Internal Medicine Journal 2005; 35: 240–246
K. MORWOOD,1 D. GILLIS,2 W. SMITH3 and F. KETTE3
1Queensland Health Pathology Service, Princess Alexandra Hospital Campus, Brisbane, Queensland,
2Immunology Department, Institute of Medical and Veterinary Science, 3Immunology Department, Royal Adelaide
Hospital, Adelaide, South Australia, Australia
Abstract of aspirin-sensitive asthma. The clinical management of
Aspirin-sensitive asthma is a common and often under- aspirin-sensitive asthma is complicated by the lack of diag-
diagnosed disease affecting up to 20% of the adult nostic testing, other than challenge procedures. Other
asthmatic population. It is associated with more severe aspects of management include management of the under-
asthma, requires increased use of inhaled and oral cortico- lying asthma and avoidance of NSAID in the majority
steroids, more presentations to hospital and a risk of of patients. Other considerations in the management of
life-threatening reactions with aspirin/non-steroid anti- patients with aspirin-sensitive asthma include the role
inflammatory drug (NSAID) ingestion. Aspirin-sensitive of leukotriene modifying agents, aspirin desensitization,
asthma is often accompanied by severe rhinosinusitis and the use of other agents, such as roxithromycin. The
and recurrent nasal polyposis, causing significant impair- management of nasal polyposis in patients with aspirin-
ment of patients’ quality of life. The pathogenesis of sensitive asthma often needs to be considered as a sepa-
aspirin-sensitive asthma is complex and involves chronic rate issue, and requires a team approach. (Intern Med J
eosinophilic inflammatory changes, with evidence of 2005; 35: 240–246)
increased mast cell activation. The cyclo-oxygenase path-
ways play a major role in the respiratory reactions that
develop after aspirin ingestion. The cysteinyl-leukotrienes Key words: aspirin-sensitivity, asthma, nasal polyposis,
have also been shown to play a role in the pathogenesis Samter’s triad, aspirin desensitization.
Aspirin-like compounds have been used since the time of Beers described and characterized the aggressive mucosal
Hippocrates (∼400 BC), when the bark of the white disease associated with aspirin sensitivity, thus the name
‘Samter’s Triad’ entered common usage.4
willow was used as an antipyretic agent. Its use was also
described during Roman times, and again in the 1700s Urticaria, angioedema and anaphylaxis can occur as a
as a treatment for ‘Ague’ (fever).1 The chemical struc- result of aspirin/non-steroidal anti-inflammatory drug
ture was described and subsequently modified in the (NSAID) ingestion. There is also a subgroup of patients
1800s to produce the stable compound acetylsalicylic with chronic urticaria in whom the urticaria is exacer-
acid, which is now called aspirin. Bayer released this bated by NSAID ingestion. This review will focus on
onto the market in 1899 as an analgesic and antipyretic aspirin sensitivity as it relates to asthma and the upper
agent.1,2 The benefits of aspirin as an analgesic, anti- respiratory tract, and will not discuss other aspirin asso-
inflammatory and, more recently, antithrombotic agent ciated conditions further.
have been increasingly recognized, and, with easy avail-
ability, it is used widely throughout the community. EPIDEMIOLOGY
Soon after it was marketed as an analgesic agent, it
Estimates of the prevalence of aspirin sensitivity vary,
was recognized that severe attacks of asthma could occur
depending on the methodological approach. A questionnaire-
after the ingestion of aspirin. In 1922, Widal et al. described
based survey of three asthmatic populations in Western
the clinical symptoms of aspirin sensitivity, asthma and
Australia has shown the prevalence of aspirin sensitivity
nasal polyps, and subsequently performed the first
to be 10–11%.5 Two population-based surveys, conducted
aspirin desensitization.3 Many years later, Samter and
in Finland6 and Poland,7 have shown that the prevalence
of aspirin-sensitive asthma was 1.2% and 0.6%, respec-
tively in the general population, and 8.8% and 4.3%,
Correspondence to: Karen Morwood, Immunology Registrar, Queensland
Health Pathology Service, Princess Alexandra Hospital Campus, Ipswich respectively in patients with asthma. Another group has
Road, Wooloongabba, Brisbane, Qld 4102, Australia. undertaken oral aspirin challenge on consecutive asth-
matic patients to find prevalence rates in the order of
15–20%,8 concluding that history alone is not a reliable
Received 12 January 2004; accepted 15 October 2004.
guide to aspirin sensitivity. Importantly, in the analysis
of this population of 500 aspirin-sensitive asthmatics,
Potential conflicts of interest: There are no potential conflicts or funding
18% were unaware of their aspirin-sensitive status prior
for the work to declare on hehalf of any of the authors.
