Long Covid — mechanisms, risk factors, and management


Fatigue Fatigue is more profound than being overtired; it is unrelenting exhaustion and a constant state of weariness that reduces a person’s energy, motivation, and concentration.

Following the SARS outbreak, up to 60% of patients reported ongoing fatigue at 12 months following recovery from the acute illness.

In Long Covid, fatigue is one of the most reported manifestations, with the ONS estimating the five week prevalence of fatigue to be 11.9% among people who have had covid-19. Fatigue is a common persisting symptom regardless of severity of the acute stage of covid-19. One cross-sectional study found that 92.9% and 93.5% of hospitalized and non-hospitalized covid-19 patients, respectively, reported ongoing fatigue at 79 days following onset of illness. Many other cross-sectional and cohort studies report that chronic fatigue is the most frequently reported symptom following recovery from acute covid-19, with one showing no association between covid-19 severity and long term fatigue.

These findings show that fatigue is a major manifestation of Long Covid.

Possible mechanisms Chronic fatigue following viral infection may be the result of miscommunication in the inflammatory response pathways; however, a cross-sectional analytical study found no association between pro-inflammatory markers and long term fatigue in covid-19 patients with persisting fatigue. It is likely that a range of central, peripheral, and psychological factors play a role in the development of post-covid-19 fatigue. A narrative review explains that congestion of the glymphatic system and the subsequent toxic build-up within the central nervous system (CNS), caused by an increased resistance to cerebrospinal fluid drainage through the cribriform plate as a result of olfactory neuron damage, may contribute to post-covid-19 fatigue. Hypometabolism in the frontal lobe and cerebellum has also been implicated in covid-19 patients with fatigue and is likely caused by systemic inflammation and cell mediated immune mechanisms, rather than direct viral neuro-invasion. It is unknown whether this finding continues into Long Covid.

Negative psychological and social factors associated with the covid-19 pandemic have also been linked to chronic fatigue. Lastly, peripheral factors such as direct SARS-CoV-2 infection of skeletal muscle, resulting in damage, weakness, and inflammation to muscle fibers and neuromuscular junctions may contribute to fatigue. Overall, it is probable that several factors and mechanisms play a role in the development of post-covid-19 fatigue.

Figure 2 further outlines these possible mechanisms.

Figure 2 - fatigue Possible mechanisms causing post-covid-19 fatigue. A range of central, peripheral, and psychological factors may cause chronic fatigue in long covid. Chronic inflammation in the brain, as well as at the neuromuscular junctions, may result in long term fatigue. In skeletal muscle, sarcolemma damage and fiber atrophy and damage may play a role in fatigue, as might a number of psychological and social factors

Post-COVID-19 fatigue has been compared with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with many overlaps between the two. Symptoms common to both ME/CFS and Long Covid include

  • fatigue

  • neurological/pain

  • neurocognitive/psychiatric

  • neuroendocrine, autonomic, and immune symptoms

with both ME/CFS and Long Covid patients having long symptom durations, reduced daily activity, and post-exertional malaise. ME/CFS remains enigmatic, therefore, research into Long Covid may assist in developing understanding of ME/CFS and vice versa.


Breathlessness is common in people with Long Covid. The ONS estimates that shortness of breath has a prevalence of 4.6% at five weeks post-covid-19 infection, regardless of presence of acute respiratory symptoms or disease severity. Abnormalities in diffusion capacity for carbon monoxide, total lung capacity, forced expiratory volume in the first second, forced vital capacity, and small airway function, have been seen in hospitalized covid-19 patients at time of discharge, approximately one month following onset of symptoms,

showing that lung function in people who have had covid-19 may take time to recover.

Several studies have found that dyspnea is a common manifestation following covid-19 infection, and one study reported that 43.4% of 143 patients assessed were still experiencing dyspnea at 60 days after covid-19 onset.

Possible mechanisms As covid-19 is principally a respiratory illness, acute illness can cause substantial damage to the lungs and respiratory tract via SARS-CoV-2 replication inside endothelial cells, resulting in endothelial damage and an intense immune and inflammatory reaction. Those who overcome the acute infection may develop long term lung abnormalities, leading to dyspnea; however, most individuals who develop long term breathing difficulties post-covid-19 have no signs of permanent or longlasting lung damage. It is likely that only those at high risk of developing breathing difficulties, including older people, those who endure acute respiratory distress syndrome, those who have extended hospital stays, and those with pre-existing lung abnormalities, are prone to develop fibrotic-like changes to lung tissue. The fibrotic state observed in some patients with ongoing dyspnea may be provoked by cytokines such as interleukin-6, which is raised in covid-19 and is involved in the formation of pulmonary fibrosis. Pulmonary vascular thromboembolisms have been observed in patients with covid-19 and may have detrimental consequences in patients with Long Covid. An overview of the possible mechanism causing dyspnea is outlined in Figure 2 -dyspnea

Figure 2 -dyspnea In the alveoli of the lungs: (A) Chronic inflammation results in the sustained production of pro-inflammatory cytokines and reactive oxygen species (ROS) which are released into the surrounding tissue and bloodstream. (B) Endothelial damage triggers the activation of fibroblasts, which deposit collagen and fibronectin resulting in fibrotic changes. (C) Endothelial injury, complement activation, platelet activation, and platelet-leukocyte interactions, release of pro-inflammatory cytokines, disruption of normal coagulant pathways, and hypoxia may result in the development of a prolonged hyperinflammatory and hypercoagulable state, increasing the risk of thrombosis.

