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2.  Detection of Pneumonia Associated Pathogens Using a Prototype Multiplexed Pneumonia Test in Hospitalized Patients with Severe Pneumonia 
PLoS ONE  2014;9(11):e110566.
Severe pneumonia remains an important cause of morbidity and mortality. Polymerase chain reaction (PCR) has been shown to be more sensitive than current standard microbiological methods – particularly in patients with prior antibiotic treatment – and therefore, may improve the accuracy of microbiological diagnosis for hospitalized patients with pneumonia. Conventional detection techniques and multiplex PCR for 14 typical bacterial pneumonia-associated pathogens were performed on respiratory samples collected from adult hospitalized patients enrolled in a prospective multi-center study. Patients were enrolled from March until September 2012. A total of 739 fresh, native samples were eligible for analysis, of which 75 were sputa, 421 aspirates, and 234 bronchial lavages. 276 pathogens were detected by microbiology for which a valid PCR result was generated (positive or negative detection result by Curetis prototype system). Among these, 120 were identified by the prototype assay, 50 pathogens were not detected. Overall performance of the prototype for pathogen identification was 70.6% sensitivity (95% confidence interval (CI) lower bound: 63.3%, upper bound: 76.9%) and 95.2% specificity (95% CI lower bound: 94.6%, upper bound: 95.7%). Based on the study results, device cut-off settings were adjusted for future series production. The overall performance with the settings of the CE series production devices was 78.7% sensitivity (95% CI lower bound: 72.1%) and 96.6% specificity (95% CI lower bound: 96.1%). Time to result was 5.2 hours (median) for the prototype test and 43.5 h for standard-of-care. The Pneumonia Application provides a rapid and moderately sensitive assay for the detection of pneumonia-causing pathogens with minimal hands-on time.
Trial Registration
Deutsches Register Klinischer Studien (DRKS) DRKS00005684
doi:10.1371/journal.pone.0110566
PMCID: PMC4232251  PMID: 25397673
3.  Inflammatory response in mixed viral-bacterial community-acquired pneumonia 
BMC Pulmonary Medicine  2014;14:123.
Background
The role of mixed pneumonia (virus + bacteria) in community-acquired pneumonia (CAP) has been described in recent years. However, it is not known whether the systemic inflammatory profile is different compared to monomicrobial CAP. We wanted to investigate this profile of mixed viral-bacterial infection and to compare it to monomicrobial bacterial or viral CAP.
Methods
We measured baseline serum procalcitonin (PCT), C reactive protein (CRP), and white blood cell (WBC) count in 171 patients with CAP with definite etiology admitted to a tertiary hospital: 59 (34.5%) bacterial, 66 (39.%) viral and 46 (27%) mixed (viral-bacterial).
Results
Serum PCT levels were higher in mixed and bacterial CAP compared to viral CAP. CRP levels were higher in mixed CAP compared to the other groups. CRP was independently associated with mixed CAP. CRP levels below 26 mg/dL were indicative of an etiology other than mixed in 83% of cases, but the positive predictive value was 45%. PCT levels over 2.10 ng/mL had a positive predictive value for bacterial-involved CAP versus viral CAP of 78%, but the negative predictive value was 48%.
Conclusions
Mixed CAP has a different inflammatory pattern compared to bacterial or viral CAP. High CRP levels may be useful for clinicians to suspect mixed CAP.
doi:10.1186/1471-2466-14-123
PMCID: PMC4118651  PMID: 25073709
Community-acquired pneumonia; Viral pneumonia; Biomarkers
4.  Predicting treatment failure in patients with community acquired pneumonia: a case-control study 
Respiratory Research  2014;15(1):75.
Introduction
Treatment failure in community-acquired-pneumonia (CAP) patients is associated with a high mortality rate, and therefore are a matter of great concern in clinical management. Those patients have increased mortality and are a target population for randomized clinical trials.
Methods
A case–control study was performed in patients with CAP (non-failure cases vs. failure cases, discriminating by late and early failure). CRP, PCT, interleukin 1, 6, 8 and 10 and TNF were determined at days 1 and 3 of hospitalization.
