Regional moderate hyperthermia for mild-to-moderate COVID-19 (TherMoCoV study): a randomized controlled trial

{ 'indexed': { 'date-parts': [[2023, 12, 23]], 'date-time': '2023-12-23T00:20:19Z', 'timestamp': 1703290819552}, 'reference-count': 45, 'publisher': 'Frontiers Media SA', 'license': [ { 'start': { 'date-parts': [[2023, 12, 22]], 'date-time': '2023-12-22T00:00:00Z', 'timestamp': 1703203200000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': ['frontiersin.org'], 'crossmark-restriction': True}, 'abstract': '<jats:sec><jats:title>Background</jats:title><jats:p>To prevent COVID-19 progression, ' 'low-cost alternatives that are available to all patients are needed. Diverse forms of ' 'thermotherapy have been proposed to prevent progression to severe/critical ' 'COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>The aim of ' 'this study is to evaluate the efficacy and safety of local thermotherapy to prevent disease ' 'progression in hospitalized adult patients with mild-to-moderate ' 'COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A multicenter, ' 'open-label, parallel-group, randomized, adaptive trial is used to evaluate the efficacy and ' 'safety of local thermotherapy to prevent disease progression in hospitalized adult patients ' 'with mild-to-moderate COVID-19. Eligible hospitalized adult patients with symptoms of ' 'COVID-19 with ≤5\u2009days from symptom onset, meeting criteria for mild or moderate ' 'COVID-19, were randomly assigned to the intervention consisting of local thermotherapy via an ' 'electric heat pad in the thorax (target temperature range 39.5–42°C) continuously for 90\u2009' 'min, twice daily, for 5\u2009days, or standard care. The main outcome was the proportion of ' 'patients who progressed to severe-to-critical COVID-19 or death. Patients were randomized in ' 'a 1:1 ratio through a centralized computer-generated sequence of minimization with a random ' 'component of 20%. Participants and medical staff were not blinded to the ' 'intervention.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>One-hundred ' 'and five participants (thermotherapy <jats:italic>n</jats:italic>\u2009=\u200954, control ' '<jats:italic>n</jats:italic>\u2009=\u200951) with a median age of 53 (IQR: 41–64) years were ' 'included for analysis after the early cessation of recruitment due to the closure of all ' 'temporal COVID-19\u2009units (target sample size\u2009=\u2009274). The primary outcome of ' 'disease progression occurred in 31.4% (16/51) of patients in the control group vs. 25.9% ' '(14/54) of those receiving thermotherapy (risk difference\u2009=\u20095.5%; 95%CI: ' '−11.8–22.7, <jats:italic>p</jats:italic>\u2009=\u20090.54). Thermotherapy was well tolerated ' 'with a median total duration of thermotherapy of 900 (IQR: 877.5–900) min. Seven (13.7%) ' 'patients in the control group and seven (12.9%) in the thermotherapy group had at least one ' 'AE (<jats:italic>p</jats:italic>\u2009=\u20090.9), none of which were causally attributed to ' 'the intervention. No statistically significant differences in serum cytokines (IL-1β, IL-6, ' 'IL-8, IL-10, IL-17, and IFN-γ) were observed between day 5 and baseline among ' 'groups.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Local ' 'thermotherapy was safe and well-tolerated. A non-statistically significant lower proportion ' 'of patients who experienced disease progression was found in the thermotherapy group compared ' 'to standard care. Local thermotherapy could be further studied as a strategy to prevent ' 'disease progression in ambulatory settings.</jats:p><jats:p><jats:bold>Clinical Trial ' 'registration</jats:bold>: <jats:ext-link>www.clinicaltrials.gov</jats:ext-link>, identifier: ' 'NCT04363541.