ASSIGNMENT ON Diseases of heart valves -Infective endocarditis.

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DISEASES OF HEART VALVES: INFECTIVE ENDOCARDITIS

1. DEFINITION

Infective endocarditis (IE) is a microbial infection of the endocardial surface of the heart, primarily affecting the cardiac valves, leading to the formation of vegetations composed of thrombotic debris, inflammatory cells, and microorganisms, often associated with destruction of the underlying cardiac tissue. The aorta, aneurysmal sacs, other blood vessels, prosthetic devices, and cardiovascular implantable electronic devices (e.g., pacemakers) may also be involved.

Although fungi, rickettsiae (agents of Q fever), and chlamydial species can cause endocarditis, the vast majority of cases are bacterial. - Robbins & Kumar Basic Pathology, p. 368

2. CLASSIFICATION

IE is traditionally classified based on the tempo and severity of the clinical course:

Feature	Acute IE	Subacute IE
Onset	Rapid (days)	Insidious (weeks to months)
Causative organism	S. aureus (highly virulent)	Viridans streptococci (low virulence)
Valve involved	Previously healthy or damaged	Previously damaged/deformed
Destructiveness	Highly destructive	Relatively less destructive
Mortality	High, even with treatment	Lower; most recover with antibiotics

Note: A clear delineation between acute and subacute endocarditis is not always possible; many cases fall along the spectrum. Modern classification also considers causative organism, involved valve, and "pace" of clinical disease.

Robbins & Kumar Basic Pathology, p. 368; Goldman-Cecil Medicine, p. 700

3. EPIDEMIOLOGY

Incidence in the United States: approximately 10,000 to 20,000 new cases per year, accounting for about 1 case per 1,000 hospital admissions.
In developing countries (where rheumatic fever is still endemic): younger adults with rheumatic heart disease; subacute course; caused by viridans group streptococci (VGS).
In developed countries: older patients with health care exposure; acute illness caused primarily by S. aureus; worse outcomes.
Injection drug use (IDU): a significant contributing factor due to the opioid epidemic, predominantly causing right-sided (tricuspid) endocarditis with S. aureus.
Braunwald's Heart Disease, p. 3533; Goldman-Cecil Medicine, p. 700-701

4. PREDISPOSING CONDITIONS (RISK FACTORS)

More Common

Mitral valve prolapse (especially with regurgitation) - the leading pre-existing risk factor in developed countries
Degenerative valvular disease (especially in elderly)
Injection drug use
Congenital heart disease (uncorrected ventricular septal defect)
Previous endocarditis
Prosthetic heart valves (account for 10-20% of all IE cases)

Less Common

Rheumatic heart disease (historically dominant; now less common)
Idiopathic hypertrophic subaortic stenosis
Coarctation of the aorta
Complex congenital heart disease

Host Factors

Neutropenia, immunodeficiency, malignancy
Diabetes mellitus
Alcohol or intravenous drug use
HIV infection (independent risk factor in IDUs, risk increasing as CD4 count decreases)
End-stage renal disease on hemodialysis
Goldman-Cecil Medicine, Table 61-1, p. 700; Robbins & Kumar, p. 368

5. ETIOLOGY (MICROBIOLOGY)

The three most common causes worldwide are staphylococci, streptococci, and enterococci:

Organism	Setting	Type of IE
Streptococcus viridans	Community-acquired; damaged/deformed valves; oral flora	Subacute
Staphylococcus aureus	Healthcare settings; IV drug users; healthy valves	Acute
Enterococci	GI/GU sources; elderly	Variable
HACEK group*	Normal oral flora; fastidious organisms	Subacute
Coagulase-negative staphylococci	Prosthetic valves; healthcare-associated	Subacute
Fungi (Candida, Aspergillus)	Immunocompromised; IV drug users; prosthetic valves	Acute/subacute
Gram-negative bacilli	Rare; IV drug users	Variable

*HACEK = Haemophilus, Aggregatibacter (formerly Actinobacillus), Cardiobacterium, Eikenella, Kingella

Culture-negative endocarditis: ~10% of all cases - due to prior antibiotic therapy or fastidious organisms (Bartonella, Coxiella, Brucella, Tropheryma whipplei).
Robbins & Kumar, p. 368; Goldman-Cecil Medicine, p. 701

6. PATHOGENESIS

Infective endocarditis follows a predictable sequence of events:

Endothelial damage - Turbulent blood flow, mechanical trauma, or foreign bodies cause disruption of the smooth endothelial surface.
Sterile vegetation (NBTE) - Aggregation of platelets, fibrin, and coagulation molecules forms a "sterile vegetation" (nonbacterial thrombotic endocarditis).
Bacteremia - Transient bacteremia (from dental procedures, surgery, IV drug use, GI/GU sources, or occult sources) seeds the sterile vegetation.
Microbial adhesion and proliferation - Certain organisms (especially staphylococci and streptococci) express specific adhesins to attach to damaged surfaces. Bacteria proliferate within the vegetation, achieving loads of 10⁹ to 10¹¹ colony-forming units per gram of tissue.
Metastatic infection - Emboli shed from friable vegetations seed organs with high blood flow (kidneys, spleen, brain), causing septic infarcts and mycotic aneurysms.

