Increased disease severity during COVID-19 related hospitalization in black non-hispanic, hispanic and medicaid-insured young children.

Background: The COVID-19 pandemic has disproportionately affected marginalized groups in the United States. Although most children have mild or asymptomatic COVID-19, some experience severe disease and long-term complications. However, few studies have examined health disparities in severe COVID-19 outcomes among US children. Objective: To examine disparities in the clinical outcomes of infants and children aged <5 years hospitalized with COVID-19 by race/ethnicity and payer status. Methods: Children aged <5 years hospitalized with an admission diagnosis of COVID-19 (April 2021-February 2023) were selected from the PINC AI™ Healthcare Database. Hospital outcomes included length of stay (LOS), intensive care unit (ICU) admission, oxygen supplementation, invasive mechanical ventilation (IMV), and prolonged duration of each outcome. Multivariable logistic regression models compared hospitalization outcomes by race/ethnicity and payer status. Results: Among 10,190 children (mean age: 0.9 years, 56.5% male, 66.7% Medicaid-insured), race/ethnicity was distributed as follows: White non-Hispanic (35.1%), Hispanic (any or Unknown race; 28.3%), Black non-Hispanic (15.2%), Other race/ethnicity (8.9%) and Unknown (12.5%). Payer status varied by race/ethnicity. White non-Hispanic children had the highest proportion with commercial insurance (42.9%) while other racial/ethnic groups ranged between 13.8% to 26.1%. Black non-Hispanic children had the highest proportion with Medicaid (82.3%) followed by Hispanic children (76.9%). Black non-Hispanic children had higher odds of prolonged outcomes: LOS (adjusted odds ratio [aOR] = 1.20, 95% confidence interval [CI]:1.05-1.38), ICU days (aOR = 1.44, 95% CI: 1.07-1.93), and IMV days (aOR = 1.80, 95% CI: 1.09-2.97) compared to White non-Hispanic children. Similar patterns were observed for Hispanic and children of Other race/ethnicity. Medicaid-insured and children with other insurance had higher odds of prolonged LOS and oxygen days than commercially insured patients. Conclusion: There were disparities in clinical outcomes of COVID-19 by race/ethnicity and insurance type, particularly for prolonged-duration outcomes. Further research is required to fully comprehend the causes and consequences of these disparities and develop strategies to reduce them while ensuring equitable healthcare delivery.

Using a data-driven approach to define post-COVID conditions in US electronic health record data.

OBJECTIVE: To create a data-driven definition of post-COVID conditions (PCC) by directly measure changes in symptomatology before and after a first COVID episode. MATERIALS AND METHODS: Retrospective cohort study using Optum® de-identified Electronic Health Record (EHR) dataset from the United States of persons of any age April 2020-September 2021. For each person with COVID (ICD-10-CM U07.1 "COVID-19" or positive test result), we selected up to 3 comparators. The final COVID symptom score was computed as the sum of new diagnoses weighted by each diagnosis' ratio of incidence in COVID group relative to comparator group. For the subset of COVID cases diagnosed in September 2021, we compared the incidence of PCC using our data-driven definition with ICD-10-CM code U09.9 "Post-COVID Conditions", first available in the US October 2021. RESULTS: The final cohort contained 588,611 people with COVID, with mean age of 48 years and 38% male. Our definition identified 20% of persons developed PCC in follow-up. PCC incidence increased with age: (7.8% of persons aged 0-17, 17.3% aged 18-64, and 33.3% aged 65+) and did not change over time (20.0% among persons diagnosed with COVID in 2020 versus 20.3% in 2021). For cases diagnosed in September 2021, our definition identified 19.0% with PCC in follow-up as compared to 2.9% with U09.9 code in follow-up. CONCLUSION: Symptom and U09.9 code-based definitions alone captured different populations. Maximal capture may consider a combined approach, particularly before the availability and routine utilization of specific ICD-10 codes and with the lack consensus-based definitions on the syndrome.

Definition and measurement of post-COVID-19 conditions in real-world practice: a global systematic literature review.

