Obtaining patient phenotypes in SARS-CoV-2 pneumonia, and their association with clinical severity and mortality.

BACKGROUND: There exists consistent empirical evidence in the literature pointing out ample heterogeneity in terms of the clinical evolution of patients with COVID-19. The identification of specific phenotypes underlying in the population might contribute towards a better understanding and characterization of the different courses of the disease. The aim of this study was to identify distinct clinical phenotypes among hospitalized patients with SARS-CoV-2 pneumonia using machine learning clustering, and to study their association with subsequent clinical outcomes as severity and mortality. METHODS: Multicentric observational, prospective, longitudinal, cohort study conducted in four hospitals in Spain. We included adult patients admitted for in-hospital stay due to SARS-CoV-2 pneumonia. We collected a broad spectrum of variables to describe exhaustively each case: patient demographics, comorbidities, symptoms, physiological status, baseline examinations (blood analytics, arterial gas test), etc. For the development and internal validation of the clustering/phenotype models, the dataset was split into training and test sets (50% each). We proposed a sequence of machine learning stages: feature scaling, missing data imputation, reduction of data dimensionality via Kernel Principal Component Analysis (KPCA), and clustering with the k-means algorithm. The optimal cluster model parameters -including k, the number of phenotypes- were chosen automatically, by maximizing the average Silhouette score across the training set. RESULTS: We enrolled 1548 patients, each of them characterized by 92 clinical attributes (d=109 features after variable encoding). Our clustering algorithm identified k=3 distinct phenotypes and 18 strongly informative variables: Phenotype A (788 cases [50.9% prevalence] - age ∼ 57, Charlson comorbidity ∼ 1, pneumonia CURB-65 score ∼ 0 to 1, respiratory rate at admission ∼ 18 min-1, FiO2 ∼ 21%, C-reactive protein CRP ∼ 49.5 mg/dL [median within cluster]); phenotype B (620 cases [40.0%] - age ∼ 75, Charlson ∼ 5, CURB-65 ∼ 1 to 2, respiration ∼ 20 min-1, FiO2 ∼ 21%, CRP ∼ 101.5 mg/dL); and phenotype C (140 cases [9.0%] - age ∼ 71, Charlson ∼ 4, CURB-65 ∼ 0 to 2, respiration ∼ 30 min-1, FiO2 ∼ 38%, CRP ∼ 152.3 mg/dL). Hypothesis testing provided solid statistical evidence supporting an interaction between phenotype and each clinical outcome: severity and mortality. By computing their corresponding odds ratios, a clear trend was found for higher frequencies of unfavourable evolution in phenotype C with respect to B, as well as more unfavourable in phenotype B than in A. CONCLUSION: A compound unsupervised clustering technique (including a fully-automated optimization of its internal parameters) revealed the existence of three distinct groups of patients - phenotypes. In turn, these showed strong associations with the clinical severity in the progression of pneumonia, and with mortality.

Pneumococcal Serotypes Associated with Community-Acquired Pneumonia Hospitalizations in Adults in Spain, 2016-2020: The CAPA Study.

Newer higher valency pneumococcal conjugate vaccines (PCVs) have the potential to reduce the adult community-acquired pneumonia (CAP) burden. We describe the evolution and distribution of adult community-acquired pneumonia (CAP) serotypes in Spain, focusing on serotypes contained in the 20-valent PCV (PCV20). This was a prospective, observational study of chest X-ray (CXR)-confirmed CAP in immunocompetent adults hospitalized in one of four Spanish hospitals between November 2016 and November 2020. Pneumococci were isolated from cultures and detected in urine using BinaxNow® and Pfizer serotype-specific urinary antigen tests UAD1 and UAD2. We included 1948 adults hospitalized with CXR-CAP. The median age was 69.0 years (IQR: 24 years). At least one comorbidity was present in 84.8% (n = 1653) of patients. At admission, 76.1% of patients had complicated pneumonia. Pneumococcus was identified in 34.9% (n = 680) of study participants. The PCV20 vaccine-type CAP occurred in 23.9% (n = 465) of all patients, 68.4% (n = 465) of patients with pneumococcal CAP, and 82.2% (83/101) of patients who had pneumococcus identified by culture. Serotypes 8 (n = 153; 7.9% of all CAP) and 3 (n = 152; 7.8% of all CAP) were the most frequently identified. Pneumococcus is a common cause of hospitalized CAP among Spanish adults and serotypes contained in PCV20 caused the majority of pneumococcal CAP.

