Clinical trial NCT05736939: Gender Differences in the Recovery Rate Following PR in Patients With Long COVID-19
Official title: Gender Differences in the Recovery Rate Following a Hybrid Pulmonary Rehabilitation Programme in Patients With Long COVID-19 Syndrome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Post Acute COVID-19 Syndrome
Keywords: Post-Acute COVID-19 Syndrome
Pulmonary Rehabilitation
Muscle strength
Quality of life
Lead sponsor: National and Kapodistrian University of Athens
Sponsor class: OTHER
First posted: 2023-02-21
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Τhe study population consists of patients who have been diagnosed with long COVID-19 based on the persistence of fatigue at least three months following hospital discharge due to COVID-19. All patients participated in a pulmonary rehabilitation programme which is provided in these patients by our clinic.

Brief summary: The goal of this retrospective analysis is to compare the magnitude of improvement in respiratory and peripheral muscle strength, following the completion of a hybrid pulmonary rehabilitation programme, in men and women with long COVID-19 syndrome. The main question it aims to answer is the following:

• does gender limits the effects of a hybrid pulmonary rehabilitation programme on respiratory and peripheral muscle strength?

Detailed description: As of January 2023, more than 500 million people have been affected by Severe Acute Respiratory Distress Syndrome-Coronavirus-2 (SARS-COV-2) globally. In Greece, since January 2020 there have been more than 5 million confirmed cases of COVID-19 and more than 35,000 deaths. Based on this data, it seems that the majority of patients recover (even those requiring hospital admission) but present with persistent symptoms at least three months after the acute illness, a condition defined as 'Long COVID-19'. The most commonly reported symptoms include long-standing fatigue, dyspnoea, muscle and joint pain, sleep disturbances, short-term memory loss and brain fog.

This syndrome affects a large group of patients, and according to World Health Organisation it imposes a great burden on the healthcare systems worldwide. Consequently, it is important to identify preventable risk factors for 'Long COVID-19' in order to address the complex needs of these patients and reduce the prevalence of this new long-term condition.

According to the Post-hospitalisation COVID-19 study (PHOSP-COVID) which has included adults with COVID-19 discharged from United Kingdom hospitals, the main risk factors associated with worse recovery at 1 year involved obesity, need for invasive mechanical ventilation during the acute illness and female sex. Other studies evaluating the prevalence of 'Long COVID-19' in the two sexes found that female patients were more likely to have one or more symptoms 12 months following the acute phase of the disease. Despite the fact that lengths of hospital and ICU stay were reduced in women compared to men, female sex proved to be an independent risk factor for the development of ongoing symptoms, among which were fatigue, dyspnoea, muscle aches and generalised weakness. The autoimmune hypothesis could account for the higher incidence of 'Long COVID-19' syndrome in women. According to this hypothesis, the immune response for both genetic and hormonal factors is stronger in women compared to men and hence autoimmune reactions are more prevalent in women.

Guidelines have been published suggesting the implementation of pulmonary rehabilitation (PR) programmes for the management of patients with 'Long COVID-19' syndrome. According to recently published systematic reviews, pulmonary rehabilitation is beneficial for patients with long COVID-19 syndrome in terms of quality of life, muscle strength, walking capacity and sit-to-stand performance. Whether reduced recovery prognosis and long-lasting ongoing symptoms in women adversely affect the outcome of rehabilitation is still unknown. This is an important issue for healthcare systems when considering management strategies for people with 'Long COVID-19' syndrome. Furthermore, tele-rehabilitation programmes are feasible and effective in improving physical capacity, quality of life and symptoms in adult survivors of COVID-19.

Accordingly, the present study looked into the effect of a hybrid rehabilitation programme (including out-patient and home-based sessions) on physical and mental health outcomes in previously hospitalised women and men with 'Long COVID-19' syndrome. It was hypothesised that the magnitude of improvement in women would be less compared to men.

Eligibility criteria: Inclusion Criteria:

* Hospitalisation due to Sars-COV-2 infection.
* Presence of persistence fatigue assessed via FACIT questionnaire.

