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Autoimmunity Reviews 9 (2009) 117–123

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Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

Acute rheumatic fever and its consequences: A persistent threat to developing nations in the 21st century
Jennifer L. Lee, Stanley M. Naguwa, Gurtej S. Cheema, M. Eric Gershwin ⁎
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, United States

a r t i c l e

i n f o

a b s t r a c t
Acute rheumatic fever (ARF) is an autoimmune, multi-system response secondary to molecular mimicry following Lancefield group A streptococcus (GAS) pharyngitis; it is now most commonly found in the pediatric populations of developing nations. The major source of morbidity and mortality of ARF stems from rheumatic heart disease (RHD), although the cardinal symptoms of the disease also include polyarthritis, Sydenham's chorea, subcutaneous nodules, and erythema marginatum. Therapy is aimed towards treating the initial GAS infection, using anti-inflammatory medications for acute symptoms and surgery to correct RHD. Secondary prevention is crucial, given the high risk of recurrence, and includes long-term antibiotic prophylaxis. However, vaccination towards GAS may soon be on the horizon, which may assist in both decreasing the risk of initial infection in naïve patients and helping to lower the risk of recurrence. © 2009 Elsevier B.V. All rights reserved.

Article history: Received 12 March 2009 Accepted 6 April 2009 Available online 19 April 2009 Keywords: Rheumatic fever Rheumatic heart disease Group A streptococcus pharyngitis Sydenham's chorea

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . Pathogenesis and association with group A . . . . . . . . Clinical presentation . . . . . . . . . . . . . . . . . . . 4.1. Carditis . . . . . . . . . . . . . . . . . . . . . . 4.2. Arthritis . . . . . . . . . . . . . . . . . . . . . 4.3. Neuropsychiatric manifestations . . . . . . . . . . 4.4. Skin findings . . . . . . . . . . . . . . . . . . . 4.5. Presentation in children younger than 5 years of age 5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Post-streptococcal reactive arthritis . . . . . . . . 5.2. The link between ARF and other rheumatic diseases 6. Pathology . . . . . . . . . . . . . . . . . . . . . . . . 7. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 8. Prognosis and predictors of disease course . . . . . . . . 9. Treatment . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Antibiotic prophylaxis for rheumatic heart disease . 10. Prevention . . . . . . . . . . . . . . . . . . . . . . . 10.1. Primary prevention . . . . . . . . . . . . . . . . 10.2. Secondary prevention . . . . . . . . . . . . . . . 10.3. Potential for vaccination . . . . . . . . . . . . . . 11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . Take-home messages . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2. 3. 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 118 118 119 119 119 119 120 120 120 120 120 121 121 121 121 121 121 121 122 122 122 123 123

⁎ Corresponding author. Tel.: +1 530 752 2884; fax: +1 530 752 4669. E-mail address: megershwin@ucdavis.edu (M.E. Gershwin). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.04.002

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1. Introduction Acute rheumatic fever (ARF) is a constellation of symptoms that stems from a nonsuppurative, auto-inflammatory multi-system response following infection by group A streptococcus (GAS), or Streptococcus pyogenes. Particularly because of its chronic effects on cardiac valves, termed rheumatic heart disease (RHD), ARF continues to contribute a significant amount to global morbidity and mortality. In many developing countries, RHD is the most common source of acquired heart disease in children and young adults. The recognition of symptoms comprising the syndrome of ARF dates back centuries ago, with Poynton and Paine initially reporting the potential link between streptococcal pharyngitis and rheumatic fever in 1900. Diagnosis is now centered around the 1992 updated Jones' criteria, which includes carditis, polyarthritis, erythema marginatum, Sydenham's chorea, and subcutaneous nodules, in the setting of a preceding GAS infection.

