Endothelial Damage, Neutrophil Extracellular Traps and Platelet Activation in COVID-19 vs. Community-Acquired Pneumonia: A Case-Control Study.

COVID-19 has been a diagnostic and therapeutic challenge. It has marked a paradigm shift when considering other types of pneumonia etiology. We analyzed the biomarkers related to endothelial damage and immunothrombosis in COVID-19 in comparison to community-acquired pneumonia (CAP) through a case-control study of 358 patients with pneumonia (179 hospitalized with COVID-19 vs. 179 matched hospitalized with CAP). Endothelial damage markers (endothelin and proadrenomedullin), neutrophil extracellular traps (NETs) (citrullinated-3 histone, cell-free DNA), and platelet activation (soluble P-selectin) were measured. In-hospital and 1-year follow-up outcomes were evaluated. Endothelial damage, platelet activation, and NET biomarkers are significantly higher in CAP compared to COVID-19. In-hospital mortality in COVID-19 was higher compared to CAP whereas 1-year mortality and cardiovascular complications were higher in CAP. In the univariate analysis (OR 95% CIs), proADM and endothelin were associated with in-hospital mortality (proADM: CAP 3.210 [1.698-6.070], COVID-19 8.977 [3.413-23.609]; endothelin: CAP 1.014 [1.006-1.022], COVID-19 1.024 [1.014-1.034]), in-hospital CVE (proADM: CAP 1.623 [1.080-2.439], COVID-19 2.146 [1.186-3.882]; endothelin: CAP 1.005 [1.000-1.010], COVID-19 1.010 [1.003-1.018]), and 1-year mortality (proADM: CAP 2.590 [1.644-4.080], COVID-19 13.562 [4.872-37.751]; endothelin: CAP 1.008 [1.003-1.013], COVID-19 1.026 [1.016-1.037]). In conclusion, COVID-19 and CAP showed different expressions of endothelial damage and NETs. ProADM and endothelin are associated with short- and long-term mortality.

Understanding the Host in the Management of Pneumonia. An Official American Thoracic Society Workshop Report.

Pneumonia causes a significant burden of disease worldwide. Although all populations are at risk of pneumonia, those at extremes of age and those with immunosuppressive disorders, underlying respiratory disease, and critical illness are particularly vulnerable. Although clinical practice guidelines addressing the management and treatment of pneumonia exist, few of the supporting studies focus on the crucial contributions of the host in pneumonia pathogenesis and recovery. Such essential considerations include the host risk factors that lead to susceptibility to lung infections; biomarkers reflecting the host response and the means to pursue host-directed pneumonia therapy; systemic effects of pneumonia on the host; and long-term health outcomes after pneumonia. To address these gaps, the Pneumonia Working Group of the Assembly on Pulmonary Infection and Tuberculosis led a workshop held at the American Thoracic Society meeting in May 2018 with overarching objectives to foster attention, stimulate research, and promote funding for short-term and long-term investigations into the host contributions to pneumonia. The workshop involved participants from various disciplines with expertise in lung infection, pneumonia, sepsis, immunocompromised patients, translational biology, data science, genomics, systems biology, and clinical trials. This workshop report summarizes the presentations and discussions and important recommendations for future clinical pneumonia studies. These recommendations include establishing consensus disease and outcome definitions, improved phenotyping, development of clinical study networks, standardized data and biospecimen collection and protocols, and development of innovative trial designs.

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.

Lymphopenic community-acquired pneumonia is associated with a dysregulated immune response and increased severity and mortality.

OBJECTIVES: Lymphopenic (<724 lymphocytes/µL) community-acquired pneumonia (L-CAP) is an immunophenotype with an increased risk of mortality. We aimed to characterize the l-CAP immunophenotype though lymphocyte subsets and the inflammatory response and its relationship with severity at presentation and outcome. METHODS: Prospective study of 217 immunocompetent patients hospitalized for CAP. Lymphocyte subsets (CD4+, CD8+, CD19+, and natural killer [NK] cells) and inflammatory cytokines were analyzed on days 1 and 4, and immunoglobulin subclasses were analyzed on day 1 in a nested group. RESULTS: 39% of patients showed l-CAP, with decreased levels of all lymphocyte subsets with a partial recovery of CD4+ and CD8+ cells by day 4. l-CAP patients exhibited higher initial severity and systemic levels of interleukin (IL)-8, IL-10, granulocyte colony-stimulating factor, and monocyte chemoattractant protein-1. Initial IgG2 levels were lower in patients with <724 lymphocytes/µL and positively correlated with ALC, CD4+, and CD19+ cell counts. Low CD4+ counts (<129 cells/µL) also independently predicted 30-day mortality after adjusting for age, gender, and the CURB-65 score. CONCLUSIONS: l-CAP is characterized by CD4+ depletion, a higher inflammatory response, and low IgG2 levels that correlated with greater severity at presentation and worse prognosis. l-CAP is an immunophenotype useful for rapidly recognizing severity.

Initial Inflammatory Profile in Community-acquired Pneumonia Depends on Time since Onset of Symptoms.

