What are the long term social, neurological, cardiovascular and respiratory effects of COVID-19?

Supervised by: Yuhui Zhou, BA (Hons). Yuhui is a 5th year medical student at the University of Cambridge. She gained a First class degree in her intercalated year studying Pathology. She has an interest in Cancer & Immunology and has been awarded a Wellcome Trust Biomedical Vacation Scholarship to study host responses to infection.

Introduction:

There are various types of coronaviruses that can cause disease in both animals and humans around the world. Human coronaviruses are also known as HCoV. It is mainly known to cause infections of the upper and lower respiratory tract, but there have also been signs of symptoms involving the nervous system. Since the beginning of December 2019, there has been a SARS-CoV-2 pandemic, which has also been referred to colloquially as COVID-19. The most common symptoms are a fever and cough, fatigue, sputum production, dyspnea (shortness of breath), sore throat, nausea and vomiting. As of today, there is no definite cure, and the best method of prevention is through quarantine and vaccination.

SARS-CoV-2 Modes of Entry into the Brain :

At the beginning of the pandemic, researchers deduced that neurological symptoms were present in 36.4% of patients and were more common in patients with severe infection (45.5%) according to their respiratory status (1). Now, a research team from NYU Grossman School of Medicine determined that 91% of patients, whether or not they had a neurological diagnosis when first hospitalized, had such problems six months after going home (2). As COVID-19 is studied further, researchers are continually learning more about the disease. SARS-CoV-2 is linked through two main modes of entry into the Central Nervous System: ACE-2 receptors and Olfactory nerves. SARS-CoV-2 belongs to the β-coronavirus family Coronaviridae (3). Like other members of the Coronaviridae family, they bind to specific glycoprotein receptors on the cell membrane. The SARS-CoV-2 virus possesses the ability to enter a host’s body through connection with angiotensin-converting enzyme-2 (ACE-2) and S protein-mediated fusion. ACE-2 is a protein receptor found in many cell types and tissues including the lungs, heart, blood vessels, kidneys, liver and gastrointestinal tract (4). ACE-2 is also present in epithelial cells, including ones found on the lungs, along with neurons in the brain. SARS-CoV-2 has been detected in the brains of infected patients, almost exclusively in neurons, suggesting the distribution of ACE-2 to the Central Nervous System (5).

The S1 domain contains specific receptor binding domains that can bind to ACE-2 to gain entry into digestive epithelial and respiratory cells. The virus penetrates the cell through S protein-mediated fusion with the viral envelope or endosomal membrane (6). Alone, binding proteins like S1 can cause damage when detaching from the virus, which causes inflammation (7). The S-domain on the SARS-CoV-2 virus has certain receptor binding domains that enable it to bind to ACE-2 and interact with the membrane of epithelial and respiratory cells (8). The S1 protein can cause the brain to release cytokines. In severe cases of infection, cytokine storms occur due to the immune system overexerting itself in an attempt to kill the virus. Cytokine storms can leave a patient with brain fog, cognitive issues and fatigue (7).

SARS-CoV-2 may also enter the brain through olfactory mucosa. In a recent study, researchers analyzed 33 samples of tissue taken from patients who died of COVID-19. Samples from four different regions of the brain were tested for traces of S1 and S2 spike proteins and SARS-CoV-2 genetic material (9). Researchers concluded that neuroanatomical structures connecting the eyes, mouth, and nose with the brain stem contained the most viral material (10). The olfactory mucosa was discovered to have the highest viral load, which is consistent with the virus infecting the Central Nervous System (11). There were some limitations to this study, including whether a nasal route to the brain exists for SARS-CoV-2 after prolonged viral exposure. It is also important to study the long-term effects in order to weigh the damage of high viral loads.