Post-COVID-19 conditions (PCC) is an umbrella term that encompasses a range of signs, symptoms and conditions present weeks after the acute phase of a SARS-CoV-2 infection. This systematic literature review summarises the heterogeneous methodology used to measure PCC across real-world studies and highlights trends by region, age group, PCC follow-up period and data source. METHODS: Medline, EMBASE and the Cochrane Library were searched and supplemented with conference and grey literature searches. Eligible studies included individuals with (1) PCC or (2) a positive SARS-CoV-2 test or COVID-19 diagnosis who were followed over time. Included studies were published in English between 1 January 2020 and 14 November 2022. FINDINGS: Of 291 publications included, 175 (60%) followed individuals with confirmed COVID-19 over time for PCC and 116 (40%) used a prespecified PCC definition. There was substantial heterogeneity in study design, geography, age group, PCC conditions/symptoms assessed and their classification and duration of follow-up. Among studies using a prespecified PCC definition, author-defined criteria (51%) were more common than criteria recommended by major public health organisations (19%). Measurement periods for PCC outcomes from date of acute COVID-19 test were primarily 3 to <6 months (39.2%), followed by 6 to <12 months (27.5%) and <3 months (22.9%). When classified by organ/system, constitutional-related PCC were the most frequently assessed in adult (86%) and paediatric (87%) populations. Within constitutional symptoms, fatigue was most frequently assessed in adult (91.6%) and paediatric (95.0%) populations, followed by fever/chills (37.9% and 55%, respectively). CONCLUSIONS: PCC definitions are heterogenous across real-world studies, which limits reliable comparisons between studies. However, some similarities were observed in terms of the most frequently measured PCC-associated symptoms/conditions, which may aid clinical management of patients with PCC.CRD42022376111.

Persons diagnosed with COVID-19 in England in the Clinical Practice Research Datalink (CPRD): a cohort description.

OBJECTIVE: To create case definitions for confirmed COVID-19 diagnoses, COVID-19 vaccination status and three separate definitions of high risk of severe COVID-19, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID-19 epidemiology in England. DESIGN: Retrospective cohort study. SETTING: Electronic healthcare records from primary care (Clinical Practice Research Datalink, CPRD) linked to secondary care data (Hospital Episode Statistics) data covering 24% of the population in England. PARTICIPANTS: 2 271 072 persons aged 1 year and older diagnosed with COVID-19 in CPRD Aurum between 1 August 2020 and 31 January 2022. MAIN OUTCOME MEASURES: Age, sex and regional distribution of COVID-19 cases and COVID-19 vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalised for COVID-19 (primary diagnosis code of ICD-10 U07.1 'COVID-19'). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the UK (National Health Service Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritisation for vaccination). RESULTS: Compared with national estimates, CPRD case estimates under-represented older adults in both the primary care (age 65-84: 6% in CPRD vs 9% nationally) and hospitalised (31% vs 40%) cohorts, and over-represented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East vs 15% nationally). The majority of non-hospitalised cases and all hospitalised cases had not completed primary series vaccination. In primary care, persons meeting high-risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score. CONCLUSIONS: CPRD primary care data are a robust real-world data source and can be used for some COVID-19 research questions, however, limitations of the data availability should be carefully considered. Included in this publication are supplemental files for a total of over 28 000 codes to define each of three definitions of high risk of severe disease.

Health Care Resource Utilization and Costs Associated With COVID-19 Among Pediatrics Managed in the Community or Hospital Setting in England: A Population-based Cohort Study.

BACKGROUND: Although COVID-19 morbidity is significantly lower in pediatrics than in adults, the risk of severe COVID-19 may still pose substantial health care resource burden. This study aimed to describe health care resource utilization (HCRU) and costs associated with COVID-19 in pediatrics 1-17 years old in England. METHODS: A population-based retrospective cohort study of pediatrics with COVID-19 using Clinical Practice Research Datalink (CPRD Aurum) primary care data and, where available, linked Hospital Episode Statistics Admitted Patient Care secondary care data. HCRU and associated costs to the National Health Service were stratified by age, risk of severe COVID-19 and immunocompromised status, separately for those with and without hospitalization records (hospitalized cohort: COVID-19 diagnosis August 2020-March 2021; primary care cohort: COVID-19 diagnosis August 2020-January 2022). RESULTS: This study included 564,644 patients in the primary care cohort and 60 in the hospitalized cohort. Primary care consultations were more common in those 1-4 years of age (face-to-face: 4.3%; telephone: 6.0%) compared with those 5-11 (2.0%; 2.1%) and 12-17 years of age (2.2%; 2.5%). In the hospitalized cohort, mean (SD) length of stay was longer [5.0 (5.8) days] among those 12-17 years old (n = 24) than those 1-4 [n = 15; 1.8 (0.9) days] and 5-11 years old [n = 21; 2.8 (2.1) days]. CONCLUSIONS: Most pediatrics diagnosed with COVID-19 were managed in the community. However, hospitalizations were an important driver of HCRU and costs, particularly for those 12-17 years old. Our results may help optimize the management and resource allocation of COVID-19 in this population.