</jats:p></jats:sec>', 'DOI': '10.3389/fmed.2023.1256197', 'type': 'journal-article', 'created': { 'date-parts': [[2023, 12, 22]], 'date-time': '2023-12-22T04:23:10Z', 'timestamp': 1703218990000}, 'update-policy': 'http://dx.doi.org/10.3389/crossmark-policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Regional moderate hyperthermia for mild-to-moderate COVID-19 (TherMoCoV study): a randomized ' 'controlled trial', 'prefix': '10.3389', 'volume': '10', 'author': [ {'given': 'Javier', 'family': 'Mancilla-Galindo', 'sequence': 'first', 'affiliation': []}, {'given': 'Ashuin', 'family': 'Kammar-García', 'sequence': 'additional', 'affiliation': []}, { 'given': 'María de Lourdes', 'family': 'Mendoza-Gertrudis', 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device?', 'volume': '51', 'author': 'Hampton', 'year': '2023', 'journal-title': 'J Law Med Ethics'}, { 'key': 'ref6', 'doi-asserted-by': 'publisher', 'first-page': '1909', 'DOI': '10.1016/S0140-6736(23)01012-7', 'article-title': 'No time for complacency on COVID-19 in Europe', 'volume': '401', 'author': 'Flahault', 'year': '2023', 'journal-title': 'Lancet'}, { 'key': 'ref7', 'doi-asserted-by': 'publisher', 'first-page': '96', 'DOI': '10.1186/s13104-023-06366-3', 'article-title': 'Association between distance to community health care facilities and ' 'COVID-19–related mortality across U.S. counties in the COVID-19–vaccine ' 'era', 'volume': '16', 'author': 'Huang', 'year': '2023', 'journal-title': 'BMC Res Notes'}, { 'key': 'ref8', 'doi-asserted-by': 'publisher', 'first-page': 'm3379', 'DOI': '10.1136/bmj.m3379', 'article-title': 'A living WHO guideline on drugs for covid-19', 'volume': '370', 'author': 'Lamontagne', 'year': '2020', 'journal-title': 'BMJ'}, { 'key': 'ref9', 'doi-asserted-by': 'publisher', 'first-page': 'o1282', 'DOI': '10.1136/bmj.o1282', 'article-title': 'The black market for covid-19 antiviral drugs', 'volume': '377', 'author': 'Plata', 'year': '2022', 'journal-title': 'BMJ'}, { 'key': 'ref10', 'doi-asserted-by': 'publisher', 'first-page': '202', 'DOI': '10.1080/02656736.2021.1883127', 'article-title': 'Exploring the rationale for thermotherapy in COVID-19', 'volume': '38', 'author': 'Mancilla-Galindo', 'year': '2021', 'journal-title': 'Int J Hyperth'}, { 'key': 'ref11', 'doi-asserted-by': 'publisher', 'first-page': '918', 'DOI': '10.1080/02656736.2018.1440015', 'article-title': 'Are infectious diseases and microbiology new fields for thermal therapy ' 'research?', 'volume': '34', 'author': 'Gazel', 'year': '2018', 'journal-title': 'Int J Hyperth'}, { 'key': 'ref12', 'doi-asserted-by': 'publisher', 'first-page': '292', 'DOI': '10.12688/f1000research.23299.1', 'article-title': 'Turning up the heat on COVID-19: heat as a therapeutic intervention', 'volume': '9', 'author': 'Cohen', 'year': '2020', 'journal-title': 'F1000Research'}, { 'key': 'ref13', 'doi-asserted-by': 'publisher', 'first-page': '110363', 'DOI': '10.1016/j.mehy.2020.110363', 'article-title': 'Hydrothermotherapy in prevention and treatment of mild to moderate ' 'cases of COVID-19', 'volume': '146', 'author': 'Ramirez', 'year': '2021', 'journal-title': 'Med Hypotheses'}, { 'key': 'ref14', 'doi-asserted-by': 'publisher', 'first-page': '102594', 'DOI': '10.1016/j.ctim.2020.102594', 'article-title': 'Sauna bathing frequency in Finland and the impact of COVID-19', 'volume': '2021', 'author': 'Liikkanen', 'year': '2020', 'journal-title': 'Complement Ther Med'}, { 'key': 'ref15', 'doi-asserted-by': 'publisher', 'first-page': '1', 'DOI': '10.3389/fimmu.2020.556335', 'article-title': 'A potential bioelectromagnetic method to slow down the progression and ' 'prevent the development of ultimate pulmonary fibrosis by COVID-19', 'volume': '11', 'author': 'Masaud', 'year': '2020', 'journal-title': 'Front Immunol'}, { 'key': 'ref16', 'doi-asserted-by': 'publisher', 'first-page': '225', 'DOI': '10.1089/ther.2023.0030', 'article-title': 'Core warming of coronavirus disease 2019 patients undergoing mechanical ' 'ventilation: a pilot study', 'volume': '13', 'author': 'Bonfanti', 'year': '2023', 'journal-title': 'Ther Hypothermia Temp Manag'}, { 'key': 'ref17', 'doi-asserted-by': 'publisher', 