Results
A total of 253 patients were included in this study where 83 patients presented treatment failure. Of these, 40 (48.2%) had early failure. A discriminative effect was found for a higher CURB-65 score among late failure patients (p = 0.004). A significant increase on day 1 of hospitalization in CRP (p < 0.001), PCT (p = 0.004), IL-6 (p < 0.001) and IL-8 (p = 0.02), and a decrease in IL-1 (p = 0.06) in patients with failure was observed compared with patients without failure. On day 3, only the increase in CRP (p < 0.001), PCT (p = 0.007) and IL-6 (p < 0.001) remained significant. Independent predictors for early failure were higher IL-6 levels on day 1 (OR = 1.78, IC = 1.2-2.6) and pleural effusion (OR = 2.25, IC = 1.0-5.3), and for late failure, higher PCT levels on day 3 (OR = 1.60, IC = 1.0-2.5), CURB-65 score ≥ 3 (OR = 1.43, IC = 1.0-2.0), and multilobar involvement (OR = 4.50, IC = 2.1-9.9).
Conclusions
There was a good correlation of IL-6 levels and CAP failure and IL-6 & PCT with late CAP failure. Pleural effusion and multilobar involvement were simple clinical predictors of early and late failure, respectively.
Trial registration
IRB Register: http://2009/5451.
doi:10.1186/1465-9921-15-75
PMCID: PMC4099489  PMID: 24996572
Treatment failure; Cytokines; Pneumonia; Community acquired pneumonia
6.  Passive smoking at home is a risk factor for community-acquired pneumonia in older adults: a population-based case–control study 
BMJ Open  2014;4(6):e005133.
Objective
To assess whether passive smoking exposure at home is a risk factor for community-acquired pneumonia (CAP) in adults.
Setting
A population-based case-control study was designed in a Mediterranean area with 860 000 inhabitants >14 years of age.
Participants
1003 participants who had never smoked were recruited.
Primary and secondary outcome measures
Risk factors for CAP, including home exposure to passive smoking, were registered. All new cases of CAP in a well-defined population were consecutively recruited during a 12-month period.
Methods
A population-based case-control study was designed to assess risk factors for CAP, including home exposure to passive smoking. All new cases of CAP in a well-defined population were consecutively recruited during a 12-month period. The subgroup of never smokers was selected for the present analysis.
Results
The study sample included 471 patients with CAP and 532 controls who had never smoked. The annual incidence of CAP was estimated to be 1.14 cases×10–3 inhabitants in passive smokers and 0.90×10−3 in non-passive smokers (risk ratio (RR) 1.26; 95% CI 1.02 to 1.55) in the whole sample. In participants ≥65 years of age, this incidence was 2.50×10−3 in passive smokers and 1.69×10−3 in non-passive smokers (RR 1.48, 95% CI 1.08 to 2.03). In this last age group, the percentage of passive smokers in cases and controls was 26% and 18.1%, respectively (p=0.039), with a crude OR of 1.59 (95% CI 1.02 to 2.38) and an adjusted (by age and sex) OR of 1.56 (95% CI 1.00 to 2.45).
Conclusions
Passive smoking at home is a risk factor for CAP in older adults (65 years or more).
doi:10.1136/bmjopen-2014-005133
PMCID: PMC4067857  PMID: 24928592
EPIDEMIOLOGY
7.  Phenotyping community-acquired pneumonia according to the presence of acute respiratory failure and severe sepsis 
Respiratory Research  2014;15(1):27.
Background
Acute respiratory failure (ARF) and severe sepsis (SS) are possible complications in patients with community-acquired pneumonia (CAP). The aim of the study was to evaluate prevalence, characteristics, risk factors and impact on mortality of hospitalized patients with CAP according to the presence of ARF and SS on admission.
Methods
This was a multicenter, observational, prospective study of consecutive CAP patients admitted to three hospitals in Italy, Spain, and Scotland between 2008 and 2010. Three groups of patients were identified: those with neither ARF nor SS (Group A), those with only ARF (Group B) and those with both ARF and SS (Group C) on admission.
