 Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 1 - Long-term outcomes of different rehabilitation programs in patients with long COVID syndrome: a cohort prospective study Irina A. Grishechkina (1) Andrey A. Lobanov (1), Sergey V. Andronov (1), Andrey P. Rachin (1), Anatoliy D. Fesyun (1,2), Elena P. Ivanova (1), Stefano Masiero (3,4), Maria Chiara Maccarone (3) (1) National Medical Research Center, Moscow, Russia; (2) Moscow State University of Food Production, Moscow, Russia; (3) Physical Medicine and Rehabilitation School, Department of Neuroscience, University of Padova, Padua, Italy; (4) Department of Neuroscience, Rehabilitation Unit, University of Padova, Padua, Italy, Italy. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Abstract After the resolution of the acute SARS-COV-2 infection, an important percentage of patients do not fully recover and continue to present several symptoms. Nevertheless, there is a lack of data in the literature on the effects of rehabilitation programs on medium- and long-term long COVID symptoms. Therefore, the aim of this study was to evaluate the long-term outcomes after rehabilitation programs in long COVID syndrome patients. A prospective cohort study was conducted from August 2021 to March 2022, involving 113 patients with long COVID syndrome. The patients in the experimental group (EG, n=25) received a tailored and multidisciplinary rehabilitative program, involving aquatic exercises, respiratory and motor exercises, social integration training and neuropsychologic sessions, LASER therapy and magnetotherapy. Patients in the other three comparison groups received eastern medicine techniques (CG1), balneotherapy and physiotherapy (group CG2), self-training and home-based physical exercise (CG3). Once the several rehabilitation protocols had been performed, a structured telephone contact was made with the patients after 6 months ± 7 days from the end of the rehabilitation treatment, in order to record the frequency of hospital ad-missions due to exacerbation of post-exacerbation syndrome, death or disability, and the need for other types of care or drugs. The patients in the comparison groups were more likely to request therapeutic care for emerging long COVID symptoms (χ2=6.635, p=0.001; χ2=13.463, p=0.001; χ2=10.949, p=0.001, respectively), as well as more likely to be hospitalized (χ2=5.357, p=0.021; χ2=0.125, p=0.724; χ2=0.856, p=0.355, respectively) when compared to the patients of the EG. The relative risk (RR) of hospital admissions in the observed cohort was 0.143 ±1,031 (СI: 0.019; 1.078); 0.580±1,194 (CI: 0.056; 6.022); 0,340±1,087 (CI: 0.040; 2.860). The RR of hospital admissions for patients with long COVID syndrome was reduced by 85.7%; 42.0% and 66.0%, respectively, when the experimental rehabilitation technique was employed. In conclusion, a tailored and multidisciplinary rehabilitative program seems to have a better preventive effect not only in the short term, but also over the next 6 months, avoiding the new onset of disabilities and the use of medicines and specialist advice, than other rehabilitative programs. Future studies will need to further investigate these aspects to identify the best rehabilitation therapy, also in terms of cost- effectiveness, for these patients. Key Words: Long COVID syndrome; rehabilitation; exercise therapy; relative risk; balneotherapy; health resort medicine. Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 After resolution of the acute SARS-COV-2 infection, an important percentage of patients does not fully recover and continue to present several symptoms. This condition of persistence of signs and symptoms that continue or develop after acute SARS CoV-2 infection has been called long COVID syndrome.1 The syndrome is characterized by the presence of symptoms for at least 2 months and the impossibility to e-plain them with an alternative diagnosis. Common symptoms include Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 2 - fatigue, breath-lessness, cognitive dysfunction, as well as a number of other symptoms that can lead to the impairment in carrying out daily activities and self-care.2- 7 These symptoms can be intermittent or recurrent over time.1 The pathogenetic mechanisms of long COVID syndrome are still debated, but long-term tissue damage and pathological inflammation (related to virus persistence, immune dysregulation and autoimmune reactions) seem to play a role in the medium- and long- term persistence of symptoms.3,4,8 Additionally, patients in the early stages of rehabilitation after the acute COVID-19 infection can present impaired microcirculation and reduced capacity to