<scp>Multidisciplinary</scp> collaborative consensus guidance statement on the assessment and treatment of fatigue in <scp>postacute</scp> sequelae of <scp>SARS‐CoV</scp>‐2 infection (<scp>PASC</scp>) patients

Abstract

Large numbers of individuals who have been infected with SARS-CoV-2, the virus responsible for COVID-19, continue to experience a constellation of symptoms long past the time that they have recovered from the acute stages of their illness. Often referred to as "long COVID," these symptoms, which can include fatigue, shortness of breath, palpitations, cognitive dysfunction ("brain fog"), sleep disorders, fevers, gastrointestinal symptoms, anxiety, depression, and others, can persist for months and can range from mild to incapacitating. Although still being defined, these effects can be collectively referred to as postacute sequelae of SARS-CoV-2 infection (PASC).1 The magnitude of this problem is not yet known, but given the millions of individuals worldwide who have had, or will have, COVID-19, the societal impacts are likely to be profound and long lasting.2-5 It is widely acknowledged that systematic study is needed to develop an evidence-based approach for caring for patients with PASC. At present, there is a dearth of rigorous scientific evidence regarding effective assessment and treatment of PASC that prevents the creation of evidence-based clinical guidelines. However, the U.S. health system is currently seeing an increase in the number of patients presenting with PASC, and there is an urgent need for clinical guidance in treating these patients. The goal of this, and future statements, is to provide practical guidance to clinicians in the assessment and treatment of patients presenting with PASC. This Consensus Guidance Statement on fatigue is the first of a series focused on the most prominent PASC symptoms. The American Academy of Physical Medicine and Rehabilitation (AAPM&R) Multi-Disciplinary PASC Collaborative ("PASC Collaborative") was created, in part, to develop expert recommendations and guidance from established PASC centers with extensive experience in managing patients with PASC. The PASC Collaborative is following an iterative, development approach to achieve consensus on assessment and treatment recommendations for a series of Consensus Guidance Statements focused on the most prominent PASC symptoms. These statements were developed by a diverse team of experts, with input from patient representatives with a history of PASC, and integrate current experience and expertise with available evidence to provide tools to clinicians treating patients. There is an intentional focus on health equity as disparities in care and outcomes are critically important to address. Beyond patient care, the hope is that a broadened understanding of current patient care practices will help identify areas of future research. A full description of the methodology is also published in this issue.6 We acknowledge that the definition of PASC is evolving, and there are various factors that contribute to diagnosis. The PASC Collaborative sought input from patient representatives with a history of PASC and patient-led research initiatives to inform recommendations. For example, previous literature has suggested that PASC be defined as the continuation of symptoms beyond 3 or 4 weeks from the onset of acute infection.7 Other definitions of PASC include symptoms lasting longer than 3 months.8 Based on feedback of patient representatives that earlier evaluation, diagnosis, and management can improve access to beneficial interventions, for the purpose of this Consensus Guidance Statement, we recommend expanded assessment if symptoms are not improving 1 month after acute symptom onset. These Consensus Guidance Statements are intended to reflect current practice in patient assessment, testing, and treatments. They should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors. Fatigue is a feeling of weariness, tiredness, or lack of energy. It can be physical, cognitive, or emotional, mild to severe, intermittent to persistent, and affect a person's energy, motivation, and concentration. Fatigue can negatively affect an individual's sense of well-being and quality of life and generally lacks objective markers. Fatigue during an acute viral illness is common; however individuals with PASC are often presenting with long lasting and debilitating fatigue after recovery from their acute viral illness.5 Further discussion on the definition and impact of fatigue can be found in the Institute of Medicine's 2015 report on chronic fatigue syndrome (Chapter 4).9 Individuals are seeking care from their clinicians for fatigue following COVID-19. Among nonhospitalized adults with a history of COVID-19 and enrolled in an integrated health system in Georgia, approximately two thirds had at least one outpatient medical encounter between 1 and 6 months after their diagnosis.10 Approximately two thirds of these patients received a new primary diagnosis, with fatigue being one of the most common based on International Classification of Diseases, Tenth Revision codes.10 In another study describing the long-term health consequences for individuals hospitalized with COVID-19, the most common symptoms were fatigue or muscle weakness (63%) and sleep difficulties (26%).11 Anxiety and depression were also common, reported by 23% of patients. Greater than 20% of patients had performances on the 6-minute walk test below the lower-limit of normal.11 The Patient Led Research Collaborative, a self-organized group of individuals with PASC who conduct patient-led research around the long COVID experience, conducted a study of self-reported symptoms of individuals enrolled in support groups for PASC.12 A majority (96%) of individuals who completed the survey self-identified as having PASC reported symptoms beyond 90 days. The most common early symptoms were fatigue, cough, shortness of breath, headaches, muscle aches, chest tightness, and