Immune and metabolic markers for identifying and investigating severe Coronavirus disease and Sepsis in children and young people (pSeP/COVID ChYP study): protocol for a prospective cohort study.

INTRODUCTION: Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system's biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases. More recently, specific gene signatures were identified to discriminate between COVID-19 and its associated inflammatory sequelae. Through the current prospective cohort study, we aim to evaluate immune and metabolic blood markers which discriminate between sepses (including COVID-19) from other acute illnesses in critically unwell children and young persons, up to 18 years of age. METHODS AND ANALYSIS: We describe a prospective cohort study for comparing the immune and metabolic whole-blood markers in patients with sepsis, COVID-19 and other illnesses. Clinical phenotyping and blood culture test results will provide a reference standard to evaluate the performance of blood markers from the research sample analysis. Serial sampling of whole blood (50 µL each) will be collected from children admitted to intensive care and with an acute illness to follow time dependent changes in biomarkers. An integrated lipidomics and RNASeq transcriptomics analyses will be conducted to evaluate immune-metabolic networks that discriminate sepsis and COVID-19 from other acute illnesses. This study received approval for deferred consent. ETHICS AND DISSEMINATION: The study has received research ethics committee approval from the Yorkshire and Humber Leeds West Research Ethics Committee 2 (reference 20/YH/0214; IRAS reference 250612). Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites. TRIAL REGISTRATION NUMBER: NCT04904523.

Factors Associated With Mortality Among Homeless Older Adults in California: The HOPE HOME Study.

Importance: The population of homeless older adults is growing and experiences premature mortality. Little is known about factors associated with mortality among homeless older adults. Objective: To identify the prevalence and factors associated with mortality in a cohort of homeless adults 50 years and older. Design, Setting, and Participants: In this prospective cohort study (Health Outcomes in People Experiencing Homelessness in Older Middle Age [HOPE HOME]), 450 adults 50 years and older who were homeless at baseline were recruited via venue-based sampling in Oakland, California. Enrollment occurred in 2 phases, from July 2013 to June 2014 and from August 2017 to July 2018, and participants were interviewed at 6-month intervals. Exposures: Baseline and time-varying characteristics, including sociodemographic factors, social support, housing status, incarceration history, chronic medical conditions, substance use, and mental health problems. Main Outcomes and Measures: Mortality through December 31, 2021, based on state and local vital records information from contacts and death certificates. All-cause mortality rates were compared with those in the general population from 2014 to 2019 using age-specific standardized mortality ratios with 95% CIs. Results: Of the 450 included participants, median (IQR) age at baseline was 58.1 (54.5-61.6) years, 107 (24%) were women, and 360 (80%) were Black. Over a median (IQR) follow-up of 55 (38-93) months, 117 (26%) participants died. Median (IQR) age at death was 64.6 (60.3-67.5) years. In multivariable analyses, characteristics associated with mortality included a first episode of homelessness at 50 years and older (adjusted hazard ratio [aHR], 1.62; 95% CI, 1.13-2.32), homelessness (aHR, 1.82; 95% CI, 1.23-2.68) or institutionalization (aHR, 6.36; 95% CI, 3.42-11.82) at any follow-up compared with being housed, fair or poor self-rated health (aHR, 1.64; 95% CI, 1.13-2.40), and diabetes (aHR, 1.55; 95% CI, 1.06-2.26). Demographic characteristics, substance use problems, and mental health problems were not independently associated. All-cause standardized mortality was 3.5 times higher (95% CI, 2.5-4.4) compared with adults in Oakland. The most common causes of death were heart disease (n = 17 [14.5%]), cancer (n = 17 [14.5%]), and drug overdose (n = 14 [12.0%]). Conclusions and Relevance: The cohort study found that premature mortality was common among homeless older adults and associated factors included late-life homelessness and ongoing homelessness. There is an urgent need for policy approaches to prevent and end homelessness among older adults in the US.

Analysis of Emergency Department Encounters Among High Users of Health Care and Social Service Systems Before and During the COVID-19 Pandemic.

