Infective endocarditis in children and adolescents: a different profile with clinical implications.

BACKGROUND: Our aim was to compare pediatric infective endocarditis (IE) with the clinical profile and outcomes of IE in adults. METHODS: Prospective multicenter registry in 31 Spanish hospitals including all patients with a diagnosis of IE from 2008 to 2020. RESULTS: A total of 5590 patients were included, 49 were <18 years (0.1%). Congenital heart disease (CHD) was present in 31 children and adolescents (63.2%). Right-sided location was more common in children/adolescents than in adults (46.9% vs. 6.3%, P < 0.001). Pediatric pulmonary IE was more frequent in patients with CHD (48.4%) than in those without (5.6%), P = 0.004. Staphylococcus aureus etiology tended to be more common in pediatric patients (32.7%) than in adults (22.3%), P = 0.082. Heart failure was less common in pediatric patients than in adults, due to the lower rate of heart failure in children/adolescents with CHD (9.6%) with respect to those without CHD (44.4%), P = 0.005. Inhospital mortality was high in both children, and adolescents and adults (16.3% vs. 25.9%; P = 0.126). CONCLUSIONS: Most IE cases in children and adolescents are seen in patients with CHD that have a more common right-sided location and a lower prevalence of heart failure than patients without CHD. IE in children and adolescents without CHD has a more similar profile to IE in adults. IMPACT: Infective endocarditis (IE) in children and adolescents is often seen in patients with congenital heart disease (CHD). Right-sided location is the most common in patients with CHD and heart failure is less common as a complication compared with patients without CHD. Infective endocarditis (IE) in children/adolescents without CHD has a more similar profile to IE in adults. In children/adolescents without CHD, locations were similar to adults, including a predominance of left-sided IE. Acute heart failure was the most frequent complication, seen mainly in adults, and in children/adolescents without CHD.

Outpatient Parenteral Antibiotic Treatment for Infective Endocarditis: A Prospective Cohort Study From the GAMES Cohort.

BACKGROUND: Outpatient parenteral antibiotic treatment (OPAT) has proven efficacious for treating infective endocarditis (IE). However, the 2001 Infectious Diseases Society of America (IDSA) criteria for OPAT in IE are very restrictive. We aimed to compare the outcomes of OPAT with those of hospital-based antibiotic treatment (HBAT). METHODS: Retrospective analysis of data from a multicenter, prospective cohort study of 2000 consecutive IE patients in 25 Spanish hospitals (2008-2012) was performed. RESULTS: A total of 429 patients (21.5%) received OPAT, and only 21.7% fulfilled IDSA criteria. Males accounted for 70.5%, median age was 68 years (interquartile range [IQR], 56-76), and 57% had native-valve IE. The most frequent causal microorganisms were viridans group streptococci (18.6%), Staphylococcus aureus (15.6%), and coagulase-negative staphylococci (14.5%). Median length of antibiotic treatment was 42 days (IQR, 32-54), and 44% of patients underwent cardiac surgery. One-year mortality was 8% (42% for HBAT; P < .001), 1.4% of patients relapsed, and 10.9% were readmitted during the first 3 months after discharge (no significant differences compared with HBAT). Charlson score (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.04-1.42; P = .01) and cardiac surgery (OR, 0.24; 95% CI, .09-.63; P = .04) were associated with 1-year mortality, whereas aortic valve involvement (OR, 0.47; 95% CI, .22-.98; P = .007) was the only predictor of 1-year readmission. Failing to fulfill IDSA criteria was not a risk factor for mortality or readmission. CONCLUSIONS: OPAT provided excellent results despite the use of broader criteria than those recommended by IDSA. OPAT criteria should therefore be expanded.

Antimicrobial management of Tropheryma whipplei endocarditis: the Spanish Collaboration on Endocarditis (GAMES) experience.

