• Tanvi Sheth

Risk Factors: From Covid to Long Covid and beyond

Chronic diseases like diabetes, hypertension, heart disease and so on tend to be predispositions to Covid, as well as potential sequelae of the infection. Similar to such health afflictions, psychological, psychiatric and neurological conditions can also be both antecedents to as well as consequences of getting Covid. In the same breath, we examine rare disorders linked to Long Covid (also known as Post-Acute Sequelae of Covid-19 or PASC). PASC refers to a number of residual as well as new neurological, immunological and cardiovascular chronic symptoms that patients may experience after resolution of acute Covid.

In this blog we focus on the bidirectional nature of risk factors (such as neurological, inflammatory, and psychological) which are implicated in a Covid-19 infection and how they may show up as biomarkers of rare disorders implicated in PASC.

Source: Sukocheva et al. (2021)

Immunological Factors

The word “immunity” has been touted throughout the pandemic as a protector against the viral infection. However, the role of the immune system in Covid-19 is complex. A close interaction between the virus SARS-CoV-2 and the immune system of an individual results in COVID-19 disease (Paces, Strizova, Smrz & Cerny, 2020). If the virus is not successfully contained, production of proinflammatory cytokines such as interleukin-6, and the recruitment of neutrophils and myeloid cells follows (Gubernatorova et al., 2020). This leads to hyperinflammation, and in some cases, a cytokine storm which can cause a worse prognosis and increased chances of fatality (Chen and Quach, 2021).

Speaking of which, persistent immune inflammatory responses can lead to Long Covid. In fact, it has often been observed that certain post-infection symptoms commonly follow acute viral infections like SARS-CoV-2. (Bannister, 1988). This means that recovering from Covid-19 does not guarantee returning to one’s usual state of health. Immune imbalance is also the reason why a subset of patients experience phenomena like fatigue, post-exertional malaise and cognitive dysfunction, to name a few. Such symptoms overlap with the diagnostic criteria for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), a complex neuroinflammatory illness marked by persistent fatigue that is unrelieved by rest, in combination with a range of other debilitating symptoms such as autonomic disturbances, endocrine dysfunction, and impaired cellular energy metabolism & ion transport (Sukocheva et al., 2021).

The nervous system pathophysiology seen during Long Covid indicates a potential predisposition to develop ME/CFS. On one hand, there is a possible link between high levels of IL-6 and the development of PASC, whereas on the other, the contribution of IL-6 leading to chronic fatigue has already been observed in numerous studies (Ghali et al., 2020). Besides this, overproduction of pro-inflammatory cytokines that may facilitate development of ME/CFS as well as cause complications in Covid, can lead to serious tissue and organ damage (Sukocheva et al., 2021). Therefore, it is imperative to collect evidence which can identify any potential linkages between Long Covid-19 and Chronic Fatigue Syndrome with adequate longitudinal symptom monitoring. While it is currently difficult for clinicians to diagnose a person as having ME/CFS due to PASC, if symptoms like fatigue, malaise and brain fog are debilitating and persistent for longer than 6 months, then they must be dealt with in a more sustainable manner.

Psychosocial Factors

Source: Kaye et al. (2021)

Psychosocial factors such as socio-economic status, education, and chronic stress can also cause the innate immune system to be overactive leading to a higher inflammatory response, and adaptive immune system to be less effective which results in lower cytotoxicity (Vindegaard & Benros, 2020). This has been seen in people who have mental illnesses or disorders, who generally exhibit increased psychological distress. Besides this population, another demographic has also recently fallen prey to major stress - healthcare workers (Uphoff et al., 2021). The general public, on the other hand, has been experiencing increased stress due to economic and social factors as a result of the pandemic. Marginalised groups, which already experienced socio-economic discrimination pre-pandemic, have seen a rise in healthcare disparities. There are also certain psychosocial/behavioural features like childhood adversity, history of depression, trait anxiety, loneliness, catastrophizing, sleep disturbances, and physical inactivity that predispose a Covid infection (Yang et al., 2020).

