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Biomedical subjects

S M Harding

Publications and source records attributed to S M Harding.

At least 19 recordsLinked to original sources

Gastroesophageal reflux, asthma, and mechanisms of interaction.

Gastroesophageal reflux (GER) is a potential trigger of asthma. The esophagus and lung interact through a variety of mechanisms. Esophageal acid-induced bronchoconstriction can be provoked by a vagally mediated reflex, whereby acid in the distal esophagus produces airway responses; by neural enhancement of bronchial reactivity, whereby esophageal acid augments airway hyperresponsiveness; or by microaspiration, in which small amounts of esophageal acid in the upper airway cause significant airway responses. Interestingly, even in the microaspiration model, the vagus nerve plays a significant role. Neurogenic inflammation in the lung may occur with either vagally mediated mechanisms or with microaspiration. The prevalence of reflux symptoms, esophagitis, and abnormal esophageal acid contact time is higher in patients with asthma than in control populations. Potential mechanisms, whereby asthma may predispose to the development of GER, include autonomic dysregulation, an increased pressure gradient differential between the thorax and the abdomen, a high prevalence of hiatal hernia, alterations in crural diaphragm function, and bronchodilator medication use. Further research will help define how the esophagus and lung interact.

Asthma↗

What is a necessary knowledge base for sleep professionals?

Sleep medicine is multidisciplinary, and sleep medicine professionals should be trained to evaluate and treat all 88 sleep disorders. Sleep medicine specialists require a fund of knowledge that goes beyond what is obtained during a pulmonary fellowship. Skills required for a pulmonary sleep professional include: sleep medicine, neurobiology, psychiatry, neuro-psychology, neurology, pediatrics, and even limited exposure in otolaryngology, oral maxillofacial surgery, and dentistry. There is a paucity of published information concerning curricular requirements. Required skills for a sleep professional include proficiency in the clinical skills of sleep medicine as well as the technical skills of polysomnography. There is a very large knowledge content area requirement in both the basic sciences of sleep and the clinical aspects of sleep medicine. There are also important clinical skills content areas. As with all medical professionals, sleep professionals should have the highest ethical standards and a strong sense of responsibility toward their patients. A sleep medicine professional also has to be knowledgeable about administrative and legal aspects specific to sleep medicine. This essay reviews a sleep professional knowledge base model with emphasis on the requirements for a pulmonary sleep professional.

Health Knowledge, Attitudes, Practice↗

Prediction formulae for sleep-disordered breathing.

Prediction formulae for sleep-disordered breathing can be useful for excluding a diagnosis, establishing an a priori probability of having a positive test, and for prioritizing patient testing. In general, prediction models have high sensitivity but low specificity. In a study analyzing the performance of four previously described prediction models, sensitivities ranged from 76% to 96%, specificities ranged from 13% to 54%, while positive predictive values ranged between 69% and 77%. The models were useful in identifying patients with a respiratory disturbance index of > or = 20 so that these patients could undergo alternative diagnostic testing strategies. The Berlin Questionnaire was tested in primary care settings and was able to identify high-risk patients fairly accurately. A regression neural network performed well with a sensitivity of 99%, a specificity of 80%, a positive predictive value of 88%, and a negative predictive value of 98%. In obese snorers, a regression model utilizing daytime arterial O2 saturation and specific respiratory conductance was effective for excluding obstructive sleep apnea (OSA). In congestive heart failure patients, risk factors for central sleep apnea include male gender, atrial fibrillation, age >60 years, and wake time PaCO2 <38 mm Hg. In children, risk factors for sleep apnea include obesity, African-American race, sinus problems, and persistent wheezing. There are also racial anthropomorphic differences in OSA patients, with whites having a tendency towards brachycephaly facial types (reduced anterior-posterior cranial dimension) and African-Americans having a tendency toward leptoproscopic facial types (longer facial height and decreased facial width). Further refinement of prediction formulae will improve diagnostic accuracy.

Diagnosis, Differential↗

The potential role of gastroesophageal reflux in asthma.

