Fatigue in the COVID-19 pandemic
Authors: Domenico Azzolino, Matteo Cesari
Journal: The Lancet Healthy Longevity (2022)

Beyond diseases and syndromes, there are some other conditions, such as fatigue, which are frequently reported by older people and represent unmet clinical needs. In particular, fatigue is one of the most reported symptoms both during and after COVID-19 infection. Fatigue cannot be completely explained by a single disease or unique pathogenetic mechanism. The most promising mechanisms underlying the condition include inflammation, mitochondrial dysfunction, sleep alterations, autonomic nervous system abnormalities, and poor nutritional status.1Zengarini E Ruggiero C Pérez-Zepeda MU et al.Fatigue: relevance and implications in the aging population.Exp Gerontol. 2015; 70: 78-83Google Scholar All these mechanisms are also a common thread of COVID-19 infection (table) and many recovered patients, the so-called long haulers, face long-term physical, cognitive, and psychological symptoms, including fatigue, which represents one of the most persistent and debilitating post-COVID-19 symptoms.2Rudroff T Fietsam AC Deters JR Bryant AD Kamholz J Post-COVID-19 fatigue: potential contributing factors.Brain Sci. 2020; 10E1012Google Scholar Some convalescent patients might face long-lasting respiratory complications, mainly due to the COVID-19 fibrotic lung damage resulting in increased morbidity, long-term disability, and even death. Fatigue might be due to the excessive respiratory effort related to respiratory complications (ie, dyspnoea, pneumonia, and acute respiratory distress syndrome). However, the lack of a gold standard for assessment of fatigue, as well as the subjective nature of the symptom, make it a condition that is poorly considered. Fatigue is observed in many medical conditions, including cancer, neurodegenerative disorders, rheumatological disease, and heart failure, but can also be an isolated symptom with unknown underlying causes, as in the case of chronic fatigue syndrome.1Zengarini E Ruggiero C Pérez-Zepeda MU et al.Fatigue: relevance and implications in the aging population.Exp Gerontol. 2015; 70: 78-83Google Scholar In older people, but also in the context of COVID-19 infection, it is often difficult to differentiate fatigue from mood disorders, depression, and sleepiness, which frequently occur simultaneously.2Rudroff T Fietsam AC Deters JR Bryant AD Kamholz J Post-COVID-19 fatigue: potential contributing factors.Brain Sci. 2020; 10E1012Google Scholar, 3Resnick HE Carter EA Aloia M Phillips B Cross-sectional relationship of reported fatigue to obesity, diet, and physical activity: results from the third national health and nutrition examination survey.J Clin Sleep Med. 2006; 2: 163-169Google Scholar COVID-19 is characterised by increased production of pro-inflammatory cytokines, which can result in the so-called cytokine storm, determining the most severe forms of the disease.4Bonnet B Cosme J Dupuis C et al.Severe COVID-19 is characterized by the co-occurrence of moderate cytokine inflammation and severe monocyte dysregulation.EBioMedicine. 2021; 73103622Google Scholar Myalgias, muscle loss, and weakness are frequently observed in patients with COVID-19 and might persist for several months after infection, which can be partly explained by direct virus entry into muscle cells via the angiotensin-converting enzyme 2 receptor, determining local inflammation.5Bauer JM Morley JE Editorial: COVID-19 in older persons: the role of nutrition.Curr Opin Clin Nutr Metab Care. 2021; 24: 1-3Google Scholar This augmented inflammatory response might lead to mitochondrial dysfunction, further exacerbating muscle loss. Chronic low-grade inflammation and mitochondrial dysfunction are observed in some chronic conditions that are characterised by the presence of fatigue6Lacourt TE Vichaya EG Chiu GS Dantzer R Heijnen CJ The high costs of low-grade inflammation: persistent fatigue as a consequence of reduced cellular-energy availability and non-adaptive energy expenditure.Front Behav Neurosci. 2018; 12: 78Google Scholar and have been evoked as hallmarks of ageing, playing a major role in the aetiopathogenesis of sarcopenia.7López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging.Cell. 2013; 153: 1194-1217Google Scholar Since mitochondria are the hub of energy production, energy shortage related to mitochondrial dysfunction (but also resulting from inflammatory processes) might result in decreased stamina and increased fatigue.6Lacourt TE Vichaya EG Chiu GS Dantzer R Heijnen CJ The high costs of low-grade inflammation: persistent fatigue as a consequence of reduced cellular-energy availability and non-adaptive energy expenditure.Front Behav Neurosci. 