Persistent Respiratory Failure and Re-Admission in Patients with Chronic Obstructive Pulmonary Disease Following Hospitalization for COVID-19.

Background: Chronic obstructive pulmonary disease (COPD) has been associated with worse clinical evolution/survival during a hospitalization for SARS-CoV2 (COVID-19). The objective of this study was to learn the situation of these patients at discharge as well as the risk of re-admission/mortality in the following 12 months. Methods: We carried out a subanalysis of the RECOVID registry. A multicenter, observational study that retrospectively collected data on severe acute COVID-19 episodes and follow-up visits for up to a year in survivors. The data collection protocol includes general demographic data, smoking, comorbidities, pharmacological treatment, infection severity, complications during hospitalization and required treatment. At discharge, resting oxygen saturation (SpO2), dyspnea according to the mMRC (modified Medical Research Council) scale and long-term oxygen therapy prescription were recorded. The follow-up database included the clinical management visits at 6 and 12 months, where re-admission and mortality were recorded. Results: A total of 2047 patients were included (5.6% had a COPD diagnosis). At discharge, patients with COPD had greater dyspnea and a greater need for prescription home oxygen. After adjusting for age, sex and Charlson comorbidity index, patients with COPD had a greater risk of hospital re-admission due to respiratory causes (HR 2.57 [1.35-4.89], p = 0.004), with no significant differences in survival. Conclusion: Patients with COPD who overcome a serious SARS-CoV2 infection show a worse clinical situation at discharge and a greater risk of re-admission for respiratory causes.

Expert Consensus: Main Risk Factors for Poor Prognosis in COVID-19 and the Implications for Targeted Measures against SARS-CoV-2.

The clinical evolution of patients infected with the Severe Acute Respiratory Coronavirus type 2 (SARS-CoV-2) depends on the complex interplay between viral and host factors. The evolution to less aggressive but better-transmitted viral variants, and the presence of immune memory responses in a growing number of vaccinated and/or virus-exposed individuals, has caused the pandemic to slowly wane in virulence. However, there are still patients with risk factors or comorbidities that put them at risk of poor outcomes in the event of having the coronavirus infectious disease 2019 (COVID-19). Among the different treatment options for patients with COVID-19, virus-targeted measures include antiviral drugs or monoclonal antibodies that may be provided in the early days of infection. The present expert consensus is based on a review of all the literature published between 1 July 2021 and 15 February 2022 that was carried out to establish the characteristics of patients, in terms of presence of risk factors or comorbidities, that may make them candidates for receiving any of the virus-targeted measures available in order to prevent a fatal outcome, such as severe disease or death. A total of 119 studies were included from the review of the literature and 159 were from the additional independent review carried out by the panelists a posteriori. Conditions found related to strong recommendation of the use of virus-targeted measures in the first days of COVID-19 were age above 80 years, or above 65 years with another risk factor; antineoplastic chemotherapy or active malignancy; HIV infection with CD4+ cell counts < 200/mm3; and treatment with anti-CD20 immunosuppressive drugs. There is also a strong recommendation against using the studied interventions in HIV-infected patients with a CD4+ nadir <200/mm3 or treatment with other immunosuppressants. Indications of therapies against SARS-CoV-2, regardless of vaccination status or history of infection, may still exist for some populations, even after COVID-19 has been declared to no longer be a global health emergency by the WHO.