OBJECTIVES: Tropheryma whipplei has been detected in 3.5% of the blood culture-negative cases of endocarditis in Spain. Experience in the management of T. whipplei endocarditis is limited. Here we report the long-term outcome of the treatment of previously reported patients who were diagnosed with infective endocarditis (IE) caused by T. whipplei from the Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España (GAMES) and discuss potential options for antimicrobial therapy for IE caused by T. whipplei. PATIENTS AND METHODS: Seventeen patients with T. whipplei endocarditis were recruited between 2008 and 2014 in 25 Spanish hospitals. Patients were classified according to the therapeutic regimen: ceftriaxone and trimethoprim/sulfamethoxazole, doxycycline + hydroxychloroquine and other treatment options. RESULTS: Follow-up data were obtained from 14 patients. The median follow-up was 46.5 months. All patients completed the antibiotic treatment prescribed, with a median duration of 13 months. Six patients were treated with ceftriaxone and trimethoprim/sulfamethoxazole (median duration 13 months), four with doxycycline + hydroxychloroquine (median duration 13.8 months) and four with other treatment options (median duration 22.3 months). The follow-up after the end of the treatments was between 5 and 84 months (median 24 months). CONCLUSIONS: All treatment lines were effective and well tolerated. Therapeutic failures were not detected during the treatment. None of the patients died or experienced a relapse during the follow-up. Only six patients received antibiotic treatment in accordance with guidelines. These data suggest that shorter antimicrobial treatments could be effective.

Vitamin D nutritional status and vitamin D regulated antimicrobial peptides in serum and pleural fluid of patients with infectious and noninfectious pleural effusions.

BACKGROUND: Vitamin D and vitamin D dependent antimicrobial peptides such as Cathelicidin (LL-37) and ß-defensin 2 have an important role in innate and adaptative immunity, but their role in pleural effusions has not been studied before. METHODS: Serum and pleural fluid samples from 152 patients with pleural effusion were collected, corresponding to 45 transudates and 107 exudates, 51 infectious effusions (14 complicated and 37 non-complicated), 44 congestive heart failure effusions and 38 malignant effusions. The levels of 25 OH-vitamin D, 1,25-(OH)2-vitamin D, Vitamin D Binding Protein (VDBP), LL-37 and ß-defensin 2, both in serum and pleural fluid were evaluated in this prospective study. Differences between groups were analysed using unpaired t tests or Mann-Whitney tests. Correlations between data sets were examined using Pearson correlation coefficient or Spearman rank correlation coefficient. Diagnostic accuracy was estimated using ROC curve analysis. RESULTS: Low serum 25 OH vitamin D levels were found in all groups. Infectious effusions (IE) had higher serum and pleural fluid LL-37 levels compared to congestive heart failure or malignant effusions. Among IE, complicated had higher serum and pleural fluid LL-37 levels, and lower serum ß-defensin-2 levels. Positive correlations were found between serum 25 OH-vitamin D levels and serum or pleural 1,25-(OH)2-vitamin D levels, and between 1,25-(OH)2-vitamin D and LL-37 serum. Diagnostic accuracy of the different molecules was moderate at best. CONCLUSIONS: Hypovitaminosis D is highly prevalent in pleural effusions. LL-37 is produced intrapleurally in IE. This production is higher in complicated IE. No evidence of pleural production of ß-defensin 2 was found in any of the groups. Diagnostic accuracy of the different molecules is at the best moderate for discriminating different types of effusions.

Tuberculosis prophylaxis with levofloxacin in liver transplant patients is associated with a high incidence of tenosynovitis: safety analysis of a multicenter randomized trial.

BACKGROUND: It is necessary to develop a safe alternative to isoniazid for tuberculosis prophylaxis in liver transplant recipients. This study was designed to investigate the efficacy and safety of levofloxacin. METHODS: An open-label, prospective, multicenter, randomized study was conducted to compare the efficacy and safety of levofloxacin (500 mg q24h for 9 months) initiated in patients awaiting liver transplantation and isoniazid (300 mg q24h for 9 months) initiated post-transplant when liver function was stabilized. Efficacy was measured by tuberculosis incidence at 18 months after transplantation. All adverse events related to the medication were recorded. RESULTS: CONSORT guidelines were followed in order to present the results. The safety committee suspended the study through a safety analysis when 64 patients had been included (31 in the isoniazid arm and 33 in the levofloxacin arm). The reason for suspension was an unexpected incidence of severe tenosynovitis in the levofloxacin arm (18.2%). Although the clinical course was favorable in all cases, tenosynovitis persisted for 7 weeks in some patients. No patients treated with isoniazid, developed tenosynovitis. Only 32.2% of patients randomized to isoniazid (10/31) and 54.5% of patients randomized to levofloxacin (18/33, P = .094) completed prophylaxis. No patient developed tuberculosis during the study follow-up (median 270 days). CONCLUSIONS: Levofloxacin prophylaxis of tuberculosis in liver transplant candidates is associated with a high incidence of tenosynovitis that limits its potential utility.

