A survey of severe asthma in Canada: results from the CASCADE practice reflective program.

BACKGROUND: Since the last guidance was published by the Canadian Thoracic Society, there have been several advances in the clinical management of severe asthma. To gain a better understanding of the current standards of care and treatment patterns of patients, the CASCADE practice reflective program was established to conduct a real-world analysis of severe asthma management among specialists in Canada with a goal of identifying areas of opportunity to enhance patient management and outcomes. METHODS: The CASCADE program was a two-part practice reflective and assessment program delivered through an on-line portal for selected specialists (Respirologists and Allergists) in Canada. The program consisted of a one-time overview survey of physician practice to establish overall practice parameters, followed by a review of at least 5 severe asthma patients to establish the current landscape of severe asthma management. RESULTS: The program collected practice overview surveys from 78 specialists (52 Respirologists, 24 Allergists, and 2 General practice physicians with an interest in respiratory disease) in 8 provinces. Practices included a variety of types in both large metropolitan centres and smaller regional settings. There were 503 patients reviewed and included in the program. Most (65%) patients were currently using a biologic treatment, 30% were biologic naive, and 5% had used a biologic treatment in the past. Most patients (53%) were reported to have mixed allergic and eosinophilic phenotypes, despite a perception that allergic, eosinophilic and mixed phenotypes were evenly balanced in the physician practice. Overall, patients currently treated with biologic agents had parameters suggesting higher control and were more satisfied with treatment. However, there was less than optimal treatment satisfaction for more than half of all patients, particularly for those patients not treated with a biologic agent. CONCLUSIONS: Phenotyping is hampered by poor availability for several assessments, and the full range of treatments are not currently fully utilized, partly due to physician familiarity with the agents and partly due to prescribing restrictions. Even when treated with biologic agents, patient satisfaction can still be improved.

A Renewed Charter: Key Principles to Improve Patient Care in Severe Asthma.

Asthma is a heterogenous respiratory disease, usually associated with chronic airway inflammation and hyper-responsiveness, which affects an estimated 339 million people worldwide. Severe asthma affects approximately 5-10% of patients with asthma, approximately 17-34 million people globally, more than half of whom have uncontrolled disease. Severe asthma carries a substantial burden of disease, including unpredictable symptoms and potentially life-threatening flare-ups. Furthermore, severe asthma has a substantial burden on health care systems and economies worldwide. In 2018, a group of experts from the clinical community, patient support groups, and professional organisations joined together to develop the Severe Asthma Patient Charter, which set out six principles to define what patients should expect for the management of their severe asthma and what should constitute a basic standard of care. Since the publication of that original Charter in 2018, several important changes have occurred, including an improved understanding of asthma and effective asthma management; several new therapies have become available; and finally, the COVID-19 pandemic has placed a spotlight on respiratory conditions, the workforces that treat them, and the fundamental importance of health care system resilience. With those developments in mind, we, representatives of the academic, clinical, and patient advocacy group communities, have updated the Charter to Improve Patient Care in Severe Asthma with a focus on six principles: (1) I deserve a timely, comprehensive assessment of my asthma and its severity; (2) I deserve a timely, straightforward referral to an appropriate specialist for my asthma when it is not well controlled; (3) I deserve to understand what makes my asthma worse; (4) I deserve access to treatment and care that reduces the impact of asthma on my daily life; (5) I deserve not to be reliant on systemic corticosteroids; (6) I deserve to be involved in decisions about my treatment and care.

Rationale for earlier treatment in COPD: a systematic review of published literature in mild-to-moderate COPD.

