and noninfectious lead-adherent echodensities, the clinical scenario often determines the diagnosis and approach to treatment. For example, an echodensity found by TEE or intracardiac echo performed for an unrelated reason is unlikely to represent CIED infection or CIED-IE [56]. The clinical manifestations of lead infection are similar to those of right-sided endocarditis [34]. (See "Right-sided native valve infective endocarditis", section on 'Clinical manifestations'.) Usually the presentation is subacute, but occasional patients present with sepsis syndrome and shock. The acute presentations are associated with more virulent organisms (eg, S. aureus). Manifestations overall include: Fever 84 to 100 percent. Chills 75 to 84 percent. Pulmonary abnormalities Clinical and/or radiographic findings consistent with pneumonia, bronchitis, lung abscess, or embolism occur in 20 to 45 percent of patients [34,35]. In particular, pulmonary embolism occurs in 11 to 40 percent of cases [3,27,34,35,59]. Abnormalities on chest imaging may provide indirect evidence of intracardiac lead or tricuspid valve infection. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 12/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Tricuspid abnormalities Tricuspid regurgitation develops in about 25 percent of patients; occasionally tricuspid stenosis results from an obstructing vegetation [2,61]. Metastatic seeding of mitral or aortic valve, bone, joints, liver, and spleen [59]. Systemic emboli Systemic emboli, including stroke, are rare but can occur in the setting of a patent foramen ovale, atrial septal defect, or unrecognized left-sided valve infection [13]. The clinical presentation of lead infection may be early onset (within three to six months of CIED implantation or generator change; approximately one-third of cases) or late onset (more than six months after CIED manipulation; approximately two-thirds of cases) [3,33-35]. In general, patients with early-onset CIED infection are recognized promptly because of the frequent concurrence of systemic symptoms and associated generator pocket infection [3,34,35]. Among patients with late-onset CIED infection, the average interval from device manipulation to the onset of symptoms is 25 months, and the symptoms are often protean and consistent with endocarditis, resulting in a delayed diagnosis [34,35]. Clinical manifestations of endocarditis are discussed further separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis" and "Right-sided native valve infective endocarditis".) Valve vegetation CIED infection can occur in association with concomitant infection of the right (or, less commonly, left) heart valves [3,59,62]. In addition, patients with a CIED may present with valvular endocarditis in the absence of device infection. The most common symptoms of valvular endocarditis are fever and chills; other symptoms include malaise, headache, myalgias, arthralgias, night sweats, abdominal pain, dyspnea, cough, and pleuritic pain. Cardiac murmurs are observed in approximately 85 percent of patients. Signs specifically suggestive of left-sided valve infection include cutaneous manifestations such as petechiae or splinter hemorrhages and systemic emboli. (See "Right-sided native valve infective endocarditis" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".) Other presentations Other presentations of CIED systemic infection include bacteremia with infection of remote sites, and in patients with epicardial leads, mediastinitis, and pericarditis. Bacteremia associated with CIED lead infection may occur in the absence of clinical evidence for endocarditis. Occasionally, remote extravascular sites (eg, bone or joint) are seeded. In patients https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 13/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up with a CIED who present with hematogenously seeded deep infection, the potential for concurrent CIED lead infection must be considered. Symptoms of mediastinitis or pericarditis may occur in the setting of patients with infection of epicardial electrodes. Both are usually associated with bacteremia: Clinical manifestations of mediastinitis include fever and chest pain. (See "Postoperative mediastinitis after cardiac surgery".) Clinical manifestations of pericarditis include fever, pleuritic chest pain, and pericardial friction rub. Pericardial effusion may be observed on echocardiogram or radiographic imaging and be accompanied by hemodynamic complications. (See "Acute pericarditis: Clinical presentation and diagnosis".) Diagnostic evaluation The clinical presentation and results of initial tests determine the need to test for a CIED systemic infection as follows: Patients who require evaluation for CIED infection Diagnostic testing for CIED systemic infection should be obtained in patients with a CIED who present with any of the following characteristics: Fever or other systemic signs of infection Overt pocket infection Pulmonary nodular infiltrates (eg, suspected