Rheumatic FeverRheumatic Fever

Agnes Therese A. Bravo

MD – III

Rheumatic FeverRheumatic Fever

• is an inflammatory disease which may develop after a Group A streptococcal infection (such as strep throat or scarlet fever)

Factors predispose to the Factors predispose to the development of RFdevelopment of RF

• site of infection

• antibody response

• age

• familial tendency

EpidemiologyEpidemiology

• ARF is identical to that of group A streptococcal upper respiratory tract infections (as in the case for streptococcal sore throat)

• ARF most often occurs in children– the peak age-related incidence is between 5 and 15

years.

• initial attacks in adults take place at the end of the second and beginning of the third decades of life.

(a) Infection of the throat with Streptococcus pyogenes results in presentation of streptococcal antigens by antigen-presenting cells such as macrophages, and priming of B cells and CD4+ T cells to produce a humoral and cell-mediated response against streptoccal antigens.

(b) Some antibodies are capable of cross-recognition of heart proteins, facilitating cellular infiltration of CD4+ T cells recognising heart-tissue proteins by molecular mimicry, triggering heart lesions.

(c) In the valvular tissue, the deposition of cross reactive antibodies increases the expression of VCAM-1, which interacts with VLA-4 expressed on the surface of T cells and facilitates cellular infiltration. Inflammatory cytokines such as TNF- and IFN- mediate the development of the lesions, and the low numbers of IL-4-producing cells contribute to the progression and maintenance of valvular lesions.

Major events triggering Rheumatic Heart Disease lesion

PathoPathogenesisgenesis

group A ß hemolytic strep organism (pharynx and tonsils)

development of ARF

direct infection by the group A

streptococcus

toxic effect of streptococcal extracellular products on

the host tissues

abnormal or dysfunctional

immune response to one or more

HHypothesis of ypothesis of AAntigenic mimicryntigenic mimicry

• similarity between the group-specific carbohydrate of the group A streptococcus and the glycoprotein of heart valves

• involves the molecular similarity among the streptococcal cell membrane, streptococcal M protein sarcolemma, and other moieties of the human myocardial cell.

PathogenesisPathogenesis

• tissue-specific antigens and major histocompatibility antigens in an attempt to define the pathogenesis.

• group A streptococcal upper respiratory tract infection results from an abnormal immune response by the human host.

PathologyPathology

• represent both exudative and proliferative reaction

• Aschoff body – typical RF lesion– fibrinoid degeneration and granulomatous inflammation,

seen specifically in myocardium

• verrucae lesion – blood cells and fibrin along the borders of the valves

– when verrucae disappears after active infection scar tissue formation occur.

Clinical ManifestationClinical Manifestation

Clinical CourseClinical Course

• Acute rheumatic attack • self limited course and improved in 1–2 months

• Chronic rheumatic disease• start as acute attack but longer in duration

• Subclinical course of RF• insidous onset with vague, nonspecific

Jones CriteriaJones Criteria

Major criteria

• Carditis: inflammation of the heart muscle which can manifest as congestive heart failure with shortness of breath, pericarditis with a rub, or a new heart murmur.

• Migratory polyarthritis: a temporary migrating inflammation of the large joints, usually starting in the legs and migrating upwards.

• Sydenham's chorea (St. Vitus' dance): a characteristic series of rapid movements without purpose of the face and arms. This can occur very late in the disease.

Major Criteria

• Erythema marginatum: a long lasting rash that begins on the trunk or arms as macules and spread outward to form a snakelike ring while clearing in the middle. This rash never starts on the face and is made worse with heat.

• Subcutaneous nodules (a form of Aschoff bodies): painless, firm collections of collagen fibers on the back of the wrist, the outside elbow, and the front of the knees. These now occur infrequently.

