COVID-19: A complex disease with a unique metabolic signature.

Plasma of COVID-19 patients contains a strong metabolomic/lipoproteomic signature, revealed by the NMR analysis of a cohort of >500 patients sampled during various waves of COVID-19 infection, corresponding to the spread of different variants, and having different vaccination status. This composite signature highlights common traits of the SARS-CoV-2 infection. The most dysregulated molecules display concentration trends that scale with disease severity and might serve as prognostic markers for fatal events. Metabolomics evidence is then used as input data for a sex-specific multi-organ metabolic model. This reconstruction provides a comprehensive view of the impact of COVID-19 on the entire human metabolism. The human (male and female) metabolic network is strongly impacted by the disease to an extent dictated by its severity. A marked metabolic reprogramming at the level of many organs indicates an increase in the generic energetic demand of the organism following infection. Sex-specific modulation of immune response is also suggested.

Delirium and IL-6 added to clinical scores improves their performance: a prospective analysis of CALL, PREDI-CO, MRS score applied to a population of patients admitted to internal medicine ward.

This study aimed to evaluate the effectiveness of various scoring systems in predicting in-hospital mortality for COVID-19 patients admitted to the internal medicine ward. We conducted a prospective collection of clinical data from patients admitted to the Internal Medicine Unit at Santa Maria Nuova Hospital in Florence, Italy, with confirmed pneumonia caused by SARS-CoV-2. We calculated three scoring systems: the CALL score, the PREDI-CO score, and the COVID-19 in-hospital Mortality Risk Score (COVID-19 MRS). The primary endpoint was in-hospital mortality. : A total of 681 patients were enrolled in the study, with a mean age of 68.8 ± 16.1 years, and 54.8% of them were male. Non-survivors had significantly higher scores in all prognostic systems compared to survivors (MRS: 13 [12- 15] vs. 10 [8-12]; CALL: 12 [10-12] vs. 9 [7-11]; PREDI-CO: 4 [3-6] vs. 2 [1-4]; all p<0.001). The receiver operating characteristic (ROC) analysis yielded the following area under the curve (AUC) values: MRS 0.85, CALL 0.78, PREDI-CO 0.77. The addition of Delirium and IL6 to the scoring systems improved their discriminative ability, resulting in AUC values of 0.92 for MRS, 0.87 for CALL, and 0.84 for PREDI-CO. The mortality rate increased significantly across increasing quartiles (p<0.001). In conclusion the COVID-19 in-hospital Mortality Risk Score (MRS) demonstrated reasonable prognostic stratification for patients admitted to the internal medicine ward with SARS-CoV-2-induced pneumonia. The inclusion of Delirium and IL6 as additional prognostic indicators in the scoring systems enhanced their predictive performance, specifically in determining in-hospital mortality among COVID-19 patients.

Profiling metabolites and lipoproteins in COMETA, an Italian cohort of COVID-19 patients.

Metabolomics and lipidomics have been used in several studies to define the biochemical alterations induced by COVID-19 in comparison with healthy controls. Those studies highlighted the presence of a strong signature, attributable to both metabolites and lipoproteins/lipids. Here, 1H NMR spectra were acquired on EDTA-plasma from three groups of subjects: i) hospitalized COVID-19 positive patients (≤21 days from the first positive nasopharyngeal swab); ii) hospitalized COVID-19 positive patients (>21 days from the first positive nasopharyngeal swab); iii) subjects after 2-6 months from SARS-CoV-2 eradication. A Random Forest model built using the EDTA-plasma spectra of COVID-19 patients ≤21 days and Post COVID-19 subjects, provided a high discrimination accuracy (93.6%), indicating both the presence of a strong fingerprint of the acute infection and the substantial metabolic healing of Post COVID-19 subjects. The differences originate from significant alterations in the concentrations of 16 metabolites and 74 lipoprotein components. The model was then used to predict the spectra of COVID-19>21 days subjects. In this group, the metabolite levels are closer to those of the Post COVID-19 subjects than to those of the COVID-19≤21 days; the opposite occurs for the lipoproteins. Within the acute phase patients, characteristic trends in metabolite levels are observed as a function of the disease severity. The metabolites found altered in COVID-19≤21 days patients with respect to Post COVID-19 individuals overlap with acute infection biomarkers identified previously in comparison with healthy subjects. Along the trajectory towards healing, the metabolome reverts back to the "healthy" state faster than the lipoproteome.

Predictors of poor outcome in tocilizumab treated patients with Sars-CoV-2 related severe respiratory failure: A multicentre real world study.

