Gender Differences in the Recovery Rate Following PR in Patients With Long COVID-19

Gender Differences in the Recovery Rate Following a Hybrid Pulmonary Rehabilitation Programme in Patients With Long COVID-19 Syndrome

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?

Study Overview

• Status: Completed
• Conditions: Post Acute COVID-19 Syndrome
• Intervention / Treatment: Other: Out-patient Pulmonary Rehabilitation

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.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

• Study Contact: Name: Nikolaos Chynkiamis, Ph.D.; Phone Number: +302107763421; Email: nikchy@thorax.org.gr
• Study Contact Backup: Name: Angelos Vontetsianos, MD; Phone Number: +302107763452; Email: agelvonte@gmail.com

Study Locations

• Greece
  • Athens, Greece
    • Sotiria Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• 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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Men with long COVID-19 syndrome; Patients were male adults (>18 years), with persistent symptoms more than 3 months since the acute phase of the COVID-19.	Other: Out-patient Pulmonary Rehabilitation; Pulmonary Rehabilitation (PR) programme consisting of 30 minutes interval aerobic exercise on cycle ergometers at 100% of peak work rate (WRpeak) and resistance exercises for the upper body. Dyspnoea and leg discomfort were recorded on the modified 1-10 Borg scale, whereas heart rate (HR) and oxygen saturation (SpO2%) were monitored by a pulse oximeter. Based on symptoms of breathlessness and fatigue reported at the end of each session, the exercise intensity was increased by 5-10% of the baseline WRpeak in the next session. The remote 24 home-based PR sessions consisted of 30 minutes walking with an individualised target of steps, recorded via the mobile app installed in the patients' mobile phone. The steps, leg discomfort and dyspnoea were reported by the patient via a physical activity diary on a weekly basis. If dyspnoea and fatigue were both <4 at the Borg scale the weekly target of steps was increased by 5-10% by the assessors.
Women with long COVID-19 syndrome; Patients were women adults (>18 years), with persistent symptoms more than 3 months since the acute phase of the COVID-19.	Other: Out-patient Pulmonary Rehabilitation; Pulmonary Rehabilitation (PR) programme consisting of 30 minutes interval aerobic exercise on cycle ergometers at 100% of peak work rate (WRpeak) and resistance exercises for the upper body. Dyspnoea and leg discomfort were recorded on the modified 1-10 Borg scale, whereas heart rate (HR) and oxygen saturation (SpO2%) were monitored by a pulse oximeter. Based on symptoms of breathlessness and fatigue reported at the end of each session, the exercise intensity was increased by 5-10% of the baseline WRpeak in the next session. The remote 24 home-based PR sessions consisted of 30 minutes walking with an individualised target of steps, recorded via the mobile app installed in the patients' mobile phone. The steps, leg discomfort and dyspnoea were reported by the patient via a physical activity diary on a weekly basis. If dyspnoea and fatigue were both <4 at the Borg scale the weekly target of steps was increased by 5-10% by the assessors.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue	Degree of fatigue will be assessed via the Functional Assessment of Chronic Illness Therapy questionnaire	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quadriceps muscle strength	Quadriceps muscle strength will be reported as maximum strength in kg	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Handgrip muscle strength	Handgrip muscle strength will be reported as maximum strength in kg	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Six minute walk distance covered	The distance that patients cover during the six minute walk test.	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Short Physical Performance Buttery test (SPPB)	SPPB is a series of test including balance, 4 meter walk and 5 sit-to-stand repetitions. The test assess the functional capacity of the patients.	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Level of daily physical activity	Level of daily physical activity will be reported as steps per day the week prior the initiation of the intervention and one week following the completion of the intervention.	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Exercise tolerance	Exercise tolerance will be assessed by performing a cardiopulmonary exercise test.	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Inspiratory muscle strength	Inspiratory muscle strength will be reported as maximum strength in centimeters water	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Expiratory muscle strength	Expiratory muscle strength will be reported as maximum strength in centimeters water	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Dyspnoea	Dyspnoea will be assessed via completion of modified Medical Research Council Dyspnoea Scale questionnaire. The score ranges from 0-4. The greater the score, the worse the dyspnoea levels	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Emotional status	Emotional status will be assessed via completion of the Hospital Anxiety and Depression. Scale questionnaire. The score ranges from 0-21 for each component (anxiety and depression). The higher the score, the higher the levels of anxiety and depression.	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Symptoms	Symptoms will be assessed via completion of the Chronic Obstructive Pulmonary Disease Assessment Tool questionnaire. The score ranges from 0-40 points. The higher the score, the worse the prognosis.	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Self-reported quality of life	Self-reported quality of life will be assessed via completion of the EuroQol-5Dimension-5Levels questionnaire.	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Post traumatic stress disorder (PTSD)	PTSD will be assessed via completion of the Impact Event Scale-Revised questionnaire.The total score ranges from 0-88. The higher the score, the higher the levels of PTSD	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)
Cardiac function	Cardiac function will be assessed via a resting echocardiography	Prior and following the completion of a 3 month pulmonary rehabilitation programme (At 0 and at 3 months)

Collaborators and Investigators

• Sponsor: National and Kapodistrian University of Athens
• Investigators: Principal Investigator: Nikolaos Chynkiamis, Ph.D., Sotiria General Hospital for Chest Diseases, Athens, Greece

Publications and helpful links

General Publications

• Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377-81.
• 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. Erratum In: Am J Respir Crit Care Med. 2016 May 15;193(10):1185.
• 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. Erratum In: Nat Med. 2021 Jun;27(6):1116.
• 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 Aug 13;56(6):2002197. doi: 10.1183/13993003.02197-2020. Online ahead of print.
• 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.
• 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.
• 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.
• 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. Erratum In: Lancet Respir Med. 2022 Jan;10(1):e9.
• 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. Erratum In: Lancet Respir Med. 2022 Jul 26;:
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Standardized lung function testing. Official statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:1-100. No abstract available.

Helpful Links

• Coronavirus cases
• Coronavirus cases

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2022
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): March 15, 2023

Study Registration Dates

• First Submitted: February 19, 2023
• First Submitted That Met QC Criteria: February 19, 2023
• First Posted (Actual): February 21, 2023

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: October 7, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Quality of life; Pulmonary Rehabilitation; Muscle strength; Post-Acute COVID-19 Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Disease; Chronic Disease; Post-Infectious Disorders; COVID-19; Syndrome; Post-Acute COVID-19 Syndrome
• Other Study ID Numbers: 24633

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The individual participant data will not be shared to any other research team. The data that will be collected retrospectively for the present study as the patients have already completed the pulmonary rehabilitation programme. The rehabilitation department of our clinic is responsible for the storage and the management of patients data. In that content, they will share with the research team the necessary data to complete our study. The research team is not authorised to share the data with other research teams or researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No