2018; 12: 78Google ScholarTablePotential determinants of fatigue in older people and in the context of COVID-19 pandemicFatigue in older peoplePost-COVID-19 fatigueInflammationLow-grade systemic inflammation (ie, inflammageing)Abnormal release of pro-inflammatory cytokines (ie, cytokine storm)Mitochondrial dysfunctionHallmark of ageing; defective immune response to viral infections (ie, immunosenescence)Increased inflammatory or oxidative stateAutonomic nervous system abnormalitiesModifications of cardiac functionCardiovascular damagePoor nutritional statusAnorexia of ageing; undernutritionAnorexia (ie, loss of taste and smell, loss of appetite); weight loss and cachexia; high catabolic conditionsObesity and physical inactivityInflammation; metabolic and endocrine alterations; reduced mobilityInflammation; immobilisation; lifestyle changes (ie, sedentary behaviour)SarcopeniaSarcopenia of ageing; sarcopenia of respiratory musclesMuscle wasting; sarcopenia of respiratory muscleSleep alterationsDaytime sleepiness; poor nocturnal sleep quality; sleep apnoea; depression; mood disordersSocial isolation; psychological distress; anxiety; obstructive sleep apnoea; daytime sleepinessRespiratory complicationsChronic obstructive pulmonary diseaseDyspnoea; acute respiratory distress syndrome; lung fibrotic damage Open table in a new tab COVID-19 infection might also be characterised by loss of taste and smell, leading to anorexia, which is an important contributor to malnutrition (ie, undernutrition). Additionally, the high catabolic response to COVID-19 infection, leading to weight loss and muscle decline, might further contribute to the manifestation of fatigue. Loss of muscle mass and strength is a whole-body process that also affects respiratory muscles.8Azzolino D Passarelli PC D'Addona A Cesari M Nutritional strategies for the rehabilitation of COVID-19 patients.Eur J Clin Nutr. 2021; 75: 728-730Google Scholar Hence, respiratory function might be further compromised by the acute muscle wasting seen during COVID-19 infection or in individuals with a sarcopenic or dysphagic background. Furthermore, reduced force of contraction of respiratory muscles can lead to so-called respiratory fatigue9Aubier M Respiratory muscle fatigue.Intensive Care Med. 1989; 15: S17-S20Google Scholar and might result in a reduced ability for expulsive airway clearance tasks, such as coughing and sneezing, contributing to an increased risk of pneumonia and other respiratory infections, and thus creating a vicious circle. Obesity, which has been evoked as one of the key risk factors associated with poor COVID-19 outcomes,10Menassa M Vriend EM Franco OH Healthy longevity in the time of COVID-19: a conceptual framework.Lancet Healthy Longev. 2021; 2: e243-e244Google Scholar has been repeatedly associated with fatigue; the release of pro-inflammatory cytokines and adipokines by adipose tissue has been described as the mechanism that mediates this finding.3Resnick HE Carter EA Aloia M Phillips B Cross-sectional relationship of reported fatigue to obesity, diet, and physical activity: results from the third national health and nutrition examination survey.J Clin Sleep Med. 2006; 2: 163-169Google Scholar Inflammatory mediators can pass the blood–brain barrier and can be transmitted as stress signals, leading to autonomic nervous system abnormalities, including fatigue. Recently, SARS-CoV-2 variants characterised by and increased transmission capacity have emerged, with a consequent net decrease in the mean age of infected people who can also experience fatigue despite their young age. Fatigue can thus be envisioned as a disorder of energy balance and availability, a sort of alert that mimics the exhaustion of the metabolic reserves of an individual (ie, frailty). In fact, some frailty instruments include, more or less explicitly, the concept of fatigue. The long-term negative effects of the pandemic might negatively affect the accumulation of the biological reserves of an individual. In other words, in the near future, we could see a high prevalence of frailty in people who survive the pandemic. MC has received honoraria from Nestlé Health Sciences for presentations at scientific meetings and to serve as member of expert advisory boards. DA declares no competing interests.