Rheumatic fever is an inflammatory disease that can develop after an infection with group A Streptococcus, typically affecting children and young adults. It is a complex condition that involves an abnormal immune response, leading to inflammation in multiple organ systems, including the heart, joints, skin, and central nervous system. The pathophysiology of rheumatic fever explains how a seemingly simple throat infection can trigger a cascade of immune reactions that may result in serious long-term complications such as rheumatic heart disease. Understanding these mechanisms is critical for early diagnosis, appropriate management, and prevention of chronic damage.
Initial Infection and Immune Activation
The pathophysiological process of rheumatic fever begins with an upper respiratory tract infection caused by group A Streptococcus (GAS). The bacteria possess several virulence factors, notably the M protein, which elicits a strong immune response. In genetically susceptible individuals, the immune system generates antibodies against these bacterial antigens. However, these antibodies may cross-react with human tissues due to structural similarities, a phenomenon known as molecular mimicry. This cross-reactivity triggers the autoimmune reactions that characterize rheumatic fever.
Molecular Mimicry and Autoimmune Response
Molecular mimicry is central to the pathophysiology of rheumatic fever. Antibodies and T cells that target GAS antigens mistakenly recognize similar epitopes in human tissues, particularly in the heart, joints, skin, and brain. This immune misdirection initiates inflammatory responses in these organs, causing tissue damage and the characteristic clinical manifestations of rheumatic fever. Both humoral and cellular immune responses contribute to the disease process, emphasizing the dual role of antibodies and T lymphocytes in mediating tissue injury.
Cardiac Involvement Carditis
Carditis is one of the most serious manifestations of rheumatic fever and involves inflammation of the endocardium, myocardium, and pericardium. The autoimmune attack results in infiltration of inflammatory cells, including macrophages, lymphocytes, and multinucleated giant cells. A hallmark lesion, known as the Aschoff body, forms in the myocardium and represents localized granulomatous inflammation and fibrinoid necrosis. Repeated episodes of carditis can lead to scarring and thickening of heart valves, particularly the mitral and aortic valves, resulting in chronic rheumatic heart disease, which is a leading cause of morbidity and mortality in affected individuals.
Joint Involvement Migratory Polyarthritis
Rheumatic fever commonly causes migratory polyarthritis, predominantly affecting large joints such as the knees, ankles, elbows, and wrists. The immune system’s inflammatory response leads to synovial membrane inflammation, producing pain, redness, swelling, and warmth. Unlike the cardiac effects, joint inflammation in rheumatic fever is usually transient and self-limiting, typically resolving without permanent damage. However, it is a prominent symptom during the acute phase and contributes to the systemic discomfort experienced by patients.
Skin and Subcutaneous Manifestations
Cutaneous involvement can include erythema marginatum, a non-itchy, ring-shaped rash, and subcutaneous nodules, which are firm, painless lumps over bony prominences. These manifestations result from immune complex deposition and local inflammatory reactions. While less frequent than cardiac or joint symptoms, skin findings are clinically significant and aid in diagnosing rheumatic fever. Recognizing these signs early can prompt timely intervention, potentially preventing more severe systemic complications.
Neurological Manifestations Sydenham’s Chorea
Sydenham’s chorea is a neurological feature that may appear weeks to months after the initial streptococcal infection. It is characterized by involuntary, rapid, and irregular movements affecting the face, hands, and feet, accompanied by emotional lability. The pathophysiology involves antibody-mediated disruption of neuronal signaling in the basal ganglia, leading to hyperkinetic movements. This manifestation highlights the systemic nature of the autoimmune response in rheumatic fever and its capacity to affect multiple organ systems beyond the musculoskeletal and cardiovascular systems.
Role of Cytokines and Inflammatory Mediators
Inflammatory mediators are central to the tissue damage observed in rheumatic fever. Cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha (TNF-α) are released during the immune response, promoting systemic inflammation. These molecules contribute to fever, malaise, and the generalized symptoms commonly observed in acute rheumatic fever. Their activity also exacerbates tissue injury in the heart and joints, reinforcing the importance of early anti-inflammatory treatment to limit damage and alleviate symptoms.
Genetic Susceptibility and Host Factors
Genetic predisposition plays a crucial role in the development of rheumatic fever. Certain human leukocyte antigen (HLA) class II alleles are associated with an increased risk of disease, influencing how the immune system recognizes and responds to bacterial antigens. Genetic factors can affect both susceptibility to initial infection and the severity of tissue involvement, explaining why some individuals develop severe complications while others experience mild or no disease. Understanding these genetic influences is important for identifying at-risk populations and implementing targeted prevention strategies.
Diagnosis and Pathophysiological Correlation
Diagnosis of rheumatic fever is primarily clinical, based on the revised Jones criteria, which include major manifestations such as carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules, as well as minor criteria like fever, arthralgia, and elevated inflammatory markers. Laboratory tests confirming recent streptococcal infection, including elevated antistreptolysin O (ASO) titers, support the diagnosis. The pathophysiology of immune cross-reactivity, inflammation, and tissue damage directly explains the clinical features used in diagnostic criteria, emphasizing the relevance of understanding underlying mechanisms in guiding effective management.
Prevention and Management Implications
Prevention of rheumatic fever focuses on prompt and adequate treatment of streptococcal infections with antibiotics such as penicillin. Preventing the initial immune sensitization is critical to avoid the autoimmune cascade responsible for tissue injury. Secondary prevention involves long-term antibiotic prophylaxis to prevent recurrent infections, which are strongly linked to progressive valve damage. Anti-inflammatory therapies, including aspirin or corticosteroids, are used to control acute inflammation, especially in cardiac and joint involvement. Understanding pathophysiology informs both preventive and therapeutic strategies, ensuring interventions target the underlying immune processes rather than just symptomatic relief.
The pathophysiology of rheumatic fever is a multifaceted interplay between infection, immune response, and systemic inflammation. Triggered by group A Streptococcus, the disease involves molecular mimicry, autoimmunity, and cytokine-mediated tissue damage affecting the heart, joints, skin, and nervous system. Genetic susceptibility influences the severity and likelihood of complications. Early diagnosis, timely antibiotic therapy, and appropriate anti-inflammatory management are essential to limit tissue damage and prevent long-term consequences such as rheumatic heart disease. Understanding these mechanisms not only enhances clinical care but also emphasizes the importance of prevention and ongoing research into autoimmune sequelae of infectious diseases.
By comprehensively examining the immune pathways, tissue-specific responses, and systemic effects, healthcare providers can improve patient outcomes through targeted interventions, early recognition, and informed monitoring strategies, reducing the global burden of rheumatic fever and its complications.