Infective Endocarditis (IE)

1. Infective Endocarditis (IE) Case Presentation November 1, 2000 Sharon Klier, MD Carmel Hospital, Haifa

2. The Patient • M.L. 76y, male, married+2 • Chief complaint: fever, weight loss, cough, weakness for 3 months • Present illness: • After Coronary Artery Bypass Graft, aortic valve replacement (AVR) in 1997. AVR was indicated for severe aortic stenosis • Asymptomatic, no signs of CHF • Three months prior, episode of fever, cough, diagnosed as left lower lobe (LLL) pneumonia. Treated with antibiotics • After termination of antibiotic regimen, fever persisted with weakness, anorexia, weight loss of 5 kg for past 3 months • No chills, headache, arthralgia, skin rash, dysuria, hematuria, shortness of breath, diarrhea, vomiting

3. Past medical history: S/P CABG, AVR 1997 Coumadin treatment Ischemic heart disease: stable angina, FC1 Hypercholesterolemia Hypertension Depression Medications: Loviran Oxopurin Pressolat Neobloc Simovil Prizma Micropirin Coumadin Medical history

4. Physical examination • General appearance: ill-looking, pale, weak, debilitated • Vitals: BP: 129/73; pulse:78; RR:18; Temp:36.8c • Eyes: pale sclera without petechiae • Skin and mucous membranes: petechiae on hard palate, no skin rash, no signs of systemic emboli • Neck: JVP not elevated (10mmHg), positive hepatojugular reflux • Heart: • PMI normal • S2 as expected of artificial valve • Holosystolic blowing murmur of severe MR, 3/6, maximal at mitral area, radiating to axilla and all other stations • Lungs: dullness on percussion in LLL, crackles ausculated in LLL • Abdomen: non tender, hepatomegaly (18 cm), no splenomegaly • Limbs: legs and sacral edema • Lymph nodes: non enlarged • Neurologic: intermittent confusion, no signs of focal neurologic deficit • Musculoskeletal: no arthritis

5. Diagnostic studies • Lab: • CBC: normocytic normochromic anemia, hemoglobin 10g/dL, reticulocytes 2.6, WBC of 9.2x109/L • Renal function: urea 25mg/dL, creatinine 1.1 g/d • Liver function: enzymes within normal limits • Protein electrophoresis: normal • Chest X ray: • Normal size of heart • LLL infiltrate • ECG: • Normal sinus rhythm • Normal axis • Left atrial enlargement • T wave inversion if inferior leads • Poor R wave progression from V1 to V4

6. Diagnostic studies • Blood cultures: • three positive cultures for enterococcus faecalis • Abdominal US: • enlarged prostate with calcification • Chest CT: • little pleural effusion, consolidation in LLL, signs of residual pneumonia • Brain CT: • small lacunar infarcts • Fundus exam: • no signs of Roth spots

7. Diagnostic studies • Transthoracic echocardiogram: • Normal hemodynamics for prosthetic aortic valve • Hyperdynamic left ventricle • Mitral annulus calcification • Mild mitral stenosis • Mild mitral regurgitation • Transesophageal echocardiogram: • Ecogenic mass on anterior mitral leaflet on atrial side of about 1cm, suggestive of vegetation • Severe MR • Good left ventricular contraction • Very mild AR

8. Summary of patient • 76 year-old male, 3 year post aortic valve replacement presented with enterococcal endocarditis on mitral valve • To be discussed: possible explanations

9. Infection of the endocardial surface Implies the physical presence of microorganisms in the lesion Heart valves most commonly effected Acute versus subacute Definition

10. Agent Streptococci Viridans streptococci Enterococci Other streptococci Staphylococci Coagulase positive Coagulase negative Gram-negative aerobic bacilli Fungi Miscellaneous bacteria Mixed infections Culture negative Percent of cases 60-80 30-40 5-18 15-25 20-35 10-27 1-3 1.5-13 2-4 <5 1-2 <5-24 Etiologic agents in IE

11. Epidemiology • Annual incidence: 15,000 to 20,000 • Forth leading cause of life-threatening infectious disease • Male:female ratio is 1.7:1 • Up to 45% involve mitral valve, 36% aortic valve