Importance: Although the general US population had fewer emergency department (ED) visits during the COVID-19 pandemic, patterns of use among high users are unknown. Objectives: To examine natural trends in ED visits among high users of health and social services during an extended period and assess whether these trends differed during COVID-19. Design, Setting, and Participants: This retrospective cohort study combined data from 9 unique cohorts, 1 for each fiscal year (July 1 to June 30) from 2012 to 2021, and used mixed-effects, negative binomial regression to model ED visits over time and assess ED use among the top 5% of high users of multiple systems during COVID-19. Data were obtained from the Coordinated Care Management System, a San Francisco Department of Public Health platform that integrates medical and social information with service use. Exposures: Fiscal year 2020 was defined as the COVID-19 year. Main Outcomes and Measures: Measured variables were age, gender, language, race and ethnicity, homelessness, insurance status, jail health encounters, mental health and substance use diagnoses, and mortality. The main outcome was annual mean ED visit counts. Incidence rate ratios (IRRs) were used to describe changes in ED visit rates both over time and in COVID-19 vs non-COVID-19 years. Results: Of the 8967 participants, 3289 (36.7%) identified as White, 3005 (33.5%) as Black, and 1513 (16.9%) as Latinx; and 7932 (88.5%) preferred English. The mean (SD) age was 46.7 (14.2) years, 6071 (67.7%) identified as men, and 7042 (78.5%) had experienced homelessness. A statistically significant decrease was found in annual mean ED visits among high users for every year of follow-up until year 8, with the largest decrease occurring in the first year of follow-up (IRR, 0.41; 95% CI, 0.40-0.43). However, during the pandemic, ED visits decreased 25% beyond the mean reduction seen in prepandemic years (IRR, 0.75; 95% CI, 0.72-0.79). Conclusions and Relevance: In this study, multiple cohorts of the top 5% of high users of multiple health care systems in San Francisco had sustained annual decreases in ED visits from 2012 to 2021, with significantly greater decreases during COVID-19. Further research is needed to elucidate pandemic-specific factors associated with these findings and understand how this change in use was associated with health outcomes.

Association of Shelter-in-Place Hotels With Health Services Use Among People Experiencing Homelessness During the COVID-19 Pandemic.

Importance: Some jurisdictions used hotels to provide emergency noncongregate shelter and support services to reduce the risk of COVID-19 infection among people experiencing homelessness (PEH). A subset of these shelter-in-place (SIP) hotel guests were high users of acute health services, and the association of hotel placement with their service use remains unknown. Objective: To evaluate the association of SIP hotel placements with health services use among a subset of PEH with prior high acute health service use. Design, Setting, and Participants: This study used a matched retrospective cohort design comparing health services use between PEH with prior high service use who did and did not receive a SIP hotel placement, from April 2020 to April 2021. The setting was 25 SIP hotels in San Francisco, California, with a daily capacity of 2500 people. Participants included PEH who were among the top 10% high users of acute medical, mental health, and substance use services and who had 3 or more emergency department (ED) visits in the 9 months before the implementation of the SIP hotel program. Data analysis for this study was performed from February 2021 to May 2022. Exposures: SIP hotel placement with on-site supportive services. Main Outcomes and Measures: The primary outcomes were ED visits, hospitalizations and bed days, psychiatric emergency visits, psychiatric hospitalizations, outpatient mental health and substance use visits, and outpatient medical visits. Results: Of 2524 SIP guests with a minimum of 90-day stays, 343 (13.6%) met criteria for high service use. Of 686 participants with high service use (343 SIP group; 343 control), the median (IQR) age was 54 (43-61) years, 485 (70.7%) were male, 283 (41.3%) were Black, and 337 (49.1%) were homeless for more than 10 years. The mean number of ED visits decreased significantly in the high-user SIP group (1.84 visits [95% CI, 1.52-2.17 visits] in the 90 days before SIP placement to 0.82 visits [95% CI, 0.66-0.99 visits] in the 90 days after SIP placement) compared with high-user controls (decrease from 1.33 visits [95% CI, 1.39-1.58 visits] to 1.00 visits [95% CI, 0.80-1.20 visits]) (incidence rate ratio [IRR], 0.60; 95% CI, 0.47-0.75; P < .001). The mean number of hospitalizations decreased significantly from 0.41 (95% CI, 0.30-0.51) to 0.14 (95% CI, 0.09-0.19) for SIP guests vs 0.27 (95% CI, 0.19-0.34) to 0.22 (95% CI, 0.15-0.29) for controls (IRR, 0.41; 95% CI, 0.27-063; P < .001). Inpatient hospital days decreased significantly from a mean of 4.00 (95% CI, 2.44-5.56) to 0.81 (95% CI, 0.40-1.23) for SIP guests vs 2.27 (95% CI, 1.27-3.27) to 1.85 (95% CI, 1.06-2.65) for controls (IRR, 0.25; 95% CI, 0.12-0.54; P < .001), as did psychiatric emergency visits, from a mean of 0.03 (95% CI, 0.01-0.05) to 0.01 (95% CI, 0.00-0.01) visits for SIP guests vs no change in the control group (IRR, 0.25; 95% CI, 0.11-0.51; P < .001). Conclusions and Relevance: These findings suggest that in a population of PEH with high use of acute health services, SIP hotel placement was associated with significantly reduced acute care use compared with high users without a placement.

