Susan J. Kunselman

Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.

BACKGROUND The issue of whether regular use of an inhaled beta2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the beta2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. METHODS Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. FINDINGS During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0.0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0.8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0.0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0.0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0.0003). There were similar genotype-specific effects in FEV1, symptoms, and use of supplementary reliever medication. INTERPRETATION Genotype at the 16th aminoacid residue of the beta2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.

Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma

BACKGROUND Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. METHODS In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). RESULTS The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003). CONCLUSIONS When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).

The Management of Patients with Advanced Carcinoid Tumors and Islet Cell Carcinomas

Among the rarest of cancers, the gastrointestinal neuroendocrine tumors (islet cell carcinomas and carcinoid tumors) present difficult and complex challenges for individual patient management. When the tumors metastasize, patients have a variety of clinical presentations including manifestations of tumor bulk and bizarre syndromes resulting from massive hormone production. Table 4. SI Units When physicians analyze therapeutic options for patients with metastatic carcinoid tumors or islet cell carcinomas, they should consider the course of the patients malignant disease, the distribution of metastasis, the severity of clinical manifestations, and the relative contributions of the hormonal syndromes and tumor bulk to symptoms and disability. The oncologist must be conservative, because these diseases frequently run an indolent course, allowing years of comfortable life with no treatment whatsoever. However, aggressive approaches may be justified when the patient develops disabling symptoms because tumor debulking or correction of mechanical problems may sometimes provide the patient with additional years of comfortable life. If the patient has a clinically dominant hormonal syndrome and has no imminent threat from tumor bulk, it is frequently possible to produce substantial palliation with minimal therapeutic risk. In earlier years, only patients with gastrinoma could be helped in this manner by the use of histamine-2 blockers (for example, adequate doses of cimetidine or ranitidine or, more recently, omeprazole [Prilosec, Merck and Company, West Point, Pennsylvania]). The development and clinical application of an analog of somatostatin (octreotide; Sandostatin, Sandoz Pharmaceuticals, East Hanover, New Jersey) has provided a novel and frequently highly effective tool for control of almost all the endocrine syndromes. Striking decreases in hormonal levels and substantial or complete relief from symptoms can be achieved in approximately 80% of patients [1, 2]. Although octreotide usually produces only minimal immediate side effects, gallstones are a frequent long-term complication. However, octreotide therapy is cumbersome to the patient and is costly. Further, most patients become resistant to this therapy; for patients with carcinoid tumor, the median interval is about 1 year and for patients with islet cell carcinomas, only a few months. For these reasons, octreotide therapy for the carcinoid syndrome should be reserved for patients with severe flushing or diarrhea. In those with islet cell carcinomas, it should be used primarily to restore the patient to a better general and nutritional status so that more aggressive and definitive therapy can be undertaken with an acceptable risk. Regression rates after systemic chemotherapy or immunotherapy (using either single drugs or drug combinations) for metastatic carcinoid tumors and islet cell carcinomas have been variable, as is typical for solid tumors [3]. For carcinoid tumors, regression rates (even with our most effective regimens) seldom exceed 20%, and the discouragingly short duration of these responses hardly justifies the risks and side effects of treatment. For this reason, we urge that systemic therapy for carcinoid tumors be carried out in a research setting. For islet cell carcinoma, however, treatment may be of true clinical value. Streptozocin (Zanosar, The Upjohn Company, Kalamazoo, Michigan) seems to have specific cytotoxicity for the islet cell carcinoma and produces credible tumor regressions in about 30% of patients. Because of its minimal hematologic toxicity, it is useful in drug combinations with chemotherapeutic agents that are dose limited by leukopenia and thrombocytopenia. In a randomized trial, fluorouracil plus streptozocin was found to produce a 45% regression rate and seemed to improve survival when compared with streptozocin alone [4]. In a recent randomized trial, the combination of doxorubicin and streptozocin increased the regression rate to 69% and produced a statistically significant increase in survival [5]. However, fewer than one third of patients have a substantive and prolonged response to chemotherapy, and it produces considerable toxicity. A special consideration in managing these patients is the usually dominant involvement of the liver in the metastatic process. For selected patients, the surgeon can make a major and usually long-lasting contribution by resection of large solitary tumor masses or well-localized clusters of metastatic lesions [6]. With modern surgical technology, operative