Infective Endocarditis (IE)

Definition

• Robbins & Kumar Basic Pathology, p. 368
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 528

Classification: Acute vs. Subacute

Epidemiology

• Global incidence: ~13.8 per 100,000 (range 5.7-35.8 per 100,000)
• Deaths due to IE have increased 131% since 1990, with ~66,322 deaths estimated
• In-hospital mortality up to 22%; 5-year mortality up to 40%
• The opioid epidemic has driven a surge in S. aureus IE from IV drug use (IVDU), particularly in rural US settings
• In developing countries with endemic rheumatic fever: younger adults with subacute VGS IE
• In developed countries/healthcare settings: older adults, S. aureus, acute IE
• Fuster and Hurst's The Heart, 15th Edition
• Braunwald's Heart Disease, Chapter on IE

Predisposing Conditions / Risk Factors

• Prosthetic heart valves (10-20% of all IE)
• Previous IE
• Congenital heart disease (bicuspid aortic valve, unrepaired cyanotic CHD)
• Mitral valve prolapse (the leading pre-existent risk factor now that RHD has declined)
• Degenerative calcific valvular stenosis
• Rheumatic heart disease (still major in developing countries)
• Hypertrophic obstructive cardiomyopathy
• Ventricular assist devices, implantable cardiac devices

• Intravenous drug use (IVDU)
• Indwelling vascular catheters / pacemaker leads
• Diabetes, immunodeficiency, malignancy, neutropenia, alcohol use
• Poor oral health / invasive dental procedures

Microbiology

• Left-sided: mitral (41.1%), aortic (37.6%) - community/healthcare IE
• Right-sided (tricuspid): characteristic of IVDU

Pathogenesis

1. Bacteremia seeds the bloodstream (dental/surgical procedure, IVDU, trivial skin breaks, gut/oral flora)
2. Endothelial disruption at sites of turbulent flow creates sterile platelet-fibrin deposits (non-bacterial thrombotic endocarditis, NBTE)
3. Circulating organisms adhere to these sterile thrombi - especially when surface receptors (e.g., fibronectin-binding proteins on S. aureus) facilitate binding
4. Organisms proliferate within the vegetation, protected from immune defenses (avascular structure - no direct blood supply, limited immune access)
5. The vegetation grows - friable, bulky, destructive - composed of fibrin, inflammatory cells, and organisms

Pathology / Morphology

• Vegetations are the hallmark - friable, bulky masses on valve cusps (usually on the line of closure, atrial surface for AV valves, ventricular surface for semilunar valves)
• Can be single or multiple, can extend onto chordae tendineae
• Can erode into myocardium → ring abscess (perivalvular abscess)
• Aortic and mitral valves most common; tricuspid in IVDU

Fig. 12.24 - Robbins, Cotran & Kumar Pathologic Basis of Disease

Fig. 12.23 - Robbins, Cotran & Kumar Pathologic Basis of Disease

• Subacute IE: granulation tissue at the vegetation base (healing), fibrosis, calcification over time
• Acute IE: minimal healing, predominant acute inflammatory infiltrate, extensive destruction

Clinical Features

• Fever (most consistent sign - present in >90%; may be low-grade or absent in elderly)
• Chills, night sweats, malaise, anorexia, weight loss ("flu-like")
• Myalgia, arthralgia
• Back pain

• New or changing cardiac murmur (majority of left-sided IE)
• Peripheral stigmata (immune complex and embolic phenomena):
  • Osler nodes - tender nodules on fingertips/toes (immune complex mediated)
  • Janeway lesions - non-tender hemorrhagic/erythematous macules on palms/soles (septic emboli - more common in acute IE)
  • Roth spots - oval retinal hemorrhages with white centers
  • Splinter hemorrhages - linear hemorrhages under nails
  • Conjunctival petechiae
• Splenomegaly
• Clubbing (in subacute IE)

Diagnosis: Modified Duke Criteria

1. Blood culture positive for IE:
   • Typical organisms (S. viridans, S. bovis, HACEK, S. aureus, community-acquired enterococci) from ≥2 separate blood cultures, OR
   • Persistently positive blood cultures (≥2 cultures drawn >12h apart; or ≥3 of 4 if drawn ≥1h apart)
   • Single positive culture for Coxiella burnetii or anti-phase 1 IgG antibody titer >1:800
2. Evidence of endocardial infection:
   • Echocardiography positive for IE (vegetation, abscess, new prosthetic valve dehiscence), OR
   • New valvular regurgitation (worsening or changing of existing murmur not sufficient)

1. Predisposing heart condition or IV drug use
2. Fever ≥38°C (100.4°F)
3. Vascular phenomena: arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial/conjunctival hemorrhage, Janeway lesions
4. Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor
5. Microbiologic evidence - positive blood culture but not meeting major criteria