2. Epidemiology The prevalence of ARF now appears to be much higher in less developed countries, particularly in indigenous and less affluent areas, and varies significantly from one region to the next (See Table 1). In 2005, it was estimated that the incidence of ARF was more than 471,000 cases per year, with 336,000 cases in those 5–14 years of age. The prevalence of RHD is estimated to range from 15.6 to 19.6 million cases worldwide, with 282,000 newly diagnosed with over 233,000 deaths attributed to RHD each year. Unfortunately, given the disease's predilection for children, over 2.4 million of these cases were in patients aged 5–14 years old [1]. A higher incidence has been reported among the aborigines of Australia, the Maoris of New Zealand, and populations in sub-Saharan Africa [2]. However, given the limitations of reports related to limited resources in many of these endemic areas,

Table 1 Collective summary of the characteristics and treatment of rheumatic fever. At-risk populations Ethnic sub-groups Maori (New Zealand) Aborigines (Australia) Pacific Islanders Sub-Saharan Africa Age groups Ages 5 to 15 Risk Factors Low socioeconomic status Overcrowding Clinical signs/ symptoms 1 Non-specific Fever ⇧ ESR, CRP Anemia Cardiac Pancarditis Pericarditis Myocarditis Arthritis Polyarticular Diagnosis (updated Jones' Criteria [12]) Major criteria Carditis Polyarthritis Treatment Antibiotics Penicillin Antiinflammatories Salicylates Corticosteroids

it is likely that numerous cases, and therefore the prevalence and incidence, of ARF and RHD are largely underestimated. A systematic review of 10 population-based studies published from 1967 to 1996 describes the worldwide incidence of ARF [3]. The highest reported annual incidence rate was 51 per 100,000 per year by a study conducted in northern India, with the mean incidence of all studies at 19 per 100,000 per year. The lowest incidence rates were found in American and Western European nations, while higher rates are found in Eastern Europe, Asia, Australasia, and the Middle East. Of note, information from Africa is not available for this study, though it is widely known that African nations have a high predominance of pediatric patients with RHD. The first episode of ARF most commonly strikes children and young adolescents, usually from ages 5–14 years old, though younger and middle-aged adults are also affected at a lower frequency. It is rare for patients to experience their initial RF episode younger than 2 years or greater than 35 years of age [2]. In a study of 541 pediatric patients with ARF at the University of Utah by Tani et al., it was found that 5% of these patients were younger than 5 years old at diagnosis [4]. In the United States, the number of ARF cases has fallen dramatically over the last half century. A national study conducted in 2000 detailing the characteristics of American pediatric patients hospitalized with ARF found that the incidence was 14.8 cases per 100,000 hospitalized children (though the true national incidence of ARF cases is b1 case per 100,000 population), with the greatest number of hospitalizations for ARF occurring in Utah, Hawaii, Pennsylvania, and New York [5]. Patients of Asian or Pacific Island descent with ARF were also more likely to be hospitalized than those who were Caucasian. Concern in the 1980s had arisen over several outbreaks in several states including Tennessee, Ohio, and Pennsylvania. However, cases have since decreased and are now mainly limited to Salt Lake City, Utah. The overall decline is believed to be due to improvements in aspects of primary prevention, including access to health care and crowding and use of antibiotics. It has also been postulated that evolving differences in the streptococcal M protein type, the main bacterial virulence factor to which host antibodies bind to confer protective immunity, has also played a role in the number of diminishing cases [6]. However, it still remains unclear why the trend has moved away from rheumatogenic strains of GAS to those that do not commonly lead to the development of RF. 3. Pathogenesis and association with group A streptococcal pharyngitis ARF is believed to be a consequence of molecular mimicry, an autoimmune phenomenon that occurs after host infection with GAS and involves both humoral and cellular immune responses. The concept of molecular mimicry is well described elsewhere. Antistreptococcal antibodies are produced by B cell lymphocytes that cross-react with host tissue epitopes, causing inflammation in various organ systems. In addition, bacterial peptide fragments, many of which are similar to host proteins, are presented to T cell lymphocytes (with a prominent role by CD4+ T cells in rheumatic valvular lesions) via major histocompatibility complex (MHC) molecules, inducing an immune response [7]. Shared epitopes are located on the M protein of GAS and human cardiac (especially myosin), synovial, and neuronal tissues. In Sydenham's chorea, antibodies are directed against neuronal cells of the basal ganglia. Other similarities have been found between hyaluronidate located in the capsule of GAS and hyaluronic acid found in human synovium, as well as between Nacetylglucosamine in the streptococcal cell wall/capsule and in human cardiac valves [7,8]. The development of RF is likely due to contributions from both genetic and environmental influences. An association with MHC Class II antigens, which help to present extracellular antigens to the T cell

