Personalized Infant Risk Prediction for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection Requiring Intensive Care Unit Admission.

Background: Currently, there are no available tools to identify infants at the highest risk of significant morbidity and mortality from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) who would benefit most from RSV prevention products. The objective was to develop and internally validate a personalized risk prediction tool for use among all newborns that uses readily available birth/postnatal data to predict RSV LRTI requiring intensive care unit (ICU) admission. Methods: We conducted a population-based birth cohort study of infants born from 1995 to 2007, insured by the Tennessee Medicaid Program, and who did not receive RSV immunoprophylaxis during the first year of life. The primary outcome was severe RSV LRTI requiring ICU admission during the first year of life. We built a multivariable logistic regression model including demographic and clinical variables available at or shortly after birth to predict the primary outcome. Results: In a population-based sample of 429 365 infants, 713 (0.2%) had severe RSV LRTI requiring ICU admission. The median age of admission was 66 days (interquartile range, 37-120). Our tool, including 19 variables, demonstrated good predictive accuracy (area under the curve, 0.78; 95% confidence interval, 0.77-0.80) and identified infants who did not qualify for palivizumab, based on American Academy of Pediatrics guidelines, but had higher predicted risk levels than infants who qualified (27% of noneligible infants with >0.16% predicted probabilities [lower quartile for eligible infants]). Conclusions: We developed a personalized tool that identified infants at increased risk for severe RSV LRTI requiring ICU admission, expected to benefit most from immunoprophylaxis.

The Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Otitis Media-Related Antibiotic Use Among Young Children in Tennessee, USA.

Otitis media (OM) is a leading cause of pediatric antibiotic use. Introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) led to reductions in OM among US children, though its impact on OM-related antibiotic use remains unclear. Among 499 683 Tennessee children <2 years of age, the OM-related antibiotic fill rate was stable after PCV13 introduction.

Human Papillomavirus Vaccine Impact on Cervical Precancers in a Low-Vaccination Population.

INTRODUCTION: Demonstrating human papillomavirus vaccine impact is critical for informing guidelines to increase vaccination and decrease human papillomavirus‒related outcomes, particularly in states with suboptimal vaccination coverage, such as Tennessee. This study examines the trends in high-grade cervical lesion incidence among Tennessee Medicaid-enrolled women aged 18-39 years and the subset of women who were screened for cervical cancer. METHODS: Using a validated claims-based model to identify incident cervical intraepithelial neoplasia Grades 2 or 3 or adenocarcinoma in situ events, annual age group‒specific incidence rates from Tennessee Medicaid billing data, 2008-2018, were calculated. Significant trends were determined by Joinpoint. Analyses were conducted in 2020. RESULTS: From 2008 to 2018, high-grade cervical lesion incidence significantly declined in women aged 18-20 years (average annual percentage change= -31.9, 95% CI= -38.6, -24.6), 21-24 years (average annual percentage change= -12.9, 95% CI= -22.3, -2.4), and 25-29 years (average annual percentage change= -6.4, 95% CI= -8.1, -4.6). Among screened women, rates significantly declined for ages 18-20 years (average annual percentage change= -20.3, 95% CI= -25.3, -15.0), 21-24 years (average annual percentage change= -10.2, 95% CI= -12.6, -7.8), and 25-29 years (average annual percentage change= -2.6, 95% CI= -3.9, -1.2). Trends from 2008 to 2018 were stable for older age groups (30-34 and 35-39 years). CONCLUSIONS: Results show reductions in high-grade cervical lesion incidence among ages most likely to have benefited from the human papillomavirus vaccine. Declines among young, screened women suggest causes other than reduction in screening. Evidence of vaccine impact in populations with low-vaccination coverage, such as Tennessee, is promising.

The Impact of the Human Papillomavirus Vaccine on High-Grade Cervical Lesions in Urban and Rural Areas: An Age-Period-Cohort Analysis.