INTRODUCTION: Despite Tocilizumab is now recognized as a concrete therapeutic option in patients with severe SARS-CoV-2 related respiratory failure, literature lacks about factors influencing the response to it in this context. Therefore, the aim of our study was to provide evidence about predictors of poor outcome in Tocilizumab treated patients in the real-world practice. MATERIALS AND METHODS: We retrospectively analyzed clinical, laboratory and chest computer tomography (CCT) data of patients firstly admitted in non Intensive Care Units (ICU) and suffering from severe respiratory failure, who were treated with the IL-6 antagonist Tocilizumab. We compared patients who died and/or required admission to ICU with oro-tracheal intubation (OTI) with those who did not. RESULTS: Two hundreds and eighty-seven patients (29.9% females) with mean age ± SD 64.1 ± 12.6 years were the study population. In-hospital mortality was 18.8%, while the composite endpoint in-hospital mortality and/or ICU admission with OTI occurred in 23.7%. At univariate analysis, patients who died and/or were admitted to ICU with OTI were significantly older and co-morbid, had significantly higher values of creatinine, C-reactive protein (CRP) and procalcitonin and lower lymphocytes count, PaO2/FiO2 ratio (P/F) and room air pulsossimetry oxygen saturation (RAO2S) at hospital admission. Computed tomography ground glass opacities (CT-GGO) involving the pulmonary surface ≥ 50% were found in 55.4% of patients who died and/or were admitted to ICU with OTI and in 21.5% of patients who did not (p=0.0001). At multivariate analysis, age ≥ 65 years (OR 17.3, 95% CI: 3.7-81.0), procalcitonin ≥ 0.14 (OR 9.9, 95%CI: 1.7-56.1), RAO2S ≤ 90% (OR 4.6, 95%CI: 1.2-17.0) and CCT-GGO involvement ≥ 50% (OR 5.1, 95%CI: 1.2-21.0) were independent risk factors associated with death and/or ICU admission with OTI. CONCLUSION: Tocilizumab has shown to improve outcome in patients with severe respiratory failure associated to SARS-CoV-2 related pneumonia. In our multicentre study focusing on Tocilizumab treated severe COVID-19 patients, age ≥ 65 years, procalcitonin ≥ 0.14 ng/mL, RAO2S ≤ 90% and CCT-GGO involvement ≥ 50% were independent factors associated with poor outcome.

Acute cardiovascular events in patients with community acquired pneumonia: results from the observational prospective FADOI-ICECAP study.

BACKGROUND: The burden of cardiovascular (CV) complications in patients hospitalised for community-acquired pneumonia (CAP) is still uncertain. Available studies used different designs and different criteria to define CV complications. We assessed the cumulative incidence of acute of CV complications during hospitalisation for CAP in Internal Medicine Units (IMUs). METHODS: This was a prospective study carried out in 26 IMUs, enrolling patients consecutively hospitalised for CAP. Defined CV complications were: newly diagnosed heart failure, acute coronary syndrome, new onset of supraventricular or ventricular arrhythmias, new onset hemorrhagic or ischemic stroke or transient ischemic attack. Outcome measures were: in-hospital and 30-day mortality, length of hospital stay and rate of 30-day re-hospitalisation. RESULTS: A total of 1266 patients were enrolled, of these 23.8% experienced at least a CV event, the majority (15.5%) represented by newly diagnosed decompensated heart failure, and 75% occurring within 3 days. Female gender, a history of CV disease, and more severe pneumonia were predictors of CV events. In-hospital (12.2% vs 4.7%, p < 0.0001) and 30-day (16.3% vs 8.9%, p = 0.0001) mortality was higher in patients with CV events, as well as the re-hospitalisation rate (13.3% vs 9.3%, p = 0.002), and mean hospital stay was 11.4 ± 6.9 vs 9.5 ± 5.6 days (p < 0.0001). The occurrence of CV events during hospitalisation significantly increased the risk of 30-day mortality (HR 1.69, 95% CI 1.14-2.51; p = 0.009). CONCLUSION: Cardiovascular events are frequent in CAP, and their occurrence adversely affects outcome. A strict monitoring might be useful to intercept in-hospital CV complications for those patients with higher risk profile. TRIAL REGISTRATION: NCT03798457 Registered 10 January 2019 - Retrospectively registered.

Safety of Anticoagulation in Patients Treated With Urgent Reperfusion for Ischemic Stroke Related to Atrial Fibrillation.

BACKGROUND AND PURPOSE: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention. METHODS: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features. RESULTS: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50-1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53-2.02]). CONCLUSIONS: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation-related acute ischemic stroke, who started on oral anticoagulant.

Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes.

INTRODUCTION: The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing. MATERIALS AND METHODS: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. RESULTS: A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80). DISCUSSION: our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events. CONCLUSIONS: Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.

Management of oral anticoagulation in very old patients with non valvular atrial fibrillation related acute ischemic stroke.

