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A. Introductionnavigator

  1. Endocarditis is inflammation of the heart lining cells called endocardium
  2. In essentially all cases, heart valve endocardium is involved, without wall tissue
  3. Over 90% of endocarditis cases are due to infection
    1. Majority of cases occur in intravenous drug abusers on right sided heart valves
    2. Cases in normal hosts are usually due to abnormal valve anatomy
    3. Noninfectious causes are found in autoimmune diseases (lupus) and serotonin syndromes
  4. Valve inflammation usually involves thrombus formation and potential for embolic spread
  5. Majority of cases have a subacute (2-8 week) insidious course
  6. Systemic symptoms (due to inflammation) and cardiac symptoms (valve damage) occur
  7. Progression with sepsis, renal failure, and/or heart failure occurs without treatment
  8. Incidence is ~30 (range 15-60) cases per million [3]

B. Etiology [1,3] navigator

  1. Endocarditis in Injection Drug Abusers (IVDA) [10]
    1. Incidence is ~2 per 1000 HIV- and 14 per 1000 HIV+ injection drug abusers per year
    2. Mortality ~7% with nearly all deaths in patients with vegetations >2cm.
    3. S. aureus ~70%: methicillin sensitive predominant, though this depends on area
    4. Streptococci ~8%: viridans [19], ß-hemolytic, oral streptococci
    5. Enterococci ~2%
    6. Polymicrobial ~9%
    7. Other bacteria ~5%
    8. Fungi ~2%
    9. Negative blood culture ~5%
    10. Pneumococcus is rare [4]
    11. HACEK Group (see below) very rare
    12. IVDA Valve Endocarditis: Tricuspid >50%, Aortic ~25%, Mitral 20%, Mixed uncommon
    13. HIV infection with CD4 counts <200/µL increases endocarditis risk >4X
  2. Endocarditis in Normal Adults with Native Valves [5,7]
    1. Abnormal valve (regurgitation or stenosis) is most often found
    2. Staphylococcus aureus 25-35%
    3. Staphylococcus epidermidis (or other coagulase negative staph) 6-10%
    4. Viridans streptococci 44% [7]
    5. Oral Streptococci 21%
    6. These include S. agalactiae, S. bovis, S. pyogenes, pneumococcus and others
    7. Enterococcus 7-10%
    8. HACEK Group 2-4%
    9. Polymicrobial 2%
    10. Other bacteria including some gram negative organisms
    11. Fungi 1%
    12. Negative Culture ~1-6%
    13. Gram negative non-HACEK 2%
    14. Age of host influence risks of specific organisms [2]
  3. Prosthetic Valve Endocarditis [11,21]
    1. Accounted for ~20% of cases of all cases of infectious endocarditis [11]
    2. Divided into early (<60 days) and late (>60 days) infection after valve surgery
    3. Most early infections are staphylococci (67%), previously majority were coauglase negative Staph; this is decreasing with increasing Staph aureaus (coag positive)
    4. About 27% of early infections have negative blood cultures
    5. Most common late infections are staphylococci (46%), with ~22% Staph aureus
    6. Streptococci are also common (35%), majority are oral streptococci (26%)
    7. Enterococci 7% and negative blood culture 7%
    8. Surgically treated patients (~50%) generally do better than medical-only treated patients
    9. Six weeks of bacteriocidal (not bacteriostatic) antibiotics strongly recommended
    10. Recurrent valve endocarditis should be treated with valve replacement
    11. Warfarin is stopped ~2 days prior to nonemergent valve replacment
    12. In emergencies, anticoagulation is reversed with fresh-frozen plasma
    13. In hospital death occurred in ~23% of cases
    14. Death increased with older age, health-care associated infection, Staph aureus, heart failure, abscess, and persistent bacteremia [11]
  4. Incidence of Bacteremia with Various Underlying Conditions
    1. Brushing Teeth: 40%
    2. Tooth extracture or periodontal surgery: 60-88%
    3. Nasotracheal suctioning, rigid bronchoscopy: 15%
    4. Catheterization of bladder: 13%
    5. Prostatectomy - sterile urine: 12%; infected urine: 60%
    6. Esophageal Dilatation: 45%
    7. Other endoscopies: 2-8%
    8. Barium Enema: 10%
    9. Normal Vaginal Delivery: 3%
    10. Cardiac Catheterization: 2%
  5. Culture Negative Endocarditis [6]
    1. Most commonly due to previous antibiotic use
    2. Bartonella has been reported
    3. Coxiella burnetii (Q Fever) [25]
    4. Bartonella species
    5. Chlamydia species
    6. HACEK Organisms
    7. Nutritionally variant (deficient) streptococci
    8. Whipple's Disease (Trophyrema whippelii) [8]
    9. Fungal infection
    10. Non-infectious cause (see below)
  6. HACEK Endocarditis [9]
    1. Accounts for ~3% of community acquired endocarditis
    2. Likely the most common cause of culture negative endocarditis
    3. These are slow growing, fastidious, Gram negative bacteria
    4. The Mnemonic "HACEK" stands for various species:
    5. Haemophilus parainfluenza, H. paraphrophilus and H. aphrophilus
      1. Actinobacillus actinomycetemcomitans
      2. Cardiobacterium hominis
      3. Eikenella corrodens
    6. Kingella kingae
    7. May be increased following dental proceedures or in persons with periodontal disease
    8. In general, physician must specifically request cultures to isolate HACEK organisms
    9. This also applies to certain fungi and to nutritionally variant streptococci
  7. Fungal Endocarditis
    1. Unusual in normal hosts; far more common in chronically ill persons
    2. Consider in neutropenic patients
    3. Patients on total parenteral nutrition (TPN)
    4. Patients with prosthetic valves
    5. Patients on good antibiotics coverage and still spiking fevers
  8. Non-Infectious Causes of Endocarditis [12]
    1. Strictly refers to non-infectious causes of valvular inflammation
    2. Most commonly associated with autoimmune diseases
    3. These include systemic lupus erythematosus, vasculitis, anti-phospholipid syndrome
    4. Anorexic Agents - dexfenfluramine, others (serotonin agonists)
    5. Carcinoid syndrome - usually with high serotonin production
    6. Non-bacterial thrombotic endocarditis - frequent embolism
    7. Atrial Myxoma