maintain an upright posture, which are largely accountable for symptoms such as fatigue, shortness of breath and low tolerance to physical exertion.9–14 Based on these findings, a rehabilitation program for patients with Long COVID syndrome was developed in the “National Medical Research Centre for Rehabilitation and Balneology” of the Ministry of Health of Russia (Patent Application # 2022113192 - 17 May 2022), incorporating the main components of respiratory rehabilitation for chronic lung diseases,15,16 balance and motor training, and a tailored aquatic exercise intervention.17 The results of this preliminary study seemed to confirm the effectiveness of physical exercise in ameliorating impaired upright posture and normalizing walking patterns. In addition, aquatic exercise carried out in mineral-rich water seemed to add a protective effect on the microcirculatory system, in the lymph flow and in tissue metabolism.14 Nevertheless, the lack of data in the literature on the effects of rehabilitation programs on medium- and long-term long COVID symptoms,18,19 and the heterogeneity in durations and contents of the few existing studies,20-23 determined the need for further investigations. Therefore, with this further analysis we aim to increasing knowledge on rehabilitation programs in patients with long COVID syndrome, evaluating also clinical outcomes in the long-term. Materials and Methods Study population This work was planned as part of an open, prospective, randomized, parallel-group study,24 to evaluate the effect of a program of aquatic exercises conducted in a bromine sodium chloride water with salinity of 120 g/dm3, diluted to 40 g/m3. Patient recruitment and follow-up were performed from August 2021 to March 2022. The study was conducted in four medical centers: the experimental group (EG) of patients was recruited in the "National Medical Research Center for Rehabilitation and Balneology" of the Ministry of Health of Russia, comparison group 1 (CG1) in the regional polyclinics in Moscow and Omsk; comparison group 2 (CG2) in a regional rehabilitation centre (the Republic of Buryatia); comparison group 3 (CG3) in another regional rehabilitation centre (Krasnodar Territory). Patients in the EG and in the CG1, CG2 and CG3 consisted of patients with long COVID syndrome who had indications for rehabilitation treatment.25 Inclusion criteria included: • age greater than 18 years old; • infection from SARS-CoV-2 virus confirmed by a Polymerase Chain Reac-tion (PCR) analysis; • diagnosis of long COVID syndrome, after the resolution of the COVID-19 acute infection (U 09.9).25 Exclusion criteria included: • refusal to sign the informed consent form; • re-infection with SARS-CoV-2 virus during the follow- up period; • participation in other rehabilitation protocols during the study period due to comorbidities; • pregnancy or lactation; • participation in other clinical studies in the year before the inclusion in this study. Study intervention The patients in the EG were recruited among the group of patients with long COVID syndrome who took part in the previous randomized clinical trial (n=25).14 Their rehabilitation program included 7-8 sessions of multidisciplinary rehabilitative interventions, involving a tailored protocol of aquatic exercises, respiratory and motor exercises, social integration training and neuropsychologic sessions, LASERtherapy and magne- totherapy .17 The CG1 (n=25) performed 7-8 sessions of a rehabilitation program that included climatotherapy, traditional oriental medicine methods (acupuncture, manual therapy, Qigong breathing), exercise therapy, LASERtherapy and magnetotherapy.26,27 Patients in CG2 (n=29) received respiratory and motor exercise therapy physiother-apy combined with inhalation of mineral water, balneotherapy with dry carbon dioxide baths and magnetotherapy for 10-15 sessions, in addition to climatotherapy.27 Pa-tients in CG3 (n=34) performed self-training and home-based physical exercise. Outcomes evaluation Once the informed consent had been signed and the several rehabilitation protocols had been performed, a structured telephone contact was made with the patients in-volved in the study after 6 months ± 7 days from the end of the rehabilitation treatment. The telephone survey was conducted by the same interviewer, to avoid differences in the compilation of the questionnaires. The following data were collected from patients or their relatives (in the case of loss of contact with the patient): extent of lung damage according to the Computerized Tomography (CT) scan during the acute COVID-19 infection, comorbidies, drugs consumption, number of hospital admissions, number of ambulance calls due to exacerbation of long COVID symptoms, new onset of disability, need for specialist consultations and eventual death of the patient and its causes. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of National Medical Research Center (Project identification code # IW, protocol # 6, 26 July 2021). Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 3 - Statistical analysis The results were processed using the Statistica for Windows, v. 8.0 software pack-age (Stat Soft Inc., США). The data were statistically processed using descriptive statis-tics and intergroup comparisons were made using the chi-square test (χ2). In addition, the relative risk of new hospital admissions in the patient cohorts was calculated. The significance of differences was considered to be established at p<0.05.24,28 Results A total of 120 patients were included in the study, 113 patients (aged between 21 and 85, mean age 58.4 years) completed the study, 7 patients (5.83%) dropped out. The majority of patients included in the study were female (30 male and 83 female patients, 26.55% and 73.45%, respectively). The four groups were comparable regarding gender (χ2=0.67, p=0.41) and age (U=4.0 Z=- 0.21, p=-0.83). The demographics characteristics, the extent of lung damage according to the CT scan during the acute COVID-19 infection and the comorbidities divided by patient group are shown in Table 1. The mean time since the onset of the acute COVID-19 infection was 6.5±2.5 months. As can be seen in Table 2, the groups differed in the frequency of new hospital ad-missions, prevailing in the comparison groups. In particular, a significantly greater number of new hospital admissions was recorded in the CG1. Indeed, after 6 months ± 7 days from the end of the rehabilitation treatment, the patients in the comparison groups were statistically significantly more likely to request therapeutic care for emerging long COVID symptoms (χ2=6.635, p=0.001; χ2=13.463, p=0.001; χ2=10.949, p=0.001, respec-tively), as well as more likely to be hospitalized (χ2=5.357, p=0.021; χ2=0.125, p=0.724; χ2=0.856, p=0.355, respectively) when compared to the patients of the EG. The relative risk (RR) of hospital admissions in the cohort of patients treated in the EG compared with the other patient groups was 0.143±1.031 (CI: 0.019; 1.078) when compared to CG1, 0.580±1.194 (CI: 0.056; 6.022) when compared to CG2, 0.340±1.087 (CI: 0.040; 2.860) when compared to CG3. The RR of hospital admissions was reduced by 85.7%; 42.0% and 66.0%, respectively, when the experimental rehabilitation technique was used. Moreover, patients in the comparison groups tended to consult a Pulmonologist more frequently, to have more General Practioners consultations (with a statistically signifi-cant difference in the comparison between EG and CG1), and to ask for an ambulance service more often during the six months due to the exacerbation of long COVID symptoms. There were no patient death or new onset of disability in any of the analyzed groups. Discussion At a time of increased morbidity due to the COVID-19 infection outcomes, it has been found that survivors of Table 1. Demographics characteristics and comorbidities divided by patient group Data Experimental group (n=25) Comparison group 1 (n=25) Comparison group 2 (n=29) Comparison group 3 (n=34) Demographics Average age, years, Me, [Q1 ; Q3] 60 [52.71] 65 [57.73] 62 [50; 73] 52 [39; 64] Under 50, abs. count (n=), % 6 (24.00 %) 4 (16.00 %) 6 (20.70 %) 16 (47.10%) 50-60 years old, abs. n=) 8 (32.00 %) 6 (24.00 %) 6 (20.70 %)) 4 (11.80%) 61-70 years old, abs. count (n=) 4 (16.00 %) 9 (36.00 %) 6 (20.70 %) 10 (29.40%) Over 70, absentee count (n) 7 (28.00 %) 6 (24.00 %) 11 (37.90 %) 4 (11.70%) Male sex, age, abs. quantity (n=) 7 (28.00 %) 5 (20.00 %) 8 (27.60 %) 10 (29.40 %) The extent of lung damage according to the CT scan in the acute phase of the disease Less than 50%, abs. quantity (n= ) 18 (72.00 %) 14 (56.00 %) 17 (58.60 %) 18 (72.00 %) 50% and more, abs. quantity (n=) 7 (28.00 %) 11 (44.00 %) 12 (41.4 %) 7 (28,00 %) Comorbid pathology Chronic Obstructive Pulmonary Disease abs. quantity (n=) 1 (4,00 %) 1 (4.00 %) 2 (6.90 %) 1 (2.90 %) Arterial hypertension, abs. quantity (n=) 16 (64.00 %) 9 (36.00 %) 16 (55.20 %) 1 (2.90 %) Coronary heart disease, abs. quantity (n=) 2 (8.00 %) 3 (12.0 %) 2 (69.0 %) 1 (2.90 %) Diabetes mellitus, abs. quantity (n=) 3 (12.00 %) 4 (16.0 %) 6 (20.70 %) 0 (0.00 %) Obesity, abs. quantity (n=) 12 (48.00 %) 0 (0.00%) 2 (6.90 %) 0 (0.00 %) Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 4 - the infection of any severity can need for rehabilitative