The optimal management of oral anticoagulation (OAC) in the acute phase of non valvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) remains controversial, especially in very old patients. Therefore, the aim of our study was to evaluate the practical management of OAC in this context. We conducted an observational retrospective study on patients 85-years old and older admitted to two Italian hospitals for NVAF-related AIS. For each patient, clinical and brain computed tomography data were recorded. Type of OAC (vitamin K antagonists, VKAs or Direct Oral Anticoagulants, DOACs), dosage and starting day after AIS were registered. For each patient 90-day all cause mortality, stroke recurrence, any bleeding and modified Rankin scale (mRS) were reported. One-hundred-seventeen patients, with mean age 89.2 ± 3.4 years, were enrolled. In-hospital and 90-day mortality (out of 109 patients) were 6% and 19.7%, respectively. OAC was started in 93 patients (80.5%), on average after 6 ± 3 days from the acute event. Of them, 88 patients (94.6%) received DOACs, while 5 (5.4%) received VKAs. Patients receiving OAC were significantly younger and suffering from less severe stroke compared with patients who did not receive OAC. Patients receiving OAC presented a reduced in-hospital (2.2% vs. 20.8%, p < 0.004) and 90-day all-cause mortality (9.4% vs. 62.5%, p < 0.001). In patients receiving DOACs, low dosages were used in 87.5% of patients. The use of OAC was not associated with an increased rate of hemorrhagic transformation (HT) during hospitalization (13.2% vs. 9.5%, p = 0.54) or any bleeding at 90-day follow-up. Severe dysphagia and mRS ≥ 4 were found to be independent risk factors for not prescribing OAC. The optimal management of OAC in very old patients suffering from NVAF-related AIS remains a dilemma. In our real world study the majority of patients received OAC as secondary prevention treatment without increase in bleeding risk. Dysphagia and severe disability were independent factors for not prescribing OAC. Further investigations aimed at identifying the optimal approach to OAC during the acute phase of NVAF-related ischemic stroke in this subgroup of patients are warranted.

Early recurrence in paroxysmal versus sustained atrial fibrillation in patients with acute ischaemic stroke.

BACKGROUND: The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear. PURPOSE: In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation. METHODS: In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke. RESULTS: A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24-2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74-2.04)). CONCLUSIONS: After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

Anticoagulation After Stroke in Patients With Atrial Fibrillation.

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P<0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Direct Oral Anticoagulants in Patients Undergoing Urgent Reperfusion for Nonvalvular Atrial Fibrillation-Related Ischemic Stroke: A Brief Report on Literature Evidence.

INTRODUCTION: The optimal timing for starting anticoagulation in the early phase of nonvalvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) remains a challenge, especially in patients undergoing urgent reperfusion by systemic thrombolysis or mechanical thrombectomy. The aim of our study was to review the literature evidence reporting on safety of direct oral anticoagulants (DOACs) starting in the early phase of NVAF-related AIS undergoing systemic thrombolysis and/or mechanical thrombectomy. MATERIALS AND METHODS: We reviewed the PubMed databases searching articles reporting on efficacy and safety of DOACs starting time within two weeks from AIS onset in patients undergoing systemic thrombolysis and/or mechanical thrombectomy. RESULTS: Three studies were selected, overall including one hundred and six patients (62 females, 58.4%). Median National Institute of Health Stroke Scale (NIHSS) score at hospital admission ranged from 9 to 13 points. Median DOACs starting time ranged from 2 to 6 days. Median CHA2DS2-VASC score ranged from 4 to 6 points. Follow-up was limited to 14 days in one study, 30 days in another, and 90 days in a third one. Overall, stroke recurrence and/or intracranial bleeding occurred in two patients (1.9%) and no patient died at follow-up. CONCLUSION: Small sample size real life studies seem to demonstrate that the introduction of DOACs in the early phase of NVAF-related AIS undergoing urgent reperfusion is efficacious and safe. Prospective RCTs are necessary to confirm these findings.

Performance of the CHA2DS2-VASc score in predicting new onset atrial fibrillation during hospitalization for community-acquired pneumonia.

