Abstract

Background

Aspirin-exacerbated respiratory disease (AERD) is a difficult-to-treat chronic inflammatory disease characterised by asthma, chronic rhinosinusitis with nasal polyposis and sensitivity to aspirin and other cyclo-oxygenase 1 (COX-1) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) [1].

Patients with AERD have been shown to have high levels of pro-inflammatory molecules [2] and low levels of anti-inflammatory ones [3], leading to damage of the respiratory mucosa [4], with resulting aggressive nasal polyposis and eosinophilic asthma [5].

Ingestion of aspirin or COX-1 NSAIDs inhibit cyclo-oxygenase 1 leading to increased availability of substrate for the lipoxygenase enzymes that produce leukotrienes, further increasing pro-inflammatory mediators and reducing protective prostaglandin E2. Acute hypersensitivity reactions can occur, leading to sudden onset bronchospasm, rhinitis, laryngospasm or even death [5].

Many AERD patients are refractory to standard medical therapy, undergo numerous surgical polypectomies and require frequent oral corticosteroids for asthma [6]. Multiple open studies show oral desensitization and daily aspirin treatment can significantly improve overall symptoms and quality of life, decrease nasal polyp formation and sinusitis, reduce the need for oral corticosteroids and sinus surgery and improve nasal and asthma scores in patient with AERD at 6 months and after one year of therapy [7]. However maintenance treatment with oral aspirin should be at least 300 mg daily, ideally 325 mg twice a day [7,8], a dose associated with gastro-intestinal or other complications in 14% of patients [9]. Oral doses of aspirin over 100 mg have been recently described as not cardio-protective and possibly detrimental to the cardiovascular system [10].

Lysine acetyl-salicylate (LAS) (Synthelabo, Paris) ,the only truly soluble form of aspirin, is less likely to damage respiratory and gastric mucosae. Direct application of LAS onto involved polyp tissue means that a higher intranasal concentration can be achieved without exposing the gut or the heart to high doses. This is an open audit of the effects of topical nasal LAS on the upper and lower respiratory tract in patients with refractory AERD.

Materials and Methods

121 patients (61 men and 60 women; mean age±standard deviation (SD), 45.6±12.6 years) with aspirin-exacerbated respiratory disease were recruited from the Rhinology Clinic at the Royal National Throat, Nose and Ear Hospital, London. All were refractory to standard medical therapy with nasal douche and intranasal corticosteroids, plus inhaled corticosteroids, β-agonists, combinations of inhaled corticosteroid plus long acting beta β-agonists and anti-leukotrienes (LTRAs). They had undergone a mean of 3.3 sinus operations. All gave written informed consent to lysine aspirin nasal challenge and verbal consent to continuation of lysine aspirin therapy at home after a positive challenge. Aspirin-sensitivity was suspected based on the patients’ histories and confirmed by nasal challenge with lysine-aspirin, as previously described [11]. This involves initial symptom scores and nasal airway measurements followed by a graduated nasal challenges with saline, followed by increasing doses of lysine aspirin starting with 5 mg aspirin equivalent ,then 10 mg, 20, 40, at 45 minute intervals, until either the patient has responded with nasal symptoms plus a 25% decrease in the nasal airway or a cumulative dose of 75 mg aspirin has been reached without any reaction. In that case oral challenge with 100 mg, then 200 mg was given. The exception was 3 patients with a convincing double positive history of previous reactions to both aspirin and another COX-1 inhibitor who did not require formal challenge [11].

Patients who consented to nasal therapy with LAS continued to take their usual medical therapy.

The project (reference 06/Q0301/6) was approved by East of England NRES Research Ethics committee.

Results

Patients

Figure 1 shows a flow diagram for the patients in this audit. Sixteen patients declined LAS treatment despite a positive challenge. Of the 105 who started treatment, three had positive histories of both aspirin and NSAID sensitivity and did not require formal LAS challenge [11] so were started on 10 mg intra-nasally.

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Figure 1

Flow diagram of patients included in audit.

Nasal symptoms occurred on the second and subsequent doses of lysine aspirin in over 95% of patients, but were less severe than those experienced after initial challenge. In most these completely abated within days to several weeks.

Twenty five patients dropped out within 3 months, 8 within two weeks: the reasons being severe worsening of nasal symptoms- (n=8) inability to maintain the daily regimen (n=5) and abdominal pains (n=2), ten patients did not return for their 3 month visit.

