Acute Rheumatic Fever (ARF)

Definition and Overview

• Rheumatology, 2-Volume Set (2022, Elsevier), p. 1045

Pathobiology / Mechanism

• The GABHS M-protein is the key virulence factor. It binds Fc portions of IgG/IgA to evade phagocytosis.
• Similarities between streptococcal proteins and human tissue antigens lead to cross-reactive antibodies and T cells targeting host tissues.
• Carditis: antibody binding + T-cell infiltration of the heart
• Arthritis: immune complex deposition in joints (sterile synovial fluid with lymphocyte predominance)
• Chorea: antibody binding to basal ganglia
• Skin manifestations (erythema marginatum, subcutaneous nodules): delayed hypersensitivity reactions

• Goldman-Cecil Medicine, p. 3042-3043

Clinical Manifestations

Carditis (Most Serious Feature)

Arthritis

Sydenham Chorea (St. Vitus Dance)

Erythema Marginatum

Subcutaneous Nodules

Diagnosis: Revised Jones Criteria (2015 AHA Update)

• Low-risk: ARF incidence <2 per 100,000 school-aged children per year OR all-age RHD prevalence ≤1 per 1000 per year
• Moderate/High-risk: higher incidence populations

Diagnosis requires:

• Initial ARF: 2 major criteria, OR 1 major + 2 minor criteria
• Recurrent ARF: 2 major, OR 1 major + 2 minor, OR 3 minor criteria
• Plus evidence of antecedent GABHS infection (throat culture, rising ASO/anti-DNase B titers, or history of scarlet fever)

Major Criteria

Minor Criteria

• Goldman-Cecil Medicine, Table 269-3; Tintinalli's Emergency Medicine

Laboratory Findings

• Elevated ESR and CRP
• Normochromic, normocytic anemia
• Leukocytosis
• Elevated antistreptolysin O (ASO) titers - rising or high titres confirm recent GABHS infection
• ECG: prolonged PR interval
• Echo: recommended to detect subclinical carditis

Treatment

1. Eradication of GABHS

• Benzathine penicillin G IM: 600,000 units if <27 kg; 1.2 million units if >27 kg (single dose)
• Oral penicillin V or amoxicillin x 10 days as alternative
• Erythromycin for penicillin-allergic patients

2. Anti-inflammatory Therapy

• Aspirin: 80-100 mg/kg/day in divided doses (max 4-8 g/day) - traditional first line
• Naproxen: 10-20 mg/kg/day divided twice daily - used successfully in small studies
• Continue NSAIDs for 1-2 weeks until all symptoms resolve (not just joint symptoms)

• Treat associated heart failure with diuretics, angiotensin receptor blockers, fluid restriction, and bed rest
• Systemic glucocorticoids in severe cases (high-quality evidence lacking)
• Valve surgery rarely needed acutely; reserved for acute valve leaflet rupture

• Usually requires no specific treatment
• Resolves within weeks to months

3. Bed Rest / Hospitalization

Secondary Prophylaxis (Crucial for Prevention of RHD)

• Benzathine penicillin G 1.2 million units IM every 4 weeks (most effective)

• Oral penicillin V 250 mg twice daily
• Oral azithromycin 250 mg daily (for penicillin-allergic patients)

• Minimum 10 years from last attack, or until age 21 (whichever is longer)
• With carditis but no residual RHD: 10 years or until age 21
• With residual RHD (mild): 10 years or until age 25
• With severe RHD / post-valve surgery: lifelong prophylaxis

Rheumatic Heart Disease (Long-term Sequela)

• Affects the mitral valve nearly 100% of the time
• Aortic valve involved in 20-30%
• Tricuspid valve: histologic disease in 15-40% but rarely clinically significant
• Pulmonic valve: rarely involved
• Mitral regurgitation is most common acute finding; mitral stenosis develops after progressive scarring and is the most common cause of mitral stenosis worldwide
• Peak prevalence in 3rd and 4th decades of life
• RHD is the most common cause of acquired valvular disease globally and leading cause of cardiac surgery in children in LMICs

Key Points Summary

• Sources: Goldman-Cecil Medicine; Tintinalli's Emergency Medicine; Rheumatology 2-Volume Set (Elsevier, 2022)

Management of Acute Rheumatic Fever - Harrison's 22E (2025)

"There is no treatment for ARF that has been proven to alter the likelihood of developing, or the severity of, RHD. With the exception of treatment of heart failure, which may be lifesaving in cases of severe carditis, the treatment of ARF is symptomatic."

