prevention of IPD among HIV-infected adults. Design:IPD and HIV surveillance in seven population-based and laboratory-based Active Bacterial Core surveillance areas. Methods:IPD cases were adults 18–64 years old with pneumococcus isolated from a normally sterile site during 1998–2007. Isolates were serotyped using the Quellung reaction. HIV/AIDS status was determined by medical record review. We calculated incidence of IPD among adults with AIDS using national case-based surveillance data. Results:Of 13 812 IPD cases among 18–64-year-olds, 3236 (23%) occurred among HIV-infected adults (with or without AIDS) and 1313 (10%) occurred among the subset of HIV-infected adults with AIDS. Compared with the period (1998–1999) before childhood 7-valent pneumococcal conjugate vaccine (PCV7) introduction in the US, the overall incidence of IPD among adults with AIDS decreased 25% from 399 to 298 cases per 100 000 by 2007 (P = 0.008). In 2006–2007, 8, 39 and 55% of IPD cases among adults with AIDS were caused by serotypes included in the 7-valent PCV, 13-valent PCV and 23-valent pneumococcal polysaccharide vaccines, respectively. Conclusion:Sustained declines in IPD have occurred among adults with AIDS in the US, but incidence remained high 7 years after PCV7 introduction. More aggressive efforts, including HIV-prevention measures and the use of new PCVs in children and possibly HIV-infected adults, are necessary to further reduce IPD among HIV-infected adults.