Short- and long-term prognosis of patients with community-acquired Legionella or pneumococcal pneumonia diagnosed by urinary antigen testing.

OBJECTIVES: To analyze the differences in short- and long-term prognosis and the predictors of survival between patients with community-acquired Legionella and Streptococcus pneumoniae pneumonia, diagnosed early by urinary antigen testing (UAT). METHODS: Prospective multicenter study conducted in immunocompetent patients hospitalized with community-acquired Legionella or pneumococcal pneumonia (L-CAP or P-CAP) between 2002-2020. All cases were diagnosed based on positive UAT. RESULTS: We included 1452 patients, 260 with community-acquired Legionella pneumonia (L-CAP) and 1192 with community-acquired pneumococcal pneumonia (P-CAP). The 30-day mortality was higher for L-CAP (6.2%) than for P-CAP (5%). After discharge and during the median follow-up durations of 11.4 and 8.43 years, 32.4% and 47.9% of patients with L-CAP and P-CAP died, and 82.3% and 97.4% died earlier than expected, respectively. The independent risk factors for shorter long-term survival were age >65 years, chronic obstructive pulmonary disease, cardiac arrhythmia, and congestive heart failure in L-CAP and the same first three factors plus nursing home residence, cancer, diabetes mellitus, cerebrovascular disease, altered mental status, blood urea nitrogen ≥30 mg/dl, and congestive heart failure as a cardiac complication during hospitalization in P-CAP. CONCLUSION: In patients diagnosed early by UAT, the long-term survival after L-CAP or P-CAP was shorter (particularly after P-CAP) than expected, and this shorter survival was mainly associated with age and comorbidities.

Residual pulmonary infiltrates, symptoms and diffusion impairment at 1-year after severe COVID-19 infection have different associated factors.

INTRODUCTION: After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia, patients may show lung sequelae on radiology and functional impairment at the 1-year follow-up. We aimed to describe the persistence of symptoms, radiological alterations, or reduced diffusing capacity of the lung for carbon monoxide (DLCO ) at 1-year follow-up in patients from the Spanish Registry RECOVID. METHODS: RECOVID collected symptom and radiological and functional lung tests data on hospitalized patients with coronavirus disease 2019 during the acute phase and at the 6- and 12-month follow-up visits. RESULTS: Of the 2500 enrolled survivors (90% admitted to the ward), 1874 had follow-up visits for up to a year. Of these, 42% continued to present with symptoms, 27% had radiological sequelae and 31% had reduced DLCO . Independently associated factors included female sex, asthma and the requirement for invasive or non-invasive mechanical ventilation. Complete radiological resolution was 72.2% at 12 months; associated factors with incomplete recovery were age, male sex, oxygen or respiratory support, corticosteroids and an initial SpO2 /FiO2 <450 or CURB-65 ≥2. Reduced DLCO was observed in 31% of patients at 12 months; associated factors were older age, female sex, smoking habit, SpO2 /FiO2 <450 and CURB-65 ≥2 and the requirement of respiratory support.At 12 months, a proportion of the asymptomatic patients showed reduced DLCO (9.5%), radiological findings (25%) or both (11%). CONCLUSIONS: The factors associated with symptom persistence, incomplete radiological resolution and DLCO <80% differed according to age, sex, comorbidities and respiratory support. The burden of symptoms, reduced DLCO and incomplete radiological resolution were considerable in patients with SARS-CoV-2 pneumonia at the 1-year follow-up after hospitalisation.

Utility of Differential White Cell Count and Cell Population Data for Ruling Out COVID-19 Infection in Patients With Community-Acquired Pneumonia.