'first-page': '137', 'DOI': '10.23736/S1973-9087.21.06892-1', 'article-title': 'Efficacy and safety of short-wave diathermy treatment for moderate ' 'COVID-19 patients: a prospective, double-blind, randomized controlled ' 'clinical study', 'volume': '58', 'author': 'Tian', 'year': '2022', 'journal-title': 'Eur J Phys Rehabil Med'}, { 'key': 'ref18', 'doi-asserted-by': 'publisher', 'first-page': '1149250', 'DOI': '10.3389/fmed.2023.1149250', 'article-title': 'Efficacy and safety of ultra-short wave diathermy on COVID-19 ' 'pneumonia: a pioneering study', 'volume': '10', 'author': 'Huang', 'year': '2023', 'journal-title': 'Front Med'}, { 'key': 'ref19', 'doi-asserted-by': 'publisher', 'first-page': '1239', 'DOI': '10.1001/jama.2020.2648', 'article-title': 'Characteristics of and important lessons from the coronavirus disease ' '2019 (COVID-19) outbreak in China', 'volume': '323', 'author': 'Wu', 'year': '2020', 'journal-title': 'JAMA'}, { 'key': 'ref20', 'doi-asserted-by': 'publisher', 'first-page': '1757', 'DOI': '10.1056/NEJMcp2009249', 'article-title': 'Mild or moderate Covid-19', 'volume': '383', 'author': 'Gandhi', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'key': 'ref21', 'doi-asserted-by': 'publisher', 'first-page': '2074', 'DOI': '10.1002/jmv.25969', 'article-title': 'Individualized prediction nomograms for disease progression in mild ' 'COVID-19', 'volume': '92', 'author': 'Huang', 'year': '2020', 'journal-title': 'J Med Virol'}, {'key': 'ref22', 'year': '2020'}, { 'key': 'ref23', 'doi-asserted-by': 'publisher', 'first-page': 'ofz053', 'DOI': '10.1093/ofid/ofz053', 'article-title': 'Comparative outcomes of adults hospitalized with seasonal influenza a ' 'or B virus infection: application of the 7-category ordinal scale. Open ' 'forum', 'volume': '6', 'author': 'Wang', 'year': '2019', 'journal-title': 'Infect Dis'}, { 'key': 'ref24', 'volume-title': 'National Early Warning Score (NEWS) 2: Standardising the assessment of ' 'acute-illness severity in the NHS, vol. 17. Updated report of a working ' 'party', 'year': '2017'}, { 'key': 'ref25', 'doi-asserted-by': 'publisher', 'first-page': 'e192', 'DOI': '10.1016/S1473-3099(20)30483-7', 'article-title': 'A minimal common outcome measure set for COVID-19 clinical research', 'volume': '20', 'author': 'Marshall', 'year': '2020', 'journal-title': 'Lancet Infect Dis'}, {'key': 'ref26', 'year': '2012'}, {'key': 'ref27', 'year': '2017'}, { 'key': 'ref28', 'doi-asserted-by': 'publisher', 'first-page': 'e3863', 'DOI': '10.1136/bmj.e3863', 'article-title': 'Problems of stopping trials early', 'volume': '344', 'author': 'Guyatt', 'year': '2012', 'journal-title': 'BMJ'}, { 'key': 'ref29', 'doi-asserted-by': 'publisher', 'first-page': 'e110761', 'DOI': '10.1371/journal.pone.0110761', 'article-title': 'OxMaR: open source free software for online minimization and ' 'randomization for clinical trials', 'volume': '9', 'author': 'O’Callaghan', 'year': '2014', 'journal-title': 'PLoS ONE'}, { 'key': 'ref30', 'doi-asserted-by': 'publisher', 'first-page': '395', 'DOI': '10.1016/j.gaceta.2018.07.013', 'article-title': 'Versión en español del software gratuito OxMaR para minimización y ' 'aleatorización de estudios clínicos', 'volume': '33', 'author': 'Guillaumes', 'year': '2019', 'journal-title': 'Gac Sanit'}, { 'key': 'ref31', 'doi-asserted-by': 'publisher', 'first-page': 'e286', 'DOI': '10.1017/S0950268820002903', 'article-title': 'Development and validation of the patient history COVID-19 (PH-Covid19) ' 'scoring system: a multivariable prediction model of death in Mexican ' 'patients with COVID-19', 'volume': '148', 'author': 'Mancilla-Galindo', 'year': '2020', 'journal-title': 'Epidemiol Infect'}, {'key': 'ref32', 'author': 'Dayim', 'year': '2023'}, { 'key': 'ref33', 'volume-title': 'R: A language and environment for statistical computing [internet]', 'year': '2023'}, { 'key': 'ref34', 'doi-asserted-by': 'publisher', 'first-page': 'e109', 'DOI': '10.1017/S0950268821001023', 