septic emboli) Unexplained bacteremia Bacteremia with S. aureus The absence of signs or symptoms of CIED pocket infection does not rule out CIED systemic infection. Patients who may not require evaluation for a CIED infection - Diagnostic testing for CIED systemic infection may not be necessary for all patients with a CIED and bacteremia. Patients with a CIED and bacteremia from a clearly defined infection remote from the CIED (eg, pneumococcal pneumonia, pyelonephritis due to Enterobacteriaceae) caused by an organism not typically associated with intravascular infection are at low risk of CIED infection. In such patients, the infection can be treated and the patient can be monitored for signs of CIED infection during follow-up. Evaluation for CIED infection The approach to evaluation of suspected CIED systemic infection is summarized in the algorithms ( algorithm 2 and algorithm 3) and includes the following tests: https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 14/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Blood cultures At least two sets of blood cultures should be obtained from separate venipuncture sites prior to initiation of empiric antimicrobial therapy [1,52]. If bacteremia is detected, follow-up blood cultures should be obtained daily after antimicrobial therapy is begun and continued until 48 to 72 hours after clearance of bacteremia is documented. Frequent blood cultures may provide additional prognostic information in those with staphylococcal bacteremia and possible CIED infection; notably the risk of recurrence is associated with the duration of staphylococcal bacteremia [41]. The approach to empiric antibiotic therapy is discussed separately. (See "Infections involving cardiac implantable electronic devices: Treatment and prevention", section on 'Empiric therapy'.) Echocardiography In all patients with suspected CIED infection, echocardiography should be performed using an approach similar to the evaluation for valvular endocarditis (ie, initial transthoracic echocardiography [TTE] with a subsequent transesophageal echo [TEE] if the TTE is negative or additional information is required to direct management) ( movie 1) [1]. TEE is better than transthoracic echocardiography for detection of lead and valve vegetations and also provides images of the lead in the proximal superior vena cava. In several studies, TEE identified vegetations on the tricuspid valve or device lead in 90 to 96 percent of patients with endocarditis; in contrast, TTE identified such findings in only 22 to 43 percent [2,27,34,35,63]. However, TEE cannot fully exclude the presence of CIED infection or endocarditis. Accordingly, when intracardiac infection is highly suspected and the TEE is negative, further testing is necessary (eg, repeat echocardiography or alternative imaging as described below) ( algorithm 3). The limitations of TEE for discriminating between infectious lead vegetations and thrombus were demonstrated in small studies: In a small case-control study that blinded echocardiographers to all clinical data, infectious and noninfectious echodensities did not differ in their echocardiographic characteristics (eg, diameter, mobility), and the reviewers' ability to correctly diagnose infectious vegetations was low (sensitivity 34 percent) [64]. Another study showed that 17 percent of patients undergoing TEE for noninfectious indications were found to have lead-based echodensities, and none of these patients manifested bacteremia during follow-up [56]. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 15/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Alternative imaging When intracardiac infection is highly suspected in patients with a negative or nondiagnostic TEE, alternative imaging with SPECT [65-67] or FDG-PET/CT to support the diagnosis may be warranted [67-73]. These technologies can assess the entire device and may also detect infected sites remote from the device. These alternative imaging modalities are not routinely used in assessing CIED infection; they may be useful for situations when CIED infection has not been confirmed (but is strongly suspected) [1,74]. The choice of a particular diagnostic modality is guided by local availability and expertise: 18F 18 FDG-PET/CT scan PET positivity depends upon uptake of F-FDG by inflammatory cells at the site of infection; its utility is uncertain in patients with leukopenia or after 18 prolonged administration of antibiotics. F-FDG-PET/CT technology may be useful for distinguishing infection of soft tissues overlying the generator from generator pocket infection and can define infection along the extracardiac course of electronic leads and 18 within the heart [67,69-72,75]. In addition, F-FDG-PET/CT can detect septic pulmonary emboli as a manifestation of lead-related endocarditis. Occasionally, this imaging may also demonstrate infection involving other sites due to bacteremia (such as vertebral osteomyelitis/discitis) or embolic events suggesting concurrent left-sided endocarditis (such as splenic or renal infarcts) [67-71,73,74]. A meta-analysis including 340 patients noted a high overall sensitivity and specificity of 18 F-FDG-PET/CT for diagnosis of CIED infection (87 and 94 percent, respectively) [73]. However, the sensitivity and specificity were higher for pocket/generator infection (93 and 98 percent, respectively) compared with lead-associated endocarditis (65 and 88 percent, respectively). The findings of another meta-analysis including 492 patients were very similar [76]. Thus, radionuclide imaging, particularly FDG-PET/CT, is uniquely useful in assessing pocket infection but can also supplement diagnostic efforts for CIED- IE when echocardiography is equivocal. 