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Archives of cardiovascular diseases
Volume 107, n° 5
pages 299-307 (mai 2014)
Doi : 10.1016/j.acvd.2014.04.008
Received : 11 January 2014 ;  accepted : 22 April 2014
Red cell distribution width predicts mortality in infective endocarditis
Le biomarqueur de distribution érythrocytaire prédicteur de la mortalité dans l’endocardite infectieuse
 

Yesim Guray a, Esra Gucuk Ipek a, , Umit Guray a, Burcu Demirkan a, Habibe Kafes a, Lale Dinc Asarcikli a, Gizem Cabuk a, Mehmet Birhan Yilmaz b
a Yuksek Ihtisas Education and Research Hospital, Department of Cardiology, Ankara, Turkey 
b Cumhuriyet University Faculty of Medicine, Department of Cardiology, Sivas, Turkey 

Corresponding author at: Mutlukervan Sitesi 1, Blok No 11, Çayyolu, Ankara 06810, Turkey.
Summary
Background

Infective endocarditis (IE) is associated with significant morbidity and mortality. Red cell distribution width (RDW) is a recently recognized biomarker of adverse outcome in a number of acute and chronic conditions.

Aim

To investigate the relationship between RDW and 1-year survival in patients with IE.

Methods

Clinical records from two tertiary centres were used to analyze data from patients with definite IE. Clinical, echocardiographic and biochemical variables were evaluated along with RDW. One-year survival status after index hospitalization was identified for each patient.

Results

One hundred consecutive patients (mean age 47.8±16.7years; 61% men) with definite IE were enrolled. According to receiver operating characteristic curve analysis, the optimal RDW cut-off value for predicting mortality was 15.3% (area under the curve 0.70; P =0.001). Forty-one patients (41%) died within 1year; of these, 88% had RDW results>15.3%. Univariate Cox proportional-hazards analysis showed that RDW>15.3%, heart failure, renal failure, cardiac abscess, severe valvular regurgitation and presence of dehiscence were associated with increased mortality. Multivariable Cox proportional-hazards analysis revealed that renal failure (hazard ratio [HR] 3.21, 95% confidence interval [CI] 1.35–7.59; P =0.008), heart failure (HR 2.77, 95% CI 1.1–6.97; P =0.03) and RDW>15.3% (HR 3.07, 95% CI 1.06–8.86; P =0.03) were independent predictors of mortality in patients with IE.

Conclusion

According to our results, mortality is high in patients with IE. RDW is a promising biomarker for predicting 1-year survival rates in these patients.

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Résumé
Justification

L’endocardite infectieuse est associée à une augmentation de la morbi-mortalité significative. La distribution érythrocytaire est un biomarqueur de description récente prédisant les complications dans différentes situations aiguës et chroniques.

Objectif

Évaluer la relation entre ce biomarqueur et la survie à un an chez des patients hospitalisés pour endocardite infectieuse.

Méthode

Les dossiers cliniques de deux centres tertiaires ont été utilisés pour analyser les informations à partir des dossiers de patients ayant une endocardite infectieuse certaine. Les données cliniques, échocardiographiques et biochimiques ont été évaluées parallèlement à l’évaluation de ce biomarqueur. La survie à un an après l’hospitalisation initiale a été identifiée pour chaque patient.

Résultats

Cent patients consécutifs (âge moyen 47,8±16,7ans ; 61 % d’hommes) ayant une endocardite infectieuse certaine ont été inclus. En utilisant l’analyse basée sur les surfaces sous la courbe ROC, la valeur seuil optimale pour ce biomarqueur prédisant la mortalité était de 15,3 % (surface sous la 0,70 ; p =0,001). Quarante et un patients (41 %) sont décédés dans l’année. Parmi eux 88 % avaient un taux de biomarqueur>15,3 %. L’analyse univariée selon le modèle proportionnel de Cox a montré qu’une valeur>15,3, la présence d’une insuffisance cardiaque, d’une insuffisance rénale, d’un abcès cardiaque, une régurgitation valvulaire significative et la présence d’une déhiscence valvulaire étaient associées à une surmortalité. L’analyse multivariée selon le modèle de Cox a indiqué que l’insuffisance rénale (hazard ratio [HR] 3,21, IC 95 % 1,35–7,59 ; p =0,008), l’insuffisance cardiaque (HR 2,77, IC 95 % 1,1–6,97 ; p =0,03) et le biomarqueur de distribution érythrocytaire>15,3 % (HR 3,07 ; IC 95 % 1,06–8,86 ; p =0,03).

