Lung transplantation for acute respiratory distress syndrome: a retrospective European cohort study.

BACKGROUND: The published experience of lung transplantation in acute respiratory distress syndrome (ARDS) is limited. The aim of this study was to investigate the contemporary results of lung transplantation attempts in ARDS in major European centres. METHODS: We conducted a retrospective multicentre cohort study of all patients listed for lung transplantation between 2011 and 2019. We surveyed 68 centres in 22 European countries. All patients admitted to the waitlist for lung transplantation with a diagnosis of "ARDS/pneumonia" were included. Patients without extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were excluded. Patients were followed until 1 October 2020 or death. Multivariable analysis for 1-year survival after listing and lung transplantation was performed. RESULTS: 55 centres (81%) with a total transplant activity of 12 438 lung transplants during the 9-year period gave feedback. 40 patients with a median age of 35 years were identified. Patients were listed for lung transplantation in 18 different centres in 10 countries. 31 patients underwent lung transplantation (0.25% of all indications) and nine patients died on the waitlist. 90% of transplanted patients were on ECMO in combination with mechanical ventilation before lung transplantation. On multivariable analysis, transplantation during 2015-2019 was independently associated with better 1-year survival after lung transplantation (OR 10.493, 95% CI 1.977-55.705; p=0.006). 16 survivors out of 23 patients with known status (70%) returned to work after lung transplantation. CONCLUSIONS: Lung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.

Predicting treatment failure in patients with community acquired pneumonia: a case-control study.

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.

Inhaled corticosteroids and systemic inflammatory response in community-acquired pneumonia: a prospective clinical study.

BACKGROUND AND OBJECTIVE: The previous use of inhaled corticosteroids (ICS) may reduce the inflammatory response and mortality in patients with community-acquired pneumonia (CAP). METHODS: We measured serum levels of several inflammatory biomarkers, as well as mortality at various time-points, in 663 consecutive patients hospitalized for CAP; 128 (19%) were receiving chronic outpatient treatment with ICS. Patients on previous oral corticosteroids were excluded from the analysis. RESULTS: On admission, patients treated with ICS were older; had been diagnosed with chronic obstructive pulmonary disease (COPD), asthma and pneumonia in the previous year more often; and had higher CAP severity risk classes and lower tumour necrosis factor (TNF)-alpha (P < 0.001) and interleukin (IL)-6 (P = 0.015) serum levels. After adjusting for potential confounders, this association persisted for TNF-alpha (P < 0.001), but not for IL-6. Mortality at 30 and 90 days tended to be lower in patients treated with ICS (P = 0.062 and 0.050, respectively), but mortality was similar after 1 year in both groups (16, 13% vs 81, 15% for patients treated and not treated with ICS, respectively). Hospital readmission rate after 1 year was higher in patients treated with ICS (49, 38% vs 109, 20%, P < 0.001). The association of ICS treatment with a previous diagnosis of pneumonia, lower levels of TNF-alpha and IL-6 on admission and higher readmission rates during follow up persisted in the subpopulation of 210 patients with COPD. CONCLUSIONS: Previous use of ICS in patients hospitalized for CAP is associated with a reduced systemic inflammatory response without any impact on long-term mortality.

Systemic corticosteroids for community-acquired pneumonia: reasons for use and lack of benefit on outcome.

BACKGROUND AND OBJECTIVE: Although the benefits of systemic corticosteroids in community-acquired pneumonia (CAP) are not clear, their use is frequent in clinical practice. We described the frequency of this practice, patients' characteristics and its clinical impact. METHODS: We investigated all adult CAP patients visited between June 1997 and January 2008 (n = 3257). RESULTS: Two hundred and sixty patients received systemic corticosteroids (8%) with a mean daily dose of 45 (33) mg (median, 36 mg/day). Patients receiving corticosteroids were older (74 (13) vs 65 (19) years), had more comorbidities (respiratory, 59% vs 38%, cardiac, 29% vs 16%, etc.), higher Pneumonia Severity Index (Fine IV-V, 76% vs 50%) and had received inhaled corticosteroids (36% vs 15%) and previous antibiotics (31% vs 23%) more frequently (P < 0.01, each). Significant predictors of corticosteroid administration were: chronic obstructive pulmonary disease (odds ratio (OR), 1.91), fever (OR, 0.59), expectoration (OR, 1.59), creatinine (+1 mg/dL, OR, 0.92), SaO(2) ≥ 92% (OR, 0.46), C-reactive protein (+5 mg/dL; OR, 0.92) and cardiac failure (OR, 1.76). Mortality (6% vs 7%; P = 0.43) and time to clinical stability (4 (3-6) vs 5 (3-7) days; P = 0.11) did not differ between the two groups, while length of hospital stay was longer for the steroid group (9 (6-14) vs 6 (3-9) days; P < 0.01). CONCLUSIONS: The main reasons for administering systemic steroids were the presence of chronic respiratory comorbidity or severe clinical presentation, but therapy did not influence mortality or clinical stability; by contrast, steroid administration was associated with prolonged length of stay. Nevertheless the steroid group did not show an increased mortality as it was expected according to the initial Pneumonia Severity Index score. Influence of steroids on outcomes of CAP need to be further investigated through randomized clinical trial.