Key point: Valve surfaces and vegetations are avascular, making antibiotic penetration and healing difficult.

Goldman-Cecil Medicine, p. 1681; Robbins & Kumar, p. 368

7. MORPHOLOGY (GROSS AND MICROSCOPIC PATHOLOGY)

Gross Appearance

Friable, bulky, potentially destructive vegetations on heart valves containing fibrin, inflammatory cells, and microorganisms (Fig. 9.20, 9.21 - Robbins).
Aortic and mitral valves are the most common sites of infection (left-sided).
Tricuspid valve is a frequent target in IV drug users (right-sided).
Vegetations may be single or multiple and can involve more than one valve.
Vegetations can erode into underlying myocardium to produce an abscess cavity (ring abscess).
Shedding of emboli is common due to friable nature.

Comparison of Vegetations in Valvular Diseases

The diagram below from Robbins Pathology compares vegetation locations across four conditions:

Comparison of vegetations in RHD, IE, NBTE, and LSE

Fig: Diagrammatic comparison of vegetations in Rheumatic Heart Disease (RHD), Infective Endocarditis (IE), Nonbacterial Thrombotic Endocarditis (NBTE), and Libman-Sacks Endocarditis (LSE). IE shows large, irregular, destructive vegetations on the valve leaflet and chordae tendineae - distinct from the smaller, non-destructive vegetations of NBTE and the line of closure deposits in RHD.

Feature	IE	NBTE	RHD
Location	Any surface; irregular; destructive	Line of closure; small	Line of closure; small, bead-like
Composition	Organisms + fibrin + PMNs	Sterile fibrin/platelets	Sterile; fibrin
Destruction	Yes (ulceration, perforation)	No	Mild sclerosis

Robbins & Kumar Basic Pathology, p. 368-369

8. CLINICAL FEATURES

Symptoms

Fever (most consistent sign; present in up to 96%) - may be absent in elderly or those with renal/cardiac failure
Constitutional symptoms: fatigue, malaise, weight loss
Musculoskeletal symptoms: arthralgia, myalgia (~50%)
Low back pain (~5-10%), even without osteomyelitis
Right-sided IE (IV drug users, device-related): pleuritic chest pain, multilobar pneumonia

Cardinal Physical Signs (Stigmata of Endocarditis)

Sign	Description	Mechanism	Frequency
Fever	Persistent, spiking	Bacteremia	96%
New or changing murmur	Regurgitant murmur	Valve destruction	48% (new), 20% (worsening)
Petechiae	Conjunctiva, palate, extremities	Microemboli	Common
Splinter hemorrhages	Linear, subungual	Microemboli in nail beds	8%
Osler nodes	Painful, red nodules on finger/toe pads	Immune complex + microemboli	3%
Janeway lesions	Painless, erythematous macules on palms/soles	Septic microemboli	5%
Roth spots	Retinal hemorrhages with pale centre	Microemboli / immune complex	2%
Splenomegaly	Enlarged spleen	Chronic infection (subacute)	11%
Clubbing	Finger clubbing	Chronic hypoxia/infection	Late feature
Embolic events	Stroke, infarcts	Vegetation fragmentation	17%

Memory aid: "From Jane's Roth Spots, Osler Hoped to Prove Clubbing" - Janeway lesions, Roth Spots, Osler nodes, Heart murmur, Petechiae, Clubbing

Goldman-Cecil Medicine, Table 61-2, p. 1694-1700; Robbins & Kumar, p. 368-369

9. LABORATORY INVESTIGATIONS

Investigation	Finding/Purpose
Blood cultures (most important)	3 sets from different sites before antibiotics; identifies causative organism
CBC	Leukocytosis (acute); normochromic normocytic anemia (subacute)
ESR / CRP	Elevated (ESR elevated in ~61% of cases)
Urine analysis	Hematuria in ~26%; proteinuria (glomerulonephritis)
Rheumatoid factor	Positive in ~5%
Procalcitonin	Guides therapy duration
Echocardiography	Primary imaging modality
Chest X-ray	Abnormal in 67-85% in right-sided IE (effusion, septic emboli)
ECG	New conduction delay suggests myocardial abscess

Echocardiography

TTE (Transthoracic Echocardiography): First-line; may miss small vegetations
TEE (Transesophageal Echocardiography): More sensitive; used when:
- TTE negative but high clinical suspicion
- Prosthetic valve involvement
- Suspected perivalvular extension
- Staphylococcal bacteremia
CT angiography / PET-CT: Useful for prosthetic valve IE or perivalvular complications
Braunwald's Heart Disease, p. 1235-1240; Goldman-Cecil Medicine, p. 1881

10. DIAGNOSIS: MODIFIED DUKE CRITERIA

The Modified Duke Criteria (Li et al., 2000) is the standard diagnostic framework, validated across diverse patient populations.

