Biological and Psychological Factors Determining Neuropsychiatric Outcomes in COVID-19

Abstract

Purpose of review: We present biological and psychological factors implicated in psychiatric manifestations of SARS-CoV-2, as well as its neuroinvasive capability and immune pathophysiology.

Recent findings: Preexisting mental illness leads to worse clinical outcomes in COVID-19. The presence of the virus was reported in the cerebrospinal fluid (CSF) and brain tissue post-mortem. Most common psychiatric manifestations include delirium, mood disorders, anxiety disorders, and posttraumatic stress disorder. "Long-COVID" non-syndromal presentations include "brain-fogginess," autonomic instability, fatigue, and insomnia. SARS-CoV-2 infection can trigger prior vulnerabilities based on the priming of microglia and other cells, induced or perpetuated by aging and mental and physical illnesses. COVID-19 could further induce priming of neuroimmunological substrates leading to exacerbated immune response and autoimmunity targeting structures in the central nervous system (CNS), in response to minor immune activating environmental exposures, including stress, minor infections, allergens, pollutants, and traumatic brain injury.

Keywords: COVID-19; Neuroinflammation; Neuroinvasion; Neuropsychiatric; Priming; SARS-CoV-2.

Fig. 1

Historic awareness of the importance of the nasal pathway in pandemics. Legend: The Plague Doctor is a reproduction of a 1856 engraving by the publishing house of Gerhart Altzenbach, a copper engraver from Cologne, Germany (approximately 1590–1672) illustrating a 1656 outfit of a physician during the medieval outbreaks of plague that spread throughout Rome and neighboring Naples. The outfit is representative of what doctors wore during the bubonic plague in Europe in hopes of protecting themselves from the disease. Protecting the nostrils and shielding the eyes were believed to be paramount. The physicians held wands to better give instructions. The beak of the mask was often filled with strongly aromatic herbs and spices with potential disinfectant effects, in hopes of protection from the miasmas or “bad air,” which at the time was thought, mistakenly, to carry the plague. Nevertheless, the intuition about the importance of the nasal pathway proved correct for other infectious disease. Indeed, the nose is a common “superhighway” to the brain for certain pathogens, including coronaviruses, to enter the central nervous system [30] (Tonelli, L. H. and Postolache, T. T. 2010), including for coronaviruses, such as COVID-19. (The picture of this engraving, The Plague Doctor, is in the public domain and was published in circa 1656 by Gerhart Altzenbach. REPRODUCED FROM https://commons.wikimedia.org/wiki/File:Gerhart_Altzenbach,_Kleidung_widder_den_Todt_Anno_1656.png. ACCESSED ON 12.20.20. Original capture: Tizenberg et al.)

Fig. 2

Reciprocal double vulnerability and sequential triggering. Legend: SARS-CoV-2 precipitates neuropsychiatric symptoms through a reciprocal double vulnerability. The virus can affect the CNS as part of a pan-organ involvement of endothelia. The virus can affect brain structure and function through direct invasion or via the effects of immune activation and inflammation, including in the choroid plexus [232]. Direct invasion occurs via neural or hematological pathways. The neural pathway is where the virus travels via the olfactory (I) and the trigeminal (V) nerves from the nasal cavity and via the vagus (X) nerves from the lungs to the CNS. From the nose, in addition to nerves I and V, a transepithelial pathway has also been described. The hematological pathway involves the virus traveling via monocytes, cells that deliver the virus through the BBB to the CNS. Both SARS-CoV-2 and inflammatory signals (molecular, cellular) can influence the resident immune cells (e.g., microglia) by priming—a process that involves molecular and structural changes and leads to over-reactivity to a multitude of stimuli. The reciprocal double vulnerability and sequential triggering concept postulates that the SARS-CoV-2 can serve both as a trigger of preexisting vulnerabilities (predispositions—including genetic factors, past infections, autoimmune and allergic processes), as well as induce a long-term secondary predisposition, consisting of a vulnerability to triggers that induce, under normal conditions, very mild neuroimmune activation (e.g., routine psychological stressors, mild infections, routine pollutants or allergens, concussions). This results in exaggerated immune, excitotoxic, and apoptotic reactions originating from primed and overactivated microglia [231]. Considering the ubiquity of stressors and exposures of daily living, this can lead to perpetuation of psychiatric syndromes as well as “long-hauling” non-specific symptoms such as headaches, fatigue, sleepiness, sleep abnormalities, and brain-fogginess (original figure and capture, Tizenberg et al.)