(Chest. 2000;118:1470-1476.)
© 2000
American College of Chest Physicians
Aspirin and Asthma*
K. Suresh Babu, MD, DNB and
Sundeep S. Salvi, MD, DNB, PhD
*
From the Department of Respiratory Cell and Molecular Biology, University of Southampton, Southampton General Hospital, Southampton, UK.
Correspondence to: K. Suresh Babu, MD, DNB, University Medicine, Level D, Centre Block, Southampton General Hospital, Southampton SO16 6YD, UK; e-mail: ksb{at}soton.ac.uk
 |
Abstract
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Aspirin is not only one of the best-documented medicines in the
world, but also one of the most frequently used drugs of all times. In
addition to its role as an analgesic, aspirin is being increasingly
used in the prophylaxis of ischemic heart disease and strokes. The
prevalence of aspirin intolerance is around 5 to 6%. Up to 20% of the
asthmatic population is sensitive to aspirin and other nonsteroidal
anti-inflammatory drugs (NSAIDs) and present with a triad of rhinitis,
sinusitis, and asthma when exposed to the offending drugs. This
syndrome is referred to as aspirin-induced asthma (AIA).
The pathogenesis of AIA has implicated both the lipoxygenase (LO) and
the cyclooxygenase (COX) pathways. By inhibiting the COX pathway,
aspirin diverts arachidonic acid metabolites to the LO pathway. This
also leads to a decrease in the levels of prostaglandin (PG)
E2, the anti-inflammatory PG, along with an increase in the
synthesis of cysteinyl leukotrienes (LTs). Evidence suggests
that patients with AIA have increased activity of LTC4
synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in
their bronchial biopsy specimens, thereby tilting the balance in favor
of inflammation. LT-modifying drugs are effective in blocking the
bronchoconstriction provoked by aspirin and are used in the treatment
of this condition. Aspirin desensitization has a role in the management
of AIA, especially in patients who need prophylaxis from thromboembolic
diseases, myocardial infarction, and stroke. This review covers the
latest understanding of pathogenesis, clinical features, and management
of AIA.
Key Words: aspirin • asthma • cyclooxygenase • desensitization • leukotrienes
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Introduction
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A hundred years have passed since Felix Hoffmann, a German chemist, developed
aspirin as a treatment for his father’s arthritis. Since then,
aspirin, or acetylsalicylic acid (ASA), has remained one of the
world’s safest, least expensive, and most consumed analgesics. In the
United States, the annual consumption of aspirin is approximately 80
billion tablets, while in the United Kingdom it is approximately 100
tons. Apart from its analgesic and antipyretic properties,
aspirin also possesses antiplatelet activity and is, therefore, used in
the prophylaxis of thromboembolism, the prevention of transient
ischemic attacks, and the reduction of the risk of morbidity and
mortality in patients with unstable angina and myocardial infarction.
The association of aspirin sensitivity, asthma, and nasal polyposis was
first described by Widal et al1
in 1922. Aspirin-induced
asthma (AIA) refers to the development of bronchoconstriction in
asthmatic individuals following the ingestion of aspirin. This syndrome
encompasses classic symptoms of chronic rhinoconjunctivitis, nasal
polyps, and asthma akin to a protracted viral respiratory infection. In
patients with AIA, acute symptoms are superimposed on a background of
chronic severe asthma. The attacks may be precipitated following the
ingestion of small amounts of aspirin or other nonsteroidal
anti-inflammatory drugs (NSAIDs). The prevalence of AIA in the
community is not certain, but patients with AIA constitute about 10 to
20% of the asthmatic population,2
3
and AIA is more
common in women. A Finnish study4
showed an overall
aspirin intolerance of 5.7% and the prevalence of AIA to be 1.2%.
Over the last few years, there has been an increased
understanding of the pathogenesis and management of AIA. This review
discusses the clinical features, the pathogenic mechanisms, and the
management of AIA.
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Pathogenesis of AIA
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Asthma is an inflammatory condition of the airways characterized
by the shedding of airway epithelium, sub-basement membrane fibrosis,
airway smooth muscle hypertrophy, excessive secretion of mucus, and
multicellular inflammation involving activated mast cells, eosinophils,
neutrophils, macrophages, basophils, and lymphocytes. In this state of
continuous inflammation, exposure to aspirin in a subset of asthmatic
patients appears to temporarily accentuate the inflammatory process,
leading to asthma exacerbations.