Treatment was stopped at the 3 month assessment in 24 patients, due to a variety of reasons including upper respiratory tract infection or acute sinusitis (n=2), exacerbation of symptoms, particularly those of asthma (n=2), worsening of nasal obstruction (n=3), lack of concordance (n=2) or lack of efficacy (n=15).

Twenty drop outs between 3 and 12 months related to lack of efficacy or difficulty with the regime, 9 subjects were lost to follow up.

At 12 months treatment was stopped in 2 patients, one because of gastrointestinal symptoms, the other lack of efficacy.

Patients who stopped and re-started LAS treatment were excluded from the 12 month analysis, leaving 27 for assessment.

Subjective Evaluation

Table 1 shows the percentage of patients who reported improvement, worsening or no change in their symptoms at 3 months and 12 months.

Table 1

Subjective changes on lysine aspirin (LAS) treatment

	At 3 months								At 12 months
	n=78		n=78		n=77		n=78		n=26		n=26		n=26		n=26
	Asthma		Rhinitis		Nasal polyps		Global		Asthma		Rhinitis		Nasal polyps		Global
Worse	16	21%	14	18%	24	31%	18	23%	3	12%	8	31%	6	23%	7	27%
Unchanged	38	49%	43	55%	26	34%	32	41%	10	38%	6	23%	6	23%	4	15%
Better	24	31%	21	27%	27	35%	28	36%	13	50%	12	46%	14	54%	15	58%
Better or the same	62	79%	64	82%	53	68%	60	77%	23	88%	18	69%	20	77%	19	73%

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Objective Measurements

Significant improvements were seen in NIPF at 3 months compared to pre-treatment values (145.4±8.7 l/min pre-treatment and 163.3±8.51 l/min at 3 months, p<0.05), this increase was sustained at 12 months (Table 2).

Table 2

Objective outcomes on lysine aspirin (LAS) treatment, –Objective scores pre-treatment and at 3 and 12 months

	Pre	3 m	12 m
NIPF (litres/min)	145.4±8.7	163.3±8.5*	160.5±15.9
Expired NO (ppb)	13.2±1.64	14.9±1.63	7.54±0.85* **
Nez du Vin	1.75±0.75	2.54±0.80*	3.13±0.64*
Nasal NO Right (ppb)	336.6±32.7	347.9±34.2	442.23±78.7
Nasal NO Left (ppb)	343.8±36.7	331.9±39.3	456.4±91.2

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*p<0.05 vs pre treatment.

**p<0.05 vs 3 m.

***p<0.05 vs 12 m.

There were improvements in nasal nitric oxide (nNO) levels in both sides of the nose at 3 and 12 months, p<0.05 for all.

Significant changes were seen in the lower respiratory tract nitric oxide levels: at 3 months there was an increase in expired nitric oxide (eNO), but at 12 months it was significantly lower (16.3±3.6 ppb pre-treatment and 7.5±0.8 ppb at 12 months, p<0.05). This reduction in eNO remains the case in patients now treated for two or more years.

There was a significant increase in the Nez du Vin smell scores at both 3 and 12 months (p<0.05 at 3, p<0.01 at 12 months).

Lung function measurements were not significantly affected at any time point.

Discussion

The patients in this audit are those with AERD refractory to standard medical and surgical therapy. AERD is a chronic inflammatory disorder of the respiratory tract [1] in which despite avoidance of aspirin and NSAIDs, mucosal inflammation of the upper and lower respiratory tracts persists and progresses [5]. Since the inflammation is progressive, a beneficial effect of treatment may be considered as lack of deterioration as well as improvement of symptoms. Based on subjective symptom evaluation the majority of patients found some benefit from nasal LAS treatment, a quarter continued regularly with a complex form of treatment for 12 months, with 73% being globally improved or stable, meaning that one patient should benefit in every 5 or 6 who are treated. This compares favourably with the number needed to treat (NNT) of 4.4 for intranasal corticosteroids, and is superior to the NNT for antihistamines which is 15.2 ,in allergic rhinitis treatment [19].

