Introduction
Rheumatic fever (RF) is an acute, diffuse, and nonsuppurative inflammatory disease that occurs as a delayed complication after an untreated or partially treated pharyngotonsillitis, the infection itself sometimes being asymptomatic. It is caused by group A β-hemolytic S treptococcus , specifically, S treptococcus pyogenes . The process is triggered by an inappropriate immunologic response, both humoral and cellular, and results from a complex interaction between individual susceptibility, environment, and bacteria. The disease is characterized by four distinct phases. The initial streptococcal pharyngotonsillitis is followed by the latent period and then by the acute and chronic phases. The chronic phase is also known as rheumatic heart disease, when the cardiac lesions remain as sequels of the acute phase. RF has the potential to involve multiple organ systems including the heart, the joints, the brain, and the subcutaneous and cutaneous tissues. Cardiac injury is the most important manifestation, and it is the damage to the heart that produces its clinical, social, and economic impact.
Both RF and chronic rheumatic heart disease continue to pose serious concerns with regard to health in many parts of the world, and present a significant challenge for those involved in providing health care. In developed countries, although its frequency has been markedly reduced since the 1950s, RF remains a risk because of its potential for resurgence. The disease still presents a high incidence in many resource-limited settings, where it is often the most frequent cardiovascular disease in people younger than 25 years. RF still maintains a noteworthy high incidence in some indigenous populations. In low- and middle-income countries, this preventable disease continues to be both socially and clinically devastating, with significant rates of morbidity and mortality. Acute episodes of RF are still a cause of death in childhood and its sequels are the major cause of cardiovascular death in children and young adults. The repercussions of the disease involve patients of all ages, since the valvar sequels can be a condition carried throughout life. The children and adolescents who are most frequently admitted to hospital with acute episodes are the same individuals who, after the fourth decade of life, will constitute large numbers when analysis is focused on invasive intervention and death. The economic impact must also be considered, not only with regard to the financial costs of clinical and surgical treatments, but also relative to the loss of productivity as the result of a disability acquired at an early age.
Historical Background
From the historical perspective, the clinical manifestations of RF had been well described prior to the recognition of the complete syndrome. Arthritis had been mentioned since the days of Hippocrates, but only in the 17th century did the French doctor Guillaume de Baillou distinguish acute articular rheumatism from the other forms of rheumatism. In the posthumous edition of the Liber de Rheumatismo et Pleuritide dorsali , published in 1642, he was the first author to use the term rheumatism to describe the acute form of arthritis. Thomas Sydenham, in England, in his book Observationes Medicae , published in 1676, provided an accurate description of the acute migratory polyarthritis as distinct from gout. He also described, 2 years later, St. Vitus’ dance, another major manifestation of RF, which we now call Sydenham chorea. Important discoveries in cardiac pathology were made in the 18th century. Warty vegetations and thickening of the valvar leaflets as an isolated postmortem feature were recognized in 1709 by Giovanni Maria Lancisi, while Raymond Vieussens in 1715 contributed a description of mitral stenosis, with calcification of the leaflets. Giovanni Battista Morgagni, in the tome De Sedibus , published in 1761, dealt with lesions of all cardiac valves and described endocardial vegetations. The association of cardiac disease and rheumatism was noted by Morgagni but deemed coincidental. In the same year, Richard Pulteney, on the basis of his observation of pathology, called attention to the association of cardiac involvement and acute articular rheumatism. Matthew Baillie, nonetheless, in his tome entitled A Series of Engravings Tending to Illustrate the Morbid Anatomy of Some of the Most Important Parts of the Human Body , gave credit for this recognition of a causal relationship between cardiac disease and rheumatism to David Pitcairn. The first full account of the pathology of RF was then provided in 1808 by Dundas, who underscored the relationship of the cardiac features to rheumatism. In 1812, a detailed report was given in On Rheumatism of the Heart by William Charles Wells, who in 1813 also described the subcutaneous nodules. This author confirmed that, although Pitcairn had failed to provide a written record, he had already by 1788 established the association between rheumatism and cardiac lesions. The introduction of the stethoscope by René Laennec in 1816 facilitated the study of cardiac diseases, but not until 1832 did Jean-Baptiste Bouillaud provide a detailed account of rheumatic cardiac disease, correlating the clinical events with the postmortem findings. In his treatise Traité clinique des maladies du coeur he introduced the term endocarditis and clarified the clinical picture, giving an accurate account of the cardiac involvement and other manifestations in patients with RF. The eponym maladie de Bouillaud for RF recognized his great contribution, distinguished by its exceptional accuracy and clinical significance. In the same year, James Hope, as had already been pointed out by Wells and Dundas, detailed and emphasized the association of acute pericarditis with RF. In the Harveian lecture of 1898, Walter Butler Cheadle offered a full description of the RF syndrome as we know it today: carditis, polyarthritis, and chorea as well as subcutaneous nodules and erythema marginatum. Thus RF was first described about 120 years ago. Subsequently, the pathognomonic and distinctive microscopic nodules of rheumatic carditis were described in 1904 by Ludwig Aschoff.
