Infective endocarditis

Basic description of Infective Endocarditis from a Clinical and Microbiological point of view with description on Pathogenesis, Clinical Manifestations, Clinical and Laboratory diagnosis.

1. Infective Endocarditis Dr. SUPRAKASH DAS Assist. Prof.

2. Introduction The term infective endocarditis (IE) denotes infection of the endocardial surface of the heart and implies the physical presence of microorganisms in the lesion. Although the heart valves are affected most commonly , the disease also may occur within septal defects or on the mural endocardium . Infections of arteriovenous shunts and of arterioarterial shunts (patent ductus arteriosus) and infections related to coarctation of the aorta are included in the following discussion because the clinical manifestations are similar. The term infective endocarditis, first used by Thayer and later popularized by Lerner and Weinstein , is preferable to the former term bacterial endocarditis, because nonbacterial pathogens, including fungi and perhaps even viruses, may be responsible for the syndrome.

3. Introduction In the past, IE was classified as ACUTE OR SUBACUTE . This distinction was based on the usual progression of the untreated disease and is mainly of historical interest. The acute form follows a fulminant course, usually with  High fever, Systemic toxicity, and leukocytosis ; Death occurs in several days to less than 6 weeks. It classically is associated with infection caused by  Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, or Neisseria gonorrhoeae.

4. Introduction The subacute form (death occurring in 6 weeks to 3 months) and the chronic form (death occurring later than 3 months) usually are considered together. They commonly occur in the setting of prior valvular disease and are characterized by  A slow, indolent course Low-grade fever, Night sweats, Weight loss, and Vague systemic complaints. These two forms of IE classically are caused by the viridans streptococci. Although useful conceptually, this classification ignores the nonbacterial forms of IE and the frequent overlap in manifestations of infection by specific organisms, such as the enterococci. The prototypic lesion of infective endocarditis, THE VEGETATION , is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells.

5. Introduction Infection most commonly involves heart valves (either native or prosthetic), but May also occur on the low-pressure side of the ventricular septum at the site of a defect , on the mural endocardium where it is damaged by aberrant jets of blood or foreign bodies, or On intracardiac devices themselves. The analogous process involving arteriovenous shunts, arterioarterial shunts (patent ductus arteriosus), or a coarctation of the aorta is called infective endarteritis. In developed countries, the incidence of endocarditis ranges from 2.6 to 7.0 cases per 100,000 population per year and remained relatively stable from 1950 to 2000. 10–30% of endocarditis cases involve prosthetic valves, greatest during the first 6 months after valve replacement. Although many species of bacteria and fungi cause sporadic episodes of endocarditis, only a few bacterial species cause the majority of cases.

6. Etiology The epidemiology of endocarditis, which has shifted in recent years, should guide diagnostic testing. Today, staphylococci and streptococci combined cause  80% of cases . Staphylococcus aureus remains the dominant pathogen, associated with  25% to 30% of cases, Coagulase-negative staphylococci account for  11% of cases. Streptococci, primarily viridans group streptococci , cause  30% of cases, with Streptococcus gallolyticus being involved in 20% to  50% of streptococcal cases. Enterococci, especially Enterococcus faecalis , account for  10% of cases. Gram-negative bacilli account for  5% of cases and include the HACEK group organisms (Haemophilus, Aggregatibacter , Cardiobacterium , Eikenella , and Kingella species ) and, less commonly Enterobacteriaceae and nonfermenting Gram-negative bacilli. Fungi are rare endocarditis causes, with Candida species being the most common. A number of uncultivable or challenging to cultivate organisms cause endocarditis, the most common of which are Coxiella burnetii , Bartonella species, and Tropheryma whipplei .

7. Etiology Pathogens vary somewhat with the clinical types of endocarditis, in part because of different portals of entry. The oral cavity, skin, and upper respiratory tract are the respective primary portals for the  Viridans streptococci, Staphylococci, and HACEK organisms (Haemophilus, Aggregatibacter ( Actinobacillus ), Cardiobacterium , Eikenella , and Kingella ) causing community-acquired native valve endocarditis. Health care–associated native valve endocarditis is the consequence of bacteremia arising from  Intravascular catheter infections, Nosocomial wound and Urinary tract infections, and Chronic invasive procedures such as hemodialysis .

