Natural history and clinical features of aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis, nasal polyposis, asthma and precipitation of asthma, and rhinitis attacks after ingestion of aspirin (ASA) and most other nonsteroidal antiinflammatory drugs (NSAIDs). Although precipitation of asthma attacks by ingestion of ASA and other NSAIDs is considered a hallmark of the syndrome, the respiratory mucosal inflammatory disease process begins and continues in the absence of ongoing or even intermittent exposure to ASA or NSAIDs. The typical patient with AERD is an adult who develops refractory chronic rhinitis in the third or fourth decade of life. The chronic rhinitis evolves into chronic eosinophilic rhinosinusitis with associated nasal polyposis. Anosmia appears in most patients. CT of the sinuses most often demonstrates pansinusitis and patients often undergo multiple sinus operations resulting in only limited temporary benefit. During the evolution of the sinus disease persistent asthma develops. Finally, if patients are exposed to ASA or NSAIDs acute respiratory reactions begin to occur. Despite subsequent avoidance of ASA and other NSAIDs, the respiratory mucosal inflammatory disease persists, often requiring systemic corticosteroids for control of both upper- and lower-respiratory tract symptoms. Adequate control of asthma can often only be accomplished with the simultaneous control of the associated rhinosinusitis. With few exceptions, once AERD develops it remains for the remainder of the patient’s life. Formerly Scripps Clinic and Green Hospital, La Jolla, CA     

Crossreacting drugs and chemicals

Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) exert their clinical effect through inhibition of prostaglandin H synthases 1 and 2, also known as cyclooxygenase. This shared effect of COX-inhibition is also the mechanism for shared adverse effects. Much of our understanding of cross-reacting drugs and chemicals with aspirin comes from studying asthmatics with aspirin-exacerbated respiratory disease (AERD). Aspirin exacerbated respiratory disease is characterized by recalcitrant sinusitis/polyposis, asthma and precipitation of asthma after ingestion of aspirin and most NSAIDs. Cross-reactions between ASA and NSAIDs occur with first exposure unlike IgE-mediated allergic drug reactions. Cross-reactions between aspirin and other drugs are dependent upon inhibition of the cyclooxygenase-1 isoenzyme. Desensitization to aspirin will result in cross-desensitization to all NSATDs that inhibit COX-1. Despite reports in the literature, there does not appear to he cross-reactions between food coloring, hydrocortisone succinate and monosodium glutamate in individuals with aspirin exacerbated respiratory disease. The new highly selective cyclooxygenase 2 inhibitors are well tolerated in AERD asthmatics who have not been desensitized to aspirin. Because low-dose ASA exerts a cardioprotective effect by irreversible inhibition of COX-1, AERD patients who are at risk for coronary artery disease should be considered for aspirin desensitization.     

Diagnostic value of clinical parameters in the prediction of aspirin-exacerbated respiratory disease in asthma

Purpose

Aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with increased asthma severity. However, oral aspirin challenge (OAC) to diagnose AERD is a time-consuming procedure, and some patients experience serious complications. Thus, we evaluated diagnostic values of non-invasive clinical parameters to predict AERD in asthmatic patients.

Methods

A total of 836 Korean subjects were recruited from an asthma cohort. They underwent OAC, and clinical parameters including the history of aspirin hypersensitivity, nasal polyposis, and chronic sinusitis of aspirin-tolerant asthma (ATA) and AERD asthmatic patients were compared.

Results

Significant differences (P<0.01) were found in eight parameters: age at diagnosis, body mass index, FEV1%, PC20, history of urticaria, nasal polyps, chronic sinusitis, and history of aspirin hypersensitivity. After logistic regression analysis based on the eight clinical parameters, nasal polyps, history of aspirin intolerance, sinusitis, and log [PC20 methacholine] remained significantly associated with AERD (P<0.05). The sensitivity and specificity of the history of aspirin hypersensitivity to predict AERD were 64.7% and 92.0%, respectively, and the positive and negative predictive values were 56.9% and 94.1%, respectively. Overall, the accuracy of the test was 88.2%. The accuracy of the tests for nasal polyps and chronic sinusitis were 67.3% and 60.4%, respectively.