Implementation of rapid and frequent SARS-CoV2 antigen testing and response in congregate homeless shelters.

BACKGROUND: People experiencing homelessness who live in congregate shelters are at high risk of SARS-CoV2 transmission and severe COVID-19. Current screening and response protocols using rRT-PCR in homeless shelters are expensive, require specialized staff and have delays in returning results and implementing responses. METHODS: We piloted a program to offer frequent, rapid antigen-based tests (BinaxNOW) to residents and staff of congregate-living shelters in San Francisco, California, from January 15th to February 19th, 2021. We used the Reach-Effectiveness-Adoption-Implementation-Maintenance (RE-AIM) framework to evaluate the implementation. RESULTS: Reach: We offered testing at ten of twelve eligible shelters. Shelter residents and staff had variable participation across shelters; approximately half of eligible individuals tested at least once; few tested consistently during the study. Effectiveness: 2.2% of participants tested positive. We identified three outbreaks, but none exceeded 5 cases. All BinaxNOW-positive participants were isolated or left the shelters. Adoption: We offered testing to all eligible participants within weeks of the project's initiation. Implementation: Adaptations made to increase reach and improve consistency were promptly implemented. Maintenance: San Francisco Department of Public Health expanded and maintained testing with minimal support after the end of the pilot. CONCLUSION: Rapid and frequent antigen testing for SARS-CoV2 in homeless shelters is a viable alternative to rRT-PCR testing that can lead to immediate isolation of infectious individuals. Using the RE-AIM framework, we evaluated and adapted interventions to enable the expansion and maintenance of protocols.

Case Report: Generalised Panniculitis as a Post-COVID-19 Presentation in Aicardi-Goutières Syndrome Treated With Ruxolitinib.

Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy. The syndrome was first described in 1984, and is characterised by upregulation of the type I interferon (IFN) pathway, which is involved in the host immune response against viral infections, including SARS-CoV-2. Whilst defects in type I IFN pathways have been described in association with severe coronavirus disease 2019 (COVID-19), less is known about the outcomes of upregulation. We describe an unusual case of generalised panniculitis as a post-COVID-19 phenomenon in a child with AGS. Our patient was initially managed with systemic steroid therapy, but due to relapse of symptoms on weaning, an alternative therapy was sought. In this case, a novel use of ruxolitinib, a JAK inhibitor, has resulted in lasting remission without complications. We discuss the probable protective role of IFN upregulation following COVID-19 infection in AGS and possible immunological mechanisms driving the panniculitis and therapeutic response in our case.

Perceived threat of COVID-19, attitudes towards vaccination, and vaccine hesitancy: A prospective longitudinal study in the UK.