Gastroesophageal reflux disease (GERD) afflicts approximately 20% of adults in the United States on a weekly basis and 40% on a monthly basis, and is also a trigger for asthma. The prevalence of GERD is higher in asthmatics compared to control groups, with 77% of asthma patients having reflux symptoms and 82% of asthmatics having abnormal esophageal acid contact times on 24-hour esophageal pH testing. Esophageal acid elicits respiratory responses including decreases in airflow, oxygen saturation, and increases in respiratory resistance, minute ventilation, and respiratory rate. Mechanisms of esophageal acid-induced bronchoconstriction include a vagally-mediated reflex, heightened bronchial reactivity, and microaspiration. Esophageal acid also produces airway neurogenic inflammatory responses with the release of substance P, tachykinins, nitric oxide, and other cytokines. Predisposing factors to GERD development in asthmatics include autonomic dysregulation, an increased pressure gradient between the thorax and the abdomen, a high prevalence of hiatal hernia, and altered crural diaphragm function. Theophylline may also potentiate GERD. Therapy of GERD improves asthma outcome. In combined studies examining 326 medically treated asthma patients, asthma symptoms improved in 69% of patients. Surgical therapy trials in 417 asthma patients show asthma symptoms improved in 79%. Management strategies for GERD in asthmatics with reflux symptoms include utilizing an empiric trial of a proton pump inhibitor for three months while measuring asthma outcomes. Since GERD may be clinically ''silent'' in asthma patients, consider 24-hour esophageal pH testing in severe asthma patients who do not have GERD symptoms. Future research will develop the association between asthma and GERD.

Journal Article↗

Chronic cough, asthma, and gastroesophageal reflux.

Gastroesophageal reflux disease (GERD) causes chronic cough and triggers asthma. Mechanisms of reflux-associated chronic cough include micro- and macroaspiration, laryngeal injury, and a vagally mediated reflex. An empiric trial of a proton pump inhibitor in patients without other etiologies of cough found through diagnostic testing may be an effective diagnostic strategy for GERD-associated cough. In GERD-associated asthma, there is evidence of neurogenic inflammation. Medical or surgical therapy of GERD results in asthma symptom improvement in about 70% of patients. A 3-month empiric trial of omeprazole, 20 mg daily, followed by esophageal pH testing in drug nonresponders, is the most cost-effective way of diagnosing asthma triggered by GERD.

Anti-Ulcer Agents↗

Efficacy and safety of dry powder fluticasone propionate in children with persistent asthma.

BACKGROUND: Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler. OBJECTIVE: To determine the efficacy and safety of dry powder FP administered once or twice daily (200 microg per day) to children with persistent asthma. METHODS: Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder FP 200 microg each morning, dry powder FP 100 microg BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV1 and morning PEF recorded at clinic visits. RESULTS: Both dry powder FP regimens significantly improved FEV1, evening PEF, and asthma symptoms at the double-blind phase endpoint (P < or = .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma (P < or = .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities. CONCLUSIONS: Once daily dosing of dry powder FP 200 microg is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.

Androstadienes↗

Complications and consequences of obstructive sleep apnea.

Obstructive sleep apnea (OSA) has many consequences. There is an independent association between OSA and hypertension. The Sleep Heart Health Study reported that hypertension prevalence increased as sleep disordered breathing severity increased. The Nurses' Health Study noted an age-adjusted relative risk of cardiovascular events of 1.46 for occasional snorers and 2.02 for regular snorers, and a risk of stroke of 1.60 for occasional snorers and 1.88 for regular snorers. Sleep apnea is also associated with pulmonary hypertension, neurocognitive effects, depressed quality of life, motor vehicle accidents, awakening headache, childhood growth interruption, pregnancy-induced hypertension, fetal growth retardation, and disruption of the patients' bed-partners' sleep quality. Further research will examine the possibility of causality, pathophysiologic mechanisms, and outcomes of therapeutic interventions for OSA on the many consequences of OSA.

Cardiovascular Diseases↗

The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms.