C. Pathophysiology navigator

  1. Valvular disease and/or abnormalities predispose to endocarditis
    1. Mitral valve prolapse (MVP) is most common valve lesion associated with endocarditis [1]
    2. MVP is only a risk for endocarditis when regurgitation or stenosis are present
    3. Libman-Sachs endocarditis due to collagen-vascular disease (such as SLE)
    4. Abnormal valves due to carcinoid syndrome may predispose to endocarditis
    5. Previous endocarditis is high risk for recurrent disease
    6. Unclear how risky dental procedures are in patients with normal valves
    7. Prophylactic antibiotics should generally be given to all patients with abnormal valves for dental and other invasive procedures (but not for uncomplicated MVP)
  2. Initial Endomyocardial damage
    1. Usually associated with (transient) bacteremia from various sources
    2. Bacteremia causes abnormal endothelial cells and endomyocardial cell damage
    3. Organisms associated with endocarditis have great ability to adhere to damaged valves
    4. These organisms have surface adhesins that mediate attachment to vegetation
  3. Platelet-Fibrin Deposition on Valve Endothelium (Endomyocardium)
    1. This is typically a non-bacterial thrombosis, but can become superinfected
    2. Immune complexes appear to play a major role initiation of platelet fibrin deposits
    3. These complexes are usually due associated with bacteremias
    4. Systemic vasculitis, serum sickness, other diseases may also induce immune complexes
  4. Adherence of bacteria to immune complexes or platelet-fibrin clots (vegetation)
    1. This can occur with primary bacteremia, or with superinfection
    2. Bacterial adhesins are MSCRAMMs and cause bacteria to adhere to damaged valve
    3. MSCRAMMs are microbial surface component reacting with adhesive matrix molecules
    4. Staphylococci have fibronectin and fibrinogen binding proteins (clumping factor)
    5. Streptococci have surface adhesins, platelet activating factors, exopolysaccharides
    6. Organization of vegetation with additional platelets, neutrophils, protease action
    7. Progression of vegetation with invasion of surrounding tissue
    8. Endocarditis may progress to, or derive from, cardiac abscess [19]
  5. Embolization
    1. Vegetation may rupture leading to systemic or pulmonary embolization
    2. Such emboli are highly virulent because they contain infectious organisms