The precipitation of an acute attack by aspirin is similar to the
immediate hypersensitivity reaction and suggests an antigen antibody
reaction. However, the skin test responses with ASA lysine are
negative, and repeated attempts to demonstrate an antibody against ASA
or its derivatives have been futile.5
Hypersensitivity
reactions to aspirin and other NSAIDs are, therefore, unlikely to be
mediated by IgE-dependent mechanisms. Consistent and reliable
identification of IgE antibodies against either aspirin or NSAIDs has
not been accomplished in patients receiving AIA, hence, the reactions
could be termed as anaphylactoid. In recent years, it has become
increasingly clear that aspirin hypersensitivity is likely to be
mediated by a deviation of the arachidonic acid metabolic pathway
toward excessive leukotriene (LT) production, which then produces all
the clinical features of AIA.
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The Lipoxygenase Pathway
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Cysteinyl LTs are derived from arachidonic acid via the
5-lipoxygenase (LO) pathway (Fig 1
). The cellular biosynthesis of LTs involves 5-LO activating protein,
which transports arachidonic acid into the cytosol to be acted on by
the enzyme 5-LO. The sequential catalytic action of 5-LO on arachidonic
acid yields LTA4, which is further hydroxylated
to LTB4 or is converted into the first of the
cysteinyl LTs, LTC4, by
LTC4 synthase. LTC4 is
exported to the extracellular space where it forms
LTD4, which in turn is cleaved to form the
6-cysteinyl analog of LTC4 known as
LTE4. The cysteinyl LTs exert their biological
action by binding to two types of G-protein-coupled 7-transmembrane
receptors, CysLT1 and CysLT2.
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Figure 1. Aspirin inhibits the COX pathway and consequently
diverts arachidonic acid metabolites to the LO pathway. This also leads
to a decrease in the levels of PGE2, the anti-inflammatory
PG. LTC4 synthase overexpression further increases the
number of cysteinyl LTs, tilting the balance toward inflammation.
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Aspirin-induced bronchoconstriction is thought to be caused by the
shunting of the arachidonic acid metabolism away from the
cyclooxygenase (COX) pathway toward the LO pathway. This results in the
increased production of LTs with the resultant bronchoconstriction.
Consistent with this finding, bronchoconstriction in patients with AIA
can be inhibited by LT receptor antagonists.6
Provocation with aspirin in AIA patients produces airflow obstruction
accompanied by the release of cysteinyl LTs into the urine and BAL
fluid.7
8
LTC4 synthase is the
rate-limiting enzyme for the synthesis of cysteinyl LTs. Bronchial
biopsy studies have revealed an overexpression of
LTC4 synthase in patients with AIA as compared to
aspirin-tolerant asthma (ATA) patients.9
The gene for
LTC4 synthase has been localized to chromosome
5q, telomeric to other candidate genes, including interleukin (IL)-3,
IL-4, IL-5, and granulocyte macrophage colony-stimulating factor, which
also have been implicated in asthma pathogenesis.10
A
genetic variant of LTC4 synthase gene promoter
has been described, which is overexpressed in the AIA
population.11
However, 30% of patients with AIA do not
have a predisposing variant of the LTC4 synthase
gene, whereas 25% of the control subjects do have it without any
consequence to their health.12
Although this will not
explain the pathophysiology of AIA in all patients in the population,
such a finding is common in conditions with multifactorial inheritance
and is predictable on the basis of nonmendelian low inheritance of AIA.
The normal expression of 5-LO in patients with AIA precludes 5-LO as a
contributing factor in the pathogenesis of AIA.13
Overexpression of the LTC4 synthase in the
bronchial wall may be the single most important determinant of acute
respiratory reactions to aspirin in subjects with AIA. In addition, the
removal of the prostaglandin (PG) E2 brake in all
subjects by NSAIDs, as described later, leads to exaggerated cysteinyl
LT synthesis only in AIA patients due to the altered threshold activity
of LTC4 synthase in their bronchial wall.
