**1. Introduction**

Coronavirus disease 2019 (COVID-19), a highly contagious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), was declared a pandemic by the World Health Organization in March 2020 [1]. As of 7 March 2021, there are over 100 million cumulative cases, with over 2.5 million deaths worldwide [2]. Within the United States alone, there have been almost 30 million cumulative cases, with over half a million deaths as of mid-March [3].

In terms of clinical profile and disease symptomatology, individuals afflicted with COVID-19 vary greatly in terms of clinical presentation [4,5]. While some individuals remain asymptomatic, others experience symptoms generally associated with other viral respiratory diseases, such as fever, cough, dyspnea, headache, and sore throat [6–8]. During the acute phase of COVID-19, various other systemic impacts including gastrointestinal, renal, hepatological, rheumatological, and neurological symptoms and complications have been reported [9,10]. While there continues to be significant public concern and research centered around the acute course and presentation of COVID-19, there is increasing public and academic interest in the chronic sequelae of the disease [11–13].

There is currently no uniform terminology for this so-called long COVID [14], or, as it has also been termed, long-haul COVID-19 [15,16], post-COVID syndrome [17], chronic

**Citation:** Wong, T.L.; Weitzer, D.J. Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)—A Systemic Review and Comparison of Clinical Presentation and Symptomatology. *Medicina* **2021**, *57*, 418. https:// doi.org/10.3390/medicina57050418

Academic Editor: Woojae Myung

Received: 26 March 2021 Accepted: 21 April 2021 Published: 26 April 2021

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COVID syndrome [18], and more recently, post-acute sequelae of SARS-COV-2 infection (PASC) [19]. There is no established case definition or diagnostic criteria, but some have suggested long COVID as being defined by persistent signs and symptoms more than four weeks after initial infection with SARS-COV-2 [20,21]. Research into the prevalence of long COVID is ongoing, but one study has estimated that over 87% of COVID patients continue to experience at least one symptom, two months after COVID symptom onset [22]. The risk for developing long COVID does not appear to be correlated with the severity of acute illness [23]. The etiologies of long COVID are uncertain, with some linking it to autoimmune condition or hyperinflammatory states after resolution of acute COVID [24–26].

The characteristics and mysterious nature of long COVID led some to sugges<sup>t</sup> a connection to a debilitating but lesser-known chronic medical condition: myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [27–29]. ME/CFS is a long-term complicated illness characterized by at least six months of fatigue and exhaustion. This illness is estimated to account for USD 18–51 billion dollars in economic costs. In total, 2.5 million Americans suffer from chronic fatigue syndrome, with one quarter of those diagnosed being house or bed bound [30]. Within the general population, the prevalence of chronic fatigue ranges between ten and forty percent. Despite this, due to a lack in diagnostic testing without consistent and established treatments, there has been disputes regarding the actual existence of chronic fatigue syndrome. As the diagnosis is mostly based upon patient's subjective feedback, this has sparked stigma that has led to dismissive behaviors in the medical community. The misconception regarding chronic fatigue syndrome may have been started because of how it was initially characterized. For example, early reports of chronic fatigue were described as a derogatory term known as the Yuppie Flu, which initially characterized the illness among young workers, with the implication of individuals trying to ge<sup>t</sup> out of their job responsibilities. However, since this time, the illness has come to be understood to rather affect a broader array of populations, but with a predominance of women being more affected than men [31]. To better understand this illness, improved knowledge of the research and definitions surrounding the illness is needed.

One of the most recent definitions of the illness was formed by the Institute of Medicine in 2015 to avoid further stigma and to promote more knowledge of chronic fatigue syndrome. At that time, the illness was redefined as systemic exertion intolerance disease, with criteria stating that a patient must have significant impairment in the ability to engage in pre-illness levels of educational, occupational, personal, or social activities. This must be due to fatigue that persists for more than 6 months, in addition to post-exertional malaise and unrefreshing sleep, which are other key features of the illness. In addition, the criteria state that a patient must have at least one of the following symptoms: orthostatic intolerance or cognitive decline. As there may be a significant impairment in overall functioning, symptoms should be present with moderate, substantial, or severe intensity with a high frequency of occurrence. These symptoms in chronic fatigue syndrome have been shown to have common onset factors and course. It has been found that during the initial duration of the illness, the most common symptoms were fatigue, pain, cognitive and sleep changes, and flu-related symptoms. As the illness progressed, other medical illnesses tended to worsen the overall course, and few patients had full remission after years of struggle, but rather remained disabled with functional impairments. The most common pattern of onset was following an infectious event, which was followed by gradual progression to consistent sickness. While there have been many theories on the causes of ME/CFS, the three most common precipitating factors have been demonstrated to be infectious illness, stress or major life event, and exposure to an environmental toxin [32]. Several studies have shown that chronic fatigue syndrome patients also react to stressors in an abnormal way, including an abnormal rise in serum cortisol and heart rate in response to the stress of waking up [33].

