Eva Polverino

Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial.

IMPORTANCE In patients with severe community-acquired pneumonia, treatment failure is associated with excessive inflammatory response and worse outcomes. Corticosteroids may modulate cytokine release in these patients, but the benefit of this adjunctive therapy remains controversial. OBJECTIVE To assess the effect of corticosteroids in patients with severe community-acquired pneumonia and high associated inflammatory response. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial conducted in 3 Spanish teaching hospitals involving patients with both severe community-acquired pneumonia and a high inflammatory response, which was defined as a level of C-reactive protein greater than 150 mg/L at admission. Patients were recruited and followed up from June 2004 through February 2012. INTERVENTIONS Patients were randomized to receive either an intravenous bolus of 0.5 mg/kg per 12 hours of methylprednisolone (n = 61) or placebo (n = 59) for 5 days started within 36 hours of hospital admission. MAIN OUTCOMES AND MEASURES The primary outcome was treatment failure (composite outcome of early treatment failure defined as [1] clinical deterioration indicated by development of shock, [2] need for invasive mechanical ventilation not present at baseline, or [3] death within 72 hours of treatment; or composite outcome of late treatment failure defined as [1] radiographic progression, [2] persistence of severe respiratory failure, [3] development of shock, [4] need for invasive mechanical ventilation not present at baseline, or [5] death between 72 hours and 120 hours after treatment initiation; or both early and late treatment failure). In-hospital mortality was a secondary outcome and adverse events were assessed. RESULTS There was less treatment failure among patients from the methylprednisolone group (8 patients [13%]) compared with the placebo group (18 patients [31%]) (P = .02), with a difference between groups of 18% (95% CI, 3% to 32%). Corticosteroid treatment reduced the risk of treatment failure (odds ratio, 0.34 [95% CI, 0.14 to 0.87]; P = .02). In-hospital mortality did not differ between the 2 groups (6 patients [10%] in the methylprednisolone group vs 9 patients [15%] in the placebo group; P = .37); the difference between groups was 5% (95% CI, -6% to 17%). Hyperglycemia occurred in 11 patients (18%) in the methylprednisolone group and in 7 patients (12%) in the placebo group (P = .34). CONCLUSIONS AND RELEVANCE Among patients with severe community-acquired pneumonia and high initial inflammatory response, the acute use of methylprednisolone compared with placebo decreased treatment failure. If replicated, these findings would support the use of corticosteroids as adjunctive treatment in this clinical population. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00908713.

Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study

This phase II, randomised, double-blind, multicentre study (NCT00930982) investigated the safety and efficacy of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis. Adults who were culture positive for pre-defined potential respiratory pathogens (including Pseudomonas aeruginosa and Haemophilus influenzae) were randomised to ciprofloxacin DPI 32.5 mg or placebo administered twice daily for 28 days (with 56 days of follow-up). Bacterial density in sputum (primary end-point), pulmonary function tests, health-related quality of life and safety were monitored throughout the study. 60 subjects received ciprofloxacin DPI 32.5 mg and 64 received placebo. Subjects on ciprofloxacin DPI had a significant reduction (p<0.001) in total sputum bacterial load at the end of treatment (-3.62 log10 CFU·g−1 (range -9.78–5.02 log10 CFU·g−1)) compared with placebo (-0.27 log10 CFU·g−1 (range -7.96–5.25 log10 CFU·g−1)); the counts increased thereafter. In the ciprofloxacin DPI group, 14 (35%) out of 40 subjects reported pathogen eradication at end of treatment versus four (8%) out of 49 in the placebo group (p=0.001). No abnormal safety results were reported and rates of bronchospasm were low. Ciprofloxacin DPI 32.5 mg twice daily for 28 days was well tolerated and achieved significant reductions in total bacterial load compared with placebo in subjects with non-cystic fibrosis bronchiectasis.

Severe Community-Acquired Pneumonia: Validation of the Infectious Diseases Society of America/American Thoracic Society Guidelines to Predict an Intensive Care Unit Admission

BACKGROUND The recent Infectious Disease Society of America/American Thoracic Society guidelines for the management of community-acquired pneumonia (CAP) in adults defined a predictive rule to identify patients with severe CAP to determine the need for intensive care unit (ICU) admission. We clinically validated this rule. METHODS We analyzed 2102 episodes of CAP in consecutively hospitalized patients over a 7-year period. The predictive rule consists of at least 1 of 2 major severity criteria (septic shock and invasive mechanical ventilation) or at least 3 of 9 minor severity criteria. We assessed the association of the predictive rule with ICU admission and mortality. RESULTS A total of 235 episodes of CAP (11%) occurred in patients who were admitted to the ICU, whereas the predictive rule identified 397 (19%) of 2102 episodes as severe CAP. The predictive rule and the decision for ICU admission agreed in 1804 (86%) of the episodes (kappa coefficient, 0.45), with a sensitivity of 71% and a specificity of 88%, similar to the 2001 American Thoracic Society guidelines (sensitivity, 66%; specificity, 90%) in predicting ICU admission. Severe CAP criteria had higher sensitivity (58% vs. 46%) and similar specificity (88% vs. 90%), compared with the 2001 American Thoracic Society guidelines in predicting hospital mortality. Invasive mechanical ventilation was the main determinant for ICU admission, followed by septic shock. In the absence of major criteria, ICU admission was not related to survival of patients with minor severity criteria. CONCLUSIONS The predictive rule to identify severe CAP is accurate for ICU admission and improved the prediction of mortality, compared with the previous American Thoracic Society guidelines. The need for ICU admission derived from minor severity criteria alone is uncertain and deserves further investigation.