Gastroesophageal reflux is a potential trigger of asthma that may be clinically silent. This study examines the prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. This prospective cohort study evaluated 26 patients with stable asthma without reflux symptoms using esophageal manometry and 24-h esophageal pH testing. Gastroesophageal reflux was considered present if esophageal acid contact times were abnormal. Demographic variables were analyzed to determine if they predicted the presence of gastroesophageal reflux. Asthma patients with asymptomatic gastroesophageal reflux were compared with 30 age-matched asthma patients with symptomatic gastroesophageal reflux. The prevalence of abnormal 24-h esophageal pH tests in asthma patients without reflux symptoms was 62% (16 of 26). Demographic variables did not predict abnormal 24-h esophageal pH tests in asthma patients with asymptomatic gastroesophageal reflux. Asthma patients with asymptomatic gastroesophageal reflux had higher amounts of proximal esophageal acid exposure (p < 0.05) compared with asthma patients with symptomatic gastroesophageal reflux. Because demographic variables do not predict abnormal 24-h esophageal pH tests in asthma patients without reflux symptoms, 24-h esophageal pH testing is required. This study suggests that gastroesophageal reflux is present in asthma patients, even in the absence of esophageal symptoms.

Adult↗

A dose-ranging study of fluticasone propionate administered once daily via multidose powder inhaler to patients with moderate asthma.

STUDY OBJECTIVE: This dose-ranging study evaluated the clinical efficacy and safety of inhaled fluticasone propionate administered once daily via a multidose powder inhaler in patients with moderate asthma (FEV(1), 45 to 75% predicted). MATERIALS AND METHODS: In this multicenter trial, 330 patients (> or = 12 years old) previously receiving inhaled corticosteroids or beta(2)-agonists alone were randomized in a double-blind manner to receive fluticasone propionate at 100, 200, or 500 microg once daily or matching placebo for 12 weeks. RESULTS: Once-daily treatment with fluticasone propionate resulted in an improvement in efficacy variables, such as FEV(1), morning and evening peak expiratory flow (PEF), asthma symptom scores, nighttime awakenings, albuterol use, and duration of study participation. A dose-related trend was observed for improvements in morning and evening PEF and albuterol use. Statistical significance for pairwise comparisons was achieved for 200 microg and 500 microg fluticasone propionate vs placebo for all efficacy variables, and for 100 microg fluticasone propionate vs placebo for morning and evening PEF at most or all time points. Drug-related adverse events were few (< or = 5%) and mostly related to the topical effects of inhaled corticosteroids. No dose-response effect or clinically relevant differences were observed in morning plasma cortisol concentrations or after cosyntropin stimulation. CONCLUSION: Once-daily treatment with fluticasone propionate was well tolerated and demonstrated some dose-related trends in improvements in lung function and asthma control in patients with moderate asthma.

Administration, Inhalation↗

Long-term efficacy and safety of fluticasone propionate powder administered once or twice daily via inhaler to patients with moderate asthma.

OBJECTIVE: To evaluate the efficacy and safety of fluticasone propionate administered as a once-daily or twice-daily regimen over a period of 1 year to patients with moderate asthma. DESIGN: Double-blind, randomized, parallel group, and placebo-controlled phase (12 weeks) and an open-label phase (54 weeks). SETTING: Multicenter study in an outpatient setting. PARTICIPANTS: Patients (n = 253; age, > or = 12 years) with a mean FEV(1) of 67% predicted normal were stratified according to baseline therapy of maintenance inhaled corticosteroids vs beta(2)-agonists alone. MEASUREMENTS AND INTERVENTIONS: Fluticasone propionate (250 microg bid or 500 microg qd) or placebo (bid) was administered via the Diskus multidose powder inhaler (Glaxo Wellcome; Research Triangle Park, NC) for 12 weeks. During open-label treatment, patients were re-randomized to once-daily or twice-daily fluticasone propionate. RESULTS: Compared to placebo, fluticasone propionate administered qd or bid significantly improved FEV(1) (p < 0.001), morning (p < 0.001) and evening peak expiratory flow (PEF; p < 0.001), asthma symptom scores (p < or = 0.001), and albuterol use (p </= 0.001), and decreased nighttime awakenings. By the end of 12 weeks, withdrawal due to lack of efficacy was significantly higher in the placebo group than in the once-daily (p = 0.001) or twice-daily (p < 0.001) groups. When comparing the two active dosing regimens, significant differences in favor of twice-daily dosing were noted in FEV(1), albuterol use, and withdrawal due to lack of efficacy. During 54 weeks of open-label treatment, FEV(1) and PEF continued to improve with both regimens, and improvements seen in the first 12 weeks were maintained in patients who switched from twice-daily to once-daily dosing. Fluticasone propionate treatment over a 54-week period was well tolerated, with few drug-related adverse events, which were primarily topical effects of inhaled corticosteroids. CONCLUSIONS: Fluticasone propionate powder improved lung function when administered either qd or bid over a 1-year period to patients with moderate asthma, with twice-daily dosing demonstrating significantly greater improvement in some efficacy parameters than once-daily dosing over the first 12 weeks of treatment. Fluticasone propionate treatment was not associated with significant systemic effects.

