Low-dose Theophylline Research Articles

Revisiting an Old Therapy

The use of theophylline for the treatment of asthma has decreased significantly over the past few decades. Nonetheless, clinicians may still encounter patients with theophylline-based asthma regimens. While theophylline’s exact mechanism of action is not defined, new theories infer that the benefit of theophylline is due to its anti-inflammatory, rather than bronchodilatory, effects. Clinical trials have explored the combination of theophylline with lower doses of corticosteroids as a steroid-sparing strategy. Complex pharmacokinetics, significant adverse effects, and interpatient variability have contributed to the decreased use of this medication for asthma. Clinicians should be cognizant of the appropriate initial dosing, variety of formulations, and timing of theophylline levels to reduce toxicity and better control asthma symptoms. This review summarizes literature supporting the use of low-dose theophylline as an adjunct to corticosteroids in asthma, as well as pharmacokinetics, drug interactions, and adverse effects associated with its traditional dosing strategy.

Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD

Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD. To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L). In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD. Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD. clinicaltrials.gov; Identifier NCT00241631.

Herb–drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats

Herb–drug interaction has become a serious problem since herbal medicine is extensively used in the modern world. This study investigates effects of Andrographis paniculata extract (APE) and its major component, andrographolide (AG), on the pharmacokinetics of theophylline, a typical substrate of cytochrome P450 1A2 enzyme, in rats. After APE or AG pretreatment for 3 days, on the fourth day rats were administered theophylline via femoral vein cannula. The blood theophylline levels were monitored by microdialysis sampling combined with HPLC-UV. The results indicated that the clearance of theophylline was significantly increased and the area under concentration–time curve (AUC) was reduced in both AG and APE pretreated groups at low-dose theophylline administration (1 mg/kg). The elimination half-life ( t 1/2β) and mean residence time (MRT) of theophylline were shortened by 14% and 17%, respectively, in the AG pretreated group when high-dose theophylline (5 mg/kg) was given. However, theophylline accumulated in rat of the group with APE pretreatment. This phenomenon suggests that some other herbal components contained in APE may interact with theophylline and retard its elimination when theophylline was administered at a high dose. Our results suggest that patients who want to use CYP1A2-metabolized drugs such as caffeine and theophylline should be advised of the potential herb–drug interaction, to reduce therapeutic failure or increased toxicity of conventional drug therapy.

Theophylline again? Reasons for believing

So, what is new for theophylline in asthma? Theophylline has been used over the last 70 years for treating patients with asthma. It is well known as a bronchodilator and the current asthma guidelines recommend it as an add-on therapy in noncontrolled asthmatics 1. More than a decade ago, Evans et al. 2 showed that adding theophylline is equally effective as doubling inhaled corticosteroid (ICS) doses for asthma control. In a recent issue of the European Respiratory Journal , Spears et al. 3 reported significant improvements in both lung function and asthma control score in smoking asthmatics who are treated with a combination of low-dose theophylline and beclomethasone compared with each drug alone. The potential relevance of this small, self-labelled pilot trial is that to our knowledge, it is the first to test an effect of this mechanism in smokers. Worldwide, one in every four asthmatics still smokes; interestingly, the prevalence of smoking in asthmatics mirrors the population prevalence of smoking in that geographic population 4. Every smoker should quit but anyone with asthma or any other respiratory condition should be offered all options and help to achieve full smoking cessation. So, what is the point? Something has changed in our scientific knowledge of the mechanism of action of theophylline in recent years. Since Ito et al. 5 described in vitro a novel …

Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.

Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD

Background:Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response mainly to cigarette smoke that flares up during exacerbations of the disease (ECOPD). Reduced activity of histone deacetylases...

Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease

Background The airway inflammation of chronic obstructive pulmonary disease (COPD) demonstrates a poor response to the anti-inflammatory actions of corticosteroids. However, long-acting β 2-agonists and low-dose theophylline are reported to have a possible anti-inflammatory effect in COPD. The aim of this study was to compare the effects of treatment between theophylline and the tulobuterol patch (transdermal patch preparation designed to yield sustained β 2-agonistic effects for 24 h) on airway inflammation in addition to quality of life (QOL) and pulmonary function in mild-to-moderate COPD. Methods The study subjects consisted of 26 patients with COPD who were treated with theophylline or tulobuterol for 8 weeks with a wash-out period of 4 weeks in a randomized open-label crossover study. We prospectively investigated the differential cell counts and levels of inflammatory markers in induced sputum before and after treatment with theophylline and tulobuterol. We also examined pulmonary function and quality of life (QOL) as assessed by St. George's Respiratory Questionnaire. Results In the induced sputum, the total inflammatory cell count and number of neutrophils were significantly reduced by treatment with low-dose theophylline. Neither of these parameters was significantly changed by treatment with tulobuterol. Pulmonary function measurements such as FEV 1, FEV 1 %pred, FVC, PEF, MEF 50, and MEF 25 were significantly improved by the treatment with low-dose theophylline but not tulobuterol. The total QOL scores, levels of interleukin 8 and myeloperoxidase in the supernatants of induced sputum, and serum levels of hypersensitive C-reactive protein were not significantly changed by either of the treatments. Conclusion These results suggest that treatment with low-dose theophylline but not the tulobuterol patch may have anti-inflammatory effects and improve pulmonary function in mild-to-moderate COPD.

