Rhematic Fever

• Delayed nonsuppurative sequalae of group A streptococcus pharyngeal infection

Pathophysiology:

• Need:
  • GAS Pharyngitis
    • Only 20-40% of pharyngitis episodes are associated with GAS infection
    • The remainder are caused by viruses or bacteria for which antibiotic treatment is not recommended
  • Genetic susceptibility
• Mechanism:
  • Molecular mimicry
  • GAStrep Pharyngitis induces a Type 3 hypersensitivity reaction
• Immune Response:
  • Antibodies against M protein of certain strains cross-react with glycoprotein antigens in the heart, joints, nerves, and other tissues
  • Only a minority of infected patients develop Rheumatic Fever (RF)
• Consequences of Recurrence:
  • Carditis:
    • Worsens with each recurrence; damage is cumulative
  • Embolization:
    • From mural thrombi
  • Infective Endocarditis:
    • Risk increases on deformed valves
  • Chronic Rheumatic Heart Disease:
    • Murmurs
    • Hypertrophy
    • Dilation
    • Heart failure
    • Arrhythmias

• Delay in Onset:
  • There is typically a 2-4 week delay between the initial streptococcal infection and the onset of RF due to the time required for the immune response to cause tissue damage.

High-Risk Groups for Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD):

1. Aboriginal People and Torres Strait Islanders:
   • Especially those living in rural or remote settings.
2. Children:
   • Predominantly seen in children aged 5–14 years.
   • Recurrent episodes can occur well into the 40s.
3. Epidemiology:
   • ARF incidence: >30/100,000 per year in 5–14 year olds.
   • RHD all-age prevalence: >2/1000.

High-Risk Groups for Rheumatic Fever:

1. Age: Most common in children aged 5 to 15 years.
2. Geographic Location: Higher incidence in developing countries and areas with poor access to healthcare.
3. Socioeconomic Factors: Poverty, overcrowding, and poor living conditions
4. History of Rheumatic Fever: Previous episode of rheumatic fever increases the risk of recurrent episodes, especially if prophylactic antibiotics are not taken.
5. Family History: Genetic predisposition may play a role. A family history of rheumatic fever can increase an individual’s risk.
6. Environmental Factors: Close contact with individuals who have GAS infections.Poor hygiene and lack of access to medical care for proper treatment of streptococcal infections.

Reasons for Increased Risk of Rheumatic Fever:

1. Age:
   • Immune System Development: Children aged 5 to 15 years are more susceptible to streptococcal infections due to the ongoing development of their immune systems.
2. Geographic Location:
   • Endemic Areas: In developing countries and specific endemic regions, healthcare infrastructure may be insufficient, leading to delayed or inadequate treatment of streptococcal infections.
   • Climate and Environmental Factors: In some regions, climatic conditions and environmental factors may facilitate the spread of streptococcal bacteria.
3. Socioeconomic Factors:
   • Poverty: Low-income families often face barriers to accessing timely and adequate healthcare.
   • Overcrowding: Crowded living conditions facilitate the transmission of infectious diseases, including GAS infections.
   • Nutrition: Poor nutrition can weaken the immune system, making individuals more susceptible to infections.
4. History of Rheumatic Fever:
   • Immune Response: Individuals with a previous episode of rheumatic fever have an altered immune response that makes them more susceptible to recurrence if exposed to GAS infections again.
   • Lack of Prophylaxis: Without regular prophylactic antibiotics, the risk of recurrence remains high.
5. Family History:
   • Genetic Predisposition: Genetic factors may predispose certain individuals to an exaggerated immune response to GAS infections, leading to rheumatic fever.
   • Shared Environment: Families living in close quarters may have shared environmental risk factors, such as exposure to the same strains of streptococcus.
6. Environmental Factors:
   • Hygiene Practices: Poor hygiene and sanitation facilitate the spread of GAS infections.
   • Access to Healthcare: Limited access to healthcare services means that infections are often untreated or inadequately treated, increasing the risk of complications.
7. Healthcare Infrastructure:
   • Availability of Medical Care: In regions with limited healthcare infrastructure, there may be a lack of medical professionals, medications, and diagnostic tools necessary for the timely treatment of streptococcal infections.
   • Public Health Initiatives: Lack of public health initiatives and awareness programs can result in delayed recognition and treatment of GAS infections.