Executive summary. Management of urinary tract infection in solid organ transplant recipients: Consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI).

Urinary tract infections (UTI) are one of the most common infections in solid organ transplant (SOT) recipients. A systematic review was performed to assess the management of UTI in SOT recipients. Recommendations are provided on the management of asymptomatic bacteriuria, and prophylaxis and treatment of UTI in SOT recipients. The diagnostic-therapeutic management of recurrent UTI and the role of infection in kidney graft rejection or dysfunction are reviewed. Finally, recommendations on antimicrobials and immunosuppressant interactions are also included.

Management of urinary tract infection in solid organ transplant recipients: Consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI).

BACKGROUND: Urinary tract infections (UTIs) are one of the most common infections in solid organ transplant (SOT) recipients. METHODS: Experienced SOT researchers and clinicians have developed and implemented this consensus document in support of the optimal management of these patients. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation. This article was written in accordance with international recommendations on consensus statements and the recommendations of the Appraisal of Guidelines for Research and Evaluation II (AGREE II). RESULTS: Recommendations are provided on the management of asymptomatic bacteriuria, and prophylaxis and treatment of UTI in SOT recipients. The diagnostic-therapeutic management of recurrent UTI and the role of infection in kidney graft rejection or dysfunction are reviewed. Finally, recommendations on antimicrobials and immunosuppressant interactions are also included. CONCLUSIONS: The latest scientific information on UTI in SOT is incorporated in this consensus document.

The IL-17 G-152A single nucleotide polymorphism is associated with pulmonary tuberculosis in northern Spain.

BACKGROUND: Interleukin 17 (IL-17) is induced during the early stages of tuberculosis infection, playing an important role in the defense against mycobacterial infection. To date, only one study performed in Chinese Han population has found an association between IL-17F sequence variants and susceptibility to tuberculosis, but no relationship has been found with another single nucleotide polymorphism (SNP) in IL-17A gene (rs2275913). METHODS: To assess if rs2275913 (G-152A) SNP, could be associated with susceptibility to pulmonary tuberculosis (PTB) in a genetically homogeneous Caucasian population, we analyzed if its allele and genotype frequencies were statistically significant in a case-control study. One hundred and ninety-two patients with active PTB and 266 blood healthy donors were enrolled in this study. RESULTS: The frequency of the GG versus GA+AA genotype was significantly more frequent in patients with PTB than in control subjects assuming a dominant model (50.52% versus 39.10% respectively, OR=1.59, 95%CI=1.09-2.31, p=0.015). Despite patients with PTB had higher serum IL-17 levels, we did not find an association of this SNP with IL-17 ex vivo production after stimulation with Mycobacterium tuberculosis (Mtb) antigens or phytohemagglutinin (PHA). CONCLUSION: Our results would suggest an association between IL-17A rs2275913 - 152G allele and GG genotype with susceptibility to PTB for the first time.

Education on antibiotic use. Education systems and activities that work.