Sydenham's chorea Erythema marginatum Subcutaneous nodules Surgery Minor criteria Valve repair Arthralgias Fever

Elevated inflammatory markers Limited access to medical Migratory Prolonged P–R care interval History of rheumatic Large joints Preceding fever (for recurrences) Streptococcal infection Neuropsychiatric Positive throat cultures Sydenham's Elevated or rising ASO chorea titers OCD/ADHD Tic disorders Cutaneous Erythema marginatum Subcutaneous nodules

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receptor, has been found to play a key role in the pathway towards activating the inflammatory cascade. In particular, HLA-DR7 has been found to be important in many different ethnic populations, while other studies have identified HLA-DR2 in African Americans and HLADR4 in Caucasian-Americans. Other non-MHC proteins that may also be influential in the autoimmune response against GAS include mannose binding lectin (MBL) and various cytokines, such as variants of tumor necrosis factor (TNF)-a and IL-1 [7,9]. Infection with GAS can present in a variety of ways, including pharyngitis, post-streptococcal glomerulonephritis, impetigo, and invasive infections, such as streptococcal toxic shock syndrome and necrotizing fasciitis. As alluded to above, certain streptococcal strains are more likely to lead to the development of ARF, termed “rheumatogenic” strains; the general consensus is that these strains are also those who are initially responsible for causing GAS pharyngitis. In the United States, the M types most frequently known to cause RF include serotypes 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29, though one study postulated that in Hawaii (a state with one of the highest incidences of RF in the nation), unusual serotypes not typical for RF caused pathology [6,8,10]. Specific characteristics of these strains have been found to cause increased virulence, including higher M protein content and mucoid colony formation, which suggests the presence of a large capsule that protects against phagocytosis [6,11]. 4. Clinical presentation Rheumatic fever (RF) can present with a variety of findings, with a latency period of 2–5 weeks after the initial episode of streptococcal pharyngitis. These symptoms can generally be categorized into musculoskeletal, cardiac, neuropsychiatric, and integumentary complaints (see Table 1). In addition, non-specific symptoms in a patient with ARF can include fever, elevated inflammatory markers, precordial or abdominal pain, tachycardia, malaise, anemia, and epistaxis [12]. Occasionally, episodes are asymptomatic, making it difficult to determine in some patients the need for secondary prophylaxis. This, unfortunately, puts them at risk for developing more severe RHD if re-infected with GAS. 4.1. Carditis 30–45% of patients with RF exhibit carditis as a manifestation of their disease. Carditis can encompass the spectrum from valvulitis to myocarditis to pericarditis [12]. Most frequently, pancarditis, or endocarditis, is seen. Initially, valvular disease involves dilatation of the valve causing regurgitation, but chronic progression can lead to stenosis. Cardiac involvement in RF can even extend to inflammation in the coronary arteries, which has mainly been found on autopsy, but does not solely meet criteria for diagnosis of carditis in ARF. The severity of rheumatic carditis ranges widely among individuals, but often lends the most significant contribution to the morbidity and mortality of RF. Its presentation can include such clinical signs and symptoms as a pericardial rub, tachycardia, an apical systolic murmur consistent with mitral regurgitation, a basal diastolic murmur consistent with aortic regurgitation, or severe congestive heart failure. In severe acute cases, RHD can lead to fatal consequences despite medical therapy. Demonstrated by a case series of 3 pediatric patients, who developed acute carditis with involvement of multiple valves and impaired systolic dysfunction, severe carditis has been likened to acute mitral regurgitation with the potential for rapid deterioration [13]. Subclinical carditis, in which valvular regurgitation seen on echocardiography does not manifest clinically as an audible murmur, can also be seen. A systematic review of the literature published in 2007 found that the weighted pooled prevalence of reported subclinical carditis was 16.8%, with 44.7% experiencing persistence or deterioration of their valve lesion during a follow-up period of

3–23 months, though it was noted that follow-up data was of poor quality [14]. However, even in the most recent meeting of the Jones Criteria Workshop, the sole finding of subclinical carditis does not yet fulfill the Jones criteria for cardiac symptoms, as it still remains unclear with current technology which findings are physiologic versus pathologic [15]. It has been estimated that 60% of those with ARF will develop RHD [1]. The risk of developing RHD has been shown to directly correlate with the severity of carditis during the initial attack. Despite regularly administrated antibiotic prophylaxis for secondary prevention, carditis has been reported to recur, though in many cases, recurrences are due to poor compliance [16]. These recurrent episodes tend to mimic the initial attack, and generally occur within the first 5 years.