Over the years, there have been various proposed models for the pathophysiology of ME/CFS. One of the most prominent potential causes of chronic fatigue syndrome includes infection with Epstein–Barr virus (EBV), being highly studied in this setting. A subset of severe chronic fatigue patients exhibit upregulation of EBV-induced gene 2, which serves as a critical gene in immune and central nervous system function. Induction of this gene by EBV could explain the variance of neurological and immune-related symptoms encountered, which has been seen in 38–55% of patients with the illness and has been associated with a variety of autoimmune diseases [34]. Studies have found many other infectious organisms to be associated with chronic fatigue syndrome, including enterovirus, cytomegalovirus, human herpesvirus-6, human parvovirus B19, hepatitis C, *Chlamydophila pneumoniae* and *Coxiella burnetii* [35]. When considering an infectious cause, it will also be important to determine how the human microbiome of persistent pathogens may drive chronic symptoms by interfering with host metabolism, gene expression and immunity. One example of this occurs as bacterial microbes modulate natural killer activity, which has been shown to be reduced in chronic fatigue patients [36]. In terms of immunological explanations, the most consistently reported are increased numbers of activated cytotoxic CD8+T cells and poorly functioning natural killer cells, increased immune activation markers, greater numbers of CD16+/CD3– natural killer cells, and the presence of interferon gamma in serum and cerebrospinal fluid [37]. Other etiologies may include metabolic and endocrine abnormalities, where the body lacks energy and drive because the cells have a problem generating and using energy from oxygen, sugars, lipids, and amino acids. In terms of metabolism, studies have revealed that patients with chronic fatigue syndrome have metabolites including sphingolipids and phospholipids that resemble a hibernation state with significantly lower than normal levels [38].

There exists a large volume of research on the pathogenesis and managemen<sup>t</sup> of ME/CFS. If long COVID is demonstrated to be a similar chronic medical illness with overlaps in clinical features and symptomatology, it may be conjectured that the existing knowledge on ME/CFS may benefit patients of long COVID. Given the statistics on disease prevalence reported by early studies into long COVID, millions of patients will stand to benefit from insights into the treatment and managemen<sup>t</sup> of their conditions. Conversely, the increasing public interest in long COVID and an outpouring of research efforts into this condition may yield additional research findings that can benefit patients suffering from ME/CFS. There is an urgen<sup>t</sup> need for studies on the similarities and differences of the symptomatology and pathophysiology of long COVID and ME/CFS. To the authors' knowledge, there has been no comparative review study into the clinical profiles of long COVID and ME/CFS. Therefore, we conducted a systemic review of the research available thus far into the symptomatology of long COVID, and compared them with known symptoms of ME/CFS based on multiple, widely accepted case definitions.

#### **2. Materials and Methods**

#### *2.1. Search Strategy*

We searched MEDLINE and PsycInfo for articles with studies into clinical profiles and symptoms of long COVID, published up to 31 January 2021. As noted in the introduction, due to the lack of uniformed terminologies for long COVID, we used broad, general search terms with the intention of capturing the widest possible array of articles in our literature search.

For MEDLINE, we used the following search terms: (Long COVID) OR (long haul covid) OR (Chronic COVID) OR (Post-COVID) OR (("Coronavirus Infections/complications" [Mesh]) AND "COVID-19" [Mesh] AND "Symptom Assessment" [Mesh]). For PsycInfo, we used the following search terms: (Long COVID) OR (long haul covid) OR (Chronic COVID) OR (Post-COVID). The titles and abstracts of the identified articles were reviewed, and the full texts of the selected studies were further examined according to the eligibility criteria. The search and review process are illustrated in Figure 1, following the PRISMA guideline for systemic reviews [39].

**Figure 1.** PRISMA flowchart.

## *2.2. Eligibility Criteria*

For the purpose of this review article, we required studies with original research data into symptoms of COVID-19, with a clearly defined timeline of at least 4 weeks after the respective study's reference beginning point, typically time of symptom onset or time of positive COVID test. The reported symptoms must be ongoing at the time of measurement. The symptoms must not be the result of known or identified disease processes that are either self-resolving or resolved with treatment.

#### *2.3. Synthesis of Results*

We performed qualitative compilation and analysis of data reported by the selected studies. Research into the clinical profile and symptomatology of long COVID is still in its infancy, and there is currently no established methodology or protocol for studying patients with long COVID. Due to the heterogeneity in many aspects of the selected studies, including study populations, data gathering methodologies, and study timelines, a quantitative analysis of the data would be mistaken and inappropriate.

Another consequence of the heterogeneity of long COVID studies and the lack of uniform case definition of long COVID is that the selected studies utilize different terminologies for signs/symptoms that are similar or even identical. As part of the analysis process of study data, we attempted to standardize the terminologies of findings and symptoms by examining the methodologies and measurement methods as described by the corresponding studies, and then further comparing those terminologies to those utilized by ME/CFS case definitions. At times, certain findings and symptoms required further research and interpretation for data analysis. One example would be the 6 min walking test (6MWT) [40], an assessment tool that has been used previously in ME/CFS studies [41,42] and is classified under post-exertional malaise for the purpose of this study.

All long COVID symptoms reported by the selected studies are mapped onto a comparison chart with known ME/CFS criteria. The ME/CFS criteria is adopted from a study by Lim et al. [43] comparing known case definitions of ME/CFS. We selected this compilation of ME/CFS case definitions for our analysis to capture the widest possible array of known ME/CFS symptoms.