Results
Among the 2,145 patients enrolled, 45% belonged to Group A, 36% to Group B and 20% to Group C. Patients in Group C were more severe than patients in Group B. Isolated ARF was correlated with age (p < 0.001), COPD (p < 0.001) and multilobar infiltrates (p < 0.001). The contemporary occurrence of ARF and SS was associated with age (p = 0.002), residency in nursing home (p = 0.007), COPD (p < 0.001), multilobar involvement (p < 0.001) and renal disease (p < 0.001). 4.2% of patients in Group A died, 9.3% in Group B and 26% in Group C, p < 0.001. After adjustment, the presence of only ARF had an OR for in-hospital mortality of 1.85 (p = 0.011) and the presence of both ARF and SS had an OR of 6.32 (p < 0.001).
Conclusions
The identification of ARF and SS on hospital admission can help physicians in classifying CAP patients into three different clinical phenotypes.
doi:10.1186/1465-9921-15-27
PMCID: PMC4015148  PMID: 24593040
Pneumonia; Sepsis; Severe sepsis; Acute respiratory failure; ARDS; CAP; Community-acquired pneumonia; Mortality; Oxygenation
8.  Importance of Aspergillus spp. isolation in Acute exacerbations of severe COPD: prevalence, factors and follow-up: the FUNGI-COPD study 
Respiratory Research  2014;15(1):17.
Background
Acute exacerbations of COPD (AECOPD) are often associated with infectious agents, some of which may be non-usual, including Aspergillus spp. However, the importance of Aspergillus spp. in the clinical management of AECOPD still remains unclear.
Objectives
The aims of the study were to analyze the prevalence and risk factors associated with Aspergillus spp. isolation in AECOPD, and to investigate the associated clinical outcomes during a 1-year follow-up period.
Methods
Patients presenting with an AECOPD requiring hospitalization were prospectively included from four hospitals across Spain. Clinical, radiological and microbiological data were collected at admission and during the follow-up period (1, 6 and 12 months after discharge), and re-admissions and mortality data collected during the follow-up.
Results
A total of 240 patients with severe AECOPD were included. Valid sputum samples were obtained in 144 (58%) patients, and in this group, the prevalence of Aspergillus spp. isolation was 16.6% on admission and 14.1% at one-year follow-up. Multivariate logistic-regression showed that AECOPD in the previous year (OR 12.35; 95% CI, 1.9-29.1; p < 0.001), concurrent isolation of pathogenic bacteria (OR 3.64; 95% CI 1.65-9.45, p = 0.001) and concomitant isolation of Pseudomonas aeruginosa (OR 2.80; 95% IC, 1.81-11.42; p = 0.001) were the main risk factors for Aspergillus spp. isolation.
Conclusions
The main risk factors for Aspergillus spp. isolation were AECOPD in the previous year and concomitant isolation of Pseudomonas aeruginosa. However, although Aspergillus spp. is often isolated in sputum samples from patients with AECOPD, the pathogenic and clinical significance remains unclear.
doi:10.1186/1465-9921-15-17
PMCID: PMC3996133  PMID: 24517318
9.  A week seems to be weak: tailoring duration of antibiotic treatment in Gram-negative ventilator-associated pneumonia 
Critical Care  2013;17(1):106.
The optimal length of antimicrobial therapy has not been extensively studied for a great majority of infections and, in critically ill patients affected by ventilator-associated pneumonia, is a persisting and unsolved issue confronting clinicians. The integration of biomarkers, clinical judgment, and microbiologic eradication might help to define a shorter duration for some ventilator-associated pneumonia episodes due to non-fermenting Gram-negative bacilli, but until these strategies are implemented in clinical practice for individualizing antibiotic treatment, a short-course duration does not seem to tailor a long benefit.
doi:10.1186/cc11899
PMCID: PMC4057223  PMID: 23336300
11.  Effects of internet-based training on antibiotic prescribing rates for acute respiratory-tract infections: a multinational, cluster, randomised, factorial, controlled trial 
Lancet  2013;382(9899):1175-1182.
