NSAID-exacerbated Respiratory Disease Research Articles

The Frequency of Nonsteroidal Anti-Inflammatory Drug Hypersensitivity in Children with Asthma

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the second-most frequent drug type to cause hypersensitivity reactions in children. Asthma is one of the risk factors for NSAID hypersensitivity (NSAID-H) in adult patients. There are limited number of studies evaluating NSAID-H among children with asthma. Our aim was to assess the frequency of confirmed NSAID-H and evaluate the classification of NSAID-H in children with asthma. Methods: Patients followed with a diagnosis of asthma in our Pediatric Allergy Clinic were evaluated for NSAID-H. Patients were questioned whether they had used NSAIDs, and if they experienced any reaction with these drugs. A control group was also questioned for reactions to NSAID use. Results: 976 children with asthma and 2,000 healthy children as a control group were included in this study. The mean age of the patients with asthma was 10.61 ± 4.21 years and 59.5% were male. Ten (1%) had a reaction history to NSAIDs. NSAID-H was confirmed in 9 (0.9%) who were tested with the suspected drugs. Six of these were classified as “single NSAID-induced urticaria/angioedema or anaphylaxis” and 3 were classified as “NSAIDs-exacerbated respiratory disease.” In the control group, only 1 subject had a reaction history to acetylsalicylic acid and no reaction developed in the provocation test. Conclusions: In our study, NSAID-H was found more frequent in children with asthma than in the control group. Children with asthma should be evaluated for reactions to NSAIDs during hospital visits.

Evaluation of the basophil response in patients with NSAID-exacerbated respiratory disease (NERD) after nasal provocation test with lysine-aspirin (NPT-LASA)

Evaluation of the basophil response in patients with NSAID-exacerbated respiratory disease (NERD) after nasal provocation test with lysine-aspirin (NPT-LASA)

Establishing a Safe Administration of ASA in Cardiovascular Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity with Skin and/or Respiratory Involvement

Background: A history of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with cross-intolerance to several drugs is common in some patients with coronary artery disease. We present a series of patients with acute coronary syndrome undergoing ASA desensitization prior to a possible stent to evaluate the short- and long-term efficacy and safety. The aim was to evaluate the outcomes of an ASA desensitization protocol developed by our center based on the guidelines proposed by the EAACI drug allergy expert recommendations. Methods: We developed a desensitization protocol that was based on both the patient characteristics and onset of reaction after NSAIDs, including premedication with a leukotriene antagonist and the H1-antagonist antihistamine. The clinical entities were NSAID-induced urticaria and/or angioedema in the absence of chronic spontaneous urticaria (NIUA) and NSAID-exacerbated respiratory disease (NERD). Results: A total of 23 patients were challenged or desensitized with ASA: 19 NIUA and 4 NERD. All patients tolerated the protocol at the different times of 30, 45, 90, and 120 min. The dosages of oral ASA that were given included 10, 21, 41, 81, and 162 mg (cumulative dose 315 mg). One patient reacted during the procedure and 1 during follow-up. Symptoms were limited to the skin without manifestations in other organs. All patients tolerated the required dose of ASA within 30–120 min. Those requiring urgent catheterization were desensitized within 90 min. Conclusions: Our protocol addresses challenge or desensitization with the contribution of a specialist allergist. It provides an effective, dynamic, safe, and short administration of 81 mg or higher of ASA in patients with a history of NSAID hypersensitivity with skin involvement.

Salicylate Food Intolerance and Aspirin Hypersensitivity in Nasal Polyposis.

