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Published in the Spring 2006 issue of Allergy Today. For more articles like this, subscribe to Allergy Today, click here.


It is well documented that some people who are sensitive to a chemical found in food called salicylates can react to aspirin. But now researchers are investigating a link between this, asthma and nasal polyps. Associate Professor Rohan Ameratunga explains


Samter’s triad




For reasons that are unclear, some patients become sensitised to chemicals in foods called salicylates. This can manifest as adverse reactions to aspirin and other non-steroidal anti-inflammatory drugs. The presumed link between salicylate sensitivity and Aspirin hypersensitivity is explained below. Salicylate sensitivity can manifest in several ways including anaphylactoid reactions, urticaria (hives), or a condition called Samter’s triad. Some asthmatic patients also experience worsening of asthma after taking aspirin or non-steroidal anti-inflammatory drugs. These are described below.

Anaphylactoid reactions are the most dangerous manifestations of aspirin/non-steroidal drug hypersensitivity and need to be treated immediately with adrenaline and other drugs. While there are some patients who have sensitivity to only one drug, most patients will react to other non-steroidal anti-inflammatory drugs. In general paracetamol is safe although systemic reactions do occur occasionally. This may be partly dose related, as many aspirin-sensitive patients react to paracetamol only in doses above 1000mg.

Most patients suffering from chronic urticaria do not have an identifiable trigger for their hives. There is experimental evidence this may represent an autoimmune disorder with IgG antibodies directed against mast (allergy) cells. About 20-30 per cent of patients with urticaria are hypersensitive to aspirin and other non-steroidal drugs. This can manifest as breathing problems or swelling (angioedema). These patients must avoid this group of drugs. A diet low in salicylates (see below) can also be helpful in many of these patients.

Patients who have Samter’s triad manifest nasal polyps, aspirin sensitivity as well as asthma. For reasons that are unclear, they become sensitised to salicylates in foods, which presumably perpetuates the inflammation in the nose, lungs and sinuses. This would seem to be the most logical explanation for the continuing nasal inflammation in the absence of continued intake of aspirin-like drugs. This has not been formally documented in the peer-reviewed medical literature.

A significant proportion of asthmatic patients are also sensitive to aspirin and non-steroidal drugs and this can cause flares in asthma in these individuals. Recent information suggests that up to 21 per cent of all asthmatic adults and 5 per cent of asthmatic children are sensitive to aspirin. In many cases patients may not realise they are sensitive to this group of drugs until either they have undergone a formal drug challenge or taken these drugs for other conditions. Some reactions to these drugs can be very severe.

Over-the-counter preparations for coughs and other conditions frequently contain aspirin or other non-steroidal drugs. It is very important for patients to advise their pharmacist and doctor about their hypersensitivity. Most patients with a proven drug allergy should carry a MedicAlert emblem.

The theoretical basis for aspirin/salicylate sensitivity has not been determined with complete certainty. Aspirin and NSAIDs inhibit the enzyme Cycloxygenase 1 and may lead to an imbalance of prostaglandins in the lung and sinuses. This may lead to an imbalance of chemical mediators known as Leukotrienes. (Ed’s note: if you have no idea what these chemicals are and how they work, read Dr Greg Murison’s easy-to-understand and exciting explanation of the immune system in the Allergy New Zealand National Conference section from page 40.)

Diagnosis


Currently there are no laboratory tests that can confirm aspirin sensitivity. If there is doubt about the diagnosis, a careful challenge can be undertaken. Aspirin (acetyl salicylic acid) carries a major salicylate load and can therefore be used to determine if a patient is salicylate sensitive. Aspirin challenges are undertaken primarily to confirm salicylate sensitivity in patients with suspected Samter’s triad. Patients are advised not to take an antihistamine 72 hours prior to the challenge, as it may mask a reaction to the drug.

During an aspirin challenge, patients are given a graded dose of aspirin over several hours. The challenge is considered positive if patients develop untoward manifestations such as angioedema (swelling), asthma, worsening sinus symptoms etc. If patients experience an adverse reaction, they must remain under medical supervision for at least two hours afterwards as some patients experience a delayed reaction up to two hours later.

Arcoxia Challenge


There is evidence in the medical literature that the newer Cycloxygenase 2 (COX2), inhibiting drugs (Coxibs, Arcoxia, Celebrix etc) can usually be used safely in patients with salicylate sensitivity. To confirm this, patients may be offered an Arcoxia challenge. Again, the drug is administered over two hours. Patients must remain under observation for an hour afterwards. It should be noted that the newer Coxibs carry a slightly increased risk of myocardial infarcts. If these drugs are needed in the longer term, the risks must be carefully balanced with potential benefits. Short-term use in a patient with low cardiovascular risk factors is unlikely to be a problem.

