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Low Admission Plasma Gelsolin Concentrations Identify Community-acquired Pneumonia Patients at High Risk for Severe Outcomes.

ABSTRACT: BACKGROUND:Plasma gelsolin (pGSN) is an abundant circulating protein that neutralizes actin exposed by damaged cells, modulates inflammatory responses, and enhances alveolar macrophage antimicrobial activity. We investigated whether adults with low pGSN at hospital admission for community-acquired pneumonia (CAP) were at high risk for severe outcomes. METHODS:Admission pGSN concentrations in 455 adults hospitalized with CAP were measured using enzyme-linked immunosorbent assay. Patients were grouped into the following 4 hierarchical, mutually exclusive categories based on maximum clinical severity experienced during their hospitalization: general floor care without intensive care unit (ICU) admission, invasive respiratory or vasopressor support (IRVS), or death; ICU care without IRVS or death; IRVS without death; or death. Admission pGSN concentrations were compared across these discrete outcome categories. Additionally, outcomes among patients in the lowest quartile of pGSN concentration were compared to those in the upper 3 quartiles. RESULTS:Overall, median (interquartile range) pGSN concentration was 38.1 (32.1, 45.7) ?g/mL. Patients with more severe outcomes had lower pGSN concentrations (P = .0001); median values were 40.3 ?g/mL for floor patients, 36.7 ?g/mL for ICU patients, 36.5 ?g/mL for patients receiving IRVS, and 25.7 ?g/mL for patients who died. Compared to patients with higher pGSN concentrations, patients in the lowest quartile (pGSN ? 32.1 ?g/mL) more often required IRVS (21.2% vs 11.7%, P = .0114) and died (8.8% vs 0.9%, P < .0001). CONCLUSIONS:Among adults hospitalized with CAP, lower pGSN concentrations were associated with more severe clinical outcomes. Future studies are planned to investigate possible therapeutic benefits of recombinant human pGSN in this population.

SUBMITTER: Self WH

PROVIDER: S-EPMC6743831 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Low Admission Plasma Gelsolin Concentrations Identify Community-acquired Pneumonia Patients at High Risk for Severe Outcomes.

Self Wesley H WH Wunderink Richard G RG DiNubile Mark J MJ Stossel Thomas P TP Levinson Susan L SL Williams Derek J DJ Anderson Evan J EJ Bramley Anna M AM Jain Seema S Edwards Kathryn M KM Grijalva Carlos G CG

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20190901 7

<h4>Background</h4>Plasma gelsolin (pGSN) is an abundant circulating protein that neutralizes actin exposed by damaged cells, modulates inflammatory responses, and enhances alveolar macrophage antimicrobial activity. We investigated whether adults with low pGSN at hospital admission for community-acquired pneumonia (CAP) were at high risk for severe outcomes.<h4>Methods</h4>Admission pGSN concentrations in 455 adults hospitalized with CAP were measured using enzyme-linked immunosorbent assay. Pa ...[more]

PMID: 30561561

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Project description:IntroductionCommunity-acquired pneumonia (CAP) requiring intensive care unit (ICU) treatment commonly causes acute respiratory failure with high mortality. Kallistatin, an endogenous tissue kallikrein inhibitor, has been reported to be protective in various human diseases. The aim of this study was to assess the correlations of kallistatin with other biomarkers and to determine whether kallistatin levels have a prognostic value in severe CAP.MethodsPlasma samples and clinical data were prospectively collected from 54 patients with severe CAP requiring ICU admission. Seventeen healthy control subjects were included for comparison. Plasma kallistatin, kallikrein, and other biomarkers of inflammation (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, C-reactive protein (CRP)), and anti-coagulation (protein C, anti-thrombin III) were measured on days 1 and 4 of ICU admission. Comparison between survivors (n = 41) and nonsurvivors (n = 13) was performed.ResultsPlasma kallistatin was significantly consumed in severe CAP patients compared with healthy individuals. Lower day 1 kallistatin levels showed a strong trend toward increased mortality (P = 0.018) and higher day 1 CURB-65 scores (P = 0.004). Plasma kallistatin levels on day 1 of ICU admission were significantly decreased in patients who developed septic shock (P = 0.017) and who had acute respiratory distress syndrome (P = 0.044). In addition, kallistatin levels were positively correlated with anti-thrombin III and protein C and inversely correlated with IL-1β, IL-6, and CRP levels. In a multivariate logistic regression analysis, higher day 1 CURB-65 scores were independent predictors of mortality (odds ratio = 29.9; P = 0.009). Also, higher day 1 kallistatin levels were independently associated with a decreased risk of death (odds ratio, 0.1) with a nearly significant statistical difference (P = 0.056). Furthermore, we found that a cutoff level of 6.5 μg/ml of day 1 kallistatin determined by receiver operating characteristic curves could be used to distinguish between patients who survived in 60 days and those who did not.ConclusionsThese results suggest that kallistatin may serve as a novel marker for severe CAP prognosis and may be involved in the pathogenesis of CAP through antiinflammatory and anticoagulation effects.

