Healthy lifestyle for the prevention of post-COVID-19 multisystem sequelae, hospitalization, and death: a prospective cohort study

Background Post-COVID complications are emerging as a global public health crisis. Effective prevention strategies are needed to inform patients, clinicians and policy makers, and to reduce their cumulative burden. We aimed to investigate whether a habitual healthy lifestyle predated pandemic is associated with lower risks of multisystem sequelae and other adverse outcomes of COVID-19, and whether the potential protective effects are independent of pre-existing comorbidities. Methods The prospective population-based cohort study enrolled participants with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction test result between March 1, 2020, and March 1, 2022. Participants with no history of the related outcome one year before infection were included and followed up for 210 days. Exposures included ten modifiable healthy lifestyle factors including past or never smoking, moderate alcohol intake (≤4 times week), body mass index <30 kg/m[2][1], at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week, less sedentary time (<4 hours per day), healthy sleep duration (7-9 hours per day), adequate intake of fruit and vegetables (≥400 g/day), adequate oily fish intake (≥1 portion/week), moderate intake of red meat (≤4 portions week) and processed meat (≤4 portions week). Outcomes included multisystem COVID-19 sequelae (consisting of 75 diseases/symptoms in 10 organ systems), death, and hospital admission following SARS-CoV-2 infection, confirmed by hospital inpatient and death records. Risk was reported in relative scale (hazard ratio [HR]) and absolute scale (absolute risk reduction [ARR]) during both the acute (the first 30 days) and post-acute (30-210 days) phases of infection using Cox models. Findings A total of 68,896 participants (mean [SD] age, 66.6 [8.4]; 32,098 women [46.6%]) with COVID-19 were included. A favorable lifestyle (6-10 healthy lifestyle factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae of COVID-19 (HR, 0.64; 95% CI, 0.58-0.69; ARR, 7.08%; 95% CI, 5.98-8.09), compared with unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions were observed across all 10 prespecified organ systems including cardiovascular, coagulation, metabolic and endocrine, gastrointestinal, kidney, mental health, musculoskeletal, neurologic, and respiratory disorders, and general symptoms of fatigue and malaise. This beneficial effect was largely attributable to direct effects of healthy lifestyle, with mediation proportion ranging from 44% to 93% across organ systems. A favorable lifestyle was also associated with lower risk of post-COVID death (HR, 0.59; 95% CI, 0.52-0.66; ARR, 1.99%; 95% CI, 1.61-2.32) and hospitalization (HR, 0.78; 95% CI, 0.73-0.84; ARR, 6.14%; 95% CI, 4.48-7.68). These associations were observed after accounting for potential misclassification of lifestyle factors, and during acute and post-acute infection, in those tested positive in the hospital and community setting, and independent of vaccination status or SARS-CoV-2 variant. Interpretation Adherence to a healthy lifestyle predated pandemic was associated with substantially lower risk of complications across organ systems, death, and hospitalization following COVID-19, regardless of phases of infection, vaccination status, test setting, and SARS-CoV-2 variants, and independent of comorbidities. These findings illustrate the benefits of adhering to a healthy lifestyle to reduce the long-term adverse health consequences following SARS-CoV-2 infection. Evidence before this study We searched PubMed and MEDLINE for articles published between March 1, 2020, and December 1, 2023, using the search terms “healthy lifestyle”, “risk factor”, “post-COVID condition”, “long COVID”, “post-acute sequelae”, “prevention”, “management”, and “treatment”, with no language restrictions. Previous evidence on the prevention and management of long COVID has mainly focused on vaccination and pharmaceutical approaches, including antivirals (e.g., molnupiravir and nirmatrelvir) and other drugs (e.g., metformin). Vaccination before infection or use of antivirals in selected high-risk patients during acute infection only partially mediates the risk of COVID-19 sequelae. Evidence for the non-pharmaceutical prevention strategies are lacking. We identified only two publications on the association between healthy lifestyle and post-COVID condition, and one meta-analysis of the risk factors for long COVID symptoms. A cross-sectional study of 1981 women suggested an inverse association between healthy lifestyle factors and self-reported symptoms following infection of non-Omicron variants, which was mainly driven by BMI and sleep duration. Another study suggested an inverse prospective association between healthy lifestyle prior to infection and post-COVID cardiovascular events. High BMI and smoking are risk factors for long COVID mainly in hospitalized patients. We did not find any study that assessed the association between a composite healthy lifestyle and subsequent post-COVID complications or sequelae across organ systems, hospitalization, and death. Added value of this study In a prospective, population-based cohort of 68,896 participants with COVID-19, adherence to a healthy lifestyle prior to infection was associated with a substantially lower risk of multisystem sequelae (by 20%-36%), death (by 26%-41%), and hospital admission (by 13%-22%) following COVID-19. The reduced risk of sequelae was evident across 10 prespecified organ systems, including cardiovascular, coagulation and hematologic, metabolic and endocrine, gastrointestinal, kidney, mental health, musculoskeletal, neurologic, and respiratory disorders, as well as general symptoms of fatigue and malaise. The reduced risk of multisystem sequelae, hospitalization, and death associated with a healthy lifestyle was consistently observed across participants, regardless of their vaccination status, disease severity, and major SARS-CoV-2 variants, and largely independent of relevant comorbidities. Adherence to a healthy lifestyle prior to infection was consistently and directly associated with reduced risk of sequelae and other adverse health outcomes following COVID-19. Implications of all the available evidence The inverse association of healthy lifestyle with multisystem sequelae was even larger than those observed in previous studies of pharmaceutical interventions in non-hospitalized patients. Considering the restricted scope of currently available therapies, such as antivirals (only selected patients at higher risk are qualified during the acute infection) and limited efficacy of vaccination in preventing long COVID, adherence to a healthy lifestyle, in combination with vaccination and, if necessary, potential medications, emerges as practical prevention and care strategies to mitigate the long-term health consequences of SARS-CoV-2 infection. These strategies are of significant clinical and public health importance in reducing the overall burden of post-COVID conditions and improving preparedness for future pandemics. ### Competing Interest Statement Dr Prieto-Alhambra's department has received grant/s from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma. His research group has received consultancy fees from Astra Zeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners and UCB Biopharma have funded or supported training programmes organised by Dr Prieto-Alhambra's department. Dr Paredes has participated in advisory boards for Gilead, MSD, ViiV Healthcare, Theratechnologies and Lilly. His institution has received research support from Gilead, MSD, and ViiV Healthcare. The remaining authors declare no competing interests. ### Clinical Protocols ### Funding Statement Mr Wang is funded through the Clarendon Fund Scholarship. Dr Xie is funded through Jardine-Oxford Graduate Scholarship and a titular Clarendon Fund Scholarship. The research was partially supported by the Oxford National Institute for Health and Care Research (NIHR) Biomedical Research Centre. Dr Prieto-Alhambra is funded through an NIHR Senior Research Fellowship (grant SRF-2018-11-ST2-004). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: #ref-2