Centered Outcomes Research Institute Research Articles

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C.

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.

A Prognostic Tool for COVID-19 Decision Support: The Intermountain Risk Score Predicts Major Adverse Health Events in Patients Positive for COVID-19

Background: As the COVID-19 pandemic evolves, stratifying risk is increasingly important. The Intermountain Risk Score (IMRS) uses the complete blood count (CBC) and basic metabolic profile (BMP) as a first-line predictor of mortality and is widely validated. We hypothesized that IMRS predicts COVID-19 outcomes.Methods: Intermountain Healthcare patients aged ≥18 years were evaluated if they had CBC and BMP measured in 2019 and tested positive for COVID-19 in 2020. Viral RNA testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was conducted March 3 through November 2, 2020. IMRS used published sex-specific weightings and associations were evaluated for the composite of COVID-19 hospitalization or mortality.Findings: Among 3,883 patients, 8.2% were hospitalized, 1.6% died. Subjects with low, mild, moderate, and high-risk IMRS had the composite endpoint in 3.5% (52/1,502), 8.6% (108/1,256), 15.5% (152/979), and 28.1% (41/146), respectively. Versus low-risk, subjects in mild, moderate, and high-risk groups had HR=2.33 (95% CI: 1.67, 3.24), HR=4.01 (CI: 2.93, 5.50), and HR=8.34 (CI: 5.54, 12.57), respectively. Subjects aged Interpretation: IMRS, a simple risk score using very basic laboratory results, predicted COVID-19 hospitalization and mortality. This included important abilities to identify risk in younger adults with few diagnosed comorbidities and to predict risk prior to SARS-CoV-2 infection.Funding Statement: This study was funded by internal Intermountain departmental funds.Declaration of Interests: BDH, HTM, BSR, and JLA are inventors of clinical decision tools that are licensed to CareCentra and Alluceo. BDH is the PI of grants related to clinical decision tools that were funded by Intermountain Healthcare’s Foundry innovation program, the Intermountain Research and Medical Foundation, CareCentra, GlaxoSmithKline, and AstraZeneca. BDH is a member of the scientific advisory board of Labme.ai. KUK is PI of and BDH a co-investigator of a grant funded by the Patient- Centered Outcomes Research Institute (PCORI). IDP was supported by a grant from the National Institute of General Medical Sciences (K23GM129661). Outside the current work, IDP has received grant support from the National Institutes of Health, Centers for Disease Control, Janssen Pharmaceuticals, and Immunexpress Inc and funding to his institution from Regeneron Pharmaceuticals. The authors have no other potential conflicts of interest to report.Ethics Approval Statement: This study was approved as a data-only historical records review study with a waiver of consent by the Intermountain Healthcare Institutional Review Board.

Asthma Care and Out‐of‐Pocket Costs for Families of Children with Asthma in High‐Deductible Health Plans

Asthma is the most common pediatric chronic condition, with substantial morbidity, health care utilization, and costs. Enrollment has increased in high‐deductible health plans (HDHPs) that require families to assume greater responsibility for out‐of‐pocket (OOP) costs for asthma and other family health care needs, creating potential barriers to use of recommended asthma controller medications. Data are limited on children in HDHPs. We sought to examine changes in asthma controller medication use, exacerbations, and OOP costs for children with asthma enrolling in HDHPs and whether this varies for children in families with multiple competing health care needs.We measured OOP costs for children’s asthma care and for care for all family members in the same insurance plan, and children’s rates of 30‐day fills for asthma controller medications and exacerbations (measured by oral steroid bursts). We controlled for the number of chronic conditions among all family members, defining high illness burden as presence of ≥ 4 chronic conditions. We used a difference‐in‐differences design with models controlling for individual and employer‐level characteristics, and tested for effect modification by family illness burden using a three‐way interaction.We identified children aged 4‐17 years with persistent asthma with employer coverage in a large commercial and Medicare Advantage claims database between 2002 and 2014. We selected children with 12 months of enrollment in a plan with low or no deductible (“traditional plan”) before either switching to a HDHP or staying in the traditional plan (controls) for another 12 months. The sample included only employers offering a single deductible level.The sample included 4708 children who switched to HDHPs and 47,414 who remained in traditional plans. Children switching to HDHPs had higher OOP costs for asthma care than controls (difference‐in‐differences (DiD) $21; 95% confidence interval (CI) $14‐$28), a relative increase of 21.5% (13.5%‐29.4%). Their families had greater OOP spending (DiD $605; 95% CI $505‐$704), a relative increase of 26.8% (21.8%‐31.8%). Children in HDHPs had a relative decrease in 30‐day controller medication fills (−7.4%, 95% CI −12.0% to −2.8%) but no relative difference in exacerbations (1.3%, 95% CI −10.5% to 13.2%). There was no evidence of effect modification by family illness burden.This study found increases in OOP asthma costs for children in HDHPs and lower rates of controller medication use, but no differences in asthma exacerbations. Families experienced an increase in total OOP costs in HDHPs, although this may have been offset by lower premiums. The lack of difference in the impact of HDHP enrollment on children’s controller use in families with high illness burden suggests these families are not trading off OOP spending on children’s asthma care for OOP spending on other care.Although families face increased OOP costs in HDHPs for children’s asthma and other health care, the impact on asthma medication use and exacerbations may be moderated by the fact that medications were subject to copayments rather than the deductible in most plans in our study. Value‐based insurance designs that exempt important pediatric health services from the deductible may help reduce adverse outcomes in HDHPs.Patient‐Centered Outcomes Research Institute.

