Do we know the minimal clinically important difference (MCID) for COPD exacerbations?

Frequent exacerbations of COPD are associated with accelerated loss of lung function, declining health status, increased mortality, and increased health care costs. Thus, a key objective in the management of COPD is preventing exacerbations or at least reducing their number and severity. When new interventions are examined, their value is sometimes assessed in reference to the minimal clinically important difference (MCID), a theoretical construct that may be defined and estimated numerically in several different ways. There have been limited attempts to calculate the MCID for COPD exacerbations but a figure of 20% reduction in exacerbation frequency is occasionally cited as the "established" MCID from a single manuscript reviewing six clinical trials. Our review suggests that defining and calculating the MCID for COPD exacerbations is problematic, not only because the methodology around developing endpoints for MCIDs is inconsistent, but because the impact of exacerbation reduction is likely to be influenced dramatically by the definitions of exacerbation severity used and the population's baseline status. Reference to current literature shows that at least one other estimate for exacerbation MCID as low as 4%. MCID is sometimes estimated by expert consensus; a review of articles used to shape COPD guidelines shows frequent reference to articles in which interventions yielded exacerbation differences as low as 11%. We find no evidence of an established MCID but suggest that interventions reducing exacerbations by as little as 11% appear to be regarded widely as clinically important.

Levofloxacin 750 mg QD for five days versus amoxicillin/clavulanate 875 mg/125 mg BID for ten days for treatment of acute bacterial exacerbation of chronic bronchitis: a post hoc analysis of data from severely ill patients.

This post hoc analysis of data from a previous randomized, blinded, multicenter, parallel, noninferiority study assessed the bacterial etiology, symptom resolution, and tolerability of severe acute bacterial exacerbation of chronic bronchitis (ABECB) patients treated with either levofloxacin 750 mg QD for 5 days or amoxicillin/clavulanate 875 mg/125 mg BID for 10 days. Severe ABECB was defined as ABECB and forced expiratory volume in 1 second (FEV(1)) <50% of the predicted value, or (FEV(1)) of 50% to 65% of the predicted value plus comorbidities, or > or =4 exacerbations per year. A total of 369 patients were included in the intent-to-treat (ITT) population (187 treated with levofloxacin and 182 treated with amoxicillin/clavulanate), and 175 patients were microbiologically assessable (MA) (86 treated with levofloxacin and 89 treated with amoxicillin/clavulanate). In the ITT population, the mean age was 58.7 years, 49.1 % were male, and 48.2% were current smokers. At the on-treatment visit, a significantly higher proportion of MA patients in the levofloxacin group resolved purulent sputum production (57.5% vs 35.6%; P < 0.006), sputum production (65.4% vs 45.3%; P < 0.013), and cough (60.0% vs 44.0%; P < 0.045), compared with the amoxicillin/clavulanate group. However, no significant between-group differences were observed at posttreatment. A total of 341 pathogens were isolated, of which 143 (41.9%) were traditional ABECB flora, 181 (53.1%) were other gram-negative organisms, and 17 (5.0%) were gram-positive organisms. Overall susceptibility of the pathogens was 97.1% for levofloxacin and 90.6% for amoxicillin/clavulanate (P < 0.001). The prevalence of treatment-emergent adverse events was 42.1 % in patients who received levofloxacin and 48.6 % in those who received amoxicillin/clavulanate (95% CI,-4.0 to 17.0).

Rare Presentation of Pulmonary Alveolar Proteinosis Causing Acute Respiratory Failure.

Pulmonary alveolar proteinosis (PAP) is a rare condition characterized by dysfunctional alveolar macrophages, which ineffectively clear surfactant and typically cause mild hypoxemia. Characteristic Computed Tomography findings are septal reticulations superimposed on ground-glass opacities in a crazy paving pattern, with a clear juxtaposition between affected and unaffected parenchyma. While traditionally PAP was diagnosed via biopsy, bronchoalveolar lavage (BAL) is usually sufficient; the fluid appears milky, and on microscopic examination there are foamy macrophages with eosinophilic granules and extracellular hyaline material that is Periodic Acid-Schiff positive. Standard therapy is whole lung lavage (WLL), although novel treatments are under development. The case presented is a 55-year-old woman with six months of progressive dyspnea, who developed hypoxemic respiratory failure requiring mechanical ventilation; she had typical findings of PAP on imaging and BAL. WLL was ultimately successful in restoring adequate oxygenation. Respiratory failure of this magnitude is a rare finding in PAP.

Antimicrobial treatment of lower respiratory tract infections in the hospital setting.

