12th March 2024

Rheumatic Fever

Pathophysiology

Rheumatic fever is a multi-systemic inflammatory reaction instigated by a preceding streptococcal group A infection which was improperly or inadequately treated. The streptococcal infection typically occurs around two to three weeks prior to this syndrome. Principal organs involved include the heart, joints and skin. 

If left untreated, up to half of patients progress to chronic rheumatic heart disease, which predisposes the individual to arrhythmias, stroke and infective endocarditis. 

In developing countries, rheumatic fever continues to remain endemic and causes significant mortality and morbidity. In these nations, rheumatic heart disease is the leading cause of cardiovascular death in people aged 50 or less.  

Streptococcal pharyngitis is a relatively common infection with highest incidence between the ages of 5 to 15 years. When untreated, Group A streptococcus causes a pathological immune response. Streptococcal antibodies cross-react against myocardial tissue, synovial tissue and parts of the central nervous system. Cardiac valve involvement is caused by monoclonal antibodies initiating lymphocyte infiltration of the endothelium, further propagating the inflammatory response. 

Clinical manifestations

Signs and symptoms of rheumatic fever include: 

• Fever 
• Erythema marginatum: an annular erythema appearing as macules and papules typically on the trunk, upper arms and legs. As the lesions progress, their outer edges become raised with central clearing. 
• Arthritis: a migratory polyarthritis primarily affecting the large joints is typically seen. Arthralgia may also be present.
• Carditis can affect more than half of patients and may affect all the layers of the cardium (pancarditis) 
• Valvular regurgitation: there is typically involvement of the valvular endothelium progressing to valvular regurgitation. The mitral valve and aortic valve are most commonly affected.
• Chorea: involuntary, irregular jerking movements. Occurs due to immunological reactions affecting parts of the basal ganglia. Chorea can present up to six months after the initial streptococcal infection.
• Subcutaneous nodules: painless lumps over the extensor surfaces of wrists, elbows, knees and ankles.

Diagnosis

Diagnosis is primarily clinical, and the Jones criteria are used to facilitate diagnosis of rheumatic fever. This requires the presence of either two major criteria or one major and two minor criteria to be fulfilled in addition to evidence of a recent streptococcal group A infection. The major and minor criteria are defined below:

Major criteria

• Carditis: serial echocardiograms are required for diagnosis and further monitoring.
• Arthritis
• Chorea 
• Erythema Marginatum 
• Subcutaneous nodules  

Minor criteria

• Arthralgia: this is difficult to differentiate from arthritis and cannot be used as a criterion if arthritis is present. 
• First-degree heart block: prolonged PR interval on electrocardiogram. This cannot be used as a criterion if carditis is present.
• Fever: >39 degrees C is typically present in the first few days of illness and can be lower in subsequent weeks
• Raised acute phase reactants: ESR and CRP during the initial weeks. These are not specific for rheumatic fever. 

Recent streptococcal infection

• Evidence of recent streptococcal group A infection is provided by a positive pharyngeal culture or raised streptococcal antibody titre. Anti-streptolysin O titre (ASOT) or DNase B titre are examples of streptococcal antibodies. 

Management 

Goals of management include:

• Eradication of underlying streptococcal infection. Once a pharyngeal culture is obtained, patients are usually started on penicillin. Following an episode of rheumatic fever, antibiotic prophylaxis is recommended to prevent further episodes. 
• Suppression of the pathological immune response. NSAIDs may help relieve arthritis and arthralgia. 
• Supportive management with angiotensin-converting-enzyme inhibitors and diuretics in rheumatic fever complicated by heart failure and severe aortic regurgitation. Cardiac valve replacement or repair may also be indicated. 

References

• Webb et al. 2015. Acute Rheumatic Fever. BMJ. Available at https://pubmed.ncbi.nlm.nih.gov/26175053/
• UpToDate. Acute rheumatic fever: Clinical manifestations and diagnosis. 2017. Available at https://www.uptodate.com/contents/acute-rheumatic-fever-clinical-manifestations-and-diagnosis
• Dodu et al. ‎1989‎. Rheumatic fever and rheumatic heart disease in developing countries. Available at https://apps.who.int/iris/handle/10665/46841