12. Predisposing factors • Any type of structural heart disease • Rheumatic heart disease (37-76%) • Congenital heart disease (6-24%) • Degenerative cardiac lesions (30-40%) • Other (including prosthetic valves)

13. Pathogenesis 1.Valve surface is altered to produce a suitable site for bacterial attachment and colonization. 2. Platelets and fibrin deposit in the formation of sterile vegetation--the lesions of Nonbacterial Thrombotic Endocarditis (NBTE) 3. Bacteria reach this site and produce colonization. 4. The surface is covered with platelets and fibrin 5. Further bacterial multiplication and vegetation growth

14. Pathophysiology • Localization of IE is related to: • high pressure areas • down stream from sites where blood flows at high velocity through a narrow orifice • Transient bacteremia • Occurs whenever a mucosal surface heavily colonized with bacteria is traumatized • If preexistent NBTE, it may result in colonization and IE

15. The interaction between the microorganism and the NBTE • The adherence of the organism to NBTE is a crucial step • Organisms more frequently associated with IE adhere more readily to normal leaflets in vitro 1.Dextran production by streptococci may be a virulence factor in the pathogenesis of IE. 2. FimA is a surface adhesin of S.viridans that serves as an important colonization factor. Homologues of fimA genes were found in many S.viridans strains and enterococci. 3. Fibronectin is implicated as the host receptor within NBTE. Low-fibronectin-binding mutants of S. aureus have decrease ability to produce IE.

16. The role of platelets • Some strains of bacteria are stimulators of platelet aggregation and the release reaction • Platelet-fibrin deposition further enlarges the vegetation once the colonization occurs • Following exposure to thrombin, platelet microbicidal proteins (PMPs) are released. • PMPs show bactericidal activity against some gram-positive cocci • the resistance to PMP is a potential virulence factor and may contribute to the pathogenesis of IE • PMPs may act on the bacterial cell membrane/wall synergistically with antibiotics

17. The role of antibodies • Antibodies against cell surface components reduce the adhesion to fibrin and platelets in vitro and IE in vivo • May depend on the infecting organism

18. Immunopathologic factors • IE cause both humural and cellular response • Rheumatoid factor: • titers correlate with the level of hypergammaglobulinemia and decrease with therapy • possible blocking activity of the IgG opsonic activity (react with the Fc fragment) • Antinuclear antibodies: • may contribute to the musculoskeletal manifestations, low-grade fever, or pleuritic pain • Circulating immune complexes: • Connected with long duration of illness, extravascular manifestations, hypocomplemenemia • May cause diffuse glomerulonephritis, and some of the peripheral manifestations such as Osler nodes

19. Pathologic changes: Heart • Vegetation location: along the line of closure of a valve leaflet • Mitral valve more common; anterior leaflet more common • Lesion consists primarily of: fibrin, platelet aggregates, and bacterial masses • With treatment, healing occurs by fibrosis and occasionally calcification • Infection may lead to leaflet perforation, rupture of chordae tendinae, interventricular septum, or papillary muscle • Embolic phenomena are common (15-35%). Most frequently involving: renal, splenic, coronary, or cerebral circulation. • Risk for emboli is increased when vegetation >1cm.

20. Pathologic changes: Kidney • Pathological processes: abscess, infarction, glomerulonephritis (focal, segmental), membranoproliferative GN • May be normal is size or slightly swollen • 10 to 15% of IE exhibit immune complex GN (as in SLE). Supporting IC rather than emboli: 1. Bacteria rarely seen in lesion 2. GN can occur with right-sided IE 3. GN is rare in acute IE even though large vegetation result in metastatic abscess formation 4. IF staining reveals IC-typical distribution 5. Antibacterial antibodies eluted from lesions

21. Pathologic changes:Mycotic aneurysms • Develop during active IE • More common with S.viridans • May arise by the following mechanisms: • direct bacterial invasion of the arterial wall with subsequent abscess formation or rupture • septic or bland emoblic occlusion of the vasa vasorum • immune complex deposition with resultant injury to arterial wall • Tend to occur at bifurcation areas; middle cerebral artery is most common • Clinically silent until rupture