Exclusion Criteria:

Exclusion criteria include presence of any of the following list within 3 months prior to informed consent:

* participation in another clinical trial
* occurrence of myocardial infarction
* hospitalisation for unstable angina
* stroke
* coronary artery bypass graft (CABG)
* percutaneous coronary intervention (PCI)
* implantation of a cardiac resynchronisation therapy device (CRTD)
* active treatment for cancer or other malignant disease
* uncontrolled congestive heart disease (NYHA class \>3)
* acute psychosis or major psychiatric disorders or continued substance abuse

Primary outcomes:
measure: Fatigue
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Secondary outcomes:
measure: Quadriceps muscle strength
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Handgrip muscle strength
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Inspiratory muscle strength
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Expiratory muscle strength
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Dyspnoea
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Emotional status
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Symptoms
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Self-reported quality of life
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Post traumatic stress disorder (PTSD)
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Six minute walk distance covered
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Short Physical Performance Buttery test (SPPB)
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Level of daily physical activity
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Exercise tolerance
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
measure: Cardiac function
timeFrame: Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Sotiria Hospital
Study officials:
affiliation: Sotiria General Hospital for Chest Diseases, Athens, Greece
name: Nikolaos Chynkiamis, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Goertz YMJ, Van Herck M, Delbressine JM, Vaes AW, Meys R, Machado FVC, Houben-Wilke S, Burtin C, Posthuma R, Franssen FME, van Loon N, Hajian B, Spies Y, Vijlbrief H, van 't Hul AJ, Janssen DJA, Spruit MA. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome? ERJ Open Res. 2020 Oct 26;6(4):00542-2020. doi: 10.1183/23120541.00542-2020. eCollection 2020 Oct.
citation: Carfi A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020 Aug 11;324(6):603-605. doi: 10.1001/jama.2020.12603.
citation: Evans RA, McAuley H, Harrison EM, Shikotra A, Singapuri A, Sereno M, Elneima O, Docherty AB, Lone NI, Leavy OC, Daines L, Baillie JK, Brown JS, Chalder T, De Soyza A, Diar Bakerly N, Easom N, Geddes JR, Greening NJ, Hart N, Heaney LG, Heller S, Howard L, Hurst JR, Jacob J, Jenkins RG, Jolley C, Kerr S, Kon OM, Lewis K, Lord JM, McCann GP, Neubauer S, Openshaw PJM, Parekh D, Pfeffer P, Rahman NM, Raman B, Richardson M, Rowland M, Semple MG, Shah AM, Singh SJ, Sheikh A, Thomas D, Toshner M, Chalmers JD, Ho LP, Horsley A, Marks M, Poinasamy K, Wain LV, Brightling CE; PHOSP-COVID Collaborative Group. Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study. Lancet Respir Med. 2021 Nov;9(11):1275-1287. doi: 10.1016/S2213-2600(21)00383-0. Epub 2021 Oct 7.
citation: PHOSP-COVID Collaborative Group. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. Lancet Respir Med. 2022 Aug;10(8):761-775. doi: 10.1016/S2213-2600(22)00127-8. Epub 2022 Apr 23.
citation: Wynberg E, van Willigen HDG, Dijkstra M, Boyd A, Kootstra NA, van den Aardweg JG, van Gils MJ, Matser A, de Wit MR, Leenstra T, de Bree G, de Jong MD, Prins M; RECoVERED Study Group. Evolution of Coronavirus Disease 2019 (COVID-19) Symptoms During the First 12 Months After Illness Onset. Clin Infect Dis. 2022 Aug 24;75(1):e482-e490. doi: 10.1093/cid/ciab759.
citation: Thompson EJ, Williams DM, Walker AJ, Mitchell RE, Niedzwiedz CL, Yang TC, Huggins CF, Kwong ASF, Silverwood RJ, Di Gessa G, Bowyer RCE, Northstone K, Hou B, Green MJ, Dodgeon B, Doores KJ, Duncan EL, Williams FMK; OpenSAFELY Collaborative; Steptoe A, Porteous DJ, McEachan RRC, Tomlinson L, Goldacre B, Patalay P, Ploubidis GB, Katikireddi SV, Tilling K, Rentsch CT, Timpson NJ, Chaturvedi N, Steves CJ. Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat Commun. 2022 Jun 28;13(1):3528. doi: 10.1038/s41467-022-30836-0.
citation: Boscolo-Rizzo P, Guida F, Polesel J, Marcuzzo AV, Capriotti V, D'Alessandro A, Zanelli E, Marzolino R, Lazzarin C, Antonucci P, Sacchet E, Tofanelli M, Borsetto D, Gardenal N, Pengo M, Tirelli G. Sequelae in adults at 12 months after mild-to-moderate coronavirus disease 2019 (COVID-19). Int Forum Allergy Rhinol. 2021 Dec;11(12):1685-1688. doi: 10.1002/alr.22832. Epub 2021 Jun 9. No abstract available.
