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, married2
• 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
Medical 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

4
Physical examination

• General appearance ill-looking, pale, weak,
  debilitated
• Vitals BP 129/73 pulse78 RR18 Temp36.8?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
Definition

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

10
Etiologic agents in IE

• 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
• lt5
• 1-2
• lt5-24

11
Epidemiology

• Annual incidence 15,000 to 20,000
• Forth leading cause of life-threatening
  infectious disease
• Malefemale ratio is 1.71
• 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 gt1cm.

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 changesMycotic 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 (gt30 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 gt400c (gt95)
• Nonspecific symptoms (weakness, weight loss,
  night sweats)
• Audible heart murmur (gt85 of cases)
• Petechiae (20-40)
• Osler nodes (10-25)
• Janeway lesions (lt5)
• Splinter hemorrhages (10-30)
• Roth spots (lt5)
• Clubbing (10-20)
• Splenomegaly (25-60)
• Musculoskeletal manifestations (25-45)
• Major embolic episodes (gt30)
• 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 (gt25)
• 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 lt60
• 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 gt38c
• 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
• gt40 of patients have no underlying heart
  disease, but 95 will develop a heart murmur
• Classic peripheral signs are uncommon (lt25)
• 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 therapyIndications

• refractory CHF
• gt2 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 therapyEcho features

• Persistent vegetations after a major systemic
  embolic episode
• Large (gt1cm 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