Healthcare resource utilisation and costs of hospitalisation and primary care among adults with COVID-19 in England: a population-based cohort study.

OBJECTIVES: To quantify direct costs and healthcare resource utilisation (HCRU) associated with acute COVID-19 in adults in England. DESIGN: Population-based retrospective cohort study using Clinical Practice Research Datalink Aurum primary care electronic medical records linked to Hospital Episode Statistics secondary care administrative data. SETTING: Patients registered to primary care practices in England. POPULATION: 1 706 368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13 105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1 693 263 within the primary care cohort indexed between August 2020 and January 2022. Patients with a COVID-19-related hospitalisation within 84 days of a positive test were included in the hospitalised cohort. MAIN OUTCOME MEASURES: Primary and secondary care HCRU and associated costs ≤4 weeks following positive COVID-19 test, stratified by age group, risk of severe COVID-19 and immunocompromised status. RESULTS: Among the hospitalised cohort, average length of stay, including critical care stays, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75-84 (£8942) and ≥85 years (£8835) than in those aged <50 years (£7703). While few (6.0%) patients in critical care required mechanical ventilation, its use was higher in older adults (50-74 years: 8.3%; <50 years: 4.3%). HCRU and associated costs were often greater in those at higher risk of severe COVID-19 than in the overall cohort, although minimal differences in HCRU were found across the three different high-risk definitions. Among the primary care cohort, general practitioner or nurse consultations were more frequent among older adults and the immunocompromised. CONCLUSIONS: COVID-19-related hospitalisations in older adults, particularly critical care stays, were the primary drivers of high COVID-19 resource use in England. These findings may inform health policy decisions and resource allocation in the prevention and management of COVID-19.

Estimated Effectiveness of Coadministration of the BNT162b2 BA.4/5 COVID-19 Vaccine With Influenza Vaccine.

Importance: No data comparing the estimated effectiveness of coadministering COVID-19 vaccines with seasonal influenza vaccine (SIV) in the community setting exist. Objective: To examine the comparative effectiveness associated with coadministering the BNT162b2 BA.4/5 bivalent mRNA COVID-19 vaccine (BNT162b2-biv [Pfizer BioNTech]) and SIV vs giving each vaccine alone. Design, Setting, and Participants: A retrospective comparative effectiveness study evaluated US adults aged 18 years or older enrolled in commercial health insurance or Medicare Advantage plans and vaccinated with BNT162b2-biv only, SIV only, or both on the same day between August 31, 2022, and January 30, 2023. Individuals with monovalent or another brand of mRNA bivalent COVID-19 vaccine were excluded. Exposure: Same-day coadministration of BNT162b2-biv and SIV; receipt of BNT162b2-biv only (for COVID-19-related outcomes) or SIV only (for influenza-related outcomes) were the comparator groups. For adults aged 65 years or older, only enhanced SIVs were included. Main Outcomes and Measures: COVID-19-related and influenza-related hospitalization, emergency department (ED) or urgent care (UC) encounters, and outpatient visits. Results: Overall, 3 442 996 individuals (57.0% female; mean [SD] age, 65 [16.7] years) were included. A total of 627 735 individuals had BNT162b2-biv and SIV vaccine coadministered, 369 423 had BNT162b2-biv alone, and 2 445 838 had SIV alone. Among those aged 65 years or older (n = 2 210 493; mean [SD] age, 75 [6.7] years; 57.9% female), the coadministration group had a similar incidence of COVID-19-related hospitalization (adjusted hazard ratio [AHR], 1.04; 95% CI, 0.87-1.24) and slightly higher incidence of emergency department or urgent care encounters (AHR, 1.12; 95% CI, 1.02-1.23) and outpatient visits (AHR, 1.06; 95% CI, 1.01-1.11) compared with the BNT162b2-biv-only group. Among individuals aged 18 to 64 years (n = 1 232 503; mean [SD] age, 47 [13.1] years; 55.4% female), the incidence of COVID-19-related outcomes was slightly higher among those who received both vaccines vs BNT162b2-biv alone (AHR point estimate range, 1.14-1.57); however, fewer events overall in this age group resulted in wider CIs. Overall, compared with those who received SIV alone, the coadministration group had a slightly lower incidence of most influenza-related end points (AHR point estimates 0.83-0.93 for those aged ≥65 years vs 0.76-1.08 for those aged 18-64 years). Negative control outcomes suggested residual bias and calibration of COVID-19-related and influenza-related outcomes with negative controls moved all estimates closer to the null, with most CIs crossing 1.00. Conclusions and Relevance: In this study, coadministration of BNT162b2-biv and SIV was associated with generally similar effectiveness in the community setting against COVID-19-related and SIV-related outcomes compared with giving each vaccine alone and may help improve uptake of both vaccines.