Aspirin-sensitive asthma 241
had sinus surgery.12 The time to recurrence after surgery
Table 1 Non-steroid anti-inﬂammatory drugs to avoid
for nasal polyps is much shorter in patients with aspirin-
Benzydamine Ketoprofen Phenylbutazone
sensitive disease than in other patients with nasal polyps.14
Diclofenac Ketorolac Piroxicam
Diﬂunisal Mefenamic acid Sulindac
Ibuprofen Meloxicam Tenoxicam
Indomethacin Naproxen Tiaprofenic acid Reactions to aspirin resemble immediate hypersensitivity
reactions, however, specific antibodies to aspirin/NSAID
are rarely shown in aspirin-sensitive individuals. Addi-
tionally there is cross-reactivity between NSAID that do
not have structural similarities, thus suggesting pharma-
to challenge.8 In patients with a history of asthma and
cological rather than immunological mechanisms in the
nasal polyps, the prevalence of aspirin sensitivity is
majority of patients.
increased to approximately 30%.9,10
CLINICAL ASPECTS Aspirin-sensitive asthma is a disease of chronic airways
Aspirin-sensitive asthma is an acquired syndrome. Aspirin- inflammation, however, there are several important
induced reactions occur 2–3 h after the ingestion of oral differences between asthmatics that are aspirin-sensitive
aspirin or NSAID. The reactions are usually: broncho- and aspirin tolerant.
spasm, profuse rhinorrhoea, conjunctival injection, peri- The bronchial mucosa of patients with aspirin-sensitive
orbital oedema and generalized flushing. Patients may asthma has a marked eosinophilia, with four times more
have any or all of these symptoms, and the reactions can eosinophils than other asthmatics, and 15 times more
than normal bronchial mucosa.15 Studies have shown
vary in individuals.
absolute numbers of mast cells to be both increased16
Patients who develop the aspirin triad (asthma, nasal
and decreased,17 however, there is consistently increased
polyps, aspirin sensitivity) typically develop perennial
rhinitis in their third decade, after a viral upper respira- mast cell activation. This is evident, both when the
tory tract infection; in the subsequent 1–5 years asthma patient is stable, and after aspirin provocation, with
and aspirin sensitivity develop. Nasal polyps become increased levels of the stable metabolites of prostaglandin
clinically apparent within a further 5 years. Approxi- D2, and tryptase in plasma, however, urinary levels of
these metabolites were not increased.15–18
mately 30% develop nasal polyps prior to the diagnosis
of asthma, however, in less than 10% the diagnosis of The focus of much of the research on the pathogenesis
asthma and nasal polyps is made simultaneously. Once of aspirin sensitivity has targeted abnormalities in the
aspirin sensitivity develops it is usually lifelong.11,12 arachidonic acid pathway.
Patients with aspirin-sensitive asthma have high
frequency of admission to hospital, and more presenta-
tions to the emergency department.12 Two surveys of Aspirin acts as an anti-inflammatory agent via the inhibi-
aspirin-sensitive asthmatics have shown that approxi- tion of cyclo-oxygenase (COX) pathways, and several
mately 80% of patients were on long-term inhaled or critical observations suggest that it is also involved in the
oral steroids for control of their asthma, with 50% of aspirin-sensitive state.