22. Pathologic changes • CNS • cerebral emboli (>30% of IE) • mycotic aneurysms • Spleen • infarctions (44% of autopsy cases) • enlargement associated with hyperplasia of lymphoid follicles, increase in secondary follicles, focal necrosis • abscess • Lung • associated with right-sided IE • pulmonary embolism, acute pneumonia, pleural effusion, or empyema

23. Pathologic changes • Skin • petechiae, may result from local vasculitis or emboli • Osler nodes, painful nodes on finger or toe pads • immune complexes in dermal vessels • Janeway lesions (due to septic emboli), painless plaques on palms or soles • splinter hemorrhage (linear lines beneath fingernails) • Eye • Roth spots

24. Clinical manifestations • Contributed by these processes: 1. The infectious process on the valve, including the local intracardiac complications 2. Bland or septic embolization to any organ 3. Constant bacteremia 4. Circulating immune complexes

25. Clinical manifestations • Fever, rarely >400c (>95%) • Nonspecific symptoms (weakness, weight loss, night sweats) • Audible heart murmur (>85% of cases) • Petechiae (20-40%) • Osler nodes (10-25%) • Janeway lesions (<5%) • Splinter hemorrhages (10-30%) • Roth spots (<5%) • Clubbing (10-20%) • Splenomegaly (25-60%) • Musculoskeletal manifestations (25-45%) • Major embolic episodes (>30%) • Neurologic deficits

26. Lab findings • Hematology • Anemia: normochromic, normocytic, low serum iron, low iron-binding capacity (70-90%) • Thrombocytopenia (5-15%) • Leukocytosis (20-30%) • Histiocytes (>25%) • Elevated ESR, with mean value of 57mm/hr (90-100%) • Hypergammaglobulinemia (20-30%) • Urinalysis • Proteinuria (50-65%) • Microscopic hematuria (30-60%) • Red cell casts (12%)

27. Lab findings • Serology • Rheumatoid factor (40-50%) • Circulating immune complexes • Antinuclear antibodies • Complement • Blood culture • Most important lab test • Positive cultures in 97% of cases

28. Procedures • Echo • TTE • is rapid, noninvasive • specificity: 98% • sensitivity: <60% • TEE • higher ultrasonic frequencies, improve spatial resolution • specificity: 94% (prosthetic valve: 88-100%) • sensitivity: 76-100% (prosthetic valve: 86-94%) • Cath • hemodyanmic and anatomic info for surgical intervention

29. Duke Criteria for IE diagnosis Major criteria • Positive blood culture for infective endocarditis • Typical microorganism for IE from 2 separte blood cultures • Viridans streptococci, Streptococcus bovis, HACEK group or, • Community-acquired staphylococcus aureus or enterococci, in the absence of a primary focus, or • Persistently positvie blood cultures for any microorganism, or • All of 3, or majority of 4 or more separate blood cultures, with first and last specimens drawn at least 1 hour apart • Evidence of endocardial involvement • Findings on echo positive for IE • Oscillating intracardiac mass on valve or supporting structures or in the path of regurgitant jets, or on iatrogenic devices, in the absence of an alternative anatomic explanation, or • Abscess, or • New partial dehiscence of prosthetic valve, or • New valvular regurgitation

30. Duke Criteria for IE diagnosis Minor criteria • Predisposition: predisposing heart condition or intravenous drug use • Fever: >38°c • Vascular phenomena: arterial embolism, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, Janeway lesions • Immunological phenomena: glomerulnephritis, Osler nodes, Roth spots, rheumatoid factor • Echocardiogram: findings consistent with IE but not meeting major criterion above • Microbiologic evidence: positive blood culture but not meeting major criterion above, or serologic evidence of active infection with organism consistent with IE