interven-tions due to the so-called long COVID syndrome .2,3,5-8,29 This implies the development of tailored rehabilitation services, in order to target the different rehabilitative needs of these patients.2,3,6,8,15,29 Due to the complexity of the long COVID syndrome, previous studies that evaluated the individual rehabilitation approaches have shown that they range from self-exercises aimed at increasing physical activity,30,31 and traditional convalescent programs,32,33 to the use of complex, high-tech rehabilitation strategies,34 involving different organs and systems. Subsequently, worldwide many rehabilitation programs are being developed, taking into account the severity of patients’ dominant symptoms, the resources available from local health systems and the need to comply with anti- epidemic measures.20,23,35 However, so far there is a shortage of studies evaluating the medium- and long- term outcomes of different rehabilitation pro-grams.36-40 Our study tries to bridge this gap, evaluating different kind of rehabilitative protocols at six months. In the future, these findings could be employed to develop further analysis to assess the clinical and economic effects of the specific rehabilitation programs.15,20,27,41-45 Based on our results, a tailored and multidisciplinary rehabilitative program, in-volving aquatic exercises, respiratory and motor exercises, social integration training and neuropsychologic sessions, LASER therapy and magnetotherapy, seemed to reduce the request for long COVID symptoms care and the need for hospitalization. Moreover, the need for specialist consultations and ambulance calls seemed to be reduced after the multidisciplinary experimental protocol. Therefore, we can conclude from our preliminary data presented above that the use of this experimental program seemed to have a preventive effect lasting 6 months, reducing the relative risk of new hospital admissions and the need for therapy and other types of care due to a less frequent exacerbation of the symptoms. Since the economic cost of a treatment is evaluated by calculating not only the direct expenses, but also the indirect medical, as well as non-medical costs, our results suggest a reduction in overall expenses for patients treated with a multidisciplinary and personalized protocol. In addition, an interesting point addressed by this paper is the possibility of offering patients with long COVID syndrome different rehabilitation strategies, which go beyond the hospital setting. As already suggested, among the extra-hospital settings, the spa set-ting seems to be suitable for the multidisciplinary care of these patients, benefiting from a team composed of numerous professional figures and from several rehabilitation strategies.46-48 For long COVID patients, a comprehensive rehabilitative approach comprising a multidisciplinary and multi-professional team, offering neuromuscular, cardiorespiratory, and psychological interventions, is strongly recommended.49 In spa setting, neuromotor rehabilitation with aquatic muscle strength and balance exercises, respiratory exercises, and educative and psychologically supportive interventions, should be conveyed to COVID-19 survivors.46,50-52 Implementing health resort medi-cine and balneotherapy strategies into the rehabilitation programs can reduce the COVID-19 financial burden on healthcare systems, particularly in countries where health resort medicine is commonly accessible and can help patients to ameliorate Table 2. Outcomes in the patient cohort during the 6-month period and need for other types of care Data Experimental group (n=25) Comparison group 1 (n=25) Comparison group 2 (n=29), Comparison group 3 (n=34) Outcomes of post-COVID 19 syndrome after 6 months Hospital admissions, abs. quantity., (n=), (%) 1 (4.00%) 7 (28.00%)** 2 (6.90 %) 4 (11.76 %) Disabilities, abs. quantity, (n=), (%) 0 (0.00%) 0 (0.00%)* 0 (0.00%)* 0 (0.00%)* Deaths, abs. quantity, (n=), (%) 0 (0.00%) 0 (0.00%)* 0 (0.00%)* 0 (0.00%)* Need for specialist consultations and ambulance calls General practitioner, abs. quantity, (n=), (%) 4 (16.00%) 17 (68.00%) ** 19 (65.52%)** 20 (58.82%)** Pulmonologist, abs. quantity, (n=), (%) 0 (0.00%) 4 (16.00 %) * 4 (13.79%)* 3 (8.82%)* Ambulance calls, abs. quantity, (n=), (%) 0 (0.00%) 0 (0.00 %) * 3 (10.34%)* 4 (11.76%)* * criterion not applicable; ** Differences are statistically significant p<0.05 Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 5 - their func-tional status after the acute infection, in order to return to their previous status. In conclusion, a tailored and multidisciplinary rehabilitative program, involving aquatic