Disparities in human papillomavirus (HPV) vaccination exist between urban (metropolitan statistical areas (MSAs)) and rural (non-MSAs) regions. To address whether the HPV vaccine's impact differs by urbanicity, we examined trends in cervical intraepithelial neoplasia grades 2 or 3 and adenocarcinoma in situ (collectively, CIN2+) incidence in MSAs and non-MSAs among Tennessee Medicaid (TennCare)-enrolled women aged 18-39 years and among the subset screened for cervical cancer in Tennessee, United States. Using TennCare claims data, we identified annual age-group-specific (18-20, 21-24, 25-29, 30-34, and 35-39 years) CIN2+ incidence (2008-2018). Joinpoint regression was used to identify trends over time. Age-period-cohort Poisson regression models were used to evaluate age, period, and cohort effects. All analyses were stratified by urbanicity (MSA versus non-MSA). From 2008-2018, 11,243 incident CIN2+ events (7956 in MSAs; 3287 in non-MSAs) were identified among TennCare-enrolled women aged 18-39 years. CIN2+ incident trends (2008-2018) were similar between women in MSAs and non-MSAs, with largest declines among ages 18-20 (MSA average annual percent change (AAPC): -30.4, 95% confidence interval (95%CI): -35.4, -25.0; non-MSA AAPC: -30.9, 95%CI: -36.8, -24.5) and 21-24 years (MSA AAPC: -14.8, 95%CI: -18.1, -11.3; non-MSA AAPC: -15.1, 95%CI: -17.9, -12.2). Significant declines for ages 18-20 years began in 2008 in MSAs compared to 2010 in non-MSAs. Trends were largely driven by age and cohort effects. These patterns were consistent among screened women. Despite evidence of HPV vaccine impact on reducing CIN2+ incidence regardless of urbanicity, significant declines in CIN2+ incidence were delayed in non-MSAs versus MSAs.

Improving Cervical Precancer Surveillance: Validity of Claims-Based Prediction Models in ICD-9 and ICD-10 Eras.

Background: Human papillomavirus vaccine (HPV) impact on cervical precancer (cervical intraepithelial neoplasia grades 2+ [CIN2+]) is observable sooner than impact on cancer. Biopsy-confirmed CIN2+ is not included in most US cancer registries. Billing codes could provide surrogate metrics; however, the International Classification of Diseases, ninth (ICD-9) to tenth (ICD-10) transition disrupts trends. We built, validated, and compared claims-based models to identify CIN2+ events in both ICD eras. Methods: A database of Davidson County (Nashville), Tennessee, pathology-confirmed CIN2+ from the HPV Vaccine Impact Monitoring Project (HPV-IMPACT) provided gold standard events. Using Tennessee Medicaid 2008-2017, cervical diagnostic procedures (N = 8549) among Davidson County women aged 18-39 years were randomly split into 60% training and 40% testing sets. Relevant diagnosis, procedure, and screening codes were used to build models from CIN2+ tissue diagnosis codes alone, least absolute shrinkage and selection operator (LASSO), and random forest. Model-classified index events were counted to estimate incident events. Results: HPV-IMPACT identified 983 incident CIN2+ events. Models identified 1007 (LASSO), 1245 (CIN2+ tissue diagnosis codes alone), and 957 (random forest) incident events. LASSO performed well in ICD-9 and ICD-10 eras: 77.3% (95% confidence interval [CI] = 72.5% to 81.5%) vs 81.1% (95% CI = 71.5% to 88.6%) sensitivity, 93.0% (95% CI = 91.9% to 94.0%) vs 90.2% (95% CI = 87.2% to 92.7%) specificity, 61.3% (95% CI = 56.6% to 65.8%) vs 60.3% (95% CI = 51.0% to 69.1%) positive predictive value, 96.6% (95% CI = 95.8% to 97.3%) vs 96.3% (95% CI = 94.1% to 97.8%) negative predictive value, 91.0% (95% CI = 89.9% to 92.1%) vs 88.8% (95% CI = 85.9% to 91.2%) accuracy, and 85.1% (95% CI = 82.9% to 87.4%) vs 85.6% (95% CI = 81.4% to 89.9%) C-indices, respectively; performance did not statistically significantly differ between eras (95% confidence intervals all overlapped). Conclusions: Results confirmed model utility with good performance across both ICD eras for CIN2+ surveillance. Validated claims-based models may be used in future CIN2+ trend analyses to estimate HPV vaccine impact where population-based biopsies are unavailable.

Rates of hospitalization for urinary tract infections among medicaid-insured individuals by spina bifida status, Tennessee 2005-2013.