Conclusions

Among clinical parameters associated with AERD, the history of aspirin hypersensitivity has the best positive and negative predictive values for the oral aspirin challenge test. Because the false-positive and -negative rates were still high, additional non-invasive methods are needed to reduce the rate of false outcomes.     

Safety of high-dose rofecoxib in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by progressive sinusitis, nasal polyposis, and asthma that begins and continues in the absence of exposure to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Cross-sensitivity to all NSAIDs that inhibit cyclooxygenase-1 (COX-1) occurs in these individuals. Reactions to aspirin and NSAIDs in patients with AERD are largely due to inhibition of COX-1. Despite accumulating data on the safety of COX-2 selective inhibitors in AERD, concern still remains that high doses of a COX-2 inhibitor may be sufficient to induce a cross-reaction. OBJECTIVE: To determine whether high-dose rofecoxib cross-reacts in patients with AERD and asthma. METHODS: Sixty asthmatic patients underwent blinded placebo-controlled oral challenges with 50 mg of rofecoxib. Aspirin sensitivity was subsequently confirmed in all patients with the use of single-blinded aspirin challenges. RESULTS: None of the 60 patients experienced any symptoms, changes in nasal examination results, or declines in lung function during rofecoxib challenge. All 60 patients experienced respiratory reactions to aspirin challenge, with a mean provoking dose of 57 mg. The exact 1-sided 95% confidence interval for the underlying probability of 50 mg of rofecoxib inducing respiratory cross-reactions in patients with AERD is 0 to 0.05, or 0% to 5%. CONCLUSIONS: These results confirm the lack of cross-reactivity of aspirin and the highly selective COX-2 inhibitors in AERD. We suggest that it is time for the labeling of highly selective COX-2 inhibitors to reflect these data and for the warning that patients with AERD in particular and asthmatic patients in general avoid selective COX-2 inhibitors to be removed.     

Aspririn and nonsteroidal anti-inflammatory drug hypersensitivity

Acetylsalicylic acid (ASA) or aspirin and nonsteroidal anti-inflammatory drug (NSAID) sensitivities encompass a diverse group of both pharmacological and hypersensitivity reactions. Conventionally, hypersensitivities include aspirin-exacerbated respiratory disease (AERD), ASA-induced urticaria, and anaphylaxis. With an increasing prevalence of coronary artery disease in an aging population, aspirin continues to play a significant role in cardiac prophylaxis in a large patient population. Invariably, the clinician will encounter patients with clear indications for aspirin therapy but a history of aspirin sensitivity. Although protocols have been established for aspirin challenge and desensitization, it is not always an efficacious or safe procedure. This article reviews the different classifications of ASA/NSAIDs hypersensitivities to better guide the clinician in dealing with this patient population. History of crossrelativities between multiple NSAIDs implies a non-IgE-mediated process. Similarly, a history of monosensitivity to one NSAID implies an IgE-mediated process, although specific antibodies are often elusive. Despite the name, AERD can potentially be exacerbated by all cyclooxygenase (COX) inhibitors based on dose-dependent inhibition of COX-1. Aspirin desensitization can be achieved to improve both upper and lower respiratory symptoms for most patient with AERD. Aspirin desensitization can usually be achieved for those in need of the antiplatelet effects of aspirin, with the exception of those with aspirin-induced urticaria and baseline chronic urticaria. However, desensitization should only be attempted in those with stable coronary artery disease because the process of desensitization carries the inherent risk of anaphylaxis/anaphylactoid reaction, which may further increase cardiac demand and bring about ischemic injury. Therefore, desensitization is reserved until coronary artery disease is stabilized.     