OBJECTIVES: Using the Health Belief Model as a conceptual framework, we investigated the association between attitudes towards COVID-19, COVID-19 vaccinations, and vaccine hesitancy and change in these variables over a 9-month period in a UK cohort. METHODS: The COPE study cohort (n = 11,113) was recruited via an online survey at enrolment in March/April 2020. The study was advertised via the HealthWise Wales research registry and social media. Follow-up data were available for 6942 people at 3 months (June/July 2020) and 5037 at 12 months (March/April 2021) post-enrolment. Measures included demographics, perceived threat of COVID-19, perceived control, intention to accept or decline a COVID-19 vaccination, and attitudes towards vaccination. Logistic regression models were fitted cross-sectionally at 3 and 12 months to assess the association between motivational factors and vaccine hesitancy. Longitudinal changes in motivational variables for vaccine-hesitant and non-hesitant groups were examined using mixed-effect analysis of variance models. RESULTS: Fear of COVID-19, perceived susceptibility to COVID-19, and perceived personal control over COVID-19 infection transmission decreased between the 3- and 12-month surveys. Vaccine hesitancy at 12 months was independently associated with low fear of the disease and more negative attitudes towards COVID-19 vaccination. Specific barriers to COVID-19 vaccine uptake included concerns about safety and efficacy in light of its rapid development, mistrust of government and pharmaceutical companies, dislike of coercive policies, and perceived lack of relaxation in COVID-19-related restrictions as the vaccination programme progressed. CONCLUSIONS: Decreasing fear of COVID-19, perceived susceptibility to the disease, and perceptions of personal control over reducing infection-transmission may impact future COVID-19 vaccination uptake.

Giant coronary artery aneurysm as a feature of coronavirus-related inflammatory syndrome.

A 5-month-old female infant was admitted to hospital with a history of fever and rash during the recent coronavirus pandemic. She had significantly elevated inflammatory markers and the illness did not respond to first line broad spectrum antibiotics. The illness was later complicated by coronary artery aneurysms which were classified as giant despite treatment with intravenous immunoglobulin, steroids and immunomodulators. The infant had COVID-19 antibodies despite an initial negative COVID-19 PCR test. This case highlights the association of atypical Kawasaki like illness and paediatric multisystem inflammatory syndrome-temporarily associated with COVID-19 infection.

Assessment of a Hotel-Based COVID-19 Isolation and Quarantine Strategy for Persons Experiencing Homelessness.

Importance: Several jurisdictions in the United States have secured hotels to temporarily house people experiencing homelessness who require isolation or quarantine for confirmed or suspected coronavirus disease 2019 (COVID-19). To our knowledge, little is known about how these programs serve this vulnerable population outside the hospital setting. Objective: To assess the safety of a hotel-based isolation and quarantine (I/Q) care system and its association with inpatient hospital capacity. Design, Setting, and Participants: This retrospective cohort study of a hotel-based I/Q care system for homeless and unstably housed individuals in San Francisco, California, was conducted from March 19 to May 31, 2020. Individuals unable to safely isolate or quarantine at home with mild to moderate COVID-19, persons under investigation, or close contacts were referred from hospitals, outpatient settings, and public health surveillance to 5 I/Q hotels. Of 1009 I/Q hotel guests, 346 were transferred from a large county public hospital serving patients experiencing homelessness. Exposure: A physician-supervised team of nurses and health workers provided around-the-clock support, including symptom monitoring, wellness checks, meals, harm-reduction services, and medications for opioid use disorder. Main Outcomes and Measures: Characteristics of I/Q hotel guests, program retention, county hospital readmissions, and mean length of stay. Results: Overall, the 1009 I/Q hotel guests had a median age of 44 years (interquartile range, 33-55 years), 756 (75%) were men, 454 (45%) were Latinx, and 501 (50%) were persons experiencing sheltered (n = 295) or unsheltered (n = 206) homelessness. Overall, 463 (46%) received a diagnosis of COVID-19; 303 of 907 (33%) had comorbid medical disorders, 225 of 907 (25%) had comorbid mental health disorders, and 236 of 907 (26%) had comorbid substance use disorders. A total of 776 of 955 guests (81%) completed their I/Q hotel stay; factors most strongly associated with premature discontinuation were unsheltered homelessness (adjusted odds ratio, 4.5; 95% CI, 2.3-8.6; P < .001) and quarantine status (adjusted odds ratio, 2.6; 95% CI, 1.5-4.6; P = .001). In total, 346 of 549 patients (63%) were transferred from the county hospital; of 113 ineligible referrals, 48 patients (42%) had behavioral health needs exceeding I/Q hotel capabilities. Thirteen of the 346 patients transferred from the county hospital (4%) were readmitted for worsening COVID-19. Overall, direct transfers to I/Q hotels from emergency and outpatient departments were associated with averting many hospital admissions. There was a nonsignificant decrease in the mean hospital length of stay for inpatients with confirmed or suspected COVID-19 from 5.5 to 2.7 days from March to May 2020 (P = .11). Conclusions and Relevance: To support persons experiencing homelessness during the COVID-19 pandemic, San Francisco rapidly and safely scaled a hotel-based model of I/Q that was associated with reduced strain on inpatient capacity. Strategies to improve guest retention and address behavioral health needs not met in hotel settings are intervention priorities.