99m Tagged WBC scan Scintigraphy ( Tc-labeled white blood cell) and SPECT/CT have been used for the detection and localization of CIED infections [66]. SPECT/CT is able to locate inflammation better than scintigraphy, which has poor spatial resolution. SPECT/CT has good sensitivity for pocket infection. In patients with a suspected CIED 18 infection and recent cardiac surgery, scintigraphy may be more specific than F-FDG- PET/CT, which may be positive, particularly around implanted material, for two to three months after surgery due to sterile inflammation (false positive) [68]. Cardiac CT angiography (CCTA) CCTA (with or without EKG gating), has poorer sensitivity than echocardiography for lead vegetations. It can be combined with https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 16/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up enhanced chest CT to evaluate for pocket infection or hematogenous pulmonary findings which would indirectly support a diagnosis of CIED infection. Use of CCTA should be limited to situations in which radionuclide imaging is unavailable [74]. Evaluation for associated endocarditis Patients with a CIED who are undergoing evaluation for a CIED infection or who have unexplained bacteremia caused by an organism that commonly causes endocarditis are at high risk for right-sided or left-sided endocarditis; these patients should be evaluated for endocarditis, which typically includes a TEE. The approach to testing and interpretation of tests for endocarditis are discussed separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on 'Diagnosis'.) Diagnosis Our approach The diagnosis of CIED systemic infection is established if a patient with a CIED has a fever or systemic signs of infection and one of the following ( algorithm 2): Clinically evident pocket infection and positive blood cultures. TEE with valve or lead vegetation in the context of other signs and symptoms of systemic infection (as distinguished from fibrin stranding, which can be found on leads that have been in place over an extended period). Because of significant overlap in appearance between infectious and noninfectious vegetations, the clinical history, physical examination, and microbiology results supporting CIED infection should inform the interpretation of lead-based echodensities. In patients with nondiagnostic TEE or in whom TEE cannot be done, an alternative imaging modality (such as FDG-PET/CT, SPECT/CT, or CCTA) can identify evidence of CIED infection or endocarditis. The choice of a particular diagnostic modality will be guided by local availability and expertise. (See 'Evaluation for CIED infection' above.) Blood cultures demonstrate (see 'Bacteremia' above): Any isolation of the following organisms: S. aureus (especially in the absence of a clear portal of entry, occurring within three months of device manipulation, or persisting or recurring in spite of appropriate antimicrobial therapy) (see 'Bacteremia' above) Candida species https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 17/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up High-grade bacteremia (defined as 2 or more separate blood cultures positive for the same organism, drawn 1 hour apart) with the following organisms: Coagulase-negative staphylococci. Cutibacterium (formerly Propionibacterium) species. Other high-grade bacteremia without clear portal of entry (especially due to an organism that commonly causes endocarditis, such as alpha-hemolytic streptococci, beta-hemolytic streptococci, enterococci). A single positive blood culture for coagulase-negative staphylococci or Cutibacterium species may represent skin contamination. In such cases, blood cultures should be repeated to evaluate for high grade bacteremia. If repeat cultures are confounded by antibiotic therapy and clinical suspicion for CIED infection persists, consider pursuing further imaging (FDG-PET/CT) if available; further management should be guided by consultation with infectious disease expertise. Culture and histopathology of the vegetation/lead tip consistent with infection. Proposed diagnostic criteria The European Heart Rhythm Association proposed diagnostic criteria for CIED-IE modeled after the modified Duke Criteria for infective endocarditis; these criteria categorize cases