Blood culture time to positivity in non-ß-hemolytic streptococcal bacteremia as a predictor of infective endocarditis-a retrospective cohort study.

Non-ß-hemolytic streptococci (NBHS) cause infective endocarditis (IE) and a short blood culture time to positivity (TTP) is associated with risk of IE in bacteremia with other pathogens. In this retrospective population-based cohort study, we investigate if TTP is associated to IE or mortality. Of 263 episodes with NBHS bacteremia, 28 represented IE and the median TTP did not differ significantly between episodes with IE (15 h) and non-IE (15 h) (p=0.51). TTP was similar among those who survived and those who died within 30 days. However, TTP significantly differed when comparing the different streptococcal groups (p<0.001).

The Clinical Impact of Implementation of a Multidisciplinary Endocarditis Team.

BACKGROUND: Infectious endocarditis is associated with substantial in-hospital mortality of 15%-20%. Effective management requires coordination between multiple medical and surgical subspecialties, which can often lead to disjointed care. Previous European studies have identified multidisciplinary endocarditis teams as a tool for reducing endocarditis mortality. METHODS: The multidisciplinary endocarditis team was formed in May 2018. The group developed an evidence-based algorithm for management of endocarditis that was used to provide recommendations for hospitalized patients over a 1-year period. Mortality outcomes were then retroactively assessed and compared to a historical control utilizing propensity matching. RESULTS: Between June 2018 and June 2019 the team provided guideline-based recommendations on 56 patients with Duke Criteria-definite endocarditis and at least 1 American Heart Association indication for surgery. The historical control included 68 patients with definite endocarditis and surgical indications admitted between July 1, 2014, and June 30, 2015. In-hospital mortality decreased significantly from 29.4% in 2014-2015 to 7.1% in 2018-2019 (P < .0001). There was a non-significant increase in the rate of surgical intervention after implementation of the team (41.2% vs 55.4%; P = 0.12). Propensity score matching demonstrated similar results. CONCLUSIONS: Implementation of a multidisciplinary endocarditis team was associated with a significant 1-year decrease in all-cause in-hospital mortality for patients with definite endocarditis and surgical indications, in the presence of notable differences between the 2 studied cohorts. In conjunction with previous studies demonstrating their effectiveness, these data support the idea that widespread adoption of endocarditis teams in North America could improve outcomes for this patient population.

Linezolid for infective endocarditis: A structured approach based on a national database experience.

ABSTRACT: Current data on the frequency and efficacy of linezolid (LNZ) in infective endocarditis (IE) are based on small retrospective series. We used a national database to evaluate the effectiveness of LNZ in IE.This is a retrospective study of IE patients in the Spanish GAMES database who received LNZ. We defined 3 levels of therapeutic impact: LNZ < 7 days, LNZ high-impact (≥ 7 days, > 50% of the total treatment, and > 50% of the LNZ doses prescribed in the first weeks of treatment), and LNZ ≥ 7 days not fulfilling the high-impact criteria (LNZ-NHI). Effectiveness of LNZ was assessed using propensity score matching and multivariate analysis of high-impact cases in comparison to patients not treated with LNZ from the GAMES database matched for age-adjusted comorbidity Charlson index, heart failure, renal failure, prosthetic and intracardiac IE device, left-sided IE, and Staphylococcus aureus. Primary outcomes were in-hospital mortality and one-year mortality. Secondary outcomes included IE complications and relapses.From 3467 patients included in the GAMES database, 295 (8.5%) received LNZ. After excluding 3 patients, 292 were grouped as follows for the analyses: 99 (33.9%) patients in LNZ < 7 days, 11 (3.7%) in LNZ high-impact, and 178 (61%) in LNZ-NHI. In-hospital mortality was 51.5%, 54.4%, and 19.1% respectively. In the propensity analysis, LNZ high-impact group presented with respect to matched controls not treated with LNZ higher in-hospital mortality (54.5% vs 18.2%, P = .04). The multivariate analysis showed an independent relationship of LNZ use with in-hospital mortality (odds ratio 9.06, 95% confidence interval 1.15--71.08, P = .03).Treatment with LNZ is relatively frequent, but most cases do not fulfill our high-impact criteria. Our data suggest that the use of LNZ as definitive treatment in IE may be associated with higher in-hospital mortality.

