Carlos G. Grijalva

Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus: A Cohort Study

BACKGROUND The effects of sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized. OBJECTIVE To compare the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death. DESIGN Retrospective cohort study. SETTING National Veterans Health Administration databases linked to Medicare files. PATIENTS Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded. MEASUREMENTS Composite outcome of hospitalization for acute myocardial infarction or stroke, or death, adjusted for baseline demographic characteristics; medications; cholesterol, hemoglobin A1c, and serum creatinine levels; blood pressure; body mass index; health care utilization; and comorbid conditions. RESULTS Among 253 690 patients initiating treatment (98 665 with sulfonylurea therapy and 155 025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with sulfonylureas per 1000 person-years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score-matched cohort analysis; and in sensitivity analyses. LIMITATION Most of the veterans in the study population were white men; data on women and minority groups were limited but reflective of the Veterans Health Administration population. CONCLUSION Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.

The burden of respiratory syncytial virus infection in young children.

BACKGROUND The primary role of respiratory syncytial virus (RSV) in causing infant hospitalizations is well recognized, but the total burden of RSV infection among young children remains poorly defined. METHODS We conducted prospective, population-based surveillance of acute respiratory infections among children under 5 years of age in three U.S. counties. We enrolled hospitalized children from 2000 through 2004 and children presenting as outpatients in emergency departments and pediatric offices from 2002 through 2004. RSV was detected by culture and reverse-transcriptase polymerase chain reaction. Clinical information was obtained from parents and medical records. We calculated population-based rates of hospitalization associated with RSV infection and estimated the rates of RSV-associated outpatient visits. RESULTS Among 5067 children enrolled in the study, 919 (18%) had RSV infections. Overall, RSV was associated with 20% of hospitalizations, 18% of emergency department visits, and 15% of office visits for acute respiratory infections from November through April. Average annual hospitalization rates were 17 per 1000 children under 6 months of age and 3 per 1000 children under 5 years of age. Most of the children had no coexisting illnesses. Only prematurity and a young age were independent risk factors for hospitalization. Estimated rates of RSV-associated office visits among children under 5 years of age were three times those in emergency departments. Outpatients had moderately severe RSV-associated illness, but few of the illnesses (3%) were diagnosed as being caused by RSV. CONCLUSIONS RSV infection is associated with substantial morbidity in U.S. children in both inpatient and outpatient settings. Most children with RSV infection were previously healthy, suggesting that control strategies targeting only high-risk children will have a limited effect on the total disease burden of RSV infection.

Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis

BACKGROUND Routine infant immunisation with seven-valent pneumococcal conjugate vaccine (PCV7) began in the USA in 2000. Although invasive pneumococcal disease has declined substantially, the programmes effect on hospital admissions for pneumonia is unknown. We therefore assessed the effect of the programme on rates of all-cause and pneumococcal pneumonia admissions. METHODS Data from the Nationwide Inpatient Sample, the largest inpatient database available in the USA, were analysed with an interrupted time-series analysis that used pneumonia (all-cause and pneumococcal) admission rates as the main outcomes. Monthly admission rates estimated for years after the introduction of PCV7 vaccination (2001-2004) were compared with expected rates calculated from pre-PCV7 years (1997-1999). The year of vaccine introduction (2000) was excluded, and rates of admission for dehydration were assessed for comparison. FINDINGS At the end of 2004, all-cause pneumonia admission rates had declined by 39% (95% CI 22-52) for children younger than 2 years, who were the target population of the vaccination programme. This annual decline in all-cause pneumonia admissions of 506 (291-675) per 100,000 children younger than 2 years represented about 41,000 pneumonia admissions prevented in 2004. During the 8 study years, 10,659 (2%) children younger than 2 years admitted with pneumonia were coded as having pneumococcal disease; these rates declined by 65% (47-77). This decline represented about 17 fewer admissions per 100,000 children in 2004. Admission rates for dehydration for children younger than 2 years remained stable over the study period. INTERPRETATION The reduction in all-cause pneumonia admissions in children younger than 2 years provides an estimate of the proportion of childhood pneumonias attributable to Streptococcus pneumoniae in the USA that are vaccine preventable. Our results contribute to the growing body of evidence supporting the beneficial effects of the pneumococcal conjugate vaccines in children.

Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults

BACKGROUND Community-acquired pneumonia is a leading infectious cause of hospitalization and death among U.S. adults. Incidence estimates of pneumonia confirmed radiographically and with the use of current laboratory diagnostic tests are needed. METHODS We conducted active population-based surveillance for community-acquired pneumonia requiring hospitalization among adults 18 years of age or older in five hospitals in Chicago and Nashville. Patients with recent hospitalization or severe immunosuppression were excluded. Blood, urine, and respiratory specimens were systematically collected for culture, serologic testing, antigen detection, and molecular diagnostic testing. Study radiologists independently reviewed chest radiographs. We calculated population-based incidence rates of community-acquired pneumonia requiring hospitalization according to age and pathogen. RESULTS From January 2010 through June 2012, we enrolled 2488 of 3634 eligible adults (68%). Among 2320 adults with radiographic evidence of pneumonia (93%), the median age of the patients was 57 years (interquartile range, 46 to 71); 498 patients (21%) required intensive care, and 52 (2%) died. Among 2259 patients who had radiographic evidence of pneumonia and specimens available for both bacterial and viral testing, a pathogen was detected in 853 (38%): one or more viruses in 530 (23%), bacteria in 247 (11%), bacterial and viral pathogens in 59 (3%), and a fungal or mycobacterial pathogen in 17 (1%). The most common pathogens were human rhinovirus (in 9% of patients), influenza virus (in 6%), and Streptococcus pneumoniae (in 5%). The annual incidence of pneumonia was 24.8 cases (95% confidence interval, 23.5 to 26.1) per 10,000 adults, with the highest rates among adults 65 to 79 years of age (63.0 cases per 10,000 adults) and those 80 years of age or older (164.3 cases per 10,000 adults). For each pathogen, the incidence increased with age. CONCLUSIONS The incidence of community-acquired pneumonia requiring hospitalization was highest among the oldest adults. Despite current diagnostic tests, no pathogen was detected in the majority of patients. Respiratory viruses were detected more frequently than bacteria. (Funded by the Influenza Division of the National Center for Immunizations and Respiratory Diseases.).

Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings.

CONTEXT During the 1990s, antibiotic prescriptions for acute respiratory tract infection (ARTI) decreased in the United States. The sustainability of those changes is unknown. OBJECTIVE To assess trends in antibiotic prescriptions for ARTI. DESIGN, SETTING, AND PARTICIPANTS The National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data (1995-2006) were used to examine trends in antibiotic prescription rates by antibiotic indication and class. Annual survey data and census denominators were combined in 2-year intervals for rate calculations. MAIN OUTCOME MEASURES National annual visit rates and antibiotic prescription rates for ARTI, including otitis media (OM) and non-ARTI. RESULTS Among children younger than 5 years, annual ARTI visit rates decreased by 17% (95% confidence interval [CI], 9%-24%), from 1883 per 1000 population in 1995-1996 to 1560 per 1000 population in 2005-2006, primarily due to a 33% (95% CI, 22%-43%) decrease in OM visit rates (950 to 634 per 1000 population, respectively). This decrease was accompanied by a 36% (95% CI, 26%-45%) decrease in ARTI-associated antibiotic prescriptions (1216 to 779 per 1000 population). Among persons aged 5 years or older, ARTI visit rates remained stable but associated antibiotic prescription rates decreased by 18% (95% CI, 6%-29%), from 178 to 146 per 1000 population. Antibiotic prescription rates for non-OM ARTI for which antibiotics are rarely indicated decreased by 41% (95% CI, 22%-55%) and 24% (95% CI, 10%-37%) among persons younger than 5 years and 5 years or older, respectively. Overall, ARTI-associated prescription rates for penicillin, cephalosporin, and sulfonamide/tetracycline decreased. Prescription rates for azithromycin increased and it became the most commonly prescribed macrolide for ARTI and OM (10% of OM visits). Among adults, quinolone prescriptions increased. CONCLUSIONS Overall antibiotic prescription rates for ARTI decreased, associated with fewer OM visits in children younger than 5 years and with fewer prescriptions for ARTI for which antibiotics are rarely indicated. However, prescription rates for broad-spectrum antibiotics increased significantly.