Aspirin and nonsteroidal anti-inflammatory drug hypersensitivity

Acetylsalicylic acid (ASA) or aspirin and nonsteroidal anti-inflammatory drug (NSAID) sensitivities encompass a diverse group of both pharmacological and hypersensitivity reactions. Conventionally, hypersensitivities include aspirin-exacerbated respiratory disease (AERD), ASA-induced urticaria, and anaphylaxis. With an increasing prevalence of coronary artery disease in an aging population, aspirin continues to play a significant role in cardiac prophylaxis in a large patient population. Invariably, the clinician will encounter patients with clear indications for aspirin therapy but a history of aspirin sensitivity. Although protocols have been established for aspirin challenge and desensitization, it is not always an efficacious or safe procedure. This article reviews the different classifications of ASA/NSAIDs hypersensitivities to better guide the clinician in dealing with this patient population. History of crossrelativities between multiple NSAIDs implies a non-IgE-mediated process. Similarly, a history of monosensitivity to one NSAID implies an IgE-mediated process, although specific antibodies are often elusive. Despite the name, AERD can potentially be exacerbated by all cyclooxygenase (COX) inhibitors based on dose-dependent inhibition of COX-1. Aspirin desensitization can be achieved to improve both upper and lower respiratory symptoms for most patient with AERD. Aspirin desensitization can usually be achieved for those in need of the antiplatelet effects of aspirin, with the exception of those with aspirin-induced urticaria and baseline chronic urticaria. However, desensitization should only be attempted in those with stable coronary artery disease because the process of desensitization carries the inherent risk of anaphylaxis/anaphylactoid reaction, which may further increase cardiac demand and bring about ischemic injury. Therefore, desensitization is reserved until coronary artery disease is stabilized.     

The blocking effect of essential controller medications during aspirin challenges in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: The blocking effect of controller medications for asthma could have an effect on the outcome of aspirin challenges in patients suspected of having aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To evaluate whether there was any blocking effect of long-acting beta2-agonists, systemic corticosteroids, and/or inhaled corticosteroids alone or as co-therapy with leukotriene modifier drugs (LTMDs). METHODS: Between 1981 and 2004, 678 patients with suspected AERD were admitted for aspirin challenge and desensitization. All patients had asthma, chronic sinusitis, nasal polyposis, and at least 1 historical reaction to a nonsteroidal anti-inflammatory drug. Asthma controller medications taken during aspirin challenge were recorded and analyzed with respect to their potential effects on 4 possible outcomes of aspirin challenge, namely, naso-ocular reaction, lower airway reaction, classic upper and lower airway reaction, or a negative challenge result. RESULTS: When compared with AERD patients who received no controller medications, the combined use of LTMDs, inhaled corticosteroids, and long-acting beta2-agonists led to a statistically significant change in aspirin challenge outcomes (P = .009), mainly shifting the reaction from a classic upper and lower respiratory tract reaction to naso-ocular reactions only. LTMDs appeared to have the strongest effect (P < .001) in blocking lower respiratory tract reactions. Systemic corticosteroids did not have the same effects. Blocking of both upper and lower respiratory tract reactions to aspirin as a result of taking controller medications did not occur. CONCLUSION: Controller medications are frequently needed to stabilize airways of patients with AERD. LTMDs alone or in combination with other controllers blocked lower respiratory tract reactions during aspirin challenge in some patients with AERD but did not change the overall rate of positive aspirin challenge results and did not lead to false-negative challenges.     

Prevention and treatment of reactions to NSAIDs

Avoidance of ASA and other NSAIDs prevents the reactions and careful attention to clinical history along with patient education are important. However, blanked advice to avoid all NSAIDs is no longer reasonable. Except for AERD and chronic urticaria, cross-reactivity with other NSAIDs does not occur. A physician can definitively prove this by giving the patient another NSAID in their office and observing no reaction. Furthermore, for patients with AERD and chronic urticaria, they can be given the new selective COX-2 inhibitors (rofecoxib and celecoxib) without any cross-reactivity. All AERD patients can be desensitized to ASA and treated with ASA indefinitely. However, ASA desensitization in chronic urticaria is not possible. Underlying mild and moderate AERD responds well to topical and systemic corticoster-oids and leukotriene modifiers. However, the severe forms of the disease should be desensitized to ASA and treated with this drug on a long term basis. In the future, new drugs that prevent eosinophil activation and chemotaxis or enhance eosinophil apoptosis are likely to be useful. Specific blockers of the second cystLT receptor would also be useful. Ultimately as the genetics of these heterogeneous disorders are unraveled, gene substitution therapy may be the ultimate answer.     