sore throat. The most frequent symptoms reported after 6 months were fatigue, postexertional malaise, and cognitive dysfunction. Greater than 85% of individuals experienced relapses of their symptoms, with exercise, physical or mental activity, and stress being the main triggers. In addition, 42.5% reported requiring a reduced work schedule compared to pre-illness and 22.3% were not working at the time of survey because of their health conditions.12 Fatigue is among the most common persistent symptoms following COVID-19 in both individuals that have been hospitalized (p = 24.6%, confidence interval [CI] 20.11-29.72) and those that have not been hospitalized (p = 37.1%, CI 26.54-49.06).13 Although fatigue likely improves over time, it can persist beyond 6 months.2, 5, 7 As noted in the PASC Collaborative methodology,6 the recommendations that follow are based on expert consensus. Specific guidance recommendations that have been approved by consensus will be noted in the tables and recommendations will be followed by additional discussion (Table 1). The following basic lab workup should be considered in new patients or those without lab workup in the 3 months before visit including complete blood count with differential, chemistries including renal and hepatic function tests, thyroid stimulating hormone, c-reactive protein or erythrocyte sedimentation rate, and creatinine kinase. Other laboratory tests may be considered based on the results of these tests or if there is specific concern for comorbid conditions as outlined in Table 2. It is not unusual for individuals to have persistent and fluctuating fatigue during their recovery from acute COVID-19 disease, particularly in the first 1 to 2 months. This fatigue can involve both physical and cognitive components. This document focuses on physical fatigue and a subsequent Consensus Guidance Statement will focus on cognitive issues. Additional assessment and management of post-COVID fatigue should be considered if a patient is not continuing to improve after the initial 4 weeks beyond symptom onset, if symptoms are severe, or if the patient is experiencing negative impacts on quality of life. In cases of mild fatigue that is not functionally limiting, it can be monitored for improvement as part of the natural recovery from COVID-19. Symptoms: Chest pains, palpitations, sweating, nausea, fatigue, leg swelling, shortness of breath - at rest/on exertion/lying flat/waking up at night, dizziness on standing, feeling faint/fainting Signs: Pallor, tachypnea, tachycardia, diaphoresis, pulmonary rales, lower extremity edema, hypotensive sitting/standing - orthostatic hypotension, presyncopal/syncopal, poor activity tolerance/endurance Symptoms: Shortness of breath – at rest/on exertion, cough, wheeze, fatigue, poor activity tolerance Signs: Tachypnea, tachycardia, cough, hypoxia/low pulse oximeter, pulmonary wheezes/rhonchi/"Velcro" rales, poor activity tolerance/endurance Symptoms: Palpitations, fatigue, dizziness, weight gain/loss, sense of chills/fever, irregular menstrual cycle, poor diabetic control, excessive thirst/urination Signs: Tachycardia, poor activity tolerance, weight gain/loss, low/elevated temperature, elevated finger-stick/urine glucose, ketotic (fruity) breath Symptoms: Rash, joint/muscle pain and stiffness, fever, mouth sores/ulcers, cold/pale/blue/red fingers, sharp chest pain, numbness/tingling/burning in fingers/toes, blurry/decreased vision Signs: Rash, arthropathy – swelling/warmth/decreased ROM, myopathy – tenderness/weakness, fever, Raynaud's phenomena, pleuritic pain on deep breathing, altered sensation, decreased visual acuity Symptoms: Anxiety, irritability, chest tightness, low frustration tolerance, depression, fatigue, mood swings, palpitations, change in memory/recall Signs: flat affect/low mood, emotional lability that is, crying/laughing inappropriately, limited impulse control, psychosis Symptoms: Poor sleep - hard to fall asleep/wakes frequently/wakes early, nonrestorative/refreshing sleep - "tired" on waking, snoring, frequent urination at night, bad dreams/nightmares, falls asleep during the day, morning headaches Signs: Snoring, restless legs, observed apneic episodes, hypertension, arrhythmias, narcolepsy, congestive heart failure, impaired neurocognition, poorly controlled mood disorder In patients presenting with fatigue, it is important to consider the evaluation of fatigue and diminished activity tolerance as related but distinct conditions. As these two symptoms may intersect, the differential etiologies of fatigue should be considered in conjunction with a separate differential for lowered activity tolerance. When evaluating the etiology of fatigue, the following should be considered as central or contributing factors: sleep disorders, endocrine disorders, nutritional disorders, chronic infectious disorders, autoimmune/inflammatory disorders, cardiac disorders, respiratory disorders, psychiatric disorders, malignancies, drug reactions, and adult-onset metabolic disorders (See Table 2). Diminished activity tolerance is the inability or reduced ability to perform physical activity at the normally expected frequency, intensity level, or duration for people of that age, size, gender, and muscle mass. Individuals may experience unusually severe postexercise pain, fatigue, nausea, vomiting, or other negative effects. When evaluating the etiology of diminished activity tolerance, the following disorders or system dysfunctions should be considered as central or contributing factors: pulmonary, cardiovascular, and/or neuromuscular systems. The presentation of fatigue in individuals with PASC may appear similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a complex syndrome that often occurs following viral illness. A 2015 Institute of Medicine report on ME/CFS created specific diagnostic criteria as outlined in Table 3.9 The specific pathophysiology behind ME/CFS has yet to be discovered. The Centers for Disease