INTRODUCTION: The main aim of this study was to assess the utility of differential white cell count and cell population data (CPD) for the detection of COVID-19 in patients admitted for community-acquired pneumonia (CAP) of different etiologies. METHODS: This was a multicenter, observational, prospective study of adults aged ≥18 years admitted to three teaching hospitals in Spain from November 2019 to November 2021 with a diagnosis of CAP. At baseline, a Sysmex XN-20 analyzer was used to obtain detailed information related to the activation status and functional activity of white cells. RESULTS: The sample was split into derivation and validation cohorts of 1065 and 717 patients, respectively. In the derivation cohort, COVID-19 was confirmed in 791 patients and ruled out in 274 patients, with mean ages of 62.13 (14.37) and 65.42 (16.62) years, respectively (p<0.001). There were significant differences in all CPD parameters except MO-Y. The multivariate prediction model showed that lower NE-X, NE-WY, LY-Z, LY-WY, MO-WX, MO-WY, and MO-Z values and neutrophil-to-lymphocyte ratio were related to COVID-19 etiology with an AUC of 0.819 (0.790, 0.846). No significant differences were found comparing this model to another including biomarkers (p=0.18). CONCLUSIONS: Abnormalities in white blood cell morphology based on a few cell population data values as well as NLR were able to accurately identify COVID-19 etiology. Moreover, systemic inflammation biomarkers currently used were unable to improve the predictive ability. We conclude that new peripheral blood biomarkers can help determine the etiology of CAP fast and inexpensively.

Estimating the risk of bacteraemia in hospitalised patients with pneumococcal pneumonia.

OBJECTIVE: To construct a prediction model for bacteraemia in patients with pneumococcal community-acquired pneumonia (P-CAP) based on variables easily obtained at hospital admission. METHODS: This prospective observational multicentre derivation-validation study was conducted in patients hospitalised with P-CAP between 2000 and 2020. All cases were diagnosed based on positive urinary antigen tests in the emergency department and had blood cultures taken on admission. A risk score to predict bacteraemia was developed. RESULTS: We included 1783 patients with P-CAP (1195 in the derivation and 588 in the validation cohort). A third (33.3%) of the patients had bacteraemia. In the multivariate analysis, the following were identified as independent factors associated with bacteraemia: no influenza vaccination the last year, no pneumococcal vaccination in the last 5 years, blood urea nitrogen (BUN) ≥30 mg/dL, sodium <130 mmol/L, lymphocyte count <800/µl, C-reactive protein ≥200 mg/L, respiratory failure, pleural effusion and no antibiotic treatment before admission. The score yielded good discrimination (AUC 0.732; 95% CI: 0.695-0.769) and calibration (Hosmer-Lemeshow p-value 0.801), with similar performance in the validation cohort (AUC 0.764; 95% CI:0.719-0.809). CONCLUSIONS: We found nine predictive factors easily obtained on hospital admission that could help achieve early identification of bacteraemia. The prediction model provides a useful tool to guide diagnostic decisions.

Leukocyte differential and reactive lymphocyte counts from Sysmex XN analyzer in the evaluation of SARS-CoV-2 infection.

BACKGROUND: Leukocyte differential present certain features in COVID 19 patients. RE-LYMP (reactive lymphocytes) is an extended inflammation parameter (EIP) reported by XN analyzer (Sysmex Corporation, Kobe, Japan) reflect the activation of lymphocytes triggered by infections. We aimed to assess the clinical utility of these parameters as biomarkers for the rapid detection of COVID 19. METHODS: The study group included 200 COVID 19 and 167 patients with other infections at admission. Differences of leukocyte differential, neutrophil/lymphocyte ratio (NLR) and EIP among groups were assessed with the Kruskal-Wallis test; parameters statiscally different in the groups were tested with Receiver operating characteristic (ROC) curve analysis to assess their diagnostic performance in distinguishing SARS-CoV-2 infections. The reliability of the selected parameters was evaluated in a validation group of 347 patients (160 COVID 19 and 187 other infections). RESULTS: NLR performed well to discard viral infections, area under curve (AUC) 0.988 (95%CI 0.973 - 0.991) and RE-LYMP was useful to distinguish COVID 19 and bacterial infections AUC 0.920 (95%CI 0.884 - 0.948); the two conditions NLR> 3.3 RE-LYMP> 0.6% was applied to the validation group and 153 out of 160 COVID 19 patients were correctly distinguished (95.6%). CONCLUSIONS: Early diagnosis of SARS-CoV-2 infection is critical for better caring of patients and to reduce the threat of nosocomial infection for professionals. Leukocyte differential and RE-LYMPH could assist in a preliminary differential diagnosis of the disease.

