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.     

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.     

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.     

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     

The natural history and clinical characteristics of aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinitis, nasal polyps, asthma, and precipitation of asthma and rhinitis attacks after ingestion of aspirin (ASA) and most nonsteroidal anti-inflammatory drugs (NSAIDs). Most information about the disease in the United States has come from small samples of patients. OBJECTIVE: The purpose of this study was to examine the natural history and clinical characteristics of 300 AERD patients, referred to our institution for aspirin desensitization. METHODS: All potential AERD patients were evaluated using a standard questionnaire that included information about clinical characteristics and natural progression of their disease, previous history of reactions to ASA and other NSAIDs, current use of medications, and ethnic backgrounds. All patients underwent oral ASA challenges to prove they had AERD. RESULTS: From patients' history we found that the average age at onset of AERD was 34 years, and that 57% were female. Counting ASA as an NSAID, 33% had previously reacted on two occasions to NSAIDs and 36% on more than three occasions to NSAIDs, whereas only 27% had reacted to one NSAID before they came to us for evaluation. Our patients had averaged 5.5 episodes of sinusitis per year. There were no significant differences in the clinical characteristics or use of medications between genders. Ethnicity was heterogeneous in most participants. CONCLUSIONS: AERD begins in the third decade of life and in both sexes. The disease progressed over the 13 years between historical onset and current evaluation, with more sinusitis and need for controller medications over time. There was no ethnic or familial distribution of AERD.     

Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin disorders.

BACKGROUND: Previous studies show skin reactions after exposure to acetaminophen and/or nimesulide to occur in about 10% of patients with a history of urticaria induced by aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). This fact is surprising since cross-reactivity among different NSAIDs should not occur among subjects without a history of chronic urticaria. OBJECTIVE: To detect risk factors for intolerance to alternative drugs such as acetaminophen and nimesulide in different groups of patients with a history of adverse skin reactions (urticaria/angioedema, or anaphylaxis) after the ingestion of aspirin and other NSAIDs. METHODS: Two hundred fifty-six patients with a history of recent pseudoallergic skin reactions caused by NSAIDs underwent elective oral challenges with increasing doses of both acetaminophen and nimesulide. Patients were divided into three groups: A = 69 subjects with chronic urticaria, B = 163 otherwise normal subjects with a history of urticaria after the ingestion of aspirin, and C = 24 otherwise normal subjects with a history of urticaria after the ingestion of pyrazolones but aspirin-tolerant. RESULTS: Forty-eight (19%) patients reacted to acetaminophen and/or nimesulide. Similar numbers of patients with chronic urticaria (23%) and of normal subjects with a history of aspirin-induced urticaria (19%) did not tolerate one of the alternative drugs challenged. Pyrazolones-intolerant patients showed the lowest number of reactors (4%). Aspirin intolerance represented a risk factor for acetaminophen- and/or nimesulide-induced urticaria (RR = 5.4). A history of anaphylactoid reactions induced by NSAID represented a risk factor for urticaria after the ingestion of the alternative study drugs (RR = 5.7). Atopic status was associated with a higher risk of reactivity to nimesulide: this drug induced urticaria in 11/47 (23%) atopics versus 18/209 (9%) non-atopics (P < .005; RR = 3.2). A history of intolerance to antibacterial drugs was not associated with a higher prevalence of reactivity against acetaminophen and/or nimesulide. CONCLUSIONS: In at least 20% of patients with a history of urticaria/angioedema or anaphylaxis induced by aspirin or other NSAIDs, but without a history of chronic urticaria, cross-reactivity with other NSAIDs occurs. Atopy as well as a history of aspirin-induced anapylactoid reactions seem to represent relevant risk factors for intolerance to alternative NSAIDs. In view of these findings, aspirin-intolerant patients with such clinical features should be submitted to peroral tolerance tests with at least two alternative substances in order to avoid potentially severe reactions.     

Leukotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria.

BACKGROUND: About 30% of patients with chronic urticaria experience flares of hives and/or angioedema after ingesting either aspirin or nonsteroidal anti-inflammatory drugs. In such patients, cross-reactivity to all NSAIDs seems to occur suggesting a mechanism dependent on cyclooxygenase inhibition. OBJECTIVE: To evaluate the preventive effect of leukotriene receptor antagonists on urticaria exacerbations induced by NSAIDs in a patient with chronic urticaria. METHODS: A 59-year-old woman with a 2-year history of recurrent urticaria exacerbated by different NSAIDs including aspirin 500 mg (2 episodes), piroxicam 20 mg, and nimesulide 100 mg (1 episode each) was studied. Acetaminophen 375 mg and floctafenine 50 mg induced a marked flare of urticaria/angioedema in a single-blind, placebo-controlled challenge. RESULTS: The patient was totally urticaria free during a 3-week course of montelukast 10 mg once a day. After montelukast withdrawal, a gradual relapse of urticaria/angioedema occurred along with a further acute urticaria/angioedema episode after a single piroxicam, 20-mg tablet. Zafirlukast 20 mg twice daily was started. After some days the patient was urticaria-free again, and after 3 weeks she tolerated a 6-day course of injective piroxicam (20 mg once a day) without any problem. To date the patient is still urticaria-free. CONCLUSION: Leukotriene receptor antagonists may prevent the severe urticaria/angioedema exacerbations which follow the use of NSAIDs in some patients with chronic urticaria.     