Clinical outcomes of COVID-19 and influenza in hospitalized children <5 years in the US.

Introduction: We compared hospitalization outcomes of young children hospitalized with COVID-19 to those hospitalized with influenza in the United States. Methods: Patients aged 0-<5 years hospitalized with an admission diagnosis of acute COVID-19 (April 2021-March 2022) or influenza (April 2019-March 2020) were selected from the PINC AI Healthcare Database Special Release. Hospitalization outcomes included length of stay (LOS), intensive care unit (ICU) admission, oxygen supplementation, and mechanical ventilation (MV). Inverse probability of treatment weighting was used to adjust for confounders in logistic regression analyses. Results: Among children hospitalized with COVID-19 (n = 4,839; median age: 0 years), 21.3% had an ICU admission, 19.6% received oxygen supplementation, 7.9% received MV support, and 0.5% died. Among children hospitalized with influenza (n = 4,349; median age: 1 year), 17.4% were admitted to the ICU, 26.7% received oxygen supplementation, 7.6% received MV support, and 0.3% died. Compared to children hospitalized with influenza, those with COVID-19 were more likely to have an ICU admission (adjusted odds ratio [aOR]: 1.34; 95% confidence interval [CI]: 1.21-1.48). However, children with COVID-19 were less likely to receive oxygen supplementation (aOR: 0.71; 95% CI: 0.64-0.78), have a prolonged LOS (aOR: 0.81; 95% CI: 0.75-0.88), or a prolonged ICU stay (aOR: 0.56; 95% CI: 0.46-0.68). The likelihood of receiving MV was similar (aOR: 0.94; 95% CI: 0.81, 1.1). Conclusions: Hospitalized children with either SARS-CoV-2 or influenza had severe complications including ICU admission and oxygen supplementation. Nearly 10% received MV support. Both SARS-CoV-2 and influenza have the potential to cause severe illness in young children.

Controlling for Differential Regression-To-The-Mean via Propensity Scores: A Simulation Study.

Purpose: Regression-to-the-mean (RTM) is a statistical phenomenon that may occur in epidemiologic studies where inclusion in the study cohort is contingent upon experiencing a laboratory/clinical measurement beyond a defined threshold. When differential across treatment groups, RTM could bias the final study estimate. This poses substantial challenges in observational studies that index patients upon experiencing extreme laboratory or clinical values. Our objective was to investigate propensity score-based methods as a tool for mitigating this source of bias via simulation. Methods: We simulated a noninterventional comparative effectiveness study, comparing treatment with romiplostim to standard-of-care therapies for immune thrombocytopenia (ITP), a disease characterized by low platelet counts. Platelet counts were generated from normal distributions according to the underlying ITP severity, a strong confounder of treatment and outcome. Patients were assigned treatment probabilities based upon ITP severity, which created varied levels of differential and non-differential RTM. Treatments were compared via the difference in median platelet counts during 23 weeks of follow-up. We calculated four summary metrics of the platelet counts measured prior to cohort entry and built six propensity score models to adjust for those variables. We adjusted for these summary metrics using inverse probability of treatment weights. Results: Across all simulated scenarios, propensity score adjustment reduced bias and increased precision of the treatment effect estimator. Adjusting for combinations of the summary metrics was most effective at reducing bias. Adjusting for the mean of prior platelet counts or the difference between the cohort-qualifying platelet count and the largest prior count eliminated the most bias when assessed individually. Conclusion: These results suggest that differential RTM could be reasonably addressed by propensity score models with summaries of historical laboratory values. This approach can be easily applied to any comparative effectiveness or safety study, though investigators should carefully consider the best summary metric for their data.