Conclusion

Nos résultats suggèrent qu’il existe une surmortalité chez les patients ayant une endocardite infectieuse. Ce biomarqueur paraît intéressant pour prédire la survie à un an chez les patients hospitalisés pour endocardite infectieuse confirmée.

The full text of this article is available in PDF format.

Keywords : Infective endocarditis, Outcome, Red cell distribution width

Mots clés : Endocardite infectieuse, Suivi, Distribution érythrocytaire

Abbreviations : IE, RDW, ROC


Background

Infective endocarditis (IE) is an endovascular infection of the heart that usually affects valvular structures and, with increasing frequency, implants within the heart, such as prosthetic valves or pacemaker electrodes. There have been significant improvements in the treatment of most cardiovascular diseases in recent decades; however, prognosis still remains poor in IE. The current in-hospital mortality rate is around 20%, while long-term mortality can be as high as 40% [1, 2, 3].

Identifying patients at increased risk of adverse outcomes is challenging due to the broad spectrum of the cardiac pathology and infecting organisms. Right-sided native-valve IE usually has a benign course, with even a short-term antibiotic regimen being sufficient, while prosthetic IE or device-related IE can be more severe, requiring different management strategies [4]. The causative organism can differ depending on the history of surgery, drug abuse, healthcare contact, invasive procedures, immunosuppression and even geographical differences [3]. Although some clinical predictors have been identified to estimate poor outcome, the course of the disease can still differ in each individual [5]. A biomarker that predicts outcome would be helpful in clinical practice to identify high-risk patients that need more aggressive treatment.

Red cell distribution width (RDW) – a measure of red blood cell size heterogeneity – has been used traditionally in the differential diagnosis of anaemia, as it can increase in cases of haemolysis, blood transfusion or ineffective erythropoiesis. Recent studies have shown that elevated RDW is associated with adverse outcome in various clinical settings, including thromboembolic events, cardiovascular diseases and respiratory diseases [6, 7, 8, 9]. The prognostic implications of RDW in IE have not been studied. In the present study, we aimed to investigate the relationship between RDW and 1-year survival in patients with IE.

Methods
Study patients

Between January 2008 and January 2011, patients diagnosed with definite IE (according to the modified Duke criteria) at Cumhuriyet University Faculty of Medicine and Yuksek Ihtisas Education and Research Hospitals were enrolled in this study [10]. Patients with chronic liver disease and those with a history of haematological disease other than anaemia (such as leukaemia, myeloproliferative diseases or bone marrow infiltration) were excluded. The prospective data of 100 consecutive IE patients were analysed retrospectively. In addition to RDW levels on admission, clinical, echocardiographic and laboratory findings were recorded for each subject. Predisposing heart diseases, including prosthetic valve, pre-existing valvular disease (rheumatic heart disease and degenerative valves), congenital heart disease, implantable cardiac device, nosocomial infection, previous history of IE, malignancy and immunosuppression were assessed.

Complications during hospitalization, such as heart failure, renal failure, abscess formation, embolic events (excluding cerebral), cerebrovascular events and surgical treatment for IE, were recorded. Duration of hospital stay and in-hospital mortality were noted. Cerebrovascular events were defined in case of the following presentations: intracranial haemorrhage; ischaemic stroke; or transient ischaemic attacks. Renal failure was defined by serum creatinine concentration>2mg/dL during hospital stay. Anaemia was defined according to the World Health Organization criteria (haemoglobin<13g/dL in men and<12g/dL in women). The study endpoint was the incidence of all-cause death within 1year after index hospitalization. Clinical event data were collected during the follow-up period for all patients by reviewing medical files and by telephone contact. The study was performed in accordance with the Declaration of Helsinki for human research and was approved by the local ethics committee.