morbidity and mortality have been reduced to acceptable levels. Among 40 such patients reported by McEntee and colleagues [6], only a single postoperative death occurred. Usually, however, the diffuse nature of hepatic metastasis precludes effective surgical debulking. Therefore, hepatic artery infusion of various drugs has been attempted but with little documented evidence of success. Occlusion of hepatic arterial flow is attractive, because metastatic tumor neovascularity and oxygenation derive almost entirely from the hepatic artery. In contrast, hepatocytes are resilient, and viability may be maintained through the portal vein until rearterialization occurs. Although many researchers have shown that hepatic artery occlusion effectively shrinks primary or metastatic cancer in the liver, for the more common and more aggressive malignant diseases, tumor regrowth occurs so quickly that any net gain is difficult to discern. Because carcinoid tumors and islet cell carcinomas usually grow slowly, lasting benefit may be possible using hepatic artery occlusion. This review documents our experience with hepatic arterial occlusion, by either surgical ligation or embolization, in selected patients with neuroendocrine tumors and hepatic-dominant metastatic disease. Although frequent and substantial tumor regressions were produced, the duration of these regressions, even with these indolent neoplasms, was discouragingly short. We therefore developed and tested a regimen of sequential hepatic arterial occlusion and chemotherapy with the hope that regressions could be enhanced and prolonged. For chemotherapy, we elected to give each of the drugs that have been most active for these tumors when used alone (that is, fluorouracil, streptozocin, doxorubicin, and dacarbazine [DTIC]). Methods Patient Selection All patients selected for study had histologically confirmed carcinoid tumor or islet cell carcinoma with metastasis clinically limited to or dominant in the liver. They were ambulatory and maintaining a reasonable state of oral nutrition (at least 1200 calories daily). One or more measurable parameters of malignant disease were required to serve as objective indicators of response to therapy. For liver metastasis, this required clearly demarcated lesions on liver imaging that measured at least 5 cm in greatest diameter using radioisotope scanning or at least 3 cm in diameter using computed tomography or magnetic resonance imaging. Alternatively, if the patient had malignant hepatomegaly with a distinct liver edge extended at least 5 cm below the xiphoid or costal margins on quiet respiration, this was also used as a marker for response to therapy. In the absence of measurable liver involvement, hormonal assays could be used alone as markers for response to therapy, if they were greater than twice the upper limit of normal. Contraindications to study entry were a total serum bilirubin level more than 51.3 mol/L (3 mg/dL), previous radiation therapy to the liver or hepatic arterial chemotherapy, and the standard contraindications for each of the involved cytotoxic drugs. In practice, protocol entry was limited to those patients who, in the judgment of the physician, had clinically significant symptoms related to tumor bulk or to the endocrine syndrome or had extensive metastasis associated with abnormal test results for liver function. Treatment Hepatic artery occlusion was done by surgical ligation in those patients who had other specific indications for abdominal surgery (for example, an obstructing carcinoid tumor of the small bowel) or for those patients in whom catheterization and embolization were not considered to be technically feasible. For all other patients, occlusion was done by catheterization and embolization. Before hepatic artery occlusion by either method, the anatomy of the hepatic vasculature was determined by angiography. If any evidence of portal vein occlusion or compromise of portal vein flow was noted, occlusion was not done. In patients having operative tumor devascularization, the hepatic artery was approached for ligation through the gastrohepatic ligament of the lesser omentum. The primary right and left hepatic arteries were ligated and divided individually distal to the gastroduodenal artery. Dearterialization was completed by division of the entire gastrohepatic omentum from the diaphragm to the bile duct. Any accessory or replaced hepatic arteries were also identified, ligated, and divided; lymphoareolar tissue in the hepatoduodenal ligament was also divided. Cholecystectomy was done to avoid gallbladder ischemia. For occlusion by embolization, the hepatic artery was selectively catheterized with injection of embolic material, usually gel foam or polyvinyl alcohol or both. Because of the technical difficulty encountered in the procedure, the pretreatment impairment of liver function, and the total mass and distribution of hepatic metastasis, eight patients had embolization done at two or three sittings separated by 3 to 4 work-week intervals. After hepatic artery occlusion, the patient was observed in the hospital for a minimum of 5 days to monitor complications. In some instances, prophylactic antibiotics were used. The patient was released from hospital when there was no clinical evidence of complications, definite recovery of abnormal test results for liver function, and reduction of fever. Sequential chemother

Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial

BACKGROUND Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid. METHODS In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967. FINDINGS After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures. INTERPRETATION In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine. FUNDING National Institutes of Health.

