Background: Fatigue is among the most common symptoms of the long-term effects of coronavirus (long COVID). This study aims to compare the effectiveness of osteopathic manipulative treatment (OMT) combined with physiotherapy treatment (PT) compared to PT alone on fatigue and functional limitations after two months post randomization in adults with long COVID.

Methods: This is a study protocol for a two-arm, assessor-blinded, pragmatic randomized controlled superiority trial. Seventy-six participants will be randomly allocated to OMT+PT or PT. The PT includes usual care interventions including motor and respiratory exercises targeting cardiorespiratory and skeletal muscle functions. The OMT entails direct, indirect, visceral, and cranial techniques. Patients will be evaluated before and after a 2-month intervention program, and at 3-month follow-up session. Primary objectives comprise fatigue and functional limitations at 2-month post randomization as assessed by the fatigue severity scale and the Post-COVID Functional State scale. Secondary objectives comprise fatigue and functional limitations at 3 months, and the perceived change post-treatment as assessed by the Perceived Change Scale (PCS-patient).

The coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-COVID-19-is causing a substantial increase in hospitalizations leading to overloads in global health systems. Long-term effects of coronavirus-long COVID-comprise of the effects of COVID-19 that lasts for weeks or even months beyond the acute infection. Long COVID includes a wide spectrum of respiratory, neurologic, cardiovascular, gastrointestinal, and musculoskeletal symptoms, and an increased risk of death. There are more than 50 known possible sequelae in long COVID, such as chronic fatigue, and the clinical manifestations may persist for weeks after the acute infection [6], leading to a decrease in quality of life. This condition reinforces the demand for healthcare and the need for a comprehensive approach for patients with long COVID.

Physiotherapy interventions may be required for patients with long COVID aiming to manage symptoms, prevent and restore the patients' functional status and enabling them to perform activities of daily living. The physiotherapy approach for patients with long COVID includes motor and respiratory rehabilitation aiming at maintaining and/or improving joint mobility, muscle strength, and functional capacity. A systematic review highlighted that to improve the rehabilitation in patients, especially in older adults with a severe respiratory illness on admission and after post ICU, some exercise regimens and habits can bring hope, confidence, and functional independence. The authors suggest this may be generalized to those treated for COVID-19, but maybe with personalized care. However, there is a lack of consensus on outcomes measures.

Osteopathy is a healthcare system that aims to promote the balance of physiological function, support homeostasis and encourage wellbeing. In 1918, during the Spanish flu in the United States, osteopathy presented itself as one of the health resources made available to help fight the epidemic. In 2007, OMT once again presented itself as a possibility to help restore health to individuals affected by the H5N1 avian flu. It is worth noticing though these studies are of the lowest evidence, often collections of research that is not directly relevant to the condition and with no indication of clinical relevance; also, most of them comprise hypothetical opinions on this matter. Studies on the OMT combined with standard medical care show that OMT can collaborate in the recovery of health in various clinical conditions, including shortening the length of stay and in-hospital mortality rates in the elderly with more severe pneumonia. Altogether, the interest in the field but absence of reliable data justified an effort to assess the effects of OMT on fatigue in people with long COVID. If found effective, OMT may be recommended as an adjunct to other interventions for this population.

Fatigue is one of the most common and persistent sequelae in long COVID. Fatigue is often a disabling symptom related to several clinical conditions related to systemic inflammatory processes. Pain and fatigue, for example, may overlap, suggesting that biological mechanisms, which include peripheral and central components, and identifiable neuronal networks, are present in both conditions. In a systematic review of the effects of OMT on chronic inflammatory diseases, the data proved inconsistent but safe, suggesting more robust trials are warranted. Hence, the primary aim of this trial is to test whether OMT combined with PT (OMT+PT) is superior to PT alone on fatigue and functional limitations two months post randomization in adults with long COVID. Secondarily, this trial will investigate the effectiveness of OMT+PT and PT alone on fatigue, functional status, and perceived change post-treatment 3 months post-randomization in this population.

Inclusion Criteria: comprise age equal to or above 18 years; essential and clinical criteria for long COVID at baseline assessment (confirmed preceding infection with SARS-CoV-2, individuals referred for rehabilitation reporting fatigue as major symptom [35]; and ability to understand Portuguese well enough to be able to fill in the questionnaires

Exclusion Criteria: comprise conditions in which fatigue is also a major complain such as suspected or diagnosed chronic and/or neurological diseases (e.g., Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease); pre-existing, chronic diseases affecting the musculoskeletal system (e.g., fibromyalgia).

To ensure the expectation of treatment is equally balanced between the groups the participants will not be aware of the study hypothesis regarding the between-group comparisons. It is not possible to blind the clinicians regarding the groups and the participants regarding their treatment. The outcome assessor and statistician will be blind to the allocations of groups.