Summary
Background
High-volume prescribing of antibiotics in primary care is a major driver of antibiotic resistance. Education of physicians and patients can lower prescribing levels, but it frequently relies on highly trained staff. We assessed whether internet-based training methods could alter prescribing practices in multiple health-care systems.
Methods
After a baseline audit in October to December, 2010, primary-care practices in six European countries were cluster randomised to usual care, training in the use of a C-reactive protein (CRP) test at point of care, in enhanced communication skills, or in both CRP and enhanced communication. Patients were recruited from February to May, 2011. This trial is registered, number ISRCTN99871214.
Results
The baseline audit, done in 259 practices, provided data for 6771 patients with lower-respiratory-tract infections (3742 [55·3%]) and upper-respiratory-tract infections (1416 [20·9%]), of whom 5355 (79·1%) were prescribed antibiotics. After randomisation, 246 practices were included and 4264 patients were recruited. The antibiotic prescribing rate was lower with CRP training than without (33% vs 48%, adjusted risk ratio 0·54, 95% CI 0·42–0·69) and with enhanced-communication training than without (36% vs 45%, 0·69, 0·54–0·87). The combined intervention was associated with the greatest reduction in prescribing rate (CRP risk ratio 0·53, 95% CI 0·36–0·74, p<0·0001; enhanced communication 0·68, 0·50–0·89, p=0·003; combined 0·38, 0·25–0·55, p<0·0001).
Interpretation
Internet training achieved important reductions in antibiotic prescribing for respiratory-tract infections across language and cultural boundaries.
Funding
European Commission Framework Programme 6, National Institute for Health Research, Research Foundation Flanders.
doi:10.1016/S0140-6736(13)60994-0
PMCID: PMC3807804  PMID: 23915885
12.  Relationship between the Use of Inhaled Steroids for Chronic Respiratory Diseases and Early Outcomes in Community-Acquired Pneumonia 
PLoS ONE  2013;8(9):e73271.
Background
The role of inhaled steroids in patients with chronic respiratory diseases is a matter of debate due to the potential effect on the development and prognosis of community-acquired pneumonia (CAP). We assessed whether treatment with inhaled steroids in patients with chronic bronchitis, COPD or asthma and CAP may affect early outcome of the acute pneumonic episode.
Methods
Over 1-year period, all population-based cases of CAP in patients with chronic bronchitis, COPD or asthma were registered. Use of inhaled steroids were registered and patients were followed up to 30 days after diagnosis to assess severity of CAP and clinical course (hospital admission, ICU admission and mortality).
Results
Of 473 patients who fulfilled the selection criteria, inhaled steroids were regularly used by 109 (23%). In the overall sample, inhaled steroids were associated with a higher risk of hospitalization (OR=1.96, p = 0.002) in the bivariate analysis, but this effect disappeared after adjusting by other severity-related factors (adjusted OR=1.08, p=0.787). This effect on hospitalization also disappeared when considering only patients with asthma (OR=1.38, p=0.542), with COPD alone (OR=4.68, p=0.194), but a protective effect was observed in CB patients (OR=0.15, p=0.027). Inhaled steroids showed no association with ICU admission, days to clinical recovery and mortality in the overall sample and in any disease subgroup.
Conclusions
Treatment with inhaled steroids is not a prognostic factor in COPD and asthmatic patients with CAP, but could prevent hospitalization for CAP in patients with clinical criteria of chronic bronchitis.
doi:10.1371/journal.pone.0073271
PMCID: PMC3764164  PMID: 24039899
14.  Compliance with Guidelines-Recommended Processes in Pneumonia: Impact of Health Status and Initial Signs 
PLoS ONE  2012;7(5):e37570.