History and Examination

Preceding Illness:

1. Symptoms:
   • Typically follows streptococcal pharyngeal infection.
   • Symptoms develop 2-4 weeks after infection.
2. Cultures:
   • Throat cultures may be taken to identify group A streptococcus.
3. Timing:
   • Symptoms appear 2-4 weeks post-infection.

Vital Signs:

1. Fever:
   • Low-grade fever.

Cardiovascular System (CVS):

1. Symptoms:
   • Chest pain or discomfort.
   • Dyspnea.
2. Signs:
   • New onset mitral regurgitation (MR) or other murmurs.
   • Pericardial rub.
   • Palpitations.
   • Heart failure.

Rheumatological:

1. Symptoms:
   • Pain more than clinical inflammation.
   • Migratory arthritis involving large joints, usually starting in the legs.
   • Each joint affected for < 1 week but often overlap.

Rash:

1. Erythema Marginatum:
   • Non-pruritic rash with pale centers on the trunk and proximal limbs.

Central Nervous System (CNS) – Sydenham Chorea:

1. Symptoms:
   • Abrupt, purposeless, nonrhythmic involuntary movements, worse on one side.
   • Muscular weakness (milking sign).
   • Emotional instability.

Dermatology:

1. Subcutaneous Nodules:
   • <2 cm, firm, painless nodules over bony surfaces or near tendons.
2. Erythema Annulare:
   • Non-pruritic rash with pale centers on the trunk and proximal limbs.

Differentials

• Septic arthritis (including gonococcal arthritis)/   osteomyelitis
• Reactive arthritis
• Viral arthritis (CMV, EBV, rubella vaccination, hepatitis)
• Rheumatic fever
• Juvenile idiopathic arthritis
• Rheumatoid arthritis, IBD, SLE, vasculitis,  sarcoidosis
• Haemarthrosis
• MSK injury/ trauma/ fall (perthes,  SUFE)
• Gout/ pseudogout
• Non-­accidental injury

Diagnosis & Investigations

• Currently, there is no diagnostic laboratory test for ARF, so diagnosis remains a clinical decision based on the identification of major and minor

Confirm Diagnosis using Jones’ Criteria

• Definite initial episode of ARF :
  • 2 major  Or
  • 1 major + 2 minor 

+  evidence of preceding GAS 

• Definite recurrent episode of ARF in a patient with known past ARF or RHD
  • 2 major   OR
  • 1 major and 1 minor  OR
  • 3 minor manifestations 

+ evidence of a preceding GAS infection 

5 major:

1. Carditis
2. Arthritis
   • High Risk Groups : Aseptic mono arthiritis
   • Low Risk Groups : Polyarthiritis
3. Chorea
4. Erythema marginatum
5. SC nodules

4 minor:

1. Arthritis
   1. High Risk Groups : Monoarthralgia
   2. Low Risk Groups : Polyarthralgia or aseptic monoarthritis
2. Fever
3. Elevated ESR/CRP
4. Prolonged PR interval on ECG

Evidence of preceding streptococcal infection:

• Positive throat culture for GA b-haemolytic strep or
• Positive rapid streptococcal antigen test or
• Elevated or risking streptococcal antibody titre (most often antistreptolysin O, others include anti-DNAse B, streptokinase, antihyaluronidase)

Investigations:

• Evidence of preceding streptococcal infection:
• All suspected cases of ARF (except those with chorea or low-grade subacute carditis) should have elevated serum streptococcal serology:
  • ASOT (Antistreptolysin O titer) + anti-DNase B titres
    • if available (repeat 10–14 days later if first test not confirmatory)
    • The false negatives rate is 20-30%, reduce false negative with anti-DNase B titre 
    • False positives can result from liver disease and tuberculosis.