Only 3.8% of 105 patients reported gastro- intestinal side effects - approximately a quarter of the rate found with oral aspirin desensitization. There was a high drop out rate. Lack of any funding for this project meant that not all patients attended follow up visits, largely because of expense and time off work. The complexity of making up a new solution each day then putting it into the nose in the head upside down position without missing out more than a day defeated many of the remaining drop outs, None had any serious adverse event. The number of subjects known to have left because of side effects of therapy was nineteen.

However, at 3 and 12 months for all symptom groups (global, asthma, rhinitis and nasal polyps), there were some patients whose symptoms were worse than previously. Our data suggest that those with later onset disease and positive skin prick tests improve more than those with onset less than 40 years and negative skin prick tests. The reasons for this are unknown but could relate to staphylococcal enterotoxin effects which are more notable later in the disease course [20].

The effects on asthma were objectively assessed by comparing lung function tests, and exhaled nitric oxide levels before treatment and at 3 and 12 months. Exhaled nitric oxide (eNO),which reflects eosinophilic inflammation of the lower respiratory tract ,showed significant changes with an increase at 3 months that could indicate aspirin–induced mast cell degranulation in the lower respiratory tract by aspirin swallowed after nasal insertion, however this was reversed with further treatment and increased dose of lysine aspirin with a significant decrease at 12 months, maintained in patients continued on LAS therapy (data not shown). The fall in eNO at 12 months and the significantly better asthma outcomes in those on LAS therapy suggests that treatment mainly directed at the upper airway also protects the lower. However there may also be a selection bias, as those in whom the lower respiratory tract was adversely affected by LAS, and those who were non-concordant with medication, would no longer be continuing on treatment. A double blind, placebo-controlled trial would be ideal, but difficult because of blinding and funding.

The mechanism of action of LAS used in this way is uncertain and it is unlikely that patients taking 75 mg nasally are fully desensitized, though they are tolerating a dose of aspirin which is optimal for cardiovascular protection [10]. In this respect LAS is likely to be superior to the NSAID ketorolac, (the only topical form available in the USA) which is detrimental to the cardiovascular system; and to oral desensitization, where the higher doses used [7] are possibly not cardio-protective and are more likely to cause gastrointestinal bleeding. Our previous work has shown that cysteinyl LT1receptors are upregulated in AERD in nasal biopsies [21] and that the percentages of mucosal CD45+leukocytes expressing cysteinyl leukotriene LT 1 receptors were significantly (p<0.0001) elevated in aspirin-sensitive, but not in aspirin-tolerant patients [22]. In a small double-blind, placebo- controlled, cross over study using 16 mg LAS intra-nasally, we found a reduction in Cys LT1 receptors after 2 weeks, maintained at 6 months, compared to saline placebo [21].

In an n of 1 study with patients as their own controls using LAS at 30 mg intra-nasally in addition to routine therapy, there was significant improvement in polyp grade and NIPF [23]. Aspirin itself is an anti- inflammatory and this may be relevant, however topical aspirin was not effective in a double-blind study in aspirin tolerant(AT) polyps [24] which makes this simple explanation unlikely. It is probable that the mechanism of action relates more specifically to aspirin sensitivity and involves graduated degranulation of mast cells and eosinophils in the nasal mucosa, plus a reduction in leukotriene receptors, which we have shown previously at lower doses of intranasal lysine aspirin [21]. In addition lysine itself has activity against herpes simplex which may be implicated in AERD pathogenesis [25]. Further double-blind studies involving mediator release, mucosal genomics, biomics and proteomics are needed.

Conclusions

This audit shows that for selected patients with refractory AERD nasal LAS treatment can reduce airway inflammation, improve symptoms, asthma outcomes and sense of smell. Advantages of nasal LAS are a reduced incidence of gastrointestinal side- effects and a dose compatible with cardio-protection when compared to oral desensitization; disadvantages include the need for daily preparation of the solution and the strict treatment regime. Since therapy with aspirin, nasally or orally is inexpensive and relatively safe it should be tried in recalcitrant AERD before monoclonal antibodies, such as anti- IgE or anti-IL5 [26,27].

Appendix

Competing interests

The author declares that they have no competing interest.

Authors’ contributions

RH created the database of results and wrote the paper, GKS, RM and SG assessed the patients clinically, YCD organized follow up visits and made airway, nitric oxide and smell measurements, PP sent out the asthma questionnaires and analysed results, GKS oversaw the study and finalized the paper which was read and approved by all authors.

References