COVID-19 Pathogenesis

The clinical disease course of COVID-19 begins with the SARS-CoV-2 virus entering the nose/mouth to create a respiratory infection, which eventually activates the human innate immune response to kill the virus, and this triggers inflammation to help fight the infection. However, this inflammation can rapidly change from being helpful to harmful, and trigger the mortal danger known as the “cytokine storm”. So the key to treating a COVID-19 infection is killing the virus while controlling inflammation.

Infection

The SARS-CoV-2 virus is a respiratory infection that first replicates in airway epithelial cells in the upper respiratory tract, then migrates down the lower respiratory tract to target alveolar epithelial cells, vascular endothelial cells and macrophages in the lung. The infection and the destruction of these cells triggers the human body’s innate immune response.

Delayed Symptoms

The SARS-CoV-2 virus effectively delays the activation of the human body’s innate immune response (i.e., symptoms), which is why the onset of symptoms occurs an average of 7 days after infection.  Within 5-6 days of symptoms onset, SARS-CoV-2 viral load reaches its peak.

Killing SARS-CoV-2 Virus

Once the innate immune system is finally activated (i.e., after symptoms appear), the focus is on killing the SARS-CoV-2 virus.  White blood cells have begun to kill the SARS-CoV-2 virus (anti-pathogen immune response).  At this point, decreasing the viral burden is a key to a milder clinical course and full recovery.  In most individuals, the innate immune system clears the infection in the lung, the immune response recedes and patients recover.

Controlling Inflammation

Inflammation (cytokine activation by white blood cells) is an integral part of every innate immune response against pathogens.  Controlling the inflammatory response is as important as targeting the virus.  However, inflammation in COVID-19 can escalate out-of-control (i.e., inflammatory cytokine storm), and this can pose a mortal danger.  At this point, maintaining safe levels of inflammation (anti-inflammatory immune response) is a key to staying alive.  Uncontrolled inflammation leads to inflicts multi-organ damage leading to organ failure, especially of the cardiac, hepatic and renal systems.  The cytokine storm in response to the viral infection and/or secondary infections can result in symptoms of sepsis, which is the cause of death in 28% of fatal COVID-19 cases.

Preventing Lung Injury

Severe COVID-19 cases progress to acute respiratory distress syndrome (ARDS) on average around 8 – 9 days after symptom onset.  ARDS may lead directly to respiratory failure, which is the cause of death in 70% of fatal COVID-19 cases.

Preventing Secondary Infections

Acute Respiratory Distress Syndrome (ARDS) seen in severe COVID-19 is characterized by difficulty in breathing and low blood oxygenation level.  As a result, some patients may succumb to secondary bacterial and fungal infections, which is the cause of death in 70% of fatal COVID-19 cases. In addition, the innate immune response to the SARS-CoV-2 viral infection and/or secondary infections can result in a ‘cytokine storm’ and symptoms of sepsis that are the cause of death in 28% of fatal COVID-19 cases.

Anticoagulation

Increased risk of thrombosis has been described in COVID-19, with approximately 50% incidence of thrombitic events, usually a pulmonary embolism (PE), in ICU patients with COVID-19 pneumonia. The intimate association between inflammation and thrombosis suggests an anti-inflammatory/anti-viral therapeutic treatment approach should be considered in parallel with anti-coagulation.

Forming Antibodies

Activated white blood cells also signal the acquired immune system response, which begins to develop specific SARS-CoV-2 virus antibodies around 7 days after symptoms.  This is when the immune response switches from killing mode (i.e. protective in the short term) to an antigen-specific immune response mode (i.e. providing long-term protection against future infections).  The key is maintaining the delicate balance between mounting an effective immune response on the one hand and damage to one’s self on the other hand.