The first report of a possible connection between a bacterial infection and RF had been suggested by Mantle in 1887, but it was not until early 1930s that the causal relationship between infection by the β-hemolytic streptococcus and RF was established. From then on, data about the disease was gathered in many other fields. Todd, in 1932, introduced a method for measuring one of the antibodies developed by the human body after the contact with the bacteria. Then, a year later, Rebecca Lancefield classified Streptococcus into five distinct groups. Subsequently, continuous administration of sulfanilamide was shown to prevent recurrences followed in 1950 and 1951 with demonstration that adequate treatment of streptococcal pharyngitis with penicillin prevented the disease.
As early as 1944, Thomas Duckett Jones had proposed a set of clinical and laboratorial data to guide and reduce the overdiagnosis of RF. The Jones criteria were subsequently modified and updated by the Committee of the American Heart Association. Subclinical carditis, diagnosed by echocardiography and Doppler, has been included in the last revision, published in the year 2015. Jones criteria have long been recognized as guidelines for the diagnosis of the first episode of the acute phase. The knowledge of the action of antibiotics in preventing the disease, and the systematization of the diagnosis by means of the important Jones criteria, heralded a new era of studies.
Epidemiology
RF has a universal distribution, although significant differences in the rates of incidence and prevalence depend on the interaction of characteristics of the etiologic agent and its human host, besides environmental and socioeconomic conditions. RF has almost disappeared in developed countries; it remains rampant in countries and regions characterized by poverty, overcrowding, and lack of adequate health care. Due to the causal relationship of streptococcal pharyngotonsillitis and RF, the epidemiology of the two diseases is closely related. As with most diseases, factors responsible for the occurrence of RF may pertain to the host, the environment, or the pathogen, or a combination of all three. A genetic predisposition has been previously suggested based on association of rheumatic heart disease with certain haplotypes such as HLA DR2, DR4, DR1, and DRw6; however it has not been convincingly proven. A meta-analysis of twin studies showed a concordance risk of RF of 44% in monozygotic and 12% in dizygotic twins. RF is more frequent among children and adolescents between the ages 5 and 15 years, and has a peak of incidence around the ages of 8 to 9 years. These ages coincide with the peak of streptococcal pharyngotonsillitis in school-aged children; this infection is found to be less common in late adolescence and in adults. Likewise, RF is uncommon in children younger than 4 years and exceedingly rare under the age of 2 years. Data from Brazil revealed that 2.5% of patients had their first episode before age 3 years. In a study from India, Aschoff bodies were found in one-tenth of autopsied cases, the majority from patients between 16 and 40 years of age, indicating a recent attack of carditis. Under special circumstances, such as focal epidemics of streptococcal infections in military populations or closed institutions, the incidence of RF can increase in adults.
RF occurs in all populations, and shows equal frequency in both genders. The exception is Sydenham chorea, which is more common in females, and is hardly ever seen in males after puberty. RF has usually been reported as a disease of the temperate climates, but currently it is more prevalent in warm tropical climates, especially in low- and middle-income countries. Similarly, the influence of seasonal variation in the rates of incidence is now less defined, but in general follows that of streptococcal infections, which are most commonly observed in late winter and early spring. The disease is reputed to be more frequent in urban centers than in rural communities, but this is probably due to overcrowding. Although data thus far are inconclusive, it has been suggested that there is an increased susceptibility to RF in certain ethnic groups. The aboriginals of Australia’s Northern Territory, and the Polynesians, both from rural areas, show a markedly increased incidence of the disease. In Hawaii, wide differences in the prevalence of chronic rheumatic heart disease have been documented in Samoan schoolchildren when compared with white Hawaiians. Similarly, higher frequencies of RF and chronic rheumatic heart disease have been found in the Maori population of New Zealand, and among black schoolchildren in South Africa. Data from India show a more severe or malignant disease, with multivalve involvement and congestive heart failure even in the first attack of RF. Many factors, however, can overlap and interfere in the calculations of the incidence of RF and the prevalence of chronic rheumatic heart disease, since different rates can be found under diverse environmental conditions for any given population. In this context, besides the role played by the bacteria and human host, other factors, such as differences in patterns of living conditions and streptococcal exposure, in addition to quality of and access to health care, are important and can impact the geographical distribution of the disease, as well as the severity of its sequels.