31. Enterococcus as an etiologic agent • Normal inhabitants of the GI tract, occasionally anterior urethra • Catalase negative and non-motile • Grow well in sodium azide, 40% bile, 6.5% NaCl, 0.1% methylene blue, and can survive at 56c for 30 minutes or at pH of 9.6. • Responsible for 5-18% of IE • Mostly subacute and affect men (mean age 59) after genitourinary manipulations or women (mean age 37) after obstetrics procedures • >40% of patients have no underlying heart disease, but 95% will develop a heart murmur • Classic peripheral signs are uncommon (<25%) • Cure is difficult because of intrinsic resistance to many antibiotics • E. faecalis 85% of enterococcal IE

32. Therapy • Complete eradication takes weeks, relapses may occur. This is due to: 1. The infection exists in an area of impaired host defense and is tightly encased in a fibrin meshwork 2. The bacteria reach very high population densities, such that the organism may exist in a state of reduced metabolic activity and cell division • Aspirin may decrease the growth of vegetative lesions and prevent cerebral emboli

33. Therapy: General principles • Etiologic agent must be isolated in pure culture. MIC and MBC should be determined • Parenteral antibiotics are recommended over oral drugs • Bacteriostatic antibiotics are generally ineffective • Antibiotic combinations should produce a rapid effect • Selection of antibiotics should be based on susceptibility tests, and treatment should be monitored clinically and with antimicrobial blood levels • Blood cultures should be obtained during the early phase of therapy to ensure eradication • Use of anticoagulants during therapy for native valve IE is not recommended. With mechanical valves, anticoagulation should be maintained (if indicated) within therapeutic range

34. Therapy of enterococcal IE • Enteraococci is the third most common form of IE and the most resistant to therapy. • Mortality rate is 20%. Relapses may occur. • Cell wall active antibiotics plus an aminoglycoside are synergistic and produce a bacteriocidal effect against most strains • General accepted regimen: • Penicillin G, 18-30 million units/day IV, or ampicilline, 12g/d IV, in divided doses q4d, plus gentamycin, 1mg/kg IV q8d, both X 4-6 weeks • Vancomycin, 15mg/kg IV q12d, plus gentamyicn as above, both 4 to 6 weeks.

35. Prognostic signs • S. aureus, fungal infections • Previous IE • Cyanotic heart disease • CHF • Embolic phenomena • Rupture of a mycotic aneurysm • Lack of response to antimicrobial therapy • Prosthetic valve endocarditis • Periannular extension of infection

36. Surgical therapy:Indications • refractory CHF • >2 serious systemic embolic episode • uncontrolled infection • physiologically significant valve dysfunction as demonstrated by echo • ineffective antimicrobial therapy • resection of mycotic aneurysms • most cases of prosthetic valve IE (caused by more antibiotic-resistant pathogens) • local suppurative complications including perivalvular or myocardial abscesses

37. Surgical therapy:Echo features • Persistent vegetations after a major systemic embolic episode • Large (>1cm diameter) anterior mitral valve vegetation • Increase in vegetation size 4 weeks after antibiotic therapy • Acute mitral insufficiency • Valve perforation or rupture • Periannular extension of infection

38. The Patient • MIC of E. faecalis • Vancomycin 2 g • Penicilline 1 g • Gentamycin 3 g • Choice of therapy: • Ampicillin: 2g x 6 • Gentamycin: 60mg x 3 later 60mg/18h • Course of treatment: • creatinine level increased to 1.8g/d • DD: nephrotoxicity, GN, embolic abscess, ACE inhibitor toxicity • RBC casts negative -- rule out GN • if complement level normal -- suggests toxicity • if complement decrease -- suggests IC complication • lack of physical signs (hematuria, fever, pain) -- rule out embolic abscess • Treatment + 3 days: blood culture is positive • Treatment + 10 days: blood culture is negative but pending

39. Patient with AVR but IE on native valve • Possible explanations: • Technical limitation - vegetation not detected • Mitral valve was stenotic and regurgitant • Complete emboli from aortic valve

40. Conclusions • No absolute indications for surgery, however, it may be suggestive due to: • Location of vegetation • Severe mitral regurgitation • Needs a follow up echo to determine: • Vegetation size (currently borderline) • Mitral regurgitation severity • Aortic valve condition • Local complications