The pathophysiology of COVID-19 describes the complex biological processes that occur from the moment the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) enters the body until widespread disease develops. This viral infection is not limited to the respiratory tract; it triggers a cascade of events that impact multiple organ systems throughout the body. Understanding these mechanisms reveals why the disease presents with such a varied and often severe spectrum of symptoms. Disease progression involves a delicate balance between the virus’s direct destructive effects and the host’s immune response, which can, in turn, become harmful.
Viral Entry and Initial Respiratory Infection
The initial step of infection relies on the interaction between the virus and human cells. SARS-CoV-2 uses its spike (S) protein to latch onto the Angiotensin-Converting Enzyme 2 (ACE2) receptor found on host cells. ACE2 is highly concentrated in the epithelial cells lining the respiratory and gastrointestinal tracts, making these the primary targets. The virus must also be “primed” by host cell proteases, particularly TMPRSS2, which cleaves the spike protein to facilitate membrane fusion.
Following successful entry, the virus hijacks the host cell machinery to replicate, leading to the destruction of the infected cells. This destruction is most pronounced in the lungs, where the virus infects Type II alveolar epithelial cells. These cells produce surfactant, which keeps the lung air sacs (alveoli) open. The death of these cells disrupts the delicate barrier necessary for oxygen exchange between the air and the bloodstream.
The resulting damage causes fluid and inflammatory debris to accumulate in the alveoli, a condition known as viral pneumonia. This localized infection impairs the lung’s ability to transfer oxygen into the blood, causing cough and shortness of breath. If the infection is not contained, the subsequent immune response can contribute to a wider systemic problem.
Host Immune Dysregulation and Hyperinflammation
As the virus replicates, the body mounts an immune response that, in severe cases, becomes maladaptive and excessive. While a typical immune response involves the controlled release of signaling molecules called cytokines, some patients develop a state of hyperinflammation known as a “cytokine storm.” This storm is characterized by the excessive production of pro-inflammatory cytokines, chemokines, and other mediators by activated immune cells, such as macrophages and T-cells.
Specific pro-inflammatory molecules, including Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-1 (IL-1), are released into the circulation at high concentrations. This massive systemic release drives inflammation throughout the body, far beyond the initial site of infection. Paradoxically, many patients with severe disease also show signs of lymphopenia (a low count of lymphocytes). This suggests a failure of the adaptive immune system to effectively control viral spread, even as the innate immune system is over-activated.
The systemic inflammation caused by the cytokine storm directly damages healthy tissues and organs. High levels of circulating inflammatory mediators are associated with disease severity and contribute significantly to the progression to multi-organ failure. This unchecked inflammatory state sets the stage for widespread vascular damage.
Endothelial Injury and Coagulation Cascade
A defining feature of severe COVID-19 is the widespread injury to the endothelium, the thin layer of cells lining all blood vessels. The virus can directly infect endothelial cells, as they also express the ACE2 receptor. Indirect damage from circulating inflammatory cytokines further compromises the integrity of this lining.
Damage to the endothelium exposes pro-coagulant surfaces, triggering intense activation of the coagulation cascade. Endothelial cells normally provide an anti-clotting surface, but when injured, they release prothrombotic factors. This shift leads to a hypercoagulable state, meaning the blood is excessively prone to clotting.
This excessive clotting manifests as the formation of microthrombi, or tiny blood clots, that clog the small vessels, particularly within the lungs. This microangiopathy impairs blood flow and oxygen exchange, compounding the respiratory failure caused by alveolar damage. In the most severe cases, this process can lead to Diffuse Intravascular Coagulation (DIC), where widespread clotting consumes the body’s clotting factors, paradoxically leading to both clotting and bleeding complications.
Resulting Systemic Organ Dysfunction
The culmination of direct viral damage, hyperinflammation, and widespread vascular injury results in the failure of multiple major organ systems. The initial lung injury rapidly progresses to Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition where inflamed, fluid-filled lungs cannot adequately oxygenate the blood. ARDS is the leading cause of death in severe COVID-19 patients, stemming from alveolar cell destruction and microvascular thrombosis.
Beyond the respiratory system, the heart and circulatory system are frequently affected, often resulting in myocardial injury and cardiac dysfunction. This damage is related both to systemic inflammation and to the potential direct infection of ACE2-expressing heart muscle cells, which can lead to arrhythmias or heart failure. Elevated levels of cardiac injury markers are commonly observed in severe cases.
Acute Kidney Injury (AKI) is another common complication, occurring in a significant percentage of intensive care patients. AKI causes are multi-factorial, including severe hypoxia and septic shock caused by systemic illness, as well as microthrombi clogging the small vessels of the kidneys. Neurological manifestations, such as stroke or neuroinflammation, can also occur, driven by the hypercoagulable state and the systemic inflammatory response.