Aspirin desensitization in patients with AERD

All patients with aspirin exacerbated respiratory disease (AERD) can be desensitized to ASA. After achieving this state, patients can then take ASA daily without adverse effect. ASA desensitization can be maintained indefinitely as long as the patient takes ASA each day. Crossdesensitization with older NSAIDs also occurs. After ASA desensitization, patients can take daily ASA in order to treat their underlying respiratory disease. In AERD patients treated with ASA 650 BID for at least a year, 115/172 (67%) improved in their clinical courses while decreasing systemic and topical corticosteroids. Sixteen failed to improve, 24 stopped ASA because of intractable side effects (gastritis or hives) and 17 patients discontinued ASA treatment in the first year of study for unrelated reasons. Therefore, treatment with daily ASA is a significant therapeutic option for patients afflicted with AERD. It should be used for AERD patients who do not respond to topical corticosteroids and leukotriene modifier drugs. Those who respond to systemic steroids or have intractable or recurrent nasal polyps are particularly well-suited for this therapeutic intervention.     

Failure of tacrolimus to prevent aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease

BACKGROUND: In patients with aspirin-exacerbated respiratory disease (AERD), pretreatment with asthma controller medications (leukotriene modifiers, inhaled or systemic corticosteroids, and salmeterol) partially modifies the severity of aspirin-induced asthmatic reactions. OBJECTIVE: A recent study showed that pretreatment with tacrolimus completely prevented aspirin-induced respiratory reactions and might allow silent aspirin desensitization. METHODS: Ten patients with rhinosinusitis, nasal polyps, and asthma had a history of asthma attacks after ingesting aspirin and nonsteroidal anti-inflammatory drugs. All underwent baseline oral aspirin challenges and had typical respiratory reactions. They were then randomized to receive tacrolimus (0.1 mg/kg weight; 8 patients) or placebo (2 patients) in a double-blind protocol before rechallenge with aspirin using the previous provoking dose of aspirin. In addition, respiratory reactions sustained by 50 consecutive patients with AERD during 2004 were recorded, analyzed, and compared with the tacrolimus/placebo-treated patients to determine whether there were any differences. RESULTS: Tacrolimus pretreatment failed to block respiratory reactions to provoking doses of aspirin in 5 of 8 patients with AERD, and in the other 3 patients did not block higher doses of aspirin. The results of oral aspirin challenges in the control population of 50 patients were compared with either the baseline or postchallenge data from the tacrolimus-pretreated or placebo-pretreated patients with AERD, and there were no significant differences. CONCLUSIONS: Use of tacrolimus as add-on pretreatment to prevent reactions to aspirin in patients with AERD or to achieve the goal of silent aspirin desensitization could not be accomplished.     

Update on Recent Advances in the Management of Aspirin Exacerbated Respiratory Disease

Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1*301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.     

Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and chronic sinusitis.

BACKGROUND: A definitive diagnosis of aspirin-exacerbated respiratory disease (AERD) requires a positive oral aspirin challenge (OAC), but predicting which patients will have positive challenges is often difficult. OBJECTIVE: To analyze information about historical aspirin- and nonsteroidal anti-inflammatory drug (NSAID)-associated respiratory reactions and clinical characteristics as potential markers to predict positive OACs. METHODS: A total of 243 patients underwent OACs. Data related to previous reactions and clinical characteristics of patients were correlated with the result of the OACs. RESULTS: Without prior exposure to aspirin or NSAIDs, the chance of a positive OAC was 5 in 12 (42%) but was 198 in 231 (86%) for those with a history of aspirin- and NSAID-associated asthma attacks. Sex, atopy, number of sinus infections per year, and number of sinus surgical procedures were not associated with positive OACs. Patients with 2 or more prior aspirin- and NSAID-associated respiratory reactions had an 89% chance of having a positive OAC vs single reactors (80%; P = .04). Mild or moderate prior reactions were associated with 84% or 80% positive OACs, whereas 100% of the 45 patients with severe prior reactions had positive OACs (P = .007). Except for hospitalizations, treatment locations of prior reactions (home or emergency department) did not seem to make any difference. Logistic regression identified age, sense of smell, and multiple prior reactions as independent risk factors associated with positive OACs. CONCLUSIONS: Age younger than 40 years, poor sense of smell, multiple prior respiratory reactions, and severe prior asthmatic reactions associated with aspirin and NSAIDs significantly increased the chances of a positive OAC.     