Administration, Inhalation↗

Pharmacokinetics of fluticasone propionate inhaled via the Diskhaler and Diskus powder devices in patients with mild-to-moderate asthma.

OBJECTIVE: The aim of these studies was to compare the pharmacokinetics of inhaled fluticasone propionate (FP) after repeated administration via the Diskus or Diskhaler dry powder inhalers (DPIs) to patients with mild-to-moderate asthma. METHODS: Both studies evaluated the pharmacokinetics of inhaled administration of FP via a DPI to patients with mild-to-moderate asthma, according to a randomised, double-blind, placebo-controlled design. In the first study, FP 100 microg or 500 microg was administered twice daily via the Diskhaler for 6 weeks and, in the second, FP 500 microg was administered via the Diskus or Diskhaler for 12 weeks. RESULTS: In the first study, plasma FP concentrations could be detected consistently only with the higher dose; the lower dose produced concentrations close to or below the 0.025 microg/L quantification limit of the radioimmunoassay used. From detailed analysis of a subgroup of patients receiving the 500 microg dosage, steady-state plasma FP concentrations were attained within one week of commencing treatment. After 4 weeks, the maximum plasma FP concentration (Cmax) in this subgroup was 0.096 microg/L [95% confidence interval (CI) 0.066-0.141] and the area under the plasma FP concentration-time curve up to the last quantifiable concentration (AUClast) was 0.491 microg/L x h (95% CI: 0.256-0.940). The steady-state to single dose accumulation ratio for FP after twice-daily administration varied between patients: a ratio of approximately 1.7 was recorded after comparison of Cmax at week 4 and day 1. In the second study, the point estimate of the Diskus to Diskhaler ratio for Cmax in all patients was 0.91 (90% CI: 0.76-1.10) after 4 weeks' treatment. From a detailed analysis of a subgroup of patients, the corresponding ratio for AUClast at the same time point was 1.15 (90% CI: 0.69-1.94), indicating no significant difference in systemic exposure to FP between the 2 devices. Steady-state kinetics were achieved by week 1: the point estimate ratios of Cmax and AUClast at week 4 compared with week 1 were 0.88 (90% CI: 0.66-1.16) and 0.95 (90% CI: 0.66-1.36), respectively. Administration of FP via either DPI had no effect on plasma cortisol levels over the 12-hour postdose period. CONCLUSION: In patients with asthma receiving repeated inhaled doses of FP, the systemic exposure (AUC) after inhalation from the Diskus was similar to that from the Diskhaler, with no difference between the DPIs in the effects on cortisol suppression. The 2 DPIs therefore have very similar pharmacokinetic profiles.

Administration, Inhalation↗

Fluticasone propionate powder and lack of clinically significant effects on hypothalamic-pituitary-adrenal axis and bone mineral density over 2 years in adults with mild asthma.