COPD is progressive and typically begins many years before a definite diagnosis is made. As the rate of decline in lung function may be faster in the initial stages of the disease, early intervention could be beneficial to control symptoms and affect disease progression and outcomes. A systematic review of published literature relating to mild-to-moderate COPD (patients with FEV(1) ≥50% predicted) was performed to evaluate the level of impairment and natural history or disease progression over time, and impact of interventions on the outcomes of patients with early-stage disease. Of the 79 published articles included in this analysis, 31 reported randomized controlled trials; the remaining 48 articles reported studies of non-randomized and/or observational design. Nine of the randomized controlled trials were ≥6 months' duration, enabling assessment of outcomes over time. Most of the randomized controlled trials were in patients with moderate COPD (GOLD stage II); few included patients with the mildest stages of the disease (i.e., stage I). The results show that even patients with milder or moderate COPD can have substantial limitations and physical impairment, which worsen over time. Encouragement of smoking cessation, in conjunction with management of symptoms and treating activity limitation and exacerbations by appropriate non-pharmacologic and pharmacologic management at the earliest possible stage, could positively affect the impact and progression of the disease.

Tracheobronchial involvement as a sole manifestation of relapsing polychondritis.

STUDY OBJECTIVES: To report the clinical, imaging, and pathologic manifestations of case series of patients in whom the only systemic expression of relapsing polychondritis (RP) was their airway complications. DESIGN: Retrospective review of the medical records of all patients with respiratory complications of RP between 1995 and 2007. SETTING: Tertiary care, university-affiliated hospital. RESULTS: Three patients with RP had just lower airway manifestations as the only sign of their RP. All 3 were women, aged 44, 49, and 54 years. All had an abnormal chest computed tomography scan, although 2 had a completely normal chest x-ray. All had positive tracheal biopsy, which was consistent with the diagnosis of respiratory chondritis. Pulmonary function tests showed severe reduction in forced expiratory volume in 1 second in all patients. Bronchoscopy revealed tracheal narrowing with variable degrees of inflammation and collapsibility in all patients. Two of the 3 patients underwent tracheal and bronchial stent insertion. Pharmacotherapy included prednisone, methotrexate, cyclophosphamide, and leflunomide. The overall outcome was poor. Two patients died as a result of respiratory complications, 25 and 30 months from diagnoses, and 1 is still alive with follow-up of 85 months after presentation. CONCLUSIONS: Lower airway manifestations of RP can be the only sign of the disease. RP has to be considered in the differential diagnosis of patients with recent onset of progressive dyspnea and severe airflow limitation even without other systemic signs of cartilage damage.

Predictors of a more favourable response to combined therapy with salmeterol and fluticasone as initial maintenance therapy in asthma.

BACKGROUND: Orally inhaled corticosteroids represent the usually recommended initial controller therapy for most patients with persistent asthma. Some patients might benefit from earlier use of a combination of an inhaled corticosteroid and an orally inhaled long-acting beta agonist, however. We wished to identify clinical characteristics of patients which would enable one to identify a sub-group of patients who would benefit most from initiating sustained controller therapy with combination therapy. METHODS: We carried out a secondary analysis of five randomized clinical trials including 1606 subjects in order to examine whether differences in baseline characteristics of patients might predict a greater preferential response to combination therapy with salmeterol and fluticasone. RESULTS: Subjects whose asthma had been present for 10 or more years were 2.2 times more likely to achieve well-controlled asthma by 12 weeks on combination therapy, while subjects with a shorter duration of asthma were only 1.4 times as likely to achieve asthma control with combination therapy as opposed to inhaled corticosteroids alone. None of the other factors examined including symptom frequency or severity, rescue beta-agonist use, severity of lung function impairment or degree of reversibility, was able to distinguish subjects who would benefit preferentially from such combination therapy. CONCLUSIONS: Longer duration of asthma might be used to identify subjects who will benefit more from combined maintenance therapy with a long-acting beta agonist and an inhaled corticosteroid rather than an inhaled corticosteroid alone.