The relationship between historical aspirin-induced asthma and severity of asthma induced during oral aspirin challenges

BACKGROUND: Historical aspirin- or nonsteroidal anti-inflammatory drug (NSAID)-induced reactions might provide predictive information about the severity of reactions in patients with aspirin-exacerbated respiratory disease (AERD) undergoing oral aspirin challenge (OAC). OBJECTIVE: We sought to assess the relationship between historical aspirin- or NSAID-induced bronchial reactions and the severity of bronchial reactions during OAC in patients with AERD. METHODS: Data regarding the provoking doses, treatments, and treatment settings of historical aspirin/NSAID-induced reactions were recorded, analyzed, and compared with the provoking doses, maintenance regimens, and observed decreases in FEV(1) that occurred during OAC in 210 consecutive patients referred with suspected AERD. RESULTS: Of 147 patients who reported seeking acute medical care for their historical aspirin/NSAID-induced asthma attacks, 101 (69%) were treated in an emergency department and released, and 46 (31%) required hospitalization. During OAC in these 147 subjects, 23 (16%) had a 20% to 29% decrease and 14 (10%) had a 30% or greater decrease in FEV(1) values from baseline. Of the 46 patients previously hospitalized for aspirin/NSAID-induced asthma attacks, 9 (20%) had a 20% to 29% decrease and 6 (13%) had a 30% or greater decrease in FEV(1) during OAC. By contrast, of the 63 patients who treated their prior aspirin/NSAID-induced reactions at home, 5 (8%) had a 20% to 29% decrease and 5 (8%) had a 30% or greater decrease in FEV(1) during OAC (P = not significant for both). CONCLUSION: The severity of the historical aspirin/NSAID-induced asthma attack was not predictive of asthma severity during OAC. CLINICAL IMPLICATIONS: These data provide further reassurance regarding the safety of outpatient aspirin desensitization.     

Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a disease of intense eosinophilic inflammation that can produce fibrosis, hyperplasia, and remodeling. OBJECTIVE: To investigate the usefulness of quantifying severity of chronic hyperplastic eosinophilic sinusitis in predicting the presence of AERD. METHODS: Data were compared between asthmatic patients who reported exacerbations after aspirin ingestion and those who did not. The primary outcome measure was severity of sinusitis using a validated computed tomography (CT) scan-based scoring system. Indices of lower airway remodeling and other markers of inflammation were also evaluated. RESULTS: Twenty-one patients with AERD were compared with 19 patients with aspirin-tolerant asthma (ATA). Patients were well matched for asthma severity as shown by their similar lung function as measured by postbronchodilator forced expiratory volume in 1 second. Patients with AERD were distinguished by their sinus CT scores (AERD patients: 16.9; 95% confidence interval [CI], 13.4-21.3; ATA patients: 6.2; 95% CI, 4.2-9.1; P < .001), and they were considerably more likely to have nasal polyps (AERD patients: 90%; ATA patients: 26%; P < .001). In addition, AERD patients demonstrated increased total lung capacity (AERD patients: 107.9%; 95% CI, 99.9%-117.6%; ATA patients: 98.0%; 95% CI, 93.7%-102.5%; P = .05), reflecting a trend toward increased air trapping. No significant differences occurred in diffusing capacity, exhaled nitric oxide, eosinophilia, or exhaled breath condensate pH. CONCLUSIONS: AERD can be distinguished from ATA by the extent of hyperplasia on CT scan and the presence of nasal polyps. We hypothesize that AERD represents a remodeling process that affects both the upper and lower airways.     

Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma

BACKGROUND: Patients with aspirin sensitivity experience hyperplastic sinusitis and nasal polyposis. We speculated that similar mechanisms could be acting in the lower airway and that these individuals would demonstrate more severe asthma and irreversible loss of lung function. OBJECTIVE: We sought to investigate the role of aspirin-exacerbated respiratory disease (AERD) as a risk factor for the development of irreversible airway obstruction. METHODS: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is a multicenter observational study of subjects with severe or difficult-to-treat asthma. Data were compared between subjects who reported asthma exacerbation after aspirin ingestion and those who did not. The primary measure of bronchodilator-resistant obstruction (possible remodeling) was the maximally achieved postbronchodilator spirometry averaged over the 3-year duration of the study. RESULTS: Adult subjects (>/=18 years) with AERD (n = 459) were compared with subjects with non-aspirin-sensitive asthma (n = 2848). Subjects with AERD had significantly lower mean postbronchodilator percent predicted FEV(1) compared with subjects with non-aspirin-sensitive asthma (75.3% vs 79.9%, P < .001). Differences in spirometry between the 2 cohorts persisted after controlling for potential confounding variables. In addition, subjects with AERD were more likely to have severe asthma by means of physician assessment (66% vs 49%, P < .001), to have been intubated (20% vs 11%, P < .001), to have a steroid burst in the previous 3 months (56% vs 46%, P < .001), and to have required high-dose inhaled corticosteroids (34% vs 26%, P < .001). CONCLUSIONS: These data suggest that aspirin sensitivity is associated with increased asthma severity and possible remodeling of both the upper and lower airways.     

Safety of meloxicam in aspirin-hypersensitive patients with asthma and/or nasal polyps. A challenge-proven study

BACKGROUND: The anti-inflammatory actions of acetylsalicylic acid (ASA)/non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be due to inhibition of COX-2, whereas the side effects such as gastric damage and aspirin-induced asthma are mediated through inhibition of COX-1. Therefore, a new class of drugs with COX-2 selectivity may be well tolerated by patients with ASA/NSAIDs hypersensitivity. OBJECTIVE: We investigated whether subjects with asthma and/or nasal polyps (NP) and analgesic intolerance proven by oral ASA provocation test tolerated the selective COX-2 inhibitor, meloxicam. METHODS: All subjects were first challenged with ASA using a 2-day, single-blind, placebo-controlled oral provocation test. Thereafter, the subjects showing positive response to ASA provocation underwent a single-blind, placebo-controlled challenge with a cumulative dose of 7.5 mg of meloxicam on 2 separate days. One and three fourths of the divided doses of placebo and the active drug were given at 1-hour intervals. Clinical symptoms, lung function, and blood pressure were monitored during these challenge protocols. RESULTS: Twenty-one patients with asthma and/or NP (10 males and 11 females; mean age: 38.4 +/- 2.9 years) who reacted to ASA challenges were enrolled in the study. Response to ASA provocation was rhinitis + bronchospasm in 13, and extrabronchial reactions in 8 (isolated rhinitis in 3) patients. Mean PD(20) was 163.4 +/- 39.9 mg ASA among patients who reacted with bronchospasm to ASA. Only 1 patient reacted to meloxicam challenge at a cumulative dose of 7.5 mg. CONCLUSION: This study indicates that 7.5 mg of meloxicam is a safe alternative treatment for ASA-hypersensitive asthma and/or NP patients with proven hypersensitivity via oral ASA challenges.     

Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity

Purpose

Identification of tolerable alternative analgesics is crucial for management in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients. We investigated cross-reactivity of acetaminophen and celecoxib according to the type of aspirin/NSAID hypersensitivity and aimed to determine the risk factors for cross-intolerance.

Methods

We retrospectively reviewed the medical records of patients intolerant to aspirin and NSAIDs who had undergone an acetaminophen and/or celecoxib oral provocation test. Aspirin/NSAID hypersensitivity was classified into 4 types according to a recently proposed classification: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated chronic urticaria (AECU), aspirin-induced acute urticaria/angioedema (AIAU), and NSAID-induced blended reaction (NIRD).

Results

A total of 180 patients with hypersensitivity to aspirin and NSAIDs were enrolled; 149 acetaminophen provocation test results and 145 celecoxib provocation test results were analyzed. The overall cross-reaction rates to acetaminophen and celecoxib were 24.8% and 10.3%, respectively. There was a significant difference in the cross-reactivity to acetaminophen according to the type of NSAID hypersensitivity. Cross-reactivity to acetaminophen was highest in the AECU group (43.9%), followed by the AERD (33.3%), NIBR (16.7%), and AIAU (12.5%) groups. Underlying chronic urticaria was more prevalent in patients with cross-intolerance to both acetaminophen (P=0.001) and celecoxib (P=0.033). Intolerance to acetaminophen was associated with intolerance to celecoxib (P<0.001).