• Rapid antigen test
  • Turnaround time of 1-3 hours
  • sensitivity of 86% and specificity of 96%
  •  cost only $5-$10 compared with $30 for throat cultures
  • But unfortunately DOES NOT attract an MBS rebate.
• Bloods – ESR/CRP, FBC (chronic anaemia)
• ECG (heart block)
• U/A (GN for CTD)
• Imaging:
  • Serial CXR (cardiomegaly due to carditis, monitor course)
  • Echo (acute carditis, valvular regurgitation/stenosis, chamber size and function, pericardial effusion)
• Tests for alternative diagnoses, depending on clinical features
  • Repeated blood cultures, if possible endocarditis
  • Joint aspirate (microscopy and culture) for possible septic arthritis
  • Copper, ceruloplasmin, antinuclear antibody, drug screen for choreiform movements
  • Serology and autoimmune markers for arboviral, autoimmune or reactive arthritis

Immediate Management

• Goals: symptomatic relief + eradication of GAS + prophylaxis

Symptomatic Relief:

1. Aspirin:
   • Children: 80-100 mg/kg/day
   • Adults: 4-8 g/day
   • Maintain until asymptomatic and ESR/CRP levels normalize.
2. Antihistamines:
   • For rash relief.
3. Cardiac Involvement:
   • Severe carditis may lead to cardiomegaly, CHF, 3rd degree heart block.
   • Treat as per acute pulmonary oedema (APO) protocols (e.g., Frusemide, ACE inhibitors).
   • Prednisone: 2 mg/kg/day PO for 1-2 weeks, then taper over 2 weeks.
   • Valve Surgery: Indicated for heart failure due to regurgitant lesions refractory to medical therapy. Repair is preferred over replacement.
4. Chorea:
   • Usually no treatment required.
   • If necessary:
     • Carbamazepine: 7-20 mg/kg/day (typically 7-10 mg/kg/day) given tds.
     • Valproic acid: 15-20 mg/kg/day (can increase to 30 mg/kg/day) given tds.

Antibiotic Therapy:

1. All Cases:
   • Single-dose IM Benzathine penicillin G (preferred):
     • ≥20 kg: 900 mg (1,200,000 U)
     • <20 kg: 450 mg (600,000 U)
   • OR 10 days of oral Phenoxymethylpenicillin (Penicillin V):
     • Child: 250 mg bd
     • Adolescent and Adult: 500 mg bd
   • If allergic to penicillin:
     • Erythromycin:
       • Child: 20 mg/kg up to 800 mg bd for 10 days
       • Adult: 800 mg bd for 10 days
2. Family Contacts:
   • Throat swab for culture.
   • If positive, administer penicillin therapy.

General Care:

1. Rest:
   • Strict bed rest is not necessary for most patients.
   • Plan care to include rest periods.
2. Age-Appropriate Activities:
   • Provide suitable activities for the patient’s age.
3. Family Involvement:
   • Involve the family in care and provide education about the condition.
4. School Notification:
   • Notify the school teacher about the patient’s condition and care requirements.
5. Discharge Planning:
   • Prepare for discharge to a primary care facility.
   • Ensure follow-up care is arranged.

Long-term Management

Late Complications of Acute Rheumatic Fever (ARF)

Rheumatic Heart Disease (RHD):

1. Progression:
   • Carditis worsens over time with cumulative damage.
   • Onset typically 10-20 years after the original attack.
   • Occurs in approximately 50% of ARF patients who had evidence of carditis.
2. Valve Involvement:
   • Mitral Valve: Most commonly affected.
   • Aortic Valve: Less commonly affected.
3. Mitral Stenosis (MS):
   • Classic finding in chronic RHD.
   • Surgical correction indicated in the presence of left atrial (LA) enlargement.
   • Balloon mitral valvuloplasty preferred for younger patients.
4. Complications:
   • Embolisation: From mural thrombi.
   • Infective Endocarditis: Increased risk on deformed valves.
5. Chronic RHD Manifestations:
   • Murmurs
   • Hypertrophy
   • Dilation
   • Heart failure
   • Arrhythmias