U.S. Hospitalizations for Pneumonia after a Decade of Pneumococcal Vaccination

BACKGROUND The introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into the U.S. childhood immunization schedule in 2000 has substantially reduced the incidence of vaccine-serotype invasive pneumococcal disease in young children and in unvaccinated older children and adults. By 2004, hospitalizations associated with pneumonia from any cause had also declined markedly among young children. Because of concerns about increases in disease caused by nonvaccine serotypes, we wanted to determine whether the reduction in pneumonia-related hospitalizations among young children had been sustained through 2009 and whether such hospitalizations in older age groups had also declined. METHODS We estimated annual rates of hospitalization for pneumonia from any cause using the Nationwide Inpatient Sample database. The reason for hospitalization was classified as pneumonia if pneumonia was the first listed diagnosis or if it was listed after a first diagnosis of sepsis, meningitis, or empyema. Average annual rates of pneumonia-related hospitalizations from 1997 through 1999 (before the introduction of PCV7) and from 2007 through 2009 (well after its introduction) were used to estimate annual declines in hospitalizations due to pneumonia. RESULTS The annual rate of hospitalization for pneumonia among children younger than 2 years of age declined by 551.1 per 100,000 children (95% confidence interval [CI], 445.1 to 657.1), which translates to 47,000 fewer hospitalizations annually than expected on the basis of the rates before PCV7 was introduced. The rate for adults 85 years of age or older declined by 1300.8 per 100,000 (95% CI, 984.0 to 1617.6), which translates to 73,000 fewer hospitalizations annually. For the three age groups of 18 to 39 years, 65 to 74 years, and 75 to 84 years, the annual rate of hospitalization for pneumonia declined by 8.4 per 100,000 (95% CI, 0.6 to 16.2), 85.3 per 100,000 (95% CI, 7.0 to 163.6), and 359.8 per 100,000 (95% CI, 199.6 to 520.0), respectively. Overall, we estimated an age-adjusted annual reduction of 54.8 per 100,000 (95% CI, 41.0 to 68.5), or 168,000 fewer hospitalizations for pneumonia annually. CONCLUSIONS Declines in hospitalizations for childhood pneumonia were sustained during the decade after the introduction of PCV7. Substantial reductions in hospitalizations for pneumonia among adults were also observed. (Funded by the Centers for Disease Control and Prevention.).

Initiation of Tumor Necrosis Factor-α Antagonists and the Risk of Hospitalization for Infection in Patients With Autoimmune Diseases

CONTEXT Although tumor necrosis factor (TNF)-α antagonists are increasingly used in place of nonbiologic comparator medications, their safety profile remains incomplete. OBJECTIVES To determine whether initiation of TNF-α antagonists compared with nonbiologic comparators is associated with an increased risk of serious infections requiring hospitalization. DESIGN, SETTING, AND PATIENTS Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998-2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare. TNF-α antagonists and nonbiologic regimens were compared in disease-specific propensity score (PS)-matched cohorts using Cox regression models with nonbiologics as the reference. Baseline glucocorticoid use was evaluated as a separate covariate. MAIN OUTCOME MEASURE Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-α antagonists or nonbiologic regimens. RESULTS Study cohorts included 10,484 RA, 2323 IBD, and 3215 psoriasis and spondyloarthropathies matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91-1.21]). Among patients with IBD, rates were 10.91 (TNF-α antagonists) and 9.60 (comparator) per 100 person-years (aHR, 1.10 [95% CI, 0.83-1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-α antagonists) and 5.37 (comparator) per 100 person-years (aHR, 1.05 [95% CI, 0.76-1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07-1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02-1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections. CONCLUSION Among patients with autoimmune diseases, compared with treatment with nonbiologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.

National Impact of Universal Childhood Immunization With Pneumococcal Conjugate Vaccine on Outpatient Medical Care Visits in the United States