Association of corticotropin-releasing hormone receptor-2 genetic variants with acute bronchodilator response in asthma.

Corticotropin-releasing hormone receptor (CRHR)-2 participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short-acting beta2-agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma. We investigated 28 single nucleotide polymorphisms in CRHR2 for associations with acute bronchodilator response to albuterol in 607 Caucasian asthmatic patients recruited as part of the Childhood Asthma Management Program. Replication was conducted in two Caucasian adult asthma cohorts--a cohort of 427 participants enrolled in a completed clinical trial conducted by Sepracor Inc. (Massachusetts, USA) and a cohort of 152 participants enrolled in the Clinical Trial of Low-Dose Theophylline and Montelukast conducted by the American Lung Association Asthma Clinical Research Centers. Five variants were significantly associated with acute bronchodilator response in at least one cohort (P<or=0.05). Variant rs7793837 was associated in Childhood Asthma Management Program and Low-Dose Theophylline and Montelukast (P=0.05 and 0.03, respectively) and haplotype blocks residing at the 5' end of CRHR2 were associated with response in all three cohorts. We report for the first time, at the gene level, replicated associations between CRHR2 and acute bronchodilator response. Although no single variant was significantly associated in all three cohorts, the findings that variants at the 5' end of CRHR2 are associated in each of three cohorts strongly suggest that the causative variants reside in this region and its genetic effect, although present, is likely to be weak.

Sleep Quality in Asthma: Results of a Large Prospective Clinical Trial

Rationale. Previous studies have suggested that asthmatics have an increased incidence of sleep disturbances. However, these studies have been limited by reliance on population surveys or small numbers of participants. Objectives. We sought to measure sleep quality and daytime sleepiness in a cohort of symptomatic asthmatics and to measure the effects of improved asthma control on sleep quality. Methods. Data were collected in sub-study of a large multi-center randomized double-masked controlled trial of mild-moderate asthmatics evaluating the effect of low-dose theophylline on asthma control in comparison to montelukast and placebo. Each participant was administered sleep symptom questionnaires at randomization and at the final visit (6 months after randomization). These included the Pittsburgh Sleep Quality Questionnaire (PSQI) and the Epworth Sleepiness Scale (ESS). Measurements and main results. Data were available for 487 participants. Baseline mean values were: age 40 ± 15 years, 74% female, forced expiratory volume in 1 second (FEV1) 79 +16 percent predicted, Juniper Asthma Control Questionnaire (ACQ) score 2.35 ± 0.63, PSQI 7.8 ±4, and ESS 8.5 ±4.9. There were no significant differences in the PSQI or ESS between the three treatment groups. Significant correlations were found at baseline between the global PSQI score and ACQ and quality of life and marginally with lung function. Significant correlation existed between improvements in PSQI and ESS with improved asthma control and quality of life. Conclusions. Sleep disturbances are common in asthmatics and are associated with asthma control and quality of life. Clinicians caring for asthmatics may need to complete a more detailed sleep history in patients with poorly controlled asthma. In addition, low-dose theophylline does not seem to impair sleep quality in asthmatics.

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

The Effect of Montelukast and Low-Dose Theophylline on Cardiovascular Disease Risk Factors in Asthmatics

Recent studies have implicated the 5-lipoxygenase/leukotriene (LT) pathway in cardiovascular disease (CVD), which may have important implications for asthmatics because several drugs that target this pathway are currently used to treat asthma. We sought to determine whether montelukast, a cysteinyl LT antagonist, and low-dose theophylline affected serum inflammatory and lipid CVD risk factors in a recently completed clinical trial in asthmatic patients. Patients were randomized to receive either montelukast (10 mg/d), theophylline (300 mg/d), or placebo. A baseline run-in period of 7 to 14 days was followed by treatment for 6 months. Serum levels of C-reactive protein (CRP), interleukin-6, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density cholesterol (HDL-C) were measured 1 month and 6 months after treatment. Patients with moderate-to-severe asthma receiving montelukast (n = 60) had significantly lower serum CRP compared to placebo (n = 73) after 1 month (1.7 mg/L vs 3.2 mg/L, respectively; p < 0.006) and 6 months of treatment (2.3 mg/L vs 3.5 mg/L, respectively; p < 0.04). At both time points, serum levels of all lipids were also significantly lower in the montelukast and theophylline groups compared to placebo, but these effects were primarily observed in individuals who were also receiving inhaled corticosteroids as monotherapy for asthma. Asthmatic patients receiving montelukast and, to some extent, low-dose theophylline have lower levels of CVD-associated inflammatory biomarkers and lipid levels. These observations suggest these asthma medications may have some beneficial value in asthmatics with respect to CVD risk, although the effects on HDL-C levels should also be taken into consideration.