8. Etiology Prosthetic valve endocarditis arising within 2 months of valve surgery is generally the result of intraoperative contamination of the prosthesis or a bacteremic postoperative complication. The nosocomial nature of these infections is reflected in their primary microbial causes:  Coagulase-negative staphylococci( CoNS ), S. aureus, Facultative gram-negative bacilli, Diphtheroids , and Fungi. The portals of entry and organisms causing cases beginning >12 months after surgery are similar to those in community acquired native valve endocarditis. Endocarditis occurring among injection drug users, especially when infection involves the tricuspid valve, is commonly caused by S. aureus strains, many of which are methicillin-resistant.

9. Etiology Left-sided valve infections in addicts have a more varied etiology and involve abnormal valves, often ones damaged by prior episodes of endocarditis. A number of these cases are caused by  Pseudomonas aeruginosa and Candida species, and sporadic cases are due to unusual organisms such as Bacillus, Lactobacillus, and Corynebacterium species. Polymicrobial endocarditis is more common among injection drug users .

10. Etiology From 5 to 15% of patients with endocarditis have negative blood cultures; in one-third to one-half of these cases, cultures are negative because of prior antibiotic exposure. The remainder of these patients are infected by fastidious organisms, such as  Nutritionally variant organisms ( Granulicatella and Abiotrophia species), HACEK organisms, and Bartonella species. Some fastidious organisms that cause endocarditis do so in characteristic epidemiologic settings  Coxiella burnetii in Europe, Brucella species in the Middle East). Tropheryma whipplei

11. Pathogenesis Unless it is injured, the endothelium is resistant to infection by most bacteria and to thrombus formation. Endothelial injury (e.g., at the site of impact of high velocity blood jets or on the low-pressure side of a cardiac structural lesion) causes aberrant flow and Allows either direct infection by virulent organisms or the development of an uninfected platelet-fibrin thrombus—a condition called nonbacterial thrombotic endocarditis (NBTE) . The thrombus subsequently serves as a site of bacterial attachment during transient bacteremia . The cardiac conditions most commonly resulting in NBTE are  Mitral regurgitation, Aortic stenosis, Aortic regurgitation, Ventricular septal defects, and Complex congenital heart disease.

12. Pathogenesis These conditions result from rheumatic heart disease (particularly in the developing world, where rheumatic fever remains prevalent), mitral valve prolapse, degenerative heart disease, and congenital malformations. NBTE also arises as a result of a hypercoagulable state (marantic endocarditis). Organisms that cause endocarditis generally enter the bloodstream from mucosal surfaces, the skin, or sites of focal infection. Except for more virulent bacteria (e.g., S. aureus) that can adhere directly to intact endothelium or exposed subendothelial tissue, microorganisms in the blood adhere to sites at NBTE. If resistant to the bactericidal activity of serum and the microbicidal peptides released locally by platelets, the organisms proliferate and induce a procoagulant state at the site by eliciting tissue factor from adherent monocytes or, in the case of S. aureus, from monocytes and from intact endothelium. Fibrin deposition combines with platelet aggregation, stimulated by tissue factor and independently by proliferating microorganisms, to generate an infected vegetation.

13. Pathogenesis The organisms that commonly cause endocarditis have surface adhesin molecules, collectively called microbial surface components recognizing adhesin matrix molecules (MSCRAMMs) , that mediate adherence to NBTE sites or injured endothelium. Fibronectin-binding proteins  Clumping factor (a fibrinogen- and fibrin-binding surface protein) on S. aureus, and glucans or FimA (a member of the family of oral mucosal adhesins) on streptococci facilitate adherence. In the absence of host defenses , organisms enmeshed in the growing platelet-fibrin vegetation proliferate to form dense microcolonies. Organisms deep in vegetations are metabolically inactive (nongrowing) and relatively resistant to killing by antimicrobial agents. Proliferating surface organisms are shed into the bloodstream continuously.