Prognostic impact of cardiac surgery in left-sided infective endocarditis according to risk profile.

OBJECTIVE: To evaluate the prognostic impact of urgent cardiac surgery on the prognosis of left-sided infective endocarditis (LSIE) and its relationship to the basal risk of the patient and to the surgical indication. METHODS: 605 patients with LSIE and formal surgical indication were consecutively recruited between 2000 and 2020 among three tertiary centres: 405 underwent surgery during the active phase of the disease and 200 did not despite having indication. The prognostic impact of urgent surgery was evaluated by multivariable analysis and propensity score analysis. We studied the benefit of surgery according to baseline mortality risk defined by the ENDOVAL score and according to surgical indication. RESULTS: Surgery is an independent predictor of survival in LSIE with surgical indication both by multivariable analysis (OR 0.260, 95% CI 0.162 to 0.416) and propensity score (mortality 40% vs 66%, p<0.001). Its greatest prognostic benefit is seen in patients at highest risk (predicted mortality 80%-100%: OR 0.08, 95% CI 0.021 to 0.299). The benefit of surgery is especially remarkable for uncontrolled infection indication (OR 0.385, 95% CI 0.194 to 0.765), even in combination with heart failure (OR 0.220, 95% CI 0.077 to 0.632). CONCLUSIONS: Surgery during active LSIE seems to significantly reduce in-hospital mortality. The higher the risk, the higher the improvement in outcome.

Gender Based Analysis of a Population Series of Patients Hospitalized with Infective Endocarditis in Portugal - How do Women and Men Compare?

Abstract Background: The impact of gender on the outcome of patients hospitalized with infective endocarditis (IE) is not fully understood. Objective: To verify the association between gender and the clinical profile of patients hospitalized with IE, treatment strategies, and clinical outcomes. Methods: This is a retrospective nationwide study of patients hospitalized with IE, based on hospital admissions between 2010 and 2018 in Portugal. Descriptive statistics were used to present variables. An inferential analysis was performed using multiple logistic regression. A 95% confidence interval and a 5% significance level were considered. Results: In total, 3266 (43.1%) women and 4308 (56.9%) men were hospitalized with IE. The women were older (76 vs 69 years old, p<0.001), more frequently presented arterial hypertension (39.8% vs 35.4%, p<0.001) and atrial fibrillation (29.5% vs 21.2%, p<0.001), and had less cardiovascular comorbidities. Acute heart failure was more common in women (32.9 vs 26.9%, p<0.001) and acute renal failure (13.6% vs 11.7%, p<0.001) and sepsis (12.1% vs 9.1%, p<0.001), in men. Women were less likely to undergo cardiac surgery (OR 0.48 - 95%CI 0.40-0.57, p<0.001) and had a higher postoperative mortality (OR 1.84, 95% CI 1.19-2.84, p=0.006). In-hospital mortality rates were comparable between genders (20.3% vs 19.6%, p=0.45). Conclusions: Women were less likely to undergo cardiac surgery when hospitalized with IE, and the female gender was a predictor factor for postoperative mortality. Overall, in-hospital mortality was not influenced by gender. Further research is necessary to fully clarify the impact of gender on IE management and outcomes.

Contemporary Trends and Outcomes of Prosthetic Valve Infective Endocarditis in the United States: Insights from the Nationwide Inpatient Sample.

BACKGROUND: Prosthetic valve endocarditis (PVE) carries high mortality and morbidity as compared to native valve endocarditis (NVE). Contemporary data on PVE are lacking, we aimed to study contemporary trends, outcomes, and burden of PVE using nationally representative data. METHODS: We used the National Inpatient Sample from 2000 to 2017 to identify patients admitted with PVE using ICD-9-CM and ICD-10 codes. Risk-adjusted rates were calculated using an Analysis of Covariance (ANCOVA) with the Generalized Linear Model (GLM). Trends were assessed with linear regression and Pearson's Chi-square when appropriate. Binomial logistic regression was used to assess predictors of in-hospital mortality. RESULTS: We identified 43,602 hospitalizations for PVE. PVE hospitalizations increased from 1803 in 2000 to 3450 in 2017. Risk-adjusted mortality decreased from 10.7% in 2002 to 7.3% in 2017 (P<0.01). Logistic regression analysis on mortality showed increase association with age (OR, 1.021, 95%CI [1.017-1.024], p<0.01), Hispanics (OR, 1.493, 95%CI [1.296-1.719], p<0.01) and patients with drug abuse (OR, 1.233, 95%CI [1.05-1.449], p=0.01). Co-morbid conditions like congestive heart failure (OR, 1.511, 95%CI [1.366-1.673], p<0.01), renal failure (OR, 1.572, 95%CI [1.427-1.732], p<0.01) and weight loss (OR, 1.425, 95%CI [1.093-1.419], p<0.01) were also associated with higher mortality. CONCLUSIONS: Over the years the adjusted in-hospital mortality in PVE has trended down but the average cost of stay has increased despite decrease in length of stay.

