Hematologic Parameters as Predictors of Long-Term Mortality in Infective Endocarditis Patients

Background

Infective endocarditis (IE) is an endothelial infection that is associated with high mortality and morbidity rates [1]. The diagnosis of IE has increased significantly with the development of echocardiography and nuclear imaging technology in recent years [1]. Despite developments in the diagnosis and treatment of IE, the in-hospital mortality and morbidity rates remain high [1–3]. With early identification of high-risk patients, more aggressive prompt treatment can be initiated for this targeted population, and the prognosis may improve. Comorbidity, cardiac or non-cardiac complications, the microorganism causing the infection, and echocardiographic findings of the patient are the known prognostic markers [1]. Older age, prosthetic valve involvement, heart failure, septic shock, cerebral complications, history of hemodialysis, periannular complications such as abscess, and S. aureus infection are strong predictors of poor in-hospital outcomes [1,4]. However, no hematological or biochemical parameters are currently recommended to classify patients with IE. Recent studies have focused on widely used and inexpensive inflammatory markers in IE [5]. The co-occurance of low lymphocyte count with high neutrophil count in severe infection constitutes the classic cellular shift in white blood cells. Previous studies have reported a relationship between hematological parameters and in-hospital mortality in IE patients [6,7]. Therefore, the purpose of this study was to evaluate the relationship between hematological parameters obtained at the time of admission and long-term mortality in 155 patients with IE at a single center in Turkey.

Material and Methods

ETHICS STATEMENT:

Approval was obtained from Adnan Menderes University Faculty of Medicine, Non-Invasive Clinical Research Ethics Committee (approval no. 2022/102). The requirement for patient informed consent was waived because of the retrospective nature of this study.

STUDY DESIGN AND PARTICIPANTS:

The patients with definite IE according to the modified Duke Criteria [2], diagnosed between January 2011 and April 2022 in Adnan Menderes University Faculty of Medicine, Aydın, Turkey were screened in the study. Diagnostic categories were defined as follows: direct evidence of vegetative growth in a histologic or bacteriologic study of the involved tissue or satisfying 2 major criteria or 1 major and 3 minor criteria or 5 minor criteria for IE. A total of 225 patients diagnosed with IE were scanned from the system. Seventy patients were excluded from the study because of missing or repetitive data. Finally, data on 155 patients were included in the study. Only those for whom all laboratory and echocardiographic data were available were enrolled. The all-cause mortality was assessed through telephone contact information recorded in the system. Turkish consensus report were used for the diagnosis and management of IE patients [3].

DATA COLLECTION AND MEASUREMENT:

Venous blood samples of all patients were collected at hospital admission, and at least 3 sets of blood cultures were performed for each patient before starting antibiotic treatment. The biochemical analysis results, including glucose, urea, creatinine, total protein, albumin, globulin, and CRP, were measured using an Ar-chitect C8000 analyzer (Abbot Park, IL, USA). CRP was also measured in the collected blood samples. Procalcitonin levels were measured by chemiluminescent immuno-assay using an auto-analyzer (Maglumi 600, Shaanxi, China and Abbott Alınıtyı system, USA). Complete blood count (CBC) parameters were measured using a Sysmex K-1000auto-analyzer (Block Scientific, Bohemia, NY, USA). Neutrophil-to-lymphocyte ratio (NLR) was directly calculated from CBC results.

STATISTICAL ANALYSIS:

For descriptive statistics, mean±standard deviation was used to present continuous data with normal distribution. Median with minimum-maximum values was applied for continuous variables without normal distribution. Numbers and percentages were used for categorical variables. The Shapiro-Wilk, Kolmogorov-Smirnov, and Anderson-Darling tests were used to assess the normal distribution of numerical variables.

The Pearson chi-square and Fisher’s exact tests were used to compare the differences between categorical variables in 2×2 tables. The Fisher Freeman Halton test was used in RxC tables.

The independent-samples t test was used to compare 2 independent groups where numerical variables had a normal distribution. The Mann-Whitney U test was applied for the variables without normal distribution in comparing 2 independent groups.

The receiver operating characteristic (ROC) analysis with the Youden index was used to determine the optimum value of the NLR that predicts mortality. The area under the ROC (AUC) curve and corresponding 95% confidence interval (CI) were calculated. Based on the appropriate cut-off value of the NLR, specificity and sensitivity were also calculated for the parameters with AUC value.

Univariate and multivariate Cox proportional hazard models and logistic regression analysis were performed to analyze the factors that impact the development of mortality. Hazard ratio (HR) with 95% CI was calculated.

Jamovi (version 2.2.5.0) and JASP (version 0.16.1) were used for statistical analysis. The significance level (P value) was determined at 0.05 in all statistical analyses.