'article-title': 'Obesity is a strong risk factor for short-term mortality and adverse ' 'outcomes in Mexican patients with COVID-19: a national observational ' 'study', 'volume': '149', 'author': 'Vera-Zertuche', 'year': '2021', 'journal-title': 'Epidemiol Infect'}, { 'key': 'ref35', 'doi-asserted-by': 'publisher', 'first-page': 'e28823', 'DOI': '10.1002/jmv.28823', 'article-title': 'Statins in hospitalized COVID-19 patients: a systematic review and ' 'meta-analysis of randomized controlled trials', 'volume': '95', 'author': 'Ren', 'year': '2023', 'journal-title': 'J Med Virol'}, { 'key': 'ref36', 'doi-asserted-by': 'publisher', 'first-page': '3577', 'DOI': '10.1111/bcp.15331', 'article-title': 'Cardiovascular drugs and COVID-19 clinical outcomes: a systematic ' 'review and meta-analysis of randomized controlled trials', 'volume': '88', 'author': 'Asiimwe', 'year': '2022', 'journal-title': 'Br J Clin Pharmacol'}, { 'key': 'ref37', 'doi-asserted-by': 'publisher', 'first-page': '100553', 'DOI': '10.1016/j.xcrm.2022.100553', 'article-title': 'Advancing the inclusion of underrepresented women in clinical research', 'volume': '3', 'author': 'Bierer', 'year': '2022', 'journal-title': 'Cell Rep Med'}, { 'key': 'ref38', 'doi-asserted-by': 'publisher', 'first-page': '988666', 'DOI': '10.3389/fmed.2022.988666', 'article-title': 'D-dimer levels and characteristics of lymphocyte subsets, cytokine ' 'profiles in peripheral blood of patients with severe COVID-19: a ' 'systematic review and meta-analysis', 'volume': '9', 'author': 'Zhang', 'year': '2022', 'journal-title': 'Front Med'}, { 'key': 'ref39', 'doi-asserted-by': 'publisher', 'first-page': '1', 'DOI': '10.3389/fimmu.2022.946730', 'article-title': 'Time evolution of cytokine profiles associated with mortality in ' 'COVID-19 hospitalized patients', 'volume': '13', 'author': 'Sánchez-de Prada', 'year': '2022', 'journal-title': 'Front Immunol'}, { 'key': 'ref40', 'doi-asserted-by': 'publisher', 'first-page': '102763', 'DOI': '10.1016/j.ebiom.2020.102763', 'article-title': 'Longitudinal characteristics of lymphocyte responses and cytokine ' 'profiles in the peripheral blood of SARS-CoV-2 infected patients', 'volume': '55', 'author': 'Liu', 'year': '2020', 'journal-title': 'EBioMedicine'}, { 'key': 'ref41', 'doi-asserted-by': 'publisher', 'first-page': '1123', 'DOI': '10.1080/22221751.2020.1770129', 'article-title': 'Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 ' 'are disease severity predictors', 'volume': '9', 'author': 'Han', 'year': '2020', 'journal-title': 'Emerg Microbes Infect'}, { 'key': 'ref42', 'doi-asserted-by': 'publisher', 'first-page': '100100', 'DOI': '10.1016/j.hpopen.2023.100100', 'article-title': 'Health-care policies during the COVID-19 pandemic in Mexico: a ' 'continuous case of heterogeneous, reactive, and unequal response', 'volume': '5', 'author': 'Bautista-Reyes', 'year': '2023', 'journal-title': 'Health Policy Open'}, { 'key': 'ref43', 'doi-asserted-by': 'publisher', 'first-page': '594', 'DOI': '10.1183/09031936.06.00075005', 'article-title': 'Prevalance of oxygen desaturation and use of oxygen at home in adults ' 'at sea level and at moderate altitude', 'volume': '27', 'author': 'Perez-Padilla', 'year': '2006', 'journal-title': 'Eur Respir J'}, { 'key': 'ref44', 'first-page': '101', 'article-title': 'Pruebas de función respiratoria, ¿cuál y a quién?', 'volume': '70', 'author': 'Vargas-Domínguez', 'year': '2011', 'journal-title': 'Neumol Cir Torax'}, { 'key': 'ref45', 'first-page': '5', 'article-title': 'Saturación de oxígeno en adultos mayores de la Ciudad de México', 'volume': '53', 'author': 'Rivera Pérez', 'year': '2008', 'journal-title': 'An Méd'}], 'container-title': 'Frontiers in Medicine', 'original-title': [], 'link': [ { 'URL': 'https://www.frontiersin.org/articles/10.3389/fmed.2023.1256197/full', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 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