The Evolution and Distribution of Pneumococcal Serotypes in Adults Hospitalized With Community-Acquired Pneumonia in Spain Using a Serotype-Specific Urinary Antigen Detection Test: The CAPA Study, 2011-2018.

BACKGROUND: Spain introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in the childhood National Immunization Program in 2015-2016 with coverage of 3 doses of 94.8% in 2018. We assessed the evolution of all pneumococcal, PCV13 vaccine type (VT), and experimental PCV20-VT (PCV13 + serotypes 8, 10A, 11A, 12F, 15B, 22F, 33F) hospitalized community-acquired pneumonia (CAP) in adults in Spain from 2011-2018. METHODS: A prospective observational study of immunocompetent adults (≥18 years) admitted to 4 Spanish hospitals with chest X-ray-confirmed CAP between November 2011 and November 2018. Microbiological confirmation was obtained using the Pfizer serotype-specific urinary antigen detection tests (UAD1/UAD2), BinaxNow test for urine, and conventional cultures of blood, pleural fluid, and high-quality sputum. RESULTS: Of 3107 adults hospitalized with CAP, 1943 were ≥65 years. Underlying conditions were present in 87% (n = 2704) of the participants. Among all patients, 895 (28.8%) had pneumococcal CAP and 439 (14.1%) had PCV13-VT CAP, decreasing from 17.9% (n = 77) to 13.2% (n = 68) from 2011-2012 to 2017-2018 (P = .049). PCV20-VT CAP occurred in 243 (23.8%) of those included in 2016-2018. The most identified serotypes were 3 and 8. Serotype 3 accounted for 6.9% (n = 215) of CAP cases, remaining stable during the study period, and was associated with disease severity. CONCLUSIONS: PCV13-VT caused a substantial proportion of CAP in Spanish immunocompetent adults 8 years after introduction of childhood PCV13 immunization. Improving direct PCV13 coverage of targeted adult populations could further reduce PCV13-VT burden, a benefit that could be increased further if PCV20 is licensed and implemented.

Predictors of mortality of COVID-19 in the general population and nursing homes.

The factors that predispose an individual to a higher risk of death from COVID-19 are poorly understood. The goal of the study was to identify factors associated with risk of death among patients with COVID-19. This is a retrospective cohort study of people with laboratory-confirmed SARS-CoV-2 infection from February to May 22, 2020. Data retrieved for this study included patient sociodemographic data, baseline comorbidities, baseline treatments, other background data on care provided in hospital or primary care settings, and vital status. Main outcome was deaths until June 29, 2020. In the multivariable model based on nursing home residents, predictors of mortality were being male, older than 80 years, admitted to a hospital for COVID-19, and having cardiovascular disease, kidney disease or dementia while taking anticoagulants or lipid-lowering drugs at baseline was protective. The AUC was 0.754 for the risk score based on this model and 0.717 in the validation subsample. Predictors of death among people from the general population were being male and/or older than 60 years, having been hospitalized in the month before admission for COVID-19, being admitted to a hospital for COVID-19, having cardiovascular disease, dementia, respiratory disease, liver disease, diabetes with organ damage, or cancer while being on anticoagulants was protective. The AUC was 0.941 for this model's risk score and 0.938 in the validation subsample. Our risk scores could help physicians identify high-risk groups and establish preventive measures and better follow-up for patients at high risk of dying.ClinicalTrials.gov Identifier: NCT04463706.