• Harrison's Principles of Internal Medicine, 22E, p. 2900

Initial Assessment (Investigations - Table 371-3)

• Electrocardiogram (ECG)
• Echocardiogram (all possible ARF cases - to confirm diagnosis and establish baseline severity of carditis)
• Complete Blood Count (CBC)
• CRP
• Streptococcal serology (ASO and anti-DNase B)

• Throat swab / skin sore swab
• Blood cultures
• Synovial fluid aspirate (cell count, microscopy, culture, gonococcal PCR)
• Pregnancy test
• Creatinine/UEC (NSAIDs can affect renal function)

• Autoantibodies, dsDNA, anti-CCP
• Urine for N. gonorrhoeae and C. trachomatis
• Serology for viral hepatitis, Yersinia, CMV, parvovirus B19, respiratory viruses

1. Antibiotics (Eradication of Group A Streptococcus)

2. Salicylates and NSAIDs (Arthritis, Arthralgia, Fever)

• Used once the diagnosis is confirmed
• Not of proven value for carditis or chorea

Aspirin (traditional first-line)

• 50-60 mg/kg/day, up to a maximum of 80-100 mg/kg/day (4-8 g/day in adults) in 4-5 divided doses
• Monitor for salicylate toxicity: nausea, vomiting, tinnitus - reduce dose if present

Naproxen (now preferred by many clinicians)

• 10-20 mg/kg/day in twice-daily doses
• Safer than aspirin (fewer GI side effects, no risk of Reye syndrome), with the advantage of twice-daily dosing

Duration and tapering:

• When acute symptoms substantially resolve (usually within first 2 weeks), reduce dose
• Continue at lower dose for a further 2-4 weeks
• Fever, joint symptoms, and elevated acute-phase reactants may rebound up to 3 weeks after stopping - this is not a recurrence and can be managed by briefly recommencing anti-inflammatory agents

3. Carditis and Congestive Heart Failure

Glucocorticoids (Controversial)

• Two meta-analyses have failed to show benefit of glucocorticoids over placebo or salicylates for short- or long-term carditis outcomes
• However, those studies are >40 years old and used older agents
• Recent data suggest corticosteroids improve laboratory, radiologic, and echocardiographic parameters
• Many clinicians treat severe carditis causing heart failure with glucocorticoids to reduce acute inflammation and hasten resolution of failure
• If used: Prednisone or prednisolone 1-2 mg/kg/day (max 80 mg/day), usually for a few days up to a maximum of 3 weeks

Heart Failure Management

• Standard heart failure therapy per guidelines (diuretics, ACE inhibitors/ARBs, fluid restriction)

4. Bed Rest

• Long-term bed rest (once the cornerstone of management) is no longer widely recommended
• Bed rest as needed while arthritis/arthralgia are present and in patients with heart failure
• Once symptoms are well controlled, gradual mobilization as tolerated

5. Chorea (Sydenham Chorea)

• Medications do not alter the duration or outcome of chorea
• Mild cases: managed by providing a calm environment
• Severe chorea - pharmacological options:
  • Carbamazepine or sodium valproate are preferred over haloperidol
  • Response may not be seen for 1-2 weeks
  • Medication should be continued for 1-2 months (or as long as symptoms persist)
• Chorea resolves spontaneously within weeks to months

6. Secondary Prophylaxis

• Benzathine penicillin G 1.2 million units IM every 3-4 weeks

6. Other Measures

• ARF Registry: enroll all confirmed cases
• Health education: patient and family counseling on the importance of prophylaxis and seeking early treatment of sore throats
• Close follow-up: to confirm diagnosis, manage symptoms, and commence preventive measures

Key Harrison's principle: Symptomatic treatment only - no proven disease-modifying therapy exists. The focus is on GABHS eradication, symptom relief, and preventing recurrence via long-term secondary prophylaxis.

Heart Failure - Management per Harrison's 22E (2025)

Classification Used

1. HFrEF - Heart Failure with Reduced Ejection Fraction (EF ≤40%)
2. HFpEF - Heart Failure with Preserved Ejection Fraction (EF ≥50%)
3. ADHF - Acute Decompensated Heart Failure

A. CHRONIC HFrEF - Pharmacological Management

The Four Pillars (Disease-Modifying Therapy)

1. RAAS Blockade: ACEi / ARB / ARNI

• Both ACEi and ARBs recommended for all HFrEF patients regardless of symptom burden
• Titrate to maximum tolerated dose - outcomes are dose-dependent (ATLAS, HEAAL trials)
• Inability to titrate = poor prognostic marker; may signal advanced HF

2. Beta-Blockers

• Addition to ACEi/ARB gives a further 35% reduction in mortality
• Only three agents proven to improve survival - restrict use to:
  • Carvedilol
  • Bisoprolol
  • Metoprolol succinate (extended-release)
• Agents with intrinsic sympathomimetic activity (xamoterol, bucindolol) - no survival benefit
• Sequence: Does not matter whether beta-blocker or ACEi started first (CIBIS III trial) - what matters is that both reach optimally titrated doses in a timely manner

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone (RALES trial), Eplerenone (EPHESUS/EMPHASIS trials)
• Indicated in NYHA class II-IV on background ACEi/ARB + beta-blocker
• Benefits: further reduction in morbidity and mortality; antagonize aldosterone-driven sodium retention, fibrosis, and endothelial dysfunction
• Monitoring essential: serum potassium and renal function (risk of hyperkalemia, especially in CKD)

4. SGLT-2 Inhibitors

• Newest pillar of HFrEF therapy
• Dapagliflozin (DAPA-HF) and Empagliflozin (EMPEROR-Reduced)
• Reduce HF hospitalizations, cardiovascular death, and progressive renal decline
• Effective regardless of diabetes status

5. Diuretics (Symptomatic Relief)

• Loop diuretics (furosemide, torsemide, bumetanide) - first-line for volume overload
• Do not reduce mortality but essential for symptom control (dyspnea, edema)
• Thiazides can be added for diuretic resistance

6. Digoxin

• Reduces HF hospitalizations but no mortality benefit (DIG trial)
• Reserved for symptomatic patients in sinus rhythm despite optimized neurohormonal therapy, or for rate control in atrial fibrillation
• Narrow therapeutic index; maintain serum level 0.5-0.9 ng/mL

7. Ivabradine

• Selective I-f channel inhibitor (reduces heart rate)
• Indicated in patients in sinus rhythm with resting HR ≥70 bpm despite maximally tolerated beta-blocker + ACEi/ARB, NYHA II-III
• SHIFT trial: reduced composite of CV death and HF hospitalization

8. Hydralazine + Isosorbide Dinitrate

• V-HeFT II: inferior to enalapril
• Useful in patients intolerant to both ACEi and ARBs (e.g., bilateral renal artery stenosis, severe renal failure)
• Particularly beneficial in Black patients (A-HeFT trial)

Anticoagulation

• Atrial fibrillation + HFrEF: oral anticoagulation indicated
• Sinus rhythm: no benefit shown (WARCEF trial - warfarin vs. aspirin: no difference in primary outcome; ischemic stroke reduction with warfarin offset by major bleeding)
• Rivaroxaban at low dose in sinus rhythm: no benefit (recent trial)
• Aspirin supported in ischemic cardiomyopathy without contraindications, but benefit-risk less clear in elderly

Other Agents

• Omega-3 fatty acids (PUFA): modest clinical benefit in HFrEF (GISSI-HF trial)
• Thiamine: small studies suggest benefit in HFrEF with deficiency; routine supplementation not yet recommended

B. DEVICE THERAPY IN HFrEF

Cardiac Resynchronization Therapy (CRT)

• Indicated for NYHA class II-IV with LVEF ≤35% and QRS ≥150 ms (LBBB morphology)
• Reduces mortality, HF hospitalizations, and improves symptoms and exercise tolerance

Implantable Cardioverter-Defibrillator (ICD)

• SCD accounts for ~50% of HF deaths, proportionally highest in early/milder HFrEF
• Primary prevention indications:
  • NYHA class II-III + LVEF <35% (any etiology) on optimal medical therapy for ≥3 months
  • Post-MI + LVEF ≤30% (even if asymptomatic)
  • No benefit within 40 days of an MI
• Recent Danish trial: prophylactic ICD in non-ischemic systolic HF - no significant mortality reduction overall; benefit in patients <60 years old
• Not appropriate: NYHA class IV refractory HF not candidates for transplant; terminal illness with life expectancy <6 months

C. ACUTE DECOMPENSATED HEART FAILURE (ADHF)

Step 1: Identify and Treat Precipitating Factors

• Non-adherence to medications or salt/fluid restriction
• Offending medications: NSAIDs, thiazolidinediones, TNF inhibitors, selected antidepressants, some cancer therapies, herbal preparations
• Coronary ischemia - investigate in all at-risk patients (invasive or non-invasive)
• Arrhythmias - may require antiarrhythmics, cardioversion, or catheter ablation
• Valvular heart disease - assess by echo
• Infection, pulmonary embolism

Step 2: Phenotype-Based Management (Figure 265-2)

Vasopressor/Inotrope/Vasodilator Therapy Table

Pulmonary Artery Catheter

• Low-output HF or cardiogenic shock requiring vasopressor/MCS
• Diuretic resistance
• Combined cardiorenal dysfunction where goals are unclear
• Suspected pulmonary arterial hypertension

Poor Prognosis Markers in ADHF (Registry Data):

• BUN >43 mg/dL
• Systolic BP <115 mmHg
• Creatinine >2.75 mg/dL
• Elevated natriuretic peptides (BNP/NT-proBNP) and troponins

D. SURGICAL THERAPY IN HFrEF

Coronary Artery Bypass Grafting (CABG)

• For ischemic cardiomyopathy with multivessel CAD + viable/hibernating myocardium
• STICH trial (EF ≤35%): CABG had lower cardiovascular deaths and combined CV events at 10 years vs. medical therapy alone (no significant early benefit)
• Revascularization most robustly supported when angina + LV failure coexist
• Revascularization for LV failure without angina: remains controversial
• Viability testing (hibernation) before CABG did not independently predict outcomes (STICH ancillary)

Cardiac Transplantation

• For end-stage HF refractory to all medical and device therapy
• Limited by donor availability

Ventricular Assist Devices (VADs)

• Bridge to transplantation or destination therapy in advanced HFrEF

E. HFpEF Management

• No therapies proven to reduce mortality in HFpEF
• SGLT-2 inhibitors (empagliflozin - EMPEROR-Preserved; dapagliflozin - DELIVER trial): reduce HF hospitalizations - current best evidence
• Management focuses on:
  • Treating underlying causes (hypertension, AF, obesity, diabetes)
  • Diuretics for volume overload and symptom relief
  • Rate control in AF

F. Exercise and Cardiac Rehabilitation

• Supervised exercise training is safe and beneficial in stable chronic HFrEF
• HF-ACTION trial: exercise training improved QOL and reduced HF hospitalizations
• Prescribe for all stable, ambulatory HFrEF patients

Summary: Drug Titration Principle (Harrison's 22E)

"In the absence of symptoms to suggest hypotension (fatigue and dizziness), pharmacotherapy may be uptitrated every 2 weeks in stable ambulatory patients as tolerated."