patients being on both inhaled and oral corticosteroids, The two major enzymes in this pathway are COX1, an
with a mean dose equivalent of 8 mg/day of oral pred- enzyme that is constitutively expressed in airway mucosa,
nisone. An additional 30% of the patients were on and COX2, an enzyme that is induced with pro-
inhaled steroids alone, although at a higher average dose inflammatory signals. Recently, other COX enzymes,
than the general asthmatic population. Twenty per cent including COX3 have been described, but their role in
of patients had required intravenous steroids in the year aspirin sensitivity is yet to be fully delineated, however,
prior to survey.11,12 In a survey of 145 patients who had COX3 appears to be inhibited by paracetamol, which
required intubation for asthma, 25% were aspirin-sensi- neither COX1 or -2 are, and may explain the patients
who are both aspirin and paracetamol sensitive.19 Both
tive, thus suggesting that this group of patients has more
severe asthma. Ingestion of aspirin was not necessarily COX1 and -2 are expressed in normal respiratory
the cause of the reaction requiring intubation, which epithelium, and are not upregulated in the mucosa in
patients with stable asthma or chronic bronchitis.20
demonstrates that they may have unstable disease
despite appropriate avoidance.13 The evidence that the COX pathway is involved in
Patients with aspirin-sensitive asthma often suffer respiratory tract reactions in aspirin-sensitive individuals
from aggressive rhinosinusitis and nasal polyposis, with includes:
• NSAID with COX1 inhibitory activity all produce the
frequent recurrence after surgery despite avoidance of
aspirin reaction in sensitive individuals21
aspirin. Patients with aspirin-sensitive asthma, 99% of
• There is a correlation between the potency of COX
299 patients, were shown to have mucosal abnormalities
on imaging of their sinuses. The patients in this cohort inhibition and potency to induce the bronchospasm.
This is particularly related to COX1 inhibition22
had an average of 5.5 episodes of sinusitis requiring anti-
• NSAID that lack COX1 inhibition do not produce a
biotics per year, and they had undergone an average of
three sinus operations. Only 6% of patients had never
Internal Medicine Journal 2005; 35: 240–246
242 Morwood et al.
• Prostaglandin E2 (PGE2) inhalation prevents the but this was not shown in a population in the USA; this
aspirin reaction in patients who have challenge proven population included patients with mild, moderate and
aspirin sensitivity.23 severe aspirin-sensitive asthma.36
In addition, there is diminished COX2 expression and Clinical evidence for the role of Cys-LT in the broncho-
activation in nasal polyp tissue from aspirin-sensitive spasm, related to aspirin sensitivity, comes from the use
patients.24 COX2 may inhibit COX1 activity and there- of leukotriene modifying drugs. These drugs do not
fore decrease synthesis of cysteinyl leukotrienes. Therefore, block the reaction to aspirin in sensitive individuals;
the reduction in COX2 activity in aspirin-sensitive indi- however, they convert the reaction from predominately
viduals, along with inhibition of COX1 by aspirin, may bronchospasm to a predominately upper airways reac-
together contribute to reduced PGE2 production, tion. This suggests that the Cys-LT play a greater role in
resulting in the clinical manifestation of aspirin-induced the lower airways, however, do not account entirely for
the aspirin-sensitive state.37
However, there is significant evidence that the above
mechanism does not completely explain aspirin-induced DIAGNOSIS
symptoms and signs. The abnormalities in the COX
The history of a characteristic clinical reaction after
pathways have been shown in nasal polyp tissue,25 but
aspirin or NSAID ingestion, particularly in a member of
not in the lower airways. The baseline levels of PGE2 and
a susceptible subgroup (i.e. severe asthmatic, polypoid
other prostanoids are not decreased in either broncho-
rhinosinusitis or chronic urticaria) may be sufficient for
alveolar lavage26 or nasal lavage27 when compared to
diagnosis. The diagnosis of aspirin-sensitive asthma
aspirin-tolerant patients, and these levels decrease to the
should be confirmed with challenge if the history is
same extent after aspirin challenge in both aspirin-
unclear. Importantly, relying on a history of reaction
sensitive and aspirin- tolerant asthmatics.26,27 Therefore,
alone may be misleading.8 Aspirin sensitivity is an
aspirin is likely to interfere with other inflammatory
acquired phenomenon that often occurs after the onset
of rhinitis, polyposis and asthma, thus patients may not
Lipoxygenase pathways have had previous reactions to aspirin. Many asthmatic
patients will avoid aspirin and NSAID because of the
The cysteinyl leukotrienes (Cys-LT; LT C4, LT D4, LT
perceived risk of reactions, also complicating the history.