Biomarkers and community-acquired pneumonia: tailoring management with biological data.

Community-acquired pneumonia (CAP) is the leading cause of death from infectious diseases worldwide, with an incidence of 0.3 to 0.5% in the adult population. A new diagnostic and prognostic approach relies on evaluation of biomarkers as an expression of the host's inflammatory response against the microorganism. C-reactive protein (CRP), procalcitonin (PCT), and cytokines are the most frequently studied, whereas pro-adrenomedullin (pro-ADM), pro-vasopressin (pro-VNP), and others are currently obtaining promising results. Their usefulness for diagnosis is limited, although PCT has been successfully used to guide prescription of antibiotics in patients with suspected CAP. Nevertheless, the accuracy of PCT in distinguishing between bacterial or viral infection and safely withholding antibiotics in CAP is the subject of debate. Analysis of systemic biomarkers in addition to clinical scores [Pneumonia Severity Index (PSI) or CURB-65 (confusion, urea, respiratory, blood pressure, >65 years)/CRB-65 (confusion, respiratory, blood pressure)] has been shown to improve 30 day mortality prediction and absence of severe complications. Pro-ADM is probably the biomarker that correlates most strongly with mortality prediction. During treatment, ~15% of hospitalized CAP patients develop treatment failure, and almost 6% may manifest rapidly progressive pneumonia. Initially increased and persistent raised levels of biomarkers and cytokines have been shown to identify patients at risk of treatment failure, thereby aiding clinical management. Data from the literature appear to support the use of biomarkers in routine clinical practice to improve the decision making in CAP.

Invasive scedosporiosis in lung transplant recipients: A nine-year retrospective study in a tertiary care hospital.

BACKGROUND: Scedosporium species and Lomentospora prolificans (Sc/Lp) are emerging molds that cause invasive disease associated with a high mortality rate. After Aspergillus, these molds are the second filamentous fungi recovered in lung transplant (LT) recipients. AIMS: Our objective was to evaluate the incidence, risk factors and outcome of Sc/Lp infections in LT recipients at a tertiary care hospital with a national reference LT program. METHODS: A nine-year retrospective study was conducted. RESULTS: During this period, 395 LT were performed. Positive cultures for Sc/Lp were obtained from twenty-one LT recipients. Twelve patients (incidence 3.04%) developed invasive scedosporiosis (IS). In 66.7% of the patients with IS the invasive infection was defined as a breakthrough one. The main sites of infection were lungs and paranasal sinuses. Most of the patients received combination antifungal therapy. The IS crude mortality rate after 30 days was 16.7%, and 33.3% after a year. CONCLUSIONS: Our study highlights improved survival rates associated with combination antifungal therapy in LT recipients and underlines the risk of breakthrough infections in patients with allograft dysfunction on nebulized lipidic amphotericin B prophylaxis. In addition to pretransplant colonization, acute or chronic organ dysfunctions seem to be the main risk factors for IS.

Systemic Inflammation during and after Bronchiectasis Exacerbations: Impact of Pseudomonas aeruginosa.

Bronchiectasis is a chronic structural disease associated with exacerbations that provoke systemic inflammation. We aimed to evaluate the systemic acute proinflammatory cytokine and its biomarker profiles during and after exacerbations and its relationship with the severity of episode, microbiological findings, and the bronchiectasis severity index. This prospective observational study compared exacerbation and stable groups. Cytokine (interleukins (IL)-17a, IL-1ß, IL-6, IL 8; tumor necrosis factor-alpha (α)) and high-sensitivity C-reactive protein (hsCRP) levels were determined by multiplex analysis on days 1, 5, 30, and 60 in the exacerbation group and on day 1 in the stable group. We recruited 165 patients with exacerbations, of which 93 were severe (hospitalized). Proinflammatory systemic IL-17a, IL-1ß, IL-8, and tumor necrosis factor-α levels increased similarly on days 1 and 5 in severe and non-severe episodes, but on day 30, IL-17a, IL-8, and IL-6 levels were only increased for severe exacerbations. The highest IL-17a level occurred in patients with chronic plus the acute isolation of Pseudomonas aeruginosa. At 30 days, severe exacerbations were independently associated with higher levels of IL-17 (Odds ratio (OR) 4.58), IL-6 (OR 4.89), IL-8 (OR 3.08), and hsCRP (OR 6.7), adjusted for age, the bronchiectasis severity index, and treatment duration. Exacerbations in patients with chronic P. aeruginosa infection were associated with an increase in IL-17 and IL-6 at 30 days (ORs 7.47 and 3.44, respectively). Severe exacerbations elicit a higher systemic proinflammatory response that is sustained to day 30. Patients with chronic P. aeruginosa infection had impaired IL-17a reduction. IL-17a could be a useful target for measuring systemic inflammation.

Pneumonic and non-pneumonic exacerbations in bronchiectasis: Clinical and microbiological differences.

OBJECTIVES: Despite the clinical relevance of exacerbations in bronchiectasis (BE), little is known about the microbiology and outcomes of pneumonic (CAP) vs. non-pneumonic (NOCAP) exacerbations. METHODS: This study compares clinical and microbiological characteristics of CAP vs. NOCAP in adults with BE. We performed a multicenter prospective observational study of consecutive cases of NOCAP and CAP from four Spanish hospitals (2011-2015). RESULTS: We recruited 144 patients, 47 of them CAP (33%) cases. CAP patients were older, with a larger representation of males, more comorbidities, higher arterial hypertension and COPD but less chronic bronchial infection and previous history of exacerbations. Clinical presentation was similar, excepting creatinine, C-reactive protein (C-RP), glucose and leukocytes which were higher in CAP. C-RP of 8.38 mg/dL showed a significant predictive discrimination for CAP. Streptococcus pneumoniae and Pseudomonas aeruginosa were the first causes of CAP and NOCAP, respectively. The rate of microbiological concordance with previous chronic bronchial infection was variable. Main clinical outcomes (mortality, length of stay, etc.) were similar in the two groups. Chronic bronchial infection and history of frequent exacerbations (≥ 2/year) were associated with a reduced risk of CAP. CONCLUSIONS: CAP and NOCAP in BE had similar clinical presentation with the exception of fever, leukocytosis, and C-RP. Microbiology also differed. A cut-off value of C-RP ≥ 8.38 mg/dL can predict CAP in bronchiectasis.

Predictors of Severe Sepsis among Patients Hospitalized for Community-Acquired Pneumonia.

BACKGROUND: Severe sepsis, may be present on hospital arrival in approximately one-third of patients with community-acquired pneumonia (CAP). OBJECTIVE: To determine the host characteristics and micro-organisms associated with severe sepsis in patients hospitalized with CAP. RESULTS: We performed a prospective multicenter cohort study in 13 Spanish hospital, on 4070 hospitalized CAP patients, 1529 of whom (37.6%) presented with severe sepsis. Severe sepsis CAP was independently associated with older age (>65 years), alcohol abuse (OR, 1.31; 95% CI, 1.07-1.61), chronic obstructive pulmonary disease (COPD) (OR, 1.75; 95% CI, 1.50-2.04) and renal disease (OR, 1.57; 95% CI, 1.21-2.03), whereas prior antibiotic treatment was a protective factor (OR, 0.62; 95% CI, 0.52-0.73). Bacteremia (OR, 1.37; 95% CI, 1.05-1.79), S pneumoniae (OR, 1.59; 95% CI, 1.31-1.95) and mixed microbial etiology (OR, 1.65; 95% CI, 1.10-2.49) were associated with severe sepsis CAP. CONCLUSIONS: CAP patients with COPD, renal disease and alcohol abuse, as well as those with CAP due to S pneumonia or mixed micro-organisms are more likely to present to the hospital with severe sepsis.

Pneumonia presenting with organ dysfunctions: Causative microorganisms, host factors and outcome.

Community-acquired pneumonia (CAP) is a serious infection that may occasionally rapidly evolve provoking organ dysfunctions. We aimed to characterize CAP presenting with organ dysfunctions at the emergency room, with regard to host factors and causative microorganisms, and its impact on 30-day mortality. 460 of 4070 (11.3%) CAP patients had ≥2 dysfunctions at diagnosis, with a 30-day mortality of 12.4% vs. 3.4% in those with one or no dysfunctions. Among them, the most frequent causative microorganisms were Streptococcus pneumoniae, gram-negatives and polymicrobial etiology. Independent host risk factors for presenting with ≥2 dysfunctions were: liver (OR 2.97) and renal diseases (OR 3.91), neurological disorders (OR 1.86), and COPD (OR 1.30). Methicillin-resistant Staphylococcus aureus (OR 6.41) and bacteraemic episodes (OR 1.68) had the higher independent risk among microorganisms. The number of organ dysfunctions vs. none increased at 30-day mortality: three organs (OR 11.73), two organs (OR 4.29), and one organ (OR 2.42) whereas Enterobacteria (OR 3.73) were also independently related to mortality. The number of organ dysfunctions was the strongest 30-day mortality risk factor while Enterobacteriaceae was also associated with poorer outcome. The assessment of organ dysfunctions in CAP should be implemented for management, allocation and treatment decisions on initial evaluation.

Severity and outcomes of community acquired pneumonia in asthmatic patients.

BACKGROUND: Limited information is available about clinical outcomes and microbiology of community-acquired pneumonia in asthma. METHODS: We prospectively studied 4079 CAP patients over a 12-years period and found 139 (3.4%) asthmatic patients. RESULTS: Asthmatics showed younger age (57 ± 19 vs. 66 ± 19 years), less males (32% vs. 68%) and less active smokers (15% vs. 25%). Moreover, they had used more frequently inhaled corticosteroids (ICs, 53% vs. 17%, p < 0.001) and antibiotics (32% vs. 24%, p = 0.041). In comparison with non asthma-CAP, asthmatics showed at admission more pleuritic pain and dyspnoea but less severe pneumonia (PSI, CURB-65, PaO(2)/FIO(2) ratio; p < 0.05). No differences were observed in CAP microbiology, being Streptococcus pneumoniae the most frequent isolate. Clinical outcomes in asthmatic patients were similar to the general population (mortality, mechanical ventilation, etc.) but with a shorter median length of stay (6 [3; 9] vs. 7 [4; 10] days, p = 0.023). The chronic use of ICs did not influence clinical presentation and outcomes among asthmatic patients. CONCLUSIONS: Asthmatics were younger and showed similar clinical presentation. Consistently with PSI, asthmatics showed similar outcomes than the general population. The microbial aetiology of CAP in asthma did not differ from the general population and antibiotic therapy should follow current guidelines.

Systemic inflammatory pattern of patients with community-acquired pneumonia with and without COPD.

BACKGROUND: Several clinical studies have evaluated the role of COPD in patients with community acquired pneumonia (CAP). We investigated the systemic inflammatory response of patients with CAP (CAP 1 COPD) and patients without associated COPD (CAP only). METHODS: Clinical, microbiologic, and immunologic data were collected from 367 prospective patients on admission to hospital during a 3-year period. Comparative analyses were performed between patients with CAP 1 COPD (n 5 117) and those with CAP only (n 5 250) and between patients with and without domiciliary use of inhaled corticosteroids (ICSs) and oral corticosteroids. RESULTS: Detailed characteristics of clinical severity and prognosis (mortality on hospitalization and at 30 and 90 days) were similar between the CAP 1 COPD and CAP-only groups. The readmission rate and the frequency of previous pneumonia were higher in the group of patients with CAP 1 COPD. On day 1 (admission to hospital), patients with CAP 1 COPD had significantly lower serum levels of tumor necrosis factor- a , IL-1, and IL-6 compared with the CAP-only group; levels of the remaining inflammatory biomarkers (C-reactive protein, procalcitonin, IL-8, and IL-10) were similar at days 1 and 3. The exclusion of patients with domiciliary use of ICS and oral corticosteroids confirmed lower levels of TNF- a on day 1 in patients with CAP 1 COPD. Finally, lower levels of IL-6 were found only among those patients with COPD who were currently using ICS. CONCLUSIONS: Our prospective study demonstrates a different, disease-specific, early inflammatory pattern between patients with CAP with and without associated COPD. These findings are not completely corticosteroid mediated.

Thrombocytosis is a marker of poor outcome in community-acquired pneumonia.

BACKGROUND: Thrombocytosis, often considered a marker of normal inflammatory reaction of infections, has been recently associated with increased mortality in hospitalized patients with community-acquired pneumonia (CAP). We assessed the characteristics and outcomes of patients with CAP and thrombocytosis (platelet count ≥ 4 × 105/mm3) compared with thrombocytopenia (platelet count < 105/mm3) and normal platelet count. METHODS: We prospectively analyzed 2,423 consecutive, hospitalized patients with CAP. We excluded patients with immunosuppression, neoplasm, active TB, or hematologic disease. RESULTS: Fifty-three patients (2%) presented with thrombocytopenia, 204 (8%) with thrombocytosis, and 2,166 (90%) had normal platelet counts. Patients with thrombocytosis were younger (P < .001); those with thrombocytopenia more frequently had chronic heart and liver disease (P < .001 for both). Patients with thrombocytosis presented more frequently with respiratory complications, such as complicated pleural effusion and empyema (P < .001), whereas those with thrombocytopenia presented more often with severe sepsis (P < .001), septic shock (P = .009), need for invasive mechanical ventilation (P < .001), and ICU admission (P = .011). Patients with thrombocytosis and patients with thrombocytopenia had longer hospital stays (P = .004), and higher 30-day mortality (P = .001) and readmission rates (P = .011) than those with normal platelet counts. Multivariate analysis confirmed a significant association between thrombocytosis and 30-day mortality (OR, 2.720; 95% CI, 1.589-4.657; P < .001). Adding thrombocytosis to the confusion, respiratory rate, and BP plus age ≥65 years score slightly improved the accuracy to predict mortality (area under the receiver operating characteristic curve increased from 0.634 to 0.654, P = .049). CONCLUSIONS: Thrombocytosis in patients with CAP is associated with poor outcome, complicated pleural effusion, and empyema. The presence of thrombocytosis in CAP should encourage ruling out respiratory complication and could be considered for severity evaluation.

Pneumonic and nonpneumonic exacerbations of COPD: inflammatory response and clinical characteristics.

BACKGROUND: Community-acquired pneumonia (CAP) is a frequent event in patients with COPD, although it is not currently considered an acute exacerbation of COPD (AECOPD). To our knowledge, no studies have compared the inflammatory response of patients with COPD who develop CAP or AECOPD. The aim of our study was to compare clinical and evolutive manifestations and biologic signaling of AECOPD and CAP + COPD. METHODS: Prospective data were collected from 249 consecutively hospitalized patients with COPD. Comparative analyses were performed in patients with AECOPD (n = 133) and patients with CAP + COPD (n = 116). Measures of clinical characteristics, blood biomarkers, and evolution were recorded on admission, after 3 and 30 days, and in a follow-up period of 30 days, 90 days, and 1 year. RESULTS: Patients with CAP + COPD had higher FEV1 compared with patients with COPD without pneumonia. In-hospital and long-term outcomes (1 year) were similar for both populations. However, patients with AECOPD had more readmissions, and patients with CAP had more prior episodes of pneumonia. At day 1 and day 3, patients with CAP + COPD had significantly (P < .001) higher serum levels of C-reactive protein (CRP), procalcitonin, tumor necrosis factor-α, and IL-6. Repetition of the analyses after stratifying patients based on severity of disease, current inhaled pharmacotherapy, and noninfectious AECOPD cause confirmed higher levels of the same biomarkers in patients with CAP + COPD. Chills, pleuritic pain, sputum purulence, and CRP levels at day 1 were independent clinical predictors of CAP + COPD. CONCLUSIONS: Our study confirms that two different clinical and inflammatory profiles exist in hospitalized patients with COPD in response to CAP (stronger response) and AECOPD, although with similar short-term and long-term outcomes.

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-1ß, 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.