4.2. Arthritis Arthritis is likely the most common symptom of RF, occurring in 60–80% of patients, and is often the first presentation of the disease [8]. It is most frequently polyarticular, migratory (with episodes lasting 2 to 3 days in each joint), and non-deforming. Large joints are mostly affected, particularly the knees, ankles, elbows, and wrists. Uncommonly, ARF can present as a monoarticular arthritis, particularly in those already treated with non-steroidal anti-inflammatory medications (NSAIDs), which can be difficult to distinguish from septic arthritis. The duration of each arthritic attack usually lasts a maximum of 4 weeks, and can also often mimic joint symptoms from a viral infection [17]. Given the arthritis is non-specific, other conditions on the differential should include reactive arthritis, connective tissue diseases, sickle-cell disease, leukemia, and lymphoma [18]. Rarely, patients with chronic RF can develop Jaccoud's arthropathy, reducible deformities of the affected joints. However, this arthropathy is now more commonly seen in systemic lupus erythematosus (SLE) patients who have suffered chronic, recurrent bouts of arthritis secondary to uncontrolled or untreated inflammation.

4.3. Neuropsychiatric manifestations Sydenham's chorea (or St. Vitus' dance), occurs in approximately 10% of patients, and is a well-known, but not exclusive, neurologic manifestation of rheumatic fever. Chorea can also be found in a number of conditions, including systemic lupus erythematosus, encephalitis, Lyme disease, and drug intoxication [2]. Typical characteristics of chorea include involuntary, purposeless, nonrhythmic movements, usually of the face and extremities, while the patient is awake; weakness; and emotional lability. It can also be accompanied by frequent falls, dysarthria, and difficulties in concentration [18]. In RF, chorea is most often seen in older children and young adolescents, with a slightly higher predisposition in the female population, and is usually found late in the disease course. In a Turkish study of 65 patients by Demiroren et al., 78.5% had generalized chorea, with a 37.9% rate of recurrence. 70.5% of the 61 patients that underwent echocardiography were also found to have valvular involvement [19]. However, chorea has been seen as an isolated symptom of RF, and can be used to make a presumptive diagnosis with its presence alone. Interestingly, isolated chorea usually is not associated with elevated inflammatory markers, in contrast to other manifestations of RF. It tends to remit with or without therapy, but often can recur with similar symptoms [18]. A possible association between ARF and several psychiatric conditions has also been reported in several studies, including obsessive compulsive disorder (OCD), tic disorders, major depression, and attention deficit hyperactivity disorder (ADHD) [18,20].

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4.4. Skin findings Cutaneous manifestations of RF tend to be very rare and are selflimited. The classic appearance of erythema marginatum is an evanescent, pink rash, usually found on the trunk and the extremities, and spares the face [12]. Subcutaneous nodules are painless, and can be found on the extensor surfaces of the wrists, elbows, knees and ankles. 4.5. Presentation in children younger than 5 years of age

In 2002, the updated Jones criteria were reviewed at the Jones Criteria Workshop, with panel members confirming the continued validity of the updated criteria set forth in 1992. The use of echocardiography was recognized in visualizing rheumatic valvular disease, but they maintained that this imaging modality should not be used as a sole determinant of carditis in the absence of an auscultated murmur. In addition, it was noted that a single laboratory test alone was still unavailable to make an adequate diagnosis of ARF or its recurrent episodes [15]. 5.1. Post-streptococcal reactive arthritis

