Angioedema is characterized by abrupt, localized swelling of the deeper layers of skin and underlying tissues, often affecting the face, throat, tongue, and extremities. This swelling occurs when fluid leaks from small blood vessels into the surrounding tissues. The COVID-19 pandemic raised concerns about whether the viral infection or subsequent vaccination efforts could trigger this reaction. This article explores the complex relationship between angioedema, the novel coronavirus, and the vaccines developed to combat it.
Understanding Angioedema
Angioedema is a temporary, non-pitting swelling involving the deep dermis, subcutaneous tissues, and mucosal surfaces. This differentiates it from urticaria, or hives, which affects only the superficial layer of the skin. The swelling results from increased vascular permeability driven by the release of specific chemical mediators. The condition is separated into two main types based on these mediators: histamine-mediated and bradykinin-mediated angioedema.
The histamine-mediated type is the most common form, often linked to allergic reactions to foods, insect bites, or medications, and frequently presents alongside hives. In this scenario, mast cells release histamine, causing blood vessels to dilate and become leaky.
The bradykinin-mediated type occurs due to the excessive production or inadequate breakdown of bradykinin, a potent vasodilator peptide. This form typically does not involve hives or itching.
The distinction between these two pathways dictates the appropriate medical treatment. Bradykinin-mediated angioedema can be hereditary, acquired, or induced by medications like Angiotensin-Converting Enzyme (ACE) inhibitors. This non-histaminergic form is concerning when it affects the upper airway, potentially leading to obstruction.
Angioedema Related to Acute COVID-19 Infection
Angioedema has been documented as a rare complication during active SARS-CoV-2 infection, often presenting as swelling of the lips or tongue. The mechanism centers on the virus’s interaction with the body’s Renin-Angiotensin-Aldosterone System (RAAS). SARS-CoV-2 gains entry into cells by binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor.
Viral binding leads to a downregulation of ACE2, reducing the enzyme’s function on the cell surface. A key function of ACE2 is breaking down bradykinin, a substance that increases vascular permeability and causes swelling. The reduction in ACE2 activity can thus lead to an accumulation of bradykinin, potentially triggering a bradykinin-mediated angioedema attack.
In reported cases, the angioedema has often been non-histaminergic, appearing without hives or itching, and responding poorly to standard allergy treatments. This presentation supports a bradykinin-driven pathology linked to the viral disruption of the RAAS. Systemic inflammation in severe COVID-19 cases may also compound this effect by activating pathways that lead to vascular leakage.
Angioedema Associated with COVID-19 Vaccines
Angioedema has been observed in a small number of individuals following COVID-19 vaccination. These reactions fall into two categories: immediate allergic reactions and delayed-onset swelling. Immediate reactions are rare, typically IgE-mediated hypersensitivity responses occurring within minutes of vaccination, sometimes escalating to anaphylaxis.
The suspected cause of many immediate reactions is an excipient, or inactive ingredient, used in the vaccine formulation. Messenger RNA (mRNA) vaccines, such as Pfizer and Moderna, contain polyethylene glycol (PEG) to stabilize the lipid nanoparticles. PEG is a known potential allergen and is suspected to be the trigger for immediate angioedema and anaphylaxis in sensitive individuals.
Viral vector vaccines, such as AstraZeneca and Johnson & Johnson, use polysorbate 80, which is structurally similar to PEG and can cause cross-reactive allergic responses. Delayed-onset angioedema occurs hours or days after vaccination and is generally not considered a severe, life-threatening allergic reaction. Severe allergic reactions following vaccination remain extremely rare events, and safety protocols monitor recipients immediately after the shot.
Diagnosis and Management
Diagnosing angioedema requires careful assessment to determine the underlying mechanism, as treatment varies significantly between the two types. The presence of concurrent urticaria and itching strongly suggests a histamine-mediated cause, commonly associated with vaccine reactions. A lack of hives and a gradual onset of swelling may point toward a bradykinin-mediated mechanism, often implicated in acute viral infection.
For a suspected histamine-mediated episode, standard management includes the immediate administration of antihistamines and corticosteroids to reduce inflammation. If the swelling is severe and involves the airway, an injection of epinephrine is administered to open the breathing passage. These treatments are effective for allergic angioedema.
Bradykinin-mediated angioedema, such as that linked to RAAS dysregulation during active COVID-19 infection, does not respond well to standard allergy medications. Treatment for this non-histaminergic form requires specific therapies like bradykinin receptor antagonists (e.g., icatibant) or C1 esterase inhibitor concentrates to address the biochemical imbalance. If sudden, unexplained swelling occurs, particularly involving the tongue, lips, or throat, seek immediate medical attention for prompt diagnosis and intervention.