BACKGROUND. Since introduction of the heptavalent pneumococcal conjugate vaccine in the United States in 2000, rates of invasive pneumococcal disease have declined. However, the national impact of heptavalent pneumococcal conjugate vaccine on pneumonia and otitis media remains unknown. OBJECTIVES. We compared national rates of outpatient visits for pneumonia and otitis media in children before and after heptavalent pneumococcal conjugate vaccine introduction. METHODS. Rates of ambulatory visits for pneumococcal and nonspecific pneumonia, otitis media, and other acute respiratory infections were compared before (1994–1999) and after (2002–2003) heptavalent pneumococcal conjugate vaccine introduction using the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. To evaluate vaccine effects while accounting for temporal variability, ratios of pneumococcal-related disease rates in children <2 years old (vaccine target population) and in children 3 to 6 years old (not routinely vaccinated) were evaluated using a Poisson regression analysis. For children <2 years old, the differences between observed and expected rates were the estimated vaccine effects. RESULTS. After the introduction of heptavalent pneumococcal conjugate vaccine, otitis media visit rates declined by 20% in children aged <2 years. This decline represented 246 fewer otitis media visits per 1000 children aged <2 years annually. There were no significant decreases in outpatient visit rates for pneumonia or other acute respiratory infections for children aged <2 years. CONCLUSIONS. After heptavalent pneumococcal conjugate vaccine introduction, national rates of otitis media visits declined significantly in children <2 years old. Persistence of this trend will produce a significant reduction of the otitis media burden and further enhance the cost-effectiveness of heptavalent pneumococcal conjugate vaccine.

Respiratory Syncytial Virus–Associated Hospitalizations Among Children Less Than 24 Months of Age

BACKGROUND: Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization among infants. However, estimates of the RSV hospitalization burden have varied, and precision has been limited by the use of age strata grouped in blocks of 6 to ≥12 months. METHODS: We analyzed data from a 5-year, prospective, population-based surveillance for young children who were hospitalized with laboratory-confirmed (reverse-transcriptase polymerase chain reaction) RSV acute respiratory illness (ARI) during October through March 2000–2005. The total population at risk was stratified by month of age by birth certificate information to yield hospitalization rates. RESULTS: There were 559 (26%) RSV-infected children among the 2149 enrolled children hospitalized with ARI (85% of all eligible children with ARI). The average RSV hospitalization rate was 5.2 per 1000 children <24 months old. The highest age-specific rate was in infants 1 month old (25.9 per 1000 children). Infants ≤2 months of age, who comprised 44% of RSV-hospitalized children, had a hospitalization rate of 17.9 per 1000 children. Most children (79%) were previously healthy. Very preterm infants (<30 weeks’ gestation) accounted for only 3% of RSV cases but had RSV hospitalization rates 3 times that of term infants. CONCLUSIONS: Young infants, especially those who were 1 month old, were at greatest risk of RSV hospitalization. Four-fifths of RSV-hospitalized infants were previously healthy. To substantially reduce the burden of RSV hospitalizations, effective general preventive strategies will be required for all young infants, not just those with risk factors.

Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine

OBJECTIVE. Streptococcus pneumoniae is an important cause of otitis media in children. In this study we estimated the effect of routine childhood immunization with heptavalent pneumococcal conjugate vaccine on frequent otitis media (3 episodes in 6 months or 4 episodes in 1 year) and pressure-equalizing tube insertions. PATIENTS AND METHODS. The study population included all children who were enrolled at birth in TennCare or selected upstate New York commercial insurance plans as of July 1998 and continuously followed until 5 years old, loss of health plan enrollment, study outcome, or end of the study. We compared the risk of developing frequent otitis media or having pressure-equalizing tube insertion for 4 birth cohorts (1998–1999, 1999–2000, 2000–2001, and 2001–2002) by using Cox regression analysis. We used data from the National Immunization Survey to estimate the heptavalent pneumococcal conjugate vaccine uptake for children in these 4 birth cohorts in Tennessee and New York. RESULTS. The proportion of children in Tennessee and New York who received at least 3 doses of heptavalent pneumococcal conjugate vaccine by 2 years of age increased from ≤1% for the 1998–1999 birth cohort to ∼75% for the 2000–2001 birth cohort. By age 2 years, 29% of Tennessee and New York children born in 2000–2001 had developed frequent otitis media, and 6% of each of these birth cohorts had pressure-equalizing tubes inserted. Comparing the 2000–2001 birth cohort to the 1998–1999 birth cohort, frequent otitis media declined by 17% and 28%, and pressure-equalizing tube insertions declined by 16% and 23% for Tennessee and New York children, respectively. For the 2000–2001 to the 2001–2002 birth cohort, frequent otitis media and pressure-equalizing tubes remained stable in New York but increased in Tennessee. CONCLUSIONS. After heptavalent pneumococcal conjugate vaccine introduction, children were less likely to develop frequent otitis media or have pressure-equalizing tube insertions.