A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s (FEV(1)) than those patients who have stopped smoking. OBJECTIVES: To assess the effect of tiotropium on pre-dose (trough) FEV(1) in patients with COPD followed in Canada. METHODS: A total of 913 patients were randomly assigned to receive either tiotropium 18 mug once daily (n=608) or placebo (usual care minus inhaled anticholinergics) (n=305) for 48 weeks in the present randomized, double-blind, parallel-group study. The effect of tiotropium on measurements of lung function (FEV(1), FEV(6) and forced vital capacity), symptoms, health-related quality of life (St George's Respiratory Questionnaire) and exacerbations were examined. RESULTS: Tiotropium improved trough FEV(1) in both current and ex-smokers compared with placebo. Baseline FEV(1) in smokers and ex-smokers was 1.03 L and 0.93 L, respectively (P<0.001). At week 48, the mean difference between the tiotropium and placebo groups was 0.14+/-0.04 L (P<0.001) in the smoker group and 0.08+/-0.02 L (P<0.0001) in the ex-smoker group. Tiotropium also significantly improved trough forced vital capacity and FEV(6) compared with placebo throughout the treatment period (P<0.05, for all). Furthermore, tiotropium significantly improved the St George's Respiratory Questionnaire total score compared with placebo at week 48 (40.9 versus 43.7 units, P<0.005). CONCLUSIONS: Compared with the placebo group, tiotropium provides sustained improvements in lung function in patients with COPD, with improvements for smokers and ex-smokers.

Pneumonia severity index in the immunocompromised.

BACKGROUND: The pneumonia severity index (PSI) accounts for many comorbidities, but not immunosuppression. OBJECTIVES: To document the utility of the PSI to predict mortality in immunocompromised patients (IP) with community-acquired pneumonia (CAP). METHODS: Charts of 284 patients with immunosuppression and CAP were reviewed, and these patients were compared with a contemporary sample of non-IP with CAP. The ability of the PSI to predict mortality was assessed by using multiple logistic regression. Discrimination of the PSI was studied by using the concordance index. RESULTS: Thirty-nine of 284 IP died. Mortality varied according to the etiology of the immunosuppression. Patients with HIV, solid organ transplantation or treatment with immunosuppressive drugs (n=118) had a low in-hospital mortality (4.3%) and were classified as low risk. IP with hematological malignancies, chemotherapy, chest radiation or marrow transplantation (n=166) had a high mortality (20%) and were classified as high risk. Compared with non-IP, low-risk IP had similar PSI-controlled mortality (OR=0.9, P=0.80), whereas high-risk IP had significantly greater mortality (OR=2.8, P<0.0001). The concordance index revealed similar discrimination for the PSI in low-risk IP (0.77) and in non-IP (0.7), but inferior discrimination in high-risk patients (0.6). CONCLUSIONS: Patients with CAP and immunosuppression can be divided into low-risk and high-risk groups. The low-risk IP have mortality similar to non-IP and can be risk stratified by using the PSI.

Everolimus in pulmonary transplantation: pharmacokinetics and exposure-response relationships.

BACKGROUND: In this study we evaluated exposure, safety and efficacy data from an international trial of everolimus. We sought to identify a tolerated and efficacious range for blood levels of this agent in maintenance lung transplant recipients. METHODS: In a randomized, double-blind, multicenter trial, 213 maintenance lung transplant recipients received either everolimus 1.5 mg twice daily (n = 101) or azathioprine 1 to 3 mg/kg/day (n = 112) with cyclosporine and corticosteroids. At 15 visits over the first 2 years of the trial, we obtained 826 everolimus trough (C0) blood samples. We used median-effect analysis to assess relationships between everolimus C0 vs efficacy and safety responses. RESULTS: Everolimus administration began at 1.5 mg twice daily and was progressively lowered over the first 2 months to an average of 1.2 +/- 0.4 mg twice daily, which was maintained thereafter. This dose yielded median C0 levels of 6.6 ng/ml (10th to 90th percentiles: 2.8 to 11.8 ng/ml). Over this range of everolimus C0, freedom from a decline in pulmonary function with bronchiolitis obliterans syndrome and freedom from biopsy-proven acute rejection were both > or = 88%. The incidence of increased cholesterol (> 6.5 mmol/liter), increased triglycerides (> 2.9 mmol/liter) and transiently decreased platelet count (< 100 x 10(9)/liter) rose significantly with increasing C0. Infections and drug-related adverse events were not significantly related to exposure. CONCLUSIONS: A tolerated and efficacious concentration range for everolimus in maintenance lung transplantation appears to be 3 to 12 ng/ml when used in conjunction with cyclosporine and corticosteroids. This range should be prospectively assessed with possible refinement as more clinical experience is gained.