MAJOR CRITERIA

1. Blood Culture Positive for IE

Typical microorganisms from 2 separate blood cultures: viridans streptococci, S. bovis, HACEK group, S. aureus, or community-acquired enterococci in the absence of a primary focus; OR
Microorganisms consistent with IE from persistently positive blood cultures (≥2 positive cultures drawn >12 hours apart; or all 3, or majority of ≥4 separate cultures)
Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer ≥1:800

2. Evidence of Endocardial Involvement

Echocardiogram positive for IE: oscillating intracardiac mass on valve or supporting structure, in the path of regurgitant jets, or on implanted material, without alternative explanation; or abscess; or new partial dehiscence of prosthetic valve; OR
New valvular regurgitation (worsening or changing of preexisting murmur is not sufficient)

MINOR CRITERIA

Predisposing condition: IV drug use or predisposing cardiac condition
Fever ≥38°C
Vascular phenomena: arterial embolism, septic pulmonary emboli, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions
Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor
Echocardiogram findings consistent with endocarditis but not meeting major criteria
Microbiologic evidence: positive blood cultures not meeting major criteria or serologic evidence of active infection

Classification

Category	Criteria
Definite IE	2 major criteria OR 1 major + 3 minor OR 5 minor criteria (or pathological proof)
Possible IE	1 major + 1 minor OR 3 minor criteria
Rejected IE	Firm alternative diagnosis; resolution with ≤4 days antibiotics; no pathological evidence

Goldman-Cecil Medicine, p. 1757-1796; Fuster and Hurst's The Heart 15e, p. 1203-1207

11. COMPLICATIONS

Cardiac Complications

Valvular regurgitation / heart failure - most common cause of death; from leaflet destruction or perforation
Perivalvular abscess (ring abscess) - most common with aortic valve IE; presents with new AV conduction block on ECG
Pericarditis / myocarditis
Fistula formation between cardiac chambers

Embolic Complications (Most common non-cardiac complications)

Systemic emboli (in left-sided IE): stroke, renal infarction, splenic infarction, mesenteric ischemia, peripheral arterial occlusion
Pulmonary emboli (in right-sided IE): septic pulmonary emboli, pneumonia, pleural effusion
Mycotic aneurysms: from bacterial infection of arterial walls at embolic sites; can rupture

Neurological Complications (~15-30%)

Embolic stroke (ischemic most common)
Intracranial hemorrhage (from mycotic aneurysm rupture or hemorrhagic transformation)
Brain abscess
Meningitis

Renal Complications

Immune complex glomerulonephritis (hematuria, proteinuria, renal failure) - from glomerular trapping of antigen-antibody complexes
Renal infarction from emboli
Antibiotic-related nephrotoxicity (aminoglycosides, vancomycin)

Other Complications

Musculoskeletal: osteomyelitis, septic arthritis, vertebral osteomyelitis (causing back pain)
Splenic abscess
Robbins & Kumar, p. 368-369; Goldman-Cecil Medicine, p. 1973-1974

12. TREATMENT

General Principles

All patients with IE should be managed inpatient in a medical center with an experienced multidisciplinary "Endocarditis Team" (infectious disease + cardiology + cardiac surgery).
Treatment involves prolonged IV antibiotic therapy (usually 4-6 weeks) guided by blood cultures and sensitivity testing.
Empiric therapy is initiated in acutely ill patients, high-risk patients (prosthetic valves), or those with complications.
Stable patients with subacute presentation without complications can be observed and blood cultures obtained before starting antibiotics.