BACKGROUND: Individuals with spina bifida are at increased risk for urinary tract infection (UTI), however there are few population-based investigations of the burden of UTI hospitalizations. OBJECTIVE: We assessed rates and risk factors for UTI hospitalization in individuals with and without spina bifida. METHODS: We conducted a retrospective cohort study to estimate rates of UTI hospitalization by spina bifida status. We included individuals enrolled in Tennessee Medicaid who lived in one of the Emerging Infections Program's Active Bacterial Surveillance counties between 2005 and 2013. Spina bifida was primarily defined and UTI hospitalizations were identified using International Classification of Diseases, Ninth Revision diagnoses. We also studied a subset without specific health conditions potentially associated with UTI. We used Poisson regression to calculate rate ratios (RR) of UTIs for individuals with versus without spina bifida, adjusting for race, sex and age group. RESULTS: Over the 9-years, 1,239,362 individuals were included and 2,493 met criteria for spina bifida. Individuals with spina bifida had over a four-fold increased rate of UTI hospitalization than those without spina bifida-in the overall study population and in the subset without specific, high-risk conditions (adjusted rate ratios: 4.41, 95% confidence intervals: 3.03, 6.43) and (4.87, 95% CI: 2.99, 7.92), respectively. We detected differences in rates of UTI hospitalization by race and sex in individuals without spina bifida that were not seen among individuals with spina bifida. CONCLUSIONS: Individuals with spina bifida had increased rates of UTI hospitalizations, and associated demographic patterns differed from those without spina bifida.

Trends in anogenital wart incidence among Tennessee Medicaid enrollees, 2006-2014: The impact of human papillomavirus vaccination.

INTRODUCTION: Evidence of human papillomavirus (HPV) vaccine impact on anogenital warts (AGWs) by race or urbanicity in the US is lacking. We evaluated HPV vaccine impact in Tennessee by assessing AGW trends among Tennessee Medicaid (TennCare) enrollees aged 15-39 years from 2006-2014. METHODS: Persons with incident AGWs were identified using diagnosis/pharmacy codes from TennCare billing claims. We calculated sex-specific annual AGW incidence by age group, race, and urbanicity; estimated annual percent changes (APCs) using log-linear models; and performed pairwise comparisons by race and urbanicity. RESULTS: AGW incidence decreased among females aged 15-19 (APC = -10.6; P < 0.01) and 20-24 years (APC = -3.9; P = 0.02). Overall trends were similar between Whites and Blacks, and between those living in metropolitan statistical areas (MSAs) and non-MSAs. Rates among males aged 15-19 years began decreasing after 2010. Among enrollees aged 25-39 years, rates increased or were stable. CONCLUSIONS: Following introduction of the HPV vaccine in 2006, AGWs decreased among age groups most likely to be vaccinated. The change in trend among young males after 2010 suggests early herd effects. Our findings indicate vaccine effects and support the importance of improving adherence to current vaccination recommendations for preventing AGWs and other HPV-related diseases.

Changes in Otitis Media Episodes and Pressure Equalization Tube Insertions Among Young Children Following Introduction of the 13-Valent Pneumococcal Conjugate Vaccine: A Birth Cohort-based Study.

BACKGROUND: The impact of 13-valent pneumococcal conjugate vaccine (PCV13) introduction on the occurrence of first and subsequent otitis media (OM) episodes in early childhood is unclear. We compared the risk of OM episodes among children age <2 years before and after PCV13 introduction, accounting for the dependence between OM episodes. METHODS: We identified consecutive annual (July-June) cohorts of Tennessee Medicaid-enrolled children (2006-2014) from birth through age 2 years. We identified OM episodes using coded diagnoses (we classified diagnoses <21 days apart as the same episode). We modeled adjusted hazard ratios (aHRs) for OM comparing 7-valent pneumococcal conjugate vaccine (PCV7)-era (2006-2010) and PCV13-era (2011-2014) birth cohorts, accounting for risk factors and dependence between first and subsequent episodes. Secondary analyses examined pressure equalization tube (PET) insertions and compared the risk of recurrent OM (≥3 episodes in 6 months or ≥4 episodes in 12 months) between PCV7- and PCV13-era birth cohorts. RESULTS: We observed 618 968 OM episodes and 24 875 PET insertions among 368 063 children. OM and PET insertion rates increased during the PCV7 years and declined after PCV13 introduction. OM and PET insertion risks were lower in the 2013-2014 cohort compared with the 2009-2010 cohort (aHRs [95% confidence interval], 0.92 [.91-.93] and 0.76 [.72-.80], respectively). PCV13 introduction was associated with declines in the risk of first, subsequent, and recurrent OM. CONCLUSIONS: The transition from PCV7 to PCV13 was associated with a decline of OM among children aged <2 years due to a reduction in the risk of both the first and subsequent OM episodes.