Pharmacodynamic target attainment analysis against Streptococcus pneumoniae using levofloxacin 500 mg, 750 mg and 1000 mg once daily in plasma (P) and epithelial lining fluid (ELF) of hospitalized patients with community acquired pneumonia (CAP).

The pharmacokinetics and pharmacodynamics of levofloxacin in patients with respiratory infections such as community-acquired pneumonia (CAP) are poorly documented. This work aimed at assessing the pharmacodynamic target attainment against Streptococcus pneumoniae using levofloxacin 500 mg, 750 mg and 1000 mg administered once daily in plasma (P) and epithelial lining fluid (ELF) of hospitalized patients with community acquired pneumonia. The pharmacokinetics of levofloxacin in elderly (>/=65 years) compared with younger patients (<65 years) hospitalized with CAP were simulated. Susceptibility data with S. pneumoniae from our ongoing national surveillance study (Canadian Respiratory Organism Susceptibility Study-CROSS) were then used to produce pharmacodynamic indices of AUC(0-24)/MIC(all.) Monte Carlo simulations were then used to analyse target attainment of levofloxacin using doses of 500 mg, 750 mg and 1000 mg once daily to achieve free drug AUC(0-24)/MIC(all) >/= 30-100 versus S. pneumoniae in patients with CAP. Pharmacokinetics of levofloxacin simulated after 500 mg, 750 mg and 1000 mg once daily dosing resulted in levofloxacin volume of distribution: elderly patients = younger patients, while levofloxacin clearance was: elderly patients < younger patients. Levofloxacin t(1/2) values were longer in elderly patients (9.8 +/- 2.5h) than younger patients with CAP (7.4 +/- 2.5h). Free levofloxacin AUC(0-24) as well as AUC(0-24)/MIC(all) for S. pneumoniae were higher in elderly patients than younger patients. Monte Carlo simulation using levofloxacin 500 mg yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 in P and ELF (95.7% and 98.1%) in elderly and younger patients (72.7% and 80.6%) respectively. Levofloxacin 750 mg and 1000 mg once daily had probability of achieving free-drug AUC(0-24)/MIC(all) of 30 in P/ELF of 98.1%/98.6% and 99.2%/99.0%, respectively, in elderly patients compared with 89.9%/94.1% and 95.2%/96.5%, respectively, for younger patients. Probability of achieving of AUC(0-24)/MIC(all) of 100 in P or ELF was very low in both patient populations at different doses except in the case of elderly patients receiving levofloxacin in a dose of 1000 mg once daily P/ELF of 78.5%/87.0%. We conclude that levofloxacin pharmacokinetics in elderly patients with CAP are markedly different from those of younger patients. Levofloxacin 750 mg OD provides high probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 in both plasma and epithelial lining fluid in patients with CAP including younger patients. Levofloxacin 500 mg OD provides high probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 in elderly patients with CAP, although we favour the 750 mg dosing in these patients as well. Levofloxacin 750 mg OD results in high probability of pharmacodynamic target attainment and improved bacteriological outcome against S. pneumoniae in patients with CAP.

Efficacy of exclusively oral antibiotic therapy in patients hospitalized with nonsevere community-acquired pneumonia: a retrospective study and meta-analysis.

