**4. Discussions**

To the authors' knowledge, this is the first review article to examine and compare the symptoms of ME/CFS and long COVID. While there are notable findings when the symptoms reported by the selected long COVID studies were juxtaposed with existing ME/CFS case definitions, it is first worth discussing the quality and design of the selected studies. Though COVID-19 has occupied the public consciousness since the early parts of 2020 [63–65], long COVID did not become a subject of public and academic interest until the latter half of 2020, as evidenced by the publication date of the earliest long COVID study included in our paper, July 2020 [22]. The majority of the included studies were published at the end of 2020/beginning of 2021. The research into long COVID is still in its infancy, though there have been ongoing calls for more research and funding into this potentially devastating chronic medical condition [66–68].

For the purpose of this systemic review, the implications are such that there is no uniform long COVID case definition, terminologies, and study methods, which leads to a heterogeneity in the study data that precludes quantitative analysis. For one, there is a huge disparity in terms of the timeline of studies, with the time of assessment ranging from a month to 6 months after symptom onset. The studies also vary greatly in assessment methodologies; while some studies utilized patient questionnaires (Goertz et al. [44], Petersen et al. [48], etc.), others utilized in-person evaluations and assessment tools (Townsend et al. [49], Ortelli et al. [56], etc.). Within individual studies, as the authors of one of the studies pointed out, external validity of the studies may be limited due to biases (Goertz et al. [44]). Yet, it is important to keep in mind that the presented studies in this article represent some of the earliest research into symptoms of long COVID, and thus they are hugely valuable in their research into long COVID symptomatology, as well as their insight into future study designs and research protocol into long COVID.

In this systemic review study, the reported symptoms of long COVID from 21 selected studies were compared to a compilation of ME/CFS symptoms from multiple case definitions [43], including Institute of Medicine [69], Fukuda et al. [70], International Consensus Criteria [71], and Canadian Consensus Criteria [72]. The results sugges<sup>t</sup> a high degree of similarities between long COVID and ME/CFS. Out of 29 listed ME/CFS symptoms, all but 4 were reported by at least one long COVID study. It is particularly notable that all three major criteria symptoms, namely fatigue, reduced daily activity, and post-exertional malaise, were reported by multiple studies. Furthermore, fatigue was specifically noted in 12 of the 21 selected studies, which likely suggests fatigue as a predominant symptom of patients suffering from long COVID.

Despite the findings from this comparison, it may be too early to establish a direct causal relationship between long COVID and the development of ME/CFS. Specifically, many of the patients described do not meet the criteria for ME/CFS due to limitations of the studies in regard to duration of symptoms. The diagnosis of ME/CFS requires that the symptoms have been present for at least 6 months. Only three of the selected studies involved the assessment of patients more than 6 months after the onset of their COVID symptoms (Huang et al. [45], Taboada et al. [47], Ludvigsson [57]). The rest of the selected studies range from 37 days to 4 months. It is worthwhile pointing out that within these three studies, 63% of patients from one study reported fatigue (Huang et al. [45]) and 47.5% of patients from another reported decreased functional status (Taboada et al. [47]). In other words, a significant number of patients continue to suffer from long COVID symptoms after 6 months, seemingly at levels comparable to data from studies involving shorter time courses. While the heterogeneity in the study populations and assessment methods preclude meta-analysis of the patient data, it may be suggested that the long COVID symptoms reported by patients in other shorter-duration studies may not resolve completely by 6 months. It has previously been suggested that, even using conservative methodologies, an estimated 10% of patients with COVID-19 may develop chronic illness meeting the definition of ME/CFS [28]. With over 100 million cumulative COVID-19 cases

worldwide as of March 2021 [2], the disease burden of this ME/CFS-like chronic illness will likely be devastating.

Aside from similarities in clinical features, long COVID and ME/CFS appear to have certain commonalities in their pathophysiology. As noted in the introduction, the pathogenesis of ME/CFS has been linked to multiple underlying processes including immune system dysregulation, hyperinflammatory state, oxidative stress, and autoimmunity [73]. A particular phenotype of ME/CFS has been termed post-infectious fatigue syndrome, and it has been linked to acute viral infections such as Epstein–Barr virus (EBV) and human parvovirus (HPV)-B19 [74,75]. While the etiology of long COVID is likely multifaceted and the research is still ongoing, it has been similarly linked to inflammatory state and dysregulated immune response [76,77], further underlying the resemblance between long COVID and ME/CFS [78].

Some of the included studies in this review also attempted to characterize the underlying pathophysiology of the long COVID symptoms, and the findings have been mixed. Ortelli et al. [56] noted that their study patients exhibited markedly elevated serum interleukin-6 (IL-6) levels, suggesting the role of hyperinflammation in the pathogenesis of long COVID. However, Townsend et al. [51] did not find any correlation between the patients' fatigue severity and their serum level of inflammatory markers. Alhiyari et al. [61] noted that the patient in their case report experienced a cough for at least 4 months, and this is likely attributable to the development of pulmonary fibrosis post-COVID. Townsend et al. [49], on the other hand, noted that only a small percentage of their study patients developed pulmonary fibrosis and that this does not appear to be linked with their symptom severity. Further research into the pathogenesis of long COVID and the correlation between acute illness severity and subsequent long COVID symptoms is needed.

With the early research and studies suggesting, at least on certain levels, similarities between the clinical presentation and etiologies of long COVID and ME/CFS, it would be important to consider the implication in the treatment paradigms for both conditions. It would appear that long COVID has so far avoided the earlier obscure fate of ME/CFS, with an outpouring of public and expert acknowledgement for its status as a medical illness and its significant long-term health impact [79–82]. Many have attested to the importance of providing patient support and monitoring patients' chronic symptoms post-COVID, as well as the need for further research into long COVID [83–85]. Though there is no established treatment protocol for patients with long COVID symptoms, many have acknowledged and suggested the need and benefits of rehabilitation [86,87]. With the consideration that long COVID and ME/CFS may share certain underlying pathological processes, some have suggested that ME/CFS treatment modalities, such as antioxidant therapies, may be beneficial for COVID symptoms [78,88]. In addition, as in the cases with patients with ME/CFS, patients with long COVID may also benefit from developing an energy managemen<sup>t</sup> plan with a team of interdisciplinary physicians [89]. This may include understanding the patients' activity threshold and managing daily energy expenditure in order to maintain a healthy active lifestyle while reducing symptom flare-ups. Looking ahead to the future, it may be suggested that the research into long COVID and the ongoing research into ME/CFS may have a symbiotic relationship, with advances made in each medical illness being able to benefit patients suffering from long COVID and ME/CFS.

#### *Limitations and Future Directions*

The results of this review sugges<sup>t</sup> many potential avenues for further exploration and research. While this review provides a qualitative analysis of the similarities and differences between symptoms of long COVID and ME/CFS, a quantitative analysis further delineating the characteristics of both conditions would be warranted. Such an analysis would require further research into the clinical presentation of long COVID, with studies involving standardized methodologies. Investigations into the various contributing factors to long COVID symptoms, including severity of acute disease, history of medical illness, and patient demographics would be beneficial for a future review of ME/CFS and long COVID.