Long-acting Opioid Use and the Risk of Serious Infections: A Retrospective Cohort Study.

BACKGROUND: Although evidence from animal and human studies indicates opioid analgesics increase susceptibility to infections, it is unclear whether the risk varies by specific opioid. We compared the risk of serious infection among patients initiating long-acting opioid analgesics with and without previously reported immunosuppressive properties. METHODS: We conducted a retrospective cohort study of Tennessee Medicaid enrollees age ≥18 years initiating long-acting opioids (1995-2015). Hospitalizations for serious infection were identified using validated coding algorithms. We used multivariable Poisson regression models to calculate adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) to compare the infection risk among patients using long-acting opioids with known immunosuppressive properties (morphine, fentanyl, methadone) to the infection risk among patients using long-acting opioids without known immunosuppressive properties (oxycodone, oxymorphone, tramadol) accounting for demographics, opioid dose, comorbidities and pain conditions, medication use, frailty indicators, and healthcare encounter history using exposure propensity scores. We further compared users of individual long-acting opioids to long-acting morphine users (considered the prototypical immunosuppressive opioid). RESULTS: Among the 61 240 patients initiating opioids with immunosuppressive properties and 22 811 patients initiating opioids without immunosuppressive properties, we identified 1906 serious infections. Nonimmunosuppressive opioid users had a lower rate of infections than immunosuppressive opioid users (aIRR:0.78 [CI: 0.66-0.91]). Among individual opioids, oxycodone users had a lower rate of infection than morphine users (aIRR:0.73 [CI: 0.60-0.89]). There were no significant differences in the infection risk between other opioids and morphine. CONCLUSION: The risk of serious infections among long-acting opioid users varies by opioid type. Providers should carefully consider the risk of serious infections when making pain management decisions.

Association Between Maternal 2nd Trimester Plasma Folate Levels and Infant Bronchiolitis.

Objectives Viral bronchiolitis is the most common cause of infant hospitalization. Folic acid supplementation is important during the periconceptional period to prevent neural tube defects. An area of investigation is whether higher prenatal folate is a risk factor for childhood respiratory illnesses. We investigated the association between maternal 2nd trimester plasma folate levels and infant bronchiolitis. Methods We conducted a retrospective cohort analysis in a subset of mother-infant dyads (n = 676) enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study and Tennessee Medicaid. Maternal folate status was determined using 2nd trimester (16-28 weeks) plasma samples. Bronchiolitis diagnosis in the first year of life was ascertained using International Classification of Diagnosis-9 codes from Medicaid administrative data. We used multivariable logistic regression to assess the adjusted association of prenatal folate levels and infant bronchiolitis outcome. Results Half of the women in this lower-income and predominately African-American (84%) study population had high levels of folate (median 2nd trimester level 19.2 ng/mL) and 21% of infants had at least one bronchiolitis healthcare visit. A relationship initially positive then reversing between maternal plasma folate and infant bronchiolitis was observed that did not reach statistical significance (poverall = .112, pnonlinear effect = .088). Additional adjustment for dietary methyl donor intake did not significantly alter the association. Conclusions for Practice Results did not confirm a statistically significant association between maternal 2nd trimester plasma folate levels and infant bronchiolitis. Further work is needed to investigate the role of folate, particularly higher levels, in association with early childhood respiratory illnesses.

Validation of discharge diagnosis codes to identify serious infections among middle age and older adults.