BACKGROUND: Although inhaled corticosteroids are widely used for the treatment of inflammation in asthma, prospective, long-term, placebo-controlled trials characterizing their systemic safety with chronic use are lacking. OBJECTIVE: This study was designed to prospectively evaluate the long-term safety of inhaled fluticasone propionate therapy. METHODS: Fluticasone propionate powder, 500 microgram, or placebo was administered twice daily by means of the Diskhaler for 104 weeks to 64 adults with mild persistent asthma in a randomized, double-blind, parallel-group study. Primary safety variables were measured at baseline and every 6 months thereafter. Although evaluation of efficacy was not an objective of this study, pulmonary function testing was performed at monthly intervals. RESULTS: Two years of treatment with fluticasone propionate had no significant effects on the skeletal system. No clinically significant changes were observed in ophthalmic parameters (glaucoma and posterior subcapsular cataracts). Mean change from baseline in lumbar spine (L1 to L4 ) bone density at week 104 was not significantly different between fluticasone propionate (-0.006 +/- 0.008 g/cm2) and placebo (-0.007 +/- 0.010 g/cm2). Markers of bone formation (serum osteocalcin) and resorption (urinary N-telopeptide) did not differ significantly between treatment groups. The effects of fluticasone propionate treatment on the hypothalamic-pituitary-adrenal axis were minimal, with no alterations in morning plasma cortisol concentrations and minor but statistically significant decreases in poststimulation mean peak plasma cortisol concentrations (P =.021) and 8-hour plasma cortisol area under the curve values (P =.020) at week 104. Drug-related adverse events were primarily topical effects of inhaled corticosteroids. Pulmonary function improved significantly during 2 years of fluticasone propionate treatment. CONCLUSION: Fluticasone propionate powder, 500 microgram twice daily for up to 2 years, was efficacious and well tolerated, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis, bone density, or ophthalmic parameters in adults with mild asthma.

Adolescent↗

Gastroesophageal reflux and asthma: insight into the association.

Gastroesophageal reflux (GER) is a potential trigger of asthma. GER symptoms are more prevalent in asthma patients compared with control populations, with a prevalence of approximately 75%. GER symptoms are associated with respiratory symptoms and inhaler use. GER may also occur without esophageal symptoms. Abnormal esophageal acid contact times are also more prevalent in patients with asthma compared with control populations, with a prevalence of 80%. Pathophysiologic mechanisms of esophageal acid-induced bronchoconstriction include a vagally mediated reflex, heightened bronchial reactivity, and microaspiration. Esophageal acid may increase minute ventilation without evidence of bronchoconstriction. Esophageal acid is associated with the release of substance P in the bronchial mucosa, resulting in airway edema. Medical antireflux therapy with proton pump inhibitors results in asthma symptom improvement in approximately 70% of patients, similar to surgical results. Predictors of asthma response include the presence of regurgitation, proximal acid reflux, esophagitis healing with therapy, reflux-associated respiratory symptoms, or nocturnal asthma. Management of GER in adult patients with asthma should include a 3-month trial of high-dose proton pump inhibitor while monitoring asthma outcome. GER should be considered as a potential asthma trigger in all patients.

Asthma↗

Fluticasone propionate powder: oral corticosteroid-sparing effect and improved lung function and quality of life in patients with severe chronic asthma.