All over the world, pharyngotonsillitis is one of the most prevalent infections caused by the β-hemolytic streptococcus. It accounts for up to one-third of the throat infections in children, and up to one-tenth in adults. Although streptococcal infections are very frequent, only a few individuals develop RF. It is calculated that under endemic conditions, 0.3% of untreated infections, and 3% in epidemics, will lead to a first episode of RF. Despite the fact that group A Streptococcus has continued to constitute about 30% of all pharyngitis in children over the past five decades, the occurrence of RF in industrialized countries has fallen to a great extent. The reasons for this selective decline are not entirely clear. It is presumed to be linked to change in the epidemiology of Streptococcus pharyngitis with a shift from rheumatogenic to nonrheumatogenic strains. In some of the Aboriginal population of the Northern Territory of Australia, RF has occurred secondary to pyoderma rather than pharyngitis, and group C and G Streptococci rather than group A Streptococci. An analysis of emm type distribution shows a variation in the molecular epidemiology of group A Streptococcus (GAS) infections in Africa and the Pacific in comparison with that observed in high-income countries.
Recurrences of RF, as a consequence of inadequate prophylaxis, are more frequent in low- and middle-income countries, where predisposing factors to streptococcal infections still persist. The risk of subsequent attacks increases with the number of previous attacks, with the continued exposure to streptococcal infections, and falls with age. The recurrence rate is higher during the first 5 years subsequent to the acute episode, particularly in the first 2 years. Likewise, the risk of other attacks is higher in patients receiving oral secondary prophylaxis when compared to parenteral medication. The clinical features of subsequent attacks show a tendency to mimic those seen in the initial attack. Prospective follow-up to identify predictors of significant chronic rheumatic valvar disease shows that almost half of recurrences occur in the first 2 years of the disease ( Fig. 54.1 ).
In spite of a decline in both frequency and severity, RF still remains a risk. According to a recent published study a total of over 33.4 million individuals are affected by rheumatic heart disease worldwide. In low- and middle-income countries, the incidence of RF is still very high, with a wide variation from 1.0 to 254 for each 100,000 of the population. Regions with the highest rates are likely to have the least accurate data with substantial underreporting. In some high-income countries, there are population groups that live in poverty and have high rates of RF and rheumatic heart disease, as in the indigenous populations of northern and central Australia and New Zealand. The Aboriginal population living in the Northern Territory of Australia has the highest documented incidence rate of RF at 153 to 380 cases per 100,000 children aged 5 to 14 years. More than 300,000 cases of RF occur in children and adolescents aged from 5 to 14 every year. Although a downward trend has been noticed worldwide, the rates in some areas are similar to those found in developed countries at the turn of the 20th century. Investigations in the Aboriginal communities in northern Australia suggest a lifetime risk for having RF to be as high as 5% to 7%.
RF, nonetheless, has now become rare in developed countries, where the incidence is estimated at below 1 for each 100,000 of the population. The reasons for this decline of up to 100-fold over the last 50 to 60 years are not completely understood. Several factors are involved, but none can explain this decline when considered in isolation. It has been attributed to the decreasing rheumatogenic potential of group A streptococcal strains, and to changes in susceptibility of the human host, besides the modifications in the environment. In this context, the increased nutrition and better living conditions, as a consequence of improvements in social and economic standards, have contributed to reduce the spread of infecting agent. Other determining factors are the better availability of health care and the advent of antimicrobial agents. The widespread use of antibiotics has accelerated the decrease of the disease in terms of both morbidity and mortality. A fourfold acceleration of the decline was observed after the introduction of penicillin and other antibiotics. Furthermore, the establishment of stricter clinical criteria enhanced the accuracy of the diagnosis, and consequently reduced overdiagnosis. Technological advances in laboratory diagnosis also improved the differential diagnosis from other cardiac diseases, such as congenital structural diseases, myocarditis, and mitral valvar prolapse, which in a clinical setting had often been misdiagnosed as RF.
Despite the apparent control, the disease had resurged in the United States of America by the mid-1980s. During the last 2 decades of the 20th century, outbreaks were reported in distinct geographical regions of the country among different age groups, mainly schoolchildren and young adults in military bases. The outbreaks showed an unexpected pattern, occurring among white, middle-class patients with ready access to health care and antibiotic therapy. Between 1985 and 1988, a national survey was performed in cities of 24 states of the United States, and showed evidence of an increase in the number of cases from 5 to 12 times when compared to the previous decade. Isolated reports of increased frequency of RF also came from Europe. With the collapse of USSR, the incidence of RF also increased significantly in the formal central Soviet Republics, approaching 233 per 100,000 in children in Kyrgyzstan.
No isolated factor can be held responsible for the epidemiologic changes in both the disappearance and the reappearance of RF, and the underlying reasons have still to be completely explained. It has been questioned whether the outbreaks represented a true risk of return of the disease, or simply were an oscillation in its declining profile of incidence.
