Validity of SOFA score as a prognostic tool for critically ill elderly patients with acute infective endocarditis

The


Introduction
The epidemiology of infective endocarditis (IE) is changing with a growing proportion of patients who are elderly [1].The incidence of IE in elderly patients is 4.6 times higher than in the general population, with delayed diagnosis [2,3].Medical or surgical treatment for IE in elderly patients remains controversial because of associated high incidence of morbidity and mortality [4].Accordingly, early identification of patients with an elevated risk of death from IE is essential to improve outcomes in elderly patients.The sequential organ failure assessment (SOFA) score has been confirmed as an effective prognostic tool in the management of sepsis, as well as in IE patients [5][6][7].However, limited data is available on the prognostic value of SOFA in patients with IE who are elderly.
We conducted the first multicenter prospective observational study that evaluated the prognostic value of the SOFA score for in-hospital and long-term mortality of patients aged 65 years and older who were treated for acute IE.

Patient enrollment
A multicenter prospective observational trial involving acute IE in elderly patients (≥65 years) was conducted at 3 university-affiliated medical centers (Shenzhen People's Hospital, Longgang District People's Hospital of Shenzhen and Guangdong General Hospital) in China.Using modified Duke criteria for IE diagnosis [8], a total of 348 patients diagnosed with IE were consecutively screened from January 2015 to December 2019.After exclusion of patients with age <65 years, patients not requiring ICU admission (n = 210), patients with prior IE diagnoses (n = 10) and repeat hospitalizations (n = 17), 111 elderly patients with acute IE requiring ICU were included in this study.IE was categorized as either acute (developing over hours or 14 days) or subacute (progressive over 2 weeks to months).Surgery was performed provided that surgical criteria were met.Conservative drug therapy was initiated in circumstances of extremely poor health conditions or inability to afford the expense of operation.

Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki.The protocol was approved by the Ethics Committee of Shenzhen People's Hospital (approval number: SZLY0122).All participants provided informed consent prior to participation in the study.

Data collection
Transthoracic echocardiography and SOFA score were assessed within 24 hours of admission.Transesophageal echocardiography was performed if necessary.Serum samples were collected and analyzed immediately upon admission [C-reactive protein (CRP), 0-5 mg/L; erythrocyte sedimentation rate (ESR), 20 mm/h].Follow-up data were acquired by telephone at 1 month, 3 months, 6 months and 12 months after discharge from hospitalization.

Study endpoints
The primary study endpoint was in-hospital mortality.Secondary endpoint measures included other predictors of in-hospital mortality and all cause death during follow-up.

Statistical analysis
Statistical analysis was performed by SPSS 22.0 (Chicago, IL, USA).Data were reported as mean ± standard deviation (SD) or counts (percentage).Group comparison of continuous data was conducted by Student's t-test, analysis of variance (ANOVA) or Kruskal-Wallis test.Group comparison of categorical data was calculated by Chi-square or Fisher Exact test.Optimal cut-off points for SOFA scores were calculated by receiver operator characteristic curve (ROC) analysis.Univariable and multivariable logistic regression analyses were applied to evaluate adjusted odds ratio (OR) for inhospital mortality, and reported with 95% confidence intervals (CI).Kaplan-Meier curves, evaluated with log-rank tests and Cox proportional-hazards models, were used to evaluate the long-term survival.Hazard ratios (HR) are also reported with 95% CI.Statistical significance was defined as p < 0.05.

Discussion
This study aims to evaluate the utility of SOFA for predicting mortality in critically ill elderly patients with acute IE.The major findings are: (i) a strong predictive value of high SOFA for in-hospital mortality; (ii) high SOFA was associated with long-term mortality; (iii) additionally, age, diabetes mellitus and surgical treatment were independent predictors of clinical outcomes.
With an increase in life expectancy, elderly people susceptible to infectious diseases are more common than ever for physicians.In particular, acute IE in elderly patients is a severe and challenging disease for cardiologists, with high inhospital mortality rates ranging from 24.9% to 45.3% [9,10].Early identification of prognostic factors may offer the opportunity to improve the clinical outcomes of these patients.The SOFA score assesses respiration, coagulation, liver and renal function, cardiovascular health and the central nervous system, using fraction of inspiration O2, platelet count, serum bilirubin and creatinine, blood pressure/pressor use, and the Glasgow coma score, reflecting the severity of organ failure and predicting underlying comorbidities [11,12].A SOFA score of 2 or more has been recommended as a crite-rion for sepsis and has been confirmed as a significant predictor of ICU mortality [7].Therefore, it is reasonable to expect that obtaining a SOFA score on admission could predict the severity and prognosis of acute IE.
In our study, SOFA ≥6 (OR, 6.38) could predict inhospital mortality with sensitivity 76.47% and specificity 71.28% (AUC, 0.796, 95% CI, 0.814-0.904).The score of AUC in our study was much lower than that in the study of Nobuhiro (AUC, 0.915, sensitivity 76.9%, specificity 89.6%), which included coagulase negative bacteremia patients without IE as control group, but the cut-off point (6) was similar.Kim and colleagues found that a higher SOFA cut-off value (7 [4, 11] vs. 3 [1,5], p < 0.001) predicted poor outcomes in IE with Staphylococcus aureus [13] bacteremia (SAB).The mortality rate for methicillin-resistant SAB (MRSAB) is 32% and for methicillin susceptible SAB (MSSAB) is 14%, both higher than in other infections.Wei found that increased CRP and red blood cell distribution width, especially in combination, were associated with in-hospital mortality in patients with blood culture-negative infective endocarditis [14].Other biochemical markers such as troponin, B-Type Natriuretic Peptide and D-dimer are reliable prognostic biomarkers associated with adverse outcomes in patients with IE [15][16][17].However, sensitivity and specificity were lower than in our study.
Advanced age (OR, 2.31) has been associated with poor prognosis in acute IE.Our results were in accordance with studies by Netzer [18] and Selton-Suty [19], who found that mortality was higher in elderly patients (>65 or >70 years, respectively) than in younger ones (25% vs. 11% or 28% vs. 13.5%,respectively).Another study showed mortality rates up to 32% in patients aged >60 years [20].In-hospital mortality in our study was 15.32%, lower than in previous studies.This may be attributed to a high percentage (81.98%) of the elderly patients in our study receiving surgical treatment, which our data showed to be associated with better outcomes (OR, 0.21 for mortality).Our results were in accordance with those observed by Di Salvo [1], in which in-hospital mortality in patients who received surgery was lower than in those treated without surgery, and elderly patients who received surgical treatment had better outcomes (11% mortality).
Our data also showed that high SOFA (SOFA ≥6, HR, 3.38) was associated with long-term mortality.SOFA-based assessment could be performed at admission, allowing for an evidence-based decision-making process for prognostic management.SOFA was initially proposed for organ dysfunction quantification in general critically ill patients, and was further confirmed as a prognostic tool for mortality prediction [21].Additionally, patient characteristics, including older age (HR, 2.85) and diabetes mellitus (HR, 3.99), were main factors leading to adverse prognosis.These results are in agreement with the study of Lin and Duval [22,23], in which age and diabetes mellitus were significantly associated with the short-time outcome in patients with IE.Though early surgery reduced incidence of in-hospital and 1-year mortal- ity in patients with native or prosthetic valve IE [24], fewer elderly patients with acute IE received surgical treatment.In fact, cardiovascular surgeons frequently refuse to operate on a patient over 80 years of age and hesitate for patients from 75 to 80 years old due to higher perioperative or postoperative complications and mortality.However, the ratio of morbidity and mortality in patients who have undergone surgery treatment was reduced in our study, which may be ascribed to improved surgical techniques.In our study, sur-gical treatment was performed in 81.98% of patients and was confirmed as a strong predictor (HR, 0.24) of good outcome with follow-up in elderly patients.With the development of surgeon experience and advancement in surgical techniques, success rates of surgery are higher and complication rates are lower than previously.Accordingly, surgical treatment was almost routinely recommended for IE in this study.Age alone should probably not be regarded as a contraindication to surgery.A more frequent use of surgery and greater co- operation between cardiologists and geriatricians could help improve the management of elderly patients with IE [25].
We should acknowledge the limitations of the present study.First, this is a prospective observational trial involv-ing a small population.Thus, there might be a bias in data selection and analysis.Secondly, younger IE patients (age <65 years) were excluded; therefore, the comparison between SOFA scores of different ages (age <65 years and age >65 years) with mortality in acute IE was lacking.Finally, the SOFA score may differ significantly during hospital stay.Evaluation of SOFA scores including different periods during hospitalization needs further study.

Fig. 1 .
Fig. 1.The ROC curves for SOFA in predicting in-hospital mortality in elderly IE patients.

Fig. 3 .
Fig. 3. Kaplan-Meier analysis (A), Cox regression analysis (B) and Cox proportional-hazards model (C) of SOFA score for survival over 3 years of follow-up.