14. Pathogenesis The pathophysiologic consequences and clinical manifestations of endocarditis—other than constitutional symptoms, which probably result from cytokine production—arise from  Damage to intracardiac structures; Embolization of vegetation fragments, Leading to infection or infarction of remote tissues; Hematogenous infection of sites during bacteremia ; and Tissue injury due to the deposition of circulating immune complexes or immune responses to deposited bacterial antigens.

15. Schematic representation of the sequence of events of a patient with IE who has a severe evolution and finally dies of multiple organ failure.

16. Clinical Manifestations The clinical syndrome of infective endocarditis is highly variable and spans a continuum between acute and subacute presentations. The causative microorganism is primarily responsible for the temporal course of endocarditis. β- Hemolytic streptococci, S. aureus, and pneumococci typically result in an acute course, although S. aureus occasionally causes subacute disease . Endocarditis caused by Staphylococcus lugdunensis (a coagulase-negative species) or by enterococci may present Acutely . Subacute endocarditis is typically caused by viridans streptococci, enterococci, CoNS , and the HACEK group. Endocarditis caused by Bartonella species and the agent of Q fever, C. burnetii , is exceptionally indolent . In patients with subacute presentations, fever is typically low-grade and rarely exceeds 39.4 C (103 F); in contrast, Temperatures of 39.4 –40 C (103 –104 F) are often noted in acute endocarditis.

17. Clinical Manifestations  Cardiac Heart murmurs Congestive heart failure Abscess formation Varying degree of heart block Coronary artery emboli Myocardial infraction

18. Clinical Manifestations  Non Cardiac Septic embolization mimicking some of these lesions ( Subungual hemorrhage , Osler’s nodes ) Nonspecific inflammatory arthritis Back pain Embolic events—often with infarction—involving the extremities, spleen, kidneys, bowel, or brain Embolic strokes Aseptic or purulent meningitis, intracranial hemorrhage , seizures, and encephalopathy. Microabscesses in brain and meninges occur commonly in S. aureus endocarditis Immune complex deposition on the glomerular basement membrane causes diffuse hypocomplementemic glomerulonephritis and renal dysfunction

19. Septic Emboli Osler’s Node Osler’s node on the anterior surface of the distal phalange of the long finger. The purplish area was tender to palpation.

20. Osler’s node on the toe pad of the fourth toe. Note the multiple petechiae on the foot. Janeway’s Lesion Janeway lesions occur on the palms and soles and are nontender and usually hemorrhagic

21. Conjunctival petechiae in a patient with bacterial endocarditis. Roth spots

22. Clinical & Laboratory Diagnosis The diagnosis of infective endocarditis is established with certainty only when vegetations obtained at cardiac surgery, at autopsy, or from an artery (an embolus are examined histologically and microbiologically. Nevertheless, a highly sensitive and specific diagnostic schema— known as the Duke criteria —has been developed on the basis of clinical, laboratory, and echocardiographic findings. Documentation of two major criteria, or, one major and three minor criteria, or of five minor criteria allows a clinical diagnosis of definite endocarditis. The diagnosis of endocarditis is rejected if  An alternative diagnosis is established Symptoms resolve and do not recur with ≤4 days of antibiotic therapy Surgery or autopsy after ≤4 days of antimicrobial therapy yields no histologic evidence of endocarditis. Illnesses not classified as definite endocarditis or rejected are considered cases of possible infective endocarditis when either one major and one minor criterion or three minor criteria are identified.

23. Echocardiography Imaging with echocardiography allows  Anatomic confirmation of infective endocarditis, Sizing of vegetations, Detection of intracardiac complications, and Assessment of cardiac function. Transthoracic echocardiography (TTE) is noninvasive and exceptionally specific; however, it cannot image vegetations <2 mm in diameter, and in 20% of patients it is technically inadequate because of emphysema or body habitus.

