Endocarditis and Rheumatic Fever

• Endocarditis and Rheumatic Fever are the focus.
• The material was revised on Feb 19, 2025.

Infective Endocarditis (IE) Learning Objectives

• Recognize different clinical presentations in adults and children.
• Describe the pathophysiology.
• List risk factors for development.
• List lab investigations and recognize findings.
• Describe the incidence and microbiology in prosthetic valves.
• Summarize the management.

Pathophysiology & Prevention Requirements

• Predisposing risk factors are required for infective endocarditis
• A port of entry for bacteria into the bloodstream
• The competence of the host's immune response

Ports of entry for infective endocarditis

• These can include skin, oral cavity, GI, and GU infections
• Examples of oral cavity entry points include extractions, periodontal surgery, implants, and oral biopsies
• Any manipulation of the gingival or periapical region can be a port of entry
• IV drug use, unsafe vessel puncture, and healthcare exposures can directly inoculate the bloodstream with bacteria
• Platelet and fibrin aggregation on the heart valve leads to proinflammatory cytokines, which cause bacteria to attach and form a biofilm
• Biofilms consist of exopolysaccharide matrix and bacteria adhered to the surface

High Risk Factors for IE

• Previous IE= highest risk
• Prosthetic valves/material, intravenous drug users (PWID), or staphylococcal IE
• Surgically implanted prosthetic valves or with any material used for valve repair
• PVE has > 2x higher mortality rate than NVE
• Bioprosthetic valves in the aortic (AV) or mitral valves (MV) have a higher risk than mechanical valves
• Ventricular assist devices increase risk
• Congenital heart disease (CHD), excluding isolated valve abnormalities, increases risk
• Adults with CHD have a 27-44x higher risk of IE than the general population (1.3/1000)
• Kids with CHD 0.41/1000 have a slightly increased risk
• Higher risk for untreated cyanotic CHD or CHD repaired with prosthetic material

Intermediate Risk Factors for IE

• Rheumatic heart disease
• Non-rheumatic degenerative valve disease
• Isolated congenital valve abnormalities including bicuspid AV
• Cardiovascular implanted electronic devices (CIED)
• Hypertrophic cardiomyopathy
• Solid organ transplant recipients often develop nosocomial IE
• IE in Solid organ transplant is usually within the 1st year after transplant
• Most common pathogens are S. aureus and Aspergillus fumigatus

Prevention of IE

• Amoxicillin 2g po x1 is the safest and most commonly used antibiotic
• If allergic to Amoxicillin, use Cephalexin 2g po x1 or Azithro-/Clarithromycin 500mg x1
• Antibiotic prophylaxis prevents Streptococcal IE
• Antibiotic Prophylaxis is only for high-risk IE patients
• Cardiac transplant recipients with valve regurgitation warrant prophylaxis
• The relationship between dental procedures and bacteremia is not straightforward
• Tooth brushing, flossing, and chewing can cause low-level bacteremia
• Prophylaxis is recommended for dental procedures with gingival or periapical aspect of tooth manipulation or oral mucosa perforation
• More evidence is needed to make recommendations for GI, GU, Respiratory, or Skin and Soft Tissue procedures

Clinical Presentation: History of Cardiac & Non-Cardiac Risk Factors

• Cardiac risk factors include previous IE, valvular heart disease, prosthetic valve, central venous or arterial catheter, transvenous cardiovascular implanted electronic device (CIED), congenital heart disease
• Non-cardiac risk factors include central venous catheter, injecting drugs, immunosuppression, recent dental or surgical procedures, recent hospitalization, haemodialysis

Clinical Presentation

• Consider IE in all patients with sepsis or fever of unknown origin with risk factors
• IE can present acutely, subacutely, or chronically, and with low-grade or no fever
• Non-specific symptoms like general malaise is common
• Fever is present in 77.7% of cases
• Positive blood cultures lead to suspicion.
• Heart failure (27.2%) is a complication
• Embolic events (25.3%) are a complication
• Conduction abnormalities (11.5%) are a complication

Physical Exam

• Absence of clinical signs does NOT rule out IE
• A new murmur is present in 64.5% of cases
• Stigmata of IE are seen in severe S. aureus IE and subacute Streptococcal spp.
• More common signs include Splinter hemorrhages, roth spots, glomerulonephritis, and subconjunctival hemorrhages

Investigations for Endocarditis

• 3 to 4 sets of blood cultures from a peripheral vein are needed
• Requires aerobic + anaerobic flasks
• Blood cultures should be taken BEFORE antibiotics
• Antibiotics before blood cultures reduces the sensitivity to 96-98%
• Most common cause of culture negative endocarditis is antibiotics before blood cultures are taken
• Could also be due to fastidious bacteria: Bartonella hensalae (Cat scratch), T. whipplei, Coxiella burnetti (Q fever).
• Could be due to fungi

