Improving COVID-19 Disease Severity Surveillance Measures: Statewide Implementation Experience.

Measurement of the burden of COVID-19 on U.S. hospitals has been an important element of the public health response to the pandemic. However, because of variation in testing density and policies, the metric is not standardized across facilities. Two types of burdens exist, one related to the infection control measures that patients who test positive for SARS-CoV-2 require and one from the care of severely ill patients receiving treatment of COVID-19. With rising population immunity from vaccination and infection, as well as the availability of therapeutics, severity of illness has declined. Prior research showed that dexamethasone administration was highly correlated with other disease severity metrics and sensitive to the changing epidemiology associated with the emergence of immune-evasive variants.On 10 January 2022, the Massachusetts Department of Public Health began requiring hospitals to expand surveillance to include reports of both the total number of "COVID-19 hospitalizations" daily and the number of inpatients who received dexamethasone at any point during their hospital stay. All 68 acute care hospitals in Massachusetts submitted COVID-19 hospitalization and dexamethasone data daily to the Massachusetts Department of Public Health over a 1-year period. A total of 44 196 COVID-19 hospitalizations were recorded during 10 January 2022 to 9 January 2023, of which 34% were associated with dexamethasone administration. The proportion of patients hospitalized with COVID-19 who had received dexamethasone was 49.6% during the first month of surveillance and decreased to a monthly average of approximately 33% by April 2022, where it has remained since (range, 28.7% to 33%).Adding a single data element to mandated reporting to estimate the frequency of severe COVID-19 in hospitalized patients was feasible and provided actionable information for health authorities and policy makers. Updates to surveillance methods are necessary to match data collection with public health response needs.

Factors associated with the speed and scope of diffusion of COVID-19 therapeutics in a nationwide healthcare setting: a mixed-methods investigation.

BACKGROUND: The global COVID-19 pandemic is an opportunity to evaluate factors associated with high levels of adoption of different therapeutics in a real-world setting. The aim of this nationwide, retrospective cohort study was to evaluate the diffusion and adoption of novel therapeutics with an emerging evidence basis and to identify factors that influenced physicians' treatment decisions. METHODS: Cohort creation: A cohort of Veteran patients with a microbiologically confirmed diagnosis of SARS-CoV2 were identified, and cases were classified by disease severity (outpatient, inpatient with mild and severe disease, intensive care unit ICU]). After classification of disease severity, the proportion of cases (outpatients) and admissions (inpatients) in each category receiving each type of medication were plotted as a function of time. Identification of milestones and guidance changes: Key medications used for the management of COVID-19 milestones in the release of primary research results in various forms (e.g. via press release, preprint or publication in a traditional medical journal), policy events and dates of key guidelines were identified and plotted as a timeline. After a timeline was created, time points were compared to changes in medication use, and factors potentially impacting the magnitude (i.e. proportion of patients who received the treatment) and the speed (i.e. the slope of the change in use) of practice changes were evaluated. RESULTS: Dexamethasone and remdesivir, the first two medications with clinical trial data to support their use, underwent the most rapid, complete and sustained diffusion and adoption; the majority of practice changes occurred after press releases and preprints were available and prior to guideline changes, although some additional uptake occurred following guideline updates. Medications that were not "first in class", that were identified later in the pandemic, and that had higher perceived risk had slower and less complete uptake regardless of the strength and quality of the evidence supporting the intervention. CONCLUSIONS: Our findings suggest that traditional and social media platforms and preprint releases were major catalysts of practice change, particularly prior to the identification of effective treatments. The "first available treatment in class" impact appeared to be the single most important factor determining the speed and scope of diffusion.

Factors Associated With Severe COVID-19 Among Vaccinated Adults Treated in US Veterans Affairs Hospitals.

Importance: With a large proportion of the US adult population vaccinated against SARS-CoV-2, it is important to identify who remains at risk of severe infection despite vaccination. Objective: To characterize risk factors for severe COVID-19 disease in a vaccinated population. Design, Setting, and Participants: This nationwide, retrospective cohort study included US veterans who received a SARS-CoV-2 vaccination series and later developed laboratory-confirmed SARS-CoV-2 infection and were treated at US Department of Veterans Affairs (VA) hospitals. Data were collected from December 15, 2020, through February 28, 2022. Exposures: Demographic characteristics, comorbidities, immunocompromised status, and vaccination-related variables. Main Outcomes and Measures: Development of severe vs nonsevere SARS-CoV-2 infection. Severe disease was defined as hospitalization within 14 days of a positive SARS-CoV-2 diagnostic test and either blood oxygen level of less than 94%, receipt of supplemental oxygen or dexamethasone, mechanical ventilation, or death within 28 days. Association between severe disease and exposures was estimated using logistic regression models. Results: Among 110 760 patients with infections following vaccination (97 614 [88.1%] men, mean [SD] age at vaccination, 60.8 [15.3] years; 26 953 [24.3%] Black, 11 259 [10.2%] Hispanic, and 71 665 [64.7%] White), 10 612 (9.6%) had severe COVID-19. The strongest association with risk of severe disease after vaccination was age, which increased among patients aged 50 years or older with an adjusted odds ratio (aOR) of 1.42 (CI, 1.40-1.44) per 5-year increase in age, such that patients aged 80 years or older had an aOR of 16.58 (CI, 13.49-20.37) relative to patients aged 45 to 50 years. Immunocompromising conditions, including receipt of different classes of immunosuppressive medications (eg, leukocyte inhibitor: aOR, 2.80; 95% CI, 2.39-3.28) or cytotoxic chemotherapy (aOR, 2.71; CI, 2.27-3.24) prior to breakthrough infection, or leukemias or lymphomas (aOR, 1.87; CI, 1.61-2.17) and chronic conditions associated with end-organ disease, such as heart failure (aOR, 1.74; CI, 1.61-1.88), dementia (aOR, 2.01; CI, 1.83-2.20), and chronic kidney disease (aOR, 1.59; CI, 1.49-1.69), were also associated with increased risk. Receipt of an additional (ie, booster) dose of vaccine was associated with reduced odds of severe disease (aOR, 0.50; CI, 0.44-0.57). Conclusions and Relevance: In this nationwide, retrospective cohort of predominantly male US Veterans, we identified risk factors associated with severe disease despite vaccination. Findings could be used to inform outreach efforts for booster vaccinations and to inform clinical decision-making about patients most likely to benefit from preexposure prophylaxis and antiviral therapy.

Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial.

IMPORTANCE AND OBJECTIVE: The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. DESIGN: Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. SETTING: 5 VA Medical Centers. PARTICIPANTS: Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. INTERVENTIONS: Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. MAIN OUTCOMES AND MEASURES: The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. RESULTS: Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. CONCLUSIONS AND RELEVANCE: This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. TRIAL REGISTRATION: Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Impact of prior SARS-CoV-2 infection on incidence of hospitalization and adverse events following mRNA SARS-CoV-2 vaccination: A nationwide, retrospective cohort study.

BACKGROUND: Previous studies evaluated the SARS-CoV-2 vaccine safety or compared adverse events following vaccination to those from infection. Limited data about the impact of prior infection on post-vaccine adverse events are available. The objective of this study was to evaluate the impact of prior SARS-CoV-2 infection on outcomes shortly after vaccination using a longitudinal design. METHODS: Nationwide, multicenter, retrospective cohort study of hospitalization, death, and pre-specified adverse event rates among Veterans who received mRNA vaccines within the Veterans Health Administration between 12/11/2020 and 8/31/2021. Daily incidence rates were compared before and after vaccine doses, stratified by history of microbiologically-confirmed SARS-CoV-2. RESULTS: 3,118,802 patients received a first dose and 2,979,326 a second, including 102,829 with a history of SARS-CoV-2 infection. Daily incident hospitalization rates were unchanged before and after the second dose among patients without previous infection (28.8/100,000 post-dose versus 28.6/100,000 pre-dose, p = 0.92). In previously-infected patients, the hospitalization rate increased above baseline one day following vaccination (158.2/100,000 after dose 2 versus 57.3/100,000 pre-dose, p < 0.001), then returned to baseline. Chart review indicated vaccine side effects, such as fever, constitutional symptoms, weakness, or falls, as the definite (39%) or possible (18%) cause of hospitalization. Affected patients had mean age 75, and 90% had at least one serious comorbidity. Hospitalizations were brief (median 2 days), with rapid return to baseline health. Worse baseline health among previously-infected patients prevented conclusions about mortality risk. CONCLUSIONS: Two-dose mRNA vaccine regimens are safe in a population with many comorbidities. Transient increased risks of hospitalization were identified among patients with prior SARS-CoV-2, absolute risk ∼1:1000. Findings support additional study regarding the optimal dosing schedule in this population. FUNDING: None.

Reconsidering 'minimal risk' to expand the repertoire of trials with waiver of informed consent for research.

BACKGROUND: Progress in therapeutic research is slowed by the regulatory burden of clinical trials, which provide the best evidence for guiding treatment. There is a long delay from evidence generation to adoption, highlighting the need for designs that link evidence generation to implementation. OBJECTIVE: To identify clinical trial designs that confer minimal risk above that inherent in clinical care, to obviate the need for cumbersome consenting processes to enrol patients in prospective clinical research studies. These designs extend the scope of the Learning Healthcare System, a framework for leveraging retrospective 'big data' to advance clinical research, to include data collected from prospective controlled trials. SUMMARY: Pragmatic trials may use simplified eligibility criteria, unblinded interventions and objective outcome measures that can all be monitored through the electronic health records (EHR), to reduce costs and speed study conduct. Most pragmatic trials continue to suffer from substantial regulatory burden. Written consent to participate in research can be waived only if the research produces minimal risk above what is encountered in everyday life. However, the 'consent' processes for prescribing Federal Drug Administration-approved medications in clinical medicine are informal, even when they involve decisions of uncertain benefit and higher levels of risk. We propose that trial designs that mimic clinical decision-making in areas of uncertainty (clinical equipoise) and in which no data are generated outside of usual care (ideally by EHR embedding) confer minimal additional risk. Trial designs meeting this standard could, therefore, be conducted with minimal documentation of consent, even when interventions contain different risks. To align with risk encountered in clinical practice, allocation to treatment arms should change (adaptive randomisation) as data are collected and analysed. Embedding of informatics tools into the EHR has the additional benefit that, as adaptive randomisation progresses, evidence-generation transitions into implementation via decision-support tools-the ultimate realisation of the Learning Healthcare System.