Project description:BackgroundExcessive inflammation contributes to the morbidity and mortality of severe coronavirus disease 2019 (COVID-19) pneumonia. Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse experimental models of infectious and noninfectious inflammation.MethodsIn a blinded, randomized study, 61 subjects with documented COVID-19 pneumonia having a World Health Organization (WHO) Severity Score of 4 to 6 and evidence of a hyperinflammatory state were treated with standard care and either adjunctive rhu-pGSN 12 mg/kg or an equal volume of saline placebo given intravenously at entry, 12 hours, and 36 hours. The prespecified coprimary outcomes were survival without major respiratory, hemodynamic, or renal support on Day 14 and the incidence of serious adverse events (SAEs) during the 90-day study period.ResultsAll subjects receiving ≥1 dose of study drug were analyzed. Fifty-four of 61 subjects (88.5%) were WHO severity level 4 at entry. The proportions of subjects alive without support on Day 14 were 25 of 30 rhu-pGSN recipients (83.3%) and 27 of 31 placebo recipients (87.1%). Over the duration of the study, WHO Severity Scores improved similarly in both treatment groups. No statistically significant differences were observed between treatment groups at any time point examined. Two subjects died in each group. Numerically fewer subjects in the rhu-pGSN group had SAEs (5 subjects; 16.7%) or ≥ Grade 3 adverse events (5 subjects; 16.7%) than in the placebo group (8 subjects [25.8%] and 9 subjects [29.0%], respectively), mostly involving the lungs. Three rhu-pGSN recipients (10.0%) were intubated compared to 6 placebo recipients (19.4%).ConclusionsOverall, subjects in this study did well irrespective of treatment arm. When added to dexamethasone and remdesivir, no definitive benefit was demonstrated for rhu-pGSN relative to placebo. Safety signals were not identified after the administration of 3 doses of 12 mg/kg rhu-pGSN over 36 hours. The frequencies of SAEs and intubation were numerically fewer in the rhu-pGSN group compared with placebo.

Project description:BackgroundThere continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage.MethodsWe measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls.ResultsPhospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution.ConclusionsThe results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.

Project description:IntroductionMultiplex polymerase chain reaction (mPCR) for respiratory virus testing is increasingly used in community-acquired pneumonia (CAP), however data on one-year outcome in intensive care unit (ICU) patients with reference to the causative pathogen are scarce.Materials and methodsWe performed a single-center retrospective study in 123 ICU patients who had undergone respiratory virus testing for CAP by mPCR and with known one-year survival status. Functional status including dyspnea (mMRC score), autonomy (ADL Katz score) and need for new home-care ventilatory support was assessed at a one-year post-ICU follow-up. Mortality rates and functional status were compared in patients with CAP of a bacterial, viral or unidentified etiology one year after ICU admission.ResultsThe bacterial, viral and unidentified groups included 19 (15.4%), 37 (30.1%), and 67 (54.5%) patients, respectively. In multivariate analysis, one-year mortality in the bacterial group was higher compared to the viral group (HR 2.92, 95% CI 1.71-7.28, p = 0.02) and tended to be higher compared to the unidentified etiology group (p = 0.06); but no difference was found between the viral and the unidentified etiology group (p = 0.43). In 64/83 one-year survivors with a post-ICU follow-up consultation, there were no differences in mMRC score, ADL Katz score and new home-care ventilatory support between the groups (p = 0.52, p = 0.37, p = 0.24, respectively). Severe dyspnea (mMRC score = 4 or death), severe autonomy deficiencies (ADL Katz score ≤ 2 or death), and major adverse respiratory events (new home-care ventilatory support or death) were observed in 52/104 (50.0%), 47/104 (45.2%), and 65/104 (62.5%) patients, respectively; with no difference between the bacterial, viral and unidentified group: p = 0.58, p = 0.06, p = 0.61, respectively.ConclusionsCAP of bacterial origin had a poorer outcome than CAP of viral or unidentified origin. At one-year, impairment of functional status was frequently observed, with no difference according to the etiology.

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Low Admission Plasma Gelsolin Concentrations Identify Community-acquired Pneumonia Patients at High Risk for Severe Outcomes.

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Low Admission Plasma Gelsolin Concentrations Identify Community-acquired Pneumonia Patients at High Risk for Severe Outcomes.

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