It has been postulated that the youngest patients with ARF may present with a different clinical syndrome in contrast to their older counterparts. In a retrospective study by Tani et al., it was found that those children who developed RF (as diagnosed by the Jones criteria) at an age younger than 5 years old had a higher incidence of moderate to severe carditis, manifested by cardiomegaly with or without congestive heart failure, but a lower likelihood of having chorea [4]. In addition, their clinical presentation was more likely to include arthritis and erythema marginatum. 5. Diagnosis An accurate diagnosis is imperative in any patient suspected to have ARF, as misdiagnosis can potentially involve long-term, unnecessary antibiotic therapy. On the other hand, underdiagnosis, particularly with milder initial presentations, can lead to unrecognized recurrent bouts of RF that can result in significant chronic carditis. An article by Williamson et al. addresses several such pitfalls in reaching a diagnosis [17], including the frequent absence of a history of sore throat in younger patients who have difficulty relaying symptoms to their caregivers and the difficulty in recognizing and diagnosing a preceding streptococcal infection. To help facilitate appropriate diagnosis, criteria were initially characterized by Dr. T. Duckett Jones in 1944, which have been revised several times throughout the years by the American Heart Association. The most recently updated set of criteria was set forth in 1992, and is meant to be applied for the diagnosis of the first episode of ARF only (See Table 1). These guidelines recommend that a practitioner initially determines the likelihood of a preceding GAS infection [12]. To do so, one should have a high clinical suspicion in the setting of positive throat cultures or high or rising anti-streptolysin O (ASO) titers, given that symptoms of ARF usually emerge concomitantly with a peak in antibody titers. Sensitivity in detecting true streptococcal infection increases when these two tests are used in combination with the presence of other streptococcal antibodies, including anti-DNase B and antihyaluronidase [21]. For a diagnosis of ARF, presenting symptoms are divided into major and minor criteria. Major criteria include: (1) carditis, (2) polyarthritis, (3) Sydenham's chorea, (4) erythema marginatum, and (5) subcutaneous nodules. Minor criteria include both clinical (arthralgias and fever, usually above 39 degrees Celsius) as well as objective aspects (elevated acute phase reactants of disease, such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), and a prolonged P–R interval on EKG) [12]. For one to fulfill the criteria of ARF, an individual must have two major or one major and two minor manifestations plus a clinical setting that points towards a preceding GAS infection. The authors of the updated guidelines also state that a presumptive diagnosis of ARF can be made in the absence of the above criteria in the following instances: if isolated chorea is present without any other manifestation; if longstanding carditis is seen without any other symptom; or if, in a patient with a history of ARF or RHD, a single major or several minor criteria are fulfilled. This latter scenario is termed a recurrent episode of rheumatic fever, and is due to reinfection by GAS.

Post-streptococcal reactive arthritis (PSRA) is a known entity that is associated with GAS infection, but it is still unclear if it is truly a separate condition from ARF or represents a component of the same spectrum. It, like RF, occurs after infection with GAS, and can be a monoarticular or polyarticular arthritis, but does not exhibit the full constellation of symptoms of RF. It also appears that, while the arthritis found in ARF is quite responsive to salicylates, patients with PSRA do not respond as well to treatment. Barash et al. attempted to develop an objective approach to help distinguish between these two diseases by retrospectively examining 159 patients with PSRA and 68 patients with ARF [22]. They found that both groups had the same proportion of positive throat cultures for GAS, and had similar latency periods, measured in terms of the interval between the onset of pharyngitis and the onset of arthritis (approximately 15 days for both). However, all patients with ARF had carditis (while all those with PSRA did not), and there was a trend towards a higher percentage of patients with ARF having fever N38 °C, more active joints, and a migratory arthritis. In addition, the resolution of arthritic symptoms was much more rapid in the patients with ARF than with PSRA. From this information, they were able to formulate an equation to help distinguish ARF from PSRA (with a sensitivity of 79% and a specificity of 87.5%) using the highest predictors between the two groups: ESR, CRP, duration of joint symptoms in response to antiinflammatory medications, and relapse of joint symptoms after cessation of treatment. 5.2. The link between ARF and other rheumatic diseases Symptoms of ARF can often mimic those of other autoimmune diseases, particularly given the frequency of arthralgias and arthritis seen in these patients, and it can sometimes be difficult to determine the true underlying diagnosis. Recently, in a sample of 53 pediatric patients in Paraguay initially diagnosed by their general practitioners with ARF, 44.6% were actually later found to have a rheumatologic etiology for their symptoms [23]. These diagnoses included juvenile idiopathic arthritis, patellofemoral syndrome, SLE, and reactive arthritis. In addition, ARF should always remain in the differential for septic arthritis, particularly when diagnostic arthrocentesis of a monoarticular arthritis yields sterile synovial fluid in patients living in endemic areas. It is also especially important to be cognizant of an abnormal cardiac murmur in conjunction with these symptoms. In a study of 157 RF patients by Harlan et al., 3 patients were found to have a monoarticular arthritis with sterile synovial fluid, with all initially being treated for septic arthritis, but were later found on follow-up to have significant carditis, ultimately leading to a diagnosis of RF [24]. Other etiologies to consider when faced with monoarticular arthritis in pediatric patients, of course, are certain subsets of juvenile idiopathic arthritis and Lyme disease. In rare case reports, ARF has been postulated to co-exist with other rheumatic phenomena. A series of 3 retrospective pediatric cases were discussed by Eisenstein and Navon-Elkan in which features of Henoch–Schonlein purpura appeared to concomitantly occur with ARF. This continues to raise the possibility that GAS infection may