Laboratory

Blood samples were obtained after admission, following overnight fasting. Baseline RDW, haemoglobin, haematocrit, platelet count and white blood cell count values were measured using an automated haematology analyser. C-reactive protein, glucose and creatinine concentrations were measured accordingly. At least three sets of blood samples for cultures were obtained from each patient immediately after hospital admission. Any other available fluid, tissue (valves, vegetations or intracardiac abscesses removed at surgery) or foreign body samples (pacemaker leads, catheters) were used to isolate microorganisms.

Echocardiography

All patients underwent two-dimensional transthoracic echocardiography within 24hours of admission. Echocardiographic examinations were performed with the Vivid 7 system (GE Healthcare, Wauwatosa, WI, USA) in two participating centres. Transoesophageal echocardiography was performed when image quality with transthoracic echocardiography was insufficient for an accurate diagnosis or in cases of high clinical suspicion of IE, prosthetic valve involvement and suspicion of complications. Vegetation, abscess formation and valvular destruction, such as perforation of leaflet and chordal rupture, were evaluated. Vegetation size was measured by using different echocardiographic windows; the maximal length was obtained. Existence of rocking motion of the prosthetic valve with an excursion of>15° in at least one direction gave the diagnosis of dehiscence. Left ventricular ejection fraction was calculated by the modified Simpson's method. Severe valvular regurgitation was identified according to guideline recommendations [11]. Pulmonary artery systolic pressure was estimated by continuous wave Doppler imaging of the tricuspid regurgitation using the Bernoulli equation [12].

Statistics

Continuous variables were expressed as mean±standard deviation or median with interquartile range; categorical variables were expressed as number and percentage. A chi-square test or Fisher's exact test was performed to compare categorical variables. The normality of distributions of variables was assessed using the Kolmogorov-Smirnov test. Student's t -test was used for normally distributed continuous variables; the Mann-Whitney U test was used when the distribution was skewed. The discrimination of RDW for 1-year survival was evaluated using the area under the receiver operating characteristic (ROC) curve. The optimal cut-off point for ROC curves was determined for maximizing the sensitivity and specificity of the RDW values. Patients with IE were categorized into two groups on the basis of the cut-off value. Kaplan-Meier cumulative survival curves were used to display survival in two patient subgroups and log-rank values were calculated to assess the statistical significance. Univariate Cox proportional-hazards analyses were used to evaluate the relationship between variables and overall mortality. Variables that had a P value<0.1 in the univariate analysis were used in a multivariable Cox proportional-hazards model to determine the independent prognostic factors of mortality. The results of the regression analysis are presented as hazard ratios and 95% confidence intervals. All statistical analyses were performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA). A P value of 0.05 was considered statistically significant.

Results

One hundred patients, who met the inclusion criteria, with men comprising 61% of the cohort, were enrolled in our study. The mean age was 47.8±16.7years. The mean duration of hospital stay was 34.95±19.4days. Staphylococcus species were the most common microorganisms. Prosthetic valves were the prominent predisposing factor in the study cohort. There were 45 cases of prosthetic valve IE, 36 cases of native-valve IE, 10 cases of congenital heart disease-related IE and nine cases of device-related IE. Twenty-six patients died during the index hospitalization. Forty-one patients (41%) died within 1year. Table 1 shows the differences between survivors and non-survivors regarding demographic, clinical and echocardiographic properties. Renal failure, heart failure, cardiac abscess and severe valvular regurgitation were significantly more common among non-survivors, whereas having surgery due to IE was associated with lower mortality.