Comparison of mortality, stroke, and relapse for methicillin-resistant versus methicillin-susceptible Staphylococcus aureus infective endocarditis: a retrospective cohort study.

The purpose of this study was to compare survival, relapse, and stroke for patients with methicillin-resistant Staphylococcus aureus (MRSA) vs methicillin-susceptible S. aureus (MSSA) infective endocarditis (IE). In this retrospective study, the primary outcome of death and secondary outcomes of stroke and relapse were compared using multivariable Cox proportional hazards regression. Surgical treatment was adjusted for as a time-dependent variable. In total, 355 patients with at least one episode of IE caused by S. aureus were included. Patients with MRSA IE had higher mortality than those with MSSA IE (HR 1.34, 95% CI 1.01-1.77), but did not have a higher risk of stroke (HR 0.75, 95% CI 0.43-1.32) or relapse (HR 0.89, 95% CI 0.26-3.05). The cumulative incidence of relapse was very small. Among patients with IE caused by S. aureus MRSA infection is associated with higher mortality than MSSA infection.

Surgical treatment of infective endocarditis in intravenous drug abusers.

BACKGROUND: Despite current progress in antibiotic therapy and medical management, infective endocarditis remains a serious condition presenting with high mortality rates. It also is a life-threatening complication in patients with a history of chronic intravenous drug abuse. In this study, we analyzed our institutional experience on the surgical therapy of infective endocarditis in patients with active intravenous drug abuse. The aim of the study is to identify the predictive factors of mortality and morbidity in this subgroup of patients. METHODS: Between 2007 and 2020, a total of 24 patients (7 female, mean age 38.5 ± 8.7) presenting with active intravenous drug abuse underwent a surgical treatment for the infective endocarditis at out center. The primary endpoint was survival at 30th day after the surgery. The secondary composite endpoint included freedom from death, recurrent endocarditis, re-do surgery, and postoperative stroke during the follow-up period. Mean follow-up was 4.2 ± 4.3 years. RESULTS: Staphylococcus species was the most common pathogen detected in the preoperative blood cultures. Infection caused by Enterococcus species as well as liver function impairment were identified as mortality predictor factors. Logistic EuroSCORE and EusoSCORE-II were also predictive factors for mortality in univariate analysis. Survival at 1 and 3 years was 78 and 72% respectively. Thirty-day survival was 88%. 30-day freedom from combined endpoint was 83% and after 1 and 3 years, 69 and 58% of the patients respectively were free from combined endpoint. Five patients (20.8%) were readmitted with recurrent infective endocarditis. CONCLUSION: In patients presenting with active intravenous drug abuse, treatment of infective endocarditis should be performed as aggressively as possible and should be followed by antibiotic therapy to avoid high mortality rates and recurrent endocarditis. Early intervention is advisable in patients with an infective endocarditis and enterococcus species in the preoperative blood cultures, liver function deterioration as well as cardiac function impairment. Attention should be also payed to addiction treatment, due to the elevated relapse rate in patients who actively inject drugs. However, larger prospective studies are necessary to support our results. As septic shock is the most frequent cause of death, new treatment options, e.g. blood purification should be evaluated.

Epidemiology of infective endocarditis before versus after change of international guidelines: a systematic review.