Nursing home-acquired pneumonia: a 10 year single-centre experience

Background Pneumonia among nursing home (NH) residents has increased considerably in recent years, but it remains unclear whether it should be considered as community-acquired pneumonia (CAP) or a new category of infection. Methods 150 consecutive cases of NH-acquired pneumonia (NHAP) (from 1 February 1997 to 1 July 2007) were analysed. Results Patients (median age, 82 years; range, 77–87 years) showed numerous co-morbidities, (neurological, 55%; pulmonary, 38%; cardiac, 35%) and severe disability for daily activities (partial, 32%; total, 31%). Cases of NHAP were mainly classified as mild to moderate according to the CRB-65 score (CRB-65 classes 0–1 and 2, 41% each). In-hospital and 30-day mortality were 8.7% and 20%, respectively. Aetiology was defined in 57 cases (38%). The most common isolates were Streptococcus pneumoniae (58%), Enterobacteriaceae (Gram-negative bacteria (GNB)) (9%), atypical bacteria (7%), respiratory viruses (5%), methicillin-resistant Staphylococcus aureus (MRSA) (5%) and Legionella pneumophila (5%). The most frequent causes of treatment inadequacy were use of β-lactams alone (25%) and lack of aspiration assessment (15%). Prognostic factors of 1-month mortality were neurological comorbidities (OR 4.5; 95% CI 1.3 to 15.7; p=0.020), septic shock (OR 6.6; 95% CI 1.3 to 34.0; p=0.025), pleural effusion (OR 3.6; 95% CI 1.1 to 11.7; p=0.036) and isolation of GNB or MRSA (OR 16.4; 95% CI 2.1 to 128.9; p=0.008). Conclusions The patients show clinical characteristics (eg, age and co-morbidities) comparable with those with hospital-acquired pneumonia. However, microbiological and mortality data of patients with NHAP are more similar to the data of those with CAP. Isolation of GNB or MRSA was associated with increased mortality risk. CAP empirical antibiotic coverage is still indicated in NHAP, although specific risk factors for multidrug-resistant infections should be assessed on an individual basis.

Etiology of Non–Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity

RATIONALE Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. OBJECTIVES The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. METHODS We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. MEASUREMENTS AND MAIN RESULTS Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patients management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. CONCLUSIONS Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease.

European Respiratory Society guidelines for the management of adult bronchiectasis

Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines. The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature. A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy. These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes. The publication of the first ERS guidelines for bronchiectasis http://ow.ly/wQSO30dU0nE

Impact of Age and Comorbidity on Cause and Outcome in Community-Acquired Pneumonia

BACKGROUND Prolonged life expectancy has currently increased the proportion of the very elderly among patients with community-acquired pneumonia (CAP). The aim of this study was to determine the influence of age and comorbidity on microbial patterns in patients over 65 years of age with CAP. METHODS This study was a prospective observational study of adult patients with CAP (excluding those in nursing homes) over a 12-year period. We compared patients aged 65 to 74 years, 75 to 84 years, and > 85 years for potential differences in clinical presentation, comorbidities, severity on admission, microbial investigations, causes, antimicrobial treatment, and outcomes. RESULTS We studied a total of 2,149 patients: 759 patients (35.3%) aged 65 to 74 years, 941 patients (43.7%) aged 75 to 84 years, and 449 patients (20.8%) aged > 85 years. At least one comorbidity was present in 1,710 patients (79.6%). Streptococcus pneumoniae was the most frequent pathogen in all age groups, regardless of comorbidity. Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa accounted for 9.1% of isolates, and Haemophilus influenzae, 6.4%. All these pathogens were isolated only in patients with at least one comorbidity. Mortality increased with age (65-74 years, 6.9%; 75-84 years, 8.9%; > 85 years, 17.1%; P < .001) and was associated with increased comorbidities (neurologic; OR, 2.1; 95% CI, 1.5-2.1), Pneumonia Severity Index IV or V (OR, 3.2; 95% CI, 1.8-6.0), bacteremia (OR, 1.7; 95% CI, 1.1-2.7), the presence of a potential multidrug-resistant (MDR) pathogen (S. aureus, P. aeruginosa, Enterobacteriaceae; OR, 2.4; 95% CI, 1.3-4.3), and ICU admission (OR, 4.2; 95% CI, 2.9-6.1) on multivariate analysis. CONCLUSIONS Age does not influence microbial cause itself, whereas comorbidities are associated with specific causes such as H. influenzae and potential MDR pathogens. Mortality in the elderly is mainly driven by the presence of comorbidities and potential MDR pathogens.

