Cardiopulmonary Exercise Tests in Patients With Long COVID (PREPP-19)

Interrogative Approaches Identify Causes of Physical Impairment in Those Affected by Post COVID-19 Morbidity (Long COVID) - an International Multicenter Observational Study

The value of clinical cardiopulmonary exercise testing (CPET) within healthcare settings has been established in the last decade. CPET methods remain highly relevant in the COVID-19 endemic phase and should be used to assess those recovering from COVID-19 (SARS-CoV-2) infection. This diagnostic tool could play an integral role in disease prognostication and evaluate the integrative response to incremental exercise. Date from such assessments can enable practitioners to characterise cardio-respiratory fitness and identify reasons for physical impairment or abnormal cardio-respiratory function. More than 50% of patients admitted to hospital will experience cardiorespiratory issues and significant morbidity during their recovery and will require significant rehabilitative support. In this context, measurements obtained from an assessment of cardio-respiratory responses to physiological stress could provide insight regarding the integrity of the pulmonary-vascular interface and characterisation of any impairment or abnormal cardio-respiratory function. Current approaches to rehabilitation are being developed on existing knowledge from Severe Acute Respiratory Syndrome (SARS) and Acute Respiratory Distress Syndrome (ARDS) related illness. These provide important insight but do not provide insight into the novel challenges provided by COVID-19.

Study Overview

• Status: Completed
• Conditions: Long COVID; COVID Long-Haul
• Intervention / Treatment: Procedure: 2 day cardiopulmonary exercise test

• Study Type: Observational
• Enrollment (Actual): 146

Contacts and Locations

Study Locations

• India
  • Bengaluru, India
    • Ramaiah Medical College
• United Kingdom
  • Newcastle Upon Tyne, United Kingdom
    • Northumbria University
  • Derbyshire
    • Derby, Derbyshire, United Kingdom
      • University of Derby
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom
      • Sheffield Hallam University
• United States
  • Illinois
    • Chicago, Illinois, United States, 60607
      • University of Illinois at Chicago

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients will be assessed according to the eligibility criteria and recruited directly from Long COVID Clinics in the UK (Derbyshire Community Health Services, Sheffield Teaching Hospitals NHS Foundation Trust and Northumbria NHS Trust), the University of Illinois Post-COVID-19 Clinic, (Chicago, USA) and the Ramiah Medical Centre Post COVID Centre (Bangalore, India). Long COVID patients will be assessed according to the eligibility criteria and recruited following referral or contact with a long COVID clinic or having suspected or confirmed long COVID. Social media and targeted recruitment from established pages will be used to advertise the opportunity to engage with the trial for those in proximity

Description

Inclusion Criteria:

• • Aged 18 to 65 years old

  • Diagnosed with COVID-19
  • Still suffering from symptoms of COVID-19, 3 months after initial infection
  • Sufficient English language comprehension and cognitive ability to understand the study protocol, give informed consent and follow instructions.

Exclusion Criteria:

• • <18 years of age

  • Admitted to or received treatment from Intensive Care Units
  • Unconfirmed COVID-19 test diagnosis
  • Unable to understand verbal or written information in English
  • Achieving a grade 0 or 1 on the PCFS.
  • Unstable angina
  • Uncontrolled hypertension, that is, resting systolic blood pressure (SBP) >180mmHg, or resting diastolic blood pressure (BP) (DBP) >110mmHg
  • Orthostatic blood pressure drop of >20 mmHg with symptoms
  • Significant aortic stenosis (aortic valve area 120 bpm)
  • Acute pericarditis or myocarditis
  • Decompensated HF
  • Third degree (complete) atrioventricular (AV) block without pacemaker
  • Recent embolism
  • Acute thrombophlebitis
  • Resting ST segment displacement (>2 mm)
  • Uncontrolled diabetes mellitus
  • Severe orthopaedic conditions that would prohibit exercise
  • Other metabolic conditions, such as acute thyroiditis, hypokalaemia, hyperkalaemia or hypovolaemia (until adequately treated)
  • Severe grade 3 rejection (cardiac transplantation recipients Appendix N).