Coronavirus Disease 2019 Severity and Risk of Subsequent Cardiovascular Events.

BACKGROUND: Little is known about the relationship between coronavirus disease 2019 (COVID-19) severity and subsequent risk of experiencing a cardiovascular event (CVE) after COVID-19 recovery. We evaluated this relationship in a large cohort of United States adults. METHODS: Using a claims database, we performed a retrospective cohort study of adults diagnosed with COVID-19 between 1 April 2020 and 31 May 2021. We evaluated the association between COVID-19 severity and risk of CVE >30 days after COVID-19 diagnosis using inverse probability of treatment-weighted competing risks regression. Severity was based on level of care required for COVID-19 treatment: intensive care unit (ICU) admission, non-ICU hospitalization, or outpatient care only. RESULTS: A total of 1 357 518 COVID-19 patients were included (2% ICU, 3% non-ICU hospitalization, and 95% outpatient only). Compared to outpatients, there was an increased risk of any CVE for patients requiring ICU admission (adjusted hazard ratio [aHR], 1.80 [95% confidence interval {CI}, 1.71-1.89]) or non-ICU hospitalization (aHR, 1.28 [95% CI, 1.24-1.33]). Risk of subsequent hospitalization for CVE was even higher (aHRs, 3.47 [95% CI, 3.20-3.76] for ICU and 1.96 [95% CI, 1.85-2.09] for non-ICU hospitalized vs outpatient only). CONCLUSIONS: COVID-19 patients hospitalized or requiring critical care had a significantly higher risk of experiencing and being hospitalized for post-COVID-19 CVE than patients with milder COVID-19 who were managed solely in the outpatient setting, even after adjusting for differences between these groups. These findings underscore the continued importance of preventing severe acute respiratory syndrome coronavirus 2 infection from progressing to severe illness to reduce potential long-term cardiovascular complications.

Utilization of nonguideline concordant antibiotic treatment following acute otitis media in children in the United States.

PURPOSE: Acute otitis media (AOM) is a common indication for antibiotics in children. We sought to characterize the frequency of nonguideline concordant antibiotic therapy for AOM in the United States, by agent and duration. METHODS: Using national administrative claims data (2016-2019), we identified children aged 6 months to 17 years with an oral antibiotic dispensed within 3 days of a new diagnosis of suppurative AOM. Use of nonguideline concordant agents and durations, defined based on national treatment guidelines, were summarized by age, race, rurality, region, and insurance type. Subsequent oral antibiotic dispensing within the year after AOM diagnosis was also evaluated. We created sunburst diagrams to visualize longitudinal patterns of within-person antibiotic utilization for AOM, by agent and duration. RESULTS: We identified 789 424 eligible commercially-insured and 502 239 medicaid-insured children. Among commercially insured children, 35% received nonguideline concordant agents for AOM, including cefdinir (16%), amoxicillin-clavulanate (12%), and azithromycin (7%). Fewer children age <2 years received a nonguideline concordant initial agent (27%) compared to age ≥6 years (41%). More children age <2 years received three or more antibiotics over the following year (34% vs. 3% for children age ≥6 years). The most common treatment duration was 10 days for all ages; treatment duration for the initial antibiotic was nonguideline concordant for 95% and 89% of children age 2-5 years and ≥6 years, respectively. Patterns were similar for medicaid-insured children. CONCLUSIONS: Nonguideline concordant antibiotic use is common when treating AOM in children, including use of broad-spectrum agents and longer-than-recommended antibiotic durations.

Use of the Postacute Sequelae of COVID-19 Diagnosis Code in Routine Clinical Practice in the US.