Patients Driving the Clinical Trial Designs – Democracy in Clinical Research

Many of the clinical trials remain inefficient owing to the low retention rate, and an impact on the power of the study. In addition, regulatory bodies recommend including the patients' experience, especially, patient-reported outcomes, while making clinical decisions, and approvals. Patient centricity has reached the stage where patients are both willing and required to participate in clinical trial designs, regulatory review and experts on other panels. Efforts are being made in the right direction and there are multiple aspects that have been or are being addressed. The current article focuses on how to include patients in clinical trial designs, the benefits, challenges, and solutions. This means patients who were merely the participants until now, they will be the drivers of trials now, and hence the clinical trials will be more efficient and productive. There is a drive to enhance patients' participation in clinical trial designs, especially, visits, efficacy outcomes and their expectations with the treatment. Patients want to remain informed, right from before participation to the completion of the trial. Patients are now an important part of regulatory review, as apparent from recent initiatives by the FDA and EMA. This will enhance patients' awareness, and bring ownership and transparency. Various patient organizations, advocacy groups have made some great suggestions and taken initiatives in this direction. Clinical Trials Transformation Initiative, European Patient's Academy on Therapeutic Innovation, and Patient- Centered Outcomes Research Institute are a few key initiatives. However, there is a set of challenges emanating from the complexity of trials, associated with unique mechanism of action of drugs, their efficacy and safety profiles, which has to be dealt with properly. Overall, the pharma domain is at the verge of putting the patient in the spotlight, to achieve a near-real democracy, where the clinical research is the by the patient, for the patient, and, of the patient.

1107Reduction of cardiovascular disease risk factors in rural, medically under-served, socioeconomically distressed, high-risk individuals: a randomized controlled trial

Abstract Background People in rural, socioeconomically distressed areas of the world suffer from marked cardiovascular disease (CVD) disparities. Despite the CVD disparities seen in rural, distressed areas, efforts directed toward CVD risk reduction and prevention are limited. We conducted a randomized, controlled trial to determine the effect of an individualized, culturally appropriate, self-care CVD risk reduction intervention (HeartHealth) compared to referral of patients to a primary care provider for usual care on the following CVD risk factors: tobacco use, blood pressure, lipid profile, body mass index, depressive symptoms, and physical activity levels. Methods The study protocol and intervention were developed with a community advisory board of lay community members, business owners, local government officials, church leaders, and healthcare providers. We enrolled 355 individuals living in Appalachia with two or more CVD risk factors. The intervention was delivered in person to groups of 10 or fewer individuals over 12 weeks. In the first session, participants chose their CVD risk reduction goals. HeartHealth was designed to provide participants with self-care skills targeting CVD risk reduction while reducing barriers to risk reduction found in austere rural environments. The targeted CVD risk factors were measured at baseline and 4 and 12 months post-intervention. Repeated measures data were analyzed with mixed models. Results More individuals in the intervention group compared to the control group met their lifestyle change goal (50% vs 16%, p<0.001). The intervention produced a positive impact on systolic blood pressure (p=0.002, time X group effect), diastolic blood pressure (p=0.001, time x group), total cholesterol (p=0.026, time x group), high density lipoprotein (p=0.002, time x group), body mass index (p=0.017, time x group), smoking status (p=0.01), depressive symptoms (p=0.01, time x group), and steps per day (p=0.001, time x group). Compared to the control group, improvement was seen at 4 months in these risk factors and the positive changes were maintained through 12 months. There were no differences seen across time by group in low density lipoprotein or triglyceride levels. Conclusion Interventions like HeartHealth that focus on self-care and that are derived in collaboration with the community of interest are effective in medically underserved, socioeconomically distressed rural areas. Acknowledgement/Funding Patient Centered Outcomes Research Institute