BACKGROUND: Cardiovascular events are common during hospitalization for community-acquired pneumonia (CAP), with new onset atrial fibrillation (NOAF) being the second most relevant complication. In this study, we aimed to investigate the role of CHA2DS2-VASc score in predicting NOAF during hospitalization for CAP. METHODS: Patients admitted for CAP were prospectively assessed using CHA2DS2-VASc. The end-point of the study was the occurrence of any objectively documented episode of NOAF during hospitalization in patients that were in sinus rhythm at hospital admission. RESULTS: Of 468 patients enrolled (median age 76 years), 48 (10.3%) experienced NOAF during hospitalization. They were older, had more comorbidities, more severe pneumonia, and higher CHA2DS2-VASc than those who remained in sinus rhythm (4.4 ±â€¯1.6 vs 3.4 ±â€¯1.9, respectively; p < .0001). There was a direct relationship between CHA2DS2-VASc score and risk of NOAF. At ROC curve analysis, a CHA2DS2-VASc score > 3 was the most accurate cut-off for prediction of NOAF (AUC 0.653; 95% CI 0.577-0.729; p = .001). In two different multivariable models, each CHA2DS2-VASc point increase and a score > 3 both were independently associated with NOAF (HR 1.3; 95% CI 1.09-1.55; p = .003 and 2.3; 95% CI 1.19-4.44; p = .007, respectively). CONCLUSIONS: CHA2DS2-VASc score is an accurate and independent predictor of NOAF in patients with CAP, and a score > 3 features a population at high risk of developing the arrhythmia during hospitalization. This simple and effective tool should be incorporated in the evaluation of patients hospitalized for CAP, with implications ranging from arrhythmic prevention to anticoagulation management.

Direct oral anticoagulants in the early phase of non valvular atrial fibrillation-related acute ischemic stroke: focus on real life studies.

Strong evidence for the use of direct oral anticoagulants (DOACs) in the early phase of non valvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) is lacking, because this kind of patients were excluded from phase III randomized clinical trials (RCT) and ad hoc RCTs are ongoing. In the latest years a lot of real life studies on this topic have been published. The aim of our review was to focus on these. We reviewed the PubMed databases searching articles reporting on DOACs starting time within 2 weeks from AIS onset. We selected fifteen studies, eight with retrospective, six with prospective observational and one with a prospective, open-label, single arm design. Overall, 2920 patients (47.8% females) were included. In twelve studies median or mean age of patients was over 75 years. Mean or median NIHSS ad hospital admission was ≤ 12 in all studies. About one-third of patients (32.4%) received urgent reperfusion by systemic thrombolysis or mechanical thrombectomy. About one-fifth of patients (22.8%) had large infarct size. Median starting time of DOACs was reported in thirteen studies and it ranged from 2 to 8 days. About one-half of patients (45.9%) received a low dose of DOACs. In studies reporting on median or mean CHA2DS2-VASC score, it was ≥ 3 in all. In studies reporting on median or mean HAS-BLED score, it was ≥ 2 in all. Ninety-day follow-up was available for nine studies, overall including about 2200 patients. Incidence of 90-day TIA/stroke recurrence, symptomatic haemorrhagic transformation or intracranial bleeding and all cause mortality was 2.25%, 0.90% and 1.5%, respectively. The real life evidence suggests that early starting of DOACs in patients with NVAF-related AIS is safe and associated with low recurrence risk and all-cause mortality.

A Hypothesis-Generating Study of the Combination of Aspirin plus Macrolides in Patients with Severe Community-Acquired Pneumonia.

While the inflammatory response to severe pneumonia is paramount in limiting and resolving the infection, excessive inflammation can lead to deleterious effects. We theorized that patients with severe community-acquired pneumonia (CAP) who were treated with macrolides and aspirin would receive benefit beyond that of conventional antibiotic therapy. An observational study was conducted with patients with severe CAP. All patients were admitted to 5 teaching hospitals (in Italy, the United States, Japan, and China), and data were gathered from their electronic medical records. Severe pneumonia was defined according to Infectious Diseases Society of America/American Thoracic Society criteria. Patients were divided into 4 groups, i.e., (i) the aspirin-only group (ASG), (ii) the macrolide-only group (MG), (iii) the aspirin plus macrolide group (ASMG), or (iv) the neither aspirin nor macrolide group (NASMG). Survival rates for the 4 groups were evaluated after adjustment for confounders and after weighting by propensity score. A total of 1,295 patients were included in the analysis. There were 237 patients (18.3%) in the ASG, 294 (22.7%) in the MG, 148 (11.4%) in the ASMG, and 616 (47.6%) in the NASMG. The mortality rate at 30 days was 15.5% in the ASMG, compared to 28.2% in the NASMG, 23.8% in the MG, and 21.1% in the ASG. After propensity score analysis, receipt of aspirin plus macrolide (hazard ratio, 0.71 [95% confidence interval, 0.58 to 0.88]; P = 0.002) was associated with a higher 30-day survival rate. This is a hypothesis-generating study in which data suggest that the combination of aspirin plus a macrolide improves 30-day survival rates for patients with severe CAP. Further randomized studies will need to be undertaken to confirm this phenomenon.

Hemorrhagic Transformation in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Time to Initiation of Oral Anticoagulant Therapy and Outcomes.

Background In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation ( HT ). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT , (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT . Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3-8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0-6.0) of those without HT ; 53.1% of patients with  HT were deceased or disabled compared with 35.8% of those without HT . On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24-2.35). Conclusions In patients with HT , anticoagulation was initiated about 12 days later than patients without HT . This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability.