Nicolas Garin

β-Lactam Monotherapy vs β-Lactam-Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia A Randomized Noninferiority Trial

IMPORTANCE The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. OBJECTIVE To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONS Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. MAIN OUTCOMES AND MEASURES Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCE We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00818610.

Sensitivity and Predictive Value of 15 PubMed Search Strategies to Answer Clinical Questions Rated Against Full Systematic Reviews

Background Clinicians perform searches in PubMed daily, but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge. Little is known about the performance of search strategies when they are applied to answer specific clinical questions. Objective To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions. Methods We used Cochrane systematic reviews to identify relevant trials for 30 clinical questions. Search terms were extracted from the abstract using a predefined procedure based on the population, interventions, comparison, outcomes (PICO) framework and combined into queries. We tested 15 search strategies that varied in their query (PIC or PICO), use of PubMed’s Clinical Queries therapeutic filters (broad or narrow), search limits, and PubMed links to related articles. We assessed sensitivity (recall) and positive predictive value (precision) of each strategy on the first 2 PubMed pages (40 articles) and on the complete search output. Results The performance of the search strategies varied widely according to the clinical question. Unfiltered searches and those using the broad filter of Clinical Queries produced large outputs and retrieved few relevant articles within the first 2 pages, resulting in a median sensitivity of only 10%–25%. In contrast, all searches using the narrow filter performed significantly better, with a median sensitivity of about 50% (all P < .001 compared with unfiltered queries) and positive predictive values of 20%–30% (P < .001 compared with unfiltered queries). This benefit was consistent for most clinical questions. Searches based on related articles retrieved about a third of the relevant studies. Conclusions The Clinical Queries narrow filter, along with well-formulated queries based on the PICO framework, provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages. These results can help clinicians apply effective strategies to answer their questions at the point of care.

Adjunctive Corticotherapy for Community Acquired Pneumonia: A Systematic Review and Meta-Analysis

Background Community-acquired pneumonia (CAP) induces lung and systemic inflammation, leading to high morbidity and mortality. We systematically reviewed the risks and benefits of adjunctive corticotherapy in the management of patients with CAP. Methods We systematically searched Pubmed, Embase and the Cochrane Library for randomized controlled trials comparing adjunctive corticotherapy and antimicrobial therapy with antimicrobial therapy alone in patients with CAP. The primary outcome was 30-day mortality. Secondary outcomes were length of hospital stay, time to clinical stability and severe complications. Results 14 trials (2077 patients) were included. The reported 30-day mortality was 7.9% (80/1018) among patients treated with adjunctive corticotherapy versus 8.3% (85/1028) among patients treated with antimicrobial therapy alone (RR 0.84; 95%CI 0.55 to1.29). Adjunctive corticotherapy was associated with a reduction of severe complications (RR 0.36; 95%CI 0.23 to 0.56), a shorter length of stay (9.0 days; 95%CI 7.6 to 10.7 vs 10.6 days; 95%CI 7.4 to 15.3) and a shorter time to clinical stability (3.3 days; 95% CI 2.8 to 4.1 vs 4.3 days; 95%CI 3.6 to 5.1). The risk of hyperglycemia was higher among patients treated with adjunctive corticotherapy (RR 1.59; 95%CI 1.06 to 2.38), whereas the risk of gastro-intestinal bleeding was similar (RR 0.83; 95%CI 0.35 to 1.93). In the subgroup analysis based on CAP severity, a survival benefit was found among patients with severe CAP (RR 0.47; 95%CI 0.23 to 0.96). Conclusion Adjunctive corticotherapy is associated with a reduction of length of stay, time to clinical stability, and severe complications among patients with CAP, but the effect on mortality remains uncertain.

Acute Respiratory and Cardiovascular Admissions after a Public Smoking Ban in Geneva, Switzerland

Background Many countries have introduced legislations for public smoking bans to reduce the harmful effects of exposure to tobacco smoke. Smoking bans cause significant reductions in admissions for acute coronary syndromes but their impact on respiratory diseases is unclear. In Geneva, Switzerland, two popular votes led to a stepwise implementation of a state smoking ban in public places, with a temporary suspension. This study evaluated the effect of this smoking ban on hospitalisations for acute respiratory and cardiovascular diseases. Methods This before and after intervention study was conducted at the University Hospitals of Geneva, Switzerland, across 4 periods with different smoking legislations. It included 5,345 patients with a first hospitalisation for acute coronary syndrome, ischemic stroke, acute exacerbation of chronic obstructive pulmonary disease, pneumonia and acute asthma. The main outcomes were the incidence rate ratios (IRR) of admissions for each diagnosis after the final ban compared to the pre-ban period and adjusted for age, gender, season, influenza epidemic and secular trend. Results Hospitalisations for acute exacerbation of chronic obstructive pulmonary disease significantly decreased over the 4 periods and were lowest after the final ban (IRR = 0.54 [95%CI: 0.42–0.68]). We observed a trend in reduced admissions for acute coronary syndromes (IRR = 0.90 [95%CI: 0.80–1.00]). Admissions for ischemic stroke, asthma and pneumonia did not significantly change. Conclusions A legislative smoking ban was followed by a strong decrease in hospitalisations for acute exacerbation of chronic obstructive pulmonary disease and a trend for reduced admissions for acute coronary syndrome. Smoking bans are likely to be very beneficial for patients with chronic obstructive pulmonary disease.

Inclusion into a heart failure critical pathway reduces the risk of death or readmission after hospital discharge.

BACKGROUND Evidence-based therapies can lower the risk of death or hospital admission in heart failure (HF) patients, but are underprescribed. Critical pathways are one means of supporting systematic use of evidence-based recommendations. METHODS Patients admitted for HF in one hospital in 2009 and included in a critical pathway were compared with a control group of patients admitted in 2007. The primary endpoint was the risk of death or readmission within 90 days after discharge. The hazard ratio of death or readmission was evaluated in a multivariate Cox proportional hazard model adjusting for age, sex, co-morbidities, and length of stay. RESULTS Three hundred and sixty-three patients were evaluated (151 in the critical pathway and 212 in the control group). Adjusted hazard ratio for death or readmission at 90 days was 0.72 (95 CI 0.51-1.00, p=0.049). Adhesion to guidelines was significantly better for patients included in the critical pathway (p=0.004), with more frequent prescription of beta-blockers (70.9% (95% CI 62.9-78.0) vs. 56.6% (95% CI 49.6-63.4), p=0.006), and evaluation of left ventricular ejection fraction (LVEF, 73.5% (95% CI 65.7-80.3) vs. 57.5% (95% CI 50.6-64.3), p=0.002). Patients with reduced LVEF seem to have benefited the most from the inclusion in the critical pathway. CONCLUSIONS Implementation of a critical pathway for patients hospitalized for HF was associated with a 28% reduction of the relative risk of death or readmission and improved adhesion to guidelines.

Determining prognosis in acute exacerbation of COPD

Background Acute exacerbations are the leading causes of hospitalization and mortality in patients with COPD. Prognostic tools for patients with chronic COPD exist, but there are scarce data regarding acute exacerbations. We aimed to identify the prognostic factors of death and readmission after exacerbation of COPD. Methods This was a retrospective study conducted in the Department of Internal Medicine of Geneva University Hospitals. All patients admitted to the hospital with a diagnosis of exacerbation of COPD between 2008 and 2011 were included. The studied variables included comorbidities, Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity classification, and biological and clinical parameters. The main outcome was death or readmission during a 5-year follow-up. The secondary outcome was death. Survival analysis was performed (log-rank and Cox). Results We identified a total of 359 patients (195 men and 164 women, average age 72 years). During 5-year follow-up, 242 patients died or were hospitalized for the exacerbation of COPD. In multivariate analysis, age (hazard ratio [HR] 1.03, 95% CI 1.02–1.05; P<0.0001), severity of airflow obstruction (forced expiratory volume in 1 s <30%; HR 4.65, 95% CI 1.42–15.1; P=0.01), diabetes (HR 1.47, 95% CI 1.003–2.16; P=0.048), cancer (HR 2.79, 95% CI 1.68–4.64; P<0.0001), creatinine (HR 1.003, 95% CI 1.0004–1.006; P=0.02), and respiratory rate (HR 1.03, 95% CI 1.003–1.05; P=0.028) on admission were significantly associated with the primary outcome. Age, cancer, and procalcitonin were significantly associated with the secondary outcome. Conclusion COPD remains of ominous prognosis, especially after exacerbation requiring hospitalization. Baseline pulmonary function remains the strongest predictor of mortality and new admission. Demographic factors, such as age and comorbidities and notably diabetes and cancer, are closely associated with the outcome of the patient. Respiratory rate at admission appears to be the most prognostic clinical parameter. A prospective validation is, however, still required to enable the identification of patients at higher risk of death or readmission.

Prevalence and clinical characteristics of the DSM IV major depression among general internal medicine patients

OBJECTIVE The aim of this study was to investigate the prevalence and clinical characteristics of the DSM IV major depressive disorder (MDD) among patients admitted to the General Internal Medicine Service of the Geneva University Hospital. METHOD 557 patients admitted to the IM of the Geneva University Hospital aged 18 to 70 were investigated. Each subject was assessed by a clinical psychologist using the SCID (Structured Clinical Interview Depression for DSM-IV) questionnaire. RESULTS 69 patients (12.4%) met diagnostic criteria for MDD (men: 8.8%, women: 16.9%, p=.004). Among subjects with major depression, depressed mood (97%), fatigue (91%), and diminished interest and pleasure (81%) were the most prevalent symptoms. Recurrent thoughts of death were present in 48% of depressed patients. CONCLUSIONS This study raises further evidence that an elevated proportion of patients admitted to an acute care general internal medicine facility meet DSM IV criteria for MDD with nearly half of depressed patients suffering from recurrent thoughts of death. It emphasizes the necessity of a targeted, continuous, and active support given by the psychiatry liaison service in the internal medicine setting.

Predictors and Implications of Early Clinical Stability in Patients Hospitalized for Moderately Severe Community-Acquired Pneumonia

Background Assessment of early response to treatment is crucial for the management of community-acquired pneumonia (CAP). Objective To describe the predictors and the outcomes of early clinical stability Methods We did a secondary analysis of a multicentre randomized controlled trial on CAP treatment in which 580 patients hospitalized for moderately severe CAP were included. The association between demographic, clinical and biological variables available at inclusion and early clinical stability (stabilization of vital signs within 72 hours with predetermined cut-offs) was assessed by multivariate logistic regression. The association between early clinical stability and mortality, severe adverse events, and length of stay was also tested. Results Younger age (OR 0.98, 95% CI 0.96–0.99), lower platelet count (OR per 10 G/L increment 0.96, 95% CI 0.94–0.98), lower respiratory rate (OR 0.94, 95% CI 0.90–0.97), absence of hypoxemia (OR 0.58, 95% CI 0.40–0.85), lower numbers of co-morbid conditions (OR 0.82, 95% CI 0.69–0.98) and signs or symptoms (OR 0.78, 95% CI 0.68–0.90) were significantly associated with early clinical stability. Patients with early clinical stability had lower 90-days mortality (3.4% vs. 11.9%, p<0.001), fewer admissions to the intensive care unit (2.7% vs. 8.0%, p = 0.005) and a shorter length of stay (6.0 days, IQR 4.0–10.0 vs. 10.0 days, IQR 7.0–15.0, p<0.001). Conclusions Patients with younger age, less co-morbidity, fewer signs or symptoms, less respiratory compromise, and a lower platelet count are more likely to reach early clinical stability. Patients without early clinical stability have a worse prognosis and warrant close scrutiny.

Time to antibiotics administration and outcome in community-acquired pneumonia: Secondary analysis of a randomized controlled trial

BACKGROUND The association between early antibiotic administration and outcomes remains controversial in patients hospitalized for community-acquired pneumonia. METHODS We performed a secondary analysis of a randomized controlled trial comparing two antibiotic treatment strategies for patients hospitalized for moderately severe CAP. The univariate and multivariate associations between time to antibiotic administration (TTA) and time to clinical stability were assessed using a Cox proportional hazard model. Secondary outcomes were death, intensive care unit admission and hospital readmission up to 90days. RESULTS 371 patients (mean age 76years, CURB-65 score≥2 in 52%) were included. Mean TTA was 4.35h (SD 3.48), with 58.5% of patients receiving the first antibiotic dose within 4h. In multivariate analysis, number of symptoms and signs (HR 0.876, 95% CI 0.784-0.979, p=0.020), age (HR 0.986, 95% CI 0.975-0.996, p=0.007), initial heart rate (HR 0.992, 95% CI 0.986-0.999, p=0.023), and platelets count (HR 0.998, 95% CI 0.996-0.999, p=0.004) were associated with a reduced probability of reaching clinical stability. The association between TTA and time to clinical stability was not significant (HR 1.009, 95% CI 0.977-1.042, p=0.574). We found no association between TTA and the risk of intensive care unit admission, death or readmission up to 90days after the initial admission. CONCLUSION In patients hospitalized for moderately severe CAP, a shorter time to antibiotic administration was not associated with a favorable outcome. These findings support the current recommendations that do not assign a specific time frame for antibiotics administration.

Differential Association of Cx37 and Cx40 Genetic Variants in Atrial Fibrillation with and without Underlying Structural Heart Disease

Atrial fibrillation (AF) appears in the presence or absence of structural heart disease. The majority of foci causing AF are located near the ostia of pulmonary veins (PVs), where cardiomyocytes and vascular smooth muscle cells interdigitate. Connexins (Cx) form gap junction channels and participate in action potential propagation. Genetic variants in genes encoding Cx40 and Cx37 affect their expression or function and may contribute to PV arrhythmogenicity. DNA was obtained from 196 patients with drug-resistant, symptomatic AF with and without structural heart disease, who were referred for percutaneous catheter ablation. Eighty-nine controls were matched for age, gender, hypertension, and BMI. Genotyping of the Cx40 −44G > A, Cx40 +71A > G, Cx40 −26A > G, and Cx37 1019C > T polymorphisms was performed. The promoter A Cx40 polymorphisms (−44G > A and +71A > G) showed no association with non-structural or structural AF. Distribution of the Cx40 promoter B polymorphism (−26A > G) was different in structural AF when compared to controls (p = 0.03). There was no significant difference with non-structural AF (p = 0.50). The distribution of the Cx37 1019C > T polymorphism was different in non-structural AF (p = 0.03) but not in structural AF (p = 0.08) when compared to controls. Our study describes for the first time an association of drug-resistant non-structural heart disease AF with the Cx37 1019C > T gene polymorphism. We also confirmed the association of the Cx40 − 26G > A polymorphism in patients with AF and structural disease.