Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases

Gottschalk, Carl Gunnar; Peterson, Daniel L.; Armstrong, Jan; Knox, Konstance K.; Roy, Avik

doi:10.1186/s13027-023-00485-z

Cited by 17 publications

(9 citation statements)

References 190 publications

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“…As such, this multifactorial condition displays over 200 symptoms and affects multiple tissues, organs, and biological systems (i.e., ears, eyes, head, nose, throat, kidney, brain, cardiopulmonary, endocrine, gastrointestinal (GI), musculoskeletal, neuropsychiatric, and systemic) to varying degrees. So far, immune dysregulation, autoimmunity, dysautonomia, endothelial dysfunction (ED), occult viral persistence, reactivation of pre-existing chronic viral infections as well as coagulopathies are some of the main underlying pathophysiological mechanisms described ( Ahamed and Laurence, 2022 ; Al-Ramadan et al, 2021 ; Amenta et al, 2020 ; Camargo-Martínez et al, 2021 ; Carod-Artal, 2021 ; Choutka et al, 2022 ; Cortés-Telles et al, 2021 ; Doykov et al, 2020 ; Fernández-de-Las-Peñas et al, 2021 ; Gottschalk et al, 2023 ; Lee et al, 2021 ; Mantovani et al, 2022 ; McFarland et al, 2021 ; Oronsky et al, 2023 ; Silva Andrade et al, 2021 ; Song et al, 2021 ; Toniolo et al, 2021 ; Touyz et al, 2021 ; Townsend et al, 2021 ; Wirth and Scheibenbogen, 2021 ; Wong et al, 2021 ). Although PASC has been described as ‘a mysterious mix of symptoms with no clear pattern’, it bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), certain phenotypic clusters are emerging in the literature.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Sherif

Gómez

Connors

et al. 2023

eLife

127

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COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein–Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, 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 specific patients.

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Section: Introductionmentioning

confidence: 99%

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Sherif

Gómez

Connors

et al. 2023

eLife

127

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“…Among the long-term symptoms, in our study we found that fatigue, hair loss, shortness of breath, and concentration and memory problems were the most commonly reported by individuals with LCS, which is consistent with previous findings [ 46 – 48 ]. Previous research has shown that the production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, interferon (IFN)-γ, and TNF-α leads to the recruitment and activation of Th1 and Th17 cells on microglia, resulting in nerve fiber demyelination, which may explain the chronic muscle fatigue and neurological disorders in individuals with LCS [ 33 , 49 , 50 ]. In addition, persistent inflammation, lung fibrosis, and damage to pulmonary vasculature caused by pro-inflammatory cytokines such as IL-6 may potentially contribute to long-term respiratory symptoms [ 1 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

The demographic, laboratory and genetic factors associated with long Covid-19 syndrome: a case–control study

Torki,

Hoseininasab,

Moradi

et al. 2024

Clin Exp Med

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Long Covid-19 syndrome (LCS) manifests with a wide range of clinical symptoms, yet the factors associated with LCS remain poorly understood. The current study aimed to investigate the relationships that demographic characteristics, clinical history, laboratory indicators, and the frequency of HLA-I alleles have with the likelihood of developing LCS. We extracted the demographic characteristics and clinical histories from the medical records of 88 LCS cases (LCS+ group) and 96 individuals without LCS (LCS− group). Furthermore, we evaluated the clinical symptoms, serum levels of interleukin (IL)-6 and tumor necrosis factor-α, laboratory parameters, and the frequencies of HLA-I alleles. Following this we used multiple logistic regression to investigate the association these variables had with LCS. Subjects in the LCS+ group were more likely to have experienced severe Covid-19 symptoms and had higher body mass index (BMI), white blood cell, lymphocyte counts, C-reactive protein (CRP), and IL-6 levels than those in the LCS− group (for all: P < 0.05). Moreover, the frequencies of the HLA-A*11, -B*14, -B*38, -B*50, and -C*07 alleles were higher in the LCS+ group (for all: P < 0.05). After adjusting for the most important variables, the likelihood of suffering from LCS was significantly associated with BMI, CRP, IL-6, the HLA-A*11, and -C*07 alleles, as well as a positive history of severe Covid-19 (for all: P < 0.05). Our study showed that a history of severe Covid-19 during the acute phase of the disease, the HLA-A*11, and -C*07 alleles, higher BMI, as well as elevated serum CRP and IL-6 levels, were all associated with an increased likelihood of LCS.

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“…The reactivation of the latent Epstein–Barr virus (EBV), but not the acute mononucleosis infection, has been reported in long COVID syndrome [ 27 , 28 , 29 , 30 ]. Not only EBV reactivation but the immune response to EBV reactivation has been shown to reflect myalgia encephalomyelitis (ME) or chronic fatigue syndrome (CFS)-like symptoms in long COVID syndrome [ 29 , 31 ]. Varicella–zoster virus (VZV) reactivations have also been well-documented following COVID-19 [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Associations of Serum Calprotectin, Arterial Stiffness and Long COVID Symptoms in Dalmatian Kidney Transplant Recipients

Đogaš,

Novak,

Babić

et al. 2023

Viruses

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We aimed to explore long COVID symptoms, serum calprotectin levels, and the parameters of arterial stiffness in Dalmatian kidney transplant recipients (KTRs) and their possible associations. A cross-sectional, single-center case-control study on 98 KTRs who had recovered from COVID-19 was performed. Long COVID symptoms were explored via standardized questionnaires assessing quality of life, and serum calprotectin was also measured. Out of 98 KTRs with a mean age of 62 years, 63 (64.3%) were men. Medical history, clinical and laboratory parameters, and arterial stiffness measurements were obtained for each study participant. Difficulties with mobility were present in 44.3% of the KTRs, while difficulties with self-care were present in 6.2%, difficulties with usual activities were demonstrated by 35.1%, pain in the extremities was present in 52.5%, and anxiety and depression were present in 26.8%. Our results showed significant differences regarding serum calprotectin levels in clinical manifestations of acute COVID-19 and follow-up laboratory parameters. The most significant positive predictors of the serum calprotectin value in the KTRs were respiratory insufficiency, acute kidney failure, the prescription of antihypertensives, leukocyte and neutrophil counts, the neutrophil/lymphocyte ratio and lactate dehydrogenase levels. Negative predictors were the time since COVID-19, high-density lipoprotein levels, kidney function parameters, and the lymphocyte count. To conclude, serum calprotectin has emerged as a possible promising biomarker for subclinical allograft rejection; however, further studies are needed to better understand this subject.

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Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases

Cited by 17 publications

References 190 publications

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

The demographic, laboratory and genetic factors associated with long Covid-19 syndrome: a case–control study

Associations of Serum Calprotectin, Arterial Stiffness and Long COVID Symptoms in Dalmatian Kidney Transplant Recipients

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