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The COX Pathway
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The metabolism of arachidonic acid via the COX pathway leads to
the generation of prostanoids, which are important signaling molecules
that are produced both in normal physiologic as well as in inflammatory
conditions. The airway inflammatory cells produce both
proinflammatory prostanoids like PGD2 and
PGF2
and anti-inflammatory PGs like
PGE2.14
15
The notion that asthma exacerbations might result from the specific
inhibition of a single enzyme (namely, COX) has gained both
experimental and clinical support. The COX enzymes exist in two
isoforms, COX-1 and COX-2. COX-1 is the housekeeping enzyme expressed
in cells at baseline, while COX-2 is induced during inflammation and
mainly enhances synthesis of inflammatory prostanoids. The results of
bronchial biopsy studies show no difference in expression of COX-1 or
COX-2 between subjects with and without AIA.16
In
addition, airway lavage fluid after ASA-lysine does not show any
alteration in the levels of COX-1 and COX-2 in patients with
AIA.9
The results of segmental bronchial challenge with
aspirin in patients with AIA and ATA have revealed no changes in the
levels of PGD2, PGF2,
and PGF2 in the AIA group, but have demonstrated
significantly decreased levels in the ATA group, who acted as control
subjects. The levels of PGE2 and thromboxane
B2 were decreased in the AIA and the ATA
groups.17
The normal levels of PGD2,
PGF2, and PGF2 in the
AIA group, in contrast to the decreased levels of proinflammatory
eicosanoids and the decreased levels of PGE2,
produce a characteristic disturbance leading to the precipitation of an
asthmatic attack. Hence, the altered synthesis of some PGs after
interaction with ASA/NSAIDs and COX enzymes seems crucial in the
pathogenesis of AIA.
The initial event in AIA appears to be the interruption of the
synthesis of PGE2. PGE2 has
profound regulatory effects on other inflammatory systems. It reduces
LT synthesis by inhibiting 5-LO, inhibits cholinergic transmission,
prevents mediator release from mast cells, and prevents
ASA-precipitated bronchoconstriction.12
Hence, it is
possible that PGE2 may act as a brake for the
inflammatory responses. Alterations in the COX pathway by NSAIDs in
patients with AIA might suggest an anomaly of COX-1 or COX-2, but no
evidence of genetic polymorphism or mutation has been reported in AIA
patients. Alternatively, in the presence of aspirin, COX-2 is modified
enzymatically to form 5-hydroxyeicosatetraenoic acid instead of
PGs.18
This putative pathway could generate 5-LO products
and could account for the effects of AIA.
The evidence that supports the role of COX in the pathogenesis of AIA
includes the following: (1) precipitation of bronchoconstriction by
NSAIDs with anti-COX activity, while NSAIDs deprived of this activity
are well-tolerated; (2) a positive correlation with the potency of
NSAIDs to inhibit COX and their potency to induce asthmatic attacks;
and (3) cross-desensitization to other NSAIDs after desensitization to
aspirin.
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Inflammation in AIA
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Chronic, persistent inflammation is the hallmark of patients with
AIA.19
Eosinophils are consistently found in blood, nasal,
and bronchial secretions as well as in bronchial biopsy specimens of
patients afflicted with AIA.9
Macrophages are present
throughout the respiratory tract and are prominent in the bronchial
wall and lumen,20
while T-lymphocyte counts do not differ
from those in patients with other types of asthma or in control
subjects.19
The airway expression of IL-5 is also markedly
increased in patients with AIA.21
IL-5 is the key
regulator of eosinophil lineage and is involved in eosinophilopoeisis
and in eosinophil recruitment, activation, maturation, and survival
enhancement. Bronchial biopsy studies also have revealed that
eosinophils are the predominant cells containing
LTC4 synthase, the essential enzyme in the LT
pathway. The increased number of eosinophils and the presence of an
increased amount of LTC4 synthase activity may be
responsible for the pathophysiology of AIA.