RDW was significantly increased in fatal cases (P =0.01). Figure 1 shows median RDW values in survivors and non-survivors. According to ROC curve analysis, the optimal cut-off value of RDW results on admission for predicting 1-year mortality was>15.3%, with 88% sensitivity and 53% specificity (area under the curve 0.70, 95% CI 0.59–0.80; P =0.001). To evaluate associations between RDW and clinical outcome, patients were divided into two groups according to this RDW cut-off value (≤15.3% vs.>15.3%). The properties of these subgroups were compared, as shown in Table 2. In-hospital complications such as heart failure, renal failure, cerebrovascular events and severe valvular regurgitation were more common in patients with increased RDW. Systolic pulmonary artery pressures were elevated in this group compared with in the lower RDW group. Also, C-reactive protein concentrations were higher and Staphylococcus aureus infection was more common in patients with increased RDW.



Figure 1


Figure 1. 

Comparison of median red cell distribution width (RDW) values in survivors and non-survivors.

Zoom

According to Kaplan-Meier survival analysis, there was a significant reduction in survival rates within 1year in patients with increased RDW compared with in the lower RDW group (P =0.0001). Figure 2 displays survival curves in these patient subgroups, derived from Kaplan-Meier survival analysis. Results of the univariate and multivariable Cox proportional-hazards analyses for mortality are listed in Table 3. RDW>15.3%, heart failure, renal failure, cardiac abscess, severe valvular regurgitation and presence of dehiscence were associated with increased mortality in the univariate Cox proportional-hazards analysis. In the multivariable Cox proportional-hazards analysis, RDW>15.3%, renal failure and heart failure remained independent predictors of mortality in IE.



Figure 2


Figure 2. 

Kaplan-Meier survival curves in patients with lower and higher red cell distribution width (RDW) values. Cum: cumulative.

Zoom

Discussion

In our study cohort, 41 (41%) patients died during the follow-up period of 1year; among the fatal cases, 26 (26%) patients died during hospital stay. IE related complications, in-hospital mortality rate and overall mortality rate were higher compared with results published previously [1, 2, 3]. The participating institutions were both tertiary care centres and the patient group may have had more co-morbid conditions than the general population, as more severe or complicated cases may have been referred from other institutions. The mean age of the study subjects was lower and prosthetic valve was more common compared with European data, probably due to higher prevalence of rheumatic valve disease in our country [3, 13].

The most remarkable finding of our study was the association of RDW with outcome. Survival was significantly lower in the increased RDW group, with higher in-hospital and overall mortality rates. In the Cox proportional-hazards analysis, elevated RDW on admission was an indicator of 1-year survival before and after adjusting for other potential confounders. In addition to its relationship with mortality, complications of IE and in-hospital events were more common in subjects with elevated RDW. Our results suggest that RDW may become a valuable biomarker for estimating poor outcome in these patients. To the best of our knowledge, this is the first study that has evaluated the association of RDW with mortality in IE.

RDW is a recently proposed biomarker of adverse outcomes. Studies have reported that higher RDW is an independent predictor of mortality in a broad spectrum of cardiovascular diseases, such as heart failure, stable coronary disease, acute coronary syndrome, acute pulmonary embolism and pulmonary hypertension [6, 8, 9, 14, 15]. Besides mortality, RDW also predicts morbidity, such as recurrent hospital admissions or recurrent infarctions in patients with acute coronary syndromes [15, 16].

Although information regarding the role of RDW in IE is not available in the literature, it has been studied in systemic infections and inflammatory diseases. In a recent study, an association between RDW and mortality was demonstrated in patients with severe sepsis and septic shock [17]. In another study, elevated RDW levels were related to increased short-term mortality in patients with gram-negative bacteraemia [18]. Braun et al. found that elevated RDW predicted longer hospital stay, intensive care admissions and 90-day mortality in young patients with community-acquired pneumonia [19]. In a study by Hu et al., RDW was correlated with disease activity in systemic lupus erythematosus, a chronic disease that resembles IE, with immune complexes and active inflammatory status [20]. Similar results were observed in a study of inflammatory bowel disease [21]. According to our findings, C-reactive protein was increased in patients with elevated RDW, suggesting that inflammatory status was more aggravated in these patients. In a study of 3845 outpatients, RDW had a strong relationship with C-reactive protein, independent of confounding factors [22].