SARS-CoV-2 can also infect star-shaped cells in the brain, whose function is to provide fuel to neurons that send signals throughout the brain and body. These star-shaped glial cells, called astrocytes, stop producing fuel for neurons when infected with the coronavirus. Astrocytes are crucial in the Blood-Brain Barrier’s regulation of molecules in the Central Nervous system. They are mainly composed of Endothelial cells which work with other pericytes and astrocytes to create a neurovascular unit that lines the brain vessels. As part of their role, they are essential for the formation of cells in the Blood-Brain Barrier through the secretion of gliotransmitters including Glutamate, D-serine, and ATP. Secreted gliotransmitters regulate synaptic transmission by binding to presynaptic and postsynaptic receptors. Astrocytes defend the blood-brain barrier and neurons from infection because they are more resistant to COVID-19 than neurons. However, even a few infected astrocytes can spread the virus to neurons nearby. Activated astrocytes release gliotransmitters during vesicular exocytosis. Moreover, astrocytes secrete long-chain saturated free fatty acids and phosphatidylcholines which prompt cellular death in damaged neurons. Although these lipids have no measurable effect on healthy cells, they can target coronavirus-infected cells, leading to widespread astrocyte death and decreased neuron function. This, along with structural changes in the brain due to the disease, could explain the “brain fog” and psychiatric issues that develop in some cases of COVID-19 (12). Specifically, COVID-19 infected patients’ neurological symptoms include confusion, headaches, disorientation, dizziness, and loss of senses like taste and smell (13). A recent study concluded that 89% of SARS-CoV-2 patients in need of intensive care displayed many neurological symptoms including headaches, nausea, vomiting, and trouble breathing spontaneously (14).

Effects on the brain

As outlined in the study titled “Neurologic manifestations in hospitalized patients with COVID-19”, the neurological manifestations of COVID-19 have indirect neurological consequences (e.g. paralysis due to a stroke), direct consequences on the CNS, and also complications after infection (15). COVID-19, caused by the SARS-CoV-2 virus, leaves its mark on the brain by causing functional deficiencies via its different methods of invasion and replication (16). With new strains of viruses, researchers often look at viruses in the same family for answers. SARS-CoV, which is closely related to SARS-CoV-2, is neuroinvasive and they both enter human cells through the binding of the S-spike protein to the ACE2 receptor (17). ACE2 receptors are widely seen in the brain because they are significant in the “renin-angiotensin system in the brain” (18). This indicates that SARS-CoV-2 may have the ability to invade the CNS like SARS- CoV.

A study was carried out by researchers at the Institute of Biomedicine of the Sahlgrenska Academy to see changes caused by the virus in the brains of 47 patients. 2 CNS plasma biomarkers were measured and compared to controls: neurofilament light chain protein (NfL) and glial fibrillary acid protein (GFAP) (19). NfL distinguishes problems with intra-axonal transport of neurons, while GFAP marks damage to astrocytes, which are cells of the CNS. Severe COVID patients have shown higher plasma concentrations of both. During follow-up, as GFAP decreased, NfL increased, possibly hinting at “more delayed axonal injury” (19). Other studies analyzed data from the UK BioBank and found “a more pronounced reduction in grey matter thickness and contrast in the lateral orbitofrontal cortex” in the brain (20). “A relative increase of diffusion indices” marked tissue damage in areas of the brain, as recorded by researchers based at the University of Oxford and at Imperial College (21). Overall, measures of brain size were reduced while the volume of cerebrospinal fluid increased, implying the lessening of brain cells (diffuse atrophy) in the patients (22). Through post-mortem examinations of the brains of 3 COVID-19 patients, “Prof. Iwasaki found SARS-CoV-2 in the cortical neurons of one of the three” (23). Micro-infarcts were also present in all of their brains, suggesting a disruption of brain connections (23). By infecting rats through the nasal passages, a team of researchers showed that SARS-CoV-2 caused “severe illness in rodents through rapid invasion of the brain even after the initial impact on the lungs” (24). The virus presents itself in much larger quantities in the brain, making it likely to cause visible symptoms both during infection and in the long term.

