Heritability of temperature and theeffects of ageing on temperatureregulation: An observational multi-cohortstudy

Introduction Ageing affects homeostasis and immunosenescence, resulting inaberrant fever and immune responses to infection in older adults.This study assesses heritability of basal temperature and exploreseffects of ageing on basal temperature and temperature inresponse to SARS-CoV-2 infection. Methods Observational study using multiple cohorts. Participants: (a) Twinvolunteers: 1089 healthy adults enrolled in Twins-UK, mean age59 (17);tympanic temperature measurements;(b) Community-based: 3972 adults using the COVID Symptom Study mobileapplication, age 43 (13);self-reported test-positive for SARS-CoV-2 infection;self-reported temperature measurements;(c)Hospitalised: cohorts of 520 and 757 adult patients withemergency admission to two teaching hospitals between01/03/2020-04/05/2020, age 62 (17) and 68 (17) respectively;RT-PCR-confirmed SARS-CoV-2 infection. Analysis (a) heritability analysed using saturated and ACE univariatemodels;linear mixed-effect model for associations between basaltemperature and age, sex and BMI. (b&c) multivariable linearregression for associations between temperature and age, sex and BMI;multivariable logistic regression for associations betweenfever(>/= 37.8°C) and age, sex and BMI. Results Basal temperature in twins demonstrated 50% heritability(95%CI[42-57%]). In healthy twin, community-based and hospitalised cohorts, increasing age is associated with lowertemperatures, and increasing BMI with higher temperatures: (a)Twins (age:p < 0.001;BMI:p = 0.002);(b) Community-based (age:p < 0.001;BMI: p < 0.001);(c) Hospitalised (1st hospital: age: p = 0.106;BMI: p = 0.033;2nd hospital: age: p < 0.001;BMI: p = 0.010).Increasing age was negatively and BMI positively associated withfever (1st hospital: Age: OR = 0.99, p = 0.033;BMI: OR = 1.00, p = 0.045;2nd hospital: Age: OR = 0.99, p = 0.010;BMI: OR 1.02, p = 0.038). Conclusions Heritability of basal temperature suggests a genetic component tothermoregulation. Associations observed between increasing ageand lower temperatures and higher BMI and higher temperaturesare important in understanding effects of ageing and obesity onbasal temperature and the fever response. In older adults, findingshave important implications for defining fever thresholds and diagnosing infections, including SARS-CoV-2.

144 Probable Delirium is A Presenting Symptom of COVID-19 in Frail, Older Adults: A Study of Hospitalised and Community-Based Cohorts

Introduction COVID-19 exhibits a more severe disease course in older adults with frailty. Awareness of atypical presentations is critical to facilitate early disease identification. This study aimed to assess how frailty affects presenting symptoms of COVID-19 in older adults. Methods Observational study of two distinct cohorts: (i) Hospitalised patients aged 65 and over;unscheduled admission to a large London teaching hospital between March 1st, 2020-May 5th, 2020;COVID-19 confirmed by RT-PCR of nasopharyngeal swab (n = 322);(ii) Community-based adults aged 65 and over enrolled in the COVID Symptom Study mobile application between March 24th (application launch)-May 8th, 2020;self-report or report-by-proxy data;reported test-positive for COVID-19 (n = 535). Multivariable logistic regression analysis performed on age-matched samples of both cohorts to determine associations between frailty and symptoms of COVID-19 including delirium, fever and cough. Results Hospital cohort: there was a significantly higher prevalence of delirium amongst the frail sample, with no difference in fever or cough. Of those presenting with delirium, 10/53 (18.9%) presented with delirium as the only documented symptom. Community-based cohort: there was a significantly higher prevalence of probable delirium in the frail sample, and also of fatigue and shortness of breath. Of those reporting probable delirium, 28/84 (33%) did not report fever or cough. Conclusions This study demonstrates a higher prevalence of delirium as a presenting symptom of COVID-19 infection in older adults with frailty compared to their age-matched non-frail counterparts. Clinicians should suspect COVID-19 in frail older adults presenting with delirium. Early detection facilitates infection control measures to mitigate against catastrophic spread and preventable hospitalisations and deaths amongst this population. Our findings emphasise the need for systematic frailty assessment for all acutely ill older patients in both hospital and community settings, as well as systematic evaluation of any change in mental status.

Optimal symptom combinations to aid COVID-19 case identification: Analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Diagnostic value of cutaneous manifestation of SARS-CoV-2 infection.

BACKGROUND: One of the challenging aspects of SARS-CoV-2 infection is its diverse multisystemic disease presentation. OBJECTIVES: To evaluate the diagnostic value of cutaneous manifestations of SARS-CoV-2 infection and investigate their duration and timing in relation to other COVID-19 symptoms. METHODS: We used data from 336 847 UK users of the COVID Symptom Study app to assess the diagnostic value of body rash or an acral rash in SARS-CoV-2 infection, and data from an independent online survey of 11 544 respondents to investigate skin-specific symptoms and collect their photographs. RESULTS: Using data from the app, we show significant association between skin rashes and a positive swab test result (odds ratio 1·67, 95% confidence interval 1·42-1·97). Strikingly, among the respondents of the independent online survey, we found that 17% of SARS-CoV-2-positive cases reported skin rashes as the first presentation, and 21% as the only clinical sign of COVID-19. Together with the British Association of Dermatologists, we have compiled a catalogue of images of the most common skin manifestations of COVID-19 from 400 individuals (https://covidskinsigns.com), which we have made publicly available to assist clinicians in recognition of this early clinical feature of COVID-19. CONCLUSIONS: Skin rashes cluster with other COVID-19 symptoms, are predictive of a positive swab test, and occur in a significant number of cases, either alone or before other classical symptoms. Recognizing rashes is important in identifying new and earlier cases of COVID-19.

Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.