Evaluation of the Effectiveness of a Spa Treatment for People With Post-Covid 19 Conditions.

Justification/context

Most of the studies initially published involved cohorts of patients hospitalized during the initial phase. The French Covid-19 cohort, which studied 1137 patients after hospitalization for SARS-CoV-2 infection, showed that 60% complained of at least one symptom still present at 6 months, 24% three or more persistent symptoms, and that 29% of those with a professional activity had not returned to work (1). At 12 months, 34% of women and 23% of men were still on sick leave (2). The susceptibility of adults seems to increase with age, number of symptoms in the acute phase, body mass index, female sex and absence of vaccination (3). The evolution of post-covid disease fluctuates over time (4).

Studies of cohorts of patients followed up in primary care show that post-covid affliction affects people with both severe and mild forms of the disease. As part of the virtual ambulatory follow-up program (CoviCare), 410 people testing positive for COVID-19 at Geneva University Hospital were followed up 7 to 9 months after diagnosis: 39.0% reported residual symptoms. Analysis of a prospective cohort of 247 Norwegian patients followed at home showed that 52% of young adults aged 16 to 30 had symptoms at 6 months, including loss of taste and/or smell (28%), fatigue (21%), dyspnea (13%), impaired concentration (13%) and memory impairment (11) A literature review of quality of life in post-covid conditions conducted between March 2020 and March 2021 (12 studies involving 4828 patients) showed that the combined prevalence of poor quality of life (EQ-VAS) was estimated at 59%. Meta-regression analysis showed that poor quality of life was significantly higher in patients with ICU admission and fatigue. At 2 months, an alteration in quality of life defined by a 10-point difference on the EQ-5D-5L analog scale was noted in 44% of hospitalized patients. The study by Logues et al, involving 177 patients in the United States, showed that 30% of outpatients had an altered quality of life at 9 months, defined as a 10-point decrease in the EQ-VAS compared with the previous situation, versus 2% of non-infected control subjects. Menges et al studied quality of life using the EQ-5D-5L scale in 431 patients in Zurich, 89% of whom were non-hospitalized. They showed that 53% of participants reported difficulties in at least one dimension of the EQ-5D-5L. The dimensions most frequently affected were pain/discomfort (39%) and anxiety/depression (31%).

Primary objective:

To compare the efficacy of a spa-based rehabilitation and support protocol (Protocol B) versus a conventional primary care rehabilitation and support protocol (Protocol A) on changes in overall quality of life at 2 months in patients suffering from post-Covid-19 symptoms who did not warrant́ hospitalization for treatment of the initial phase of Covid

Secondary objectives:

The secondary objectives of this project are:

* Compare changes in overall quality of life at 12 months between Protocols A and B. * Compare short- (M2) and medium- (M12) term changes in persistent symptoms between Protocols A and B. * Compare short (M2) and medium (M12) term changes in other dimensions of quality of life according to Protocols A and B: mobility, autonomy, usual activities, pain/discomfort, anxiety/depression. * Compare the effect of protocol B versus protocol A on return to work (nature, delay and volume). * Analyze post-covid-19 symptom profiles and their association with post-infection quality-of-life trajectories. * Analyze and compare the mechanisms and conditions of efficacy of protocols A and B (dose of intervention received, appropriateness of the intervention to the realities of the field and the needs of the target population, patient commitment and satisfaction).

Primary outcome:

The primary endpoint of this study is the change in utility score derived from quality of life and measured by the EQ-5D-5L at inclusion (V0) and at 2 months after inclusion (V2).

Secondary outcomes:

* Variation in mean utility score (EQ-5D-5L) calculated in each management group (protocol A and protocol B) between V0 and V3, V4 and V5 (including Vend). * Variation in the following parameters : number of symptoms and symptom clusters, rating by symptom scales and tests (Appendices), asthenia (Chalder fatigue scale (5) sleep disorders (Insomnia Severity Index́ (ISI) (6)), pain (visual analog pain scale (25)), anxiety-depression (HAD scale (7), post-traumatic stress (PCL-5 scale (8)), dyspnea (mMRC-modified Medical Research Council scale) and modified Borg scale (9,10)), lower-limb muscular strength (standing-sitting test, (11,12), 6-minute stepper test (13), postural balance on posturography platform, with sensitization by modification of somato-sensory afferents (foam tray) and visual (virtual realitý goggles) (14,15), balance tests (monopodal support eyes open and closed). * Variation in scores for the 5 items and the visual analog scale (VAS) comprising the EQ-5D-5L questionnaire. * Data on return to work (time taken to return to work part-time or full-time, modified post, etc.). * Number of medical consultations, consumption of physiotherapy, psychology and other paramedical care, analgesics, anxiolytics, antidepressants, systemic or inhaled corticoids, bronchodilators and antihistamines not included in the protocol.

Methods:

This is a regional multicenter randomized controlled open-label study. Patients will be randomized 1:1 per center into two different intervention arms:

* Control arm (Protocol A): dry rehabilitation protocol for 3 weeks and psychological support for 8 weeks * Intervention arm (Protocol B): natural mineral water rehabilitation protocol for 3 weeks and psychological support for 8 weeks.

Each included patient will be followed-up for one year with 5 different visits: at inclusion (V0), at one month (V1), at 2 months (V2), at 6 months (V3) and at 12 months (V4).