The implications of changes in the brain caused by SARS-CoV-2 vary and have only recently been studied more in-depth. Whittaker et al. (2020) performed a systematic review of 31 articles, selected out of a total of 339, based on criteria outlined in the study. Seven of these articles reported Guillain-Barré syndrome, which impacts nerves in the limbs (25). In an article titled “A Prospective Clinical Study of Detailed Neurological Manifestations in Patients with COVID-19”, 34.7% of 239 patients had encountered neurological implications, the most common being headaches (27.6%). “Dizziness, disturbances of consciousness, disturbances in smell and taste, cerebrovascular disturbances, seizures and myalgia” were also noted as the other neurological implications (26). In a different study, with a case series of 214 patients, Mao et al. (2020) found a similar percentage of neurological symptoms (36.4%). However, these symptoms were also detected to have a higher prevalence (45.5%) of severely infected patients (14). In the study titled “Neurological manifestations in hospitalized patients with COVID-19” by Romero-Sanchez et al. (2020), a larger sample of 841 hospitalized COVID-19 patients was analyzed and the findings showed that 57.4% developed “some form of neurological symptom” (27). The chances of getting the listed symptoms were higher in patients with existing neurological disorders (28). Hampshire et al. (2020) examined long-term cognitive impairment in a sample size of 81,337 Great British Intelligence Test participants. They found that both inpatients and outpatients suffered from cognitive impairments described as “brain fog” (29).

The Respiratory Effects of SARS-CoV-2

COVID-19 infection with severe acute respiratory syndrome has caused global panic regarding the long-term effects that it is having on people’s lungs and breathing. It creates this effect by damaging the walls and lining of the air sacs, and as your body fights the infection, it causes the lining to fill up with pus and inflame, making it harder to breathe. The virus does not have the same impacts on everyone’s lungs. Those who are able to recover more quickly will sustain less damage on the alveoli where oxygen diffuses. However, people with lung complications such as a chronic lung injury will be less capable of dealing with the virus. The damage that is dealt to the lungs greatly depends on a person’s lifestyle, including whether they smoke, their diet, and other factors.

Regardless of the severity, damage done to the lungs and the scarring of the tissue on the alveoli is what causes these long-term effects of COVID-19 in the lungs. For some people, it can take months to recover from the damage and let the body replace the scarred tissue on the alveoli, and this scarring leads to difficulties in diffusing oxygen into the body through the air sacs and capillaries. Some side effects caused by this include shortness of breath, difficulty breathing, coughing, headaches, and chest pains. These side effects can be minimal or very extreme depending on the amount of damage. In one study, restrictive lung impairment was observed in 50% of post-COVID-19 cases. In addition, a mild diffusion defect was detected in 35% of the post-COVID-19 group. COVID-19 pneumonia has an impact on lung function in terms of restrictive lung impairment and mild diffusion defects even up to three months after recovery. The overall effect on the person’s lungs depends on their lifestyle, health, genetics, and many other factors, so it is difficult to predict exactly how it will affect any given person, but these long-term side effects are present within many people recovering from COVID-19.

The Cardiovascular Effects of SARS-CoV-2

Similar to the neurological system, ACE2 (the receptor-binding domain of SARS-CoV-2) plays a key role in the effect COVID-19 has on the cardiovascular system. ACE2 allows for strong bonding to the human ACE2 receptor, which plays a pivotal role in the pathogenesis of the virus (30). In the same way that it operates in the brain, the S-domain on the SARS-CoV-2 virus has certain receptor-binding domains that enable it to bind to ACE-2 and interact with the membrane of epithelial cells (31), therefore allowing the virus to enter through the membrane. Disruption of this critical protective pathway, caused by the virus, could lead to heart failure, myocardial infarction or hypertension (32). The two more prominent long-term cardiovascular effects are myocardial injuries and arrhythmias.

Up to 20%-30% of patients hospitalized with COVID-19 display evidence of myocardial distress (33). However, in most cases, these issues are only recognized at a later stage. This is due to the fact that atypical presentations and screenings for COVID-19 pay more attention to respiratory symptoms, such as fever and cough, as opposed to cardiovascular symptoms such as heart palpitations and chest tightness. This leads to delayed diagnosis, not only of myocardial injuries, but also COVID-19 itself. During the epicentre of the epidemic in Italy, sudden cardiac death was said to have been the cause of death for many of the non-hospitalized patients with mild SARS-CoV-2 symptoms (34). It could be inferred from this that acute myocarditis could be one of the first clinical manifestations of SARS-CoV-2, and an important one at that. This is due to the fact that myocarditis can evolve into overt or subclinical myocardial dysfunction, as well as sudden death (as seen in the case of Italy). Patients recovering from COVID-19 may still be at risk of subclinical and possibly overt cardiovascular abnormalities. Additionally, patients that have ostensibly recovered cardiac function may still be at risk of cardiomyopathy and cardiac arrhythmias. In a long-term follow-up study of 1,142 patients (mean age 40.2 years old) who recovered from acute myocarditis, 6%-8% experienced heart failure hospitalizations. Moreover, in one study of long-term survival in 112 patients with biopsy-proven myocarditis, an ejection fraction of ≤40% was only a borderline predictor of mortality (P=.052), suggesting that a substantial number of patients with preserved left ventricular function died during follow-up (33).