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contribute to the pathogenesis of both diseases, though this remains controversial [25]. 6. Pathology Pathological examination of valves affected by RF carditis reveals that the mitral valve is most commonly affected, followed by the aortic, tricuspid and, uncommonly, pulmonic valve. Pathologic findings include thickening of the valve leaflets and chordae, mitral annular dilation, and chordal elongation [26]. Aschoff nodules are a signature pathological finding in RF carditis, and are found most frequently in the subendocardium. They are aggregates of cells that originate from macrophages and histiocytes, and can be found in the company of lymphocytes and plasma cells. The histology of subcutaneous nodules reveals fibrinoid degeneration and necrosis of collagen surrounded by mononuclear inflammatory cells [27]. 7. Imaging Echocardiography is the mainstay of diagnostic imaging for ARF, though this is by no means a perfect modality, as it is often difficult to distinguish healthy variant versus pathologic valvular disease by echocardiography alone. As stated earlier, valvular disease seen exclusively on echocardiography in the absence of an auscultated murmur does not currently fit the criteria for diagnosing carditis. In a recent attempt by Carapetis et al. to find an adequate screening tool for RHD in endemic areas, auscultation was found to miss 54% of those with RHD when confirmed with echocardiography. However, the likelihood of finding pathology on portable echocardiography was significantly raised if an abnormal murmur was found initially on clinical exam [28]. 8. Prognosis and predictors of disease course If left untreated, an episode of RF tends to resolve on its own within 3 months, but can result in chronic cardiac damage. Approximately 65–75% of patients recover from an episode of carditis without any future consequences, though the likelihood of full resolution is much lower if carditis is severe, or of course, if recurrent episodes occur [2,21]. Overall prognosis in RF, as a result, is largely dependent on the degree of RHD that an individual suffers from, as this is the main cause of morbidity and mortality in these patients. In a study by Meira et al., a group of children and adolescents in Brazil were followed by clinical examination and Doppler echocardiography for a mean of 5.4 years after their initial episode of ARF. It was found that the risk of developing significant chronic RHD was independently associated with moderate or severe carditis, recurrent episodes of rheumatic fever, and a mother's low educational level [29]. 9. Treatment Treatment of RF involves a two-pronged approach, with one arm focused on treating the streptococcal infection with antibiotics (the drug of choice being penicillin), and the other aimed towards using anti-inflammatory medications to treat the symptoms of RF (see Table 1). Anti-inflammatory therapy mainly includes salicylates and steroids, though intravenous immunoglobulin has also been reported to be used in carditis. Recommended doses for salicylates are 80– 100 mg/kg/day for children and 4–8 g/day for adults for 2 weeks, then decreased to 60–70 mg/kg/day for an additional 3–6 weeks. Prednisone, the preferred steroid, is usually dosed initially at 1–2 mg/kg/ day, with a maximum of 80 mg/day, and then tapered after 2–3 weeks by 20–25% each week [21]. In rheumatic carditis, most practitioners tend to use steroids for severe disease (including congestive heart failure, significant valvular disease, and pericarditis), while salicylates are usually reserved for