A clear association between allergy and nasal polyposis (NP) is not determined and the role of food intolerance in patients with NP is not investigated by oral food challenge (OFC). To investigate the relation of salicylate food intolerance and atopy in patients with NP according to recurrence and aspirin sensitivity. A cross sectional multicenter study was done in two tertiary centers for allergy in Iran. Adult patients with NP were selected for the study that had been referred to allergy clinics. The oral aspirin challenge (OAC) test was performed to identify aspirin exacerbated respiratory disease (AERD) and the OFC test was used to investigate food intolerance. Atopic evaluation was performed by skin-prick tests, nasal smear and blood eosinophil count as well as serum total IgE. One hundred and nineteen Iranian patients (female to male ratio 1.05) with NP were enrolled (mean age, 38 ± 11 years). Recurrence of nasal polyposis was 64.7%. OAC was performed in all cases; 43.79% cases had aspirin hypersensitivity. In addition, OFC tests determined that 69.9% of patients had salicylate food allergy. Salicylate food intolerance was significantly higher in NP cases with AERD than in aspirin tolerant patients (p<0.05). Yet, positive skin prick test was not associated with NP recurrence and AERD. Atopy and NSAID exacerbated respiratory disease; therefore, they can both be considered as predictors of NP recurrence. Our study also showed that salicylate food intolerance was associated with AERD in nasal polyposis.

Nasal Responses and Safety of L-ASA Nasal Provocation Test in a Large Series of Patients with NSAID-Exacerbated Respiratory Disease (NERD)

Nasal Responses and Safety of L-ASA Nasal Provocation Test in a Large Series of Patients with NSAID-Exacerbated Respiratory Disease (NERD)

Hypersensitivity Reactions to Non-Steroidal Anti-Inflammatory Drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the leading causes of hypersensitivity reactions to drugs, and they are classified in two groups: those induced by nonspecific immunological mechanisms (non-allergic or cross-intolerance (CI) reactions), or by specific immunological mechanisms (allergic or selective reactions (SR)). The pathogenesis of CI is associated with their pharmacological activity (COX-1 inhibition), with symptoms due to an imbalance in the arachidonic acid pathway, independently of their chemical structure. SRs are mediated by specific IgE- or by a T-cell response and can be induced by a single NSAID or a class of chemically related NSAIDs, with patients tolerating chemically unrelated compounds. NSAIDs hypersensitivity reactions have been classified in five main groups: i) NSAIDs-exacerbated respiratory disease (NERD); ii) NSAIDs-exacerbated cutaneous disease (NECD); iii) NSAIDs-induced urticaria/angioedema (NIUA); iv) Single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA); v) Single NSAID-induced delayed reactions (SNIDRs). Although this classification described above is widely accepted by most authors some phenotypes such as blended reactions do not fit. Therefore more research is needed in this topic.

Potential Biomarkers for NSAID-Exacerbated Respiratory Disease.

Asthma is a common chronic disease with several variant phenotypes and endotypes. NSAID-exacerbated respiratory disease (NERD) is one such endotype characterized by asthma, chronic rhinosinusitis (CRS) with nasal polyps, and hypersensitivity to aspirin/cyclooxygenase-1 inhibitors. NERD is more associated with severe asthma than other asthma phenotypes. Regarding diagnosis, aspirin challenge tests via the oral or bronchial route are a standard diagnostic method; reliable in vitro diagnostic tests are not available. Recent studies have reported various biomarkers of phenotype, diagnosis, and prognosis. In this review, we summarized the known potential biomarkers of NERD that are distinct from those of aspirin-tolerant asthma. We also provided an overview of the different NERD subgroups.

Alcohol hyper-responsiveness in chronic rhinosinusitis with nasal polyps.

An important percentage of subjects diagnosed with chronic upper airway disease report alcohol-induced worsening of their symptoms. The prevalence and characteristics of respiratory reactions provoked by alcohol-containing drinks have not been fully investigated yet. The aim of this study was to estimate the prevalence and characteristics of alcohol hyper-responsiveness in patients with chronic airway disease and healthy controls. Furthermore, nasal inflammation was evaluated in nasal polyp patients with and without hyper-responsiveness. We evaluated the prevalence and characteristics of alcohol-induced respiratory complaints in 1281 subjects. Chronic rhinosinusitis with nasal polyps (CRSwNP) patients with and without NSAID exacerbated respiratory disease (NERD), chronic rhinosinusitis patients without nasal polyps (CRSsNP), allergic rhinitis (AR) patients and healthy controls were approached by means of a questionnaire. Inflammatory markers (eosinophilic cationic protein (ECP), IL-5, IgE, SAE-specific IgE, IL-17, TNFα and IFNγ) in tissue were then compared between alcohol hyper-responsive and non-hyper-responsive CRSwNP patients. The highest prevalence of nasal and bronchial alcohol hyper-responsiveness was observed in patients with NERD, followed by CRSwNP, and less frequent in CRSsNP, AR and healthy controls. Alcohol hyper-responsiveness is significantly more prevalent in CRSwNP patients suffering from recurrent disease and in patients with severe symptomatology. In nasal tissue of the hyper-responsive CRSwNP group, we observed significantly higher nasal levels of the eosinophilic biomarker ECP. Nasal hyper-responsiveness to alcohol is significantly more prevalent in severe eosinophilic upper airway disease.