Results

CHARACTERISTICS OF THE PATIENTS:

There were 155 patients with a mean age of 64.8 ± 14.3 years. The majority of the patients were male (58.7%) (n=91). Hypertension (50.3%) (n=78), diabetes mellitus (41.9%) (n=58), and chronic kidney disease (37.4%) (n=39) were the 3 most common comorbidities in patients with infective endocarditis. Prosthetic heart valves were the most common etiological risk factor in 39 patients (25.2%), the second most common (7.7%, n=12) was history of implantable heart device, and the third most common (7.1%, n=11) was history of infective endocarditis. Other clinical characteristics are detailed in Table 1.

Native valve involvement (69.0%) was more common than prosthetic valve (25.8%) and lead involvement (4.5%). Although we did not detect any microorganism in 89 patients (57.4%), S. aureus (23.9%) was the most common isolated microorganism in patients with infective endocarditis.

COMPARISON OF OUTCOMES:

The median NLR was significantly lower in the survivors than in non-survivors (P≤0.001). The receiver operating characteristics (ROC) curve analysis showed that NLR higher than 6.63 had the sensitivity and specificity rates of 56.84% and 81.67% in predicting mortality (AUC=0.706, 95% confidence interval: 0.627–0.776, P≤0.001) (Figure 1). Considering the survival analysis results, the median life expectancy was 2502.4 days (2108.0–2896.9 at 95% CI) for those with an NLR value of 6.63 and above, and 810.7 days (493.2–1128.2 at 95% CI) for those with an NLR value of 6.63 and below, and the 3-year mortality rate was significantly higher in those with an NLR value of 6.63 and below (P<0.001) (Figure 2).

The mitral valve was the most common anatomic location (49.7%) for vegetative lodgment. We detected abscess formation and dehiscence with a leak in 41 (26.5%) and 32 patients (20.6%), respectively.

In 71 patients (45.8%), at least 1 complication developed. Acute renal failure was the most common complication, seen in 41 patients (26.5%). We applied conservative treatment modalities in 109 patients (70.3%), whereas surgical interventions were performed in 46 patients (29.7%). The in-hospital mortality rate was 31.6%. Among the discharged patients (n=106), there were 46 non-survivors, with an out-of-hospital mortality rate of 43.4%. The overall mortality rate was 61.3%.

During the follow-up, the 1-year and 3-year mortality rates were 47.1% and 54.8%, respectively.

Older patients were more likely to die at the end of the 3-year follow-up (P=0.003). The other demographic and clinical characteristics, except for the incidences of chronic renal failure (P=0.010) and previous cancer history (P=0.020), were similar (P>0.05) (Table 2). We detected no significant difference between the patients with and without 3-year mortality regarding disease-related characteristics (Table 3).

We detected significant differences in the values of hemoglobin, white blood cell, neutrophil, lymphocyte, platelet, platelet distribution width, NLR, urea, creatinine, albumin, and procalcitonin between the patients with and without 3-year mortality (P<0.05) (Table 4).

The factors that were associated with 3-year mortality were evaluated with logistic regression analysis. A statistically significant relationship was detected between the NLR values and 3-year mortality after excluding the effects of variables such as age, the presence of CKD, the presence of cancer, and the presence of complications (P=0.006). It was also found that a 1-unit increase in the NLR value caused a 1.136-fold (95% CI, 1.037–1.243) increase in 3-year mortality (Table 5).

The rates of atrial fibrillation in electrocardiography were similar between groups (P=0.968). The vegetations of the patients who died at the end of the three-year follow-up were significantly longer and wider than those in patients who survived (P=0.033 and P=0.028). The other echocardiographic findings were similar (P>0.05) (Table 6).

The 3-year mortality was significantly associated with the development of any complication (p=0.006) and acute renal failure (P=0.003). The other comparisons revealed no significant differences (P>0.05) (Table 7). The duration of the follow-up time was significantly shorter in patients with 3-year mortality (P<0.001).

Discussion

The effects of hematological parameters on mortality in long-term follow-up of patients with definite IE were investigated in this study. The 3-year mortality was 54.8%, with a median follow-up of 341 days (2–4003 days) in 155 patients with IE, whose records were assessed. Neutrophil/lymphocyte level, which was a hematological parameter recorded at the time of admission, is an independent predictor of 3-year all-cause mortality in patients with IE.