{RCDB says - interesting there is no reference here to breathlessness due to vagus nerve dysfunction or breathing pattern disorder, or to Positional Orthostatic Tachycardia Syndrome which is associated with breathlessness. Or again to the finding of many Long Covid sufferers of frequent desaturations associated with tachycardias and or exertion}

Cardiovascular abnormalities

Cardiac injury and elevated cardiac troponin levels are associated with a significantly increased risk of mortality in patients admitted to hospital with acute covid-19 infection. Persisting cardiovascular abnormalities may be burdensome for people with Long Covid. A cohort study showed cardiac involvement, ongoing myocardial inflammation, and elevated serum troponin levels in many people with covid-19 at 71 days following diagnosis, while a large case series showed that chest pain, possibly owing to myocarditis, was a common manifestation in patients 60.3 days following onset of covid-19 symptoms, with 21.7% of the 143 patient assessed reporting chest pain. Those considered at low risk of severe covid-19, such as young, competitive athletes, have also been found to have residual myocarditis long after recovery from covid-19. In addition to cardiac complaints, studies have highlighted an emerging trend in the development of new onset postural orthostatic tachycardia syndrome (POTS) in individuals post-covid-19 infection, because of autonomic dysfunction.

{RCDB - the authors have omitted microvascular angina, cardiac arrhythmia, inappropriate sinus tachycardia and pericarditis - all known complications of Covid-19 and causes of cardiac chest pain}

Possible mechanisms ACE2 receptors are highly expressed in the heart, providing a direct route of infection for SARS-CoV-2. Studies have shown that sarcomere disruption and fragmentation, enucleation, transcriptional changes, and an intense local immune response occurs in cardiomyocytes infected by SARS-CoV-2. Pathological responses to acute cardiac injury and viral myocarditis, such as endothelial damage and microthrombosis, can lead to the development of coagulopathy, while chronic hypoxia and an increase in pulmonary arterial pressure and ventricular strain may further precipitate the incidence of cardiac injury in people who have had covid-19. Furthermore, sustained immune activation can lead to fibrotic changes and displacement of desmosomal proteins, which could be arrhythmogenic. Viral infection has previously been shown to precede POTS and, with the ACE2 receptor expressed on neurons, viral infection by SARS-CoV-2 may have direct negative consequences on the autonomic nervous system.

A complex combination of infection, an autonomic nervous system induced pro-inflammatory response, and a level of autoimmunity may all contribute to the establishment of autonomic dysfunction and POTS.

Figure 2 - Cardiovascular In the heart: (A) chronic inflammation of cardiomyocytes can result in myositis and cause cardiomyocytes death. (B) Dysfunction of the afferent autonomic nervous system can cause complications such as postural orthostatic tachycardia syndrome. (C) Prolonged inflammation and cellular damage prompts fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis. (D) Fibrotic changes are accompanied by an increase in cardiac fibromyoblasts, while damage to desmosomal proteins results in reduced cell-to-cell adhesion.

Cognition and mental health Studies have explored cognitive function and deficits in patients with covid-19 and suggest that the virus can cause septic encephalopathy, non-immunological effects such as hypotension, hypoxia, and vascular thrombosis, and immunological effects such as adaptive autoimmunity, microglial activation, and a maladaptive cytokine profile. Additionally, patients admitted to hospital with covid-19 have presented with a range of complaints including encephalopathy, cognitive impairment, cerebrovascular events/disease, seizures, hypoxic brain injuries, corticospinal tract signs, dysexecutive syndrome, an altered mental status, and psychiatric conditions. These findings reveal that neurological symptoms associated with covid-19 are common, diverse, and could pose substantial problems for rehabilitation and ongoing care following recovery from covid-19.

It is unknown who is most affected by cognitive complaints induced by covid-19 and how long they persist; however, patient experiences and published summaries of long covid have described “brain fog” to be a common and debilitating symptom.

