Returning incidentally discovered Hepatitis C RNA-seq results to COPDGene study participants.

The consequences of returning infectious pathogen test results identified incidentally in research studies have not been well-studied. Concerns include identification of an important health issue for individuals, accuracy of research test results, public health impact, potential emotional distress for participants, and need for IRB permissions. Blood RNA-sequencing analysis for non-human RNA in 3984 participants from the COPDGene study identified 228 participants with evidence suggestive for hepatitis C virus (HCV) infection. We hypothesized that incidentally discovered HCV results could be effectively returned to COPDGene participants with attention to the identified concerns. In conjunction with a COPDGene Participant Advisory Panel, we developed and obtained IRB approval for a process of returning HCV research results and an HCV Follow-Up Study questionnaire to capture information about previous HCV diagnosis and treatment information and participant reactions to return of HCV results. During phone calls following the initial HCV notification letter, 84 of 124 participants who could be contacted (67.7%) volunteered that they had been previously diagnosed with HCV infection. Thirty-one of these 124 COPDGene participants were enrolled in the HCV Follow-Up Study. Five of the 31 HCV Follow-Up Study participants did not report a previous diagnosis of HCV. For four of these participants, subsequent clinical HCV testing confirmed HCV infection. Thus, 30/31 Follow-Up Study participants had confirmed HCV diagnoses, supporting the accuracy of the HCV research test results. However, the limited number of participants in the Follow-Up Study precludes an accurate assessment of the false-positive and false-negative rates of the research RNA sequencing evidence for HCV. Most HCV Follow-Up Study participants (29/31) were supportive of returning HCV research results, and most participants found the process for returning HCV results to be informative and not upsetting. Newly diagnosed participants were more likely to be pleased to learn about a potentially curable infection (p = 0.027) and showed a trend toward being more frightened by the potential health risks of HCV (p = 0.11). We conclude that HCV results identified incidentally during transcriptomic research studies can be successfully returned to research study participants with a carefully designed process.

Targeting patients for early COVID-19 therapy; Pre-infection metabolic dysfunction, polycystic ovary syndrome and risk of severe disease in patients under 65: A Massachusetts community-based observational study.

INTRODUCTION: The demographics of those developing severe coronavirus disease (COVID-19) outcomes are shifting to younger patients. In an observational study utilizing electronic health records from a Massachusetts group medical practice, we identified 5025 patients with confirmed COVID-19 from March 1 to December 18, 2020. Of these, 3870 were under 65 years of age. We investigated the hypothesis that pre-infection metabolic or immunologic dysregulation including polycystic ovary syndrome (PCOS) increased risk of serious COVID-19 outcomes in patients under 65 years of age. MATERIALS AND METHODS: We compared those with COVID-19 related hospitalization or mortality to all other COVID-19 patients, using a case control approach. Using logistic regression and propensity score modeling, we evaluated risk of developing severe COVID-19 outcomes (hospitalization or death) in those with pre-infection comorbidities, metabolic risk factors, or PCOS. RESULTS: Overall, propensity score matched analyses demonstrated pre-infection elevated liver enzymes alanine aminotransferase (ALT) >40, aspartate aminotransferase (AST) >40 and blood glucose ≥215 mg/dL were associated with more severe COVID-19 outcomes, OR = 1.74 (95% CI 1.31, 2.31); OR = 1.98 (95% CI 1.52, 2.57), and OR = 1.55 (95% CI 1.08, 2.23) respectively. Elevated hemoglobin A1C or blood glucose levels were even stronger risk factors for severe COVID-19 outcomes among those aged < 65, OR = 2.31 (95% CI 1.14, 4.66) and OR = 2.42 (95% CI 1.29, 4.56), respectively. In logistic regression models, women aged < 65 with PCOS demonstrated more than a four-fold increased risk of severe COVID-19, OR 4.64 (95% CI 1.98, 10.88). CONCLUSION: Increased risk of severe COVID-19 outcomes in those < age 65 with pre-infection indicators of metabolic dysfunction heightens the importance of monitoring pre-infection indicators in younger patients for prevention and early treatment. The PCOS finding deserves further investigation. Meanwhile women who suffer from PCOS should be carefully evaluated and prioritized for earlier COVID-19 treatment and vaccination.