Viral infections are emerging as a common factor of morbidity
attributable to asthma exacerbations and might share this feature with
AIA, with inflammation being a common denominator. One hypothesis
suggested that in response to a virus, long after the initial exposure,
specific lymphocytes are produced that are suppressed by
PGE2, which is produced by pulmonary alveolar
macrophages. Aspirin inhibits PGE2 production,
thereby removing the brake.22
It also was observed that
virally infected cells were more prone for drug and drug
metabolite-related toxicity.23
These findings were
supported by the finding that acyclovir inhibited analgesic-induced
bronchoconstriction in patients with mild to moderate AIA and decreased
the urinary levels of LTE4.24
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Clinical Presentation
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A classic triad, first described by Samter and
Beers25
in 1968, consists of rhinitis with nasal polyps,
sinusitis, asthma, and aspirin sensitivity. Typically, the
disease often begins after a viral infection. The symptoms usually
start after the age of 10 years and peak around the third decade of
life. After the ingestion of ASA or NSAIDs, an acute asthma
exacerbation occurs within 3 h accompanied by profuse rhinorrhea,
conjunctival injection, periorbital edema, and, sometimes, a
scarlet flushing of the face and neck. Fifty percent of the patients
with AIA have chronic, severe, corticosteroid-dependent asthma,
30% have moderate asthma that can be controlled with inhaled
steroids, and the remaining 20% of patients have mild and intermittent
asthma.26
Bronchoconstriction may be severe and
life-threatening, requiring hospital admission, and, at times,
requiring mechanical ventilation. Up to 25% of hospital admissions for
acute asthma requiring mechanical ventilation may be due to NSAID
ingestion.27
Based on the clinical features, intolerance
to aspirin and other NSAIDs was divided into the following three major
groups: type A (asthmatic and/or rhinitic); type B
(urticaria/angioedema); and type C (a combination of type A and type
B).28
29
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Management and Prevention
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In most cases, the clear history should enable the physician to
make a diagnosis. Most patients have moderate or severe persistent
asthma. In doubtful cases, carefully controlled challenge testing with
aspirin or other NSAIDs is justified, however, these tests should be
performed in hospitals with full facilities for resuscitation. Lysine
aspirin by inhalation could be used for challenge testing, although it
is of value in the diagnosis of analgesic sensitivity rather than in
assessing sensitivity to specific NSAIDs. Nasal provocation tests with
lysine aspirin have been found to be safe, simple, and specific in the
diagnosis of AIA.30
There are a few practical aspects
regarding aspirin sensitivity. If asthmatic patients have healthy
sinuses on radiographs and/or CT scans, then the likelihood of having
AIA is low. Patients with clear evidence of IgE-mediated upper and
lower airway diseases have a low incidence of AIA. This could serve as
predictive information in the probable risk of AIA. The general rules
concerning the treatment of AIA do not differ from the published
guidelines of asthma management.
In the long term, patients should be advised to avoid aspirin and
products containing aspirin. NSAIDs that cross-react with aspirin also
should be avoided (Table 1
). Patients can usually take acetaminophen for mild analgesia, but
occasional cross-reactions have been observed.31
Patients
with AIA can also safely take sodium salicylate, salicylamide, choline
magnesium trisalicylate, benzydamine, chloroquine, azapropazone, and
dextropropoxiphene. These drugs are either devoid of anti-COX activity
or are weak COX-2 inhibitors. Nimesulide and meloxicam, which are
predominantly COX-2 inhibitors, induced mild bronchial obstruction but
only at high doses.32
33
It has been observed that patients with AIA sporadically
cross-react with hydrocortisone hemisuccinate, thereby provoking
bronchoconstriction.34
This cross-reactivity has been
attributed to the succinate molecule rather than to cross-sensitivity
by the fact that hydrocortisone succinate continued to induce
respiratory symptoms in ASA-desensitized patients.35
Anti-LT drugs are being used currently in the treatment of patients
with AIA.36
There are two classes of anti-LT drugs, the
5-LO inhibitors (ie, zileuton) and the specific cysteinyl LT
receptor antagonists (ie, zafirlukast, montelukast, and
pranlukast). LT-modifying drugs have been found to attenuate the
aspirin-induced bronchial reactions in AIA patients.6
37
However, a recent study has reported that a higher therapeutic dose of
aspirin overcame the protection from pretreatment with
zileuton.38
Anti-LTs also induce bronchodilation in
patients with AIA. A Swedish-Polish study39
found that
zileuton provided short-term and long-term improvement in pulmonary
function measurements compared to baseline in patients with AIA.
Montelukast also has been found to be effective in patients with
AIA.40
A few instances of Churg-Strauss syndrome (CSS)
have been reported in patients on anti-LT drug.41
The
exact mechanism of the development of CSS in patients receiving
anti-LTs remains unclear. One possibility involves the unmasking of
previously unrecognized CSS with the tapering of steroids used for the
treatment of moderate to moderately severe asthma.41
The
other possibility that the drug reaction is a hypersensitivity reaction
to anti-LTs, with individuals having an unusual eosinophil-based
response to LT receptor blockade, should also be
considered.42
Salmeterol, a long-acting ß2-agonist also has
been found to be effective in the management of AIA and also has
attenuated the bronchial hyperresponsiveness to
lysine-ASA.43
There is now good evidence to implicate the LT pathway in the
pathogenesis of AIA. The inhibition of COX-1 and COX-2 by aspirin
results in the diversion of the arachidonic acid products toward the LO
pathway, thereby paving the way for the role of LT-modifying drugs in
the management of AIA. It remains to be seen whether selective COX-2
inhibitors, which theoretically should not cross-react with aspirin
because of the preservation of PGE2, will provide
an alternative in patients with AIA.
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Aspirin Desensitization
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In aspirin-sensitive patients, there are strategies available to
administer aspirin. These subjects could be made to tolerate aspirin.