Empirical Antibiotic Therapy

Patient Type	Empirical Regimen
Native valve, community-acquired, MRSA unlikely	Nafcillin 2g IV q4h + Penicillin 4 million units IV q4h + Gentamicin 1 mg/kg IV q8h
Healthcare-associated / suspected MRSA / penicillin allergy	Vancomycin 15-20 mg/kg IV q8-12h (trough 15-20 mg/L) + Gentamicin 1 mg/kg IV q8h
Prosthetic valve	Vancomycin + Gentamicin + Rifampin 300 mg PO/IV q8h

Organism-Specific Therapy (Selected)

Organism	Drug of Choice
Viridans streptococci (penicillin-sensitive)	Penicillin G IV or Ceftriaxone for 4 weeks
S. aureus (MSSA), native valve	Nafcillin or Oxacillin for 6 weeks
S. aureus (MRSA)	Vancomycin for 6 weeks
Enterococci	Ampicillin + Gentamicin (4-6 weeks)
HACEK organisms	Ceftriaxone for 4 weeks
Candida endocarditis	Amphotericin B ± azoles + valve surgery
Bartonella	Doxycycline 6 weeks + Gentamicin 2 weeks
Coxiella (Q fever)	Doxycycline + Hydroxychloroquine (≥18 months)

Note: Rifampin is never used as monotherapy due to rapid resistance development.

Surgical Treatment

Indications for urgent/early valve surgery:

Indication	Timing
Heart failure due to severe valvular regurgitation/obstruction	Emergency/urgent
Perivalvular extension (abscess, fistula, new conduction block)	Urgent
Uncontrolled infection (persistent bacteremia >5-7 days, fungal IE)	Urgent
Prevention of embolism (large mobile vegetation >10mm with prior embolism)	Early elective
Prosthetic valve dehiscence	Urgent

Goldman-Cecil Medicine, p. 1886-2000; Braunwald's Heart Disease, p. 1230

13. ANTIBIOTIC PROPHYLAXIS

The AHA 2021 Scientific Statement updated prophylaxis guidelines:

Conditions Warranting Antibiotic Prophylaxis Before Invasive Dental Procedures:

Prosthetic cardiac valve or prosthetic material used for valve repair
History of previous IE
Congenital heart disease (unrepaired cyanotic CHD; repaired CHD with residual defects; repaired CHD within 6 months of procedure)
Cardiac transplant recipients with valvulopathy
Ventricular assist devices and implantable hearts (newly added in 2021)

Prophylaxis Regimen (Dental Procedures):

Amoxicillin 2g PO 30-60 min before procedure (preferred)
If unable to take oral: Ampicillin 2g IM/IV
Penicillin allergy: Doxycycline 100mg PO (new addition in 2021; clindamycin eliminated due to C. difficile risk)
Azithromycin/clarithromycin 500mg PO as alternative

Routine antibiotic prophylaxis is no longer recommended for GI endoscopy or urologic procedures.

Braunwald's Heart Disease, p. 1230-1233

14. PROGNOSIS

Left untreated, IE is generally fatal.
With appropriate antibiotic therapy and/or valve replacement, mortality is significantly reduced.
Adverse prognostic factors:
- Heart failure (most common cause of death)
- S. aureus etiology
- Prosthetic valve infection
- Older age, comorbidities
- Perivalvular extension/abscess
- Renal failure
- Neurological complications
In-hospital mortality ranges from 15-30% in developed countries.
Robbins & Kumar, p. 369; Goldman-Cecil Medicine, p. 1970

15. SPECIAL SITUATIONS

IV Drug Users (Right-Sided IE)

Tricuspid valve most commonly affected
S. aureus predominates
Presents with fever, septic pulmonary emboli, and multilobar pneumonia
Better prognosis than left-sided IE; more responsive to medical therapy
High risk of recurrence

Prosthetic Valve Endocarditis (PVE)

Early PVE (<12 months post-surgery): Coagulase-negative staphylococci, S. aureus, gram-negative bacilli; carries worse prognosis
Late PVE (>12 months): Similar to native valve endocarditis
TEE preferred for diagnosis; surgery often required

Healthcare-Associated IE

More than one-third of cases in non-drug-using patients
Caused primarily by S. aureus; MRSA must be considered
Sources: IV catheters, hemodialysis access, pacemakers/ICD leads

SUMMARY TABLE

Feature	Details
Definition	Microbial infection of endocardial surface/valves with vegetation formation
Most common organisms	S. aureus (acute), Viridans streptococci (subacute)
Most common risk factor (modern)	Mitral valve prolapse (developed countries)
Most common valve involved	Mitral > Aortic (left-sided); Tricuspid (IV drug users)
Hallmark lesion	Friable vegetations on valve leaflets
Diagnostic tool	Modified Duke Criteria + Blood cultures + Echocardiography
Most common complication	Heart failure (from valvular destruction)
Most common cause of death	Heart failure
Treatment	Prolonged IV antibiotics (4-6 weeks) ± valve surgery

Sources:

Robbins & Kumar Basic Pathology, pp. 368-369
Goldman-Cecil Medicine International Edition, 2 Vol Set, pp. 700-705, 1678-2000
Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, pp. 1221-1340
Fuster and Hurst's The Heart, 15th Edition, pp. 999-1022

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