Influence of the type of pathogen on the clinical course of infectious complications related to cardiac implantable electronic devices

The specific role of the various pathogens causing cardiac implantable electronic devices-(CIEDs)-related infections requires further understanding. The data of 1241 patients undergoing transvenous lead extraction because of lead-related infective endocarditis (LRIE-773 patients) and pocket infection (PI-468 patients) in two high-volume centers were analyzed. Clinical course and long-term prognosis according to the pathogen were assessed. Blood and generator pocket cultures were most often positive for methicillin-sensitive Staphylococcus aureus (MSSA: 22.19% and 18.13% respectively), methicillin-sensitive Staphylococcus epidermidis (MSSE: 17.39% and 15.63%) and other staphylococci (11.59% and 6.46%). The worst long-term prognosis both in LRIE and PI subgroup was in patients with infection caused by Gram-positive microorganisms, other than staphylococci. The most common pathogens causing CIED infection are MSSA and MSSE, however, the role of other Gram-positive bacteria and Gram-negative organisms is also important. Comparable, high mortality in patients with LRIE and PI requires further studies.

Definitions. Lead-related infective endocarditis was diagnosed using modified Duke criteria according to the 2015 ESC guidelines for the management of infective endocarditis 15 and the European Heart Rhythm Association international consensus document 16 . The diagnosis of lead-related infective endocarditis was definite in the presence of two major criteria or one major criterion and three minor criteria. According to the current guidelines 16 , cultures from extracted leads were considered as a minor criterion in the diagnosis of LRIE. Possible LRIE was diagnosed in patients with one major and one minor criterion or 3 minor criteria. Possible LRIE was also included in the current analysis.
A pocket infection was defined as local warmth, erythema, swelling, edema, and pain in or discharge from the device pocket or an erosion or impending erosion of the device without lead-related infective endocarditis 15 .
Intracardiac lead abrasion was defined as outer insulation macroscopic damage, in the intracardiac portion of the lead, usually in the first 15-20 cm from the tip, with visible discolouration, frequently with conductor externalisation, and not infrequently with purulent discharge 17 .
Transvenous lead extraction was defined according to HRS and EHRA statements [18][19][20] as a procedure involving the removal of a lead implanted for over one year or when more than just a standard stylet was required to remove the lead, or the non-implant vein approach had to be utilised. Complete procedural success of TLE was defined as removal of all targeted leads and material, with the absence of any permanently disabling complication or procedure-related death. Clinical success was achieved in patients with retention of a small part of the lead that did not negatively affect the outcome goals of the procedure [18][19][20] .
Major and minor complications were defined according to the 2018 EHRA Expert Consensus Statement on Lead Extraction 20 . They defined major complications as any of the outcomes related to the procedure, which was life-threatening or resulted in death or any unexpected event that caused persistent or significant disability. Minor complications were defined as any undesired event related to the procedure that required medical intervention or minor procedural intervention to remedy, and did not limit persistently or significantly the patient's function, threaten life or cause death.