Echocardiogram Indications

• The pretest probability of IE and the quality of the study impacts TTE sensitivity
• Negative high quality TTE may be suitable to rule out NVE
• TEE has higher sensitivity (>90%) than TTE (75% Sensitivity) for Endocarditis Diagnosis
• TTE is useful to reduce the possibility of NVE where high post-test probability remains
• Aids surgical planning or evaluates for complications like perivalvular abscess
• TEE is used for diagnosis and to detect perivalvular complications in ALL cases except in NVE if TTE good quality and conclusive
• Both TEE and TTE is recommended in suspect cardiac implantable electronic device related IE to identify vegetations
• An echocardiogram does NOT rule out endocarditis if persistent positive blood cultures despite appropriate antimicrobial therapy are present

Bloodwork & ECG

• No biomarker can diagnose IE definitively:
• Markers of sepsis: degree anemia / elevated WBC or decreased WBC, CRP, procalcitonin, ESR, or end-organ damage.
• ECG findings: 1st degree atrioventricular (AV) block, bundle branch block, complete heart block.

Role of Cardiac CT Angiography and Nuclear Imaging

• Cardiac CT angiography (CTA) is recommended for possible NVE to detect valvular lesions and confirm the IE diagnosis
• Also for diagnosing paravalvular or periprosthetic complications if an echo is inconclusive
• For brain and whole-body imaging to detect peripheral lesions or add minor diagnostic criteria
• Consider 2-[18F]-fluorodeoxyglucose (18-FDG) PET/computed tomography (CT) for strongly suspected case of PVE or cardiac device-related IE (CDIE)
• Sensitivity is 73% and Specificity 80% for PVE
• Sensitivity 87% and Specificity 94% for CDIE
• 18-FDG Pet/CT is not recommended in patients diagnosed with NVE due to its poor sensitivity (31%)
• Positive results indicates NVE

Modified Duke Criteria 2023 - Major Criteria

• Microbiologic:
  • Microorganisms commonly found to cause IE from ≥2 separate blood cultures
  • Microorganisms that occasionally or rarely cause IE from ≥3 blood cultures
  • PCR or other nucleic acid-based technique (NAT) for Coxiella burnetii, Bartonella spp, Tropheryma whipplei from blood
  • C. burnetii IgG >1:800 or isolated from 1 blood
  • Bartonella henselae IgM and IgG, or B. quintana IgG ≥1:800 culture, but there are no high-quality studies to validate cut-offs for this
• Imaging
  • Echocardiogram and/or cardiac CT showing vegetation, valvular/leaflet perforation, aneurysm, abscess, pseudoaneurysm, or intracardiac fistula
  • New valvular regurgitation on echocardiogram compared to previous imaging
  • New partial dehiscence of prosthetic valve compared to previous.
• Surgical:
  • Evidence via direct inspection during surgery that doesn't meet major imaging criteria, histologic, or microbiologic confirmation

Minor Criteria

• Predisposition:
  • Previous history of IE
  • Prosthetic valve
  • Previous valve repair
  • Congenital heart disease
  • More than mild regurgitation/stenosis
  • CIED
  • Hypertrophic obstructive cardiomyopathy
  • IVDU
• Fever: >38C
• Vascular phenomena:
  • Arterial emboli
  • Septic pulmonary infarcts
  • Cerebral/splenic abscess, mycotic aneurysm
  • Intracranial hemorrhage
  • Conjunctival hemorrhages
  • Janeway lesions
  • Purulent purpura
• Immunologic phenomena: Osler nodes, + rheumatic factor, Roth spots, immune-complex mediated GN
• Microbiologic evidence: +blood culture / PCR / culture / NAT that is consistent for IE but not meeting major criteria
• Imaging: Abnormal metabolic activity on (18F)FDG PET/CT as it relates to prosthetic valve implantation < 3 months, ascending aortic graft, cardiac device leads, or other prosthetic material
• Physical examination: new valvular regurgitation on auscultation in those without echo results

Diagnostic Definitions using Modified Duke Criteria

• Definite:
  • Pathological Criteria: Microorganism identification from appropriate sample
  • Clinical Criteria: 2 major, 1 major and 3 minor, or 5 minor
• Possible: 1 major and 1 minor or 3 minor
• Rejected (NEW):
  • Alternate diagnosis explaining signs/symptoms
  • Lack of recurrence despite antibiotics for <4 days
  • No pathologic/macroscopic evidence of IE at surgery/autopsy with antibiotic therapy
  • Does not meet criteria for IE

Management Principles of IE

• Bactericidal drugs are more effective than bacteriostatic drugs
• Slow-growing microbes in vegetations/biofilms are tolerant to most antibiotics except rifampin
• This is the reason why the duration for PVE is longer
• Aminoglycosides as an adjunct are no longer recommended

