In Search of the Holy Grail: A Specific Diagnostic Test for Rheumatic Fever
Current diagnosis of Acute Rheumatic Fever and Rheumatic Heart Disease (ARF/RHD) relies on a battery of clinical observations aided by technologically advanced diagnostic tools and non-specific laboratory tests. The laboratory-based assays fall into two categories: those that (1) detect "evidence of preceding streptococcal infections" (ASOT, anti-DNAse B, isolation of the Group A Streptococcus from a throat swab) and (2) those that detect an ongoing inflammatory process (ESR and CRP). These laboratory tests are positive during any streptococcal infection and are non-specific for the diagnosis of ARF/RHD. Over the last few decades, we have accumulated considerable knowledge about streptococcal biology and the immunopathological mechanisms that contribute to the development, progression and exacerbation of ARF/RHD. Although our knowledge is incomplete and many more years will be devoted to understanding the exact molecular and cellular mechanisms involved in the spectrum of clinical manifestations of ARF/RHD, in this commentary we contend that there is sufficient understanding of the disease process that using currently available technologies it is possible to identify pathogen associated peptides and develop a specific test for ARF/RHD. It is our view that with collaboration and sharing of well-characterised serial blood samples from patients with ARF/RHD from different regions, antibody array technology and/or T-cell tetramers could be used to identify streptococcal peptides specific to ARF/RHD. The availability of an appropriate animal model for this uniquely human disease can further facilitate the determination as to whether these peptides are pathognomonic. Identification of such peptides will also facilitate testing of potential anti-streptococcal vaccines for safety and avoid potential candidates that may pre-dispose potential vaccine recipients to adverse outcomes. Such peptides can also be readily incorporated into a universally affordable point of care device for both primary and tertiary care.
Neurobehavioral Changes Associated with Rheumatic Fever and Rheumatic Heart Disease: A Narrative Review
Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune conditions triggered by Group A Streptococcus skin or throat infections. If ARF/RHD is undetected, misdiagnosed or antibiotic treatment is not provided early, patients may develop cardiac failure, leading to premature death. Although it is an easily preventable disease, ARF/RHD remains the most significant cause of heart disease‑associated deaths in people under 25 years old, both in low- and middle-income countries and among First Nations in high‑income countries. Up to 30% of the patients with ARF/RHD present with a neurobehavioral condition – Sydenham’s chorea (SC). The clinical course of SC is mostly self-limiting and is characterized by the onset of involuntary choreiform movements and neuropsychiatric features such as obsessive‑compulsive disorder, tics, depression and anxiety, psychosis, and attention‑deficit hyperactivity disorder. While the precise mechanism as to why only a proportion of patients with ARF/RHD develop SC remains unknown, an impaired blood–brain barrier is considered to play a central role in its development. The most well‑characterized neurobehavioral outcome is stroke which may occur in isolation or as part of systemic thromboembolism. Both infective endocarditis and mitral valve disease with or without aortic valve disease increase the embolic and ischemic stroke risk. ARF/RHD is known to significantly impact the quality of life with neuropsychiatric consequences. Another neurobehavioral syndrome which occurs in the absence of ARF/RHD is “pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections” (PANDAS). PANDAS has been categorized as a subset of pediatric acute‑onset neuropsychiatric syndromes. However, establishing a diagnosis of PANDAS has been challenging. In this review, we discuss the current status of our understanding regarding the different manifestations of poststreptococcal neurobehavioral changes. Particular attention is given to ARF/RHD‑associated SC, and we highlight the areas for further research to understand the association between poststreptococcal sequelae and neurobehavioral abnormalities.