Long Haul COVID-19, an Overview of Current Research

It is apparent that patients who have shown more severe symptoms during hospitalization also had more severe manifestations of the previously mentioned symptoms. They also had worse to impaired pulmonary diffusion capacities and noticeably more abnormalities in chest imagining.

Types of long-term damage due to COVID-19

According to more recent studies, COVID-19 could pose long-term damage to survivors in four different areas, including lung injury, neuronal injury, neuro-degenerative disease and cardio-vascular issues.

Long term sequelae in lungs

In order to better explore this, it is worth explaining the underlying infectious mechanism of SARS-CoV-2 that cause lung damage. There are essentially three ways of lung injuries, which are airway inflammation, diffuse alveolar damage (DAD) and thrombosis of the alveolar micro circulation. These three effects collectively lead to impaired alveolar oxygenation, hypoxemia and acidosis. If no effective treatments were given to a patient, this long-lasting poor oxygenation will eventually lead to death or long-term sequelae after full recovery.

SARS-CoV-2 triggers inflammation in the upper respiratory tract, bronchioles, bronchi and trachea of patients caused by the release of pro-inflammatory cytokines, which subsequently lead to impaired airway ventilation function.

DAD is a result of SARS-CoV-2 binding to the angiotensin-converting enzyme 2 (ACE2) receptors that are located on the cel surfaces of type 2 pneumocytes. Upon binding to the receptors, SARS-CoV-2 viruses start to infect the cells and disrupt normal cell function, resulting in cell damage. The viral replication together with the release of pro-inflammatory cytokines leads to the characteristic DAD consequences, including cell death, exudates, desquamation of pneumocytes and formation of hyaline membranes. Besides DAD, interstitial edema and inflammatory infiltrates of syncytial cells also contribute to the impairment of alveolar gas exchange and oxygenation, causing the observed ‘out of breath’ symptom.

Coagulopathy, a condition characterized by impaired blood clotting ability, is observed in COVID-19 patients and leads to thrombosis of the alveolar microcirculation. Integrity, normality of the alveolar epithelium and proper alveolar microcirculation are essential for alveolar gas exchange, which are impaired by SARS-CoV-2 upon binding to ACE2 receptors on endothelial cells. Besides, together with the pro-inflammatory cytokines and chemokines being formed as a result of inflammation, a cascade of reactions takes place that ultimately lead to the activation of thrombosis pathway and platelet aggregation, hence the formation of thrombus in the alveolar microcirculation.

The long-term damage to the lungs due to COVID-19 might also be deduced by looking at SARS-CoV-1, which was another outbreak back in 2003 that resulted in more than 8000 cases and 900 deaths worldwide. SARS-CoV-1 and SARS-CoV-2’s nucleocapsid proteins have a similarity as high as 90%, hinting at similar infectious mechanisms, efficacy and possible similar long-term damage.

According to the findings of a 1-year-follow-up, a 2-year-follow-up and a 15-year-follow-up study on SARS-CoV-1 survivors, it was consistently found that abnormalities on chest X-ray imagining still remained among these survivors. Since abnormalities of chest imagining were already detected by the previously mentioned study on 1733 COVID-19 survivors, this hints the possibility of long-lasting abnormality in the chest due to COVID-19 onset. These abnormalities will consequently worsen the overall life quality of a survivor. Moreover, around one-third of SARS-CoV-1 survivors still show significantly impaired lung diffusion. This is also likely to occur in COVID-19 survivors since such impaired pulmonary diffusion capacities were also being reported by COVID-19 survivors after six-month recovery. Also, one-third of SARS-CoV-1 survivors have significant pulmonary fibrosis, which is a result of lungs self-healing and remodeling as a result of severe damage to the lung tissues. Based on the before mentioned infectious routes of SARS-CoV-2 in lungs, it is clear that patients who have contracted COVID-19 are at risk of having impaired lung functions no matter via which route, and have a high likelihood of pulmonary fibrosis.

Long-term neuronal sequelae

It is now clear that SARS-CoV-2 viruses are capable of crossing the human blood-brain barrier (BBB) and entering the brain. This is worrying since drastic consequences such as neurological symptoms, fatal microthrombi and encephalitis are likely to be resulted.

Besides, ACE2 receptors are widely distributed in neurons, astrocytes and oligodendrocytes in the brain, where SARS-CoV-2 viruses could bind to and enter the brain. Once arriving at the destination, SARS-CoV-2 viruses will rapidly replicate and subsequently cause cell damage, cell death and functional impairments. Long-term neuronal sequelae are likely the consequence of neuronal damage.

ACE2 receptors are widely distributed in the brain, providing an initial target for the SARS-CoV-2 viruses to cause damage to the central nervous system (CNS) of a patient.

Damage to the CNS by SARS-CoV-2 viruses is associated with increasing the risk of Alzheimer’s disease (AD) by accelerating neuronal loss and cerebral tissue damage, while potentially being able to infiltrate the entire brain via specific movement of SARS-CoV-2. These together pose long-term neurodegenerative changes in a patient that might even last for months to years after infection.

Parkinson disease (PD), which possesses high similarity in terms of pathogenesis to AD though due to damage at different locations in the CNS, is yet another neurological disease that might be caused by SARS-CoV-2 viruses. As many clinical manifestations of covid-19 patients included hyposmia and anosmia, reduced or totally loss of the ability to detect or sense odors, which are recognized as precursor clinical symptoms of PD indicating the possible correlation between SARS-CoV-2 and PD.

Last but not least, SARS-CoV-2 might also correlate to the onset of multiple sclerosis (MS), demyelination at focal gray and white matter in the brain and inflammation-induced diffuse neurodegeneration, since some similar neurological changes to MS were reported in covid-19 patients.

Long-term cardiovascular sequalae

SARS-CoV-2 might also cause cardiovascular (CV) complications since a high amount of ACE2 receptors are present in the heart, where SARS-CoV-2 viruses bind. Below, various cardiovascular complications resulting from SARS-CoV-2 will be covered.

Severe SARS-CoV-2 infection has been reported to induce aggression to the myocardium, muscular tissue of the heart. This results in myocarditis, an inflammation of the heart muscle, which impairs the electrical system and reduces the pumping ability of the heart, and subsequently causes rapid or abnormal heart rhythms. Though the underlying mechanism of such effect is yet unknown, it is speculated to be as a result of viral replication and dissemination within the cardiomyocytes. Besides, as mentioned repeatedly, the pro-inflammatory cytokines being produced upon infection also contribute to the myocardial damages.

Heart failure was also reported among COVID-19 patients. This is caused by SARS-CoV-2 viruses via various possible mechanisms, including direct viral action causing myocardial injury, inflammatory damage, lack of oxygen supply and increased atherothrombotic events.

In addition to cardiovascular diseases caused by SARS-CoV-19 viruses either via direct or indirect damage to the heart, emotional stress and behavior restrictions are also associated with cardiovascular complications in some reported cases. Indicating it is not only essential to closely monitor those who have contracted COVID-19, but also take close care of those who have been under prolonged stress during the pandemic period.