D. Symptomsnavigator

  1. Most common symptoms is fever
    1. Fevers, rigors, and/or hypothermia are found in >95% of patients
    2. Fevers may be very high (>39°C, >102°F)
    3. Fevers persist or recur in over 50% of patients
    4. Fevers persisting >7 days was accompanied by cardiac infection in >50% of cases
    5. In acute disease, symptoms may progress rapidly
  2. Cardiac murmer occurs in >70% of patients
    1. Acute endocarditis may have rapid patient decompensation due to valve destruction
    2. May present with flash (acute) pulmonary edema [20]
    3. This is a surgical emergency and valve replacement is required
    4. Medical therapy alone will not be effective in this situation
  3. Systemic Symptoms
    1. Associated with increased acute phase reactants from liver and elevated IL-6
    2. Lethargy, malaise, weight loss, night sweats, and/or anorexia (>9%% of patients)
    3. Patient may be diagnosed with "Fever of Unknown Origin"
    4. Often mistaken for lymphomas or other cancers
  4. Peripheral symptoms are uncommon at presentation
    1. In the past, these symptoms were relatively common
    2. They now occur in <15% of cases
    3. Osler Nodes (small, tender, red, lymph nodes usually on pads or fingers)
    4. Janeway Lesions (red lesion on palm or sole, nontender)
    5. Splinter Hemorrhages (nail beds)
    6. Roth Spots (retinal seeding)
    7. Palpable purpura (immune complexes)
  5. Renal Embolic Disease
    1. Kidney is a common site for shedded infected emboli
    2. Pyelonephritis and/or renal abscess may occur
  6. Righ Sided Endocarditis
    1. Usually in Intravenous Drug Abusers (IVDA) involving the tricuspid valve
    2. Pulmonary (septic) emboli occur in >75% of patients with endocarditis
    3. These septic lung emboli may be apparent on chest radiography
    4. Large pulmonary abscess may develop, especially in GNR and S. aureus infections
  7. Other Signs and Symptoms
    1. May be thromboembolic and/or infectious in nature
    2. Abdominal infarctions including spleen, renal, pyelonephritis
    3. Symptoms of meningitis may develop
    4. Septic arthritis not uncommon, especially with a history of joint trauma
  8. Prognostic severity index developed for complicated adult left-sided native valve endocarditis [14]

E. Diagnosis [1]navigator

  1. Positive blood cultures with valve anomalies on echocardiography are definitive
    1. Both findings occur in about half of the cases of (subsequently confirmed) endocarditis
    2. Various sets of criteria have been developed to better predict endocarditis
    3. The Duke Criteria (below) appear to be the most sensitive in non-IVDA patients
    4. In IVDA, clinical suspicion should be very high, even without clear symptoms
  2. Microbiological Cultures
    1. Three pairs of blood cultures essential for diagnosis
    2. Blood cultures may be falsely negative due to prior antibiotics
    3. Blood cultures may be falsely positive due to poor skin preparation prior to needle-stick
    4. Skin preparation with alcoholic chlorhexidine is more efficacious than aqueous providone-iodine in preventing blood culture contamination [16]
    5. Urinalysis and culture must be performed in all patients to rule out kidney infections
    6. Sputum culture, particularly in IVDA (assess for pulmonary involvement)
    7. Consider Lumbar Puncture if symptoms develop
    8. Polymerase chain reaction (PCR) may be used if organisms not cultured
    9. PCR also useful for difficult to detect organisms such as Tropheryma whipplei
  3. Hematology
    1. Leukocytes - elevated, usually with immature (band) forms present
    2. Differential counts show mainly neutrophilia
    3. Leukopenia is generally a poor prognostic indicator
    4. Anemia, usually of chronic disease type, may be present
    5. Thrombocythemia is often present (acute phase reactant)
  4. Acute Phase Reactants
    1. Erythrocyte Sedimentation Rate (ESR) often >100mm/hr
    2. C-Reactive Protein (CRP) usually elevated, and is likely more sensitive than ESR
    3. In complicated endocarditis such as abscess, peripheral disease, CRP remains elevated [16]
    4. CRP level is well correlated with systemic Interleukin 6 (IL-6) levels
    5. Fibrinogen and D-Dimer levels are often elevated as well
    6. Platelet levels may be increased (acute phase response)
  5. Electrocardiogram (ECG)
    1. Follow to check for conduction system involvement, such as PR and/or QRS prolongation
    2. PR prolongation or higher degree heart block should be followed very closely
    3. Placement of a temporary pacemaker wire should be considered
    4. Echocardiography should be used to evaluate a possible abscess affecting conduction
  6. Echocardiography
    1. Transthoracic echocardiography (TTE) detects ~50% of vegetations
    2. Transesophageal (TEE) detects >90% of vegetations
    3. For diagnostic purposes, TEE use is cost effective if prior probability of endocarditis is 4-60% []
    4. Echocardiography is important to define extent of vegetation and its position
    5. In addition, echocardiography is used to evaluate the presence of cardiac abscess
    6. Cardiac abscess may occur and >85% are detected with TEE studies
    7. Echocardiography should be repeated when fevers recur or persist >7 days
    8. TEE is cost-effective for determining therapy duration for endocarditis in patients with catheter-associated S. aureus bacteremia [17]
    9. For patients with likelihood of endocarditis >60%, and who are unlikely to have a cardiac abscess, TEE is probably not necessary [18]
  7. Valve Involvement [1]
    1. Non-IVDA: Aortic 25-40%, Mitral 25-40%, Tricuspid ~5%, Aoric + Mitral 10-25%
    2. IVDA: Tricuspid 50-60%, Aortic 20-25%, Mitral ~15%, Pulmonic ~5%
  8. White cell scan (indium or gallium) may detect some lesions missed on echocardiogram

F. Duke Criteria for Endocarditis [1]navigator

  1. Definite Infective Endocarditis: Pathologic Criteria
    1. Microorganisms demonstrated by culture or histalogic examination in a vegetation, OR
    2. Microorganisms demonstrated in an embolic vegetation, OR
    3. Microorganisms demonstrated in an intracardiac abscess, OR
    4. Pathology showing vegetation or cardiac abscess present with active endocarditis
  2. Definite Infective Endocarditis: Clinical Criteria
    1. 2 Major criteria, OR
    2. 1 Major and 3 Minor criteria, OR
    3. 5 Minor criteria
  3. Rejected for Diagnosis of Endocarditis
    1. Firm alternate diagnosis for manifestations of endocarditis, OR
    2. Resolution of manifestations of endocarditis with antibiotic therapyfor <5 days, OR
    3. No pathologic evidence of infective endocarditis at surgery or autopsy, after antibiotic therapy for <5 days
  4. Possible Infective Endocarditis
    1. Findings consistent with, but falling short of, infective endocarditis
    2. Diagnosis is not rejected by criteria above
  5. Major Criteria
    1. Positive blood culture for infective endocarditis
    2. Evidence for endocardial involvement as seen on echocardiogram or at surgery/autopsy
    3. New valvular regurgitation (assess by echocardiography, NOT only by clinical exam)
  6. Minor Criteria
    1. Predisposing heart condition OR intravenous drug abuse
    2. Fever: temperature >100.3°F (>37.9°C)
    3. Vascular phenomena: septic emboli, arterial embolic diseaes, infarctions, others
    4. Immunologic phenomena: glomerulonephritis, rheumatoid factor, others
    5. Microbiologic evidence (not meeting major criteria) or serological evidence for infection
    6. Echocardiogram consistent with endocarditis but not meeting major criteria
  7. Utility of Duke Criteria
    1. Specificity 99%
    2. Negative predictive value 92%