Number of research participants required:

Randomization will be 1:1 per center, and the primary endpoint is the utility score derived from quality of life and measured by the EQ-5D-5L ranging from 0 (state corresponding to death) to 1 (state of perfect health). We set an alpha risk of 5% and a power of 80%. Estimating a standard deviation of the utility score between the two groups of 0.12 and a minimum difference to be highlighted of 0.05 (equivalent to 5 points out of 100), we will need to include 91 patients per group, for a total of 182 patients. Assuming 10% drop-out during the treatment period (first 3 weeks), we need to include a total of 200 patients in the 4 selected spa centers (Amnéville, Contrexéville, Vittel and Nancy).

Inclusion capacity in the various centers is as follows: Amnéville (60), Contrexéville (30), Vittel (30) and Nancy (80).

Inclusion criteria for research subjects

* Patients who have received full information on the organization of the research, who have not objected to their participation and to the use of their data, and who have given their free and informed consent in writing, * Patients aged 18 and over, * Patients with a history of symptomatic Covid-19 infection documented by RT-PCR, antigenic test, positive serology in a previously unvaccinated patient or other validated virological diagnostic test at the patient's inclusion date, * No hospitalization for treatment of the initial phase of Covid-19, * Person presenting at least two common symptoms of post-Covid disease, including fatigue, shortness of breath and cognitive dysfunction, which have appeared de novo and have been evolving for more than 12 weeks and present for more than 8 weeks, * Initial and prolonged symptoms not explained by another diagnosis with no known link to Covid-19, * Normal SpO2 at rest not decreasing beyond 4% on exercise, * Membership of a social security scheme or beneficiary of such a scheme

Criteria for non-inclusion of research subjects:

* Acute cardiovascular disease (acute coronary syndrome, arrhythmia, heart failure, venous thromboembolism, myocarditis, stroke, acute ischemia, etc.) less than 3 months old and at risk of recurrence or decompensation, * Respiratory disease: COPD, interstitial fibrosis, exercise-induced desaturation, sleep apnea, * Stroke less than 6 months old, * Pregnant women, * adults under legal protection (guardianship, curatorship, safeguard of justice), * Severe and unstabilized psychiatric pathology, severe depressive syndrome, delirious decompensation, panic attacks, anxiety-depression syndrome, * Acute and progressive conditions (infectious, cancerous and inflammatory), * Persons presenting a contraindication to hydrokinesitherapy and crenotherapy (infected dermatoses, severe immune deficiencies, inflammatory diseases in flare-ups, fecal or urinary incontinence, presence of a suprapubic or intravenous catheter, colostomy, hydrophobia. * Refusal to sign the free and informed consent form

Recruitment of research subjects (patients, controls where applicable):

The pre-selection of patients will be carried out by the structures dedicated to the care of patients suffering from post-covid conditions in the region: general practitioners, infectious disease specialists, physical medicine and rehabilitation specialists, physiotherapists. They will present the project and hand out the newsletter.

Are specially protected persons concerned? no

Prohibited period:

The person must not be included in any other intervention research during the treatment period for this research. The blackout period corresponds to the period between the inclusion visit at V0 and the V2 visit carried out at the end of the treatment period (2 months after the inclusion visit).

Compensation No compensation is planned for participants in the COVIDTHERM study.

Duration:

The inclusion period is scheduled to last 12 months, and each patient will be followed up for 12 months, for a total of 24 months

Investigation procedures and differences from usual care:

General principle:

Physiotherapists will be trained to harmonize their practices and adapt them to the specific situations of patients with post-Covid symptoms. Psychotherapy sessions will be carried out via teleconsultation, with the aim of facilitating and harmonizing the care of patients included in the study, regardless of their place of residence. Health education materials will be given to patients at the start of the treatment period, when the first assessment is carried out. Topics covered will include Understanding the post-covid condition; Understanding the psychological repercussions; Managing breathing; Managing effort; Rehabilitating the sense of smell; Managing stress; Adapting diet.

For both arms of the study, specific procedures include 3 visits to the study's investigating physician, 5 physiotherapy check-ups and 1 psychological check-up. Participants will be recruited from the population living near the resorts. Transport costs will be covered as part of the study. The prospective resorts in the Grand Est region are : Nancy Thermal, Amnéville-les-Thermes, Contrexéville and Vittel.

Protocol A: Control group Protocol A combines dry physiotherapy, psychological support and health education.

9 outpatient physiotherapy sessions over 3 weeks in the offices of private physiotherapists taking part in the study, or in suitable care facilities agreeing to take part.

1 initial psychological assessment followed by 7 psychological teleconsultations (1/week).

Protocol B: Intervention group Protocol B combines hydrokinesitherapy and hydrotherapy, psychological support and health education (kit containing health education materials).

9 hydrokinesitherapy sessions and 36 hydrothermal treatments\* will be carried out over 3 weeks in one of the spa establishments participating in the study and close to the patient's place of residence.

• Utility score (EQ-5D-5L) [Time frame: Utility score (EQ-5D-5L) measured at the 2-month visit (V2), the six-month visit (V3) and the 12-month visit (V4)]
• Number of symptoms and symptoms clusters [Time frame: Utility score (EQ-5D-5L) measured at the 2-month visit (V2), the six-month visit (V3) and the 12-month visit (V4)]
• Return to work [Time frame: Employment status requested at the 2-month visit (V2), the six-month visit (V3) and the 12-month visit (V4)]
• Medical consultations [Time frame: Number of medical consultations at the 2-month visit (V2), the six-month visit (V3) and the 12-month visit (V4)]