This is particularly important in AIA patients with coexistent
arthritis or arterial thromboembolic diseases, or after AIA patients
experience myocardial infarctions. The availability of alternate drugs
for cardiovascular and thromboembolic diseases has lead to the
utilization of aspirin desensitization in the management of
aspirin-sensitive patients with rhinosinusitis and nasal polyps. All
aspirin-sensitive patients can be successfully
desensitized.44
Oral administration is used for aspirin
desensitization, but alternative approaches, such as intrabronchial and
inhalational administration, have been tried.
Small incremental doses of aspirin are ingested over the course of 2 to
3 days until 400 to 650 mg aspirin is tolerated. Aspirin then can be
administered daily, with doses of 100 to 300 mg used for
desensitization. After each dose of aspirin, there is a refractory
period of 2 to 5 days during which aspirin and other COX inhibitors can
be taken with impunity. It is possible to maintain the tolerance state
for a long time by the administration of aspirin at proper
intervals.45
Patients maintained on aspirin
desensitization do respond to an aspirin challenge. This manifests as a
rise in the level of urinary LTE4 excretion,
however, the responses appear blunted.46
Problems that are
encountered during desensitization of an AIA patient include gastritis,
which is seen in about 20% of aspirin-treated patients.47
Cutaneous reactions to aspirin also have been observed. Patients can be
successfully desensitized but need to take the treatment regularly to
maintain the refractory state. If patients discontinue ASA for some
days, their sensitivity to ASA can revert to their predesensitization
levels, and this could precipitate an acute asthma attack on exposure
to NSAIDs.
Endonasal administration of lysine-ASA has been used in some studies
for ASA desensitization.48
Endonasal desensitization with
lysine-ASA has been found to be effective in nasal polyposis induced by
aspirin. The relapse rates of nasal polyps were significantly lower
(lysine-ASA group, 57.5%; group treated without lysine-ASA, 88%) on a
5-year follow-up.49
Aspirin desensitization by the
endonasal route may represent a valid alternative to classical surgical
approaches in patients with nasal polyposis.
Desensitization by the inhalational route also has been tried and was
based on the premise that AIA becomes refractory by repeated
provocation with lysine-ASA inhalation. This is termed as adaptive
deactivation.50
Aspirin desensitization plays an important role in the management of
post-myocardial infarction patients with AIA.51
Symptoms
of nasal inflammatory disease seem to respond well to aspirin
desensitization, which has been shown to delay the recurrence of nasal
polyp formation by an average of 6 years.48
Although the
precise mechanism of aspirin desensitization is still unclear, studies
have shown a substantial decline in the peripheral monocyte synthesis
of LTB4 in AIA patients after aspirin
desensitization.52
In addition, the cysteinyl LT receptors
were down-regulated, thereby reducing the effectiveness of the same
load of LTs.53
It was observed that in aspirin-induced
urticaria, mast cell degranulation did not occur after aspirin
desensitization.54
The increase in the level of urinary
LTE4 during aspirin challenge and its reduction
after desensitization is inversely proportional to that of thromboxane
B2 and suggests a shunting of the arachidonic
acid metabolites of the target cells.55
These findings
suggest a change in the balance between inflammatory mediators after
desensitization, leading to aspirin tolerance in the AIA population.
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Conclusion
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Up to 20% of asthmatic patients demonstrate hypersensitivity to
aspirin and NSAIDs. The underlying pathogenic mechanism of AIA appears
to be the shunting of the arachidonic acid metabolites from the COX
pathway toward the LO pathway, leading to an increased production of
LTs, which further drive the asthmatic airway inflammatory response.
Decreased production of anti-inflammatory prostanoid
PGE2 and increased activity of
LTC4 synthase, which is the rate-limiting step in
cysteinyl LT synthesis, appear to play a major role in AIA
pathogenesis. LT-modifying drugs appear to be greatly effective in the
management of AIA, while various desensitization protocols have been
developed to treat AIA, especially in patients who cannot afford to
avoid aspirin.
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Footnotes
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Abbreviations:
AIA = aspirin-induced asthma; ASA = acetylsalicylic acid;
ATA = aspirin-tolerant asthma; COX = cyclooxygenase;
CSS = Churg-Strauss syndrome; IL = interleukin;
LO = lipoxygenase; LT = leukotriene; NSAID = nonsteroidal
anti-inflammatory drug; PG = prostaglandin
Received for publication December 15, 1999.
Accepted for publication March 7, 2000.
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Abstract
Introduction