Respiratory tract infections (RTIs) that may require hospitalization include acute exacerbations of chronic bronchitis (AECB), community-acquired pneumonia (CAP), and hospital-acquired pneumonia (HAP), which includes ventilator-associated pneumonia (VAP). Healthcare-associated pneumonia (HCAP) is treated similar to HAP and may be considered with HAP. For CAP requiring hospitalization, the current guidelines for the treatments of RTIs generally recommend either a beta-lactam and macrolide combination or a fluoroquinolone. The respiratory fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin) are excellent antibiotics due to high levels of susceptibility among gram-negative, gram-positive, and atypical pathogens. The fluoroquinolones are active against > 98% of Streptococcus pneumoniae, including penicillin-resistant strains. Fluoroquinolones are also recommended for AECB requiring hospitalization. Evidence from clinical trials suggests that levofloxacin monotherapy is as efficacious as combination ceftriaxone-erythromycin therapy in the treatment of patients hospitalized with CAP. For early-onset HAP, VAP, and HCAP without the risk of multidrug resistance, ceftriaxone, ampicillin-sulbactam, ertapenem, or one of the fluoroquinolones is recommended. High-dose, short-course therapy regimens may offer improved treatment due to higher drug concentrations, more rapid killing, increased adherence, and the potential to reduce development of resistance. Recent studies have shown that short-course therapy with levofloxacin, azithromycin, or telithromycin in patients with CAP was effective, safe, and tolerable and may control the rate of resistance.

Development of an economic model to assess the cost effectiveness of treatment interventions for chronic obstructive pulmonary disease.

OBJECTIVE: To develop a Markov model that allows the cost effectiveness of interventions in patients with chronic obstructive pulmonary disease (COPD) to be estimated, and to apply the model to investigate the cost effectiveness of an inhaled corticosteroid/long-acting beta(2)-adrenoceptor agonist (beta(2)-agonist) combination (salmeterol/fluticasone propionate) versus usual care. METHODS: A Markov model consisting of four mutually exclusive disease states was constructed (mild, moderate and severe disease, and death). The transition probabilities of disease progression (for smokers and ex-smokers) and death were derived from the published medical literature. The model outputs were costs, exacerbations, survival, QALYs and cost effectiveness. The model was made fully probabilistic to reflect the joint uncertainty in the model parameters. Efficacy data for the combination of inhaled salmeterol/fluticasone propionate 50/500microg twice daily in poorly reversible COPD patients with a history of exacerbations were obtained from the 1-year TRISTAN (TRial of Inhaled STeroids ANd long-acting beta-agonists) study and applied to the model, based on patient profiles representative of COPD clinical trials. RESULTS: According to the model, the mean life expectancy with usual care alone (placebo group) was 8.95 years, which decreased to 4.08 QALYs once adjusted for quality and discounted, at a lifetime discounted cost of Can 16,415 dollars per patient (year 2002 values). Assuming that salmeterol/fluticasone propionate reduced exacerbation frequency only (base case analysis), the estimated mean survival time remained unchanged but there was an increase in the number of QALYs (4.21) for an estimated lifetime cost of Can 25,780 dollars, resulting in a cost-effectiveness ratio of Can 74,887 dollars per QALY (95% CI 21,985, 128,671) versus usual care. If a survival benefit was assumed for salmeterol/fluticasone propionate, the incremental cost per QALY was Can11,125 dollars (95% CI 8710, dominated) versus usual care. If the combination achieved around a 10% improvement in forced expiratory volume in 1 second, leading to delayed progression to more severe disease states, the benefits translated into an incremental cost per QALY of Can 49,928 dollars (95% CI 37 269, 66,006) versus usual care. CONCLUSIONS: This Markov model allows, for the first time, a means of estimating the long-term cost effectiveness and cost utility of interventions for COPD. Initial evidence suggests that for patients with poorly reversible COPD and a documented history of frequent COPD exacerbations, the addition of salmeterol (a long-acting beta(2)-agonist) to fluticasone propionate (an inhaled corticosteroid) is potentially cost effective from the Canadian healthcare payer's perspective. However, the precision of this estimate will be improved when additional data are available from clinical trials such as the ongoing TORCH (TOwards a Revolution in COPD Health) study.

Canadian guidelines for the management of acute exacerbations of chronic bronchitis.

Acute exacerbations of chronic bronchitis (AECB) account for over 1.5 million physician visits annually in Canada and are a cause of significant morbidity and mortality. This document represents a joint effort between respirologists, microbiologists, infectious disease specialists and family physicians to update the Canadian AECB guidelines published in 1994. Treatment recommendations are graded on the strength of evidence in the published literature where possible. The role for oral corticosteroid therapy in preventing treatment failures, speeding up recovery and delaying the time to next exacerbation is discussed. Risk factors for treatment failure were used to stratify patients into risk groups to help guide antibiotic treatment recommendations. The importance of emerging antimicrobial resistance to current antibiotics is reviewed and strategies to prevent future AECB episodes are suggested.

Community-acquired pneumonia and tuberculosis: differential diagnosis and the use of fluoroquinolones.

