The Effect of Adding Physician Recommendation in Digitally-Enabled Outreach for COVID-19 Vaccination in Socially/Economically Disadvantaged Populations Subtitle: A Randomized Controlled Trial (preprint)

Introduction: People from backgrounds that are economically/socially disadvantaged experienced disproportionately high COVID-19 death rates and had lower vaccination rates. Effective outreach strategies for increasing vaccine uptake during the pandemic are not fully known. Among patients receiving care at a Federally Qualified Health Center, we tested whether community engaged digitally-enabled outreach increased COVID vaccine uptake. Study Design, Setting, and Participants: A 3-parallel-arm randomized controlled trial with a hybrid effectiveness-implementation design was conducted among patients ≥18 years old on study enrollment during 2021 with 1,650 assigned in 3:10:20 ratio; 2,328 were later selected for two subsequent implementation rounds. Interventions: From April 13 to June 10, 2021, patients were proactively sent a text-messaging invitation to make an appointment for vaccination as part of the routine practice (Arm 1, n=150) with added personalized clinician recommendation alone (Arm 2, n=500) or with an explicit nudge for answers to frequently asked questions (Arm 3, n=1,000). Further implementation used messaging addressing vaccine hesitancy (n=1,323) or adverse reactions to vaccines (n=1,005). Main Outcomes and Measures: The primary outcome was the completion of the first SARS-Cov-2 vaccine dose determined at 14, 30 and 90 days after outreach. Results: Of 1,650 patients in effectiveness Arms, 61% was female. Vaccination rates for Arms 1, 2, and 3, were 6% (n=9), 5.4% (n=27) and 3.3% (n=33) at 14 days, and 11.5% (n=17), 11.6% (n=58), and 8.5% (n=85) at 90 days, respectively, which were similar in pairwise comparisons. At 90 days, vaccination rates were similar across the two implementation rounds (3.9% vs. 3.6%) and were similar to the rate (3.3%) among patients who were not selected for intervention arms or implementation rounds (n=8,671). Conclusions: Digitally-enabled outreach that included SMS messaging outreach augmented with clinician recommendations did not improve COVID-19 vaccination rates. Trial Registration: This study is registered at ClinicalTrails.gov Identifier: NC-T04952376

Researching COVID to enhance recovery (RECOVER) adult study protocol: Rationale, objectives and design (preprint)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged [≥]18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.

T-cell cellular stress and reticulocyte signatures, but not loss of naive T lymphocytes, characterize severe COVID-19 in older adults (preprint)

In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old. To understand age-specific immune pathobiology of COVID-19 we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naive T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.

Serum Neurofilament Light is Elevated in COVID-19 Positive Adults in the ICU and is Associated with Co-Morbid Cardiovascular Disease, Neurological Complications, and Acuity of Illness (preprint)

In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 were COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6+163 pg/ml) compared to COVID-neg ICU patients (19.3+5.6 pg/ml), Welchs t-test, p =.01 and healthy controls (12.3+3.1 pg/ml), Welchs t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6+.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.

Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure. (preprint)

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.