2023 Duke/ISCVID Update: Added FDG-PET/CT as an imaging major criterion (abnormal metabolic activity within 3 months of prosthetic valve implantation), expanded molecular diagnostics (PCR, sequencing), and refined minor criteria to include more specific immune and vascular phenomena. - Textbook of Clinical Echocardiography

Echocardiography

• First-line study; sensitivity 50-90% for native valve vegetations (95% specificity); ~50% for prosthetic valves
• Sensitivity for abscess: 30-50% native, only 15-35% prosthetic
• Should be performed as soon as possible in suspected IE

• Superior resolution; sensitivity ~90% for vegetation, ~87% for abscess
• Indications for TEE (after TTE):
  • TTE technically inadequate or non-diagnostic despite high clinical suspicion
  • Prosthetic valve involvement
  • S. aureus bacteremia
  • Suspected perivalvular extension/abscess
  • Suspicion of prosthetic valve IE

Treatment

Antibiotic Regimens

• The Washington Manual of Medical Therapeutics

Surgical Indications (Native Valve IE)

1. Heart failure (most common) - severe valvular regurgitation or obstruction causing acute decompensation
2. Perivalvular extension - abscess, fistula, new heart block
3. Uncontrolled infection - persistent bacteremia/fever >5-7 days despite appropriate antibiotics; organisms resistant to antibiotics (fungi, Brucella)
4. Prevention of embolism - large vegetation (>10 mm), especially with prior embolic event; rapidly increasing vegetation size
5. S. aureus infection (high-risk feature)
6. Prosthetic valve IE with any of the above, plus valve dehiscence

Prophylaxis (AHA 2021 Update)

• Prosthetic cardiac valve or material (including TAVR)
• Previous IE
• Unrepaired cyanotic CHD or repaired CHD with prosthetic material (first 6 months post-procedure)
• Cardiac valvulopathy in transplant recipients
• Ventricular assist devices and implantable hearts (added in 2021)

• Standard: Amoxicillin 2g PO, 1 hour before procedure
• Unable to take PO: Ampicillin 2g IM/IV or cefazolin/ceftriaxone 1g IM/IV within 30 min before
• Penicillin-allergic: Cephalexin 2g PO, or clarithromycin/azithromycin 500mg PO (clindamycin removed in 2021 update due to C. difficile risk); doxycycline added as an alternative
• GI/GU procedures: Routine prophylaxis not recommended

Summary: IE Management Team Approach

• Infectious diseases
• Cardiovascular medicine
• Cardiovascular surgery

• Braunwald's Heart Disease, 11th Edition - Epidemiology, pathogenesis, team management
• Fuster and Hurst's The Heart, 15th Edition - Duke criteria, echo, PVE, surgery
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Pathology and morphology
• Robbins & Kumar Basic Pathology - Classification and pathogenesis
• The Washington Manual of Medical Therapeutics - Antibiotic regimens, prophylaxis
• Textbook of Clinical Echocardiography - 2023 Duke/ISCVID criteria

Infectiousness Across Syphilis Stages

Why Secondary Syphilis Is So Infectious

"The manifestations of secondary syphilis include mucocutaneous lesions, which are highly infectious, and generalized lymphadenopathy."

1. Condyloma lata - broad, flat, moist papules in warm/moist areas (perineum, perianal region, axillae) - extremely rich in treponemes
2. Mucous patches - painless, silvery-gray erosions on oral/genital mucosa - highly infectious
3. The widespread maculopapular rash (including palms and soles) - not typically infectious because keratinized skin contains insufficient treponemes

"With the exception of mucous patches and condyloma lata, cutaneous manifestations of secondary syphilis do not contain a substantial number of treponemes and, therefore, are not typically infectious." - Fitzpatrick's Dermatology

Transmission Route in Secondary Syphilis

• Almost exclusively sexual contact with infectious lesions (condyloma lata, mucous patches)
• Lesions can be on genital, anal, or oral mucosa
• Direct skin-to-skin contact with an infectious lesion is sufficient for transmission
• Congenital transmission is also most likely during primary and secondary stages when spirochete burden is highest

Important Clinical Points

• Early latent syphilis (within the first year) can relapse back into secondary syphilis, making the patient infectious again - this is why early latent syphilis is treated with the same urgency
• Serologic tests are most sensitive in secondary syphilis - RPR/VDRL sensitivity is 100% in this stage (vs. 78-86% in primary)
• Patients in primary or secondary syphilis who are diagnosed should have all sexual contacts from the past 90 days traced and treated

• Robbins & Kumar Basic Pathology, p. 669
• Fitzpatrick's Dermatology, Chapter 170

✅ TRUE

The Numbers

Why Recurrent Infection Carries Lower Risk

1. Pre-formed maternal antibodies (IgG) - In recurrent infection, the mother has type-specific anti-HSV antibodies that cross the placenta and provide the neonate with passive protection
2. Lower viral shedding - Recurrent episodes involve far less virus at the genital tract compared to primary infection, reducing the inoculum the baby is exposed to during passage through the birth canal
3. Shorter duration of shedding - Recurrent episodes shed virus for fewer days than primary infection

"The risk of transmission to a neonate born to a mother who acquires primary genital HSV infection near the time of delivery is estimated to be 25% to 60%. The risk is considerably lower (1% to 2%) among women with recurrent, clinically evident infection."