Education is a cornerstone of antimicrobial stewardships programs, because 50% of inappropriate antimicrobial prescriptions are a consequence of an imbalance between the high levels of knowledge required for the appropriate use of antibiotics and the scarce training offered to medical specialists. For this reason, programs optimizing antimicrobial (PROA) are essentially based on support and educational activities for prescribers. The educational activities are difficult to evaluate. In our country, the application of educational activities in antimicrobial training programs is very heterogeneous, although it has improved in recent years. We recommend the following educational measures, which are prioritized in order of effectiveness. Interactive educational interventions are the most effective. These are non-compulsory interventions based on real prescriptions in clinical practice and include educational outreach visits, audits and counseling interviews with feedback and multifaceted interventions. Passive educational strategies, with posters, newsletters, and dissemination of guidelines, are only marginally effective in changing antimicrobial prescribing practices and have not shown a sustained effect. These measures need extensive professional involvement and should be combined with more active approaches. Currently, interventions can be enhanced with some teaching tools in electronic format. Both interactive and passive educational measures should be integrated into the PROA and should have institutional support. Finally, we recommend including antimicrobials in the training plans of all clinical specialties.

Post-mortem findings in Spanish patients with COVID-19; a special focus on superinfections.

Introduction: Whole-body autopsies may be crucial to understand coronavirus disease 2019 (COVID-19) pathophysiology. We aimed to analyze pathological findings in a large series of full-body autopsies, with a special focus on superinfections. Methods: This was a prospective multicenter study that included 70 COVID-19 autopsies performed between April 2020 and February 2021. Epidemiological, clinical and pathological information was collected using a standardized case report form. Results: Median (IQR) age was 70 (range 63.75-74.25) years and 76% of cases were males. Most patients (90%,) had at least one comorbidity prior to COVID-19 diagnosis, with vascular risk factors being the most frequent. Infectious complications were developed by 65.71% of the patients during their follow-up. Mechanical ventilation was required in most patients (75.71%) and was mainly invasive. In multivariate analyses, length of hospital stay and invasive mechanical ventilation were significantly associated with infections (p = 0.036 and p = 0.013, respectively). Necropsy findings revealed diffuse alveolar damage in the lungs, left ventricular hypertrophy in the heart, liver steatosis and pre-infection arteriosclerosis in the heart and kidneys. Conclusion: Our study confirms the main necropsy histopathological findings attributed to COVID-19 in a large patient series, while underlining the importance of both comorbid conditions and superinfections in the pathology.

Risk factors, clinical features, and outcomes of toxoplasmosis in solid-organ transplant recipients: a matched case-control study.

BACKGROUND: Solid-organ transplant (SOT) recipients are considered to be at increased risk for toxoplasmosis. However, risk factors for this infection have not been assessed. The aim of this study was to determine the risk factors, clinical features, and outcomes of toxoplasmosis in SOT recipients. METHODS: A multicenter, matched case-control study (1:2 ratio) was conducted between 2000 and 2009. Control subjects were matched for center, transplant type, and timing. Cases were identified from the hospitals' microbiology and transplantation program databases. Logistic regression was performed to identify independent risk factors. RESULTS: Twenty-two cases (0.14%) of toxoplasmosis were identified among 15 800 SOTs performed in 11 Spanish hospitals, including 12 heart, 6 kidney, and 4 liver recipients. Diagnosis was made by seroconversion (n = 17), histopathologic examination (n = 5), polymerase chain reaction (n = 2), and autopsy (n = 2). In a comparison of case patients with 44 matched control subjects, a negative serostatus prior to transplantation was the only independent risk factor for toxoplasmosis (odds ratio, 15.12 [95% confidence interval, 2.37-96.31]; P = .004). The median time to diagnosis following transplantation was 92 days. Primary infection occurred in 18 (81.8%) cases. Manifestations included pneumonitis (n = 7), myocarditis (n = 5), brain abscesses (n = 5), chorioretinitis (n = 3), lymph node enlargement (n = 2), hepatosplenomegaly (n = 2), and meningitis (n =1). Five patients (22.7%) had disseminated disease. Crude mortality rate was 13.6% (3 of 22 patients). CONCLUSIONS: Although uncommon, toxoplasmosis in SOT patients causes substantial morbidity and mortality. Seronegative recipients are at high risk for developing toxoplasmosis and should be given prophylaxis and receive careful follow-up.

[Daptomycin in complicated skin and soft tissue infections]. / Tratamiento con daptomicina en las infecciones complicadas de piel y partes blandas.