Importance: A new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code (U09.9 Post COVID-19 condition, unspecified) was introduced by the Centers for Disease Control and Prevention on October 1, 2021. Objective: To examine the use of the U09.9 code and describe concurrently diagnosed conditions to understand physician use of this code in clinical practice. Design, Setting, and Participants: This cohort study of US patients with an ICD-10-CM code for post-COVID-19 condition used deidentified patient-level claims data aggregated by HealthVerity. Children and adolescents (aged 0-17 years) and adults (aged 18-64 and ≥65 years) with a post-COVID-19 condition code were identified between October 1, 2021, and January 31, 2022. To identify a prior COVID-19 diagnosis, 3 months of continuous enrollment (CE) before the post-COVID-19 diagnosis date was required. Main Outcomes and Measures: Presence of the ICD-10-CM U09.9 code. Results: There were 56 143 patients (7723 female patients [61.2%]; mean [SD] age, 47.6 [19.2] years) with a post-COVID-19 diagnosis code, with cases increasing in mid-December 2021 following the trajectory of the Omicron case wave by 3 to 4 weeks. The analysis cohort included 12 622 patients after the 3-month preindex CE criteria was applied. Among this cohort, the median (IQR) age was 49 (35-61) years; however, 1080 (8.6%) were pediatric patients. The U09.9 code was used most often in the outpatient setting, although 305 older adults (14.0%) were inpatients. Only 698 patients (5.5%) had at least 1 of the 5 codes listed as possible concurrent conditions in the coding guidance. Only 8879 patients (70.4%) had a documented acute COVID-19 diagnosis code (569 [52.7%] among children), and the median (IQR) time between acute COVID-19 and post-COVID-19 diagnosis codes was 56 (21-200) days. The most common concurrently coded conditions varied by age; children experienced COVID-19-like symptoms (eg, 207 [19.2%] had cough and 115 [10.6%] had breathing abnormalities), while 459 older adults aged 65 years or older (21.1%) experienced respiratory failure and 189 (8.7%) experienced viral pneumonia. Conclusions and Relevance: This retrospective cohort study found patients with a post-COVID-19 ICD-10-CM diagnosis code following the acute phase of COVID-19 disease among patients of all ages in clinical practice in the US. The use of the U09.9 code encompassed a wide range of conditions. It will be important to monitor how the use of this code changes as the pandemic continues to evolve.

COVID-19-associated hospitalizations among children less than 12 years of age in the United States.

OBJECTIVES: To describe the characteristics, healthcare resource use and costs associated with initial hospitalization and readmissions among pediatric patients with COVID-19 in the US. METHODS: Hospitalized pediatric patients, 0-11 years of age, with a primary or secondary discharge diagnosis code for COVID-19 (ICD-10 code U07.1) were selected from 1 April 2020 to 30 September 2021 in the US Premier Healthcare Database Special Release (PHD SR). Patient characteristics, hospital length of stay (LOS), in-hospital mortality, hospital costs, hospital charges, and COVID-19-associated readmission outcomes were evaluated and stratified by age groups (0-4, 5-11), four COVID-19 disease progression states based on intensive care unit (ICU) and invasive mechanical ventilation (IMV) usage, and three sequential calendar periods. Sensitivity analyses were performed using the US HealthVerity claims database and restricting the analyses to the primary discharge code. RESULTS: Among 4,573 hospitalized pediatric patients aged 0-11 years, 68.0% were 0-4 years and 32.0% were 5-11 years, with a mean (median) age of 3.2 (1) years; 56.0% were male, and 67.2% were covered by Medicaid. Among the overall study population, 25.7% had immunocompromised condition(s), 23.1% were admitted to the ICU and 7.3% received IMV. The mean (median) hospital LOS was 4.3 (2) days, hospital costs and charges were $14,760 ($6,164) and $58,418 ($21,622), respectively; in-hospital mortality was 0.5%. LOS, costs, charges, and in-hospital mortality increased with ICU admission and/or IMV usage. In total, 2.1% had a COVID-19-associated readmission. Study outcomes appeared relatively more frequent and/or higher among those 5-11 than those 0-4. Results using the HealthVerity data source were generally consistent with main analyses. LIMITATIONS: This retrospective administrative database analysis relied on coding accuracy and inpatient admissions with validated hospital costs. CONCLUSIONS: These findings underscore that children aged 0-11 years can experience severe COVID-19 illness requiring hospitalization and substantial hospital resource use, further supporting recommendations for COVID-19 vaccination.

Lessons Learned Using Real-World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia.

Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard-of-care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 109 /L (95% CI: -59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data.

Effectiveness and Safety of Romiplostim Among Patients with Newly Diagnosed, Persistent and Chronic Immune Thrombocytopenia in European Clinical Practice.

