New research provides insight into Long COVID and ME

Authors: University of Otago July 12, 2022: Science Daily

Summary: Researchers have uncovered how post-viral fatigue syndromes, including Long COVID, become life-changing diseases and why patients suffer frequent relapses.

Arising commonly from a viral infection, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), is known to cause brain-centred symptoms of neuroinflammation, loss of homeostasis, brain fog, lack of refreshing sleep, and poor response to even small stresses.

Long-COVID has similar effects on people and is believed to also be caused by neuroinflammation.

Lead author Emeritus Professor Warren Tate, of the University of Otago’s Department of Biochemistry, says how these debilitating brain effects develop is poorly understood.

In a study published in Frontiers in Neurology, he and colleagues from Otago, Victoria University of Wellington and University of Technology Sydney, developed a unifying model to explain how the brain-centred symptoms of these diseases are sustained through a brain-body connection.

They propose that, following an initial viral infection or stressor event, the subsequent systemic pathology moves to the brain vianeurovascular pathways or through a dysfunctional blood-brain barrier. This results in chronic neuroinflammation, leading to a sustained illness with chronic relapse recovery cycles.

The model proposes healing does not occur because a signal continuously cycles from the brain to the body, causing the patient to relapse.

The creation of this model is not only important for the “huge research effort ahead,” but also to provide recognition for ME/CFS and Long COVID sufferers.

“These diseases are very closely related, and it is clear the biological basis of Long COVID is unequivocally connected to the original COVID infection — so there should no longer be any debate and doubt about the fact that post viral fatigue syndromes like ME/CFS are biologically based and involve much disturbed physiology,” Emeritus Professor Tate says.

This work will enable best evidence-based knowledge of these illnesses, and best management practices, to be developed for medical professionals.

“Patients need appropriate affirmation of their biological-based illness and help to mitigate the distressing symptoms of these very difficult life-changing syndromes which are difficult for the patients to manage by themselves.

“This work highlighted that there is a susceptible subset of people who develop such syndromes when exposed to a severe stress, like infection with COVID-19, or the glandular fever virus Epstein Barr, or in some people with vaccination that is interpreted as a severe stress.

“What should be a transient inflammatory/immune response in the body to clear the infection, develop immunity and manage the physiological stress, becomes chronic, and so the disease persists.”

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Materials provided by University of OtagoNote: Content may be edited for style and length.

Journal Reference:

  1. Warren Tate, Max Walker, Eiren Sweetman, Amber Helliwell, Katie Peppercorn, Christina Edgar, Anna Blair, Aniruddha Chatterjee. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote RelapsesFrontiers in Neurology, 2022; 13 DOI: 10.3389/fneur.2022.877772

Different SARS-CoV-2 variants may give rise to different long COVID symptoms, study suggests

Italian study of long-COVID patients suggests those infected with the Alpha variant experienced different neurological and emotional symptoms compared to those who contracted the original form of SARS-CoV-2



New research to be presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Lisbon, Portugal (23-26 April), suggests that the symptoms connected to long COVID could be different in people who are infected with different variants. The study is by Dr Michele Spinicci and colleagues from the University of Florence and Careggi University Hospital in Italy.

Estimates suggest that over half of survivors of SARS-CoV-2 infection experience post-acute sequelae of COVID-19 (PASC), more commonly known as ‘long COVID’ [1]. The condition can affect anyone—old and young, otherwise healthy, and those with underlying conditions. It has been seen in people who were hospitalised with COVID-19 and those with mild symptoms. But despite an increasing body of literature, long COVID remains poorly understood.

In this study, researchers did a retrospective observational study of 428 patients—254 (59%) men and 174 (41%) women—treated at the Careggi University Hospital’s post-COVID outpatient service between June 2020 and June 2021, when the original form of SARS-CoV-2 and the Alpha variant were circulating in the population. The patients had been hospitalised with COVID-19 and discharged 4-12 weeks before attending a clinical visit at the outpatient service and completing a questionnaire on persistent symptoms (an average [median] of 53 days after hospital discharge). In addition, data on medical history, microbiological and clinical COVID-19 course, and patient demographics were obtained from electronic medical records.

At least three-quarters 325/428 (76%) of patients reported at least one persistent symptom. The most common reported symptoms were shortness of breath (157/428; 37%) and chronic fatigue (156/428; 36%) followed by sleep problems (68/428; 16%), visual problems (55/428; 13%), and brain fog (54/428; 13%).