24. Echocardiography TTE detects vegetations in only 65% of patients with definite clinical endocarditis. TTE is not adequate for evaluating prosthetic valves or detecting intracardiac complications. TEE is safe and significantly more sensitive than TTE. It detects vegetations in >90% of patients with definite endocarditis. TEE is the optimal method for the diagnosis of  Prosthetic endocarditis or Detection of myocardial abscess, Valve perforation, or Intracardiac fistulae. A negative TEE when endocarditis is likely does not exclude the diagnosis, but rather warrants repetition of the study in 7–10 days.

25. ROLE OF BLOOD CULTURES IN DIAGNOSIS OF INFECTIVE ENDOCARDITIS Blood cultures are the standard test to determine the microbiologic etiology of infective endocarditis. Routine blood cultures incubated on modern automated, continuous-monitoring blood culture systems allow recovery of almost all easily cultivable agents of endocarditis. The American Heart Association and the European Society of Cardiology recommend at least three sets of blood cultures collected from different veni -puncture sites, with at least 1 h between the first and last draw. The British Society for Antimicrobial Chemotherapy (BSAC) recommends collection of two sets of blood cultures within 1 h of each other in patients with suspected endocarditis and acute sepsis and three sets of blood cultures spaced  6 h apart in cases of suspected subacute or chronic endocarditis. Conventionally, three sets of blood cultures, with each set including one aerobic and one anaerobic bottle, are collected. Alternatively, two sets may be collected, with two aerobic and one anaerobic bottle per set (i.e., a total of six blood culture bottles)

26. ROLE OF BLOOD CULTURES IN DIAGNOSIS OF INFECTIVE ENDOCARDITIS Standard blood culture incubation times of 5 days are adequate for recovery of almost all cultivable causes of endocarditis, including Candida species and HACEK organisms. Current blood culture systems also contain sufficient supplements to support growth of Abiotrophia and Granulicatella species (nutritionally variant streptococci). Brucella species  detection in routine blood cultures is typically achieved within the standard 5-day incubation period; notably, serologic testing may be helpful if exposures are suggestive of Brucella endocarditis. Cutibacterium acnes (formerly P. acnes) deserves special consideration, however, as some strains of this species may require prolonged blood culture incubation (e.g., 14 days). The Clinical and Laboratory Standards Institute (CLSI) guidelines recommend terminal subculture to chocolate agar if blood cultures are negative at 5 days and an endocarditis diagnosis is under consideration.

27. ROLE OF BLOOD CULTURES IN DIAGNOSIS OF INFECTIVE ENDOCARDITIS Non- candidal fungal causes of endocarditis (e.g., Histoplasma capsulatum, Aspergillus species) are  Rare, Require specialized testing (e.g., antigen detection, specialized fungal blood cultures), and Should only be considered in patients with specific risks for these types of endocarditis  Malignancy, Injection drug use, Prolonged health care exposure, Presence of a prosthetic heart valve

28. DIAGNOSIS OF CULTURE-NEGATIVE ENDOCARDITIS Blood cultures are negative in 2% to 40% of cases of endocarditis. The causes of so-called “ culture-negative endocarditis ” fall into two categories:  Negative blood cultures due to concomitant or antecedent antibacterial therapy or The presence of an organism that does not grow in routine blood cultures, with the first being more common. Antibacterial agents should not be started in patients with suspected endocarditis until after blood cultures have been collected. For cases in which antibiotics have been administered prior to blood culture collection, consideration may be given to stopping antibiotics if possible, with recollection of blood cultures after an antibiotic-free period  7 to 10 days off antimicrobial therapy has been recommended. In patients who have not received antibiotics , the most common etiologies of culture-negative endocarditis are C. burnetii and Bartonella species , with the former accounting for 28% to 37% and the latter accounting for 12% to 28% of cases. T. whipplei causes up to 6% of cases of culture-negative endocarditis

29. DIAGNOSIS OF CULTURE-NEGATIVE ENDOCARDITIS C. acnes , a rare cause of endocarditis, may cause culture-negative endocarditis due to the requirement for prolonged blood culture incubation for growth of some strains. Mycoplasmal endocarditis, primarily caused by Mycoplasma hominis and is usually diagnosed using molecular methods. Mycoplasma pneumoniae has been considered an important cause of culture-negative endocarditis diagnosed primarily by serologic testing.