INTRODUCTION: All major international guidelines for the management of infective endocarditis (IE) have undergone major revisions, recommending antibiotic prophylaxis (AP) restriction to high-risk patients or foregoing AP completely. We performed a systematic review to investigate the effect of these guideline changes on the global incidence of IE. METHODS: Electronic database searches were performed using Ovid Medline, EMBASE and Web of Science. Studies were included if they compared the incidence of IE prior to and following any change in international guideline recommendations. Relevant studies fulfilling the predefined search criteria were categorized according to their inclusion of either adult or pediatric patients. Incidence of IE, causative microorganisms and AP prescription rates were compared following international guideline updates. RESULTS: Sixteen studies were included, reporting over 1.3 million cases of IE. The crude incidence of IE following guideline updates has increased globally. Adjusted incidence increased in one study after European guideline updates, while North American rates did not increase. Cases of IE with a causative pathogen identified ranged from 62% to 91%. Rates of streptococcal IE varied across adult and pediatric populations, while the relative proportion of staphylococcal IE increased (range pre-guidelines 16-24.8%, range post-guidelines 26-43%). AP prescription trends were reduced in both moderate and high-risk patients following guideline updates. DISCUSSION: The restriction of AP to only high-risk patients has not resulted in an increase in the incidence of streptococcal IE in North American populations. The evidence of the impact of AP restriction on IE incidence is still unclear for other populations. Future population-based studies with adjusted incidence of IE, AP prescription rates and accurate pathogen identification are required to delineate findings further in these other regions.

Midterm outcomes of early versus late surgery for infective endocarditis with neurologic complications: a meta-analysis.

BACKGROUND: Cerebral infarction (CI) remains one of the most common and fatal complications of infective endocarditis (IE), and the timing of surgery for IE with neurologic complications is controversial. As outcomes beyond the perioperative period have not been assessed with a meta-analysis previously, we conducted a meta-analysis comparing mid- to long-term outcomes of early and late surgery in patients with IE and neurologic complications. METHODS: All studies that investigated early and late surgery in patients with IE and neurologic complications were identified. The primary and secondary endpoints were all-cause mortality and recurrence, respectively. Hazard ratios (HRs) for all-cause mortality and recurrence were extracted from each study. RESULTS: Our search identified five eligible studies, which were all observational studies consisting of a total of 624 patients with IE and neurologic complications. Pooled analyses demonstrated that all-cause mortality was similar between the early and late surgery groups (HR [95% confidence interval [CI]] = 0.90 [0.49-1.64]; P = 0.10; I2 = 49%). Similarly, the recurrence rates were similar between both groups (HR [95% CI] = 1.86 [0.76-4.52]; P = 0.43; I2 = 0%). CONCLUSIONS: Our meta-analysis showed similar mortality and recurrent rates between the early and late surgery groups. The optimal timing of surgery should be individualized on a case-to-case basis.

Insight into the epidemiology of infective endocarditis in Portugal: a contemporary nationwide study from 2010 to 2018.

BACKGROUND: Nationwide hospital admissions data series have contributed to a reliable assessment of the changing epidemiology of infective endocarditis, even though conclusions are not uniform. We sought to use a recent populational series to describe the temporal trends on the incidence of infective endocarditis, its clinical characteristics and outcome results, in Portugal. METHODS: A nationwide retrospective temporal trend study on the incidence and clinical characterization of patients hospitalized with infective endocarditis, between 2010 and 2018. RESULTS: 7574 patients were hospitalized with infective endocarditis from 2010 to 2018 in Portuguese public hospitals. The average length of hospitalization was 29.3 ± 28.7 days, predominantly men (56.9%), and 47.1% had between 60 and 79 years old. The most frequent infectious agents involved were Staphylococcus (16.4%) and Streptococcus (13.6%). During hospitalization, 12.4% of patients underwent heart valve surgery and 20% of the total cohort died. After a 1-year post-discharge follow-up, 13.2% of the total initial cohort had had heart valve surgery and 21.2% in total died. The annual incidence of infective endocarditis was 8.31 per 100,000 habitants, being higher in men (9.96 per 100,000 in males versus 6.82 in females, p < 0.001) and increased with age, peaking at patients 80 years old or older (40.62 per 100,000). In-hospital mortality rate significantly increased during the analyzed period, the strongest independent predictors being ischemic or hemorrhagic stroke, sepsis, and acute renal failure. Younger age and cardiac surgery had a protective effect towards a fatal outcome. CONCLUSIONS: In Portugal, between 2010 and 2018, the incidence of infective endocarditis presented a general growth trend with a deceleration in the most recent years. Also, a significant rate of in-hospital complications, a mildly lower than expected stable surgical rate and a still high and growing mortality rate were noted.