Control and Prevention has developed treatment recommendations for ME/CFS that have been used to help develop the current treatment recommendations for PASC-related fatigue.18 However, more data are needed to understand if and in which individuals PASC-related fatigue is a manifestation of ME/CFS and in which individuals PASC-related fatigue represents a distinct process. Finally, it is important to note that the etiology of fatigue may be multifactorial in individuals with PASC and there may not be one unifying cause of PASC-related fatigue. As with any treatment plan, clinicians treating patients with PASC-related fatigue are encouraged to discuss the unknowns of PASC treatments, as well as the pros and cons of any therapeutic approach. It may also be helpful to discuss that despite the unknown time course of post-COVID symptoms, it is the experience of established PASC centers that fatigue tends to slowly improve over time. As treatment is initiated, patients should be followed for their response to treatment and impact of treatment on level of function. As with the PASC patient assessment, therapeutic options vary and should be customized based on history, comorbidities, and treatment response to date. It is important to note that if specific etiologies of fatigue are identified (see Table 2), they should be addressed as part of the treatment plan (Table 4, Recommendation #4). The current recommendations are based on the experience of the PASC Collaborative clinics and have helped to alleviate symptoms in cases in which specific contributing etiologies have not been identified or, despite addressing, symptoms persist. Additional details on techniques used by clinicians are summarized next. As treatment efficacy of therapeutic options emerges, these recommendations will be reviewed and revised on a periodic basis. An individually titrated, symptom-guided program of return to activity is recommended for patients presenting with fatigue. The goal of a rehabilitation program is to restore patients to previous levels of activity and improve quality of life. Until those goals have been achieved, the rehabilitation program should not focus on high intensity aerobic exercises or heavy weightlifting to build strength and endurance. If the rehabilitation program is advanced too quickly or is too intense, it may worsen symptoms and lead to postexertional malaise (PEM), a diagnostic criterion of ME/CFS.9 The titrated approach encourages patients to perform activities at a submaximal level to avoid exacerbation of fatigue and PEM. Activity should be adjusted in response to symptoms that develop during or after activity. Before starting this program, it is crucial for the clinician to educate the patient on recognizing perceived exertion and the use of other metrics such as heart rate or exertion scales (such as the Borg Rating of Perceived Exertion Scale) that can guide the individual toward submaximal exertional activities. Smartphones and activity trackers may also be effective methods to monitor duration and intensity of activity.19 We also recommend educating patients on energy conservation strategies to aid in recovery. One framework is the "Four Ps": Pacing, Prioritizing, Positioning, and Planning.23 Pacing is the concept of avoiding the push and crash cycle that is common in post-COVID recovery. Ways to achieve optimal pacing include keeping activity to reasonable, and often shorter, durations (or alternatively, giving more time to complete activities to avoid rushing) and including scheduled rest breaks with activities. Patients should pay attention to their body and avoid or moderate activities that lead to the need for prolonged recovery periods. Prioritizing encourages a patient to focus and decide on which activities need to get done on specific days and which activities can be postponed (or are unnecessary to do at all) to avoid overexertion and crashing. Positioning is modifying activities to make them easier to perform. For example, it may be possible for the patient to sit during an activity or have a workspace at a comfortable height with all necessary equipment within easy reach. Another example would be the use of a shower chair or bench rather than standing for showering. Planning encourages the patient to plan the day or week to avoid overexertion and to recognize energy windows. Energy windows are periods during the day when patients have more energy to complete tasks. Patients are often aware of their optimal energy window, which may vary throughout the week. Asking patients to keep a diary of good days, bad days, and energy windows is helpful for optimizing timing of therapy and activities. As such, it is important for patients to plan rest breaks. Other elements of planning include determining steps for completion of tasks and preparing for tasks ahead of time. Daily routines may also be helpful. Finally, planning may consist of gradual return to previous activities. In particular, returning to work may be of concern to individuals with PASC-related fatigue. We recommend patients work with their physicians and employers to create a specific plan for return to activities. Patients should be on to if are needed or in a limited as long as it not worsen symptoms or lead to PEM. of possible include working a limited number of working from work activities of medical equipment aid to increase additional breaks throughout the day, and the work the patient to These activities and return to work should be advanced as the patient When to rehabilitation can be helpful in the return activities and with At this time there are scientific data to support the of one specific for the management of PASC-related fatigue. nutritional recommendations should reflect the individual health a including and and limited of of and the of is also COVID-19 is with a response and PASC has been to be related to of this There has been in the between and chronic related fatigue. and and specific high in and have been