Hypertension, medications, and risk of severe COVID-19: A Massachusetts community-based observational study.

It remains uncertain whether the hypertension (HT) medications angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) mitigate or exacerbate SARS-CoV-2 infection. We evaluated the association of ACEi and ARB with severe coronavirus disease 19 (COVID-19) as defined by hospitalization or mortality among individuals diagnosed with COVID-19. We investigated whether these associations were modified by age, the simultaneous use of the diuretic thiazide, and the health conditions associated with medication use. In an observational study utilizing data from a Massachusetts group medical practice, we identified 1449 patients with a COVID-19 diagnosis. In our study, pre-infection comorbidities including HT, cardiovascular disease, and diabetes were associated with increased risk of severe COVID-19. Risk was further elevated in patients under age 65 with these comorbidities or cancer. Twenty percent of those with severe COVID-19 compared to 9% with less severe COVID-19 used ACEi, 8% and 4%, respectively, used ARB. In propensity score-matched analyses, use of neither ACEi (OR = 1.30, 95% CI 0.93 to 1.81) nor ARB (OR = 0.94, 95% CI 0.57 to 1.55) was associated with increased risk of severe COVID-19. Thiazide use did not modify this relationship. Beta blockers, calcium channel blockers, and anticoagulant medications were not associated with COVID-19 severity. In conclusion, cardiovascular-related comorbidities were associated with severe COVID-19 outcomes, especially among patients under age 65. We found no substantial increased risk of severe COVID-19 among patients taking antihypertensive medications. Our findings support recommendations against discontinuing use of renin-angiotensin system (RAS) inhibitors to prevent severe COVID-19.

Claims-based risk model for first severe COPD exacerbation.

OBJECTIVES: To develop and validate a predictive model for first severe chronic obstructive pulmonary disease (COPD) exacerbation using health insurance claims data and to validate the risk measure of controller medication to total COPD treatment (controller and rescue) ratio (CTR). STUDY DESIGN: A predictive model was developed and validated in 2 managed care databases: Truven Health MarketScan database and Reliant Medical Group database. This secondary analysis assessed risk factors, including CTR, during the baseline period (Year 1) to predict risk of severe exacerbation in the at-risk period (Year 2). METHODS: Patients with COPD who were 40 years or older and who had at least 1 COPD medication dispensed during the year following COPD diagnosis were included. Subjects with severe exacerbations in the baseline year were excluded. Risk factors in the baseline period were included as potential predictors in multivariate analysis. Performance was evaluated using C-statistics. RESULTS: The analysis included 223,824 patients. The greatest risk factors for first severe exacerbation were advanced age, chronic oxygen therapy usage, COPD diagnosis type, dispensing of 4 or more canisters of rescue medication, and having 2 or more moderate exacerbations. A CTR of 0.3 or greater was associated with a 14% lower risk of severe exacerbation. The model performed well with C-statistics, ranging from 0.711 to 0.714. CONCLUSIONS: This claims-based risk model can predict the likelihood of first severe COPD exacerbation. The CTR could also potentially be used to target populations at greatest risk for severe exacerbations. This could be relevant for providers and payers in approaches to prevent severe exacerbations and reduce costs.

Environmental triggers of COPD symptoms: a case cross-over study.

INTRODUCTION: This study investigated the hypothesis that common environmental chemical exposures with known irritant or sensitising properties trigger exacerbations for patients with chronic obstructive pulmonary disease (COPD). METHODS: We conducted a case cross-over study in 168 patients with COPD who were members of a disease management group in central Massachusetts. Participants completed a baseline health survey and several short exposure surveys. Exposure surveys were administered by a nurse when a participant telephoned to report an exacerbation (case periods) and at a maximum of three randomly identified control periods when they were not experiencing an exacerbation. We compared exposures in the week preceding an exacerbation with exposures in normal (non-exacerbation) weeks. The questionnaire assessed short-term (1 week) home, community and workplace activities and exposures that may be associated with COPD exacerbation. RESULTS: Self-reported exercise was negatively associated with exacerbation (OR=0.59, 95% CI: 0.35 to 1.00). Among the environmental chemical exposures, car and truck exhaust (OR=4.36, 95% CI: 1.76 to 10.80) and use of scented laundry products (OR=2.69, 95% CI: 1.31 to 5.52) showed strong positive effects. Self-reported respiratory infections were strongly associated with exacerbation (OR=7.90, 95% CI 4.29 to 14.50). Variations in outdoor temperature were associated with COPD exacerbation risk (moderate versus cold temperature OR=1.95, 95% CI 1.09 to 3.49 and warm versus cold OR=0.43, 95% CI: 0.26 to 0.70). CONCLUSIONS: These results suggest that some environmental chemical exposures may play a role in triggering COPD exacerbations. If confirmed, they may provide useful guidance for patients with COPD to better manage their disease.