Low salicylate diet


If patients have one of the conditions where there is sensitivity to aspirin, they may benefit from a low salicylate diet. A low salicylate diet frequently results in significant improvement in conditions such as Samter’s triad, chronic urticaria or asthma. Currently there is one dietitian in Auckland and one in Wellington who have a lot of experience in this area.

A low salicylate diet followed by moderate salicylate containing food challenges may be advised. This is based on the work undertaken at the Royal Prince Alfred Hospital in Sydney. Interestingly, some patients are able to safely consume moderate salicylate containing foods after a period of elimination. Surprisingly, there is very little published in peer-reviewed medical literature on low-salicylate diets.

Steroids


Nasal and inhaled steroids play a critical role in treating patients with Samter’s triad. Sometimes high doses of oral prednisone used for a short period can lead to shrinkage of nasal polyps and may obviate the need for surgery. Oral steroids, if given in high doses for a long time, do carry the risk of significant adverse effects including weight gain, osteoporosis, hypertension etc.

Surgery


Nasal surgery plays an important role in managing patients with nasal polyps and chronic rhinosinusitis. It is, however, very important for the underlying cause to be addressed, otherwise there will be a rapid recurrence of nasal polyps. Patients with Samter’s triad frequently have multiple nasal operations before the diagnosis is made. It is also essential for nasal steroids to be continued after surgery.

Aspirin desensitisation


This can be undertaken successfully and has the potential to help patients with Samter’s triad. Small doses of aspirin are gradually given in increasing doses over several weeks to alleviate the salicylate sensitivity. There are risks of adverse reactions including severe asthma and each increment is given under careful medical supervision. There is also a much shorter protocol, but there is a tradeoff between speed of desensitisation and risks of adverse reactions.

Desensitisation will lead to improvement in the nasal polyps and often the asthma too. Asthma treatment will need to be optimised before aspirin desensitisation. In Samter’s triad, the aspirin desensitisation will not reverse established damage, so surgery may also be needed. If surgery is needed, there is a protocol for temporarily discontinuing aspirin until after surgery because of the bleeding risk.

Desensitisation has the added advantage that many patients, who could not eat foods with a high-salicylate content, can liberalise their diet. The risk of reactions to other non-steroidal drugs is also less after aspirin desensitisation. Again, this is based on personal observation and has yet to be published in peer-reviewed medical literature.

Aspirin desensitisation does carry significant risks. It can lead to flares of asthma or other manifestations including anaphylactoid reactions. These can be life threatening. Aspirin desensitisation should only be undertaken under specialist supervision.

In some patients, aspirin desensitisation can be difficult, as the asthma can flare. In those patients asthma medications may have to be temporarily intensified. While most patients can be desensitised over a few weeks, it may take much longer in others. There are some patients with unstable asthma and low respiratory reserve where I do not attempt desensitisation because of the risk of catastrophic asthma.

Sometimes patients with Samter’s triad can benefit from aspirin desensitisation, with doses as low as 100mg. This is in contrast to the North American experience, where much higher doses of aspirin are advocated.

If aspirin desensitisation is not possible because of intractable flares of asthma or troublesome adverse effects from aspirin, a low salicylate diet and a leukotriene antagonist (see below) may be needed in the long term. In some patients, excessive bruising and bleeding can be troublesome, even at doses as low as 300mg.

It is important to be aware that aspirin desensitisation is a life-long process, and stopping aspirin will result in some of the symptoms returning. Patients on long-term aspirin are prescribed enteric coated aspirin and are routinely given a proton pump inhibiting drug (eg Omeprazole) to reduce the risks of stomach ulcers, gastritis etc. In spite of this, some patients experience intractable gastritis, reflux symptoms or even gastric bleeding. This may limit the dose of aspirin that can be administered.

Long-term aspirin use has the added benefit of reducing cardiovascular risk. If patients have established ischaemic heart disease and have aspirin sensitivity, desensitisation can be undertaken successfully to 75-100 mg of aspirin. Clopidogrel is an alternative drug for ischaemic heart disease but is currently not funded by Pharmac. Clopidogrel will not address the underlying salicylate sensitivity, but will allow a patient with ischemic heart disease and salicylate sensitivity to receive an antithrombotic drug successfully. In some patients Clopidogrel can be used temporarily while aspirin desensitisation is undertaken.

One other class of drugs that can sometimes help is the Leukotriene antagonists (Monteleukast etc). In general, however, these are less effective than aspirin desensitisation. These drugs are not currently funded although a three month course of Monteleukast (Singulair) is available free of charge.


Associate Professor Rohan Ameratunga
Adult and Paediatric Immunologist

Acknowledgement

The author wishes to thank Dr Penny Fitzharris for reviewing
this article and her helpful suggestions.