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.     

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.     

Pathogenesis of aspirin-exacerbated respiratory disease

The underlying respiratory disease is activated by unknown mechanism and results in an intense infiltration of mast cells and eosinophils into the entire respiratory mucosa. These cells synthesize leukotrienes (LTs) at a very high rate and mast cells also release histamine and tryptase and synthesize PGD₂ a vasodilator and bronchoconstrictor. Furthermore, AERD patients under synthesize from arachidonic acid (AA) a peculiar product called lipoxins, which opposes inflammation generated by leukotrienes. Finally, cysLT₁ receptors are over expressed and highly responsive to LTE₄, further augmenting the underlying inflammatory disease. This inflammatory condition is partly inhibited by synthesis of PGE₂ through COX-1. PGE₂ partially inhibits 5-lipogygenase conversion of AA to LTA₄ and blocks release of histamine and tryptase from mast cells. When COX-1 is inhibited by ASA or NSAIDs, PGE₂ synthesis stops and an enormous release of histamine and synthesis of LTs occurs. The upper respiratory reaction is mediated by both histamine and LTs but the bronchospastic reaction is mediated by LTs. The systemic effects of flush, gastric pain and hives are mediated by histamine. Aspirin desensitization can not be explained by disappearance of LT synthesis since urine LTE₄ levels are still elevated at acute ASA desensitization. However, mast cell products such as histamine, tryptase and PGD₂ are no longer released or synthesized at acute desensitization. It is more likely that a diminution in number or function of cysLT receptors accounts for the diminished inflammatory response found in ASA desensitization.     

Acute urticaria induced by oral methylprednisolone

Although corticosteroids have immunosuppressive, anti-inflammatory, and anti-allergic effects, allergic reactions are rare. We report a case involving a 52-year-old-female with acute urticaria caused by oral methylprednisolone. The patient had experienced aspirin-exacerbated respiratory disease (AERD) for 13 years with frequent asthma exacerbations. Symptoms of asthma exacerbations improved with short-term treatments of systemic steroids, including methylprednisolone or deflazacort, which had been well tolerated. However, the current admission was prompted by the development of acute generalized urticaria following the oral ingestion of methylprednisolone (8 mg) for relief of symptoms. An oral provocation test with 4 mg oral methylprednisolone led to generalized urticaria 20 minutes later, confirming the causal association. This is the first report of acute urticaria caused by oral methylprednisolone in a patient with AERD.     

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.     

Safety of parecoxib in patients with nonsteroidal anti-inflammatory drug-induced urticaria or angioedema.

BACKGROUND: Parecoxib is the first injectable cyclooxygenase 2 selective inhibitor indicated for the treatment of acute postoperative pain. OBJECTIVE: To describe the results of a challenge with parecoxib in patients with a history of urticaria or angioedema to 1 or more nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: The study was performed from October 1, 2006, through March 31, 2007, with 79 patients who historically had experienced urticaria or angioedema after use of NSAIDs. The patients underwent a single-blind challenge with parecoxib, 40 mg. RESULTS: No reaction to placebo was observed in any patient. Similarly, no reaction to parecoxib was observed in any patients in the single-class or multiple-class intolerance group. CONCLUSION: Our report demonstrates that parecoxib does not induce cross-reactivity in patients with a history of urticaria or angioedema. Hence, this finding suggests that this drug could be safely proposed as an alternative (but only after a prior challenge) in patients with previous hypersensitive reactions to NSAIDs, even if there are added risk factors such as atopy and antimicrobial allergy, who require an analgesic drug perioperatively.     

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.     

Intranasal ketorolac,diagnosis, and desensitization for aspirin-exacerbated respiratory disease

BackgroundIntranasal ketorolac has been proposed as a diagnostic test for aspirin-exacerbated respiratory disease (AERD) and a faster, safer, and reliable addition to facilitating aspirin (ASA) desensitization.ObjectiveWe conducted the first prospective study to dissect the impact of intranasal ketorolac incorporation during ASA desensitization vs standard oral protocols in concert with evaluating its diagnostic use for AERD.MethodsPatients with AERD were enrolled in a prospective open-label observational study between November 2006 and August 2013. Participants selected either one of the following desensitization protocols: intranasal ketorolac 1 day before oral ASA (group 1, combined) or ketorolac challenge with greater than 2 weeks elapsing until oral ASA (group 2, washout). All patients were on a leukotriene-modifying drug (montelukast) for at least 1 week before the challenge.ResultsA total of 20 patients were enrolled: 13 in group 1 and 7 in group 2. No significant differences were seen for baseline symptom scores or forced expiratory volume in 1 second. Group 1 exhibited significant increases for the threshold dose of ASA (P = .009), the likelihood of having silent ASA desensitization (P = .01), and decreased reaction severity to oral ASA (P = .04). There were no significant differences in reaction forced expiratory volume in 1 second, the incidence of extrapulmonary symptoms, limited nasoocular reactions, rescue treatment requirements, or time to symptom resolution. There was 100% concordance between reactions to intranasal ketorolac and oral ASA for group 2, supporting its use as a diagnostic test for AERD.ConclusionIntranasal ketorolac is a useful diagnostic test and adjunct within the combined ketorolac/ASA protocol to achieve effective, efficient, and perhaps safer desensitization to ASA for patients with AERD.     

Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid

BACKGROUND: The cause and pathogenesis of chronic urticaria are still poorly understood. IgE-independent reactions, are common in adult patients with chronic urticaria, who have daily spontaneous occurrence of weals. H(1)-receptor antagonists (antihistamines) are the major class of therapeutic agents used in the management of urticaria and angioedema. Nevertheless, chronic urticaria is often difficult to treat and may not be controlled by antihistamines alone. It has been postulated that mediators other than histamine, such as kinins, prostaglandin and leukotrienes, may be responsible for some of the symptoms in urticaria which are not controlled by antihistamines. In this study, which was randomized double-blind, placebo-controlled, we compare the clinical efficacy and safety of montelukast (MT) 10 mg given once a day and cetirizine (CET) 10 mg given once a day with placebo (PLA), in the treatment of patients with chronic urticaria who have positive challenge to acetylsalicylic acid (ASA) and/or food additives. PATIENTS AND METHODS: A group of 51 patients, ranging in age from 15 to 71 years, with chronic urticaria and positive challenge to food additives and/or ASA, participated in this study for a period of 4 weeks, starting from a 3-day run-in. The assessment of the efficacy was based on scores of daily urticaria symptoms. RESULTS: MT significantly increased the percentage of symptom-free days for hive and itch. Analysis of frequency distribution of urticaria scores for each symptom gave similar results (MT vs. CET and MT vs. PLA, P < 0.001). The interference with sleep due to their skin condition was also lower in the group treated with MT (P < 0.001). In addition, the median number of days without the rescue medication was significantly higher in the MT group (24 days) than both the CET and the PLA groups (18 days, P < 0.001, and 20 days, P < 0.001, respectively). Finally, a low incidence of adverse events was observed in this study. CONCLUSION: The results of this comparative study demonstrate that montelukast orally administered once a day is very effective for the treatment of cutaneous symptoms in patients with chronic urticaria due to food additives and/or ASA.     

Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma

Drugs inhibiting cyclooxygenase regularly cross-react with aspirin (ASA). Although some experiments suggest that acetaminophen (ACETM) is a weak inhibitor of cyclooxygenase in certain tissues, it has not been studied in human lung tissue, and controversy exists whether or not true cross-reactivity occurs between ASA and ACETM. Three ASA-sensitive subjects with asthma, who gave a history of reactions to ACETM, underwent double-blind, placebo-controlled challenges and reacted to 1000 mg of ACETM with a greater than 20% fall in FEV1. Two patients were desensitized to ASA and then were rechallenged with 1000 mg of ACETM without reaction. Two patients were desensitized to increasing doses of ACETM, achieving refractoriness to 1500 mg, but not 2000 mg. Thus, cross sensitivity between ASA and ACETM was documented when large challenge doses (1000 mg) of ACETM were used. Furthermore, cross desensitization suggests that in ASA-sensitive subjects with asthma, similar mechanisms are likely to be responsible for reactions to ASA, nonsteroidal anti-inflammatory drugs, and ACETM.     

Effect of Genetic Polymorphism of ALOX15 on Aspirin-Exacerbated Respiratory Disease

Background: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome associated with chronic inflammation in the airways coincident with chronic rhinitis, sinusitis, recurrent polyposis and asthma. Eosinophils are the key inflammatory cells in the development of AERD. AERD has been attributed to abnormalities of the arachidonic acid metabolism, but the pathogenesis of AERD is not fully understood. Our aim was to investigate the genetic contribution of the arachidonate 15-lipoxygenase gene (ALOX15) to the development of AERD. Methods: We enrolled 171 patients with AERD, 229 patients with aspirin-tolerant asthma, and 195 normal healthy controls in a Korean population. Three polymorphisms (-427G/A, -272C/A, -217G/C) in the promoter region of ALOX15 were genotyped. The functional variability of the promoter polymorphisms were analyzed by luciferase reporter activity assay. Result: No significant difference in the genotype frequency of the ALOX15 genetic polymorphism was found. Peripheral total eosinophil count was significantly higher in the patients carrying the GG genotype of the -427G/A polymorphism (p = 0.016). Similarly, the patients carrying haplotype 1 (ht1) (GCG) of -427G/A, -272C/A and -217G/C showed a significantly higher total eosinophil count compared to the other haplotypes (p = 0.008) in the AERD group. The promoter activity of the ht1 (GCG) construct was significantly higher compared to that of the ht3 (AGG) construct in A549 and U937 cells (both p < 0.001). Conclusion: These results suggest that the promoter polymorphisms of the ALOX15 gene affect ALOX15 activity leading to increased eosinophil infiltration in AERD patients.