Periostin in Exhaled Breath Condensate and in Serum of Asthmatic Patients: Relationship to Upper and Lower Airway Disease.

PurposePeriostin is considered a biomarker for eosinophilic airway inflammation and have been associated with NSAID-Exacerbated Respiratory Disease (NERD) and chronic rhinosinusitis (CRS). In this study, we aimed to evaluate periostin in exhaled breath condensate (EBC) and in serum of patients with various asthma phenotypes.MethodsThe study included 40 asthmatic patients (22 with NERD) and 17 healthy controls. All the procedures (questionnaire, spirometry, FeNO, nasal swabs, EBC collecting, and blood sampling) were performed on the same day. Periostin concentrations were measured using an ELISA kit.ResultsPeriostin was detected in EBC from 37 of 40 asthmatics and in 16 from 17 of controls. The concentration of periostin in EBC did not differ between the study groups and was not associated with NERD or asthma severity. However, the EBC periostin was significantly higher in asthmatics with CRS as compared to those without (3.1 vs 2 ng/mL, P=0.046). Patients with positive bacterial culture from nasal swabs had higher EBC periostin concentrations than those without (3.2 vs 2.1 ng/mL; P=0.046). The mean serum periostin level was higher in asthmatics with a 1-year history of exacerbation than in those without (3.2 vs 2.3 ng/mL, P=0.045). Asthmatics with skin manifestation of NSAIDs hypersensitivity had higher serum periostin levels as compared to those without (3.5 vs 2.3 ng/mL; P=0.03).ConclusionsEBC periostin levels seem to reflect intensity of upper airway disease in asthmatics, while serum levels of periostin are associated with asthma activity (exacerbations or FeNO) or NERD subphenotypes.

Discrepancies in the diagnosis and classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions in children

BackgroundHypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently encountered in daily clinical practice. The aim of this study was to determine the confirmation rates, risk factors of NSAID hypersensitivity in children and to try to classify them with a standardized diagnostic protocol. MethodsAll patients with a suspicion of NSAID-induced hypersensitivity were evaluated with European Network for drug Allergy (ENDA) recommendations. The children were classified as selective responders (SRs) or cross-intolerant (CI) depending on the drug provocation test (DPT) results. ResultsWe evaluated 106 children with a suspicion of NSAID hypersensitivity. NSAID hypersensitivity was confirmed with tests in 31 patients; 4 (12.9%) were diagnosed by skin tests and 27 (87.1%) by DPTs and two patients with a history of anaphylaxis by medical records. Eleven patients (33.3%) were classified as SRs, whereas twenty-two (66.6%) children as CIs. SRs and CIs were further classified as NSAID-induced urticaria/angioedema (n = 8), NSAID-exacerbated cutaneous disease (n = 6) and NSAID-exacerbated respiratory disease (n = 1) and single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 11). Eight (24.2%) patients could not be categorized according to ENDA/GA2LEN classification; one CI patient could not be classified based on pathomechanisms, seven CIs could not be categorized based on the underlying disease and clinical manifestations. A reaction within an hour of drug intake (aOR:3.0, 95% confidence interval: 1.18–7.67, p = 0.021), a history with multiple NSAIDs hypersensitivity (aOR:2.9, 95% confidence interval: 1.16–7.60, p = 0.022), and family history of atopy (aOR:4.0, 95% confidence interval: 1.50–10.82, p = 0.006) were found as the independent risk factors related to confirmed NSAID hypersensitivity. ConclusionsThis study suggests the presence of different phenotypes which do not fit into the current classifications in children with NSAID hypersensitivity.