Initial care has been associated with improved survival of community-acquired pneumonia (CAP). We aimed to investigate patient comorbidities and health status measured by the Charlson index and clinical signs at diagnosis associated with adherence to recommended processes of care in CAP. We studied 3844 patients hospitalized with CAP. The evaluated recommendations were antibiotic adherence to Spanish guidelines, first antibiotic dose <6 hours and oxygen assessment. Antibiotic adherence was 72.6%, first dose <6 h was 73.4% and oxygen assessment was 90.2%. Antibiotic adherence was negatively associated with a high Charlson score (Odds ratio [OR], 0.91), confusion (OR, 0.66) and tachycardia ≥100 bpm (OR, 0.77). Delayed first dose was significantly lower in those with tachycardia (OR, 0.75). Initial oxygen assessment was negatively associated with fever (OR, 0.61), whereas tachypnea ≥30 (OR, 1.58), tachycardia (OR, 1.39), age >65 (OR, 1.51) and COPD (OR, 1.80) were protective factors. The combination of antibiotic adherence and timing <6 hours was negatively associated with confusion (OR, 0.69) and a high Charlson score (OR, 0.92) adjusting for severity and hospital effect, whereas age was not an independent factor. Deficient health status and confusion, rather than age, are associated with lower compliance with antibiotic therapy recommendations and timing, thus identifying a subpopulation more prone to receiving lower quality care.
doi:10.1371/journal.pone.0037570
PMCID: PMC3358284  PMID: 22629420
15.  Pandemic and post-pandemic Influenza A (H1N1) infection in critically ill patients 
Critical Care  2011;15(6):R286.
Background
There is a vast amount of information published regarding the impact of 2009 pandemic Influenza A (pH1N1) virus infection. However, a comparison of risk factors and outcome during the 2010-2011 post-pandemic period has not been described.
Methods
A prospective, observational, multi-center study was carried out to evaluate the clinical characteristics and demographics of patients with positive RT-PCR for H1N1 admitted to 148 Spanish intensive care units (ICUs). Data were obtained from the 2009 pandemic and compared to the 2010-2011 post-pandemic period.
Results
Nine hundred and ninety-seven patients with confirmed An/H1N1 infection were included. Six hundred and forty-eight patients affected by 2009 (pH1N1) virus infection and 349 patients affected by the post-pandemic Influenza (H1N1)v infection period were analyzed. Patients during the post-pandemic period were older, had more chronic comorbid conditions and presented with higher severity scores (Acute Physiology And Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA)) on ICU admission. Patients from the post-pandemic Influenza (H1N1)v infection period received empiric antiviral treatment less frequently and with delayed administration. Mortality was significantly higher in the post-pandemic period. Multivariate analysis confirmed that haematological disease, invasive mechanical ventilation and continuous renal replacement therapy were factors independently associated with worse outcome in the two periods. HIV was the only new variable independently associated with higher ICU mortality during the post-pandemic Influenza (H1N1)v infection period.
Conclusion
Patients from the post-pandemic Influenza (H1N1)v infection period had an unexpectedly higher mortality rate and showed a trend towards affecting a more vulnerable population, in keeping with more typical seasonal viral infection.
doi:10.1186/cc10573
PMCID: PMC3388633  PMID: 22126648
16.  Viral-Reactivated Pneumonia during Mechanical Ventilation: Is There Need for Antiviral Treatment? 
Respiratory viruses are not a common cause of ventilator-associated pneumonia (VAP). Herpesviridae [Herpes simplex virus (HSV) and cytomegalovirus (CMV)] are detected frequently in the lower respiratory tract of ventilated patients. HSV is detected between days 7 and 14 of invasive mechanical ventilation (IMV); presence of the virus does not necessarily imply pathogenicity, but the association with adverse clinical outcomes supports the hypothesis of a pathogenic role in a variable percentage of patients. Bronchopneumonitis associated with HSV should be considered in patients with prolonged IMV, reactivation with herpetic mucocutaneous lesions and those belonging to a risk population with burn injuries or acute lung injury. Reactivation of CMV is common in critically ill patients and usually occurs between days 14 and 21 in patients with defined risk factors. The potential pathogenic role of CMV seems clear in patients with acute lung injury and persistent respiratory failure in whom there is no isolation of bacterial agent as a cause of VAP. The best diagnostic test is not defined although lung biopsies should be considered in addition to the usual methods before starting specific treatment. The role of mimivirus is uncertain and is yet to be defined, but the serologic evidence of this new virus in the context of VAP appears to be associated with adverse clinical outcomes.
doi:10.3389/fphar.2011.00066
PMCID: PMC3210442  PMID: 22073034
viral pneumonia; ventilator-associated pneumonia; antiviral treatment
17.  Community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis 
Critical Care  2011;15(5):R209.