OBJECTIVES: Hospitalisations for serious infections are common among middle age and older adults and frequently used as study outcomes. Yet, few studies have evaluated the performance of diagnosis codes to identify serious infections in this population. We sought to determine the positive predictive value (PPV) of diagnosis codes for identifying hospitalisations due to serious infections among middle age and older adults. SETTING AND PARTICIPANTS: We identified hospitalisations for possible infection among adults >=50 years enrolled in the Tennessee Medicaid healthcare programme (2008-2012) using International Classifications of Diseases, Ninth Revision diagnosis codes for pneumonia, meningitis/encephalitis, bacteraemia/sepsis, cellulitis/soft-tissue infections, endocarditis, pyelonephritis and septic arthritis/osteomyelitis. DESIGN: Medical records were systematically obtained from hospitals randomly selected from a stratified sampling framework based on geographical region and hospital discharge volume. MEASURES: Two trained clinical reviewers used a standardised extraction form to abstract information from medical records. Predefined algorithms served as reference to adjudicate confirmed infection-specific hospitalisations. We calculated the PPV of diagnosis codes using confirmed hospitalisations as reference. Sensitivity analyses determined the robustness of the PPV to definitions that required radiological or microbiological confirmation. We also determined inter-rater reliability between reviewers. RESULTS: The PPV of diagnosis codes for hospitalisations for infection (n=716) was 90.2% (95% CI 87.8% to 92.2%). The PPV was highest for pneumonia (96.5% (95% CI 93.9% to 98.0%)) and cellulitis (91.1% (95% CI 84.7% to 94.9%)), and lowest for meningitis/encephalitis (50.0% (95% CI 23.7% to 76.3%)). The adjudication reliability was excellent (92.7% agreement; first agreement coefficient: 0.91). The overall PPV was lower when requiring microbiological confirmation (45%) and when requiring radiological confirmation for pneumonia (79%). CONCLUSIONS: Discharge diagnosis codes have a high PPV for identifying hospitalisations for common, serious infections among middle age and older adults. PPV estimates for rare infections were imprecise.

Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases: A Nested Case-Control Study.

Background: Although certain opioid analgesics have immunosuppressive properties and increase the risk for infections in animals, the clinical effects of prescription opioid use on infection risk among humans are unknown. Objective: To test the hypothesis that prescription opioid use is an independent risk factor for invasive pneumococcal disease (IPD). Design: Nested case-control study. Setting: Tennessee Medicaid database linked to Medicare and Active Bacterial Core surveillance system databases (1995 to 2014). Patients: 1233 case patients with IPD aged 5 years and older matched to 24 399 control participants by diagnosis date, age, and county of residence. Measurements: Opioid use was measured on the basis of pharmacy prescription fills. Invasive pneumococcal disease was defined by the isolation of Streptococcus pneumoniae from a normally sterile site. The odds of current opioid use were compared between the case and control groups, accounting for known IPD risk factors. Secondary analyses categorized opioid use by opioid characteristics, applied an IPD risk score to assure comparability between exposure groups, and analyzed pneumonia and nonpneumonia IPD cases separately. Results: Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; ≥90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately. Limitations: Unmeasured confounding and measurement error, although sensitivity analyses suggested that neither was likely to affect results. Actual opioid use and other nonprescription use (such as illicit opioid use) were not measured. Conclusion: Opioid use is associated with an increased risk for IPD and represents a novel risk factor for these diseases. Primary Funding Source: National Institutes of Health.

Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Reducing Bronchiolitis Hospitalizations Among High-Risk Infants.

We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born during 1996-2008 and enrolled in the Kaiser Permanente Northern California integrated health-care delivery system. During the RSV season (November-March), the date of RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days were defined as unprotected period(s). Numbers of bronchiolitis hospitalizations were determined using International Classification of Diseases, Ninth Revision, codes during RSV season. We used a proportional hazards model to estimate risk of bronchiolitis hospitalization when comparing infants' protected period(s) with unprotected period(s). Infants who had ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when protected periods were compared with unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94) when protected periods were compared with unprotected periods. Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible for RSV immunoprophylaxis on the basis of AAP guidelines in place at birth would no longer be eligible, but nearly all infants with CLD would remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt of RSV immunoprophylaxis under the new AAP guidelines.

Changes in empyema among U.S. children in the pneumococcal conjugate vaccine era.

