Post-coronavirus Disease-2019 Fatigue

The evaluation of both cases and controls will include the following:

• Physical examination: a comprehensive physical examination, including neurological assessment of motor function.
• Blood tests: complete blood count, C-reactive protein, erythrocyte sedimentation rate, thyroid functions (TSH, fT3, fT4), kidney and liver functions, creatine phosphokinase, serum electrolytes, Epstein-Barr virus and cytomegalovirus serology testing, ferritin, and serum vitamin B12 and folate levels.
• Sleep assessment: in order to estimate the quality and characteristics of sleep, the participating individuals will independently fill the following sleep assessment questionnaires:

• Epworth sleepiness score (ESS) - to generally evaluate subjective sleepiness (was validated in Hebrew).
• Pittsburg sleep quality index (PSQI) - to evaluate the quality of sleep (was validated in Hebrew).
• Insomnia severity index (ISI) - to evaluate insomnia (a Hebrew version exists, but the questionnaire is yet to be validated).
• Depression severity questionnaire: in order to screen for depression and to estimate the degree of depression severity, the participating individuals will independently fill the patient health questionnaire-9 (PHQ-9).
• Fatigue classification tool

For chronic fatigue syndrome, the Centers for Disease Control and Prevention (CDC) adopted the clinical case definition suggested by the Institute of Medicine (IOM), and consolidated criteria. We adopted the portion on fatigue from the CDC criteria for chronic fatigue syndrome, and modified it to suit for the time frame and relations with COVID-19:

Patient has a substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for >6 weeks and is accompanied by fatigue, which is often profound, is of new onset (appeared after the diagnosis of COVID-19), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest. These symptoms are present at least half of the day time, to at least a moderately severe degree.

Each participant will independently fill a designated form in which the aforementioned criteria will be mentioned, followed by to statement from which the participant will circle the one relevant for him:

• The criteria above accurately describe my current situation.
• The criteria above do not accurately reflect my current situation.

• Assessment of exercise physiology: All participants will undergo a cardiopulmonary stress test (CPET), under the guidance of sports and exercise physicians and nursing staff. Electrocardiogram, spirometry, blood pressure and gas exchange measuring will be assessed at rest. The participants will then undergo CPET according to a modified Astrand treadmill test protocol. The test will be terminated at maximal exercise or upon the appearance of limiting symptoms . Continuous electrocardiogram and repeated blood pressure measuring will be conducted at the recovery phase. Post-exercise spirometry will also be assessed.
• Assessment of cognitive fatigue: in order to assess cognitive fatigue, all participants will undergo the visual vigilance test. This test, that was designed to be a measure of sustained attention, was previously implemented in individuals with multiple sclerosis. This test will be conducted in a designated room in which the participants will seat in front of a computer, and will independently conduct the task after being instructed by the primary investigator or one of the sub-investigators. During the task, the different alphabetical letters will be screened at a rate of 500 milliseconds per each. The tested individual will be instructed to press the space button whenever two specific letters (i.e. the target letters) are presented. A total of 600 letters will be screened, of which 120 will be the target letters. The test is to be repeated 3 times, 5 minutes for each run. The percentage of correct presses, the number of errors and the mean reaction time will be evaluated for each time period.

Inclusion criteria

• Adult individuals (age ≥18 years) recovered from COVID-19 (diagnosed using a polymerase chain reaction test from a nasopharyngeal sample), with or without lasting fatigue symptoms, which appeared following COVID-19, while at least two months have elapsed since COVID-19 diagnosis.

Exclusion criteria

• Individuals hospitalized in intensive care unit and/or required mechanical ventilation during their acute illness.
• Individuals diagnosed with pulmonary veno-thromboembolism/pulmonary infarction, on current oxygen supplementation, with sleep apnea/hypopnea syndrome or with post-COVID-19 chest imaging suggesting pulmonary fibrosis.
• Individuals with heart failure, acute coronary syndrome or percutaneous cardiac intervention during the year prior to the diagnosis.
• Individuals who underwent surgical procedure under general anesthesia during the year prior to the diagnosis.
• Individuals with cerebrovascular disease and a history of cerebrovascular accident or transient ischemic attack.
• Individuals with paralysis of the lower limbs, amputees, bedridden, those assisted with walking aids or wheelchair.
• Individuals with myopathies or myositis, degenerative neurological or muscular diseases, and myasthenia gravis.
• Individuals with pre-COVID-19 diagnosis of chronic fatigue syndrome, fibromyalgia, major depressive disorder, obstructive sleep hypopnea/apnea syndrome, or sleep disturbance necessitating pharmacotherapy.
• Individuals with chronic illnesses (autoimmune diseases and malignancies) necessitating immunosuppression (including corticosteroid therapy) or immunomodulation (including anti-cancer agents).
• Individuals with thyroid dysfunction prior to their diagnosis with COVID-19: uncontrolled hypothyroidism or hyperthyroidism and those with imbalanced thyroid stimulating hormone (TSH) level.
• Pregnant women.
• Individuals with chronic use of opioids.