Stroke-associated pneumonia according to mCDC criteria: impact on prognosis and antibiotic therapy.

Objective: The modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients. Methods: We conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis. Results: Of the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022-23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation. Interpretation: The mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.

Therapeutic effect of α7 nicotinic receptor activation after ischemic stroke in rats.

Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [18F]DPA-714 and [18F]BR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats. The assessment of brain oedema, blood brain barrier (BBB) disruption and neurofunctional progression after treatment was evaluated with T2 weighted and dynamic contrast-enhanced magnetic resonance imaging (T2 W and DCE-MRI) and neurological evaluation. The activation of α7 nAChRs resulted in a decrease of ischemic lesion, midline displacement and cell neurodegeneration from days 3 to 7 after ischemia. Besides, the treatment with PHA 568487 improved the neurofunctional outcome. Treated ischemic rats showed a significant [18F]DPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of α7 receptors displayed an increase of [18F]BR-351-PET signal in ischemic cortical regions, which resulted from the overactivation of MMP-2. Finally, the treatment with PHA 568487 showed a protective effect on BBB disruption and blood brain vessel integrity after cerebral ischemia.

IL1B and VWF variants are associated with fibrinolytic early recanalization in patients with ischemic stroke.

BACKGROUND AND PURPOSE: There is a great interindividual variability among patients with acute ischemic stroke regarding the response to intravenous tissue-type plasminogen activator treatment. The aim of this study was to identify genetic variants associated with recanalization, and thus treatment efficacy, after tissue-type plasminogen activator administration. METHODS: A total of 140 single nucleotide polymorphisms from 97 candidate genes were successfully genotyped by SNPlex in 2 cohorts, accounting for 497 prospectively recruited tissue-type plasminogen activator-treated patients, of whom 33% recanalized during tissue-type plasminogen activator infusion. Functional studies were then performed, including assessment of interleukin 1B mRNA levels and von Willebrand factor, FIII, FVII, FVIII, and FX protein activity. RESULTS: After replication, the following single nucleotide polymorphisms were associated with early recanalization: rs1143627 in IL1B gene (CC: 53.1% of recanalization, A-carriers: 32.7%; P=0.022; replication cohort: P=0.046), rs16944 in IL1B gene (AA: 50% of recanalization, G-carriers: 32%; P=0.038; replication cohort: P=0.049), and rs1063856 in the vWF gene (GG: 53.8% of recanalization, A-carriers: 31.5%; P=0.006; replication cohort: P=0.046). The functional studies revealed an association between the rs1063856 single nucleotide polymorphisms in vWF and FVIII activity (AA: 115.93%, AG: 156.07%, GG: 83.42%; P=0.005). CONCLUSIONS: Three single nucleotide polymorphisms were associated with tissue-type plasminogen activator efficacy in the Spanish population, and their mechanism of action might be associated with the activity of coagulation factors.

Role of the MMP9 gene in hemorrhagic transformations after tissue-type plasminogen activator treatment in stroke patients.

BACKGROUND AND PURPOSE: Despite the benefits of tissue-type plasminogen activator treatment, some stroke patients experience adverse hemorrhagic transformations (HT). Plasma protein levels of MMP9 have been associated with HT occurrence. We aimed to analyze the association of the MMP9 gene with HT occurrence. METHODS: We analyzed the MMP9 gene in blood samples from 885 stroke patients treated with tissue-type plasminogen activator by tag-SNP, imputed SNP, direct sequencing, and RNA expression. RESULTS: We did not observe any significant association between MMP9 genetic variations or MMP9 expression and HT occurrence. Moreover, no association was found between MMP9 expression and MMP9 polymorphisms. CONCLUSIONS: Genetic variations in the MMP9 gene are not associated with HT occurrence in tissue-type plasminogen activator-treated patients.

A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke.

OBJECTIVE: Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinical-genetic model for predicting t-PA response. METHODS: Our prospective study used SNPlex to genotype 140 single nucleotide polymorphisms (SNPs) from 97 candidate genes in 3 patient cohorts. The cohorts included 1,172 patients who were treated with t-PA; 20.9% of them developed HT as evaluated by systematic brain computed tomography scan, and 10.6% died. A predictive model was generated by logistic regression (LR). Functional studies included real time quantitative polymerase chain reaction, nephelometry, and Western blot for alpha-2-macroglobulin (A2M) and activated partial thromboplastin time measurement for coagulation factor XII (FXII). RESULTS: Replication analysis revealed that the SNP rs669 (Val1000Ile) in A2M was associated with HT, and rs1801020 (-4C>T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p < 3.57E-4). LR-based scores predicted HT occurrence (p = 9.13E-15) and in-hospital mortality (p = 8.7E-9) and were validated in an independent cohort. Val1000Ile modified A2M serum levels at baseline and after t-PA infusion, but not mRNA expression or protein structure; -4C>T affected FXII activity both prior to and after t-PA treatment. INTERPRETATION: Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population.