BACKGROUND: Parapneumonic empyema, a serious complication of pneumonia, started increasing among U.S. children before the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in 2000, and continued afterwards. This increase was due in part to pneumococcal serotypes not included in PCV7 that were included in the new 13-valent (PCV13) vaccine introduced in 2010. We assessed changes in the incidence of empyema hospitalizations among U.S. children after PCV13 introduction. METHODS: We calculated annualized empyema hospitalization rates among U.S. children <18years using Nationwide Inpatient Sample and Census data (1997-2013) for four periods based on PCV7 and PCV13 introductions. Relative rates (RR) and 95% confidence intervals (CI) were calculated by age group and sex, comparing PCV7 [early-PCV7 (2001-2005) and late-PCV7 (2006-2009)] and PCV13 (2011-2013) periods with the pre-PCV7 period (1997-1999). Secondary analyses examined changes in pneumococcal, streptococcal, staphylococcal and unspecified empyema. RESULTS: Among children <18years of age, annualized empyema hospitalization rates peaked at 3.6 per 100,000 in the late-PCV7 period compared with 2.1 per 100,000 in the pre-PCV7 period [RR: 1.70 (95% CI: 1.11-2.60)]. However, annualized rates in the post-PCV13 period declined to 2.0 per 100,000, similar to rates in the pre-PCV7 period. Empyema rates among children <2years were lower in the post-PCV13 period compared to the pre-PCV7 period [RR: 0.77 (95% CI: 0.61-0.96)], but rates in the two periods among children 2-4 and 5-17years were similar. Most empyema were of unspecified etiology. Pneumococcal and unspecified empyema declined after PCV13 introduction. CONCLUSIONS: Although empyema hospitalization rates among U.S. children peaked after PCV7 introduction, rates decreased substantially following the introduction of PCV13.

Changes in Childhood Pneumonia Hospitalizations by Race and Sex Associated with Pneumococcal Conjugate Vaccines.

Introduction of pneumococcal conjugate vaccines in the childhood immunization schedule was associated with decreases in all-cause pneumonia hospitalizations among black and white children in Tennessee, USA. Although racial disparities that existed before introduction of these vaccines have been substantially reduced, rates remain higher in boys than in girls among young children.

Opioid Analgesics and the Risk of Serious Infections Among Patients With Rheumatoid Arthritis: A Self-Controlled Case Series Study.

OBJECTIVE: Animal studies and in vitro human studies suggest that certain opioid analgesics impair crucial immune functions. This study was undertaken to determine whether opioid use is associated with increased risk of serious infection in patients with rheumatoid arthritis (RA). METHODS: We conducted a self-controlled case series analysis on a retrospective cohort of 13,796 patients with RA enrolled in Tennessee Medicaid in 1995-2009. Within-person comparisons of the risk of hospitalization for serious infection during periods of opioid use versus non-use were performed using conditional Poisson regression. Fixed confounders were accounted for by design; time-varying confounders included age and use of disease-modifying antirheumatic drugs, glucocorticoids, and proton-pump inhibitors. In additional analyses, risks associated with new opioid use, use of opioids known to have immunosuppressive properties, use of long-acting opioids, and different opioid dosages were assessed. Sensitivity analyses were performed to account for potential protopathic bias and confounding by indication. RESULTS: Among 1,790 patients with RA who had at least 1 hospitalization for serious infection, the adjusted incidence rate of serious infection was higher during periods of current opioid use compared to non-use, with an incidence rate ratio (IRR) of 1.39 (95% confidence interval [95% CI] 1.19-1.62). The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use, and new opioid use compared to non-use (IRR 2.01 [95% CI 1.52-2.66], IRR 1.72 [95% CI 1.33-2.23], and IRR 2.38 [95% CI 1.65-3.42], respectively). Results of sensitivity analyses were consistent with the main findings. CONCLUSION: In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalization for serious infection.

Maternal Folic Acid Supplementation During Pregnancy and Early Childhood Asthma.

BACKGROUND: Asthma is one of the most common chronic childhood diseases. While folic acid supplementation around conception helps prevent neural tube defects, an animal model suggests that it may be a risk factor for respiratory diseases, although epidemiologic studies have had conflicting results. We investigated the timing of folic acid-containing prescription filling during pregnancy and child asthma. METHODS: In a retrospective cohort study of 104,428 children, born 1996-2005, and their mothers enrolled in Tennessee Medicaid, we investigated the association of filling folic acid-containing prescriptions during pregnancy and childhood asthma at ages 4.5-6 years. We categorized women into exposure groups based on prescription filling centered around the first trimester: no folic acid prescription exposure, exposure in first trimester only, exposure after first trimester, and exposure in first trimester and beyond. We defined asthma using asthma-specific healthcare visits and medication fills. Using logistic regression models, we investigated the relationship adjusting for potential confounders. RESULTS: Overall 15% of children had asthma. Compared with children born to women with no folic acid prescription exposure, children born to women with exposures in the first trimester only or first trimester and later had increased relative odds of asthma (adjusted odds ratios = 1.2, 95% confidence interval = 1.1, 1.3, and 1.2, 95% confidence interval = 1.2, 1.3); no association was seen in children born to women exposed after the first trimester. CONCLUSION: Timing of folic acid-containing prescription filling during pregnancy was associated with childhood asthma. Our findings contribute to understanding of the role of prenatal nutritional supplements on child respiratory health.