In recent years, Staphylococcus aureus, the most commonly identified infectious agent causing skin and soft tissue infections (SSTIs), has shown an increase in methicillin resistance and decreased susceptibility to vancomycin. Because of its spectrum, microbiological activity, pharmacokinetics, and safety, as well as clinical experience in its use, daptomycin seems to be a highly appropriate antibiotic in the treatment of SSTIs, especially those produced by methicillin-resistant S. aureus.

Outpatient Parenteral Antibiotic Treatment vs Hospitalization for Infective Endocarditis: Validation of the OPAT-GAMES Criteria.

Background: Outpatient parenteral antibiotic treatment (OPAT) programs are increasingly used to manage infective endocarditis (IE), but current criteria for indicating OPAT are markedly conservative. We aimed to investigate whether more liberal criteria for indicating OPAT in IE can be safely used. Methods: This was a prospective multicenter nationwide cohort study (2008-2018). Rates of readmission, recurrences, and 1-year mortality were compared between hospital-based antibiotic treatment (HBAT) and OPAT. Risk factors for readmission and mortality in OPAT patients were investigated by logistic regression. Patients did not fulfill OPAT-GAMES (Grupos de Apoyo al Manejo de la Endocarditis en ESpaña) criteria if they had any of the following: cirrhosis, severe central nervous system emboli, undrained abscesses, severe conditions requiring cardiac surgery in nonoperable patients, severe postsurgical complications, highly difficult-to-treat microorganisms, or intravenous drug use. Results: A total of 2279 HBAT patients and 1268 OPAT patients were included. Among OPAT patients, 307 (24.2%) did not fulfill OPAT-GAMES criteria. Overall, OPAT patients presented higher rates of readmission than HBAT patients (18.2% vs 14.4%; P = .004), but no significant differences were found in the propensity analysis. Patients not fulfilling OPAT-GAMES criteria presented significantly higher rates of readmission than HBAT and OPAT-GAMES (23.8%, 14.4%, 16.4%; P < .001), whereas no significant differences were found in mortality (5.9%, 8%, 7.4%; P = .103) or recurrences (3.9%, 3.1%, 2.5%; P = .546). Not fulfilling OPAT-GAMES criteria was associated with higher risk of readmission (odds ratio [OR], 1.43; 95% CI, 1.03-1.97; P = .03), whereas cardiac surgery was associated with lower risk (OR, 0.72; 95% CI, 0.53-0.98; P = .03). Conclusions: OPAT-GAMES criteria allow identification of IE patients at higher risk of long-term complications to whom OPAT cannot be safely administered.

Multivalvular Endocarditis: A Rare Condition with Poor Prognosis.

Background. Infective endocarditis (IE) is a severe condition. Our aim was to describe the profile and prognosis of patients with multivalvular infective endocarditis (MIE) and compare them to single-valve IE (SIE). Methods. We used a retrospective analysis of the Spanish IE Registry (2008−2020). Results. From 4064 definite cases of valvular IE, 577 (14.2%) had MIE. In patients with MIE, the most common locations were mitral (552, 95.7%) and aortic (550, 95.3%), with mitral-aortic involvement present in 507 patients (87.9%). The most common etiologies were S. viridans (192, 33.3%) and S. aureus (113, 19.6%). MIE involved only native valves in 450 patients (78.0%). Compared with patients with SIE, patients with MIE had a similar age (69 vs. 67 years, respectively, p = 0.27) and similar baseline characteristics, but were more frequently men (67.1% vs. 72.9%, p = 0.005) and had a higher incidence of intracardiac complications (36.2% vs. 50.4%, p < 0.001), heart failure (42.7% vs. 52.9%, p < 0.001), surgical indication (67.7 vs. 85.1%, p < 0.001), surgery (46.3% vs. 56.3%), and in-hospital mortality (26.9% vs. 34.3%, p < 0.001). MIE was an independent predictor of in-hospital mortality (odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1−1.7, p = 0.004) but did not have an independent association with 1-year mortality (OR 1.1, 95% CI 0.9−1.4, p = 0.43). Conclusions. About one-seventh of the valvular IE patients had MIE, mainly due to mitral-aortic involvement. MIE is associated with a poor in-hospital prognosis. An early diagnosis and treatment of IE might avoid its spread to a second valve.

