Aspirin (acetylsalicylic acid), the prototype of non-steroidal anti-inflammatory drugs (NSAIDs), is globally one of the most frequently used over-the-counter and prescribed anti-inflammatory, anti-pyretic, analgesic and a blood-thinner drug. However, like all other drugs, it is associated with some side effects like severe gastrointestinal irritation or ulcer, some of which are quite serious.
One such side effect is the aspirin-induced asthma (AIA) or Aspirin-exacerbated asthma (AEA) or Aspirin-exacerbated respiratory disease (AERD), previously known as Samter’s triad, first reported 84 years ago. This side effect was reported shortly after the introduction of aspirin, as a savage root cause for bronchospasm (constriction of bronchi or narrowing of wind pipe, causing difficulty in breathing).
A significant fraction of asthmatic population of patients is vulnerable to disease exacerbation upon acquiring aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS).
Aspirin-induced asthma (AIA) is a clinical syndrome which develops in a distinctive paradigm of symptoms. The foremost symptom is the persistent rhinitis, followed by asthma, then aspirin intolerance and finally nasal polyposis appears.
The symptoms start appearing within 30 minutes after the ingestion of aspirin.
Frequency of the disease exceeds in adults to that of children and women are twice more likely to be affected than men. This side effect is mortal in asthmatics and is not restricted to aspirin but to all its analogues referred to as the “aspirin-like drugs”. Most common analogues include ibuprofen, naproxen, diclofenac, indomethacin, piroxicam and ketoprofen, to name a few. These drugs may vary in persistence and magnitude of exacerbation of asthma depending on their mechanism of action.
Recently, a new research conducted in Harvard Medical School’s Rheumatology, Immunology and Allergy division performed by Jeff and Penny Vinik Center for Allergic Disease Research, conjectured about new suspects that might be liable for aspirin exacerbated asthma in asthmatic patients (aspirin is not prescribed to asthmatic patients for this reason) because the disease flummox still needs to be settled out and the elements responsible for inducing the condition are yet to be ruled out. This research of clinical implication of basic research was published in The New England Journal of Medicine.
- Earlier researches demonstrated that the most plausible cause for the induction of AERD in asthmatics is the deviant function of the 5-lipoxygenase–leukotriene C4(LTC4) synthase pathway: a specific enzymatic pathway, responsible for the release of specific inflammatory mediators (cysteinyl leukotriene) produced in asthma, resulting in the precipitation of asthma.
- Aspirin brings about aberration in the 5-lipoxygenase–leukotriene C4(LTC4) synthase pathway activity by impeding a distinct enzyme, the cyclooxygenase enzyme, commonly termed as the “COX” enzyme. Inhibition of COX by aspirin results in elevated levels of cysteinyl leukotriene – the prime cysteinyl leukotriene responsible for AEA produced by leukotriene C4 (LTC4) synthase pathway.
- All other NSAIDs repress the COX enzyme function, resulting in the increase of cysteinyl leukotriene.
- Drugs, such as meclofenamate sodium and zileuton are examples of 5-LOX inhibitors to treat the condition of aspirin-induced asthma.
What Are Leukotrienes?
Leukotrienes are inflammatory trouble shooters playing a pathophysiological role in differential diseases like allergic rhinitis, asthma, as well as cardiovascular diseases and certain types of cancers. The overproduction of leukotrienes is a major cause of inflammation in asthma and allergic rhinitis.
Hampering of COX enzyme activity by aspirin results in escalation of activated mast cells prostaglandin-D2 (PGD2) – tryptase and histamine – and is arrested by the administration of mast-cell stabilizing drugs. Thus, mast-cell activation is a substantial contributor to cysteinyl leukotriene formation due to COX-1 inhibition in AERD. Mast-cell stabilizers are used prophylactically to prevent asthma attacks and the manifestations of seasonal or chronic allergic rhinitis. Cromolyn and Nedocromil are the common mast cell stabilizing drugs. Low levels of PGE2 are found in patients of AERD, which is a respiratory protective prostaglandin.
Platelets And Eosinophil
Additional contributing elements to AERD include platelets and eosinophils. Platelets contribute approximately 70% to cysteinyl leukotriene formation by expressing LTC4 synthase; an enzyme responsible for cysteinyl leukotriene formation. Whereas eosinophil count increases when inflammation is triggered and act in a similar fashion to that of platelets by producing large numbers of cysteinyl leukotriene (cys-LTs).
How Aspirin Plays Role in Exacerbation of Asthma
The activity of these inflammatory mediators (cysteinyl leukotrienes, activated mast cells, platelet activation) is kept in check by prostaglandin E2 in normal circumstances. During inflammatory conditions such as asthma, the levels of prostaglandin E2 increases in normal subjects (due to over activity of COX-2 and microsomal PGE2 synthase 1 enzymes) to keep the levels of inflammatory mediators – cysteinyl leukotrienes, activated mast cells – at constant levels or to prevent an increase in their levels in the respiratory tissues to subside inflammation.