Seroprevalence of SARS-CoV-2 antibodies in children of United Kingdom healthcare workers: a prospective multicentre cohort study protocol.

BACKGROUND: A novel coronavirus SARS-CoV-2 has been responsible for a worldwide pandemic. Children typically have very mild, or no, symptoms of infection. This makes estimations of seroprevalence in children difficult. Research is therefore required to determine the seroprevalence of SARS-CoV-2 antibodies in children. The primary objective of this study is to report the seroprevalence of SARS-CoV-2 IgM and/or IgG antibodies in healthy children at baseline, 2 months and 6 months. This is the only longitudinal UK study of seroprevalence in an exclusively paediatric population. Determining the changing seroprevalence is of vital public health importance and can help inform decisions around the lifting of paediatric specific social distancing measures such as school closures and the cancellation of routine paediatric hospital services. METHODS AND ANALYSIS: 1000 healthy children of healthcare workers aged between 2 and 15 years will be recruited from five UK sites (Belfast, Cardiff, Glasgow, London and Manchester). The children will undergo phlebotomy at baseline, 2 months and 6 months to measure IgM and/or IgG positivity to SARS-CoV-2. A sample size of 675 patients is required to detect a 5% change in seroprevalence at each time point assuming an alpha of 0.05 and a beta of 0.2. Adjusted probabilities for the presence of IgG and/or IgM antibodies and of SARS-CoV-2 infection will be reported using logistic regression models where appropriate. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London - Chelsea Research Ethics Committee (REC Reference-20/HRA/1731) and the Belfast Health & Social Care Trust Research Governance (Reference 19147TW-SW). Results of this study will be made available as preprints and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT0434740; Results.

Seroprevalence of SARS-CoV-2 antibodies in children: a prospective multicentre cohort study.

BACKGROUND: Studies based on molecular testing of oral/nasal swabs underestimate SARS-CoV-2 infection due to issues with test sensitivity, test timing and selection bias. The objective of this study was to report the presence of SARS-CoV-2 antibodies, consistent with previous infection. DESIGN: This multicentre observational cohort study, conducted between 16 April to 3 July 2020 at 5 UK sites, recruited children of healthcare workers, aged 2-15 years. Participants provided blood samples for SARS-CoV-2 antibody testing and data were gathered regarding unwell contacts and symptoms. RESULTS: 1007 participants were enrolled, and 992 were included in the final analysis. The median age of participants was 10·1 years. There were 68 (6.9%) participants with positive SARS-CoV-2 antibody tests indicative of previous SARS-CoV-2 infection. Of these, 34/68 (50%) reported no symptoms prior to testing. The presence of antibodies and the mean antibody titre was not influenced by age. Following multivariable analysis four independent variables were identified as significantly associated with SARS-CoV-2 seropositivity: known infected household contact OR=10.9 (95% CI 6.1 to 19.6); fatigue OR=16.8 (95% CI 5.5 to 51.9); gastrointestinal symptoms OR=6.6 (95% CI 3.0 to 13.8); and changes in sense of smell or taste OR=10.0 (95% CI 2.4 to 11.4). DISCUSSION: Children demonstrated similar antibody titres in response to SARS-CoV-2 irrespective of age. Fatigue, gastrointestinal symptoms and changes in sense of smell or taste were the symptoms most strongly associated with SARS-CoV-2 antibody positivity. TRIAL REGISTRATION NUMBER: NCT0434740.