G. Treatment for Common Endocarditis [1]navigator

  1. Appropriate organism coverage for 2-8 weeks for bacterial etiology
    1. Surveillance cultures should be done 5-10 days after starting therapy
    2. Appropriate therapy should be continued 4-6 weeks after cultures are negative
    3. Susceptibility testing (along with MIC determinations) is critical for these infections
    4. Antibiotics with potent killing (rather than cytostatic) activity should be used if possible
    5. Followup blood cultures 1-4 weeks after antibiotic therapy is stopped is recommended
    6. Serial CRP (ESR) determinations may be useful to predict complicated disease
    7. Anticoagulant therapy is not indicated for any patient with native valve endocarditis
    8. Anticoagulant therapy increases risk of cerebral hemorrhage or cerebral abscess
    9. Surgical vegetation resection and valve replacement may be required in severe disease
  2. Treatment options for: S. viridans and S. bovis
    1. Penicillin G (12-18 MU/24 hours iv) x 4 weeks OR
    2. Ceftriaxone 2gm iv qd (may be given im) x 4 weeks OR
    3. Penicillin G + gentamicin sulfate 1mg/kg im or iv q8 hours x 2 weeks OR
    4. Vancomycin 15mg/kg q 12 hours to max 2gm/d (renal dosing) iv x 4 weeks
    5. The last two regimens may be used for organisms relatively reistant to penicillin
    6. Once daily dosing for gentamicin (~5mg/kg IV x1) may be used in many cases
  3. Treatment options for Enterococcus
    1. Penicillin G (18-30 MU/24 hour iv) + gentamicin 1mg/kg q 8 hours x 4-6 weeks OR
    2. Ampicillin (12gm/24 hour iv) + gentamicin 1mg/kg q 8 hours x 4-6 weeks OR
    3. Vancomycin 15mg/kg q12 hours to max 2gm/d + gentamicin 1mg/kg q 8 hours x 4-6 wks
    4. Aminoglycosides are required for effective eradication of enterococcal infections
    5. Increasing high-level aminoglycoside resistance (HLAR) reduces efficacy of aminoglycosides
    6. In HLAR E. faecalis endocarditis, high dose ampicillin (2gm q4 hours) and ceftriaxone (2gm q12 hours) IV for 6 weeks showed reasonable efficacy [15]
    7. Vancomycin resistant enterococci are increasing
    8. Newer anti-enterococcal agents may be effective
    9. Antimicrobial testing is required
    10. May need surgical therapy for resistant enterococcus
  4. Native Valve Staphylococcal Endocarditis
    1. Nafcillin (Oxacillin) 2gm q4 hours iv x 4-6 wks ± gentamicin 1-2mg/kg q8 hrs for 5d OR
    2. Cefazolin 2gm q8 hours iv x 4-6 weeks ± gentamicin 1mg/kg q8 hrs for 5 days OR
    3. Vancomycin 15mg/kg q12 hours to max 2gm/d ± gentamicin 1mg/kg q 8 h for 5d
    4. Vancomycin for methicillin resistant Staph (MRSA)
    5. Daptomycin (Cubicin®) 6mg IV qd is as effective with fewer adverse effects compared with low-dose gentamicin+antistaphylococcal penicillin or vancomycin [13]
    6. In general, gentamicin can be used in serious infections (rapidly clears bacteremia)
    7. Two weeks Nafcillin+Gentamicin for sensitive S. aureus in IVDA with uncomplicated right sided endocarditis is effective
    8. In right sided endocarditis (IVDA), ciprofloxacin 750mg po bid and rifampin 300mg po bid is as effective and better tolerated than intravenous treatment
    9. TEE should be used to guide therapy duration in catheter-related endocarditis [17]
  5. Staphylococci in Patients with Prosthetic Material
    1. Vancomycin as above + rifampin 300mg q8 hr po (>6wk) + gentamicin as above for 2 wk
    2. OR: Nafcillin, oxacillin, or cefazolin as above and rifampin and gentamicin as above
    3. Rifampin + ciprofloxacin for 3-6 months cleared Staph in orthopedic implants
  6. Treatment options for HACEK Endocarditis
    1. Ceftriaxone 2gm qd iv or im x 4 weeks (or other 3rd generation cephalosporin) OR
    2. Ampicillin 12gm / 24 hours + gentamicin 1mg/kg q8 hours x 4 weeks
  7. Other Culture Negative Endocarditis (Table 2, Ref [1])
    1. Diagnostic methods in addition to culture are often required, often on surgical specimens
    2. Polymerase chain reaction (PCR) or immunohistochemistry (IHC) often used
    3. Brucella: doxycyline plus rifampin or TMP/SMX for >3 months
    4. Coxiella burnetti: doxycycline plus hydroxychloroquine or quinolone for >18 months
    5. Bartonella: ß-lactam or doxycycline plus aminoglycoside for >6 weeks
    6. Chlamydia: doxycycline or newer fluoroquinolone, unknown duration
    7. Mycoplasma: doxycycline or newer fluoroquinolone for >3 months
    8. Legionella: macrolides plus rifampin or newer fluoroquinolone for >6 months
    9. Tropheryma whippelii: TMP/SMX or ß-lactam plus aminoglycoside for long term
  8. Indications for Surgical Intervention
    1. Fungal endocarditis
    2. Valve decompensation or prosthetic heart valve infection
    3. Congestive Heart Failure (CHF)
    4. Conduction system involvement
    5. Persistent bacteremia or cardiac abscess [19]
    6. Systemic Embolization
    7. Surgery for complicated left-sided native endocarditis has improved 6-month mortality than medical therapy alone: 15% mortality with surgery versus 28% [22]