Management of S. aureus Bacteremia/Endocarditis

• A normal echocardiogram does not rule out endocarditis.
• Persistent positive blood cultures despite appropriate antibiotic coverage, particularly if S. aureus bacteremia is present, suggests IE until proven otherwise should be considered.
• Cloxacillin or cefazolin are the drugs of choice for MSSA.
• Vancomycin NOT be used for MSSA.
• Rifampin is reserved for PVE for 3-5 days.
• If patient has intracranial involvement, use cloxacillin in meningitic doses.
• Piperacillin-tazobactam or ceftriaxone should not be used for MSSA endocarditis.
• NEVER USE CLINDAMYCIN FOR STAPH AUREUS BACTEREMIA OR ENDOCARDITIS

Empiric Antimicrobial Choice:

• If the bacteria that is causing IE is unknown, consider the gram stain results and a patient's exposure history:

General Considerations

• 80-90% of endocarditis cases are from Staphylococcus species
• 30% of cases are due to S. aureus
• Coagulase-negative staphylococcus colonizes lines, devices and skin
• In 25-30% of Staphylococcus aureus bacteremia cases, endocarditis is seen
• Oral flora: Viridans group Strep - 18.7%, e.g. S. mitis, S. salivarius, S. anginosus.
• Streptococcus pneumoniae is a very rare cause.
• Enterococci account for 17.5% of cases, and were formerly part of the Streptococci group
• HACEK are slow growing and account for 3% of cases
• Candida spp. 1.2%
• Gram negative rods: are rare to cause IE

Empiric Antibiotic considerations in suspected IE.

• NVE
  • Common microorganisms: Staphylococcus aureus, Streptococci, Enterococci, HACEK -Empiric Antibiotic: Vancomycin for MSSA/MRSA, Streptococci, Enterococci
• PVE
  • Common microorganisms: Staphylococcus aureus (most common), Coagulase neg staphylococci, Streptococci, Enterococci -Empiric Antibiotic:
    • Vancomycin or Daptomycin
      • Dose Daptomycin differs between enterococcus and Staph Aureus
  • If PV replaced 1.6-2 times higher in females with worsening disease in pregnancy

Etiology of Rheumatic Fever (RF)

• RF is a complication of Group A Streptococcus (Streptococcus pyogenes) infection
• Acute rheumatic fever (ARF) appears 2-4 weeks after GAS pharyngitis
• Molecular mimicry and autoimmunity play a role in GAS triggering ARF

Epidemiology of RF

• In high-income countries, the incidence of RF is declining
• Attributed to improved hygiene, access to antibiotics and health care, reduced household crowding, and changes in GAS strain
• Low / middle-income countries and certain indigenous populations are most affected groups
• In Canada, invasive GAS rates from 2009 to 2014 were seen 10 times more, compared to rest of the Canada, specifically in NW Ontario communities
• Average time to diagnosis in NW Ontario = 88 days
• Peak incidence is between ages 5 to 15 years old, rare >30 years old
• 60% with initial ARF develop rheumatic heart disease
• Females at higher risk, particularly associated with pregnant women.

Jones Criteria for Diagnosing RF

• Required: Evidence of preceding GAS by:
  • Elevated/increasing ASOT (Anti-streptolysin O titer)
  • Elevated/increasing anti-DNAse B
  • Positive throat culture for GAS
  • Positive Rapid GAS antigen test with appropriate clinical presentation
• First episode ARF: 2 major or 1 major + 2 minor
• Recurrent ARF: 2 major or 1 major + 2 minor or 3 minor

List of 5 Major Jones Criteria

• Joints: 35-66% in 1st ARF presentations, Migratory polyarthritis, Large joints, improved with ASA or NSAIDS, and is self-limited usually lasting 4 weeks with no long-term deformity (consider monoarthritis if high-risk population)
• Carditis: 50-70% in first ARF presentation and involves endocardium, myocardium, pericardium, or valvulitis (usually mitral or aortic valves, and valvulitis is most common in this specific diagnostic class.)
• Nodules: the firm/painless protuberances located on the extensor surfaces related to joints, which includes knees, elbows, etc.
• Erythema Marginatum: the pink rash which presents with pale enters + rounded/serpiginous margins (usually shown on the trunk and proximal extremities, but not the face)
• Sydenham's Chorea: these are purposeless, involuntary, non-rhythmic, and non-stereotypical movements.

Minor Criteria

• Arthralgia
• Polyarthralgia
• Fever > 38°C
• Elevated ESR, CRP
• Prolonged PR interval on ECG
• Variable Presentation in High-risk populations
• Aseptic monoarthritis, polyarthralgia, low grade fever

Investigations of Acute Rheumatic Fever (ARF)

• No confirmatory test, so all JONES criteria must be met
• Look for evidence of GAS through:
  • Rising/increased ASOT and/or anti-DNAse B
  • Previous or current throat swab positive for GAS

•   CBC, CRP
  

•   Echocardiogram with Doppler
  

•   ECG for possible prolonged PR interval/arrhythmia
  

Treatment/Prevention

• Goals:
  • Control inflammation via: ASA or NSAID (Naproxen)
  • Manage carditis via: Glucocorticoids w/ severe heart issues and consult for valve surgery
  • Eradicate GAS via: treat patient