exercis-es, respiratory and motor exercises, social integration training and neuropsychologic sessions, LASER therapy and magnetotherapy, seemed to have a preventive effect not only in the short term, but also over the next 6 months, avoiding the new onset of disa-bilities and the use of care and specialist advice. The spa setting has also proved to be appropriate for the multidisciplinary management of this type of patient. In future, similar studies will be essential to understand what kind of treatments should be employed to target long Covid patients rehabilitation needs, even from a cost-effective point of view. List of acronyms SARS-COV-2 - Severe Acute Respiratory Syndrome COronaVirus 2 EG - experimental group CG1 - control group 1 CG2 - control group 2 CG3 - control group 3 Contributions of Authors Conceptualization, AL and IG; methodology, AL; software, SA; validation, AP and EI.; formal analysis, SA, IG and AL; investigation, IG and SA; resources, AF and AR; data curation, IG and SA; writing—original draft preparation, IG, SA and AL; writing—review and editing, EI, IG, SM, AP and MCM; visualization, SA; supervision, AR; project administration, IG; fundraising, AR and AF. All the authors have read and approved the published version of the manuscript. Acknowledgments The authors thank relatives and patients who took part in the study. The authors thank Viktor Pavlovich Bulatov for translating the article into English. Funding This research was funded by Ministry of Health of the Russian Federation, Russia, grant number NIOKRTR 121121600137-9. Conflict of Interest The authors declare no conflicts of interest. Ethical Publication Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Corresponding Author Maria Chiara Maccarone, Physical Medicine and Rehabilitation School, Department of Neuroscience, University of Padua, 35128 Padua, Italy ORCID ID: 0000-0003-2793-1334 E-mail: mariachiara.maccarone@phd.unipd.it E-mails and ORCID iD of co-authors Irina A. Grishechkina: GrishechkinaIA@nmicrk.ru ORCID iD: 0000-0002-4384-2860 Andrey A. Lobanov: alobanov89@gmail.com ORCID iD: 0000-0002-6615-733X Sergei V. Andronov: sergius198010@mail.ru ORCID iD: 0000-0002-5616-5897 Andrey P. Rachin: RachinAP@nmicrk.ru ORCID iD: 0000-0003-4266-0050 Anatoliy D. Fesyun: fad68@yandex.ru ORCID iD: 0000-0003-3097-8889 Elena P. Ivanova: IvanovaEP@nmicrk.ru ORCID iD: 0000-0002-2781-4325 Stefano Masiero: stef,masiero@unipd.it ORCID iD: 0000-0002-0361-4898 References 1. WHO: Clinical case definition post-COVID-19 by Delphi consensus. 06.10.2021. Available online: URL https://apps.who.int/iris/bitstream/handle/ 10665/ 345824/WHO-2019-nCoV-Post-COVID- 19-condition-Clinical-case-definition-2021.1- rus.pdf (accessed on 29 May 2022). 2. Asly M, Hazim A. Rehabilitation of post-COVID- 19 patients. Pan Afr Med J. 2020 Jul 9;36:168. doi: 10.11604/pamj.2020.36.168.23823. PMID: 32952812; PMCID: PMC7467884. 3. Barker-Davies RM, O'Sullivan O, Senaratne KPP, Baker P, Cranley M, Dharm-Datta S, Ellis H, Goodall D, Gough M, Lewis S, Norman J, Papadopoulou T, Roscoe D, Sherwood D, Turner P, Walker T, Mistlin A, Phillip R, Nicol AM, Bennett AN, Bahadur S. The Stanford Hall consensus statement for post-COVID-19 rehabilitation. Br J Sports Med. 2020 Aug;54(16):949-959. doi: 10.1136/bjsports-2020-102596. Epub 2020 May 31. PMID: 32475821; PMCID: PMC7418628. 4. Yong SJ. lCOVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond). 2021 Oct;53(10):737-754. doi: 10.1080/23744235.2021. 1924397. Epub 2021 May 22. PMID: 34024217; PMCID: PMC8146298. 5. Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, Walshaw C, Kemp S, Corrado J, Singh R, Collins T, O'Connor RJ, Sivan M. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation. J Med Virol. 2021 Feb;93(2):1013- 1022. doi: 10.1002/jmv.26368. Epub 2020 Aug 17. PMID: 32729939. 6. Kemp HI, Corner E, Colvin LA. Chronic pain after COVID-19: implications for rehabilitation. Br J Anaesth. 2020 Oct;125(4):436-440. doi: 10.1016/j.bja.2020.05.021. Epub 2020 May 31. PMID: 32560913; PMCID: PMC7261464. 7. Weerahandi H, Hochman KA, Simon E, Blaum C, Chodosh J, Duan E, Garry K, Kahan T, Karmen- mailto:mariachiara.maccarone@phd.unipd.it mailto:GrishechkinaIA@nmicrk.ru mailto:alobanov89@gmail.com mailto:sergius198010@mail.ru mailto:RachinAP@nmicrk.ru mailto:IvanovaEP@nmicrk.ru https://apps.who.int/iris/bitstream/handle/ Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 6 - Tuohy SL, Karpel HC, Mendoza F, Prete AM, Quintana L, Rutishauser J, Santos Martinez L, Shah K, Sharma S, Simon E, Stirniman AZ, Horwitz LI. Post-Discharge Health Status and Symptoms in Patients with Severe COVID-19. J Gen Intern Med. 2021 Mar;36(3):738-745. doi: 10.1007/s11606- 020-06338-4. Epub 2021 Jan 14. PMID: 33443703; PMCID: PMC7808113. 