30. SEROLOGIC TESTING For organisms that do not grow in routine bacterial cultures (e.g., C. burnetii ) or are especially fastidious (e.g., Bartonella species ), serologic evaluation may aid in diagnosis. Generally, these pathogens cause subacute endocarditis resulting in elevated IgG titers . In chronic Q fever with endocarditis, anti-phase I IgG C. burnetii titers of 1:800 are diagnostic . Although Bartonella endocarditis is often diagnosed by serologic testing but it may be complicated by serologic cross-reactivity; most notably, Chlamydia/Chlamydophila serologic assays demonstrate high level cross-reactivity with Bartonella species, possibly leading to erroneous diagnoses of chlamydial endocarditis. Low-level cross-reactivity has also been demonstrated between Bartonella and Coxiella. Serologic testing for extremely rare causes of endocarditis (e.g., Legionella species, Chlamydia/Chlamydophila species) is not recommended due to challenges with falsely positive results.

31. Epidemiological clues for defining the etiology of blood culture-negative infective endocarditis

32. C. burnetti /Brucella spp./Bartonella spp. T. whipplei / Mycoplasmaspp ./Legionella spp. Diagnostic workup in blood culture-negative endocarditis

33. EVALUATION OF EXCISED CARDIAC VALVULAR TISSUE  Histopathology Surgical intervention is performed in 25% to 53% of cases of endocarditis. If a microbial diagnosis has not been established at the time of surgery, excised valvular tissue should be submitted for histopathological and microbiological evaluation. Representative sections of the valvular material should be processed for histopathology. On histologic examination of excised valve tissue, patterns and degrees of inflammation will vary depending on the infecting organism. Endocarditis caused by highly virulent organisms, such as S. aureus , is often associated with  Acute inflammation characterized by extensive neutrophilic infiltration as well as Large colonies of microorganisms with associated areas of tissue destruction.

34. EVALUATION OF EXCISED CARDIAC VALVULAR TISSUE  Histopathology In cases of subacute endocarditis caused by less virulent organisms, such as Viridans group streptococci , in addition to focal colonies and neutrophilic inflammation, evidence of healing, including fibrin deposition and mononuclear inflammatory cells , may be present. In cases of endocarditis caused by Bartonella species, C. burnetii , or T. whipplei , valves primarily show chronic inflammation and may be grossly normal in appearance. Mononuclear, rather than neutrophilic, infiltration predominates and macrophages are most frequently observed. Abundant foamy macrophages are the primary finding in T. whipplei endocarditis. Histopathologically , Bartonella endocarditis typically shows marked fibrosis with minimal vegetation formation, in addition to macrophage and lymphocytic infiltration.

35. EVALUATION OF EXCISED CARDIAC VALVULAR TISSUE  Histopathology The following stains are used to identify the causative organisms  (H&E)-stain Grocott-Gomori methenamine silver (GMS). Tissue Gram stain Warthin-Starry Ziehl-Neelson Periodic acid-Schiff

36. Section of mitral valve from a case of streptococcal endocarditis showing focal basophilic bacterial colonies (arrow) at low magnification Gram stain of streptococcal endocarditis demonstrating Gram-positive cocci mixed with occasional Gram negative staining organisms (arrows;  1,000 total magnification, Twort’s Gram stain)

37. EVALUATION OF EXCISED CARDIAC VALVULAR TISSUE  Culture Current recommendations for the diagnosis of endocarditis also recommend culture of valvular tissue, with culture results being used to direct the duration of postoperative antimicrobial therapy. Gram stain of tissue processed in the microbiology laboratory may be more sensitive than histopathological Gram stain of tissue sections. In cases of blood culture-positive endocarditis, results of valve cultures may cause unnecessary confusion if valve cultures generate discrepant (i.e., falsely positive) results. In cases of blood culture-negative endocarditis, valve tissue culture still suffers from low sensitivity and specificity, although growth of an organism does allow for antimicrobial susceptibility testing. When available tissue is insufficient for all tests of interest, culture should not be prioritized over more sensitive assays, such as molecular testing.