E4) induce bronchoconstriction, oedema formation and
Several clinical features suggest an increased risk of
mucus production in airways, and therefore are media-
aspirin sensitivity in an asthmatic. These include: (i)
tors of asthma. They may play an increased role in the
severe asthma with chronic nasal congestion and profuse
aspirin-sensitive asthmatics. These patients have increased
baseline levels of cysteinyl leukotrienes in urine28 and rhinorrhea; (ii) recurrent nasal polyposis; (iii) sudden,
exhaled air29 compared to aspirin-tolerant asthmatics. severe asthma with intensive care admissions and (iv)
adult onset, non-allergic asthma.38–41
After aspirin challenge, the levels of Cys–LT increase
significantly in urine,28 sputum, expired air and bronchial There is no reliable in vitro test for aspirin-sensitive
lavage fluid30 in patients who are aspirin-sensitive, but asthma. The only validated diagnostic tool for aspirin
sensitivity is challenge. Four methods for challenge have
not in normal subjects, or aspirin-tolerant asthmatics.
been reported in the literature: nasal, bronchial, oral and
Whilst this increase is reproducible, the extent of its
increase does not allow it to be a useful diagnostic test.
In addition to the increased levels of Cys-LT in
Nasal and bronchial challenges
aspirin-sensitive individuals, there is an increased
Nasal and bronchial challenges are undertaken with
responsiveness to Cys-LT. This can be explained by an
L-lysine acetylsalicylate, a compound that is not avail-
increase in the expression of Cys-LT1 receptor in nasal
able in Australia. Guidelines for inhalational challenges
mucosa of patients with aspirin-sensitive asthma, compared
have been produced by the INTERASMA Working
to patients with non-aspirin-sensitive rhinosinusitis or
Group as these challenges are used frequently in other
nasal polyposis. Additionally, aspirin desensitization
countries.42 Inhalational bronchial challenges elicit lower
leads to a decrease in the expression of this receptor,
respiratory tract reactions only, and are a fast and easy
suggesting a possible mechanism for the therapeutic
method of challenge,43 with a similar specificity, but a
benefit of aspirin desensitization in the aspirin-sensitive
lower sensitivity than oral challenge.44 Nasal challenges
are also fast and easy, requiring only a 4-h stay in
Other abnormalities in the lipoxygenase pathways
hospital, however, they have a decreased sensitivity as
include an increase in leukotriene C4 synthetase (LTC4S)
compared to bronchial challenge. The predictive value
in bronchial biopsies, and increased LTC4S messenger
of a negative result on nasal challenge is only 78.6%.
ribonucleic acid in their eosinophils of aspirin-sensitive
Nasal challenge was introduced to try to improve the
asthmatics compared with normal subjects and aspirin-
tolerant asthmatics.32,33 A genetic polymorphism of the safety of the procedure, however, it can elicit either
upper or lower respiratory tract reactions.45
LTC4S promoter has been described in severe steroid
dependent, aspirin-sensitive asthmatics in Poland,34 and
a Japanese study subsequently confirmed that this poly-
Oral challenge with aspirin was introduced in the 1970s in
morphism was more common in aspirin-sensitive
asthmatics compared with aspirin-tolerant patients,35 Poland using a protocol of placebo and graded increments
Internal Medicine Journal 2005; 35: 240–246
Aspirin-sensitive asthma 243
of aspirin over 4 days.40 Others have used shorter proto- medications may alter the target region of the aspirin
cols with equal success.41 Oral aspirin challenge has a reaction, and that leukotrienes play a greater role in the
sensitivity of 85% in those who give a history of aspirin pathogenesis of asthma in aspirin-sensitive individuals
sensitivity, and is the current gold standard for diagnosis.41 and a lesser role in the sinonasal disease.46
Safety has been the main concern with regards to oral
challenge. This has been addressed in a recent survey
Total avoidance of all aspirin and NSAID medications is
of patients undergoing aspirin challenge at the Royal
usually recommended for patients with aspirin-sensitive
Adelaide Hospital, with a 2-day challenge procedure in
asthma/rhinitis, including avoidance of all non-selective
the general recovery area. A total of 94 procedures in 82
COX inhibitors. Surveys of aspirin-sensitive asthmatic
patients (including severe corticosteroid dependant asth-
patients, presenting for review at specialist centres, show
matics) was performed over 3 years, of which there were
that 36% of these patients have had three or more reac-
44 positive challenges. Twelve patients required admis-
tions to aspirin, 33% have had two reactions to aspirin
sion, four for observation after a positive challenge, and
and 22% have had a single reaction to aspirin.11 These
eight for social or distance reasons. The patients with a
data suggest that patients have not been counselled
positive challenge who required admission needed addi-
about the risk of repeat reactions, or about the cross
tional bronchodilator treatment, but no other treatment
reactivity of these medications (Table 1).