Analyses suggest that people with more severe forms, who required immunosuppressant drugs such as tocilizumab, were six times as likely to report long COVID symptoms, while those who received high flow oxygen support were 40% more likely to experience ongoing problems. Women were almost twice as likely to report symptoms of long COVID compared with men. However, patients with type 2 diabetes seemed to have a lower risk of developing long COVID symptoms. The authors say that further studies are needed to better understand this unexpected finding.

Researchers performed a more detailed evaluation comparing the symptoms reported by patients infected between March and December 2020 (when the original SARS-COV-2 was dominant) with those reported by patients infected between January and April 2021 (when Alpha was the dominant variant) and discovered a substantial change in the pattern of neurological and cognitive/emotional problems.

They found that when the Alpha variant was the dominant strain, the prevalence of myalgia (muscle aches and pain), insomnia, brain fog and anxiety/depression significantly increased, while anosmia (loss of smell), dysgeusia (difficulty in swallowing), ad impaired hearing were less common (figure 2 in notes to editors).

“Many of the symptoms reported in this study have been measured, but this is the first time they have been linked to different COVID-19 variants”, says Dr Spinicci. “The long duration and broad range of symptoms reminds us that the problem is not going away, and we need to do more to support and protect these patients in the long term. Future research should focus on the potential impacts of variants of concern and vaccination status on ongoing symptoms.”

The authors acknowledge that the study was observational and does not prove cause and effect, and they could not confirm which variant of the virus caused the infection in different patients—which may limit the conclusions that can be drawn.

Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

Authors: Amy D. Proal1 and Michael B. VanElzakker1,2*

The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of coronavirus disease 2019 (COVID-19). Across the globe, a subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive. This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis.


The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic of coronavirus disease 2019 (COVID-19) (Hiscott et al., 2020). Classic cases of acute COVID-19 are characterized by respiratory symptoms, fever, and gastrointestinal problems (Larsen et al., 2020). However, patients can present with a wide range of other symptoms, including neurological issues suggesting central nervous system (CNS) involvement (Harapan and Yoo, 2021). Acute COVID-19 cases range in length and severity. Many patients are asymptomatic, while others require hospitalization and ventilation (Cunningham et al., 2021). Overall, an average case of COVID-19 lasts between 1 and 4 weeks. However, across the globe, a subset of patients who sustain an acute SARS CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months (Carfì et al., 2020Davis et al., 2020Huang C. et al., 2021) (Figure 1). One study of COVID-19 patients who were followed for up to 9 months after illness found that approximately 30% reported persistent symptoms (Logue et al., 2021). These patients are being given the diagnosis Long COVID, post-acute COVID-19 syndrome (PACS), or post-acute sequelae of COVID-19.

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Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)—A Systemic Review and Comparison of Clinical Presentation and Symptomatology

Authors: Timothy L. Wong* and Danielle J. Weitzer


Background and Objectives: Long COVID defines a series of chronic symptoms that patients may experience after resolution of acute COVID-19. Early reports from studies with patients with long COVID suggests a constellation of symptoms with similarities to another chronic medical illness—myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A review study comparing and contrasting ME/CFS with reported symptoms of long COVID may yield mutualistic insight into the characterization and management of both conditions. Materials and Methods: A systemic literature search was conducted in MEDLINE and PsycInfo through to 31 January 2021 for studies related to long COVID symptomatology. The literature search was conducted in accordance with PRISMA methodology. Results: Twenty-one studies were included in the qualitative analysis. Long COVID symptoms reported by the included studies were compared to a list of ME/CFS symptoms compiled from multiple case definitions. Twenty-five out of 29 known ME/CFS symptoms were reported by at least one selected long COVID study. Conclusions: Early studies into long COVID symptomatology suggest many overlaps with clinical presentation of ME/CFS. The need for monitoring and treatment for patients post-COVID is evident. Advancements and standardization of long COVID research methodologies would improve the quality of future research, and may allow further investigations into the similarities and differences between long COVID and ME/CFS.

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 [6,7,8]. 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 [11,12,13].

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 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 [24,25,26].

The characteristics and mysterious nature of long COVID led some to suggest a connection to a debilitating but lesser-known chronic medical condition: myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [27,28,29]. 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 get 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.

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