Education About Long-Term Sequelae:

1. Understanding ARF:
   • All patients should be well-informed about the cause of ARF.
   • Importance of early treatment for sore throats and skin sores.
2. Risk Awareness:
   • Family members should be aware of their increased risk of ARF compared to the wider community.
3. Long-Term Secondary Prophylaxis:
   • Patients and families should understand the necessity of long-term secondary prophylaxis.
   • Emphasize the consequences of not adhering to recommended treatment.
4. Prophylaxis Information:
   • Clear instructions on where to go for secondary prophylaxis.
   • Provide written information about follow-up appointments with their local medical practitioner.

Primary Prophylaxis

• Target Population: Individuals, typically children, who are at risk of developing rheumatic fever following a group A Streptococcus (GAS) infection.

• Treatment of Streptococcal Pharyngitis

Timing:

• Treat within 9 days of symptom onset.

Benzathine Penicillin G (BPG):

• Administration: Deep IM injection, single dose.
• Dosage:
  • Children:
    • Weight ≥20 kg: 900 mg
    • Weight 15 to <20 kg: 675 mg
    • Weight 10 to <15 kg: 450 mg
    • Weight 6 to <10 kg: 337.5 mg
    • Weight 3 to <6 kg: 225 mg
  • Adults: 900 mg

Alternative if IM Injection Not Possible:

• Phenoxymethylpenicillin (Penicillin V):
  • Children: 10 mg/kg up to 500 mg, bd for 10 days
  • Adults: 500 mg, bd for 10 days

For Patients Hypersensitive to Penicillin:

• Erythromycin Ethyl Succinate:
  • Children: 20 mg/kg up to 800 mg, bd for 10 days
  • Adults: 800 mg, bd for 10 days

Secondary Prophylaxis for Rheumatic Fever

Objective: To prevent recurrent attacks of rheumatic fever and further cardiac damage in individuals who have already had an episode of rheumatic fever.

Target Population: Patients with a history of rheumatic fever, particularly those with rheumatic heart disease.

Goal: Prevent recurrence of Acute Rheumatic Fever (ARF)

Risk: Most common within 2 years, decreases with increasing age

Initiation: Start immediately after resolution of the acute episode

First Line:

• Benzathine Penicillin G: 1.2 million units IM every month
  • 3-weekly for severe carditis or history of valvular surgery

Second Line:

• Phenoxymethylpenicillin (Penicillin V): 250mg BD
  • Use if IM route is not possible or refused
  • Adherence should be carefully monitored

Duration:

• All persons with ARF or RHD:
  • Minimum 10 years after the most recent episode of ARF or until age 21 years (whichever is longer)

Improving Adherence to Secondary Prophylaxis

Challenges:

• Sociological factors limit the efficacy of secondary prophylaxis
• In remote Aboriginal and Torres Strait Islander communities, the availability and acceptability of health services are major barriers
• Personal factors such as injection refusal, pain of injections, or lack of knowledge/understanding of ARF and RHD are less significant

Strategies to Improve Adherence:

1. Personalised Care:
   • Patients feeling a sense of belonging to the clinic improves adherence
2. Recall Systems:
   • Extending beyond community boundaries to ensure follow-up
3. Organisational Approaches:
   • Use of registers for tracking and management
4. Routine Review and Care Planning:
   • Regular reviews and detailed care plans
5. Recall and Reminder Systems:
   • Automated or manual systems to remind patients of appointments and injections
6. Dedicated Local Staff:
   • Local staff members dedicated to secondary prophylaxis coordination
7. Aboriginal Health Workers:
   • Utilizing their expertise, community knowledge, and language skills
8. Staff Training and Awareness:
   • Improving healthcare staff’s awareness of ARF and RHD diagnosis and management
9. Minimizing Staff Turnover:
   • Ensuring continuity of care by reducing turnover
10. Reducing Injection Pain:
    • Implementing measures to minimize the pain associated with injections

By addressing these factors, the effectiveness of secondary prophylaxis programs can be significantly improved, particularly in high-risk populations such as ATSI communities.