8. Hodgson CL, Higgins AM, Bailey MJ, Mather AM, Beach L, Bellomo R, Bissett B, Boden IJ, Bradley S, Burrell A, Cooper DJ, Fulcher BJ, Haines KJ, Hopkins J, Jones AYM, Lane S, Lawrence D, van der Lee L, Liacos J, Linke NJ, Gomes LM, Nickels M, Ntoumenopoulos G, Myles PS, Patman S, Paton M, Pound G, Rai S, Rix A, Rollinson TC, Sivasuthan J, Tipping CJ, Thomas P, Trapani T, Udy AA, Whitehead C, Hodgson IT, Anderson S, Neto AS; COVID-Recovery Study Investigators and the ANZICS Clinical Trials Group. The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study. Crit Care. 2021 Nov 8;25(1):382. doi: 10.1186/s13054-021-03794-0. PMID: 34749756; PMCID: PMC8575157. 9. Sidorov VV, Lobanov AA, Grishechkina IA, Fesyun AD, Yakovlev MYU, Andronov SV, Barashkov GN, Popov AI. Narushenie mikrocirkulyacii i kletochnogo metabolizma u patientov s post-COVID-sindromom [Violation of microcirculation and cellular metabolism in patients with post-COVID syndrome]. Vestnik novyh medicinskih tekhnologij 2022, Volume 29(2), P. 64-68 [in Russian]. 10. Das S. Microcirculatory changes and thrombotic complications in COVID-19. Br J Community Nurs. 2021 Oct 2;26(10):474-480. doi: 10.12968/bjcn.2021.26.10.474. PMID: 34632792. 11. Pandolfi S, Chirumbolo S. Home therapy of COVID-19 at the earliest may greatly prevent hospitalization. Basic Clin Pharmacol Toxicol. 2021 Dec;129(6):395-396. doi: 10.1111/bcpt. 13650. Epub 2021 Sep 26. PMID: 34494369; PMCID: PMC8652880. 12. Hohberger B, Mardin CY. OCT Angiography as an Interdisciplinary Diagnostic Tool for Systemic Diseases. Klin Monbl Augenheilkd. 2021 Dec;238(12):1294-1298. English, German. doi: 10.1055/a-1654-0504. Epub 2021 Dec 8. PMID: 34879428. 13. Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, Walshaw C, Kemp S, Corrado J, Singh R, Collins T, O'Connor RJ, Sivan M. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation. J Med Virol. 2021 Feb;93(2):1013- 1022. doi: 10.1002/jmv.26368. Epub 2020 Aug 17. PMID: 32729939. 14. Lobanov AA, Irina A Grishechkina, Andronov SV, Gleb N Barashkov, Andrey I Popov, Anatoliy D Fesyun, Elena P Ivanova, Maccarone MC, Stefano Masiero. Can aquatic exercises contribute to the improvement of the gait stereotype function in patients with Long COVID outcomes? Eur J Transl Myol. 2022 Jul 14;32(3):10698. doi: 10.4081/ejtm.2022.10698. PMID: 35833897; PMCID: PMC9580543. 15. Meshcheryakova NN, Belevskij AS, Kuleshov AV Metodicheskie rekomendacii provedenie legochnoj reabilitacii u pacientov s novoj koronavirusnoj infekciej (COVID-19) vnebol'nichnoj dvuhstoronnej pnevmoniej [Guidelines for pulmonary rehabilitation in patients with novel coronavirus infection (COVID-19) community- acquired bilateral pneumonia]. Moscow, 2020. 22 p. Available online: URL https://www.spulmo.ru/upload/metodichka_po_rea bilitacii_covid.pdf (accessed on: 3 March 2022) [in Russian]. 16. Belevskij AS, Meshcheryakova NN. Legochnaya reabilitaciya [Pulmonary rehabilitation], Atmosphere: Moscow, Russian Federation, 2018; 76 p. [in Russian] ISBN: 978-5-902123-71-2. 17. Lobanov AA, Grishechkina IA, Fesyun AD, Rachin AP, Yakovlev MYu, Andronov SV, Barashkov GN, Lebedeva OD, Popov AI, Styazhkina EM, Ansokova MA, Vasil’eva VA. Investigation of the Effectiveness and Safety of a Rehabilitation Program for Patients with Long Covid Using Aquatic Training. Bulletin of Rehabilitation Medi- cine2022, Volume 21(3), P. 45-57. https://doi.org/10.38025/2078-1962-2022-21-3-45- 57 [in Russian]. 18. Carfì 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. PMID: 32644129; PMCID: PMC7349096. 19. King’s College London. ZOE Global Limited. How long does COVID-19 last? 2020. Available online: URL https://www.kcl.ac.uk/news/spotlight/zoe- covid-study-app-kings-researchers-slowed-the- spread-COVID-19 (accessed on: 12 May 2022). 20. Rutsch M, Frommhold J, Buhr-Schinner H, Djeiranachvili L, Gross T, Schüller PO, Katalinic A, Deck R. Study protocol medical rehabilitation after COVID-19 disease: an observational study with a comparison group with obstructive airway disease / Re_Co. BMC Health Serv Res. 2021 Apr 22;21(1):373. doi: 10.1186/s12913-021-06378-4. PMID: 33888104; PMCID: PMC8061875. 21. Glöckl R., Buhr-Schinner H, Koczulla AR, Schipmann R, Schultz K, Spielmanns M, Stenzel N, Dewey S. DGP-Empfehlungen zur pneumologischen Rehabilitation bei COVID-19 Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 7 - [Recommendations from the German Res-piratory Society for Pulmonary Rehabilitation in Patients with COVID-19]. Pneumologie 2020, Volume 74 (8), P. 496-504. [German.] doi:10.1055/a-1193- 9315. 