Tony Macasaet, MD, FACEP
Hypothesis: inspired by the heroic, frontline efforts of emergency physicians like Dr. Caleb Hernandez, COVID-19 may, in part, be a leukotriene/bradykinin mediated angioedema-like state, especially affecting the most distal parts of the airways and alveoli. Net effect of viral infection leading to increased vascular permeability, upper and lower airway and tissue edema, bronchospasm, excess mucin production, dysregulated inflammation, thrombosis and eventually epithelial hyperplasia and fibrosis. Fortunately like angioedema, it may be rapidly reversible if treated early with epinephrine, antimuscarinics and leukotriene blockade. Dramatic anecdotal results are consistent with a positive response, suggesting these concepts are worthy of further study.
Medications that MIGHT have benefit and my commentary on mechanisms:
Montelukast po. See review below. Use may lead to less bronchoconstriction, mucus, airway edema, inflammation, and fibrosis
Epinephrine Intramuscular (if inadequate infusion pumps). Vasoconstriction in increased contractility of course. Increases respiratory rate, bronchodilation, decreased vascular permeability and improved tissue and airway edema. This includes improved upper airway edema if present. Shifts Oxygen–hemoglobin dissociation curve, promoting better tissue oxygenation
ADH / Vasopressin IM. Arteriolar vasoconstriction and free water reabsorption.
Atropine IM. Muscarinic antagonist - causing decreased respiratory secretions.
Systemic anticoagulation
This cocktail in severe, failing COVID-19 MAY provide:
Decreased upper AND lower airway edema/bronchoconstriction, improving WOB and oxygenation
Decreased alveolar edema/flooding, loss of surfactant, failure of oxygen absorption etc etc
Decreased respiratory secretions
Improved overall perfusion and tissue oxygenation.
Strictly my own summary and discussion.
Montelukast - high affinity leukotriene receptor blocker. Evidence it blocks bradykinin too.
I had to recall that leukotrienes are signaling molecules produced in immune cells. Made from Arachidonic acid (AA). AA is of course the building block of our beloved phospholipid bilayer and part of numerous signaling molecules. AA itself may have a role in the inflammatory cascade.
Leukotrienes released from white cells bind to leukotrienes receptors on the cell wall of respiratory epithelial cells, airway smooth muscle cells, airway macrophages and other pro-inflammatory cells.
With binding, leukotrienes trigger cellular signaling, leading to effects such as:
Increased release of histamine and prostaglandins.
Heightened bronchiolar smooth muscle tone, with small airway bronchoconstriction.
Copious mucus production, increased vascular permeability, edema
Hyper-responsiveness to bronchoconstriction (some resistance to B-agonists??)
further pro-inflammatory cell recruitment.
Not to mention smooth muscle proliferation, collagen deposition, and fibrosis.
Increased mucin secretion by goblet cells and respiratory epithelial cell hypertrophy. So, snot cells on steroids!!
Increased permeability of the blood brain barrier. Dysregulation of blood-brain barrier.
Thus, there is at least biological plausibility the above cocktail of somewhat every day medications, in many a crashcart and medicine cabinet has a net benefit. Hypothesis generating.
Taking it just a little further, SARS-Cov-2 infects respiratory epithelial cells, gaining access via the ACE2 receptor on the cell wall. The receptor and the virus are involuted into the cell. Because of decreased ACE2 receptor activity, bradykinin increases (normally metabolized by ACE2). This then may lead to increased vascular permeability, bronchospasm, edema etc. etc. Again, there is research suggesting montelukast blocks bradykinin receptor activity similar to leukotrienes.
So, perhaps in the end the key will be blocking the effects of bradykinin and or leukotrienes, which may be released as part of COVID-19. That is Montelukast, and good old epinephrine, atropine, and vasopressin.
Along these lines, other medications to ponder might include: Icatibant, TXA, H1 and H2 blockers, aminophylline, and Cromolyn among others.
Mechanistically COVID-19 may be behaving in part somewhat akin to an angioedema-like process + micro pulmonary/systemic thromboembolism. Leading to catastrophic end-organ hypoxia. Antagonizing these effects may reverse the seemingly unstoppable death spiral of COVID-19.