Risk of asthma exacerbation associated with nonsteroidal anti-inflammatory drugs in childhood asthma: A nationwide population-based cohort study in Taiwan.

Patients allergic to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) who develop respiratory reactions such as bronchospasm or asthma exacerbation have aspirin-induced asthma or NSAIDs-exacerbated respiratory disease. However, large-scale studies have not been conducted to investigate the risk of aspirin/NSAIDs exposure in children with asthma. Therefore, this study evaluated the relationship between aspirin/NSAIDs and the risk of asthma exacerbation in children with asthma.This retrospective cohort study was conducted using the data of 1 million random beneficiaries of the Taiwan National Health Insurance program between 1997 and 2012. Children aged ≦18 years diagnosed with asthma by physicians were enrolled. The study population was divided into the index group (concurrently using antiasthmatic agents and NSAIDs patients) and reference group (using antiasthmatic drugs alone), and the relative risks (RRs) of hospitalizations resulting from asthma exacerbation in both groups were estimated.The rate of asthma exacerbation was higher in the index group than the reference group, resulting in asthma-related hospitalizations (RR: 1.49, 95% confidence interval [CI]: 1.37-1.61; adjusted RR: 1.41, 95% CI: 1.30-1.53). Short-term aspirin, ibuprofen, and diclofenac use probably correlated with asthma exacerbation in children with asthma. No association between long-term aspirin, ibuprofen, and diclofenac consumption and the risk of asthma exacerbation was identified in this study.

Nonsteroidal anti-inflammatory drug hypersensitivity among children.

Nonsteroidal anti-inflammatory drugs (NSAID) are the second-most frequent drugs that cause hypersensitivity reactions among children. Studies related to NSAIDs hypersensitivity in children are limited. In this study, we aimed to evaluate children admitted with suspicion of NSAIDs reaction. Between January 1, 2011, and November 30, 2014, we included patients with suspicion of NSAIDs hypersensitivity in our clinic. For evaluation, skin tests and oral provocation tests with the drug (suspected or alternative) were proposed. Reactions were classified and defined according to the latest European Academy of Allergy and Clinical Immunology position paper on NSAID hypersensitivity. During the study period, 123 patients (with 136 drug reactions) were admitted to our clinic with suspected NSAID hypersensitivity. The mean (standard deviation) age of the patients, 67 female (55%), was 83.10 ± 56.05 months. Thirteen patients described reactions to more than one chemically unrelated NSAID, and 110 patients described reactions with chemically similar drugs. Eight patients were not included because they did not have provocation tests. Thus, 115 patients were evaluated. A hundred and thirty provocations were performed. Twenty patients (17.4%) were diagnosed with NSAID hypersensitivity (13 patients diagnosed by provocation tests and 7 patients diagnosed according to their history). The most frequently encountered agent was ibuprofen (50% [10/20]). Eighty percent (16 patients) of the reactions were considered "non-cross-reactive type." Fifteen patients (75%) were classified as having single-NSAID-induced urticaria and/or angioedema, three patients were classified as having NSAID-induced urticaria and/or angioedema, one patient was classified as having NSAID-exacerbated respiratory disease, and the other patients were classified as having single-NSAID-induced delayed hypersensitivity reactions. Detailed history and drug provocation tests are important to verify NSAID hypersensitivity. The most common type is the non-cross-reactive type, and, in our study, the most common responsible drug was ibuprofen.

Different Phenotypes of Non-Steroidal Anti-Inflammatory Drug Hypersensitivity during Childhood