Impact of reducing the duration of antibiotic treatment on the long-term prognosis of community acquired pneumonia.

BACKGROUND: The optimal duration of antibiotic treatment for community-acquired pneumonia (CAP) is not well established. The aim of this study was to assess the impact of reducing the duration of antibiotic treatment on long-term prognosis in patients hospitalized with CAP. METHODS: This was a multicenter study assessing complications developed during 1 year of patients previously hospitalized with CAP who had been included in a randomized clinical trial concerning the duration of antibiotic treatment. Mortality at 90 days, at 180 days and at 1 year was analyzed, as well as new admissions and cardiovascular complications. A subanalysis was carried out in one of the hospitals by measuring C-reactive protein (CRP), procalcitonin (PCT) and proadrenomedullin (proADM) at admission, at day 5 and at day 30. RESULTS: A total of 312 patients were included, 150 in the control group and 162 in the intervention group. Ninety day, 180 day and 1-year mortality in the per-protocol analysis were 8 (2.57%), 10 (3.22%) and 14 (4.50%), respectively. There were no significant differences between both groups in terms of 1-year mortality (p = 0.94), new admissions (p = 0.84) or cardiovascular events (p = 0.33). No differences were observed between biomarker level differences from day 5 to day 30 (CRP p = 0.29; PCT p = 0.44; proADM p = 0.52). CONCLUSIONS: Reducing antibiotic treatment in hospitalized patients with CAP based on clinical stability criteria is safe, without leading to a greater number of long-term complications.

Q Fever (Coxiella Burnetii).

Q fever is a zoonotic infectious disease caused by the Coxiella burnetii bacterium. It is an obligate intracellular pathogen with a high infection capacity that proliferates exclusively in an acidified medium, forming a lysosome-like vacuole. It presents a peculiar phenomenon called "antigenic phase variation," produced by a modification in the complexity of the membrane lipopolysaccharides. Q fever can be found worldwide and presents variable clinical features and geographical distribution. It mostly affects people in rural areas who are in contact with animals. The most common type of transmission to humans is via the inhalation of aerosols containing the pathogen, especially those formed from placental derivatives. Wild animals, domestic animals, and ticks are the principal reservoirs.Diagnosis is mainly made by indirect methods such as serology or by direct methods such as microbiological cultures or tests that detect the specific DNA. Typically, there are two clinical presentations: the acute disease, which is more frequent and often asymptomatic, and a persistent focalized infection in 4 to 5% of patients, generally with a poor evolution. Treatment of the acute form in both children and adults consists of administering doxycycline, while persistent focalized infection should be treated with at least two antibiotics, such as doxycycline and hydroxychloroquine. Several measures should be undertaken to minimize exposure among people working with animals or handling birth products. Different vaccines have been developed to prevent infection, though few data are available.

Complications and hospital admission in the following 90 days after lung cryobiopsy performed in interstitial lung disease.

Transbronchial lung cryobiopsy (TBLC) is an emerging technique for the diagnosis of interstitial lung disease (ILD), but its risk benefit ratio has been questioned. The objectives of this research were to describe any adverse events that occur within 90 days following TBLC and to identify clinical predictors that could help to detect the population at risk. METHODS: We conducted an ambispective study including all patients with suspected ILD who underwent TBLC. Data were collected concerning the safety profile of this procedure and compared to various clinical variables. RESULTS: Overall, 257 TBLCs were analysed. Complications were observed in 15.2% of patients; nonetheless, only 5.4% of all patients required hospital admission on the day of the procedure. In the 30 and 90 days following the TBLC, rates of readmission were 1.3% and 3.5% and of mortality were 0.38%, and 0.78% respectively. Two models were built to predict early admission (AUC 0.72; 95% CI 0.59-0.84) and overall admission (AUC 0.76; 95% CI 0.67-0.85). CONCLUSIONS: Within 90 days after TBLC, 8.9% of patients suffered a complication serious enough to warrant hospital admission. Modified MRC dyspnoea score ≥2, FVC<50%, and a Charlson Comorbidity Index score ≥2 were factors that predicted early and overall admission.