H. Complications [9]navigator

  1. Acute and subacute valvular insufficiency
  2. Arrhythmias - especially heart block
  3. Renal Insufficiency
  4. Malaise, fatigue, weight loss
  5. Establishment of septic foci with progression to abscess
  6. Severe disease may be fatal despite antibiotic therapy
  7. Failure of CRP to decrease during therapy suggests complications

I. Prophylaxis Against Endocarditis [23,24] navigator

  1. Prophylaxis recommendations have been reduced significantly
  2. Recommended
    1. Dental procedures - only in patients with only high risk cardiac conditions
    2. Tonsillectomy or adenoidectomy
    3. Rigid bronchoscopy
    4. Surgery involving GI or upper respiratory mucosa
    5. Esophageal sclerotherapy and dilatation
    6. Gallbladder surgery
    7. Incision and drainage of infected tissues
    8. Vaginal delivery with infection present
  3. Not recommended
    1. Genitourinary or gastrointestinal procedures
    2. Intraoral injection of local anesthetic
    3. Shedding of primary teeth
    4. Tympanostomy-tube insertion
    5. Endotracheal tube insertion
    6. Bronchoscopy with flexible bronchoscope
    7. Cardiac catheterization
    8. Cesarean Section
  4. High Risk Cardiac Patients
    1. Should generally receive prophylaxis, particularly with dental conditions
    2. Previous bacterial endocarditis
    3. Prosthetic heart values
    4. Unrepaired cyanotic congenital heart disease such as tetralogy of Fallot
    5. Surgically constructed palliative shunts or conduits
    6. Within 6 months of crrection of congenital heart defects with prosthetic material / device
    7. Congential heart defect with residual defect or adjacent to prosthetic patch or device
    8. Cardiac valvulopathy after cardiac transplant
  5. Antibiotics
    1. Amoxicillin 2gm po (pediatric 50mg/kg) 1/2-1 hour before procedure
    2. Penicillin allergy: cephalexin, clindamycin, or azithromycin or clarithromycin
    3. Parenteral: ampicillin or cefazolin or ceftriaxone or clindamycin
    4. An aminoglycoside can be added in very high risk patients
  6. Efficacy
    1. Prevention may be in range of 50-90% although studies were not randomized
    2. Recommendations are mainly based on American Heart Association Expert Panels
    3. Use of platelet inhibitors, fibrin blockers, and other agents is under investigation

References navigator

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  12. Costenbader KH, Fidias P, Gilman MD, et al. 2006. NEJM. 355(12):1263 (Case Record) abstract
  13. Fowler VG Jr, Boucher HW, Corey GR, et al. 2006. NEJM. 355(7):653 abstract
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  15. Gavalda J, Len O, Miro JM, et al. 2007. Ann Intern Med. 146(8):574 abstract
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  17. Rosen AB, Fowler BG Jr, Corey GR, et al. 1999. Ann Intern Med. 130(10:810 abstract
  18. Heidenreich PA, Masoudi FA, Maini B, et al. 1999. Am J Med. 107(3):198 abstract
  19. Karchmer AW, Torchiana DF, Chae CU, et al. 2004. NEJM. 351(12):1240 (Case Record) abstract
  20. Biddinger PD, Isselbacher EM, Fan D, Shepard JO. 2005. NEJM. 352(7):709 (Case Record) abstract
  21. Darouiche RO. 2004. NEJM. 350(14):1422 abstract
  22. Vikram HR, Buenconsejo J, Hasbun R, Quagliarello VJ. 2003. JAMA. 290(24):3207 abstract
  23. Endocarditis Prophylaxis. 2007. Med Let. 49(1275):99
  24. Wilson W, Taubert KA, Gewitz M, et al. 2007. Circulation. 116:1736 abstract
  25. Raoult D, Abbara S, Jassal DS, Kradin RL. 2007. NEJM. 356(7):715 (Case Record) abstract