Conclusions

Acetaminophen and celecoxib may induce adverse reactions in a non-negligible portion of aspirin/NSAID-sensitive patients. Physicians should be aware of the possible cross-reactions of these alternative drugs and consider an oral challenge test to confirm their tolerability.     

Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria

BACKGROUND: Recent studies have found that most otherwise normal subjects with a history of acute urticaria induced by several nonsteroidal anti-inflammatory drugs (NSAIDs) show a wheal-and-flare reaction on intradermal injection of autologous serum. This phenomenon has been previously observed in patients with chronic urticaria (CU) and suggests a possible common background in CU and NSAID-induced urticaria. A relationship between these 2 conditions is further suggested by the fact that up to 30% of patients with CU have a worsening of their skin disorders after the ingestion of chemically unrelated NSAIDs. OBJECTIVE: I sought to assess whether otherwise normal subjects with multiple or single NSAID intolerance show a propensity to have CU. METHODS: Two hundred eighty otherwise normal patients with an unequivocal history of acute urticaria induced by NSAIDs seen during the last 10 years were studied. On the basis of both clinical history and oral challenge tests with at least 2 alternative NSAIDs, the patients were classified as having single or multiple NSAID intolerance. All the patients were re-evaluated within the end of 2002, 1 to 10 years after the first visit, to assess the onset of CU. One hundred allergic adults without a history of CU and of drug allergy followed up for 1 to 10 years were used as control subjects. RESULTS: One hundred fifty-nine and 121 patients were finally considered as having single or multiple NSAID intolerance, respectively. At the follow-up visit, 93 (33%) of 280 patients had CU. The prevalence of CU was very similar in subjects with single or multiple NSAID intolerance (48/159 [30%] vs 45/121 [37%], respectively; P = not significant). Only 1 (1%) of 100 atopic control subjects had CU during the follow-up period (P <.001). Among single NSAID reactors, patients who had CU had a significantly higher prevalence of intolerance to aspirin than those who did not have CU (36/48 [75%] vs 41/111 [37%], P <.001), whereas the latter had a markedly higher prevalence of intolerance to pyrazolone drugs (52/111 [47%] vs 10/48 [21%], P <.01). Altogether, only 12 (15%) of 82 patients intolerant to drugs other than aspirin versus 36 (47%) of 77 aspirin reactors had CU (P <.001). CONCLUSION: NSAID intolerance might precede the onset of CU by years. Both multiple and single NSAID reactors with a history of aspirin-induced urticaria seem at higher risk for CU than patients with a history of single intolerance to NSAIDs other than aspirin.     

Oral aspirin challenges in patients with a history of intolerance to single non-steroidal anti-inflammatory drugs

Summary Background In the clinical practice patients with a history of acute urticaria induced by a single non-steroidal anti-inflammatory drug (NSAID) and seeking for safe alternative drugs generally undergo tolerance tests with alternative NSAIDs that have little or no cyclooxygenase-1 (COX-1) enzyme inhibitory activity. This practice does not allow for the detection of single NSAID reactors and may lead to unnecessary avoidance of many potentially useful NSAIDs. OBJECTIVE: Evaluate aspirin challenge as a means to distinguish single from multiple NSAID intolerance in patients with a clinical history of acute urticaria induced by a single NSAID. Methods One hundred and seventeen otherwise normal subjects with a history of acute urticaria following the ingestion of a single NSAID (pyrazolones (n=58), nimesulide (n=17), propionic acid derivatives (n=13), aryl acetic acid derivatives (n=14), acetaminophen (n=9), piroxicam (n=5), and indometacin (n=1)) underwent single-blind placebo-controlled oral challenges with aspirin. Aspirin-intolerant subjects underwent further tolerance tests drugs exerting little or no inhibitory activity on COX-1 enzyme (including paracetamol, nimesulide, rofecoxib, tramadol, and floctafenine). Results Aspirin induced urticaria in 28/117 (24%) patients. Five out of 28 (18%) aspirin reactors did not tolerate alternative NSAID on subsequent oral challenges. Conclusion In subjects with a history of urticaria induced by a single NSAID (other than aspirin) the diagnostic workup should start with an aspirin challenge in order to detect single/multiple NSAID reactors.