Damian Sendler: Patients with acute coronavirus disease 2019 (COVID-19) and convalescent COVID-19 (sometimes referred to as “long-COVID”) report fatigue lasting from weeks to months. After completing a systematic review of post-COVID fatigue as well as a narrative review of fatigue following other infections, the COFFI investigators made recommendations for clinical and research approaches to assessing fatigue following COVID-19.
Damian Jacob Sendler: At 16–20 weeks after the onset of symptoms, a significant minority of patients in most COVID-19 cohort studies reported persistent fatigue, ranging from 13% to 33%. Many acute systemic infections, such as infectious mononucleosis, are associated with fatigue, according to data from the COFFI and other prospective cohort studies. Case rates of clinically significant Post-infective fatigue, after recognized medical and psychiatric causes have been excluded, range from 10 percent to 35 percent after six months.
Dr. Sendler: Post-COVID fatigue can be better understood by using standardized interviews, validated screening questionnaires, and investigative methods to identify end-organ damage as well as mental health conditions. COFFI investigators recommend the following:
Acute coronavirus disease 2019 (COVID-19) has been linked to some patients who do not fully recover. Long-haulers” and “long-COVID” are terms used to describe patients who continue to experience symptoms for weeks or months after the onset of the acute illness [1]. Long-COVID does not have a case definition, but fatigue and other symptoms reminiscent of an acute infection predominate. The media, the public, and the scientific and medical communities have all paid attention to the condition [2].
Many people use the term “fatigue” to describe a variety of feelings, including that of “everyday” or “physiological” fatigue, as well as that of “pathological” or “diseased” fatigue. Obvious signs of exhaustion include decreased force generation efficiency (as in myopathy) and weakness on physical examinations, but fatigue can also be a subjective experience (ie, fatigue as a symptom). Rather than simply referring to tiredness, patients who express fatigue may actually be describing symptoms such as weakness, dyspnea, difficulty concentrating, sleepiness, or depression. Because of this, it is critical to accurately describe and categorize each symptom complaint in both clinical and research settings. In the same way that pain is automatically interpreted in light of other concurrent brain processes like perceptions, emotions and thoughts, the subjective experience of fatigue is [3] automatically interpreted as well.
The acute sickness response to a wide range of pathogens is well-exemplified in evolutionary terms as a homeostatic alarm aimed at energy preservation [3]. Fever, tiredness, hypersomnia and musculoskeletal pain, anorexia and mood disturbance are just some of the physical, behavioral and psychological manifestations of this response. In many cases, symptoms persist for weeks or months after the acute infection stage has ended [5]. Patients often describe their fatigue as having both “physical” and “mental” aspects, such as a lack of energy and a general sense of heaviness (a feeling of brain fog). One of the most common characteristics is that even a small amount of physical or cognitive activity can cause a long-lasting increase in fatigue and other symptoms.
Chronic fatigue is defined as lasting more than six months [7]. As long as there are no other plausible explanations for the persistent exhaustion, and if other symptoms such as muscle and joint pain and cognitive difficulties are present, the patient may be diagnosed with CFS or, more specifically, PIFS [5, 7].
For this reason, researchers from the international Collaborative on Fatigue Following Infection (COFFI) [5] have conducted a systematic review on the epidemiology of fatigue after COVID-19 infection and a narrative review on the literature on fatigue following other infections to provide guidance on these complexities. Fatigue after COVID-19 can be assessed using clinical and research methods.
Collectively, these findings from post-infective cohorts show that (1) fatigue is a common and sometimes disabling post-infection, (2) the natural history of long-term persistent fatigue is frequently long-term, (3) the severity of acute illness and baseline psychological status and cognitive and behavioral responses to acute illness predict PIFS, (4) structured medical and psychiatric treatment is effective in alleviating fatigue after infections of various kinds, and
Damian Sendler
A validated definition of chronic fatigue after COVID-19 infection is needed for both clinical and research purposes because of the limitations of the studies in COVID-19 and evidence from other post-infective cohorts. Following current definitions of postinfective fatigue [5], we recommend that the label “post-COVID fatigue” be used when the fatigue is as follows: chronic; incapacitating to the point of interfering with most, if not all, of one’s normal activities (such as going to work or school or participating in social activities), lasting at least three months in children or adolescents, and emerging during confirmed acute COVID-19 (i.e. with a positive severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] test), with no symptom-free interval since the onset.