Validation of a New Risk Measure for Chronic Obstructive Pulmonary Disease Exacerbation Using Health Insurance Claims Data.

RATIONALE: Current chronic obstructive pulmonary disease (COPD) exacerbation risk prediction models are based on clinical data not easily accessible to national quality-of-care organizations and payers. Models developed from data sources available to these organizations are needed. OBJECTIVES: This study aimed to validate a risk measure constructed using pharmacy claims in patients with COPD. Administrative claims data were used to construct a risk model to test and validate the ratio of controller (maintenance) medications to total COPD medications (CTR) as an independent risk measure for COPD exacerbations. The ability of the CTR to predict the risk of COPD exacerbations was also assessed. METHODS: This was a retrospective study using health insurance claims data from the Truven MarketScan database (2006-2011), whereby exacerbation risk factors of patients with COPD were observed over a 12-month period and exacerbations monitored in the following year. Exacerbations were defined as moderate (emergency department or outpatient treatment with oral corticosteroid dispensings within 7 d) or severe (hospital admission) on the basis of diagnosis codes. Models were developed and validated using split-sample data from the MarketScan database and further validated using the Reliant Medical Group database. The performance of prediction models was evaluated using C-statistics. MEASUREMENTS AND MAIN RESULTS: A total of 258,668 patients with COPD from the MarketScan database were included. A CTR of greater than or equal to 0.3 was significantly associated with a reduced risk for any (adjusted odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.97); moderate (OR, 0.93; 95% CI, 0.87-1.00), or severe (OR, 0.87; 95% CI, 0.80-0.95) exacerbation. The CTR, at a ratio of greater than or equal to 0.3, was predictive in various subpopulations, including those without a history of asthma and those with or without a history of moderate/severe exacerbations. The C-statistics ranged from 0.750 to 0.761 for the development set and 0.714 to 0.761 in the validation sets, indicating the CTR performed well in predicting exacerbation risk. CONCLUSIONS: The ratio of controller to total medications dispensed for COPD is a measure that can easily be calculated using only pharmacy claims data. A CTR of greater than or equal to 0.3 can potentially be used as a quality-of-care measurement for prevention of exacerbations.

Clinical predictors of frequent exacerbations in subjects with severe chronic obstructive pulmonary disease (COPD).

BACKGROUND: Acute exacerbations are a significant source of morbidity and mortality associated with chronic obstructive pulmonary disease. Among individuals with COPD, some patients suffer an inordinate number of exacerbations while others remain relatively protected. We undertook a study to determine the clinical factors associated with "frequent exacerbator" status within a population of subjects with severe COPD. METHODS: Case-control cohort recruited from two Boston-area practices. All subjects had GOLD stage 3 or 4 (FEV(1) ≤ 50% predicted) COPD. "Frequent exacerbators" (n = 192) had an average of ≥2 moderate-to-severe exacerbations per year while "non-exacerbators" (n = 153) had no exacerbations in the preceding 12 months. Multivariate logistic regression was performed to determine the significant clinical predictors of "frequent exacerbator" status. RESULTS: Physician-diagnosed asthma was a significant predictor of frequent exacerbations. Within a subset of our cohort, the modified Medical Research Council dyspnea score and FEF (25-75%) predicted were also significant clinical predictors of frequent exacerbator status (p < 0.05). Differences in exacerbation frequency were not found to be due to increased current tobacco use or decreased rates of maintenance medication use. CONCLUSIONS: Within our severe COPD cohort, a history of physician-diagnosed asthma was found to be a significant clinical predictor of frequent exacerbations. Although traditional risk factors such as decreased FEV(1)% predicted were not significantly associated with frequent exacerbator status, lower mid-expiratory flow rates, as assessed by FEF (25-75%) predicted, were significantly associated with frequent exacerbations in a subset of our cohort.