Infective endocarditis by Klebsiella species: a systematic review.

This study aimed to systematically analyze all cases of infective endocarditis (IE) by Klebsiella species in the literature. A systematic review of PubMed, Scopus and Cochrane library (through 27th January 2021) for studies providing epidemiological, clinical, microbiological as well as treatment data and outcomes of IE by Klebsiella species was performed. In this review, a total of 66 studies were included, providing data for 67 patients. A prosthetic valve was present in 16.4%, while the most common causative pathogen was K. pneumoniae followed by K. oxytoca. The aortic valve was the most commonly infected intracardiac site, followed by the mitral valve. The diagnosis was based on transthoracic echocardiography in 46.2%, while the diagnosis was set at autopsy in 9.2% of included patients. Blood cultures were positive in 93.8%. Fever and sepsis were the most frequent clinical presentations, followed by embolic phenomena, paravalvular abscess, and heart failure. Cephalosporins, aminoglycosides, and carbapenems were the most frequently used antimicrobials. Surgical treatment along with antimicrobials was performed in 37.3% of included patients. Clinical cure was noted in 80.3%, while the overall mortality was 19.4%. Infection at the aortic valve was independently associated with mortality by IE. This systematic review gives a comprehensive description of IE by Klebsiella and provides information on epidemiology, clinical manifestations, therapeutic strategies and their outcomes.

Impact of surgical timing on survival in patients with infective endocarditis: a time-dependent analysis.

The purpose of this study was to evaluate the impact of surgical timing on survival in patients with left-sided infective endocarditis (IE). This was a retrospective study including 313 patients with left-sided IE between 2009 and 2017. Surgery was defined as urgent (US) or early (ES) if performed within 7 or 28 days, respectively. A multivariable Cox regression analysis including US and ES as time-dependent variables was performed to assess the impact on 1-year mortality. ES was associated with a better survival (aHR 0.349, 95% CI 0.135-0.902), as US (aHR 0.262, 95% CI 0.075-0.915). ES and US were associated with a better prognosis in patients with left-sided IE.

Prognostic value of pro-adrenomedullin and copeptin in acute infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is a life-threatening disease whose prognosis is often difficult to predict based on clinical data. Biomarkers have been shown to favorably affect disease management in a number of cardiac disorders. Aims of this retrospective study were to assess the prognostic role of procalcitonin (PCT), pro-adrenomedullin (pro-ADM) and copeptin in IE and their relation with disease characteristics and the traditional biomarker C-reactive protein (CRP). METHODS: We studied 196 patients with definite IE. Clinical, laboratory and echocardiography parameters were analyzed, with a focus on co-morbidities. PCT, pro-ADM and copeptin were measured on stored plasma samples obtained on admission during the acute phase of the disease. RESULTS: Pro-ADM and copeptin were significantly higher in older patients and associated with prior chronic kidney disease. Pro-ADM was an independent predictor of hospital mortality (OR 3.29 [95%C.I. 1.04-11.5]; p = 0.042) whilst copeptin independently predicted 1-year mortality (OR 2.55 [95%C.I. 1.18-5.54]; p = 0.017). A high PCT value was strictly tied with S. aureus etiology (p = 0.001). CRP was the only biomarker associated with embolic events (p = 0.003). CONCLUSIONS: Different biomarkers correlate with distinct IE outcomes. Pro-ADM and copeptin may signal a worse prognosis of IE on admission to the hospital and could be used to identify patients who need more aggressive treatment. CRP remains a low-cost marker of embolic risk. A high PCT value should suggest S. aureus etiology.

Comparing right- and left sided injection-drug related infective endocarditis.

The aim of the study was to compare background characteristics, microbiology and outcome of patients with right-sided and left-sided intravenous drug use (IDU) associated infective endocarditis (IE). A nationwide retrospective study using the Swedish Registry on Infective Endocarditis between 2008 and 2019 was conducted. A total of 586 people with IDU-IE were identified and divided into left-sided (n = 204) and right-sided (n = 382) IE. Descriptive statistics, Cox-regression and Kaplan-Meier survival estimates were used. The mean age of patients in the left-sided group was 46 years compared to 35 years in the right-sided group, p < 0.001. Left-sided IE had a higher proportion of females. Staphylococcus aureus was the causative pathogen in 48% of cases in the left-sided group compared to 88% in the right-sided group. Unadjusted and adjusted long-term survival was better in right-sided IE compared to left-sided IE. Independent predictors of long-term mortality were increasing age, end-stage renal disease, nosocomial infection, brain emboli and left-sided IE. Left-sided IE was common in people with IDU but the proportion of females with left-sided IE was low. S. aureus was twice as common in right-sided IE compared to left-sided IE, and the long-term prognosis of right sided IDU-associated IE was better compared to left-sided IE despite the fact that few were operated.

