Individual factors underlie temperature variation in sickness and in health: influence of age, BMI and genetic factors in a multi-cohort study

Introduction Ageing affects immune function resulting in aberrant fever response to infection. We assess the effects of biological variables on basal temperature and temperature in COVID-19 infection, proposing an updated temperature threshold for older adults. Methods Participants: 1. Unaffected twin volunteers: 1089 adult TwinsUK participants. 2. London hospitalised COVID-19+: 520 adults with emergency admission. 3. Birmingham hospitalised COVID-19+: 757 adults with emergency admission. 4. Community-based COVID-19+: 3972 adults self-reporting a positive test using the COVID Symptom Study mobile application. Analysis Heritability assessed using saturated and univariate ACE models; Linear mixed-effect and multivariable linear regression analysing associations between temperature, age, sex and BMI; multivariable logistic regression analysing associations between fever (≥37.8°C) and age; receiver operating characteristic (ROC) analysis to identify temperature threshold for adults ≥ 65 years. Results Among unaffected volunteers, lower BMI (p=0.001), and older age (p<0.001) associated with lower basal temperature. Basal temperature showed a heritability of 47% (95% Confidence Interval 18-57%). In COVID-19+ participants, increasing age associated with lower temperatures in cohorts (c) and (d) (p<0.001). For each additional year of age, participants were 1% less likely to demonstrate a fever (OR 0.99; p<0.001). Combining healthy and COVID-19+ participants, a temperature of 37.4°C in adults ≥65 years had similar sensitivity and specificity to 37.8°C in adults <65 years for discriminating fever in COVID-19. Conclusions Ageing affects temperature in health and acute infection. Significant heritability indicates biological factors contribute to temperature regulation. Our observations indicate a lower threshold (37.4°C) should be considered for assessing fever in older adults. Key Points ### Competing Interest Statement The app was developed by Zoe Global Limited with input from Kings College London (KCL) and Massachusetts General Hospital. The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care ### Funding Statement Support for this study was provided by the NIHR-funded Biomedical Research Centre based at GSTT NHS Foundation Trust. Zoe provided in kind support for all aspects of building, running, and supporting the app and service to all users worldwide. Investigators also received support from the Wellcome Trust, the Medical Research Council (MRC), BHF, European Union (EU), National Institute for Health Research (NIHR), Chronic Disease Research Foundation (CDRF), and the NIHR-funded BioResource, Alzheimers Society, Clinical Research Facility and Biomedical Research Centre (BRC) based at GSTT NHS Foundation Trust in partnership with KCL, NIHR Birmingham BRC, a partnership between University Hospital Birmingham NHS Trust and University of Birmingham. MNL is supported by an NIHR Doctoral Fellowship (NIHR300159). TwinsUK is funded by the Wellcome Trust, MRC, EU, CDRF, Zoe Global Ltd, the NIHR-funded BioResource, Clinical Research Facility and BRC based at Guys and St Thomas NHS Foundation Trust in partnership with KCL ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: TwinsUK main ethics was reviewed and approved by the NHS London: London Bridge Research Ethics Committee (REC reference EC/04/015) and by Guys and St Thomas NHS Foundation Trust Research and Development (R&D) in 2012. TwinsUK BioBank was approved by NHS North West: Liverpool East Research Ethics Committee (REC reference 19/NW/0187) IRAS ID 258513. The Covid Symptom Study App Ethics has been approved by KCL ethics Committee REMAS ID 18210 review reference LRS-19/20-18210. All subscribers provided consent when signing up for the app. COVIDCollab project service evaluation approved by Guys and St Thomas NHS Trust audit leads. Reference number 10777. The University Hospitals Birmingham validation was performed as part of a service evaluation with a (CARMS-16005) after approval on routinely collected anonymised dataset All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes TwinsUK data used in this study is available upon reasonable request to TwinsUK. COVIDCollab data are available upon application to the Geriatric Medicine Research Collaborative https://www.gemresearchuk.com/. App data used in this study are available to bona fide researchers through UK Health Data Research using the following link https://healthdatagateway.org/detail/9b604483-9cdc-41b2-b82c-14ee3dd705f6