Taquet et al. (2020) found that a previously diagnosed psychiatric illness is independently associated with an increased risk of being diagnosed with Covid-19 and facilitating Long Covid. This corresponds to psychological factors perpetuating features of a Covid infection. Along with this, survivors also have a significantly higher rate of psychiatric and neurological disorders. Marked elevations have been seen in the diagnosis of anxiety disorders, insomnia, as well as mood disorders like depression as a result of isolation (Nochaiwong et al., 2021). Apart from this, patients who are more stressed after diagnosis are more prone to inflammatory signalling and also report higher levels of depression when inflammation is high. This is in line with experimental evidence which shows that people who have pre-existing psychological disturbances are more sensitive to inflammatory insults (Yang et al., 2020).

The immune response that follows psychological stress also worsens the prognosis of Covid, and has been implicated in causing Multisystem Inflammatory Syndrome in children and adults (MIS-C, MIS-A) experiencing Long Covid. MIS symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms. The pathology of this hyperinflammatory syndrome is mostly unknown. Theoharides & Conti (2020) suggest that psychological stress can impact both Long Covid and may give rise to Covid-induced MIS. Chow (2021) says that since MIS occurs in the post-acute Covid phase, an antibody-mediated process or dysregulated immune response can be suspected. Second, MIS-A is likely to be an uncommon complication of SARS-CoV-2 infection among adults. As further research is dedicated to uncover its additional aspects, evidence for optimal treatment strategy must also be gathered for medical management.

Neuroimmune Factors

Neural/neuroendocrinol elements such as alterations in neural processes, diurnal cortisol, and ANS dysregulation also play a predisposing role. Coupled with immunity factors like single nucleotide polymorphisms (SNPs) in cytokine-related genes, alterations in cellular immunity, latent coral infection/activation, cell ageing, neurological abnormalities can pose as risk factors for a Covid infection.

Long-term neuropsychiatric sequelae of Covid-19 have been associated with the aforementioned proinflammatory cytokine IL-6. Such proinflammatory changes in cerebral fluid composition were shown to provoke cognitive dysfunction, impact sleep-wake cycles, and contribute to symptoms of fatigue. These psychopathologies may be fostered directly via viral infection of the CNS or through dysfunctional immune processes such as neuroinflammation as well as disruption of the blood–brain barrier and/or hypothalamic-pituitary adrenal axis (Mazza et al., 2020). Mazza et al. also suggest that stigma, social isolation, and other stressors may also contribute to these symptoms.

Another disorder that has speculative links to Long Covid-19 as a result of neural and autonomic pathway alterations and/or indirect immune-mediated mechanisms is known as Dysautonomia (DNS) (Al-kuraishy et al., 2021). DNS is a neurological disorder generally caused by dysfunction of the autonomic nervous system (ANS) that affects autonomic functions. Abnormal autonomic response and sympathetic storm are triggered in DNS leading to exercise intolerance, insomnia, fatigue, and urinary & bowel dysfunctions, to name a few. (Martínez-Lavín, 2015; Murta et al., 2020). Such symptoms correlate with observed Long Covid symptoms. The level of ANS control is regulated by cerebral cortex, reticular formation and limbic system, therefore, viral infections that cause meningitis and/or encephalitis may disturb central autonomic dysfunction leading to DSN (Silverman et al., 2005). Given the potential of SARS-CoV-2 to invade CNS (and also previous experience with Coronaviruses like MERS and SARS-CoV), meningoencephalitis in COVID-19 is a duly anticipated clinical feature. In fact, multiple reports of meningoencephalitis associated with COVID-19 have surfaced across the globe (Mondal et al., 2021). Therefore, due to the neuroinvasive nature of SARS-CoV-2, further studies are required to better understand the neurological complications associated with DSN.


As Covid-19 is further understood, it is equally important to consider the spectrum of phenomena associated with it. Immunological, psychological and neurobiological markers are a diathesis for Covid as well as Long Covid, as has been reported by a number of studies. However, after two years of the pandemic, focus must be directed towards immunological dysregulation coupled with psychological and neurological predispositions and/or responses that may be major markers for rare disorders potentially induced by Covid.



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