Section 1 

Long COVID Conditions – Fatigue may be defined as tiredness that does not go away with rest. Fatigue is characterized by moments of exhaustion. Fatigue prevents you from doing your daily tasks. Fatigue is multifaceted, making it difficult to comprehend the origin of its symptoms. Symptoms vary, but exhaustion may make even basic actions like walking across the room, preparing a meal difficult.

The specific mechanics of fatigue remain a mystery, maybe as a result of its wide definition. Fatigue is a multifactorial condition. It can be caused by some or many different causes. Here we discuss the possible mechanisms of fatigue.

Autoimmune:

In the United States of America over 20 million have an autoimmune disorder. There are more than 100 autoimmune disorders that we know. There are many more that are being discovered. The prevalence of many autoimmune diseases is on the rise as well.

The chief complaint amongst patients with autoimmune disorder is significant fatigue. 75% of them find the fatigue as severe, debilitating, and hindered them from doing routine daily duties. Fatigue, in turn leads to a variety of problems such as mood disturbances, social isolation, and inability to work. Consequently, fatigue may have a negative impact on one’s health and put a financial strain on the person, family, and community.

The kind of fatigue experienced by people with autoimmune illness varies. These variations are likely connected to the tissues, organs, cell types, brain locations, and molecular and physiological pathways that are impacted by the disease. Fatigue in autoimmune disorders may be caused by a variety of mechanisms. Several physiological processes, including oxygen and nutrient supply, metabolism, and daytime drowsiness, have been linked to exhaustion. Many of the variables that modify tiredness also affect inflammation, and vice versa.

Neuroinflammation (inflammation of the nerves) seems to be a major contributor to fatigue. Because inflammation plays such a big role in fatigue, it’s possible that inflammatory pathways and the resulting physiological changes controlled by inflammation are treatment targets for fatigue in autoimmune disease patients.

INFLAMMATION

Autoimmune disorders are linked to increased pro-inflammatory signals in the peripheral and central nervous systems. The location of the increased inflammation varies depending on the kind of autoimmune illness and how far the disease has progressed. Non-autoimmune illness and associated problems with elevated inflammation in the periphery and/or CNS, sleep disturbances, stroke, and traumatic brain injury are all linked to fatigue.  Non-inflammatory factors such as hydration status, pain, pharmaceutical interactions, muscle/exercise, hypothyroidism, radiation therapy lung function, and cardiovascular characteristics such as blood pressure, heart rate, cardiac output, and stroke volume are all known to affect fatigue Many of the non-inflammatory factors that cause tiredness are influenced by or modified by inflammatory processes.

Inflammatory mediators have been shown to alter a variety of factors that lead to exhaustion, including motivation, drowsiness, cognition, anxiety, depression, and stress. Cytokines are tiny protein molecules that play a role in cell signaling and enable cells to interact through autocrine, paracrine, and endocrine pathways. Immune responses, inflammation, cell development and maturation, and normal physiological processes are all influenced by cytokines. Nucleated cell types such as lymphocytes and macrophages, as well as microglia, astrocytes, and neurons in the CNS, release inflammatory cytokines. The role of cytokines in the genesis of tiredness is implicated by the inflammatory pathways involved. Tumor necrosis, interleukin (IL)-1 beta (IL-1)

T helper cells and macrophages, in particular, increase the production of cytokines such as IL-1, TNF-, IL-6, IL-12, IL-23, and IFN- during autoimmune illness.  As a result, therapies that target components of lymphocyte regulation systems may help people with autoimmune disorders such Sjögren’s syndrome, rheumatoid arthritis, and inflammatory bowel disease. T-cell activities are linked with macrophage activity and macrophages have a role in the pathophysiology of autoimmune disorders. Furthermore, the overall degree of localized cytokine secretion, as well as its sustained increase or attenuation, might cause overexpression or downregulation of related receptors, modulating downstream processes of cytokine synthesis.

The expression of cytokines changes during the day and in response to local activity, and they govern normal physiological activities such as mood, cognition, and sleep. As a result, it’s probable that dysregulation of inflammatory cytokines and their receptors in autoimmune illness causes cytokine homeostasis to be disrupted, contributing to fatigue. Inflammation in the peripheral nervous system may lead to inflammation in the central nervous system (CNS) and illness behaviors, which are behaviors linked to various elements of exhaustion.