Critical illness, severe acute respiratory syndrome, and long term ventilator support are known to have detrimental effects on long term cognition. Before the covid-19 pandemic, a retrospective study of 1040 ICU treated patients who had respiratory failure, shock, or both during hospital stays, found that 71% had delirium which lasted around four months following discharge. A similar study found that, at 3 months post-discharge, 40% of ICU treated patients had cognition scores like those of patients with moderate traumatic brain injury, while 26% had scores similar to patients with mild Alzheimer’s disease. Delirium was also widely reported, with a longer duration of delirium associated with worse cognition. With many covid-19 patients requiring ICU admission and mechanical ventilation, long term cognitive impairment and delirium are likely to pose considerable problems. Stroke and headache are prevalent in those recovered from acute covid-19, with the ONS estimating the 5 week prevalence of headache at 10.1% of all covid-19 survivors. Exaggerated levels of systemic inflammation, observed in some patients as a “cytokine storm,” in addition to activation glial cells, poses a substantial risk to the brain and increases the likelihood of neurological manifestations including encephalitis and stroke. Hypercoagulability and cardio-embolisms, formed because of virus related cardiac injury, are manifestations that could result in increased incidences of stroke following covid-19 infection. Covid-19 has also been associated with an increased risk of developing neurological conditions including Guillain-Barré syndrome, and neurodegenerative conditions such as Alzheimer’s disease. The pandemic has had a negative effect on mental health, with people who have had covid-19 exhibiting long term psychiatric symptoms including post-traumatic stress disorder (PTSD), depression, anxiety, and obsessive-compulsive symptoms following recovery from the acute infection. Quarantine, isolation, and social distancing also have damaging effects on mental health and cognition. A rapid review article states that the longer a person is confined to quarantine, the poorer the outcomes for their mental health, while periods of isolation and the inability to work can cause anxiety, loneliness, and financial concerns, and living through a global health crisis can lead to avoidance behaviors and behavioral changes. The mental health of the older population is greatly affected by social distancing and similar measures. By assessing the associations between loneliness, physical activity, and mental health both before and during the pandemic, one study found that negative changes of these factors were not solely owing to longitudinal situations before 2020, therefore the pandemic exerted extra unfavorable effects on loneliness, physical activity, and mental health. People living in care homes, including people with dementia, are vulnerable to covid-19 and to other impacts of the pandemic. Those with dementia in care homes have been observed to become more depressed, anxious, agitated, and lonely. Protracted social isolation has resulted in exacerbation of neuropsychiatric and behavioral disturbances, including apathy, anxiety, agitation, boredom, and confusion in dementia patients living in care homes, to a greater degree than for care home residents without dementia.

Sleeplessness is also commonly reported following recovery from covid-19, with many studies finding poor sleep quality and sleep disturbances to be frequent following recovery from acute illness.

Furthermore, a retrospective study of medical records of covid-19 patients treated in Seoul, South Korea, found that after prescriptions to treat fever, cough, and rhinorrhea, medications for sleep problems were the next most prescribed treatments. Knowledge of the covid-19 death toll also has a negative impact on quality of sleep, stress, anxiety, and other negative emotions, and sleep problems have been shown to be associated with covid-19 related loneliness. This leads us to question whether post-covid-19 sleep disturbances are a result of covid-19 infection, the negative effects of the pandemic, or a combination of both.

{RCDB - interestingly no real mention of cognitive dysfunction in those not admitted to hospital even though there are studies available to cite}

Possible mechanisms Coronaviruses including SARS-CoV-2 can infect the central nervous system (CNS) via hematogenous or neuronal retrograde neuro-invasive routes. The entry mechanism and subsequent CNS infection may explain the high incidence of neuro-inflammation seen in patients with covid-19, and may result in damaging long term effects, with associations of viral infections and chronic neuro-inflammation with neurodegenerative and psychiatric disorders already elucidated. SARS-CoV-2 may also affect the permeability of the blood-brain barrier, which would enable peripheral cytokines and other blood derived substances to enter the CNS and further drive neuro-inflammation. Thrombo-inflammatory pathways may be the cause of the increased prevalence of stroke in covid-19, while “brain fog” may evolve from PTSD or deconditioning following critical illness and invasive treatment.

Evidence suggests that a direct viral encephalitis, systemic inflammation, peripheral organ dysfunction, and cerebrovascular changes may contribute to the development of long term sequalae following covid-19.

Figure 2- Brain fog In the central nervous system: (A) The long term immune response activates glial cells which chronically damage neurons. (B) Hyperinflammatory and hypercoagulable states lead to an increased risk of thrombotic events. (C) Blood-brain barrier damage and dysregulation results in pathological permeability, allowing blood derived substances and leukocytes to infiltrate the brain parenchyma. (D) Chronic inflammation in the brainstem may cause autonomic dysfunction. (E) The effects of long covid in the brain can lead to cognitive impairment.

The article goes on to then talk about smell and taste disturbance, kidney and pancreatic inflammation. If this interests you please click on reference below.

Tomorrow I will share investigation of Long Covid symptoms and potential managements.


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