Background: Although non-steroidal anti-inflammatory drug hypersensitivity (NSAID-H) has been widely studied in adults, there is still a lack of data regarding the features and phenotypes of NSAID-H in children. Our aim was to define risk factors and different phenotypes according to clinical patterns. Methods: Patients with a history of reaction to any NSAIDs referred between January 2012 and October 2014 were included. After completing a European Network for Drug Allergy (ENDA) questionnaire, initial skin and/or oral provocation tests (OPTs) were performed for the offending drug. Additional OPTs were done with aspirin in case of NSAID-H to determine cross-reactivity. NSAID-hypersensitive patients were defined as being either a selective responder (SR) or cross-intolerant (CI) and further categorized according to either the ENDA/GA²LEN classification or an alternative scheme by Caimmi et al. [Int Arch Allergy Immunol 2012;159:306-312]. Results: Among 121 patients [58.7% male, average age 7.8 years (4.7-10.8)] with 161 NSAID-related reactions, 110 patients with 148 reactions were assessed. NSAID-H was diagnosed in 30 (27%) patients with 37 (25%) reactions. Multivariate regression analysis revealed that an immediate-type reaction and respiratory symptoms during the reaction increased the risk of a reproducible NSAID-related reaction (OR 3.508, 95% CI 1.42-8.7, p = 0.007; OR 3.951, 95% CI 1.33-11.77, p = 0.014, respectively). Additional OPTs revealed 13 SRs and 14 CIs. A family history of allergic disease was more frequent in CIs compared to SRs (57.1 vs. 15.4%, p = 0.031). Reactions belonging to CIs were more frequently characterized by angioedema compared to those of SRs (81.3 vs. 46.2%, p = 0.019). SRs and CIs were further classified as single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 13), NSAID-induced urticaria/angioedema (n = 7), NSAID-exacerbated cutaneous disease (n = 2) and NSAID-exacerbated respiratory disease (n = 1). Four CIs could not be categorized according to either classification system. One SR could not be categorized according to ENDA/GA²LEN. Conclusion: During childhood, NSAID-H exhibits different phenotypes and the majority of them can be categorized with current classification systems; however, classifications based on adult data may not exactly fit NSAID-H in paediatric patients.

Genetic variants in arachidonic acid pathway genes associated with NSAID-exacerbated respiratory disease.

NSAIDs are the most frequent cause of hypersensitivity drug reactions. We have examined the association between NSAID-exacerbated respiratory disease (NERD) and genetic variants in arachidonic acid metabolism genes. We included 250 NERD patients, 260 NSAID-tolerant asthmatic (NTA) subjects and 315 healthy controls. Significant associations with NERD were identified for: ALOX15 rs3892408 C/C homozygous genotype (NERD vs NTA; p = 0.0001, pc = 0.0011; NERD vs controls; p = 0.0001, pc = 0.0011), PTGS-1 rs5789 A/A homozygous genotype (NERD vs NTA; p = 0.0001, pc = 0.0011; NERD vs controls; p = 0.0001, pc = 0.0011), PTGS-1 rs10306135 A/A homozygous genotype (NERD vs NTA; p = 0.0009, pc = 0.0091; NERD vs controls; p = 0.0064, pc = 0.045). Differences in ALOX5 copy number variations were also found (NERD vs NTA; p = 0.010; NERD vs controls; p = 0.0001). These results improve our understanding of the underlying mechanisms of NERD and may help develop a predictive test for this pathology. Original submitted 3 November 2014; Revision submitted 2 April 2015.

NSAID-exacerbated respiratory disease: a meta-analysis evaluating prevalence, mean provocative dose of aspirin and increased asthma morbidity.

The prevalence and mean provocative dose of oral aspirin (MPDA) triggering respiratory reactions in people with asthma have been inconsistently reported, and the relationship between NSAID-exacerbated respiratory disease (NERD) and asthma morbidity was less well quantified. A systematic review was performed by identifying studies diagnosing NERD using blinded, placebo-controlled oral provocation challenge tests (OPCTs) or by self-reported history in people with asthma. Data were extracted, and effect estimates for changes in respiratory function, MPDA and asthma morbidity were pooled using random-effects meta-analysis. The prevalence of NERD in adults with asthma was 9.0% (95% CI 6-12%) using OPCTs and 9.9% (95% CI 9.4-10.5%) using self-reported history from questionnaires. The MPDA in adults with NERD was 85.8 mg (95% CI 73.9-97.6). In people with NERD, the risk of: uncontrolled asthma was increased twofold (RR 1.96 (95% CI 1.25-3.07)); severe asthma and asthma attacks was increased by 60% (RR 1.58 (95% CI 1.15-2.16) and RR 1.59 (95% CI 1.21-2.09), respectively); emergency room visits was increased by 80% (RR 1.79 (95% CI 1.29-2.49)); and asthma hospitalization was increased by 40% (RR 1.37 (95% CI 1.12-1.67)) compared to people with NSAID-tolerant asthma. Respiratory reactions triggered by oral aspirin in people with asthma are relatively common. At the population level, the prevalence of NERD was similar when measured using appropriately conducted OPCTs or by self-reported history. On average, respiratory reactions were triggered by clinically relevant doses of oral aspirin. Asthma morbidity was significantly increased in people with NERD who potentially require more intensive monitoring and follow-up.