The respiratory fluoroquinolones moxifloxacin, gemifloxacin, and high-dose levofloxacin are recommended in guidelines for effective empirical antimicrobial therapy of community-acquired pneumonia (CAP). The use of these antibiotics for this indication in areas with a high prevalence of tuberculosis (TB) has been questioned due to the perception that they contribute both to delays in the diagnosis of pulmonary TB and to the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis. In this review, we consider some of the important questions regarding the potential use of fluoroquinolones for the treatment of CAP where the burden of TB is high. The evidence suggests that the use of fluoroquinolones as recommended for 5-10 days as empirical treatment for CAP, according to current clinical management guidelines, is appropriate even in TB-endemic regions. It is critical to quickly exclude M. tuberculosis as a cause of CAP using the most rapid relevant diagnostic investigations in the management of all patients with CAP.

Pulmonary blastomycosis in a professional diver: an occupational risk.

In certain parts of the United States and Canada, and northern Ontario in particular, the dimorphic fungus Blastomyces dermatitidis is endemic and can cause infection in exposed individuals. The site of infection is usually pulmonary, causing respiratory and constitutional symptoms, but can also affect other sites in the body. Symptom severity can vary substantially from no symptoms to fatal acute respiratory distress syndrome. The present report describes a 27-year-old professional diver who had recently worked in northern Ontario, who developed symptoms of pneumonia and exhibited atypical findings on chest imaging. He was diagnosed with blastomycosis based on histopathological findings and fungal culture, and was treated with amphotericin B and itraconazole in accordance with treatment guidelines. While outdoor occupations in endemic areas increase the risk of infection, there is no literature specifically identifying professional diving as an occupational risk for blastomycosis.

Short-course fluoroquinolones in acute exacerbations of chronic bronchitis.

It is estimated that 50-70% of acute exacerbations of chronic bronchitis (AECB) are caused by bacterial infections. Appropriate selection of antimicrobials may lead to better outcomes and reduced healthcare costs. Respiratory fluoroquinolones (moxifloxacin, levofloxacin and gemifloxacin) have a broad spectrum of activity against most AECB-causing pathogens and are used as first-line treatment in patients with comorbidity, severe airway obstruction or recurrent exacerbations. We review studies, identified through a MEDLINE search, that compared clinical efficacy and speed of recovery for short-course (≤ 5 days) fluoroquinolone therapy with commonly prescribed standard therapy (≥ 7 days). Among 177 studies reporting the use of fluoroquinolones for AECB treatment, 23 used a short-course regimen, shown to be at least as effective as standard therapy of 7 or more days duration. Furthermore, evidence suggests that short-course therapy offers faster resolution of symptoms, faster rate of recovery, fewer relapses, fewer and shorter hospitalizations, and longer time between recurrences.

Clinical Aspects of Upper and Lower Respiratory Tract Infections.

Respiratory tract infections are among the most common illnesses leading to medical consultation, and are associated with significant mortality. Community-acquired pneumonia is a common illness and, while Streptococcus pneumoniae continues to be the most frequent causative agent, atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella species are now identified as additional common aetiological agents. Since clinical and roentgenographic features poorly predict the aetiological agent in most cases of community-acquired pneumonia, empirical therapy is generally recommended. Nosocomial pneumonia is the second most common hospital-acquired infection and is associated with significant mortality. Aerobic Gram-negative bacilli and Staphylococcus aureus are the predominant causative pathogens. New techniques to improve the diagnosis of nosocomial pneumonia have been introduced, but their role has not been entirely clarified. Therapy directed toward the most likely pathogens (aerobic Gram-negative species and S. aureus) on an empirical basis is recommended until more specific information is obtained. Acute exacerbations of chronic bronchitis should be treated with antimicrobial therapy directed toward S. pneumoniae, Haemophilus influenzae or Moraxella catarrhalis. Because of the emergence of ß-lactamase-producing strains of H. influenzae and M. catarrhalis, the choice of an antimicrobial agent has to be carefully considered. Group A ß-haemolytic streptococci are the most common cause of bacterial pharyngitis and penicillin remains the drug of choice. Patients suffering from otitis media and sinusitis are infected with the same organisms as those patients with acute exacerbations of chronic bronchitis and antibacterial choices are therefore similar.

The Role of Quinolones in Upper Respiratory Tract Infections.

Fluoroquinolones are widely used in clinical practice because of their advanced pharmacokinetic properties, potential activity against most bacterial species, excellent clinical responses, and few side effects. Quinolones have no role in the treatment of pharyngitis or simple otitis media. Until recently, the available fluoroquinolones were not indicated for the treatment of acute purulent sinusitis because of their perceived inactivity against Streptococcus pneumoniae. Although not generally considered to be drugs of first choice, older quinolones have efficacy similar to that of cephalosporins and b-lactams in randomized clinical trials. Well-conducted clinical trials have shown that the new fluoroquinolones are as effective as standard comparators in patients with suspected or proven acute bacterial sinusitis and may allow shorter treatment. Ciprofloxacin remains the fluoroquinolone of choice for chronic otitis media and malignant otitis media. The new "respiratory" fluoroquinolones have microbiologic and pharmacokinetic advantages over the older agents. Clinical trials have confirmed clinical activity, but superiority compared with older agents has not been conclusively shown. Trials devised to demonstrate clinical or pharmacoeconomic benefits are still required.