Infective endocarditis has a rare but life-threatening morbidity, and the mortality rate has not changed for more than 30 years despite all developments [1,6,8]. The in-hospital mortality rate of patients with IE ranges between 15% and 33% [5,10–12]. However, although the data on long-term mortality are not complete, according to recent studies, mortality rates are estimated to be 80–90% at 1 year, 70–80% at 2 years, and 60–70% at 5 years after the completion of IE treatment [1]. The in-hospital mortality rate was 31.6%, 1-year mortality was 47.1%, and 3-year mortality was 54%. These finding were similer to those of present study. The epidemiology of IE has changed over the years, with healthcare-associated IE now accounting for 25–30% of cases as a result of greater use of intravenous lines and intracardiac devices. Staphylococcus aureus is now the most prevalent cause of IE in most studies, at ~26.6% of all cases. Selton-suty et al found that the in-hospital mortality rate for patients with health care-associated IE is significantly higher than for community-acquired infection (31.1% vs 20.3%; P<0.01) [13–15]. Culture-negative IE occurs in up to 31% of all IE cases. Lack of culture in IE often poses diagnostic and therapeutic dilemmas. The most common reason for the absence of growth in the culture is previous antibiotic treatment of patients. Other causes are difficult to culture pathogens such as fungi or obligate intracellular bacteria [1]. In the present study, the rate of patients with no growth in culture was 57%. Possible reasons for the higher rate were that most of the patients who came to the clinic had received antibiotic treatment before diagnosis and were referred from external centers as complicated patients because the clinic was a tertiary center. The group with no growth in culture was one of the reasons for the higher mortality rates compared to the literature.

IE is difficult to diagnose and manage since it is a disease involving complex inflammatory processes. Also, with its complexity, it is difficult to identify higher-risk diseases in the early stages. Rapid identification of patients who have high risk of death may offer an opportunity to change the course of the disease [15]. The changes in WBC differential counts during severe infection are well known. In this regard, the progressive increase in neutrophil counts and the simultaneous decrease in lymphocyte counts in neutrophilic leukocytosis constitute the classical cellular shift in the WBC differential in response to acute bacterial infections [16–17]. Lymphocytes have a wide variety of roles in innate and adaptive immune response. T cells can regulate inflammation by interacting with various immune cells and activately suppress other leukocyte inflammatory responses. However, the causes of lymphocytopenia include increased catecholamine and cortisol levels, redistribution of lymphocytes to lymphatic organs, and apoptosis [18,19]. Although neutrophils are generally involved in the rapid response, lymphocytes are more involved in the adaptive and long-term response of the immune system, which is synonymous with physiological stress [20]. T cells are taken to the heart during cardiac inflammation and are involved in the pathophysiology of cardiac disease. Decreased lymphocyte percentage is a common finding in patients who have chronic heart failure and is associated with lower survival rates and increased need for heart transplant [21,22]. NLR in infection provides a higher predictive value than independent leukocyte differential and CRP [23–24]. Interestingly, NLR was shown to be a better predictor of mortality in patients who have advanced heart failure compared to independent absolute neutrophil and lymphocyte counts [25–27]. This can be explained partially by the finding that NLR combines 2 different immune pathways. Recently, elevated NLR levels were reported to be associated with increased mortality in various heart diseases [21–24]. NLR has been shown to be associated with in-hospital mortality in infective endocarditis patients in a few recent studies [6,7,28]. Hashimoto et al, in a study that included patients who were implanted with an intracardiac defibrillator for heart failure in 2016, with a median follow-up of 61.2 weeks, found that NLR was significantly higher in patients who died from all causes vs the surviving group [29]. In a study by Uthamalingam et al, in which 1212 patients who had acute decompensated heart failure were included, the median follow-up period was 26 months and long-term all-cause mortality was significantly higher in the group with high NLR, independent of EF [30]. In the present study, the median follow-up period was 341 days, and NLR was associated with all-cause mortality in IE patients. This marker can be a useful indicator of poor general condition.

NLR thresholds that range between 3.0 and 9.6 were used in studies of advanced heart failure, decompensated heart failure, and cardiac resynchronization therapy [25–27]. There is still no consensus on the cut-off value for identifying an abnormal NLR or when this evaluation should be made. The threshold value for NLR was 6.63 in the ROC analysis performed in the present study.

One of the limitations of the present study was that late referrals may have increased the incidence of morbidity and mortality because it was a retrospective study and was conducted in a single tertiary hospital. The study had a relatively small sample size. Also, other laboratory markers such as fibrinogen, proinflammatory cytokines, and B-type natriuretic peptide could not be evaluated, and factors such as treatment, duration, and use of antibiotics before diagnosis could not be evaluated in patients with IE, which has a wide clinical and etiological spectrum. Only blood test results at admission were analyzed because the relationship between NLR at the time of application and 3-year mortality was evaluated in the study. Further studies can be planned in the future to identify high-risk patients with echocardiography findings such as vegetation diameter and NLR-based risk scores at the time of initial presentation for IE, which has very different clinical presentation and etiology.

Conclusions

NLR was independently associated with 3-year mortality in IE patients. NLR is a parameter that can be obtained from a simple, widely available, and inexpensive test as a useful marker in predicting long-term mortality in IE patients.