Genetic Variants in Arachidonic Acid Pathway Genes Associated with Nsaids-Exacerbated Respiratory Disease

Non steroidal anti-inflammatory drugs (NSAIDs) are the most frequent cause of hypersensitivity drug reactions (HDR). The mechanism of NSAIDs-exacerbated respiratory disease (NERD) has been attributed to the inhibition of prostaglandin-endoperoxide synthases (PTGS) by NSAIDs in susceptible individuals. This leads to a reduction in prostaglandin E2production and shunts arachidonic acid metabolism toward the lipooxygenase pathway, resulting in the release of cysteinyl leukotrienes. Here, we have examined the association between NERD and polymorphisms in genes encoding PTGS, lipoxygenases and their receptors.

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: from phenotyping to genotyping.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent drugs involved in hypersensitivity drugs reactions. Both immunological and nonimmunological mechanisms can be involved. We describe the different phenotypes as well as analyze the genetic basis for NSAIDs hypersensitivity. Five major clinical entities are currently accepted in the classification of hypersensitivity reactions to NSAIDs. Three are mediated by nonspecific immunological mechanisms: NSAIDs-exacerbated respiratory disease, NSAIDs-exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema. Two are mediated by specific immunological mechanisms: single-NSAID-induced urticaria/angioedema or anaphylaxis and single-NSAID-induced delayed hypersensitivity reactions. The classification becomes more complex if we consider that in an important number of cases skin and airway involvement can occur, as well as the participation of other organs. Hypersensitivity reactions to NSAIDs are more complex than for other drugs like betalactams in terms of the number and types of reactions elicited, and mechanisms involved. As NSAIDs are the most frequent cause of drug hypersensitivity, it is feasible to gather a sufficient number of cases for undertaking pharmacogenetic studies.

Aspirin desensitization for urgent endovascular treatment of the aneurysm

Hypersensitivity reactions to aspirin (acetylsalicylic acid- ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity they pose a significant risk to patients. The authors report a case of a 48 year old woman with asthma, hypertension, obstructive sleep apnea and a NSAIDs-exacerbated respiratory disease: hypersensitivity reactions induced by aspirin and metamizol manifesting primarily as bronchial obstruction and dyspnea. She was regulary medicated with budesonide 400mg 2x/day, ipratropium bromide dry powder inhaler once a day, montelukast 10mg/day, bilastine 20mg/day and terbutaline. The patient had a giant fusiform aneurysm with carotid-cavernous sinus partially thrombosed in a subacute phase. For endovascular treatment of aneurysm, the patient need a stent placement in the left internal carotid artery under antiplatelet therapy with ASA. The patient was referred to our Department and was submitted to a desensitization protocol in an emergence context due to the risk of aneurism rupture. At the time, her asthma was not controlled so it was necessary to carry out medication with bronchodilators and oral corticosteroids while doing the procedure. The protocol followed this sequence: on the first day 5, 10, 25, 50, 75, 100 and 250mg of ASA were administered at intervals of 30 minutes. On the second day the patient performed one single dose of 500mg, without reactions. After surgery, she remained on 100mg of ASA daily without reaction. The authors sought to adapt a safe and practical protocol to allow the administration of ASA to patients with a NSAIDs-exacerbated respiratory disease. In live-saving situations is very important to reflect, reevaluate the indications and contraindications for desensitization. Note that it is possible to make a successful desensitization even in a patient with uncontrolled asthma.