38. Molecular techniques Molecular methods are increasingly utilized to aid in the diagnosis of culture-negative endocarditis and have been applied to both blood and excised valve tissue. Molecular methods used in endocarditis diagnosis include  Organism-specific pcr and Broad-range bacterial pcr followed by sequencing. Currently, these techniques are not widely available in clinical microbiology laboratories, but laboratory-developed tests (LDTs) performed in specialized reference laboratories and large clinical laboratories are available. LDTs using organism-specific primers have been developed for  C. burnetii , Bartonella species, T. whipplei , C. acnes, M. hominis & others.

39. Molecular techniques Due to the relative abundance of bacterial DNA in valve tissue versus blood, testing of cardiac valve tissue with organism-specific PCR assays is more sensitive than testing blood or serum. Broad-range bacterial PCR , with amplification primers targeting the bacterial 16S rRNA gene , is a molecular method for detecting bacteria in general. Following amplification, bacterial identification is determined by sequencing amplified DNA followed by comparison of the sequence to established databases. Although broad-range bacterial PCR has been applied to blood sources, sensitivity is superior when performed on excised valve tissue . It is recommend testing valvular tissue by broad-range bacterial PCR when histopathologic examination of excised tissue shows acute inflammation. Broad-range fungal PCR is technically possible but has low yield for endocarditis diagnosis due to the rarity of fungi as causes of endocarditis.

40. Molecular techniques For diagnosis of culture-negative endocarditis, broad-range bacterial PCR should not be performed in lieu of organism-specific PCR. Caution should be exercised in the interpretation of nucleic acid amplification test results from removed valves after completion of antibiotic therapy. Long-term persistence of bacterial DNA has been reported in patients who have completed a full course of antibiotic therapy, in some cases several years after diagnosis of endocarditis. Conversely, results can be falsely negative  Due to the presence of PCR inhibitors, The presence of microbial nucleic acid below the limit of detection of the assay being used, or Sampling error since microorganisms are often not homogenously distributed in resected valves.

41. A PROPOSED MICROBIOLOGIC AND PATHOLOGICAL DIAGNOSTIC ALGORITHM FOR ENDOCARDITIS This algorithm is intended for use in patients with clinical and/or echocardiographic findings suggestive of infective endocarditis based on the modified Duke criteria. Strong recommendations appear in boldface, with other diagnostic testing considerations shown in standard typeface. 1  Details on blood culture collection are provided in the text. 2  C. burnetii anti-phase I IgG antibody titer of  1:800 is considered positive. 3  The sensitivity of T. whipplei PCR from blood in endocarditis is unknown; a negative result should not be used to rule out T. whipplei endocarditis. 4  If surgery is not performed, consider testing for noninfectious etiologies .

42. A PROPOSED MICROBIOLOGIC AND PATHOLOGICAL DIAGNOSTIC ALGORITHM FOR ENDOCARDITIS 5  Histologic evaluation is used to evaluate for infectious and noninfectious etiologies and for correlation with microbiology test results. 6  Ideally, a representative sample of valvular tissue should be specifically collected for molecular testing in a sterile fashion in the operating room. 7  If sufficient valvular tissue is available after sampling for histopathological and molecular (microorganism-specific and broad-range) testing, consider culture and microbiology Gram stain. Due to the low sensitivity and specificity of culture, molecular testing should be prioritized over culture. 8  PAS-D, periodic acid-Schiff with diastase. Macrophages infected with T. whipplei will stain PAS positive following diastase digestion. 9  Examples include Mycoplasma hominis and Cutibacterium (formerly Propionibacterium) acnes PCR.

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