Association of folic acid supplementation during pregnancy and infant bronchiolitis.

Viral bronchiolitis affects 20%-30% of infants; because there is no known effective treatment, it is important to identify risk factors that contribute to its pathogenesis. Although adequate folate intake during the periconceptional period prevents neural tube defects, animal data suggest that higher supplementation may be a risk factor for child respiratory diseases. Using a population-based retrospective cohort of 167,333 women and infants, born in 1995-2007 and enrolled in the Tennessee Medicaid program, we investigated the association between the filling of folic acid-containing prescriptions and infant bronchiolitis. We categorized women into the following 4 groups in relation to the first trimester: "none" (no prescription filled), "first trimester only," "after first trimester," and "both" (prescriptions filled both during and after the first trimester). Overall, 21% of infants had a bronchiolitis diagnosis, and 5% were hospitalized. Most women filled their first prescriptions after the fifth to sixth weeks of pregnancy, and most prescriptions contained 1,000 µg of folic acid. Compared with infants born to women in the "none" group, infants born to women in the "first trimester only" group had higher relative odds of bronchiolitis diagnosis (adjusted odds ratio = 1.17, 95% confidence interval: 1.11, 1.22) and greater severity (adjusted odds ratio = 1.16, 95% confidence interval: 1.11, 1.22). This study's findings contribute to an understanding of the implications of prenatal nutritional supplement recommendations for infant bronchiolitis.

Spatiotemporal patterns of infant bronchiolitis in a Tennessee Medicaid population.

Respiratory syncytial virus (RSV) is a major cause of worldwide morbidity and mortality in infants, primarily through the induction of bronchiolitis. RSV epidemics are highly seasonal, occurring in the winter months in the northern hemisphere. Within the United States, RSV epidemic dynamics vary both spatially and temporally. This analysis employs a retrospective space­time scan statistic to locate spatiotemporal clustering of infant bronchiolitis in a very large Tennessee (TN) Medicaid cohort. We studied infants less than 6 months of age (N = 52,468 infants) who had an outpatient visit, emergency department visit, or hospitalization for bronchiolitis between 1995 and 2008. The scan statistic revealed distinctive and consistent patterns of deviation in epidemic timing. Eastern TN (Knoxville area) showed clustering in January and February, and Central TN (Nashville area) in November and December. This is likely due to local variation in geography-associated factors which should be taken into consideration in future modeling of RSV epidemics.

Reactive versus proactive patterns of inhaled corticosteroid use.

For patients with persistent asthma, inhaled corticosteroids (ICS) are a mainstay of controller therapy. These medications are usually prescribed to be taken daily and have been shown to be associated with decreased asthma morbidity. Adherence to daily treatment is very low in many populations in the United States. The purpose of this study is to evaluate the seasonal use of ICS prescription filling as reactive behavior primarily after an asthma exacerbation in a pediatric population. The study population is a subgroup of the Tennessee Asthma and Bronchiolitis Study. The children in this study were enrolled in Tennessee Medicaid (TennCare). The subjects had asthma and were 6 to 9 years of age during the years 2005 to 2010. Prescription filling was determined using claims data, and asthma exacerbations were defined by use of systemic rescue corticosteroids (RCS). In this cohort of 13,114 children with asthma, ICS and RCS filling were highly seasonal and trended with fall and winter peaks in asthma exacerbations. Prescription refilling was very low, with an average of three ICS fills per child who filled at least one during the study period. Among these children, 54.1% (7,096) had an asthma exacerbation during the study period. Among ICS users, 68.5% (3,441/5,020) had a disease exacerbation. ICS filling occurred overwhelmingly on the same day as RCS fills. The seasonal filling patterns of ICS coincide with asthma exacerbations. ICS adherence is low and inconsistent in this population of children with asthma. Increased adherence to ICS, particularly before the seasonal virus epidemics, could greatly reduce asthma morbidity.