Microbiology. In all patients with infectious complications, at least three aerobic and anaerobic blood cultures were performed before TLE. In order to exclude contamination, the criterion of a minimum of two positive cultures was used in the case of the physiological flora. In patients with the symptoms of local infection, a swab specimen was obtained from the generator pocket during TLE. The material drawn from the pocket was spread directly on the culture plate. In patients with suspected generalised infection, without PI symptoms, cultures from extracted leads were also done. A segment of the lead was rolled onto the solid media (Chocolate agar, McConkey agar, mannitol salt agar, and Sabouroud agar). Statistical methods. Normality was checked using the Shapiro-Wilk test, which showed that most continuous variables followed normal distribution. For uniformity, all continuous variables are presented as mean ± standard deviation and were compared using the Kruskal-Wallis ANOVA and Mann-Whitney U test. Categorical data are presented as absolute numbers and percentage and were compared using the Chi-square test with Yates correction.
A stepwise multivariable Cox regression model was used to evaluate the role of pathogens as risk factors for long-term mortality after TLE and included the following variables: gender, patient age at the time of TLE, NYHA class, LVEF, presence of artificial valve, arterial hypertension, diabetes mellitus, creatinine concentration, haemoglobin concentration, atrial fibrillation, anticoagulant and antiplatelet therapy, TLE of ICD leads (single or dual coil), presence of vegetations (LRIE), radiological success, pathogen type (MSSA, MRSA, MSSE, MRSE, MSSO, MRSO, other Gram-positive, Gram-negative pathogens, and fungi). Analyses were performed for patients with LRIE and pocket infection. In multivariable analysis, the results were presented as hazard ratio (HR) with 95% confidence interval (CI).
The Kaplan-Meier method was used to calculate the probability of event free survival depending on culture results from blood (LRIE) or pocket (PI) and in all subgroups divided according to indications for TLE (noninfectious, PI or LRIE). The log-rank test, including complete and censored data, was used to test for differences between survival curves.
A two-tailed p value < 0.05 was considered statistically significant. Statistical analysis was performed using STATISTICA 13.1 PL (TIBCO, Cracow, Poland).
In patients with suspected LRIE, besides blood cultures, 657 lead cultures from the extracted leads were analysed. Lead cultures were positive in 504 patients, including 24 patients with negative blood cultures. In these 24 patients with negative blood cultures, we identified 27 pathogens: S. epidermidis (51.85%) and other staphylococci (44.44%) were predominant.
About device-related and procedural factors, patients with LRIE had older leads (89.187 ± 69.686 vs. 82.011 ± 68.717 dwelling time, in months; p = 0.047) and more frequent intracardiac lead abrasion (29.37% vs. 21.19%; p = 0.017), whereas patients with PI underwent more CIED-related procedures (upgrading, revision of the pocket) (0.868 ± 1.065 vs. 0.816 ± 1.266; p = 0.016). The remaining factors that might influence the course of TLE did not differ between LRIE and PI subgroups. Course of the extraction procedure, radiological and clinical success rates, technical complications and major and minor complications, and mortality during follow-up did not differ between subgroups (Table 1).
LRIE patients: analysis of clinical and procedural factors according to pathogens isolated from blood. Among patients with LRIE divided according to pathogen type, males were most likely to have staphylococcal infection (especially S. aureus; 82.99%). Patients with infection caused by S. aureus were the oldest at the time of first device implantation (mean age 63.902 ± 13.664 years), whereas patients with S. epidermidis and with other staphylococci in blood cultures were the youngest at implantation (58.973 ± 14.707 and 58.320 ± 15.184 years, respectively). Mean age of all patients with LRIE during TLE was similar, regardless of the pathogen type. Patients with infection caused by S. aureus were most likely to have chronic kidney disease, whereas in patients with S. epidermidis and other staphylococci, CKD was less common. Patients with Gram-    (Table S3) Fig. 4).