22. Nesina IA, Golovko EA, Shakula AV, Figurenko NN, Zhilina IG, Khomchenko TN, Smirnova EL, Chursina VS, Koroleva AV. Experience of Outpatient Rehabilitation of Patients after Pneumonia Associated with the New Coronavirus Infection COVID-19. Bulletin of Rehabilitation Medicine 2021, Volume 20 (5), P. 4-11. doi: 10.38025/2078-1962-2021-20-5-4-11. 23. Bek LM, Berentschot JC, Hellemons ME, Huijts SM, Aerts JGJV, van Bommel J, van Genderen ME, Gommers DAMPJ, Ribbers GM, Heijenbrok-Kal MH, van den Berg-Emons RJG; CO-FLOW Collaboration Group. CO-FLOW: COvid-19 Follow-up care paths and Long-term Outcomes Within the Dutch health care system: study protocol of a multicenter prospective cohort study following patients 2 years after hospital discharge. BMC Health Serv Res. 2021 Aug 21;21(1):847. doi: 10.1186/s12913-021-06813-6. PMID: 34419032; PMCID: PMC837959624. 24. Petrie A, Sabin C. Medical Statistics at a Glance, 4th ed.; Wiley-Blackwell: USA, 2019; 208p. ISBN: 978-1-119-16781-5. 25. Vremennye metodicheskie rekomendacii. Medicinskaya reabilitaciya pri novoj koronovirusnoj infekcii (COVID-19). [Temporary guidelines. Medical rehabilitation for new coronovirus infection (COVID-19)]. Available online: URL xn–80aesfpebagmfblc0a.xn– p1ai/ai/doc/461/attach/28052020_Preg_COVID- 19_v1.pdf (accessed on 12 Feb 2022) [in Russian]. 26. Bogolyubov VM. Physiotherapy and balneology. BINOM: Russian Federation, Мoscow, 2021; 999 p. [in Russian]. 27. Understanding of guidance for acupuncture and moxibustion interventions on COVID-19 (Second edition) issued by CAAM. World Journal of Acupuncture - Moxibustion 2020, Volume 30 (1), P. 1–4. doi: 10.1016/j.wjam.2020.03.005. 28. Orlova IV. Mnogomernyjstatisticheskijanaliz v ekonomicheskihzadachah: komp'yuternoemodeliro vanie v SPSS: Uchebnoeposobie [Multivariate Statistical Analysis in Economics: Computer Simulation in SPSS: A Tutorial]; Vuzovskijuchebnik: Moscow, Russian Federation, 2014; 310 p. Available online: URL https://r- analytics.blogspot.com/2013/01/2-2-k.html [in Russian]. 29. WHO European Regional Technical Briefing. Rehabilitation after COVID-19: what we know and what resources we have. Virtual meeting hosted by the WHO Regional Office for Europe. Copenhagen: WHO Regional Office for Europe, 2022. Available online: URL: https://apps.who.int/iris/bitstream/ handle/10665/351043/WHO-EURO-2022-3995- 43754-62897-rus.pdf?sequence=1&isAllowed=y (accessed on 04 April 2022). 30. Gilmutdinova IR, Kolyshenkov VA, Lapickaya KA, Trepova AS, Vasileva VA, Prosvirnin AN, Marchenkova LA, Terentev KV, Yakovlev MY, Rachin AP, Fesyun AD, Reverchuk IV. Telemedicine platform COVIDREHAB for remote rehabilitation of patients after COVID-19. Eur J Transl Myol. 2021 May 13;31(2):9783. doi: 10.4081/ejtm.2021.9783. PMID: 33985320; PMCID: PMC8274224. 31. Bryant MS, Fedson SE, Sharafkhaneh A. Using Telehealth Cardiopulmonary Rehabilitation during the COVID-19 Pandemic. J Med Syst. 2020 May 28;44(7):125. doi: 10.1007/s10916-020-01593-8. PMID: 32462352; PMCID: PMC7253228. 32. Ansokova MA, Vasil’eva VA. Rehabilitation of a patient with acute cerebral circulation disturbance due to COVID-19. Materials of the Russian scientific-practical conference with international participation, Kursk Russian Federation, 2022. pp. 44-45. 33. Marchenkova LA, Makarova EV, Yurova OV. [The role of micronutrients in the comprehensive rehabilitation of patients with the novel coronavirus infection COVID-19]. Vopr Pitan. 2021;90(2):40- 49. [in Russian]. doi: 10.33029/0042-8833-2021- 90-2-40-49. Epub 2021 Mar 11. PMID: 34019347. 34. van Haastregt JCM, Everink IHJ, Schols JMGA, Grund S, Gordon AL, Poot EP, Martin FC, O'Neill D, Petrovic M, Bachmann S, van Balen R, van Dam van Isselt L, Dockery F, Holstege MS, Landi F, Pérez LM, Roquer E, Smalbrugge M, Achterberg WP. Management of post-acute COVID-19 patients in geriatric rehabilitation: EuGMS guidance. Eur Geriatr Med. 2022 Feb;13(1):291-304. doi: 10.1007/s41999-021-00575-4. Epub 2021 Nov 20. PMID: 34800286; PMCID: PMC8605452. 35. Rezaei N. Coronavirus Disease-COVID-19: E- book; Springer, Switzerland, 2019; 964 pp. doi: 10.1007/978-3-030-63761-3 36. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, Luo J, Huang Z, Tu S, Zhao Y, Chen L, Xu D, Li Y, Li C, Peng L, Li Y, Xie W, Cui D, Shang L, Fan G, Xu J, Wang G, Wang Y, Zhong J, Wang C, Wang J, Zhang D, Cao B. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021 Jan 16;397(10270):220-232. doi: 10.1016/S0140-6736(20)32656-8. Epub 2021 Jan 8. PMID: 33428867; PMCID: PMC7833295. 37. Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, Li Y, Cao Y, Gu J, Wu H, Shi H. Six-month Follow- up Chest CT Findings after Severe COVID-19 Pneumonia. Radiology 2021; Volume 299(1), p. E177-E186. doi:10.1148/radiol.2021203153. https://apps.who.int/iris/bitstream/ Rehabilitation programs in patients with long COVID syndrome Eur J Transl Myol 33 (2) 11063, 2023 doi: 10.4081/ejtm.2023.11063 - 8 - 38. Taboada M, Cariñena A, Moreno E, Rodríguez N, Domínguez MJ, Casal A, Riveiro V, Diaz-Vieito M, Valdés L, Álvarez J, Seoane-Pillado T. Post- COVID-19 functional status six-months after hospitalization. J Infect. 2021 Apr;82(4):e31-e33. doi: 10.1016/j.jinf.2020.12.022. Epub 2020 Dec 26. PMID: 33373650; PMCID: PMC7834022. 39. Yan X, Huang H, Wang C, Jin Z, Zhang Z, He J, Yin S, Fan M, Huang J, Chen F, Zeng Y, Han X, Zhu Y. Follow-up study of pulmonary function among COVID-19 survivors 1 year after recovery. J Infect. 2021 Sep;83(3):381-412. doi: 10.1016/j.jinf.2021.05.034. Epub 2021 May 29. PMID: 34062186; PMCID: PMC8164517. 40. Nasserie T, Hittle M, Goodman SN. Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19: A Systematic Review. JAMA Netw Open. 2021 May 3;4(5):e2111417. doi: 10.1001/jamanetworkopen. 2021.11417. PMID: 34037731; PMCID: PMC8155823. 41. Carvalho AC, Moreira J, Cubelo P, Cantista P, Branco CA, Guimarães B. Therapeutic respiratory and functional rehabilitation protocol for intensive care unit patients affected by COVID-19: a structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Apr 12;22(1):268. doi: 10.1186/s13063-021-05210-y. PMID: 33845878; PMCID: PMC8039799. 42. Carvalho AC, Moreira J, Cubelo P, Cantista P, Branco CA, Guimarães B. Therapeutic respiratory and functional rehabilitation protocol for intensive care unit patients affected by COVID-19: a structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Apr 12;22(1):268. doi: 10.1186/s13063-021-05210-y. PMID: 33845878; PMCID: PMC8039799. 43. Stam HJ, Stucki G, Bickenbach J; European Academy of Rehabilitation Medicine. COVID-19 and Post Intensive Care Syndrome: A Call for Action. J Rehabil Med. 2020 Apr 15;52(4):jrm00044. doi: 10.2340/16501977-2677. PMID: 32286675. 44. Maniscalco M, Fuschillo S, Ambrosino P, Martucci M, Papa A, Matera MG, Cazzola M. Preexisting cardiorespiratory comorbidity does not preclude the success of multidisciplinary rehabilitation in post- COVID-19 patients. Respir Med. 2021 Aug;184:106470. doi: 10.1016/j.rmed.2021. 106470. Epub 2021 May 15. PMID: 34022502; PMCID: PMC8123366. 45. Yagudina RI, Kulikov AYu, Serpik VG. Farmakoekonomika: uchebnoeposobie [Pharmaco- economics: textbook]; Phoenix: Rostov-on-Don, Russian Federation, 2018; 237p. [in Russian]. 46. Maccarone MC, Kamioka H, Cheleschi S, Tenti S, Masiero S, Kardeş S. Italian and Japanese public attention toward balneotherapy in the COVID-19 era. Environ Sci Pollut Res Int. 2021 Nov;28(43):61781-61789. doi: 10.1007/s11356- 021-15058-z. Epub 2021 Jun 29. PMID: 34185269; PMCID: PMC8239328. 47. Masiero S, Maccarone MC, Agostini F. Health resort medicine can be a suitable setting to recover disabilities in patients tested negative for COVID- 19 discharged from hospital? A challenge for the future. Int J Biometeorol. 2020 Oct;64(10):1807- 1809. doi: 10.1007/s00484-020-01947-4. Epub 2020 Jun 5. PMID: 32504142; PMCID: PMC7272594. 48. Masiero S, Maccarone MC. Health resort therapy interventions in the COVID-19 pandemic era: what next? Int J Biometeorol. 2021 Nov;65(11):1995- 1997. doi: 10.1007/s00484-021-02134-9. Epub 2021 Apr 21. PMID: 33880643; PMCID: PMC8057917. 49. Agostini F, Mangone M, Ruiu P, Paolucci T, Santilli V, Bernetti A. Rehabilitation setting during and after COVID-19: An overview on recommendations. J Rehabil Med. 2021 Jan 5;53(1):jrm00141. doi: 10.2340/16501977-2776. PMID: 33284353; PMCID: PMC8772378. 50. Maccarone MC, Masiero S. Spa therapy interventions for post respiratory rehabilitation in COVID-19 subjects: does the review of recent evidence suggest a role? Environ Sci Pollut Res Int. 2021 Sep;28(33):46063-46066. doi: 10.1007/ s11356-021-15443-8. Epub 2021 Jul 17. PMID: 34273080; PMCID: PMC8286038. 51. Maccarone MC, Magro G, Tognolo L, Masiero S. Post COVID-19 persistent fatigue: a proposal for rehabilitative interventions in the spa setting. Int J Biometeorol. 2021 Dec;65(12):2241-2243. doi: 10.1007/s00484-021-02158-1. Epub 2021 Jun 4. PMID: 34086142; PMCID: PMC8175920. 52. Masiero S, Maccarone MC, Magro G. Balneotherapy and human immune function in the era of COVID-19. Int J Biometeorol. 2020 Aug;64(8):1433-1434. doi: 10.1007/s00484-020- 01914-z. Epub 2020 Apr 16. PMID: 32300868; PMCID: PMC7160818. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submission: December 05, 2022 Revision received: January 20, 2023 Accepted for publication: January 20, 2023 Results