Introduction
The frequency and clinical significance of polymicrobial aetiology in community-acquired pneumonia (CAP) patients admitted to the ICU have been poorly studied. The aim of the present study was to describe the prevalence, clinical characteristics and outcomes of severe CAP of polymicrobial aetiology in patients admitted to the ICU.
Methods
The prospective observational study included 362 consecutive adult patients with CAP admitted to the ICU within 24 hours of presentation; 196 (54%) patients had an established aetiology.
Results
Polymicrobial infection was present in 39 (11%) cases (20% of those with defined aetiology): 33 cases with two pathogens, and six cases with three pathogens. The most frequently identified pathogens in polymicrobial infections were Streptococcus pneumoniae (n = 28, 72%), respiratory viruses (n = 15, 39%) and Pseudomonas aeruginosa (n = 8, 21%). Chronic respiratory disease and acute respiratory distress syndrome criteria were independent predictors of polymicrobial aetiology. Inappropriate initial antimicrobial treatment was more frequent in the polymicrobial aetiology group compared with the monomicrobial aetiology group (39% vs. 10%, P < 0.001), and was an independent predictor of hospital mortality (adjusted odds ratio = 10.79, 95% confidence interval = 3.97 to 29.30; P < 0.001). The trend for higher hospital mortality of the polymicrobial aetiology group compared with the monomicrobial aetiology group (n = 8, 21% versus n = 17, 11%), however, was not significantly different (P = 0.10).
Conclusions
Polymicrobial pneumonia occurs frequently in patients admitted to the ICU. This is a risk factor for inappropriate initial antimicrobial treatment, which in turn independently predicts hospital mortality.
doi:10.1186/cc10444
PMCID: PMC3334753  PMID: 21914220
18.  Telavancin versus Vancomycin for Hospital-Acquired Pneumonia due to Gram-positive Pathogens 
The results from two methodologically identical double-blind studies indicate that telavancin is noninferior to vancomycin based on clinical response in the treatment of hospital-acquired pneumonia due to Gram-positive pathogens.
Background. Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens.
Methods. Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7–21 days. The primary end point was clinical response at follow-up/test-of-cure visit.
Results. A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, –5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, –4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, –0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, –7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%).
Conclusions. The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.
doi:10.1093/cid/ciq031
PMCID: PMC3060890  PMID: 21148517
19.  Common Variants of TLR1 Associate with Organ Dysfunction and Sustained Pro-Inflammatory Responses during Sepsis 
PLoS ONE  2010;5(10):e13759.
Background
Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarkers among septic patients.
Methodology/Principal Findings
Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1β, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7th day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001≤p≤0.022), and with reduced IL-10 (0.012≤p≤0.047) and elevated CRP (0.011≤p≤0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p = 0.017) and ALI (p = 0.050) in a combined analysis with European Americans, suggesting common risk effects among studies.
Conclusions/Significance
These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.
doi:10.1371/journal.pone.0013759
PMCID: PMC2966434  PMID: 21048935
20.  Procalcitonin and C-Reactive Protein for Invasive Bacterial Pneumonia Diagnosis among Children in Mozambique, a Malaria-Endemic Area 
PLoS ONE  2010;5(10):e13226.
Background
Pneumonia is the major cause of mortality and morbidity in children worldwide. Procalcitonin (PCT) and C-reactive protein (CRP) are used in developed countries to differentiate between viral and bacterial causes of pneumonia. Validity of these markers needs to be further explored in Africa.
Methodology and Principal Findings
We assessed the utility of PCT and CRP to differentiate viral from invasive bacterial pneumonia in children <5 years hospitalized with clinical severe pneumonia (CSP) in rural Mozambique, a malaria-endemic area with high HIV prevalence. Prognostic capacity of these markers was also evaluated. Out of 835 children with CSP, 87 fulfilled definition of viral pneumonia and 89 of invasive bacterial pneumonia. In absence of malaria parasites, levels of PCT and CRP were lower in the viral group when compared to the invasive bacterial one (PCT: median = 0.21 versus 8.31 ng/ml, p<0.001; CRP: 18.3 vs. 185.35 mg/l, p<0.001). However, in presence of malaria parasites distribution between clinical groups overlapped (PCT: median = 23.1 vs. 21.75 ng/ml, p = 0.825; CRP: median = 96.8 vs. 217.4 mg/l, p = 0.052). None of the two markers could predict mortality.