suggested to have and research is syndrome with has also been suggested to a in PASC It is that individuals may not in to be a of reduced activity of the which breaks to an of in the body and include or low blood irregular and other conditions and are similar to those reported by individuals with PASC. Although there are current scientific the of a low of limited and other in PASC, have suggested improvement in It is that following have also been recommendations have been for individuals with and similar recommendations may be beneficial for PASC-related fatigue. These include but often - 3 to 4 with a low complex in to support energy and a including and There is currently not evidence to support the use of specific nutritional to help including or Fatigue related to dysfunction in individuals with PASC, orthostatic syndrome can be addressed with and and frequent are and with high and complex may help blood and symptoms. Fatigue to muscle in the context of weight is reported in PASC and can be with and protein There is a in the use of and to improve PASC-related fatigue. clinics do not use use when management has been and comorbid conditions have been patients often in and for and that may be helpful of these is needed for patient that have been suggested to alleviate chronic fatigue in other of chronic illness and include 3 and These have been suggested to support the help with and improve fatigue. It is important to note that there was consensus on the use of these and they should be considered on a recognizing the limited scientific there to be of the of the of lack of and possible effects. There are that are used for fatigue in other individuals with and that PASC clinics for PASC-related and have been used by PASC clinics for the treatment of Other that have been suggested in the treatment of ME/CFS include and are limited and evidence for these not or is of these have from the and for use in other with fatigue, but there are currently clinical their use in the PASC It is important to note that of these were recommended consensus and should be considered on a basis. There also can be effects and with of these that need to be considered to The use of has also been reported by patient to improve fatigue. Although there has not been evidence to support use in PASC-related fatigue, there is evidence that use in In the context of PASC, it is important to focus on health health and of health with the following clinicians are encouraged to the and in of SARS-CoV-2 Fatigue for guidance the of health equity with the evaluation and treatment of individuals with PASC. The health equity as of and or in health among groups defined or defined a health as of health that is with and/or and that health disparities affect groups of people who have experienced to health based on their or mental cognitive, or physical or or other to or There has been an of are contributing to health and are the factors that health and involve the in which people are and and the of and the conditions of For example, the and can include and an individual's level of and access to and other factors. care in individuals with PASC, we need to are available for those to physical and mental of include access to and/or in a the individual or for with a and and and care, and medical and mental health care that are all to the of those from When and that support health are poor health outcomes can be health disparities can be and the of the between and health in acute COVID-19 is well the of with PASC is As more data there will likely be evidence of health disparities in care and treatment options because of differential of health of testing, limited clinical and lack of and in of fatigue may be reported more in adults and in COVID-19 symptoms may be more severe in and the is a cause of fatigue because of a of and factors. In addition, people who identify with or groups may have a level of chronic fatigue that should be considered in the assessment and treatment and groups may also be at a of chronic that may increase levels of chronic fatigue. For example, individuals with lower and adults are at of which the of body and are also related to more severe consequences of Finally, those with lower may not be to access treatments. For example, they may not have the ability to get time from work to pacing recommendations or to access therapy encounter a range of to health care to and/or factors such as gender, and The and between the health care and must be by in are that are support or focused as the of that are and and consider the of and individual have a in health health and improving a deep understanding of of diverse and that with the and the of that support the health of all individuals in the PASC may have or health In addition, debilitating and symptoms with ability to work and to for and their The in have in their and to pay and health in care we recommend assessment and treatment that including and as they can be helpful for and the on individuals with limited energy from PASC or who have other the of expanded during the and have been noted to be in access for various such as and the In addition, individuals should be to when including for other and on and for work or and to PASC support PASC-related fatigue individuals and Individuals with PASC-related fatigue can experience severe and The pathophysiology fatigue after COVID-19 still research to understand this constellation of symptoms, the cause of fatigue is likely multifactorial and may be specific to the The goal of this PASC Collaborative Consensus Guidance Statement is to create a and systematic approach to the evaluation and treatment of patients presenting with PASC. The recommendations a consensus of of centers focused on the treatment of individuals with PASC. The recommendations are based on the most current available from evidence in similar and the clinical experience of treating of patients with PASC-related fatigue. 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