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.

Comparison of Physician-, Biomarker-, and Symptom-Based Strategies for Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma: The BASALT Randomized Controlled Trial

CONTEXT No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. OBJECTIVE To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma. DESIGN, SETTING, AND PARTICIPANTS A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. INTERVENTIONS For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. MAIN OUTCOME MEASURE The primary outcome was time to treatment failure. RESULTS There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). CONCLUSION Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00495157.

Effect of Polymorphism of the β2-Adrenergic Receptor on Response to Regular Use of Albuterol in Asthma

Background: Regular use of inhaled β-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the β2-adrenergic receptor (β2-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to β-agonist therapy have been inconsistent. Methods: We examined the possible effects of polymorphisms at codons 16 (β2-AR-16) and 27 (β2-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. Results: During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at β2-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 ± 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at β2-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at β2-AR-27. Conclusions: Polymorphisms of the β2-AR may influence airway responses to regular inhaled β-agonist treatment.

Predictors of response to tiotropium versus salmeterol in asthmatic adults.

BACKGROUND Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described. OBJECTIVE We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response. METHODS Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institutes Asthma Clinical Research Networks Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs). RESULTS Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not. CONCLUSION Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.

Factors affecting surgical risk in elderly patients with inflammatory bowel disease

The operative treatment of elderly patients with inflammatory bowel disease (IBD) has often been avoided in favor of medical management because of a perceived increase in surgical risk. This study sought to define the following in the elderly IBD patient population: (1) the risk of surgical management and (2) those factors affecting risk. Thirty patients with IBD, aged 60 years or more, who were surgically managed by a single surgeon over a 10-year period, were retrospectively matched to 75 patients with IBD who were less than 60 years of age; patients were matched according to sex, date of surgery, and type of surgery performed. Regression analysis using generalized estimating equation methodology to account for the matched clusters of patients was performed to evaluate the effect of age group on the complication rate, operating room time, and length of hospital stay. Presence of comorbid conditions, surgical indications, prior surgery for IBD, and the use of immunosuppressive medications were studied in multivariate models, adjusting for age group. By means of univariate analysis, the odds of complications in elderly IBD patients were shown to be statistically higher than the odds seen in younger patients (47% vs. 20%, P= 0.01). Also observed in the elderly group were a longer length of hospital stay (11.5 days vs. 7.1 days, P = 0.001) and longer operating room time (249 minutes vs. 212 minutes, P= 0.02). Multivariate analysis revealed that the effect of age remained statistically significant, even when adjusted for potential confounding variables such as comorbidity, medications, date of diagnosis of IBD, and indications for surgery. The complication outcome was significantly associated with the surgical indication, with obstruction, fistula, and bleeding having increased odds of complications as compared with other indications (odds ratio = 1.7 vs. 4.2 vs. 7.2, respectively, P= 0.02). The length of hospital stay similarly was significantly associated with the surgical indication (fistula, 10.5 days vs. bleeding, 9.8 days vs. obstruction, 7.4 days vs. other, 9.3 days; P= 0.04) and a history of prior surgery. A significant interaction for length of hospital stay was present between age group and prior surgery status (with prior surgery: old, 18 days vs. young, 6.4 days, P= 0.0001; without prior surgery: old, 9.5 days vs. young 7.3 days, P= 0.10). Elderly patients with IBD have an increased rate of postoperative complications along with an increased length of hospital stay and increased operating room time. This effect of age persists when adjusted for comorbidity and immuno-suppressive therapy. Complications are most dependent on surgical indications, with obstruction being the least and bleeding the worst predictive factors. The longest hospital stay is associated with patients who require surgery for fistulous disease and patients who have undergone previous surgery. The fact that the higher complication rate seen in older patients with IBD is associated with disease-defined surgical indications suggests that IBD in elderly patients may be more aggressive than what is observed in younger individuals.

Predicting worsening asthma control following the common cold

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean±sd increase in mini-ACQ score of 0.69±0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.