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Procedures Requiring Endocarditis Prophylaxis for Patients with Rheumatic Heart Disease (RHD):

Dental, Oral, and Respiratory Tract Procedures:

1. Dental extractions
2. Periodontal procedures
3. Dental implant placement
4. Gingival surgery
5. Initial placement of orthodontic appliances
6. Surgical drainage of dental abscess
7. Maxillary or mandibular osteotomies
8. Endodontic surgery and instrumentation
9. Placement of orthodontic bands
10. Intraligamentary local anaesthetic injections
11. Surgical repair or fixation of a fractured jaw
12. Tonsillectomy/adenoidectomy
13. Rigid bronchoscopy
14. Surgery involving the bronchial mucosa
15. Sclerotherapy of oesophageal varices
16. Dilatation of oesophageal stricture

Genitourinary and gastrointestinal procedures

1. Surgery of the intestinal mucosa or biliary tract (except for endoscopy, biopsy and percutaneous endoscopic gastrostomy)
2. Endoscopic retrograde cholangiography
3. Prostate surgery
4. Cystoscopy and urethral dilatation
5. Vaginal delivery in the presence of infection, or prolonged labour or prolonged rupture of membranes
6. Surgical procedures of the genitourinary tract in the presence of infection (e.g. urethral catheterisation, uterine dilatation and curettage, abortion, sterilisation and placement or removal of intrauterine contraceptive devices)

ADDITIONAL INFORMATION

Symptoms in detail:

• Arthritis
  • Several large joints in quick succession: knees, ankles, elbows, wrists
    • Legs first
    • Each for short time (< 1 week) but overlap 🡪 migratory
  • Earliest symptomatic manifestation
  • Symptoms – pain > inflammation
  • Investigations
    • Xray – may show effusion
    • Joint aspirate – sterile inflammatory fluid
  • Treatment
    • Aspirin or NSAIDs
• Carditis
  • Pancarditis – pericardium, epicardium, myocardium, endocardium
  • Symptoms:
    • Chest discomfort, pleuritic chest pain, pericardial rub
    • Exam –
      • Murmurs – new/changing, MR most common
  • If severe valve damage + myocarditis causing myocardial dysfunction
    • Can 🡪 heart failure
    • Most life-treathening clinical syndrome
    • Treat as APO
  • Investigations
    • ECG – heart block (all degrees)
    • CXR – cardiomegaly
    • Echo – acute carditis, valvular regurgitation/stenosis, chamber size and function, pericardial effusion
    • Antimyosin scintigraphy – 80% sensitive for carditis (any cause)
• Chorea
  • Sydneyham, chorea minor, “St Vitus dance”
  • Abrupt, purposeless, nonrhythmic involuntary movements + muscular weakness + emotional disturbance
  • Clinical signs: 
    • More marked on one side
    • Cease during sleep
    • Weakness revealed when ask to squeeze emaminer’s hands 🡪 milking sign
    • Emotional – inappropriate, crying, restless, psychosis
    • Neurological – no sensory changes, diffuse hypotonia
    • Can take to up 8 months to manifest

Subcutaneous nodules

• Firm and painless, overlying skin not attached or inflamed
• < 2cm wide
• Over bony surface or prominence or near tendons
•  Present for < 4 weeks
• Usually only in patients with carditis

• Erythema Marginatum/annulare
  • Evanscent non-pruritic rash
  • Pink/faintly red
  • Trunk, sometimes proximal limbs
  • Extends outwards while skin in centre return to normal