• Creasy & Resnik's Maternal-Fetal Medicine

"The risk of infection for an infant delivered vaginally when the mother has active recurrent genital herpes infection is 2%-5%, whereas it is 26%-56% if the maternal infection at delivery is a first episode."

• Andrews' Diseases of the Skin

Important Nuances

• 70% of neonatal HSV cases occur in mothers with no known history of genital herpes - meaning subclinical/asymptomatic shedding is the biggest source of neonatal HSV, not symptomatic recurrences
• Recurrent HSV during pregnancy does not increase the risk of abortion or low-birth-weight infants
• Scalp electrodes during delivery can increase neonatal HSV risk up to 7-fold - should be avoided if HSV shedding is possible
• Vacuum-assisted delivery increases relative risk 2-27 times
• Despite the lower risk, recurrent herpes with active lesions at delivery is still an indication for caesarean section

Management of Recurrent HSV in Pregnancy

• Suppressive acyclovir/valacyclovir from 36 weeks reduces recurrence at delivery and likelihood of caesarean section
• Routine prenatal cultures are not recommended for recurrent HSV (they don't predict shedding at delivery)
• Caesarean section is indicated if active genital lesions or prodromal symptoms are present at the time of labor
• Creasy & Resnik's Maternal-Fetal Medicine
• Andrews' Diseases of the Skin

✅ TRUE

Understanding the Two Types of Syphilis Tests

Why Treponemal Tests Cannot Monitor Treatment

"Treponemal tests remain positive in 95% of patients, even after treatment, and are not used to monitor treatment response and cannot distinguish active from treated syphilis."

• Textbook of Family Medicine

"These treponemal tests are highly specific for syphilis, but they may remain positive for life even after successful treatment and cure."

• Rosen's Emergency Medicine

What IS Used to Monitor Treatment

"After treatment for early syphilis, a persistent fall by fourfold or more (e.g., a decline from 1:32 to 1:8) is considered an adequate response."

• Harrison's Principles of Internal Medicine, 22nd Edition

• Adequate response: ≥4-fold (2-dilution) decrease in RPR/VDRL titer within 6-12 months
• Treatment failure / reinfection: <4-fold decrease, or 4-fold increase in titer
• RPR/VDRL sensitivity is 100% in secondary syphilis - the stage with highest titers

Summary

• Textbook of Family Medicine, 9th Edition
• Harrison's Principles of Internal Medicine, 22nd Edition
• Rosen's Emergency Medicine

❌ FALSE

The Jarisch-Herxheimer Reaction

"The Jarisch-Herxheimer reaction is a self-limited clinical syndrome consisting of fever, headache, flare of mucocutaneous lesions, tender lymphadenopathy, pharyngitis, malaise, myalgia, and leukocytosis. It occurs within the first 24 hours after initiating therapy. The fever peaks 6 to 8 hours after the onset, usually around 39°C (102.2°F), but it can be as high as 42°C (107.6°F)."

• Fitzpatrick's Dermatology

Timeline of the JH Reaction

Pathogenesis

Clinical Significance

• Patients must be warned before treatment that this reaction will occur
• It does not mean the antibiotic is wrong - it is actually a sign the treatment is working
• Management: rest, hydration, paracetamol (limited evidence)
• In pregnant women: JH reaction can cause premature labor or fetal distress - requires monitoring, but treatment must not be delayed given the risk of congenital syphilis
• If anaphylaxis occurs instead, this is a true penicillin allergy requiring drug change

Correction of the Statement

1. Fever does not settle in 8-12 hours - it peaks at 6-8 hours
2. Fever resolves by ~24 hours, not 8-12 hours

• Fitzpatrick's Dermatology, Chapter 170
• Creasy & Resnik's Maternal-Fetal Medicine
• Tintinalli's Emergency Medicine

❌ FALSE

What the Evidence Says

"Oral azithromycin results in defervescence in 4–6 days... Ceftriaxone and cefixime clear fever in ~1 week."

• Harrison's Principles of Internal Medicine, 22nd Edition

Why Fever Takes So Long to Settle in Typhoid

• Survives and replicates inside macrophages
• Causes a sustained, step-ladder pattern fever that persists for weeks if untreated
• Even with the correct antibiotic, the intracellular location means it takes days for the drug to clear the organism and for the host's inflammatory response to subside

Treatment Duration Note

"Therapy should be administered for at least 10 days or for 5 days after fever resolution."

• Harrison's Principles of Internal Medicine, 22nd Edition

Summary

• Harrison's Principles of Internal Medicine, 22nd Edition - Chapter on Enteric Fever