Once daily oral controller therapy with low dose theophylline or montelukast was not effective in poorly controlled asthma

Source Citation The American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit C...

Once-daily oral controller therapy with low-dose theophylline or montelukast was not effective in poorly controlled asthma

Once-daily oral controller therapy with low-dose theophylline or montelukast was not effective in poorly controlled asthma

Clinical Trial of Low-Dose Theophylline and Montelukast in Patients with Poorly Controlled Asthma

Asthma treatment guidelines recommend addition of controller medications for patients with poorly controlled asthma. We compared the effectiveness of once-daily oral controller therapy with either an antileukotriene receptor antagonist (montelukast) or low-dose theophylline added to existing medications in patients with poorly controlled asthma. We conducted a randomized, double-masked, placebo-controlled trial in 489 participants with poorly controlled asthma randomly assigned to placebo, theophylline (300 mg/d), or montelukast (10 mg/d). Participants were monitored for 24 wk to measure the rate of episodes of poor asthma control (EPACs) defined by decreased peak flow, increased beta-agonist use, increased oral corticosteroid use, or unscheduled health care visits. There was no significant difference in EPAC rates (events/person/yr) compared with placebo: low-dose theophylline, 4.9 (95% confidence interval [CI], 3.6-6.7; not significant); montelukast, 4.0 (95% CI, 3.0-5.4; not significant); and placebo, 4.9 (95% CI, 3.8-6.4). Both montelukast and theophylline caused small improvements in prebronchodilator FEV(1) of borderline significance. Nausea was more common with theophylline only during the first 4 wk of treatment. Neither treatment improved asthma symptoms or quality of life. However, in patients not receiving inhaled corticosteroids, addition of low-dose theophylline significantly (p < 0.002) improved asthma control and symptoms as well as lung function. Neither montelukast nor low-dose theophylline lowered the EPAC rate of poor asthma control in patients with poorly controlled asthma despite improved lung function. For patients not using inhaled corticosteroids, low-dose theophylline improved asthma symptom control more than montelukast or placebo, and provides a safe and low-cost alternative asthma treatment.

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

Purpose : Theophylline has recently been reported to have concurrent anti-inflammatory effects at low therapeutic plasma concentrations which are below the doses at which significants, clinically useful bronchodilatation is evident. Sustained-release formulation in capsule and dry syrup forms were developed to reduce its adverse effects and improve its clinical effects. We compared the therapeutic effects of theophylline dry syrup and capsules in children with mild asthma. Methods : Ninety children with mild asthma were randomized to receive either theophylline dry syrup (n=44) or theophylline capsules (n=46); 4 mg per kilogram of body weight, twice a day, for 12 weeks. Baseline and serial measurements of daytime and nighttime asthma symptom score were performed. Compliance scores, drug swallowing scores, and drug usability scores were measured every 4 weeks. Each scoring was rated on a scale of 0-4. Serum theophylline concentration were measured at 4 and at 12 weeks. To examine the anti-inflammatory effect of theophylline on asthma, Serum eosinophilic cationic protein as a marker of airway inflammation caused by eosinophil was measured 12 weeks pre- and post-administration. Results : The daytime and nighttime asthma symptom scores of the two groups after 4 weeks significantly improved over the baseline score. Daytime and nighttime asthma symptom scores in the dry syrup group were statistically lower at all time points except for the nighttime symptom scores at 4 weeks. Compliance scores, drug swallowing scores, and drug usability scores in the dry syrup group were significantly higher at the end time point. Only in the dry syrup group was the serum ECP at the end time point statistically lower than baseline. Conclusion : Low-dose sustained-release theophylline may be safe and effective in bronchial asthma and this effect may be mediated by its anti-inflammatory action mechanisms. Especially, when used in children with asthma, dry syrup formulation is recommended because of its higher compliance than capsule formulation.