Research priorities in bronchiectasis: a consensus statement from the EMBARC Clinical Research Collaboration.

Bronchiectasis is a disease of renewed interest in light of an increase in prevalence and increasing burden on international healthcare systems. There are no licensed therapies, and large gaps in knowledge in terms of epidemiology, pathophysiology and therapy. The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) is a European Respiratory Society (ERS) Clinical Research Collaboration, funded by ERS to promote high-quality research in bronchiectasis. The objective of this consensus statement was to define research priorities in bronchiectasis. From 2014 to 2015, EMBARC used a modified Delphi process among European bronchiectasis experts to reach a consensus on 55 key research priorities in this field. During the same period, the European Lung Foundation collected 711 questionnaires from adult patients with bronchiectasis and their carers from 22 European countries reporting important research priorities from their perspective. This consensus statement reports recommendations for bronchiectasis research after integrating both physicians and patients priorities, as well as those uniquely identified by the two groups. Priorities identified in this consensus statement provide the clearest possible roadmap towards improving our understanding of the disease and the quality of care for patients with bronchiectasis. EMBARC consensus statement identifies research priorities in bronchiectasis as determined by physicians and patients http://ow.ly/lmcj300a2iS

Microbial aetiology of healthcare associated pneumonia in Spain: a prospective, multicentre, case-control study.

Introduction Healthcare-associated pneumonia (HCAP) is actually considered a subgroup of hospital-acquired pneumonia due to the reported high risk of multidrug-resistant pathogens in the USA. Therefore, current American Thoracic Society/Infectious Diseases Society of America guidelines suggest a nosocomial antibiotic treatment for HCAP. Unfortunately, the scientific evidence supporting this is contradictory. Methods We conducted a prospective multicentre case–control study in Spain, comparing clinical presentation, outcomes and microbial aetiology of HCAP and community-acquired pneumonia (CAP) patients matched by age (±10 years), gender and period of admission (±10 weeks). Results 476 patients (238 cases, 238 controls) were recruited for 2 years from June 2008. HCAP cases showed significantly more comorbidities (including dysphagia), higher frequency of previous antibiotic use in the preceding month, higher pneumonia severity score and worse clinical status (Charslon and Barthel scores). While microbial aetiology did not differ between the two groups (HCAP and CAP: Streptococcus pneumoniae: 51% vs 55%; viruses: 22% vs 12%; Legionella: 4% vs 9%; Gram-negative bacilli: 5% vs 4%; Pseudomonas aeruginosa: 4% vs 1%), HCAP patients showed worse mortality rates (1-month: HCAP, 12%; CAP 5%; 1-year: HCAP, 24%; CAP, 9%), length of hospital stay (9 vs 7 days), 1-month treatment failure (5.5% vs 1.5%) and readmission rate (18% vs 11%) (p<0.05, each). Conclusions Despite a similar clinical presentation, HCAP was more severe due to patients’ conditions (comorbidities) and showed worse clinical outcomes. Microbial aetiology of HCAP did not differ from CAP indicating that it is not related to increased mortality and in Spain most HCAP patients do not need nosocomial antibiotic coverage.

Cytokine activation patterns and biomarkers are influenced by microorganisms in community-acquired pneumonia.

Background The inflammatory response in community-acquired pneumonia (CAP) depends on the host and on the challenge of the causal microorganism. Here, we analyze the patterns of inflammatory cytokines, procalcitonin (PCT), and C-reactive protein (CRP) in order to determine their diagnostic value. Methods This was a prospective study of 658 patients admitted with CAP. PCT and CRP were analyzed by immunoluminometric and immunoturbidimetric assays. Cytokines (tumor necrosis factor-α [TNF-α], IL-1β, IL-6, IL-8, and IL-10) were measured using enzyme immunoassay. Results The lowest medians of CRP, PCT, TNF-α, and IL-6 were found in CAP of unknown cause, and the highest were found in patients with positive blood cultures. Different cytokine profiles and biomarkers were found depending on cause: atypical bacteria (lower PCT and IL-6), viruses (lower PCT and higher IL-10), Enterobacteriaceae (higher IL-8), Streptococcus pneumoniae (high PCT), and Legionella pneumophila (higher CRP and TNF-α). PCT ≥ 0.36 mg/dL to predict positive blood cultures showed sensitivity of 85%, specificity of 42%, and negative predictive value (NPV) of 98%, whereas a cutoff of ≤ 0.5 mg/dL to predict viruses or atypicals vs bacteria showed sensitivity of 89%/81%, specificity of 68%/68%, positive predictive value of 12%/22%, and NPV of 99%/97%. In a multivariate Euclidean distance model, the lowest inflammatory expression was found in unknown cause and the highest was found in L pneumophila, S pneumoniae, and Enterobacteriaceae. Atypical bacteria exhibit an inflammatory pattern closer to that of viruses. Conclusions Different inflammatory patterns elicited by different microorganisms may provide a useful tool for diagnosis. Recognizing these patterns provides additional information that may facilitate a broader understanding of host inflammatory response to microorganisms.