After hospital discharge, patients with COVID-19-associated myocardial injury likely remain at risk for cardiovascular events (35). It should be considered that myocardial injury might result in atrial or ventricular fibrosis, the substrate for subsequent cardiac arrhythmias. An increase in myocardial injuries can lead to an increase in troponin levels, which is important as ventricular arrhythmias are higher in patients with elevated troponin levels (31). According to the NHC, among the people who died from COVID-19, 11.8% had substantial heart damage, with elevated troponin I levels, or suffered cardiac arrest during hospitalization (36). In COVID-19 patients, 16.7% had arrhythmias present, especially those in intensive care (34). Some of the more long-term effects of cardiac arrhythmias can include an increased risk of stroke and heart failure.

It is also important to mention other notable long-term cardiovascular effects such as thrombosis and tachycardia. Ackerman and his colleagues conducted a detailed necropsy-based analysis of COVID-19 decedents. These decedents with COVID-19 consistently showed endothelins, accompanying macro- and micro-vascular thrombosis within arteries, veins, arterioles, capillaries and venules in all the major organs. Endothelial cells produce microvesicles in response to inflammatory conditions, caused by myopathy. In turn, microvesicles impair vascular integrity, gap junctions, promote neutrophil binding, release NETs and facilitate tissue-level inflammation. The widespread vasculitis described in patients with COVID-19 likely contributes to thrombosis and autonomic dysregulation (33). If deep vein thrombosis occurs, it can lead to tachycardia. In a study with 121 patients initially admitted with COVID-19, tachycardia remained persistent in nearly 40% of patients within 30 days after hospital discharge. It is important to note that this could have occurred as a result of the use of hydroxychloroquine, an antimalarial drug that has been shown to be able to shorten the length of infection (34). Longstanding tachycardia could eventually be due to autonomic tone changes. (37).

Whilst the information concerning these long-term effects is subject to change as time progresses, there are ways in which we can intervene to reduce the effects of which we are currently aware. In the case of myocardial injuries, better initial screening of myocardial biomarkers would help with early diagnosis and treatments. Cardiac magnetic resonance could help to better stratify arrhythmic risk in patients who have recovered from COVID-19, who had evidence of myocardial injury at the time of infection (34). Furthermore, establishing a COVID-19 clinic alongside a team of multidisciplinary experts could help with the identification of thrombosis, as it has widespread target organ involvement (33).

Conclusion

The development of COVID-19 around the world has taken many by surprise. Unlike most other health crises of recent years, this pandemic has impacted all aspects of life. Governments continue to work with health task forces to contain this highly transmissible virus through screening, vaccination, mandates, and quarantine. COVID-19 has measurable effects on the lungs, heart, and brain. In the lungs, scar tissue causes stiffness in the lungs and contributes to difficulty breathing, while also resulting in long-term breathlessness.

People that have had COVID-19 are at greater risk of developing myocardial issues. Some patients suffering from cardiovascular symptoms of COVID-19, such as heart palpitations and a tightened chest, had delayed COVID-19 diagnosis and the disease therefore had a larger negative effect on the patients’ health. Known as Post-COVID-19 Syndrome, many of the patients who have recovered report persistent shortness of breath. The long term quality of a patient’s health may be worse in the short- and long-term. SARS-CoV-2 possesses the ability to enter a host’s body through the olfactory system or through connection with the ACE-2 enzyme.

The S1 Domain on the SARS-CoV-2 has spikes that bind to the host’s cell, initiating viral entry and the release of viral RNA. Receptors bind to the virus and are taken over by viral RNA to produce new viral proteins. Brain infections can lead to complications including strokes, nerve damage, and vascular disorders. Healthcare workers continue to manage patients with life-threatening symptoms and suggest official guidelines and mandates to keep the population safe. Although the pandemic continues today, scientists are gaining a deeper understanding of the virus, and are continually finding new interventions to fight it.

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