Minor criteria

• Fever: temperature elevation

• Arthralgia: Joint pain without swelling

• Laboratory abnormalities: increased Erythrocyte sedimentation rate, increased C reactive protein, leukocytosis

• Electrocardiogram abnormalities: a prolonged PR interval

Minor criteria

• Evidence of Group A Strep infection: positive culture for Group A Strep, elevated or rising Antistreptolysin O titer

• Previous rheumatic fever or inactive heart disease

To fulfill the Jones criteria:To fulfill the Jones criteria:

• either two major criteria, or one major criterion and two minor criteria, plus evidence of an antecedent streptococcal infection are required.

TreatmentTreatment

• two necessary therapeutic approaches – anti-streptococcal antibiotic therapy – therapy for the clinical manifestations of

the disease

Conventional antibiotic Conventional antibiotic treatmenttreatment

• started immediately: – complete 10-day course in adults of either oral

penicillin V (500 mg BID)– erythromycin (250 mg QID) for those with penicillin

allergy. • Many choose intramuscular benzathine penicillin G (a

single intramuscular injection of 1.2 million units) for the treatment of the presumed streptococcal infection; this will also serve as the first dose of secondary prophylaxis for the prevention of recolonization of the upper respiratory tract in the future. Intramuscular benzathine penicillin G has been reported to result in a transient elevation of the erythrocyte sedimentation rate, which can prove confusing in the acute phase of the disease.

Recommendations of the American Heart Recommendations of the American Heart Association and of the World Health Association and of the World Health

OrganizationOrganization

• intramuscular injection of 1.2 million units of benzathine penicillin G every 4 weeks or for oral penicillin V (250 mg twice daily) or oral sulfadiazine (1.0 g daily)

• High risk for recurrence of RF, intramuscular benzathine penicillin G given every 3 weeks is more effective in reducing the risk of recurrence

• Risk of recurrence of RF is highest during the first 5 years after the attack, secondary prophylaxis is always given for at least this period

TreatmentTreatment

• Medical therapy for the manifestations of RF depends on the clinical status of the patient.

• For adult patients with arthritis, salicylates in doses escalating to 2 g QID – very effective and marked clinical

improvement within 12 h.

TreatmentTreatment

• Salicylates may be given for 4 to 6 weeks – gradually tapered to prevent a rebound. – ESR, method use for determining the rate of taper

for salicylates– Usually this requires at least 2 weeks.

• No conclusive data to support using nonsteroidal anti-inflammatory drugs for ARF.

• No indication for the use of steroids (usually prednisone) solely for the treatment of the arthritis of RF.

Infective EndocarditisInfective Endocarditis

DefinitionDefinition

• inflammation of the endocardium• Implies bacterial presence in the lesion• Can be within septal defects or mural

endocardium

Classification– Native Valve Endocarditis– Prosthetic Valve Endocarditis (PVE)– Endocarditis due to intravenous drug abuse (IVDA)

• “Infective Endocarditis” vs “Bacterial Endocarditis”– SBE– ABE

DefinitionDefinition

• Acute Bacterial Endocarditis (ABE):– Fulminating infection– High fever– Systemic toxicity– Death in < 6 weeks

• Subacute Bacterial Endocarditis (SBE):– Indolent infection– Prior to valvular disease– Death in 6 weeks – 3 months

• “Left-sided” endocarditis– Mitral valve

DefinitionDefinition

• “Right-sided” endocarditis– Involvement of the tricuspid valve– Related to IVDA and indwelling pacemakers

• “Native-valve” endocarditis• “Prosthetic-valve” endocarditis• “Culture-Negative” endocarditis

– Fastidious isolate– Non-bacterial culprit– Antibiotics administration pre-culture

EpidemiologyEpidemiology

• Less than 5 cases per 100,000– Approximately 1 case per 1000 admissions– Unchanged for 30 years

• Greater than 50% patients over age 50– Unusual in children

• Overall mortality 16-27%– Age– Aortic valve involvement– CHF– CNS complications

