Infective Endocarditis (IE)Infective Endocarditis (IE)

Case Presentation

November 1, 2000

Sharon Klier, MD

Carmel Hospital, Haifa

The PatientThe 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

Medical historyMedical history

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

Physical examinationPhysical examination General appearance: ill-looking, pale, weak, debilitated Vitals: BP: 129/73; pulse:78; RR:18; Temp:36.8c 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

Diagnostic studiesDiagnostic 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

Diagnostic studiesDiagnostic 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

Diagnostic studiesDiagnostic 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

Summary of patientSummary of patient

76 year-old male, 3 year post aortic valve

replacement presented with enterococcal

endocarditis on mitral valve To be discussed: possible explanations

DefinitionDefinition

Infection of the endocardial surface

Implies the physical presence of microorganisms

in the lesion

Heart valves most commonly effected

Acute versus subacute

Etiologic agents in IEEtiologic agents in IE

AgentStreptococci

Viridans streptococci

Enterococci

Other streptococci

Staphylococci

Coagulase positive

Coagulase negative

Gram-negative aerobic bacilli

Fungi

Miscellaneous bacteria

Mixed infections

Culture negative

Percent of cases60-80

30-40

5-18

15-25

20-35

10-27

1-3

1.5-13

2-4

<5

1-2

<5-24

EpidemiologyEpidemiology

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

0%

10%

20%

30%

40%

50%

60%

Age

Age Distribution

<30 31-60 >60

Predisposing factorsPredisposing 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)

PathogenesisPathogenesis

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

PathophysiologyPathophysiology

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

The interaction between the The interaction between the microorganism and the NBTEmicroorganism 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 vitro1. 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.

The role of plateletsThe 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

The role of antibodiesThe 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

Immunopathologic factorsImmunopathologic 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

Pathologic changes: HeartPathologic 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.

Pathologic changes: KidneyPathologic 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 lesion2. GN can occur with right-sided IE3. GN is rare in acute IE even though large vegetation result in

metastatic abscess formation4. IF staining reveals IC-typical distribution5. Antibacterial antibodies eluted from lesions

Pathologic changes:Pathologic changes:Mycotic aneurysmsMycotic 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

Pathologic changesPathologic 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

Pathologic changesPathologic 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

Clinical manifestationsClinical 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

Clinical manifestationsClinical 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

Lab findingsLab 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%)

Lab findingsLab findings

Serology– Rheumatoid factor (40-50%)

– Circulating immune complexes

– Antinuclear antibodies

– Complement

Blood culture– Most important lab test

– Positive cultures in 97% of cases

ProceduresProcedures 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

Duke Criteria for IE diagnosisDuke Criteria for IE diagnosisMajor 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

Duke Criteria for IE diagnosisDuke 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

Enterococcus as an etiologic Enterococcus as an etiologic agentagent

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 56c 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

TherapyTherapy

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

Therapy: General principlesTherapy: 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

Therapy of enterococcal IETherapy 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.

Prognostic signsPrognostic 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

Surgical therapy:Surgical therapy:IndicationsIndications

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

Surgical therapy:Surgical therapy:Echo featuresEcho 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

The PatientThe 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

Patient with AVR but Patient with AVR but IE on native valveIE on native valve

Possible explanations:– Technical limitation - vegetation not detected

– Mitral valve was stenotic and regurgitant

– Complete emboli from aortic valve

ConclusionsConclusions

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