ＣＯＰＤにおける低用量テオフィリンの気道抵抗，呼吸筋力および高感度ＣＲＰへの影響

The purpose of this study was to evaluate the effect of low-dose theophylline on airway resistance(Raw),respiratory muscle strength and high-sensitivity CRP in patients with chronic obstructive pulmonary disease(COPD).The subjects were 11 patients with COPD(8 males ; 3 females).Raw and other pulmonary function parameters were measured by means of body plethysmography.Maximal expiratory pressure(MEP)and the maximal inspiratory pressure(MIP),the parameters of respiratory muscle strength,were measured after 4 weeks of administering low-dose theophylline when serum concentrations of theophylline were 4.7±2.9 micro g/mL.The administration of theophylline decreased Raw,significantly increased FEV 1.0,decreased CRP levels and increased MEP.High-sensitivity CRP levels were negatively correlated with MEP and MIP (R2=0.474,R2=0.657 respectively).The results of the present study suggested that high-sensitivity CRP can be used as an indicator of respiratory muscle strength in patients with COPD.

Prevention of Contrast Induced Nephropathy

Contrast induced nephropathy (CIN) is a well-known and serious complication in patients with chronic renal insufficiency undergoing coronary angiography or interventions. CIN is associated with significant morbidity and mortality. This complication results in prolonged hospital stay and substantially increases the cost of medical care. Various therapeutic measures have been evaluated for the prevention of CIN. Peri-procedural saline hydration, use of low osmolality contrast agents and limiting the amount of contrast administered are the preferred methods. In recent years, the efficacy of prophylactic hemofiltration and several pharmacological agents, including low dose dopamine, theophylline, Nacetylcysteine, and fenoldopam have been evaluated in randomized controlled trials. Conflicting results, rather than convincing conclusions, were observed in the studies of most of these agents. Meta-analysis suggested that the use of Nacetylcysteine and theophylline may be able to prevent the decline of renal function after contrast exposure. This review provides an update on the recent studies in this subject as well as a critical analysis on how available evidence could be translated to daily clinical practice.

Prevalence of Alpha-1 Antitrypsin Deficiency in Poorly Controlled Asthma—Results from the ALA-ACRC Low-Dose Theophylline Trial

In a study comparing low-dose theophylline to montelukast in poorly controlled asthmatics, 285 subjects consented to be screened for alpha-1 antitrypsin deficiency. Of the 284 for which complete data was available, 10.5% carried a deficiency gene and 2.4% were mildly deficient with an alpha-1 antitrypsin serum level of less than 20 μ M. In the non-African-American cohort, an abnormal phenotype occurred in 12% and 2.9% were mildly deficient. Baseline pulmonary function and asthma scores were not significantly different between those with normal and abnormal AAT phenotype. However those with the deficiency tended to show a greater bronchodilator response.

Positive benefits of theophylline in a randomized, double‐blind, parallel‐group, placebo‐controlled study of low‐dose, slow‐release theophylline in the treatment of COPD for 1 year

Increasing evidence suggests that low-dose theophylline has anti-inflammatory benefits and is safe in the treatment of COPD. This study aims to evaluate the efficacy and safety of low-dose, slow-release oral theophylline administered over a 1-year period in patients with COPD. A randomized, double-blind, parallel-group, placebo-controlled trial was carried out. In total, 110 participants with COPD were randomly assigned to receive slow-release theophylline (100 mg b.i.d.) or placebo for 1 year. Use of medicine and symptoms recorded by diary cards; pulmonary function, exacerbations of COPD, quality of life and the use of rescue medicine were evaluated. Superiority test was used to estimate the efficacy. Of 110 participants, 85 (77.3%) complied with the protocol, with 42 subjects in theophylline and 43 subjects on placebo. In both intention-to-treat and per-protocol population analysis, greater improvement in pre-bronchodilator FEV(1) (P = 0.038 and P = 0.070, respectively), lower frequency of COPD exacerbations (P = 0.047 and P = 0.035, respectively), fewer days of COPD exacerbations (P = 0.045 and P = 0.046, respectively), lower frequency of clinical visits (P = 0.017 and P = 0.039, respectively), greater improvement in satisfaction with treatment (P = 0.014 and P = 0.004, respectively) were found in the theophylline group than in the placebo group. In per-protocol population, greater improvements in quality of life (P = 0.047) were also observed in the theophylline group and the mean time to the first exacerbation was delayed in theophylline group in comparison with placebo group (P = 0.047). Drug-related adverse events such as stomach discomfort (3.51%), headache (3.51%), insomnia (1.75%) and palpitation (1.75%) were found in the theophylline group. Low-dose, slow-release oral theophylline is effective and well-tolerated in the long term treatment of stable COPD, although it does not improve post-bronchodilator lung function.

Allergic Rhinitis and Sinusitis in Asthma: Differential Effects on Symptoms and Pulmonary Function

Background Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. Methods A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. Results More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). Conclusion Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function. Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.