The action of aspirin is to block COX-1 which as a result blocks some of the anti-inflammatory prostaglandins involved in the respiratory system. The patients suffering from aspirin-induced asthma, the pro-inflammatory leukotrienes are overproduced which results in severe exacerbation of allergy-like symptoms.
In AERD patients the activity of these specific enzymes – COX-2 and microsomal PGE2 synthase 1 – that are responsible for PGE2 synthesis, is impaired in respiratory tissues resulting in decreased synthesis of PGE2, which is a cyto-protective or cell protecting prostaglandin. Ingestion of aspirin or other NSAIDs, further aggravates the respiratory distress as these drugs cause further inhibition of COX enzyme, more specifically COX 2 enzyme, resulting in further inhibition of prostaglandin E2 synthesis and activity.
COX enzyme exists in two forms: COX 1 and COX 2 both have different functions. Specific cytokines are certain cells of the immune system which also act as inflammatory mediators. Thymic Stromal Lymphopoietin (TSLP) and Interleukin 33 (IL-33) are the two most important cytokines that play a role in aspirin-induced asthma (AIA) and are released by skin cells (keratinocytes) and the epithelial cells of the airways.
The release of TSLP and IL-33 is induced by certain pathogens: microorganisms, allergens and chemicals. These two cytokines engage in inflammatory conditions where mast cells are known to play a role in the pathogenesis of the disease e.g., atopic dermatitis and asthma and affect several mast cell functions, including growth, survival and mediator release. Recent studies demonstrate that nasal polyp tissues from persons with AERD strongly express both interleukin-33 and TSLP. Lastly PGD2 is also a promoter of inflammation that is generated at particularly high levels in persons with AERD.
During inflammation, PGD2 attracts other inflammatory mediators – eosinophils, basophils, and lymphoid helper cells – to the site of inflammation, increasing the intensity of inflammation. PGD2 acts through specific receptors that are present on specific cells – CRTH2 and it elicits bronchoconstriction through T-prostanoid receptors.
Aspirin Desensitization: Management Of AERD
Management of AERD is achieved by aspirin desensitization, a state of aspirin tolerance, that is gradually attained by giving incremental doses (gradually increasing the doses) of aspirin over 2-3 days, until the maximum dose (600mg) is well-tolerated and achieved. After achieving this “tolerance” to aspirin by incremental doses, aspirin is then regularly administered as a daily maintenance dose of 600-1200 mg.
This desensitization procedure has led to great improvement in the underlying chronic respiratory symptoms, especially in the nose, resulting in decreased responsiveness of airways to leukotrienes (LTE4) by down regulation (decreasing the number) of cysteinyl leukotriene receptors.
Future Therapeutic Targets
The New England Journal of Medicine reported that new therapies are in progress that can either shutoff or intercept these specific receptors or the inflammatory mediators and can thus treat the condition. Currently, clinical trials are ongoing to ascertain the therapeutic efficacy of PRASUGREL: an antiplatelet drug, to occlude the cysteinyl leukotriene synthesis, as well as that of IFETROBAN: a T-prostanoid receptor antagonist (the drug will block the receptor and thus PGD2 will not be able to act on the receptor and induce bronchoconstriction or narrowing of the wind pipe) in the treatment of patients with AERD. Future therapeutic targets could include:
- Antagonists – blockers of CRTH2 – specific cells on which PGD2 acts and induces bronchoconstriction,
- Blockers of interleukin-33 and TSLP – specific substances that act in combination with mast cells,
- Monoclonal antibodies against interleukin-5 or interleukin-5 receptor that deplete tissue eosinophils,
- Analogues of protective prostaglandin, the PGE2
Clinical Indications For Aspirin
Conventional indications for prescribing aspirin include ailments such as fever, headache, dental pain, muscular aches and backache as well as prescribed in specific conditions such as rheumatic diseases – osteoarthritis or chronic poly arthritis and for irregular menses. For pain related illness, Paracetamol is the safest alternative of aspirin.
Moreover, the American Diabetes Association and the American Heart Association (AHA) jointly recommend aspirin therapy (75 to 162 mg/d) for primary prevention of heart disease for persons with diabetes, with age greater than 40 years or who have additional risk factors for heart diseases and no contraindications to aspirin therapy.
The anti-inflammatory and pain relieving properties of aspirin owe their activity to inhibition of prostaglandin biosynthesis by occluding the COX enzyme – COX enzyme is responsible for production or synthesis of prostaglandins.
In cardiovascular diseases (myocardial infarction and ischemic strokes), aspirin is given as a blood thinner because it dissolves the thrombus-blood clots by its antiplatelet action. Platelets aggregate to form clots and thicken the blood which can cause a heart attack. Aspirin inhibits platelet aggregation, thereby, preventing thickening and clotting of blood. Moreover, in cardiovascular diseases, a specific protein, the C-reactive protein levels are elevated. It is an indicator of cardiovascular disease. By diminishing the serum levels of CRP, aspirin reduces the risk of heart disease.
The major side effect of aspirin is gastrointestinal bleeding and the drug should not be taken by ulcer patients. Moreover, heart patients should only take medicine after being prescribed by a licensed health practitioner.