PURPOSE: To assess the efficacy of oral antibiotics in patients hospitalized with community-acquired pneumonia and to identify factors precluding oral therapy. METHODS: In a meta-analysis, we compared inpatient oral and parenteral therapy in community-acquired pneumonia. Studies were reviewed independently and rated by two reviewers, and results were summarized. We also performed a retrospective cohort study of hospitalized patients with community-acquired pneumonia and compared outcomes in patients treated with oral versus parenteral therapy. RESULTS: For the meta-analysis, we identified seven studies involving 1366 patients. Study exclusions included severe pneumonia or impaired oral absorption. There was no significant difference in the relative risk of mortality at the end of treatment or at follow-up. Mean length of hospital stay was shorter (6.1 days vs. 7.8 days) in patients taking oral antibiotics than in those taking the parental form. In the retrospective cohort, 18% (124/698) of patients received oral-only therapy; these patients were younger (median age, 75 vs. 78 years, P = 0.01) and had lower mean pneumonia severity index scores (101 vs. 119, P <0.0001) than those who received parenteral therapy. In multivariable models, oral-only patients had a median length of stay that was 1.3 days shorter (95% CI: 0.4% to 2.2% days; P = 0.008) and a median antibiotic cost that was 56 dollars lower (95% CI: 53 dollars to 58 dollars; P <0.0001) than that of patients in the parenteral group, but mortality was similar. CONCLUSION: Although prospective data are limited, oral antibiotics in certain hospitalized patients with community-acquired pneumonia are effective. More data are needed to identify appropriate candidates for exclusively oral antibiotic therapy.

The pulmonary effects of long-term exposure to aerosol pentamidine: a 5-year surveillance study in HIV-infected patients.

STUDY OBJECTIVES: To assess the effects of long-term exposure to aerosolized pentamidine (AP) for the prophylaxis of Pneumocystis carinii pneumonia on the pulmonary function. DESIGN: The results of pulmonary function tests (PFTs) over a period of 5 years were retrospectively analyzed in a cohort of HIV-infected individuals. SETTING: A government-funded AP clinic in a large metropolitan center in Canada. PATIENTS: Among the cohort of 1,850 HIV-positive patients who received regular AP prophylaxis between 1989 and 2001 at the AP clinic, 83 received AP for >or= 5 years. Of these 83 patients, baseline and long-term follow-up PFT data were available for 79. These subjects formed the study population for this analysis. RESULTS: The cohort was divided according to smoking status (smokers, 48%). The rate of decline of FEV(1) in the smokers over the 5-year period was statistically significant but was comparable to that expected of healthy smokers. As for the nonsmokers, there was no significant reduction in FEV(1). Flow rates at low lung volumes (ie, forced expiratory flow at 50% and 75% of FEV(1)) and low FEV(1)/FVC ratios showed significant declines in both smokers and nonsmokers. On the other hand, no significant changes in FVC, total lung capacity, residual volume, or diffusing capacity of the lung for carbon monoxide were observed. The apparent slight reduction in flow rates seems to be at the level of the small airways. CONCLUSIONS: The PFT data suggest that AP can be well-tolerated over a 5-year period in HIV-infected patients with only modest reduction in flow rates at the level of the small airways, especially in smokers.

Obliterative bronchiolitis complicating bone marrow transplantation.

Respiratory complications of bone marrow transplantation comprise the majority of its morbidity and mortality. Obstructive airways disease is the most common noninfectious respiratory complication, usually indicative of obliterative bronchiolitis (OB), which occurs in 9% of allogeneic marrow transplant patients. OB is rarely seen after autologous transplant because chronic graft versus host disease (GVH), the most commonly identified risk factor, does not occur in this setting. Alloreactive immunity is likely the cause, with donor type 2 T-helper (TH2) lymphocytes the primary mediators. OB presents at 6 to 12 months post-transplant with cough and dyspnea. Results of investigations include relatively normal or hyperinflated chest radiographs; thickened, dilated airways; and mosaic attenuation on high-resolution computed tomography (HRCT), and fixed airflow obstruction, hyperinflation, and gas trapping on physiological testing. Bronchoscopy and lavage are performed primarily to exclude infections. Transbronchial biopsy is often nondiagnostic, but because the clinical diagnosis is generally sufficient, surgical biopsy is not usually recommended. Histology reveals lymphocytic bronchiolitis, concentric bronchiolar fibrosis, and bronchiolar obliteration. Corticosteroids remain the mainstay of treatment, which is usually required for 3 to 9 months. Response is generally poor, with mortality between 40 and 100%, and lung function infrequently improves. Stabilization with permanent respiratory impairment is common. Early detection and prompt immunosuppression may improve outcomes.