Long term survival after TLE in LRIE patients: Multivariable analysis of mortality risk factors.
Factors that increased mortality risk during long-term follow-up were heart failure (higher NYHA class and lower LVEF), permanent atrial fibrillation, renal failure (higher creatinine levels), anaemia and older patient age. Infection due to MSSE was associated with better long-term survival rates (  Fig. 5).

Long-term survival after TLE in PI patients: multivariable analysis of mortality risk factors. At
long-term follow-up Candida albicans isolated from pocket cultures, diabetes, heart failure (higher NYHA class and lower LVEF), arterial hypertension, anaemia and older patient age were the risk factors for mortality in patients with PI (Table 3). www.nature.com/scientificreports/

Discussion
Infectious complications in patients with CIEDs have specific characteristics related to the foreign body reaction. There are two mechanisms of CIED infection. One mechanism involves contamination at the time of first implantation or other CIED-related procedures before TLE, with subsequent bacterial colonisation and infection spread along the leads to the endocardium. The other mechanism is associated with primary bloodstream infection 4,21 .
Infectious complications in CIED patients can be divided into local pocket infection and a generalised response i.e. lead-related infective endocarditis. Comparative analysis of patients with PI and LRIE in this study, similar to earlier reports [22][23][24] , showed that patients with generalised infection were most likely to have concomitant diseases (heart failure, diabetes, renal failure, permanent atrial fibrillation), and specific procedural factors: longer lead dwell times and intracardiac lead abrasions. PI, as compared with LRIE, was associated with a higher number of CIED-related procedures before TLE. Detailed microbiological analysis in the study population confirmed that MSSA and MSSE were the most frequent pathogens, causing infectious complications in patients with CIEDs. The incidence of these organisms has been reported to range between 17 and 45% and between 20.5 and 67%, which is comparable to that in the present study [5][6][7][8][9][10][11][12][13][14] . Our analysis also revealed a relatively frequent (11.59%) incidence of MSSO, with coagulase-negative strains such as S. hominis, S. capitis, S. haemolyticus being predominant. Isolation of CoNS usually represents a challenge for the clinician since it may result from contamination, given the generally low pathogenicity of CoNS except for S. lugdunensis which causes infections with a more severe course, resembling that of S. aureus 8 . These considerations may explain the different outcome of patients with isolation of other staphylococci in case of PI or LRIE (Figs. 4, 5).  www.nature.com/scientificreports/ Similar to earlier studies 10,14,25 this investigation confirmed the observations on risk factors and course of infections caused by S. aureus and other CoNS. S. aureus infection occurred in patients with shorter lead dwell times, whereas infection caused by S. epidermidis was more common in patients with earlier CIED-related procedures.
Apart from the most typical staphylococcal etiology in CIED infection, in this study Gram-negative bacteria caused infection in 9.12% of LRIE patients and in 5% of PI patients. Similar levels of incidence rates have been reported in recent years 26,27 . According to earlier studies, Gram-negative bacteria were rarely the primary cause of CIED infection, a milder course and lower long-term mortality characterised which, as compared with typical staphylococcal infection 28 . However, recent reports have showed that CIED is one of significant risk factors for the development of infective endocarditis because of Gram-negative organisms 26 . This study showed that Gram-negative bacteria was associated with a high rate of death among patients with LRIE and PI (43.75% and 57.14%, respectively) during 4-year follow-up after TLE. Observations about long-term prognosis in patients with CIED infection due to Gram-negative bacteria are very rare. Recent studies in populations with infective endocarditis including LRIE have shown the 15%-30% mortality rate at one-year follow-up 26,29 . The worse survival rate of patients with Gram negative infections in the current population may be related to the relatively high coexistence of other bacteria in cultures.
Analysis of long-term survival data from patients undergoing TLE because of CIED infection in our study showed the highest death rates in patients with other than staphylococci Gram positive infections (62.5% in LRIE and 100% in PI subgroup). This pathogenic group has first streptococci, corynobacteriacae and micrococci.   35 . We need further research to explain reasons behind poor long-term survival in PI patients in our study; this result can be attributed to difficulties in evaluating infection spread. This is likely because the present study documented high mortality in the PI and LRIE subgroups with the same cultures: other than Gram-positive and Gram-negative bacteria. Another important issue is the try to explain the reasons for the worse long-term survival in patients after treatment because of CIED infection. Both in LRIE and PI patients the predominant risk factors for mortality were clinical factors: patient age, heart failure, atrial fibrillation, renal failure, anaemia. In PI subgroup it was arterial hypertension, diabetes and local infection with Candida albicans. Several reports have shown a similar relationship between clinical factors and long-term survival after CIED infection 9,30,34,36,37 , but detailed analysis of risk adjusted for age, gender, race/ethnicity, and the 28 comorbidities from the Elixhauser system in a large population of PM/ICD/CRT-D recipients 32 showed that high mortality in patients with CIED infection can persist for at least 1-3 years after the infection and is device-dependent. The worse long-term prognosis in patients after treatment for CIED infection prompts us to continue looking for the causes of low efficacy of the therapy.

Study limitations
This is a retrospective analysis, and we collected the data only in two high-volume centres of TLE. Because of this limitation it is not possible to assess the causes of the high rates of negative blood and pocket cultures, which is probably related to sampling during antibiotic therapy in institutions referring patients for TLE. There is no possibility of evaluating the post-TLE course (as we refer patients to the sending institution)-duration of antibiotic treatment, which may affect long-term survival, is unknown. It is not possible, either, to test the direct causes of death during long-term follow-up.

Conclusions
CIED infection contributes to a poorer clinical course and long-term prognosis in patients undergoing transvenous lead extraction. The most common pathogens causing CIED infection are MSSA and MSSE, however special attention should be given to the adverse effects on the long-term survival in patients with other Grampositive bacteria and Gram-negative organisms in blood or pocket cultures. Clinical assessment of patients with local infection is important, as the long-term prognosis in this group is comparable to that in LRIE patients.