for their reaction. No patients required admission to the
There have been four double-blind, placebo-controlled
intensive care unit. The average time to reaction was
trials of challenge with COX2 inhibitors (two with
85 min, with a range of 30–180 min. The average dose
Celecoxib (Searle, Chicago, USA), and two with
to which patients reacted was 67.5 mg, with a range of
Rofecoxib) in patients with challenge-proven aspirin-
10–100 mg. This survey confirms that oral aspirin chal-
sensitive asthma. There were no positive reactions in
lenge can be performed safely in this group of patients
these trials. Some care should still be exercised with
these medications as there are isolated case reports of
Intravenous challenge asthma with both Celecoxib and Rofecoxib, however,
Intravenous challenge with L-lysine acetylsalicylate has they may be used safely in the majority of aspirin-sensi-
been performed, however, is not used routinely in most
centres due to concerns about safety and protocols. Paracetamol is a weak inhibitor of COX1 and inhibits
COX3, whilst low doses are usually tolerated by aspirin-
sensitive asthmatics. Thirty-four per cent of patients
with aspirin-sensitive asthma will have a cross-reaction
General with acetaminophen (paracetamol) if it is given as doses
of 1000 mg and then 1500 mg, based on single-blind
The underlying asthma should be managed according to
challenge in 50 aspirin-sensitive and 20 non-aspirin-
standard guidelines with preventative therapies, including
inhaled corticosteroids, long acting β-agonists and oral sensitive asthmatics.51 In all of the patients who reacted
to acetaminophen, the reactions were mild and only
corticosteroids when required.
22% of reactions were bronchospasm. Consequently,
Leukotriene pathway modiﬁcation patients with aspirin-sensitive asthma should be coun-
A double-blind, placebo-controlled trial of the leukotriene- selled not to take more than 1000 mg of paracetamol,
modifier montelukast was performed in patients with particularly as some new long-acting formulations contain
aspirin-sensitive asthma, who were already on moderate more than the standard 500 mg of paracetamol per
to high doses of glucocorticoids. The trial showed an tablet. Other analgesics that can be tolerated by aspirin-
improvement in forced expiratory volume in 1 s (FEV1) sensitive asthmatics include dextropropoxyphene, codeine
and peak expiratory flow rate, a decreased use of bron- and other narcotics.
chodilators, fewer asthma symptoms and fewer asthma
exacerbations, suggesting that these drugs may have a
role in some aspirin-sensitive asthmatics.37 This trial was It is possible to desensitize most or all aspirin-sensitive
patients using incremental doses of aspirin over several
short-term only and the steroid doses required for
days. Tolerance can then be maintained with daily aspirin
patient care remained stable.
therapy. A randomized, double-blind, placebo crossover
Leukotriene modifying medications cannot be relied
trial of aspirin desensitization in 25 patients with aspirin-
on to block the aspirin-induce respiratory reaction, as
sensitive asthma, showed a significant improvement in
shown in a study of 271 patients, suspected to have
symptoms of rhino-sinusitis, and a decrease in the
aspirin sensitivity by history, who underwent oral chal-
amount of nasal corticosteroids required whilst on aspirin.
lenge. Ninety-six of these patients were on leukotriene
There was, however, no change in asthma medications,
antagonists at the time of challenge. The percentage of
lower respiratory symptoms or FEV1.52
patients who reacted to aspirin was similar in both
The therapeutic role of aspirin desensitization has
groups of patients, as was the dose of aspirin to which
been addressed in three retrospective trials. One study
they reacted. However, those patients on leukotriene
compared 65 aspirin-sensitive patients who were desen-
antagonists were less likely to develop bronchospasm,
sitized with a control group who avoided all NSAID.