The mechanism of the association between increased RDW and poor outcome is unclear. RDW reflects the presence of immature and larger red blood cells in the circulation and can rise in any condition when erythrocytes are destructed or produced ineffectively. Elevation of RDW in IE may be a result of overt inflammation. The release of cytokines (such as tumour necrosis factor-α or interleukin-6) in response to inflammation decreases the half-life of red blood cells that consequently induce accelerated erythrocyte production [23, 24]. These cytokines can desensitize bone marrow erythroid precursors to erythropoietin by blocking its maturation effects and cause ineffective erythropoiesis [25, 26, 27]. Other possible mechanisms are increased oxidative stress and lower antioxidant production, which, in turn, increase the fragility of red blood cells, decrease the rate of erythroid precursor maturation and reduce erythrocyte lifespan [28, 29, 30]. In various studies, RDW predicted mortality better than haemoglobin concentrations [6, 8, 9, 14, 15, 16]. Effects of inflammation and oxidative stress on erythropoiesis by the potential mechanisms mentioned above could explain these observations. We can speculate that RDW may indicate underlying co-morbidities in the light of previous work with RDW [6, 7, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22].

IE has a broad-ranging disease course, and biomarkers may facilitate risk stratification at early stages in this complex disease. C-reactive protein was not found to be useful in identifying worse outcome according to our findings, although it was elevated in fatal cases. Unlike our results, previous studies have suggested that C-reactive protein is a predictor of mortality in IE [5, 31]. The main difference in our study was the longer follow-up period. We can hypothesize that C-reactive protein may predict short-term outcome, whereas RDW may be more successful for long-term prediction due to its possible ability to identify underlying co-morbidities. Studies have also demonstrated that elevated troponin, B-type natriuretic peptide and procalcitonin concentrations are associated with morbidity and mortality in IE [32, 33, 34, 35]. None of these studies evaluated long-term mortality and most enrolled a limited number of study subjects. Although these biomarkers may be valuable in some cases, routine follow-up would be expensive compared with RDW.

Success in prediction of adverse outcome, availability from the complete blood count and lack of expense make RDW a promising biomarker for routine clinical practice. The exact cut-off value of RDW for identifying high-risk patients differs in the literature: in some papers, the median value of the study cohorts was selected; in others, ROC curves were used for optimum cut-off levels. According to our findings and in the light of the data in the literature so far, RDW approximately above 15% is the threshold to pay attention to [9, 16]. Elevated RDW levels should alert clinicians to take more aggressive measures in order to prevent poor outcome.

Study limitations

The main limitations of the present study were retrospective design and small sample size. Referral bias may have affected our clinical data, as the participating institutions were both tertiary care centres. Being a referral centre might also have resulted in more culture negative results due to possible antibiotic use prior to hospital admission. Due to retrospective data-gathering limitations, we could not analyse the data on transfusion status or nutritional deficiencies before admission, which may have affected RDW results. Patients with end-stage renal disease were not excluded. However, after adjusting RDW for haemoglobin and creatinine concentrations by multivariable analysis, a significant association remained between RDW and mortality.

Despite the higher prevalence of prosthetic valve IE, surgery and abscess rates were lower compared with previous data. Due to local restrictions and retrospective limitations we could only gather data from the study institutions. We evaluated only the index hospitalization period and did not further follow outcome (such as surgery after discharge, reinfection or relapse) apart from mortality. Furthermore, the cardiac rhythm devices were extracted with percutaneous procedures and were not grouped under the title of surgery.

Our study population was different from those in Western countries; the patients were younger and prosthetic valves were more common. Therefore, RDW should also be tested in other populations. The specificity of RDW in detecting mortality was lower, limiting the role of RDW in exclusion. Given the higher number of tested variables compared with the number of events, we could not exclude the risk of chance finding. We did not evaluate the prognostic value of RDW in a first cohort and validate it in another cohort, which would have improved the methodology of the paper. Future prospective studies are needed to confirm our findings, with larger patient cohorts to overcome the limitations listed above.

Conclusion

Our results suggest that IE has a high mortality rate and that increased RDW is an independent predictor of mortality in these patients. The use of RDW as a prognostic marker may provide valuable information for early risk stratification in IE.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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