Predictors of mortality and adverse events in patients with infective endocarditis: a retrospective real world study in a surgical centre.

PURPOSE: Mortality in infective endocarditis (IE) is still high, and the long term prognosis remains uncertain. This study aimed to identify predictors of long-term mortality for any cause, adverse event rate, relapse rate, valvular and ventricular dysfunction at follow-up, in a real-world surgical centre. METHODS: We retrospectively analyzed 363 consecutive episodes of IE (123 women, 34%) admitted to our department with a definite diagnosis of non-device-related IE. Median follow-up duration was 2.9 years. Primary endpoints were predictors of mortality, recurrent endocarditis, and major non-fatal adverse events (hospitalization for any cardiovascular cause, pace-maker implantation, new onset of atrial fibrillation, sternal dehiscence), and ventricular and valvular dysfunction at follow-up. RESULTS: Multivariate analysis independent predictors of mortality showed age (HR per unit 1.031, p < 0.003), drug abuse (HR 3.5, p < 0.002), EUROSCORE II (HR per unit 1.017, p < 0.0006) and double valve infection (HR 2.3, p < 0.001) to be independent predictors of mortality, while streptococcal infection remained associated with a better prognosis (HR 0.5, p < 0.04). Major non-fatal adverse events were associated with age (HR 1.4, p < 0.022). New episodes of infection were correlated with S aureus infection (HR 4.8, p < 0.001), right-sided endocarditis (HR 7.4, p < 0.001), spondylodiscitis (HR 6.8, p < 0.004) and intravenous drug abuse (HR 10.3, p < 0.001). After multivariate analysis, only drug abuse was an independent predictor of new episodes of endocarditis (HR 8.5, p < 0.001). Echocardiographic follow-up, available in 95 cases, showed a worsening of left ventricular systolic function (p < 0.007); severe valvular dysfunction at follow-up was reported only in 4 patients, all of them had mitral IE (p < 0.03). CONCLUSIONS: The present study highlights some clinical, readily available factors that can be useful to stratify the prognosis of patients with IE.

Secular trends in the epidemiology and clinical characteristics of Enterococcus faecalis infective endocarditis at a referral center (2007-2018).

The aim of the study was to analyze the epidemiological and clinical changes in EFIE. All definite IE episodes treated at a referral center between 2007 and 2018 were registered prospectively, and a trend test was used to study etiologies over time. EFIE cases were divided into three periods, and clinical differences between them were analyzed. All episodes of E. faecalis monomicrobial bacteremia (EFMB) between 2010 and 2018 and the percentage of echocardiograms performed were retrospectively collected. Six hundred forty-eight IE episodes were studied. We detected an increase in the percentage of EFIE (15% in 2007, 25.3% in 2018, P = 0.038), which became the most prevalent causative agent of IE during the last study period. One hundred and eight EFIE episodes were analyzed (2007-2010, n = 30; 2011-2014, n = 22; 2015-2018, n = 56). The patients in the last period were older (median 70.9 vs 66.5 vs 76.3 years, P = 0.015) and more frequently had an abdominal origin of EFIE (20% vs 13.6% vs 42.9%, P = 0.014), fewer indications for surgery (63.3% vs 54.6% vs 32.1%, P = 0.014), and non-significantly lower in-hospital mortality (30% vs 18.2% vs 12.5%, P = 0.139). There was an increase in the percentage of echocardiograms performed in patients with EFMB (30% in 2010, 51.2% in 2018, P = 0.014) and EFIE diagnoses (15% in 2010, 32.6% in 2018, P = 0.004). E. faecalis is an increasing cause of IE in our center, most likely due to an increase in the percentage of echocardiograms performed. The factors involved in clinical changes in EFIE should be thoroughly studied.