into definite, possible, and rejected groups [1]. The criteria have not been validated, given the absence of a diagnostic "gold standard," but they provide a tool for systematic assessment for CIED-IE. The criteria use the above alternate imaging modalities as components of the classification schema; we agree with this approach. Differential diagnosis The differential diagnosis of CIED-IE includes other causes of septic pulmonary emboli and causes of bacteremia in patients with a CIED that include: Septic jugular thrombophlebitis Septic jugular thrombophlebitis is characterized by infectious involvement of the carotid sheath vessels with bacteremia (often with Fusobacterium spp); it should be suspected in patients with antecedent pharyngitis or parapharyngeal infection, septic pulmonary emboli, and persistent fever despite antimicrobial therapy. The diagnosis is established by computed tomography of the neck and upper thorax. (See "Catheter-related septic thrombophlebitis".) Lower extremity or pelvic vein thrombophlebitis Patients with septic pelvic thrombophlebitis usually present shortly after delivery or surgery with fever in the absence of localizing symptoms, which persists despite antibiotics. Radiographic studies may or https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 18/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up may not demonstrate thrombus and the diagnosis is often one of exclusion. (See "Septic pelvic thrombophlebitis".) Bacteremia associated with a remote site of infection Bacteremia (without involvement of the CIED) may occur from noncardiac sites such as the abdomen, pelvis, soft tissues, bone, or any prosthetic implant. Blood culture contamination Positive blood cultures do not always represent a true bacteremia; contamination with skin flora must be considered, particularly if the entire clinical picture does not suggest a systemic infection. Fibrous material associated with longstanding CIED leads TEE may demonstrate fibrous material, clot, or stranding; these findings do not always represent infection [55,56]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infections involving cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Cardiac implantable electronic devices (CIEDs) include pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy (CRT) devices with or without defibrillation capacity. The most important risk factor for CIED infection is recent manipulation of the device. The most common causes of CIED infection are Staphylococcus aureus and coagulase-negative staphylococci. (See 'Epidemiology' above and 'Microbiology' above.) Forms of CIED infection include pocket infection and systemic infection. These categories are not mutually exclusive, and the two forms may coexist. (See 'Forms of infection' above.) CIED pocket infection refers to infection involving the subcutaneous pocket containing the pulse generator and the subcutaneous segment of the leads, but not the transvenous segment of the leads. (See 'Definition' above.) CIED pocket infection should be suspected when there is inflammation overlying the implanted device (including erythema, swelling, warmth, pain, and tenderness), purulent https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 19/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up drainage from the pocket, deformation of the pocket, or erosion of the device or lead through the skin, in the absence of systemic symptoms. The diagnosis of isolated pocket infection is established by the presence of one or more of these manifestations in the setting of negative blood cultures and negative transesophageal echocardiography. The approach to evaluation of suspected pocket infection is summarized in the algorithm ( algorithm 1). (See 'Clinical manifestations' above and 'Diagnosis' above.) CIED systemic infection refers to infection involving the transvenous portion of the lead (particularly infection of the endocardial portion of the lead with involvement of the contiguous endocardium or tricuspid valve) or an epicardial electrode (with involvement of the epicardium). Endocarditis (due to lead vegetation and/or valve vegetation) is an important presentation of CIED systemic infection. Other presentations include bacteremia with infection of remote sites and, in patients with epicardial leads, mediastinitis and pericarditis. (See 'Definition' above and 'Clinical presentations' above.) The diagnosis of CIED systemic infection should be suspected in patients with a CIED who present with fever or other systemic symptoms of infection and have signs of a pocket infection, pulmonary nodular infiltrates (eg, suspected septic emboli), unexplained bacteremia, or bacteremia caused by S. aureus. The approach to evaluation of suspected CIED systemic infection is summarized in the algorithms ( algorithm 2 and algorithm 3). (See 'Diagnosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Blomstr m-Lundqvist C, Traykov V, Erba PA, et al. 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