milder presentations. ARF is an autoimmune disease that requires a multi-discipline effort [30,31]. Caution must be used with either therapy alone, as rebound can be seen with steroids and relapse with salicylates. Treatment duration usually lasts over a total of 12 weeks, and is often accompanied by the recommendation for bed rest over several weeks until the inflammation has calmed. Unfortunately, according to a Cochrane review published in 2003 of 8 randomized controlled trials, the use of anti-inflammatory treatment in acute carditis does not appear to improve the risk of developing cardiac lesions over the long term [32]. Heart failure is mainly treated supportively, with the use of such medications as digoxin (though patients are quite sensitive to this medication, with the danger of potentiating heart block), diuretics, and sodium nitroprusside [21,33]. Surgical options are often considered in correcting the consequences of valvular damage by bouts of rheumatic fever, particularly when stenosis or regurgitation is severe and unresponsive to medical treatment alone. In recent years, with the development of new technology, it has been demonstrated that valve repair is preferable to valve replacement in the mitral, aortic and tricuspid positions. Benefits of repair include decreasing the risk of embolic disease, surgical mortality, and the risk of bleeding associated with warfarin use necessary for prosthetic valves [26,34]. The arthritis of RF is quite responsive to salicylates and NSAIDs as well. Treatment of rheumatic chorea generally is supportive, as it tends to resolve on its own; however, it has been proposed that steroids may help to shorten the duration of symptoms, and may be potentially used to treat severe or refractory disease, though this remains controversial [35]. Other medications that may be of use in refractory chorea include carbamazepine or valproic acid, though the risks of toxicity from these medications need to be strongly considered before treatment initiated [2]. 9.1. Antibiotic prophylaxis for rheumatic heart disease RHD is also a well-known risk factor for infective endocarditis, and has been estimated to be the cause of valvular damage in 63% of these cases [1]. Because of this, they were previously categorized alongside those with prosthetic valves and congenital heart disease, and have long been recommended to undergo antibiotic prophylaxis prior to having any dental, gastrointestinal, or genitourinary procedures. In 2007, however, the AHA released updated guidelines that significantly differ from previous statements, drastically decreasing the number of patients requiring infective endocarditis (IE) prophylaxis for surgical procedures. These new guidelines are in response to weighing the risks and benefits of providing antibiotics in these situations, and to new data that a very small number of cases appear to be prevented by prophylaxis, believing that IE is much more likely to stem instead from bacteremia resulting from daily activities. They now recommend prophylaxis only prior to dental procedures and in the following individuals: those with a history of IE; those with prosthetic valves or those with prosthetic material used for cardiac valve repair; those with congenital heart disease with certain stipulations; and cardiac transplant recipients with regurgitation secondary to an abnormal valve. Patients solely with rheumatic heart disease who do not meet the above criteria now appear to have been removed from the list of those individuals needing antibiotic prophylaxis [36]. 10. Prevention 10.1. Primary prevention The goal of primary prevention of ARF is to guard against the development of the initial attack of rheumatic fever by providing appropriate antibiotics for the initial episode of GAS pharyngitis. Cost analysis for primary, secondary, and tertiary prevention of RF and RHD in Pondicherry Union Territory, India found strategies for primary

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prevention to be significantly cost effective, with strategies aimed at diagnosing and treating the initial symptoms of GAS pharyngitis [37]. The ideal treatment is a single intramuscular dose of benzathine benzylpenicillin, given the ease of compliance; however, a 10 day course of penicillin V or erythromycin (for those allergic to penicillin) can also be used [21]. Other measures that are likely to be effective, but are difficult to implement, include decreasing overcrowding and improving access to medical care and antibiotics (see Fig. 1).

only a small number of studies were available and were of rather poor quality. As a result, more research likely is necessary to formulate an optimal dosing guideline.

10.3. Potential for vaccination Efforts have long been bent towards developing a vaccine as a method of improving both primary and secondary prevention. Difficulty, of course, lies in inducing immunity against GAS without causing the autoimmune reaction that in vitro infection would normally produce. In addition, given the epidemiology of GAS infection, protection against different strains may be required, depending on the endemic region. Particular attention has been focused on the M protein, which is a virulence factor found on the surface of GAS. It contains both a C-terminus that is conserved amongst many streptococcal strains and an N-terminus that has been found to be important in inducing strain specific immunity. A multivalent vaccine that specifically targets the N-terminal antigen in 26 potential serotypes has shown promising results in adults, and may soon begin clinical trials in children. Other potential targets include SCPA, MtsA/GRAB, and the cell-wall carbohydrate. The use of IVIG has been discussed elsewhere [40].