EpidemiologyEpidemiology

• > 75% IE patients have evidence of endocarditis risk factors– History of IV drug abuse– History of rheumatic heart disease– Congenital heart disease or malformations– Mitral valve prolapse or valvular insufficiency– Ventral septal defect– Valvular stenosis– Prosthetic valve

EtiologyEtiology

Percentage of cases• Streptococci 60-80• Viridans streptococci 30-40• Enterococci 5-18• Other streptococci 15-25• Staphylococci 20-35• Coagulase-positive 10-27• Coagulase-negative 1-3• Gram-negative aerobic bacilli 1.5-13• Fungi 2-4• Miscellaneous bacteria <5• Mixed infections 1-2• Culture-negative <5-24

Pathophysiology

•Surface Alteration

•Non-Bacterial Thrombotic Embolism–Fibrin/Platelet deposition

•Bacterial attachment–Transient bacteremia

•Sheath covering–Fibrin/Platelets–Protective environment–Vegetation growth

◦109-1010 org per gram of tissue◦Valvular tissue destruction

Major CriteriaMajor Criteria

1. Positive blood culture

Typical microorganism for infective endocarditis from two separate blood cultures

- Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus

- Community-acquired enterococci in the absence of a primary focus

Persistently positive blood culture, defined as recovery of a

microorganism consistent with infective endocarditis from:- Blood cultures drawn >12 h apart; or- All of three or a majority of four or more separate blood cultures,

with first and last drawn at least 1 h apart- Single positive blood culture for Coxiella burnetii or phase I IgG

antibody titer of >1:800

Major CriteriaMajor Criteria

2. Evidence of endocardial involvementPositive echocardiogram– Oscillating intracardiac mass on valve supporting

structures or in the path of regurgitant jets or in implanted material, in the absence of an alternative anatomic explanation

– Abscess– New partial dehiscence of prosthetic valve– New valvular regurgitation (increase or change in

preexisting murmur not sufficient)

Minor CriteriaMinor Criteria

1. Predisposition: predisposing heart condition or injection drug use

2. Fever >38.0ºC (>100.4ºF)3. Vascular phenomena: major arterial emboli, septic

pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions

4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, rheumatoid factor

5. Microbiologic evidence: positive blood culture but not meeting major criterion as noted previouslya or serologic evidence of active infection with organism consistent with infective endocarditis

Clinical ManifestationsClinical Manifestations

Clinical Presentation

• Fever• Anorexia and weight loss• Malaise/weakness• Chills• Diaphoresis• Dyspnea• Cough• Focal neurologic complaints (20% cases)

Physical FindingsPhysical Findings

• Low grade fever • Cardiac examination

– Murmur– Change in murmur

• Peripheral manifestations (Classic symptoms)– Petechiae – Osler’s nodes– Splinter hemorrhages– Janeway lesions – Roth’s spots

Laboratory manifestationsLaboratory manifestations

• Hematologic– Often abnormal but not diagnostic– Anemia/pancytopenias– ESR / CRP– Rh-factor / circulating immune complexes

• Blood culture– Single most important lab test– Continuous / low grade bacteremia– Minimum of 3 sets (different sites) in first 24 h– May require >3 if previous abx administered– Hold Cultures for 3 weeks

Non-Blood-Culture Tests for Non-Blood-Culture Tests for the Etiologic Agentthe Etiologic Agent

Pathogen in vegetation can be identified by:• Culture• Microscopic exam with special stains (periodic

acid–Schiff stain for T. whipplei)• PCR to recover unique microbial DNA or 16S

rRNA• Serologic test is used to identify some

organisms causing endocarditis that are difficult to recover by blood culture: – Brucella, Bartonella, Legionella, and C. burnetii.

Echocardiography

• Transthoracic echocardiography (TTE)– Rapid– Non-invasive– 98% specificity, 60 % sensitivity– Views obstructed by obesity, COPD, chest-wall– Deformities

• Transesophageal echocardiography (TEE)– Higher ultrasonic frequency– 88-100% specificity, 86-94% sensitivity

Note: Negative TTE or TEE do not rule out vegetative IE

Work upWork up

• CBC with differential, ESR– > 3 sets of blood cultures drawn at different sites

and times• EKG & Echo

– CXR + V/Q if R. sided involvement suspected• Antibiotic sensitivity studies if Blood culture

positive• Peak / trough serum inhibitory titer (SIT) &• serum bactericidal titer (SBT)• Physical for classic findings of endocarditis• Also consider: Rh-factor and serology

Septic emboli with hemorrhage and infarction due to acute Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus Staphylococcus aureus endocarditis. endocarditis. (Courtesy of L. Baden.)(Courtesy of L. Baden.)

Computed tomography of the abdomen showing large embolic infarcts Computed tomography of the abdomen showing large embolic infarcts in the spleen and left kidney of a patient with in the spleen and left kidney of a patient with Bartonella Bartonella endocarditis.endocarditis.

Vegetations (Vegetations (arrowsarrows) due to viridans streptococcal endocarditis ) due to viridans streptococcal endocarditis involving the mitral valve.involving the mitral valve.

General approach to General approach to treatmenttreatment

• High dose, prolonged therapy

• Bactericidal

• Bacteriostatic agents combination

Streptococci treatment

• PCN MIC < 0.1 mg/L:– PCN G or ceftriaxone 4 weeks each– PCN G + gent. 2 weeks each– Vancomycin 4 weeks

• Prosthetic valve: PCN G 4 weeks + AG 2 weeks– PCN MIC > 0.1 mg/L and < 0.5 mg/L– PCN G + gent 4 weeks and 2 weeks– Vancomycin 4 weeks– PCN MIC >0.5 mg/L

Therapy of Native Valve Endocarditis:Penicillin-Sensitive Streptococci

Antibiotic RegimenDuration

(wk)

Penicillin G 12-18 MU IV every 24 h 4

Ceftriaxone 2 g IV every 24 h 4

Ceftriaxone +Gentamicin

2 g IV every 24 h1 mg/kg IV every 8 h 2

Vancomycin 1 g IV every 12 h 4

MU=million units; IV=intravenous

Therapy of Native Valve Endocarditis for Penicillin-Insensitive Streptococcia or Enterococcib

Antibiotic Regimen Duration (wk)

Penicillin G     + gentamicin

3 MU IV every 4 h1 mg/kg IV/IM every 8 h

4-6c

2-6c

Vancomycin     + gentamicind

1 g IV every 12 h1 mg/kg IV/IM every 8 h

4-6c

4-6

MU=million units; IV=intravenous; IM=intramuscularDoes assume normal renal function.aMinimum inhibitory concentration=0.1-0.5 µg/mL.bMinimum inhibitory concentration >0.5 µg/mL. May want to clarify combo for entire course.cProlonged therapy for enterococci.dGentamicin with vancomycin only for enterococci.

Enterococci treatmentEnterococci treatment

• PCN G + gent. 4-6 weeks each• Ampicillin + gent. 4-6 weeks each• Vancomycin + gent. 4-6 weeks each

Prosthetic valve: 6 week treatmentPre-treatment infection > 3 months: 6 wk tx

Note: Gentamicin / Streptomycin resistance encoded by separate genes.

AG resistant isolate may require extended (8-12 week) β-lactam Tx.

Staphylococci treatment (no Staphylococci treatment (no prosthesis)prosthesis)

• Methicillin-susceptible Staphylococci– Nafcillin + gent. 4-6 weeks + 3-5 days– 1st gen ceph + gent. 4-6 weeks + 3-5

days– Vancomycin 4-6 weeks

• Methicillin-resistant Staphylococci– Vancomycin 4-6 weeks

Limited data suggesting IVDA with MSSA infecting R. sided valves canbe tx’d with 2-weeks β-lactam course effectively.

Staphylococci treatmentStaphylococci treatment(prosthesis present)(prosthesis present)

• Methicillin-susceptible Staphylococci

• Nafcillin + rifampin + gent. >6 weeks, 2 weeks for gent.

• Methicillin-resistant Staphylococci

• Vanco + rifampin + gent.>6 weeks, 2 weeks for gent.

Therapy of Prosthetic Valve Staphylococcal Endocarditis

Isolate Antibiotic RegimenDuration

(wk)

MSSA or MSSE

Oxacillin     + gentamicin     + rifampin

2 g IV every 4 h1 mg/kg IV/IM every 8 h300 mg PO every 8 h

>6First 2>6

MRSA or MRSE

Vancomycin     + gentamicin     + rifampin

1 g IV every 12 h1 mg/kg IV/IM every 8 h300 mg PO every 8 h

>6First 2>6

MRSA=methicillin-resistant Staphylococcus aureus; MRSE=methicillin-resistant Staphylococcus epidermidis; MSSA=methicillin-sensitive Staphylococcus aureus; MSSE=methicillin-sensitive Staphylococcus epidermidis; IV=intravenous; IM=intramuscular; PO=orally. Doses assume normal renal function.

HACEKHACEK

• Slow growing, fastidious gram-negatives likely not to result in positive culture (culture-negative)

– Haemophilus spp– Actinobacillus actinomycetemcomitans– Cardiobacterium hominis– Eikenella corrodens– Kingella kingae

• Concerns– Typically sub-acute– Large vegetations / common emboli

HACEK treatment

• Should be considered ampicillin resistant

• Both β-lactam producers and nonproducers are susceptible to 3rd generation cephalosporins

• Ceftriaxone sodium 4 weeks

• Amp + gent. 4 weeks each

Therapy of Endocarditis Due to HACEK Microorganisms

Antibiotic RegimenDuration

(wk)

Ceftriaxone 2 g IV every 24 h 4

Ampicillin     + gentamicin

2 g IV every 4 h1 mg/kg IV/IM every

8 h

44

HACEK = Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species of bacteria; IV=intravenous; IM=intramuscular

Surgical indicationsSurgical indications

Definite• Hemodynamically unstable

– New or worsening CHF– Valvular dysfunction

• Uncontrolled infection – + Blood cultures > 3 days– Fungal endocarditis– Perivalvular or myocardial abscess

• Eliminate primary site of infection

Surgical IndicationSurgical Indication

Relative• Vegetation >10mm• Recurrent systemic emboli (> 2)• Mitral valve preclosure• Ruptured chordae tendineae, papillary

muscle, ventricular septum• Heart block• Infection relapse

Antibiotic prophylaxisAntibiotic prophylaxis

• One hour prior to procedure:

– 2 Gm Amoxicillin orally or

– 600 mg Clindamycin orally or

– 2 Gm Cephalexin orally or

– 500 mg Clarithromycin orally or

– 2 Gm Ampicillin intramuscularly

Prevention of Bacterial Endocarditis: Diseases at Risk for Infective Endocarditis

High Risk Moderate Risk Negligible Risk

Prosthetic heart valves

Acquired valvular dysfunction

Isolated atrial septal defect

Previous bacterial endocarditis

Hypertrophic cardiomyopathy

Surgical repair of atrial septal defect, ventricular septal defect, or patient

ductus arteriosus

Complex cyanotic congenital heart

disease

Mitral valve prolapse with regurgitation

Previous coronary artery bypass grafting

Surgically constructed pulmonary shunts

   Mitral valve prolapse without regurgitation

     Cardiac pacemakers

Causes of DeathCauses of Death

• CHF

• Embolic phenomena

• Mycotic aneurysm rupture

• Complications from cardiovascular surgery

• PVE

• Inadequate response to antibiotics

SummarySummary

• Cardio/infectious diseases

• RF pathophysiology

• Streptococci, Staphylococci, Enterococci

• Vegetations lab, clinical, physical findings

• Empiric treatment (prolonged, high dose) tailored to native or prosthetic valve, or IVDA

• Definitive therapy for each pathogen