Metallic elements in exhaled breath condensate and serum of patients with exacerbation of chronic obstructive pulmonary disease.

Biomarkers in exacerbated chronic obstructive pulmonary disease may be useful in aiding diagnosis, defining specific phenotypes of disease, monitoring the disease and evaluating the effects of drugs. The aim of this study was the characterization of metallic elements in exhaled breath condensate and serum as novel biomarkers of exposure and susceptibility in exacerbated chronic obstructive pulmonary disease using reference analytical techniques. C-Reactive protein and procalcitonin were assessed as previously validated diagnostic and prognostic biomarkers which have been associated with disease exacerbation, thus useful as a basis of comparison with metal levels. Exhaled breath condensate and serum were obtained in 28 patients at the beginning of an episode of disease exacerbation and when they recovered. Trace elements and toxic metals were measured by inductively coupled plasma-mass spectrometry. Serum biomarkers were measured by immunoassay. Exhaled manganese and magnesium levels were influenced by exacerbation of chronic obstructive pulmonary disease, an increase in their concentrations--respectively by 20 and 50%--being observed at exacerbation in comparison with values obtained at recovery; serum elemental composition was not modified by exacerbation; serum levels of C-reactive protein and procalcitonin at exacerbation were higher than values at recovery. In outpatients who experienced a mild-moderate chronic obstructive pulmonary disease exacerbation, manganese and magnesium levels in exhaled breath condensate are elevated at admission in comparison with values at recovery, whereas no other changes were observed in metallic elements at both the pulmonary and systemic level.

Adherence to inhaled corticosteroid use and local adverse events in persistent asthma.

OBJECTIVES: To measure adherence to inhaled corticosteroid (ICS) therapy using prescription claims and a patient survey, to identify local adverse events (LAEs) from the patient perspective and from medical records, and to evaluate the association between LAEs and adherence to ICS therapy. STUDY DESIGN: Survey administration and claims-based and medical record-abstracted data. METHODS: Patients aged 6 to 64 years with persistent asthma (defined using an established algorithm) and at least 2 ICS prescriptions were selected from a claims database (1999-2006) of a central Massachusetts medical group practice. Prescription claims were used to calculate the ICS medication possession ratio (MPR). A survey obtained information about patient-reported adherence to ICSs using the Morisky scale and a visual analog scale (VAS) and about LAEs using the validated Inhaled Corticosteroid Questionnaire. Medical records of survey respondents were abstracted for LAEs. RESULTS: Among 372 survey respondents, 2.7% met the claims-based measure of good adherence (MPR, > or =80%). Patient-reported adherence was much higher; 20.7% of patients were highly adherent based on the Morisky scale (score, 0) and 55.4% based on the VAS (score, > or =80%). Medical record review identified 27.2% of patients having at least 1 LAE within 1 year after the ICS index date, but 47.3% of patients reported being bothered at least "quite a lot" by LAEs. Multivariate analysis indicated that unpleasant taste was significantly related to lower adherence based on the Morisky scale (P = .02). CONCLUSIONS: Patient-reported adherence and LAEs were higher than those measured from claims or medical records. Unpleasant taste seems to be associated with lower adherence based on the Morisky scale.

Quality of life of adults with workplace exacerbation of asthma.

OBJECTIVE: A cross-sectional study collecting demographic, work history, disease, and quality-of-life (QOL) data from adults with asthma was explored for a relationship between workplace exacerbation of asthma (WEA) and QOL. STUDY DESIGN AND SETTING: The study population of adults with asthma was drawn from adults affiliated with Fallon Community Health Plan, a health maintenance organization serving Massachusetts. RESULTS: The sample consisted of 598 adults with asthma. Based on univariate analyses, study participants with WEA had a statistically significant higher Total QOL score, indicating a worse quality of life, than participants whose asthma was not work-related (2.43 vs. 1.74, P < or = 0.001), and also higher scores on the instrument's four subscales for Breathlessness, Mood Disturbance, Social Disruptions, and Health Concerns. After controlling for covariates using multiple linear regression, the relationship between WEA and the Total QOL score was statistically significant (P = 0.0004) with a coefficient of 0.54. The coefficient for WEA was also statistically significant based on regression models for all the subscales with the exception of the Breathlessness score (P = 0.08). CONCLUSION: In summary, WEA was associated with a worse QOL. Ideally, employees and employers would work together to minimize the conditions at work that contribute to WEA, which should decrease the frequency of WEA and related degradation of QOL.