Damian Jacob Markiewicz Sendler: Identifying the underlying causes of post-COVID fatigue should include the following: end-organ sequelae of acute COVID-19 illness and hospitalization; mental health conditions precipitated or exacerbated by COVID-19; and other premorbid or intercurrent disorders of which fatigue is a symptom. As a result, we recommend a thorough diagnostic process (see Supplementary Tables 2 and 3 for summaries of instruments and references). Clinical and research settings can benefit from short screening questionnaires to assess the fatigue state, such as the Chalder Fatigue Scale or the SPHERE (Supplementary Table 2), which follow the National Institute of Neurological Disorders and Stroke Common Data Elements recommendations for identifying “clinically-significant” fatigue. Given the frequency with which fatigue occurs in conjunction with other issues such as a variety of physical and mental health issues, it is reasonable to use other validated screening tools in addition to the SPHERE in order to identify patients who may also be suffering from related physical symptoms or mental health issues (Supplementary Table 2). Pain and sleep quality can also be assessed with validated instruments to screen for other relevant symptom domains. Concurrent assessment of functional status using an instrument like the SF-36 is strongly recommended for patients with clinically significant fatigue (Supplementary Table 2).
Damian Jacob Sendler
The semistructured, clinician-administered diagnostic interview schedules for (1) fatigue states (Structured Clinical Interview for Neurasthenia [SCIN]) [6] and (2) psychiatric disorders (Composite International Diagnostic Interview [CIDI]) offer an ideal approach to further assessment for research purposes in particular. The Structured Diagnostic Interview for Sleep Patterns and Disorders can also be used if screening questionnaires raise the possibility of sleep disturbance as a contributor (Supplementary Table 3).
Damien Sendler: A thorough medical history and physical examination should be performed on patients with persistent fatigue following COVID in order to determine the nature of the symptoms, their onset time, and their impact on their functional status. Premorbid and concurrent mental health issues, such as depression, anxiety, and PTSD, should be examined as part of this clinical evaluation. As a last resort, a chest x-ray is recommended, as well as a restricted list of laboratory testing (e.g., blood count; C-reactive protein, blood glucose; ferritin; B type natriuretic polypeptide) [43]. If the patient’s history or examination reveal anything concerning, it may be necessary to conduct additional tests or consult with a specialist. Pediatric services should be contacted if a child or teenager experiences post-COVID fatigue.
The diagnosis of “idiopathic post-COVID fatigue” should be used in cases where this process does not reveal an explanatory condition. A post-infectious fatigue syndrome after COVID-19 may be diagnosed in these patients [7]. As a starting point for clinical care, a diagnosis such as this provides reassurance of a generally self-limiting natural history and supportive care [44]. Additional symptoms and comorbid conditions should be documented thoroughly for research purposes, so that statistical analyses can be conducted that take these factors into account.
Idiopathic post-COVID fatigue (PIFS) remains unresolved, so a biopsychosocial approach is recommended to conceptualize research approaches to PIFS, including predisposing, precipitating and sustaining factors. Genetic and psychosocial vulnerabilities may play a role in the development of PIFS. Co-occurring disorders, such as COVID-19-related death or job loss, can exacerbate the symptoms of depression and lead to its inception [47]. It is possible that sleep disturbance, autonomic dysfunction, endocrine disturbances, reactive mood disorders like depression or anxiety, and abnormal illness beliefs and behavioral changes, such as activity patterns that are boom-bust or avoidant, can all play a role in the onset and progression of illness and disability. [48, 49, 50, 51]. The pathophysiology of idiopathic post-COVID fatigue is likely to be similar to that of PIFS. Large sample sizes, stratification by multiple contributory variables, and careful matching by, or controlling for, these variables in case-control designs are recommended for research on the predictors or associations of post-COVID fatigue.
For both clinical and research purposes, there are many unknowns about long COVID, but the lessons learned from decades of research into fatigue states after other infections highlight the need for careful clinical characterization, protocols, and a broad bio-psychosocial approach.