INTRODUCTION: Romiplostim has been approved in Europe since 2009 to treat patients with chronic primary immune thrombocytopenia (ITP). Using real-world data from seven European countries, we measured the effectiveness and safety outcomes within 24 weeks following romiplostim initiation by duration of ITP: less than 3 months ("newly diagnosed"), 3-12 months ("persistent"), and more than 12 months ("chronic"). METHODS: Adults with ITP and ≥ 1 romiplostim administration between 2009 and 2012 were included. Endpoints included durable platelet response, median platelet count, rescue therapy, bleeding and adverse events. We used inverse probability of censoring weighted estimators to estimate cumulative risk of each outcome. There were 64 newly diagnosed, 50 persistent, and 226 chronic ITP patients at romiplostim initiation. RESULTS: Durable platelet response at 24 weeks ranged from 32% [confidence interval (CI): 18-46%] in newly diagnosed patients to 53% (CI 37-68%) in persistent patients. Median platelet count during follow-up ranged from 88 (CI 80-96) × 109/L in chronic patients to 131 (CI 102-160) × 109/L in newly diagnosed patients. CONCLUSION: Regardless of ITP duration, over half of patients discontinued concomitant ITP medications. Few adverse events were observed. Although only approved for chronic patients, estimates of the romiplostim treatment effect were similar across patients being managed in European clinical practice, regardless of ITP duration at romiplostim initiation.

Who are we missing? Underrepresentation of data sources used for pharmacoepidemiology research in the United States.

PURPOSE: Research using healthcare databases often includes patients frequently excluded from clinical trials; yet it is not known whether commonly used data represents the overall population or specific sub-populations of interest. We aimed to examine population representativeness from data sources in recent research studies in the United States (US). METHODS: We identified data sources from abstracts accepted to the 34th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. The final sample included research studies using ≥1 data source from the US. We classified data sources broadly as claims, linkage, electronic health records (EHR), survey, distributed data network, and other. Studies using claims and EHRs were further classified into more specific categories, including special populations of interest (eg, children). RESULTS: We identified 356 abstracts. The majority used claims data (n = 201, 56.5%), followed by data linkages (n = 46, 12.9%), and EHR data (n = 39, 11.0%). Among EHR studies, most (n = 16, 41.0%) came from network data sources (eg, Kaiser Permanente). Almost half (49.4%) of claims-based studies used commercial claims data sources, followed by Medicare (22.1%), Medicaid (11.3%), and Medicare Supplemental (6.1%). Only 15% of studies included children in the study population (n = 53), with 8% focused on a pediatric topic (n = 27). CONCLUSIONS: We find that certain populations in the US are under-represented in pharmacoepidemiology, particularly Medicaid enrollees and children. Researchers should strive to utilize data sources that may be more representative of the US population, particularly vulnerable populations.

Lipid Testing Trends in the US Before and After the Release of the 2013 Cholesterol Treatment Guidelines.

BACKGROUND: The 2013 ACC/AHA cholesterol treatment guidelines removed the recommendation to treat adults at risk of cardiovascular disease to goal levels of low-density lipoprotein cholesterol (LDL-C). We anticipated that the frequency of LDL-C testing in clinical practice would decline as a result. To test this hypothesis, we evaluated the frequency of LDL-C testing before and after the guideline release. METHODS: We used the MarketScan® Commercial and Medicare Supplemental claims data (1/1/2007-12/31/2016) to identify four cohorts: 1) statin initiators (any intensity), 2) high-intensity statin initiators, 3) ezetimibe initiators, and 4) patients at very high cardiovascular risk (≥2 hospitalizations for myocardial infarction or ischemic stroke, with prevalent statin use). Rates of LDL-C testing by calendar year quarter were estimated for each cohort. To estimate rates in the absence of a guideline change, we fit a time-series model to the pre-guideline rates and extrapolated to the post-guideline period, adjusting for covariates, seasonality, and time trend. RESULTS: Pre- and post-guideline rates (LDL-C tests per 1,000 persons per quarter) were 248 and 235, respectively, for 3.9 million statin initiators; 263 and 246 for 1.3 million high-intensity statin initiators; 277 and 261 for 323,544 ezetimibe initiators; and 180 and 158 for 42,108 very high-risk patients. For all cohorts, observed post-guideline rates were similar to model-predicted rates. On average, the difference between observed and predicted rates was 8.5 for patients initiating any statin; 2.6 for patients initiating a high-intensity statin; 11.4 for patients initiating ezetimibe, and -0.5 for high-risk patients. CONCLUSION: We observed no discernible impact of the release of the 2013 ACC/AHA guidelines on LDL-C testing rates. Rather, there was a gradual decline in testing rates starting prior to the guideline change and continuing throughout the study period. Our findings suggest that the guidelines had little to no impact on use of LDL-C testing.