The validation of work-related self-reported asthma exacerbation.

OBJECTIVE: To determine the validity of work-related self-reported exacerbation of asthma using the findings from serial peak expiratory flow (PEF) measurements as the standard. METHODS: Adults with asthma treated in a health maintenance organisation were asked to conduct serial spirometry testing at home and at work for 3 weeks. Self-reported respiratory symptoms and medication use were recorded in two ways: a daily log completed concurrently with the serial PEF testing and a telephone questionnaire administered after the PEF testing. Three researchers evaluated the serial PEF records and judged whether a work relationship was evident. RESULTS: 95 of 382 (25%) working adults with asthma provided adequate serial PEF data, and 13 of 95 (14%) were judged to have workplace exacerbation of asthma (WEA) based on these data. Self-reported concurrent medication use was the most valid single operational definition, with a sensitivity of 62% and a specificity of 65%. CONCLUSIONS: A work-related pattern of self-reported asthma symptoms or medication use was usually not corroborated by serial PEF testing and failed to identify many people who had evidence of WEA based on the serial PEF measurements.

Case-by-case assessment of adult-onset asthma attributable to occupational exposures among members of a health maintenance organization.

OBJECTIVE: In a general population of employed persons with health insurance, what proportion of adult-onset asthma is caused by occupational exposures? METHOD: We conducted a 2-year prospective study to identify adult-onset asthma among health maintenance organization (HMO) members. Telephone interviews regarding occupational exposures, symptoms, medication use, and triggers were used to assess likelihood of work-related asthma for each case. Weighted estimating equations were used to adjust the proportion of asthma attributable to workplace exposures for factors associated with interview participation. RESULTS: Overall, 29% (95% confidence interval, 25-34%) of adult-onset asthma was attributable to workplace exposures; 26% (21-30%) and 22% (18-27%) of cases had asthma attributable to occupational irritant and sensitizer exposures, respectively. CONCLUSIONS: Occupational exposures, including irritants, are important causes of adult-onset asthma.

A longitudinal study of adult-onset asthma incidence among HMO members.

BACKGROUND: HMO databases offer an opportunity for community based epidemiologic studies of asthma incidence, etiology and treatment. The incidence of asthma in HMO populations and the utility of HMO data, including use of computerized algorithms and manual review of medical charts for determining etiologic factors has not been fully explored. METHODS: We identified adult-onset asthma, using computerized record searches in a New England HMO. Monthly, our software applied exclusion and inclusion criteria to identify an "at-risk" population and "potential cases". Electronic and paper medical records from the past year were then reviewed for each potential case. Persons with other respiratory diseases or insignificant treatment for asthma were excluded. Confirmed adult-onset asthma (AOA) cases were defined as those potential cases with either new-onset asthma or reactivated mild intermittent asthma that had been quiescent for at least one year. We validated the methods by reviewing charts of selected subjects rejected by the algorithm. RESULTS: The algorithm was 93 to 99.3% sensitive and 99.6% specific. Sixty-three percent (n = 469) of potential cases were confirmed as AOA. Two thirds of confirmed cases were women with an average age of 34.8 (SD 11.8), and 45% had no evidence of previous asthma diagnosis. The annualized monthly rate of AOA ranged from 4.1 to 11.4 per 1000 at-risk members. Physicians most commonly attribute asthma to infection (59%) and allergy (14%). New-onset cases were more likely attributed to infection, while reactivated cases were more associated with allergies. Medical charts included a discussion of work exposures in relation to asthma in only 32 (7%) cases. Twenty-three of these (72%) indicated there was an association between asthma and workplace exposures for an overall rate of work-related asthma of 4.9%. CONCLUSION: Computerized HMO records can be successfully used to identify AOA. Manual review of these records is important to confirm case status and is useful in evaluation of provider consideration of etiologies. We demonstrated that clinicians attribute most AOA to infection and tend to ignore the contribution of environmental and occupational exposures.