and more likely to have upper airways or conjunctival
Patients on aspirin had a lower number of hospital
reactions. This suggests that the leukotriene-modifying
Internal Medicine Journal 2005; 35: 240–246
244 Morwood et al.
admissions, emergency department visits, outpatient visits, function or response to challenge. This trial was not
upper respiratory tract infections and sinus operations, powered to look at clinical outcomes, and further work
compared to those avoiding NSAID. Additionally, there needs to be carried out to clarify the use of these agents
in patients with aspirin-sensitive asthma.57
was a decrease in the total amount of systemic steroids
and corticosteroid treatment courses in those being
actively treated.53 Long-term follow up of 65 patients
The management of nasal polyposis in these patients can
desensitized prior to 1996, and 172 patients desensitized
be very difficult. The initial treatment should be with
between 1995 and 2000, showed that there was a
intranasal steroids, however, higher than standard doses
decreased number of sinus infections and courses of
are often required.10 The leukotriene antagonists may
prednisone, with improvement in smell, nasal, sinus and
play a role, with the reduction of nasal symptoms with
asthma symptoms when compared to the time prior to
their use, as shown in an open audit of the use of monte-
aspirin treatment. Complications of treatment were not
luekast as add-on therapy in patients with and without
addressed in this group. In the second study (from 1995
aspirin sensitivity.58 Operative intervention with poly-
to 2000), there was a response to treatment rate of 67%,
pectomy is useful for management of nasal obstruction,
which was maintained for the duration of aspirin treat-
headaches and reduction in number of infections,59,60
ment. Twenty-eight per cent ceased treatment, 14% for
however, will not control disease in the long-term.
complications of aspirin treatment, including 14 patients
Patients will need treatment with either intranasal steroids
with significant pain associated with gastritis, and two
or leukotriene modifying medications for long-term
patients with gastrointestinal haemorrhage; highlighting
the potential risks of this treatment.54,55 control. Medical polypectomy with short course high
dose oral steroids may be useful, but again the duration
These trials suggest a benefit to treatment with aspirin
of benefit may only be brief. Longer courses are limited
desensitization, however, it is low-grade evidence and
by the side-effect profile of oral corticosteroids.
should be confirmed in larger randomized, placebo
Current recommended indications for aspirin desensi-
tization in aspirin-sensitive patients are:
Whilst the clinical syndrome of aspirin-sensitive asthma
• The need for aspirin or NSAID in the treatment of
has been described for many years, there remains much
rheumatic or thrombotic conditions
to be known. Unravelling of the pathogenesis of the
• Recurrent nasal polyposis requiring repeated surgery
aspirin-sensitive state has started, however, the role of
• Asthmatic patients who can only be controlled with
each of the mechanisms in the production of the reaction
unacceptably high doses of corticosteroids, either inter-
is still unclear. The mechanism by which these patients
mittent or continuous.
can be desensitized and the place of desensitization as a
After desensitisation, patients are maintained on
treatment option remains uncertain. The best treatment
aspirin, commonly at a dose of 600 mg twice per day.
for these patients, including the role of leukotriene
Aspirin is continued for at least 6–12 months, often
modifying agents, aspirin desensitisation and macrolide
indefinitely. The desensitized state is only maintained for
antibiotics, requires clarification in prospective clinical
2–5 days after cessation of aspirin, so if doses are missed
trials. Additionally, aspirin challenge remains the diag-
for any reason for more than 48 h, aspirin should not
nostic method of choice. Aspirin challenge can place the
be restarted, as there is a risk of a severe aspirin reaction.
patients at risk of a potentially life-threatening reaction,
If aspirin is ceased or doses missed, and there is an
and requires strict supervision by experienced clinicians.
intention to continue on therapy, the graded dose desen-
Laboratory-based diagnostic testing could potentially
sitization procedure should be repeated.55 Aspirin
replace challenge and aid in the management of these
challenge and desensitization should only be performed
by those with experience in the procedure, in centres
where monitoring facilities and high-level support are
available, as whilst it is able to be performed safely, there
is potential risk of life-threatening asthma. 1 Kohl F. A pharmacentical of the century will be 100. A historical
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