Using negative control outcomes to assess the comparability of treatment groups among women with osteoporosis in the United States.

PURPOSE: In contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications. METHODS: Using MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12-month cumulative risk difference (RD) using inverse probability of treatment and censoring weights. RESULTS: Among 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = -0.6%, 95% CI: -1.1, -0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations. CONCLUSIONS: Caution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies.

Comparative safety of high-dose versus standard-dose influenza vaccination in patients with end-stage renal disease.

BACKGROUND: High-dose influenza vaccine (HDV) is an alternative vaccination strategy in patients with end-stage renal disease (ESRD), though the safety of HDV has not been evaluated in this population. The objective of this study was to estimate the relative occurrence of adverse vaccine reactions in patients with ESRD following vaccination with HDV compared with standard-dose influenza vaccine (SDV). METHODS: Using data from the United States Renal Data System, we identified patients with ESRD aged ≥ 65 years at influenza vaccination during yearly influenza seasons from 2010 through 2016. Patients were followed after vaccination to observe serious (anaphylaxis, angioedema, seizure, encephalopathy, Guillain-Barré syndrome [GBS], and short-term, all-cause mortality) and milder (urticaria/hives, rash, pain in limb, cellulitis, myalgia/myositis, fever, nausea and vomiting, diarrhea, and syncope) adverse events. Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for HDV versus SDV were estimated with Cox proportional hazards models. RESULTS: Of 520,876 vaccinations observed (mean age = 74.7 years at vaccination; 63% white race), 7.4% were HDV. For serious events, the weighted HRs were null for seizure, encephalopathy, and mortality and inestimable due to too few cases for anaphylaxis, angioedema, and GBS. For milder vaccine reactions, the weighted HRs demonstrated generally increased risks in the HDV group, including rash (HR = 1.86; 95% CI, 1.34-2.57), diarrhea (HR = 1.26; 95% CI, 1.07-1.50), pain in limb (HR = 1.23; 95% CI, 1.12-1.34), and myalgia/myositis (HR = 1.16; 95% CI, 1.04-1.30). CONCLUSIONS: The risks of serious adverse events were low and similar between treatment groups; however, HDV recipients had increased risks of several milder adverse events compared with SDV recipients, consistent with clinical trial findings in the general population of older adults. These results add important information to inform the risk-benefit tradeoff of the use of HDV versus SDV in patients with ESRD.

Treatment Patterns Among Adults with Primary Immune Thrombocytopenia Diagnosed in Hematology Clinics in the United States.

PURPOSE: Patients with immune thrombocytopenia (ITP) have low platelet counts and an increased risk of bleeding. We described treatment patterns and clinical outcomes in routine practice in the United States (US). PATIENTS AND METHODS: Using electronic health record data from hematology/oncology clinics linked to administrative claims in the US, we studied 447 adults newly diagnosed with primary ITP from 2011 to 2016. Patients with a secondary cause of thrombocytopenia were excluded. The incidence of ITP treatment initiation, bleeding events, and rescue therapy use were estimated using competing risk models. RESULTS: At 1-year post-ITP diagnosis, 50% of patients were prescribed an oral corticosteroid, with the majority being prescribed immediately following diagnosis. Of the more common second-line options, rituximab use was the most frequent (1-year cumulative incidence: 16% [95% confidence interval: 12, 19]), followed by romiplostim (9% [7, 12] and eltrombopag (5% [3, 8]). Use of these drugs was similar at 2 years post-diagnosis. At 6 months post-ITP treatment initiation, the cumulative incidence of bleeding was similar among eltrombopag and romiplostim initiators (17% [6, 33] and 19% [9, 31], respectively) and was slightly lower in rituximab users (12% [6, 20]). However, during this same timeframe, rituximab users had a higher incidence of rescue therapy use (48% [36, 58] versus 29% [14, 46] in eltrombopag and 26% [14, 39] in romiplostim users). Although splenectomy was rare, at 6 months post-surgery nearly 20% had experienced a bleed and nearly 20% had required rescue. CONCLUSION: This study describes the health trajectory of adults with ITP who are managed in hematology clinics in the US and could inform the design of non-interventional studies of comparative effectiveness among treatments.