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
People with Long COVID; Eligibility; Aged 18 to 65 years old; Diagnosed with COVID-19; Still suffering from symptoms and experiencing functional limitations beyond 3 months after initial COVID-19 infection (quantified as PCFS grade 1 or greater).; Sufficient English language comprehension and cognitive ability to understand the study protocol, give informed consent and follow instructions.	Procedure: 2 day cardiopulmonary exercise test; Consecutive day 2 day CPET and follow up for 7 days for subjective feelings/fatigue.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiopulmonary Exercise Test- Rate of Oxygen Utilisation	Rate of Oxygen Utilisation (VO2; l/min)	During CPET1 and CPET2
Cardiopulmonary Exercise Test- Rate of carbon dioxide production	Rate of Carbon Dioxide Production (VCO2; l/min)	During CPET1 and CPET2
Cardiopulmonary Exercise Test- Respiratory Exchange Ratio	Respiratory Exchange Ratio (VO2/VCO2)	During CPET1 and CPET2
Cardiopulmonary Exercise Test: Maximal Rate of Oxygen Utilisation	Maximal Rate of Oxygen Utilisation per kg body mass (VO2max; ml/kg/min)	During CPET1 and CPET2
Cardiopulmonary Exercise Test- Respiratory Threshold	Respiratory Threshold breath by breath (l/min)	During CPET1 and CPET2
Cardiopulmonary Exercise Test- Minute Ventilation	Minute Ventilation using breath by breath (l/min)	During CPET1 and CPET2
Cardiopulmonary Exercise Test- Blood lactate	Blood Lactate Concentration from fingertip (mmol/l)	During CPET1 and CPET2
Prevalence of symptoms of post exertional Malaise	Symptom Profile post exercise protocols- Questionnaire	7 days post exercise

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood biomarkers of Inflammation- IL-6	Concentration of Interleukin 6	Day 1 and Day 2
Blood biomarkers of Inflammation- IL-1	Concentration of Interleukin 1	Day 1 and Day 2
Blood biomarkers of Inflammation- Microclots	Number of Microclots	Day 1 and Day 2
Blood biomarkers of Inflammation- D-Dimer	D-Dimer Concentration	Day 1 and Day 2
Blood biomarkers of Inflammation- CRP	C-Reactive protein Concentration	Day 1 and Day 2
Echocardiogram	12 lead echocardiogram.	Baseline, Day 1 and Day 2
Resting Systolic Blood Pressure	Systolic Blood Pressure at Rest (mmHg)	Baseline, Day 1 and Day 2
Resting Diastolic Blood Pressure	Diastolic Blood Pressure at Rest (mmHg)	Baseline, Day 1 and Day 2
Exercise Diastolic Blood Pressure	Diastolic Blood Pressure During Exercise (mmHg)	Baseline, Day 1 and Day 2
Exercise Systolic Blood Pressure	Systolic Blood Pressure During Exercise (mmHg)	Baseline, Day 1 and Day 2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom Profile Questionnaire	Description of previous and current symptom/s of Long COVID	Baseline
Quality of Life questionnaire	EQ-5D-5L	Baseline
Sleep Behavour	Pittsburgh Sleep Quality Index	Baseline
Fatigue Questionnaire- FAS	Fatigue Assessment Scale	Baseline, Day 1 and Day 2
Fatigue Questionnaire- MFI	Multidimensional Fatigue Index (MFI-20)	Baseline, Day 1 and Day 2
Medical Research Council Dyspnoea Scale	Breathlessness scale	Baseline
Post COVID-19 functional status Scale	Questionnaire to see effect of COVID-19 on physical function- 0= No Limitations; 4- Severe Limitations to function	Baseline
Cognition	Montreal cognitive assessment	Baseline
6 minute walk	6 minute walk distance (metres)	Baseline
Timed Up and Go	5m timed up and go (seconds)	Baseline
Lung Function Assessment- FEV1	Forced Expiratory Volume in 1 Second (l)	Baseline
Lung Function Assessment- FVC	Forced Vital Capacity (l)	Baseline
Lung Function Assessment- PEF	Peak Expiratory Flow Rate (l/min)	Baseline
Lung Function Assessment- MIP	Maximal Inspiratory Pressure (mmHg)	Baseline
Lung Function Assessment- MEP	Maximal Expiratory Pressure (mmHg)	Baseline
Height	measurement of body stature (m)	Baseline
Weight	Measurement of body mass (kg)	Baseline
body mass index	weight and height will be combined to report BMI in kg/m^2	Baseline

Collaborators and Investigators

• Sponsor: Sheffield Hallam University
• Collaborators: King's College London; University of Nottingham; University of Illinois at Chicago; Northumbria University; University of Derby; MS Ramaiah Medical College & Hospitals

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Actual): April 30, 2024
• Study Completion (Actual): April 30, 2024

Study Registration Dates

• First Submitted: March 26, 2024
• First Submitted That Met QC Criteria: April 30, 2024
• First Posted (Actual): May 1, 2024

Study Record Updates

• Last Update Posted (Actual): August 22, 2024
• Last Update Submitted That Met QC Criteria: August 21, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• 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; Chronic Disease; Post-Infectious Disorders; COVID-19; Post-Acute COVID-19 Syndrome
• Other Study ID Numbers: PREPP19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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