[Lights and shadows of cytomegalovirus infection in solid organ transplantation]. / Luces y sombras de la infección por citomegalovirus en el trasplante de órgano sólido.

Cytomegalovirus (CMV) develops in 30-80% of patients undergoing solid organ transplantation (SOT). The incidence and presence of symptomatic disease varies depending on the type of transplant, the presence of associated risk factors, the intensity of immunosuppression, and the prevention strategies used. The impact of CMV on SOT is due not only to the effects of CMV disease per se, but also to its multiple indirect effects resulting from its immunomodulatory role and immunoactivation caused by viral latency. The two prophylactic strategies used (universal prophylaxis and preemptive therapy) are equally useful. Both strategies have advantages and disadvantages, and uncertainties remain on the populations that should receive prophylaxis and for how long. Viral monitoring to detect CMV infection is important for diagnosis, prognosis and evaluation of treatment response. The new real-time polymerase chain reaction techniques have provided numerous advantages but standardization remains an issue and common reference values are required. Specific anti-CMV drugs are available but issues such as the role of valganciclovir versus ganciclovir, the development of resistances and optimal treatment length are still being debated. Complementary therapy with mTOR inhibitors and vaccine strategies against CMV are alternatives for which conclusive data are lacking.

[Identification of clinically relevant fungi using molecular techniques]. / Identificación de hongos de importancia clínica mediante técnicas moleculares.

OBJECTIVE: To apply a sequencing-based molecular method to identify clinically relevant fungi to species level. METHOD: Thirty-six fungi not identifiable at a species level by a conventional approach and 39 invasive clinical samples were prospectively evaluated. The results were compared with those obtained by conventional methods. RESULTS: Molecular methods allowed rapid and reliable identification of fungi at species level, including both from organisms grown in culture and those in clinical samples. CONCLUSION: Molecular methods show clear advantages for fungal identification, including rapid identification at species level and high negative predictive value.

New trends in infective endocarditis.

The present article is an update of the literature on endocarditis. A multidisciplinary group of Spanish physicians with an interest in cardiac infections selected the most important papers produced lately in the field. Two of the members of the group discussed the content of each of the selected papers, with a critical review by others members of the panel. After a review of the state of the art papers from the fields of epidemiology, new causative microorganisms (bacterial and fungal), clinical findings including those in special patients, laboratory diagnosis, prognostic factors, nosocomial endocarditis, prophylaxis, new drugs and guidelines for antibiotic treatment were discussed by the group.

GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients.

Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available.

Prevalence of Colorectal Neoplasms Among Patients With Enterococcus faecalis Endocarditis in the GAMES Cohort (2008-2017).

OBJECTIVE: To investigate the rate of colorectal neoplasms (CRNs) in patients who have Enterococcus faecalis infective endocarditis (EFIE) with available colonoscopies and to assess whether this is associated with the identification of a focus the infection. PATIENTS AND METHODS: Retrospective analysis of data from a prospective multicenter study involving 35 centers who are members of the Grupo de Apoyo para el Manejo de la Endocarditis en España [Support Group for the Management of Infective Endocarditis in Spain] cohort. A specific set of queries regarding information on colonoscopy and histopathology of colorectal diseases was sent to each participating center. Four-hundred sixty-seven patients with EFIE were included from January 1, 2008, to December 31, 2017, from whom data on colonoscopy performance and results were available in 411 patients. RESULTS: One hundred forty-two (34.5%) patients had a colonoscopy close to the EFIE episode. The overall rate of colorectal diseases was 70.4% (100 of 142), whereas the prevalence of CRN (advanced adenomas and colorectal carcinoma) was 14.8% (21 of 142), with no significant differences between the group of EFIE of unknown focus and that with an identified focus. CONCLUSION: Our study adds to prior evidence suggesting a much higher rate of CRN among patients with EFIE than in the general population of the same age and sex. In addition, our findings suggest that this phenomenon might take place both in EFIE with an unknown and an identified source of infection.