Association of Periodic Fasting with Lower Severity of COVID-19 Outcomes in the SARS-CoV-2 Pre-Vaccine Era: An Observational Cohort from the INSPIRE Registry
Authors: Horne Benjamin D. , Muhlestein Joseph B. , May Heidi T. , Le Viet T. , Bair Tami L. , Knowlton Kirk U. , Anderson Jeffrey L. ,   the INSPIRE Registry Investigators
Published: March 2022

AbstractObjectivesIntermittent fasting boosts some mechanisms of host defense against infection while modulating the inflammatory response. Lower-frequency periodic fasting is associated with greater survival and lower risk of comorbidities that exacerbate COVID-19. This study evaluated the association of periodic fasting with COVID-19 severity and, secondarily, initial diagnosis of infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).DesignProspective longitudinal observational cohort study.SettingSingle-center secondary care facility in Salt Lake City, Utah, USA with follow-up across a 24-hospital integrated healthcare system.ParticipantsPatients enrolled in the INSPIRE registry in 2013-2020 were studied if they had SARS-CoV-2 testing in March 2020-February 2021 and either tested positive (N=205) for the primary outcome evaluation or had a positive or negative test result for evaluation of the secondary outcome (n=1,524).InterventionsNo treatment assignments were made; individuals provided information about their personal practice and history of engaging in routine periodic fasting across their lifespan.Main outcome measuresThe association of periodic fasting with a composite of mortality or hospitalization as the primary outcome was evaluated by Cox regression through February 2021 and multivariable adjustments considered 36 covariables in INSPIRE patients diagnosed with COVID-19. Secondary analysis evaluated the association of fasting with testing positive for SARS-CoV-2 in INSPIRE patients evaluated for COVID-19 (n=1,524).ResultsSubjects engaging in periodic fasting (n=73, 35.6%) did so for 40.4±20.6 years (max: 81.9 years) prior to COVID-19 diagnosis. The composite outcome occurred in 11.0% of periodic fasters and 28.8% of non-fasters (p=0.013), with HR=0.61 (95% CI=0.42, 0.90) favoring fasting. Multivariable analyses confirmed this association. Other predictors of hospitalization/mortality were age, Hispanic ethnicity, prior MI, prior TIA, and renal failure, with trends for race, smoking, hyperlipidemia, coronary disease, diabetes, heart failure, and history of anxiety, but not alcohol use. In secondary analysis, COVID-19 was diagnosed in 14.3% of fasters and 13.0% of non-fasters (p=0.51).ConclusionsRoutine periodic fasting was associated with a lower risk of hospitalization or mortality in patients with COVID-19. Fasting may be a complementary therapy to vaccination that could provide immune support and hyperinflammation control during and beyond the pandemic.Trial registrationclinicaltrials.gov, NCT02450006 (the INSPIRE registry)SummaryWhat is already known on this topicDuring a period of energy restriction, fasting controls inflammation by dampening the cytokine cascade and it switches the metabolic source of energy from glucose to fats, including by increasing circulating free fatty acids such as linoleic acid.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domains bind linoleic acid in pockets that, when bound, reduce spike protein affinity for the angiotensin-converting enzyme 2.Repeated fasting boosts basal levels of some parameters related to inflammation control and host defense against infections, including galectin-3, and it ameliorates insulin resistance and cardiovascular risks such that periodic fasting is associated with greater survival and lower risk of heart failure, coronary artery disease, and type 2 diabetes.What this study addsThis study evaluated the association of periodic fasting with severity of coronavirus disease 2019 (COVID-19) and with initial infection with SARS-CoV-2 in a population where a substantial proportion of people routinely engage in periodic dry or water-only fasting, primarily for religious purposes.This observational epidemiologic study found that routine low-frequency periodic fasting for an average of >40 years was associated with a lower risk of a composite of hospitalization or mortality after COVID-19 diagnosis, suggesting that fasting deserves further investigation as a complementary approach along with vaccines for reducing COVID-19 severity.The study also found no association of periodic fasting with the onset of SARS-CoV-2 infection.Trial registrationThe Intermountain INSPIRE registry (clinicaltrials.gov, NCT02450006)TransparencyBDH affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted.CopyrightThe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above.