10.2. Secondary prevention Those individuals with a history of ARF or RHD have a high risk of becoming re-infected with GAS, predisposing them to recurrent rheumatic fever. Secondary prevention is aimed towards preventing just such an occurrence. According to the most recent WHO Guidelines, published in 2004, the antibiotic of choice in secondary prevention is penicillin [38]. The recommendations are for a continuous dosing regimen of intramuscular benzathine benzylpenicillin every 3 (in high risk populations) to 4 weeks. Twice daily oral penicillin V is also an option but, expectedly, concerns have been raised about long-term compliance given its dosing frequency. In those who are penicillin allergic, a daily oral sulfonamide can be used. It has been recommended that prophylaxis be continued for at least 5 years after the initial attack, given recurrence rates are the highest during this period [21]. The American Heart Association's most recent guidelines, published in 1995, are more explicit in detailing a longer duration of therapy. In those with residual cardiac sequelae, prophylaxis is recommended for at least 10 years after the last episode of RF and until at least 40 years of age. In those without chronic valvular disease, it is still recommended that they undergo at least 10 years of therapy or until well into adulthood [39]. In a closer look at the literature published regarding penicillin dosing for secondary prevention, a recent Cochrane review examined nine studies that researched the use of penicillin in children and adults with a history of rheumatic fever. The following conclusions were gleaned: (1) penicillin was better than placebo in preventing recurrent attacks; (2) intramuscular penicillin was preferable to oral penicillin; and (3) more frequent (performed either every 2–3 weeks) injections of penicillin appeared to be more effective than injections performed every 4 weeks. However, the authors do emphasize that

11. Conclusions Rheumatic fever, particularly because of sequelae from rheumatic heart disease, still remains a significant cause of morbidity and mortality in the developing areas of the world. Early and accurate diagnosis, using the updated Jones' criteria, is key in managing and preventing severe consequences of this disease. In particular, the diagnosis of rheumatic carditis may be helped by today's more sophisticated echocardiographic techniques, though determination of the extent of pathology of subclinical carditis is still controversial. Currently, long-term antibiotics are still the mainstay of secondary prevention, which comes, expectedly, with difficulties in compliance. The future brings new developments, including research into a vaccine directed against the various rheumatogenic strains of Streptococcus pyogenes. However, challenges still remain in inducing immunity against these strains without causing autoimmunity.

Fig. 1. Cornerstones of prevention in rheumatic fever and rheumatic heart disease.

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Take-home messages • Rheumatic fever primarily affects children and adolescents of less developed nations, particularly those residing in areas of low socioeconomic status and indigenous areas. • Rheumatic heart disease remains the most serious sequelae of rheumatic fever and causes considerable global morbidity and mortality. • Rheumatic fever is a result of molecular mimicry following infection with group A streptococcus (GAS), or Streptococcus pyogenes. • Diagnosis of rheumatic fever is dependent on the presence of multiple criteria, including carditis, polyarthritis, Sydenham's chorea, erythema marginatum, and subcutaneous nodules. • Accurate diagnosis and compliance to antibiotic prophylaxis are key to primary and secondary prevention of rheumatic fever. • Upcoming developments in the development of a vaccine against group A streptococcus may help to revolutionize the course of future rheumatic disease. References
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High alpha-defensin levels in patients with systemic lupus erythematosus Innate immunity plays a role in systemic lupus erythematosus (SLE). The objective of this study was to determine the levels of defensins, which are antimicrobial and immunomodulatory polypeptides, in SLE. Sthoeger ZM. et al. (Immunology 2009; 127: 116-22). Sera from SLE patients and healthy controls were tested for pro-inflammatory human beta-defensin 2 (hBD-2) and for alpha-defensin human neutrophil peptide 1 (HNP-1).hBD-2 could not be detected by ELISA and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast, the mean alpha-defensin level in the sera of all SLE patients (11.07 ± 13.92 ng/microl) was significantly higher than that of controls (0.12 ± 0.07 ng/microl). Moreover, 60% of patients, demonstrated very high serum levels (18.5 ± 13.36 ng/microl) and 50% showed elevated gene expression in polymorphonuclear cells. High alpha-defensin levels correlated with disease activity, but not with neutrophil count. Thus, activation and degranulation of neutrophils led to alpha-defensin secretion in SLE patients. Given the immunomodulatory role of alphadefensin, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.