4G/5G Polymorphism of Plasminogen Activator Inhibitor -1 Gene Is Associated with Mortality in Intensive Care Unit Patients with Severe Pneumonia

2009 
Background: Higher plasma and pulmonary edema fluid levels of plasminogen activator inhibitor-1 (PAI-1) are associated with increased mortality in patients with pneumonia and acute lung injury. The 4G allele of the 4G/5G polymorphism of the PAI-1 gene is associated with higher PAI-1 levels and an increased incidence of hospitalizations for pneumonia. The authors hypothesized that the 4G allele would be associated with worse clinical outcomes (mortality and ventilator-free days) in patients with severe pneumonia. Methods: The authors enrolled patients admitted with severe pneumonia in a prospective cohort. Patients were followed until hospital discharge. DNA was isolated from blood samples, and genotyping detection for the PAI-1 4G/5G polymorphism was carried out using Taqman-based allelic discrimination. Results: A total of 111 patients were available for analysis. Distribution of genotypes was 4G/4G 26 of 111 (23%), 4G/5G 59 of 111 (53%), and 5G/5G 26 of 111 (23%). Of 111 patients, 32 (29%) died before hospital discharge and 105 patients (94%) received mechanical ventilation. Patients with the 4G/4G and the 4G/5G genotypes had higher mortality (35% vs. 8%, P 0.007) and fewer ventilator-free days (median 4 vs. 13, P 0.04) compared to patients with the 5G/5G genotype. Conclusions: The 4G allele of the 4G/5G polymorphism in the PAI-1 gene is associated with fewer ventilator-free days and increased mortality in hospitalized patients with severe pneumonia. These findings suggest that PAI-1 may have a role in pathogenesis and that the 4G/5G polymorphism may be an important biomarker of risk in patients with severe pneumonia. PROCOAGULANT activity is increased and anticoagulant and fibrinolytic activities are decreased in the alveoli of patients with pneumonia. Intraalveolar fibrin deposition, which is the hallmark of many acute inflammatory lung diseases, including pneumonia, exerts beneficial effects by sealing leakage sites when the capillary endothelium and alveolar epithelial barrier are compromised. However, when this process of fibrin deposition is severe and persistent, it can have deleterious effects. Excessive fibrin deposition enhances inflammatory responses by activating endothelial cells to produce proinflammatory mediators and an increase in vascular permeability. Fibrin is degraded by plasmin, a proteolytic enzyme that is present in the tissues in the form of an inactive precursor, plasminogen. The decreased fibrinolysis in patients with pneumonia is mainly attributed to elevation in plasminogen activator inhibitor–1 (PAI-1) activity. 1– 8 PAI-1 is activated during infection and has been shown to be elevated in the air spaces of patients with ventilator-associated pneumonia, aspiration pneumonia, and acute lung injury. 2–5,8 –11 Higher plasma and bronchoalveolar lavage (BAL) fluid levels of PAI-1 levels are associated with severe disease and adverse clinical outcomes both in patients with pneumonia and in patients with the acute respiratory distress syndrome. In patients with pneumonia, PAI-1 concentration in BAL fluid is higher in patients requiring mechanical ventilation than in those who do not require
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