Conclusions
Presence of malaria parasites should be taken into consideration, either for clinical or epidemiological purposes, if using PCT or CRP to differentiate viral from invasive bacterial pneumonia in malaria-endemic areas.
doi:10.1371/journal.pone.0013226
PMCID: PMC2954814  PMID: 20976241
21.  Colour of sputum is a marker for bacterial colonisation in chronic obstructive pulmonary disease 
Respiratory Research  2010;11(1):58.
Background
Bacterial colonisation in chronic obstructive pulmonary disease (COPD) contributes to airway inflammation and modulates exacerbations. We assessed risk factors for bacterial colonisation in COPD.
Methods
Patients with stable COPD consecutively recruited over 1 year gave consent to provide a sputum sample for microbiologic analysis. Bronchial colonisation by potentially pathogenic microorganisms (PPMs) was defined as the isolation of PPMs at concentrations of ≥102 colony-forming units (CFU)/mL on quantitative bacterial culture. Colonised patients were divided into high (>105 CFU/mL) or low (<105 CFU/mL) bacterial load.
Results
A total of 119 patients (92.5% men, mean age 68 years, mean forced expiratory volume in one second [FEV1] [% predicted] 46.4%) were evaluated. Bacterial colonisation was demonstrated in 58 (48.7%) patients. Patients with and without bacterial colonisation showed significant differences in smoking history, cough, dyspnoea, COPD exacerbations and hospitalisations in the previous year, and sputum colour. Thirty-six patients (62% of those colonised) had a high bacterial load. More than 80% of the sputum samples with a dark yellow or greenish colour yielded PPMs in culture. In contrast, only 5.9% of white and 44.7% of light yellow sputum samples were positive (P < 0.001). Multivariate analysis showed an increased degree of dyspnoea (odds ratio [OR] = 2.63, 95% confidence interval [CI] 1.53-5.09, P = 0.004) and a darker sputum colour (OR = 4.11, 95% CI 2.30-7.29, P < 0.001) as factors associated with the presence of PPMs in sputum.
Conclusions
Almost half of our population of ambulatory moderate to very severe COPD patients were colonised with PPMs. Patients colonised present more severe dyspnoea, and a darker colour of sputum allows identification of individuals more likely to be colonised.
doi:10.1186/1465-9921-11-58
PMCID: PMC2883541  PMID: 20470372
22.  Bronchoscopic validation of the significance of sputum purulence in severe exacerbations of chronic obstructive pulmonary disease 
Thorax  2006;62(1):29-35.
Background
Antibiotics are commonly prescribed in exacerbations of chronic obstructive pulmonary disease (COPD). However, the role of bacteria in these exacerbations is controversial.
Objective
To identify clinical predictors of bacterial infection as a cause of exacerbation, considering the protected specimen brush (PSB) as the gold standard.
Methods
Clinical data, sputum and PSB samples were collected from 40 patients with COPD requiring hospitalisation due to severe exacerbations who had not received previous antibiotic treatment.
Results
Quantitative cultures of PSB samples (n = 40) yielded 23 potential pathogenic microorganisms (PPMs) at concentrations of ⩾102 colony‐forming units/ml in 18 (45%) patients. Sputum samples were obtained from all 40 patients. Culture of good‐quality sputum samples (n = 18) yielded 16 PPMs corresponding to 14 (35%) patients. The concordance between the PSB and sputum rate was high (κ = 0.85, p<0.002). The self‐reporting patient observation of sputum purulence (odds ratio (OR) 27.20 (95% confidence interval (CI) 4.60 to 60.69), p = 0.001), the percentage predicted forced expiratory volume in 1 s (FEV1%) <50 (OR 2.27 (95% CI 1.55 to 3.21), p = 0.014), >4 exacerbations in the past year (OR 6.9 (95% CI 0.08 to 1.08), p = 0.028) and previous hospitalisations due to COPD (OR 4.13 (95% CI 1.02 to 16.07), p = 0.041) were associated with the presence of PPMs in the distal airways. The operative characteristics for predicting distal airway infection when patients presented with purulent exacerbation were as follows: sensitivity 89.5%, specificity 76.2%, positive predicted value 77.3% and negative predicted value 88.9%.
Conclusions
The self‐reporting presence of purulence in the sputum, as well as common previous exacerbations and hospitalisations due to COPD in patients with severe airflow obstruction (FEV1% <50) predict the presence of bacterial infection in the distal airways. The use of these clinical variables may help in selecting candidates to receive antibiotic treatment.
doi:10.1136/thx.2005.056374
PMCID: PMC2111274  PMID: 16928715
23.  Maintenance of tracheal tube cuff pressure: where are the limits? 
Critical Care  2008;12(1):106.
Continuous control of tracheal tube cuff inflation using a pneumatic device resulted in severe tracheal wall damage in ventilated piglets. This damage was similar in piglets managed with manual control of cuff inflation. The periodic hyperinflation of the tube cuff used in both groups of this study may explain these results. This manoeuvre should be avoided in clinical practice.
doi:10.1186/cc6194
PMCID: PMC2374579  PMID: 18279534
24.  Ethics roundtable debate: A patient dies from an ICU-acquired infection related to methicillin-resistant Staphylococcus aureus – how do you defend your case and your team? 
Critical Care  2004;9(1):5-9.
An elderly patient dies from septic shock in the intensive care unit. This is perhaps not an unusual scenario, but in this case the sepsis happens to have been due to methicillin-resistant Staphylococcus aureus, possibly related to a catheter, and possibly transmitted from a patient in a neighbouring room by less than adequate compliance with infection control procedures. The family decides to sue. We present how experts from four different countries assess the medicolegal issues involved in this case.
doi:10.1186/cc3016
PMCID: PMC1065110  PMID: 15693971
infection control procedures; medicolegal; MRSA; transmission
25.  Inflammatory Responses in Blood Samples of Human Immunodeficiency Virus-Infected Patients with Pulmonary Infections 
We analyzed the characteristics of the inflammatory response occurring in blood during pulmonary infections in human immunodeficiency virus (HIV)-infected patients. A prospective study of consecutive hospital admissions of HIV-infected patients with new-onset radiologic pulmonary infiltrates was carried out in a tertiary university hospital from April 1998 to May 2001. Plasma cyclic AMP receptor protein (CRP), interleukin 1β (IL-1β), IL-6, IL-8, IL-10, and tumor necrosis factor alpha (TNF-α) levels were determined at the time of admission and 4, 5, and 6 days later. Patients were included in a protocol addressed to study etiology and outcome of disease. A total of 249 episodes of infection were included, with the main diagnoses being bacterial pneumonia (BP) (118 episodes), Pneumocystis carinii pneumonia (PCP) (41 episodes), and mycobacteriosis (36 episodes). For these three patient groups, at the time of admission the median CRP and cytokine levels were as follows: CRP, 10.2, 3.8 and 5 mg/dl, respectively (P = 0.0001); IL-8, 19, 3, and 2.9 pg/ml (P = 0.045); and TNF-α, 46.4, 44, and 75 pg/ml, respectively (P = 0.029). There were no significant differences in levels of IL-1β, IL-6, or IL-10 among the patient groups. A total of 23 patients died. At the time of admission, HIV-infected patients with BP had higher plasma CRP and IL-8 levels than did PCP and mycobacteriosis patients. TNF-α levels were higher in patients with mycobacteriosis. An elevated IL-8 level (>61 pg/ml) at the time of admission was an independent factor associated with higher mortality (odds ratio, 12; 95% confidence interval, 1.2 to 235.5).
doi:10.1128/CDLI.11.3.608-614.2004
PMCID: PMC404570  PMID: 15138189

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