citation: Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, Pujol JC, Klaser K, Antonelli M, Canas LS, Molteni E, Modat M, Jorge Cardoso M, May A, Ganesh S, Davies R, Nguyen LH, Drew DA, Astley CM, Joshi AD, Merino J, Tsereteli N, Fall T, Gomez MF, Duncan EL, Menni C, Williams FMK, Franks PW, Chan AT, Wolf J, Ourselin S, Spector T, Steves CJ. Attributes and predictors of long COVID. Nat Med. 2021 Apr;27(4):626-631. doi: 10.1038/s41591-021-01292-y. Epub 2021 Mar 10.
citation: Lindahl A, Aro M, Reijula J, Makela MJ, Ollgren J, Puolanne M, Jarvinen A, Vasankari T. Women report more symptoms and impaired quality of life: a survey of Finnish COVID-19 survivors. Infect Dis (Lond). 2022 Jan;54(1):53-62. doi: 10.1080/23744235.2021.1965210. Epub 2021 Aug 19.
citation: Fernandez-de-Las-Penas C, Martin-Guerrero JD, Pellicer-Valero OJ, Navarro-Pardo E, Gomez-Mayordomo V, Cuadrado ML, Arias-Navalon JA, Cigaran-Mendez M, Hernandez-Barrera V, Arendt-Nielsen L. Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study. J Clin Med. 2022 Jan 14;11(2):413. doi: 10.3390/jcm11020413.
citation: Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med. 2021 Jan;27(1):28-33. doi: 10.1038/s41591-020-01202-8. Epub 2021 Jan 13.
citation: Spruit MA, Holland AE, Singh SJ, Tonia T, Wilson KC, Troosters T. COVID-19: interim guidance on rehabilitation in the hospital and post-hospital phase from a European Respiratory Society- and American Thoracic Society-coordinated international task force. Eur Respir J. 2020 Dec 3;56(6):2002197. doi: 10.1183/13993003.02197-2020. Print 2020 Dec.
citation: Singh SJ, Barradell AC, Greening NJ, Bolton C, Jenkins G, Preston L, Hurst JR. British Thoracic Society survey of rehabilitation to support recovery of the post-COVID-19 population. BMJ Open. 2020 Dec 2;10(12):e040213. doi: 10.1136/bmjopen-2020-040213.
citation: Fugazzaro S, Contri A, Esseroukh O, Kaleci S, Croci S, Massari M, Facciolongo NC, Besutti G, Iori M, Salvarani C, Costi S; Reggio Emilia COVID-19 Working Group. Rehabilitation Interventions for Post-Acute COVID-19 Syndrome: A Systematic Review. Int J Environ Res Public Health. 2022 Apr 24;19(9):5185. doi: 10.3390/ijerph19095185.
citation: Spielmanns M, Buelow MM, Pekacka-Egli AM, Cecon M, Spielmanns S, Windisch W, Hermann M. Clinical and Functional Predictors of Response to a Comprehensive Pulmonary Rehabilitation in Severe Post-COVID-19 Patients. Microorganisms. 2021 Nov 28;9(12):2452. doi: 10.3390/microorganisms9122452.
citation: Kolodziej M, Wyszynska J, Bal-Bochenska M. COVID-19: A New Challenge for Pulmonary Rehabilitation? J Clin Med. 2021 Jul 29;10(15):3361. doi: 10.3390/jcm10153361.
citation: Dalbosco-Salas M, Torres-Castro R, Rojas Leyton A, Morales Zapata F, Henriquez Salazar E, Espinoza Bastias G, Beltran Diaz ME, Tapia Allers K, Mornhinweg Fonseca D, Vilaro J. Effectiveness of a Primary Care Telerehabilitation Program for Post-COVID-19 Patients: A Feasibility Study. J Clin Med. 2021 Sep 27;10(19):4428. doi: 10.3390/jcm10194428.
citation: D'Angelo E, Prandi E, Marazzini L, Milic-Emili J. Dependence of maximal flow-volume curves on time course of preceding inspiration in patients with chronic obstruction pulmonary disease. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 1):1581-6. doi: 10.1164/ajrccm.150.6.7952618.
citation: Koulouris N, Mulvey DA, Laroche CM, Green M, Moxham J. Comparison of two different mouthpieces for the measurement of Pimax and Pemax in normal and weak subjects. Eur Respir J. 1988 Oct;1(9):863-7.
citation: Ringqvist T. The ventilatory capacity in healthy subjects. An analysis of causal factors with special reference to the respiratory forces. Scand J Clin Lab Invest Suppl. 1966;88:5-179. No abstract available.
citation: Darling RC, Cournand A, Richards DW. STUDIES ON THE INTRAPULMONARY MIXTURE OF GASES. III. AN OPEN CIRCUIT METHOD FOR MEASURING RESIDUAL AIR. J Clin Invest. 1940 Jul;19(4):609-18. doi: 10.1172/JCI101163. No abstract available.
citation: Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, Pellegrino R, Wanger J. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005 Oct;26(4):720-35. doi: 10.1183/09031936.05.00034905. No abstract available.
citation: Standardized lung function testing. Official statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:1-100. No abstract available.
citation: Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377-81.
citation: ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available.