Early and Late Cardiovascular Events in Patients Hospitalized for Community-Acquired Pneumonia. / Eventos cardiovasculares tempranos y tardíos en pacientes ingresados por neumonía adquirida en la comunidad.

INTRODUCTION: Community-acquired pneumonia increases the risk of cardiovascular events (CVE). The objective of this study was to analyze host, severity, and etiology factors associated with the appearance of early and late events and their impact on mortality. METHOD: Prospective multicenter cohort study in patients hospitalized for pneumonia. CVE and mortality rates were collected at admission, 30-day follow-up (early events), and one-year follow-up (late events). RESULTS: In total, 202 of 1,967 (10.42%) patients presented early CVE and 122 (6.64%) late events; 16% of 1-year mortality was attributed to cardiovascular disease. The host risk factors related to cardiovascular complications were: age ≥65 years, smoking, and chronic heart disease. Alcohol abuse was a risk factor for early events, whereas obesity, hypertension, and chronic renal failure were related to late events. Severe sepsis and Pneumonia Severity Index (PSI) ≥3 were independent risk factors for early events, and only PSI ≥3 for late events. Streptococcus pneumoniae was the microorganism associated with most cardiovascular complications. Developing CVE was an independent factor related to early (OR 2.37) and late mortality (OR 4.05). CONCLUSIONS: Age, smoking, chronic heart disease, initial severity, and S. pneumoniae infection are risk factors for early and late events, complications that have been related with an increase of the mortality risk during and after the pneumonia episode. Awareness of these factors can help us make active and early diagnoses of CVE in hospitalized CAP patients and design future interventional studies to reduce cardiovascular risk.

Community-Acquired Pneumonia Patients at Risk for Early and Long-term Cardiovascular Events Are Identified by Cardiac Biomarkers.

BACKGROUND: Community-acquired pneumonia (CAP) increases the risk of cardiovascular complications during and following the episode. The goal of this study was to determine the usefulness of cardiovascular and inflammatory biomarkers for assessing the risk of early (within 30 days) or long-term (1-year follow-up) cardiovascular events. METHODS: A total of 730 hospitalized patients with CAP were prospectively followed up during 1 year. Cardiovascular (proadrenomedullin [proADM], pro-B-type natriuretic peptide (proBNP), proendothelin-1, and troponin T) and inflammatory (interleukin 6 [IL-6], C-reactive protein, and procalcitonin) biomarkers were measured on day 1, at day 4/5, and at day 30. RESULTS: Ninety-two patients developed an early event, and 67 developed a long-term event. Significantly higher initial levels of proADM, proendothelin-1, troponin, proBNP, and IL-6 were recorded in patients who developed cardiovascular events. Despite a decrease at day 4/5, levels remained steady until day 30 in those who developed late events. Biomarkers (days 1 and 30) independently predicted cardiovascular events adjusted for age, previous cardiac disease, Pao2/Fio2 < 250 mm Hg, and sepsis: ORs (95% CIs), proendothelin-1, 2.25 (1.34-3.79); proADM, 2.53 (1.53-4.20); proBNP, 2.67 (1.59-4.49); and troponin T, 2.70 (1.62-4.49) for early events. For late events, the ORs (95% CIs) were: proendothelin-1, 3.13 (1.41-7.80); proADM, 2.29 (1.01-5.19); and proBNP, 2.34 (1.01-5.56). Addition of IL-6 levels at day 30 to proendothelin-1 or proADM increased the ORs to 3.53 and 2.80, respectively. CONCLUSIONS: Cardiac biomarkers are useful for identifying patients with CAP at high risk for early and long-term cardiovascular events. They may aid personalized treatment optimization and for designing future interventional studies to reduce cardiovascular risk.