RATIONALE: Assessment of the inflammatory response can help the decision-making process when diagnosing community-acquired pneumonia (CAP), but there is a lack of information about the influence of time since onset of symptoms. OBJECTIVES: We studied the impact of the number of days since onset of symptoms on inflammatory cytokines and biomarker concentrations at CAP diagnosis in hospitalized patients. METHODS: We performed a secondary analysis in two prospective cohorts including 541 patients in the derivation cohort and 422 in the validation cohort. The time since onset of symptoms was self-reported, and patients were classified as early presenters (<3 d) and nonearly presenters. Biomarkers (C-reactive protein [CRP] and procalcitonin [PCT] in both cohorts) and cytokines in the derivation cohort (IL-1, - 6, -8, -10, and tumor necrosis factor-α) were measured within 24 hours of hospital admission. MEASUREMENTS AND MAIN RESULTS: In early presenters, CRP was significantly lower, whereas PCT, IL-6, and IL-8 were higher. Nonearly presenters showed significantly lower PCT, IL-6, and IL-8 levels. In the validation cohort, CRP and PCT exhibited identical patterns: CRP levels were 36.4% greater in patients with 3 or more days since onset of symptoms than in those with less than 3 days since symptom onset in the derivation cohort and 38.2% in the validation cohort. PCT levels were 40% lower in patients with 3 or more days since onset of symptoms in the derivation cohort and 56% in the validation cohort. CONCLUSIONS: Time since symptom onset modifies the systemic inflammatory profile at CAP diagnosis. This information has relevant clinical implications for management, and it should be taken into account in the design of future clinical trials.

Factors associated with hospitalization in bronchiectasis exacerbations: a one-year follow-up study.

BACKGROUND: Bronchiectasis (BE) is a chronic structural lung disease with frequent exacerbations, some of which require hospital admission though no clear associated factors have been identified. We aimed to evaluate factors associated with hospitalization due to exacerbations during a 1-year follow-up period. METHODS: A prospective observational study was performed in patients recruited from specialized BE clinics. We considered all exacerbations diagnosed and treated with antibiotics during a follow-up period of 1 year. The protocol recorded baseline variables, usual treatments, Bronchiectasis Severity Index (BSI) and FACED scores, comorbid conditions and prior hospitalizations. RESULTS: Two hundred and 65 patients were recruited, of whom 162 required hospital admission during the follow-up period. Independent risk factors for hospital admission were age, previous hospitalization due to BE, use of proton pump inhibitors, heart failure, FACED and BSI, whereas pneumococcal vaccination was a protective factor. The area under the receiver operator characteristic curve (AUC) was 0.799 for BSI model was 0.799, and 0.813 for FACED model. CONCLUSIONS: Previous hospitalization, use of proton pump inhibitors, heart failure along with BSI or FACED scores is associated factors for developing exacerbations that require hospitalization. Pneumococcal vaccination was protective. This information may be useful for the design of preventive strategies and more intensive follow-up plans.

Risk factors for multidrug-resistant pathogens in bronchiectasis exacerbations.

BACKGROUND: Non-cystic fibrosis bronchiectasis is a chronic structural lung condition that courses with recurrent infectious exacerbations that lead to frequent antibiotic treatment making this population more susceptible to acquire pathogens with antibiotic resistance. We aimed to investigate risk factors associated with isolation of multidrug-resistant pathogens in bronchiectasis exacerbations. METHODS: A prospective observational study was conducted in two tertiary-care hospitals, enrolling patients when first exacerbation appeared. Multidrug-resistance was determined according to European Centre of Diseases Prevention and Control classification. RESULTS: Two hundred thirty three exacerbations were included and microorganisms were isolated in 159 episodes. Multidrug-resistant pathogens were found in 20.1% episodes: Pseudomonas aeruginosa (48.5%), methicillin-resistant Staphylococcus aureus (18.2%) and Extended spectrum betalactamase + Enterobacteriaceae (6.1%), and they were more frequent in exacerbations requiring hospitalization (24.5% vs. 10.2%, p: 0.016). Three independent multidrug-resistant risk factors were found: chronic renal disease (Odds ratio (OR), 7.60, 95% CI 1.92-30.09), hospitalization in the previous year (OR, 3.88 95% CI 1.37-11.02) and prior multidrug-resistant isolation (OR, 5.58, 95% CI 2.02-15.46). The proportion of multidrug-resistant in the 233 exacerbations was as follows: 3.9% in patients without risk factors, 12.6% in those with 1 factor and 53.6% if ≥2 risk factors. CONCLUSIONS: Hospitalization in the previous year, chronic renal disease, and prior multidrug-resistant isolation are risk factors for identification multidrug-resistant pathogens in exacerbations. This information may assist clinicians in choosing empirical antibiotics in daily clinical practice.

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.

Age-related risk factors for bacterial aetiology in community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: The objective of this study was to evaluate the effect of age and comorbidities, smoking and alcohol use on microorganisms in patients with community-acquired pneumonia (CAP). METHODS: A prospective multicentre study was performed with 4304 patients. We compared microbiological results, bacterial aetiology, smoking, alcohol abuse and comorbidities in three age groups: young adults (<45 years), adults (45-64 years) and seniors (>65 years). RESULTS: Bacterial aetiology was identified in 1522 (35.4%) patients. In seniors, liver disease was independently associated with Gram-negative bacteria (Haemophilus influenzae and Enterobacteriaceae), COPD with Pseudomonas aeruginosa (OR = 2.69 (1.46-4.97)) and Staphylococcus aureus (OR = 2.8 (1.24-6.3)) and neurological diseases with S. aureus. In adults, diabetes mellitus (DM) was a risk factor for Streptococcus pneumoniae and S. aureus, and COPD for H. influenzae (OR = 3.39 (1.06-10.83)). In young adults, DM was associated with S. aureus. Smoking was a risk factor for Legionella pneumophila regardless of age. Alcohol intake was associated with mixed aetiology and Coxiella burnetii in seniors, and with S. pneumoniae in young adults. CONCLUSION: It should be considered that the bacterial aetiology may differ according to the patient's age, comorbidities, smoking and alcohol abuse. More extensive microbiological testing is warranted in those with risk factors for infrequent microorganisms.