BACKGROUND: Many patients with severe asthma are dependent on oral corticosteroids for maintenance control of their disease. Treatments that allow patients to be weaned off oral corticosteroids may help to minimize the risk of side effects associated with their chronic use. OBJECTIVE: This study evaluated whether inhaled fluticasone propionate powder could maintain pulmonary function while reducing the dose of oral prednisone in patients with chronic, severe asthma. METHODS: Oral prednisone-dependent (5 to 40 mg/day) adolescents and adults with asthma (n = 111; mean FEV1 = 61% of predicted value) were randomized to placebo or twice daily fluticasone propionate 500 or 1000 microg administered by means of a multidose powder inhaler for 16 weeks in a double-blind, parallel-group study. Patients underwent controlled prednisone reduction on the basis of predetermined asthma stability criteria. RESULTS: Oral prednisone was eliminated by 75% and 89% of patients in the twice daily 500 and 1000 microg fluticasone propionate groups, respectively, versus 9% of the placebo group (P <.001). FEV1, morning and evening peak expiratory flow, asthma symptoms, albuterol use, and nighttime awakenings improved with fluticasone propionate treatment, achieving statistical significance (P </=.009) primarily in the 1000 microg twice daily group. Hypothalamic-pituitary-adrenal axis suppression observed at baseline improved when patients were weaned off oral prednisone to fluticasone propionate. Adverse events ascribed to drug treatment were primarily topical effects of inhaled corticosteroids or those associated with prednisone withdrawal. Patient quality of life assessed by means of the Asthma Quality of Life Questionnaire was clinically and significantly improved after fluticasone propionate treatment (P </=.003). CONCLUSION: Fluticasone propionate powder (500 or 1000 microg twice daily) effectively improved lung function, adrenal function, and asthma-specific quality of life in patients with severe chronic asthma previously treated with oral prednisone while allowing most patients to be weaned off oral corticosteroid therapy.

Administration, Inhalation↗

Diskus and diskhaler: efficacy and safety of fluticasone propionate via two dry powder inhalers in subjects with mild-to-moderate persistent asthma.

BACKGROUND: Fluticasone propionate is a topically active glucocorticoid with potent antiinflammatory activity in the treatment of asthma. OBJECTIVE: This study evaluated the safety and efficacy of fluticasone propionate administered via the Diskus and Diskhaler powder delivery devices in subjects with mild-to-moderate asthma. METHODS: Fluticasone propionate (500 microg twice daily) or placebo was administered via the Diskus and Diskhaler to 213 adolescent and adult asthma subjects in a randomized, double-blind, double-dummy, parallel-group study for 12 weeks. Subjects were stratified according to baseline therapy of inhaled corticosteroids or beta2-agonists alone. Subjects were dropped from the study if they met predefined criteria for lack of efficacy. RESULTS: Fluticasone propionate improved pulmonary function both in subjects previously treated with inhaled corticosteroids or beta2-agonists alone. At endpoint, fluticasone propionate significantly improved forced expiratory volume in 1 second (P < .001), morning and evening peak expiratory flow (P < .001), and asthma symptom scores (P < or = .016), and significantly reduced nighttime awakenings (P = .016; Diskhaler group only) and rescue albuterol use (P < .001). Overall, efficacy measurements for the Diskus and Diskhaler were similar. More placebo-treated subjects (34%) withdrew from the study due to lack of efficacy than subjects in the Diskus (5%) or Diskhaler (5%) groups. The incidence and severity of adverse events were similar across groups. Measurement of plasma fluticasone propionate and cortisol concentrations showed no apparent influence of device on systemic exposure. CONCLUSION: Fluticasone propionate powder, administered via the Diskus or Diskhaler inhalation devices, was well tolerated and effective in the treatment of mild-to-moderate persistent asthma.

Administration, Inhalation↗

Gastroesophageal reflux disorders and asthma.

Gastroesophageal reflux (GERD) may trigger asthma. Approximately 77% of asthmatic people experience reflux symptoms, although GERD may be clinically silent in some. Esophagitis is found in 43% of asthmatic people, and 82% have abnormal esophageal acid contact times on esophageal pH testing. Clearly, GERD is prevalent in asthmatic people. Pathophysiologic mechanisms of acid-induced bronchoconstriction include a vagally mediated reflex and microaspiration. Whether these airway responses are clinically significant is the subject of some debate. Interestingly, peak expiratory flow rates and specific airway resistance alterations persist despite esophageal acid clearance. Preliminary evidence shows that substance P, an inflammatory mediator that causes airway edema, is released with esophageal acid. Although therapeutic studies are limited by their small population sizes and study design, up to 70% of asthmatic people have asthma improvement with antireflux therapy. Possible predictors of asthma response include patients with symptomatic esophageal regurgitation; abnormal proximal esophageal acid exposure; and, in surgical studies, those with normal esophageal motility and asthma response with medical therapy. Future research will further define the association between asthma and gastroesophageal reflux.

Asthma↗