Etiology and Pathogenesis
A broad range of clinical manifestations may occur after a streptococcal infection, varying in severity from mild and superficial dermal infection to necrotizing fasciitis or severe septicemia. Nonsuppurative sequels depend on a delayed immune-mediated host response, and include RF, acute glomerulonephritis, and reactive arthritis. As we have already discussed, the association between streptococcal pharyngotonsillitis and the subsequent development of RF was recognized in the first half of the 20th century, but the pathogenesis of the disease continues to be an area of active research. Major advances in the understanding of the pathogenic mechanisms have only recently been achieved from immunologic, molecular biologic, and genetic studies. Susceptibility to RF depends on the interaction between Streptococcus components and host factors, influenced also by environmental conditions. Both humoral and cellular delayed immune responses to streptococcal throat infection take part in the process. Their extension determines the severity of the disease in one individual. In particular, autoimmunity against the tissues of the host plays a key role in the pathogenesis and progression of the disease. Molecular mimicry between streptococcal antigens and several human tissues such as cardiac valves and myosin, cartilage, synovial and cerebral proteins has been proposed and proved to be the basic mechanism triggering autoimmunity. It is important to emphasize that bacteria are absent from the acute and chronic tissue lesions of RF.
Streptococcus and Its Antigens
Streptococcus pyogenes, or the GAS, is a gram-positive extracellular bacterium covered by an outer layer of hyaluronic acid. Its cell wall is composed of repeating units of N-acetyl D-glucosamine carbohydrates linked to a rhamnose polymer backbone ( Fig. 54.2 ).
The classification of the microorganism in serogroups is based on the serology of the mural polysaccharides, giving groups A, B, F, and G. The concept of different bacterial strains causing disease in specific target organs emerged from decades of epidemiologic studies, revealing serotypes of GAS as having a strong tendency to cause pharyngotonsillitis, and others to be associated with impetigo. Although different serogroups may also cause throat infections, there is no evidence linking bacteria from the remaining serologic groups with the development of RF.
The M, T, and R proteins on the bacterial cell surface, along with lipoteichoid acid, are involved in the adhesion of the bacteria to the host epithelial cells, and in their ability to resist phagocytosis in the human host (see Fig. 54.2 ). Thus far, it has proved possible to identify more than 100 M serotypes, based on the antigenic variation of the N-terminal portion. The M protein is particularly important in determining the virulence of the microorganism, since it promotes avid adherence to host tissues. Moreover, it is the M protein that shares structural homology with certain alpha-helical human molecules such as myosin, tropomyosin, laminin, vimentin, keratin, and laminin, thus forming the basis for the immune-mediated postinfectious sequels. Laminin is an extracellular matrix protein present in the cardiac valves, being secreted by the endothelial cells that line them.
The M protein molecule itself has a variable composition ( Fig. 54.3 ). As explained, its N-terminal portion contains the A-repeat region that produces antigenic variation. The B-repeat region also varies from serotype to serotype, while the C-repeat regions contain highly conserved epitopes. Classification of Streptococcus into class I or class II depends on whether their M protein reacts with a monoclonal antibody that targets epitopes in the C-repeat region. While class I strains are predominantly negative for the production of serum opacity factor and are recognized as rheumatogenic, class II strains produce the serum opacity factor, bind fibronectin, and are usually associated with production of glomerulonephritis. Serotypes, such as M types 1, 3, 5, 6, 14, 18, 24, have also been associated with the development of RF. An alternative means of serotyping is to sequence the gene encoding the 5′ terminal end of the M protein. A great range of genetic diversity has been shown in this fashion in isolates recovered from many different geographic locations. The identification of these so-called emm types present in a community at the time of an outbreak of RF permitted recognition of the types most commonly associated to the disease, and revealed emm types 1, 3, 5, 6, 14, 18, 24, 17, and 29 to be rheumatogenic. This concept of rheumatogenicity, however, has recently been challenged, since some types frequently associated with acute RF are infrequently found in several communities with high burdens of the disease, where new, non-M antigen typeable microorganisms have been identified. These new types probably result from genetic recombination between different strains of the GAS. It is not surprising that a clear distinction between the rheumatogenic and nonrheumatogenic strains of the GAS does not exist in areas of the world with high rates of superficial infections, since multiple genetically distinct strains circulate at the same time. Usually, a higher diversity of strains circulate in low-income areas of the world while from high-income populations a relatively limited number of emm serotypes have been recovered. This broad genetic diversity has important implications in the development of a vaccine against streptococcal infections.
Human Host
Alleles of the Human Leukocyte Antigen Associated With Rheumatic Fever
Considering that less than 3% of the patients with acute streptococcal pharyngotonsillitis develop RF, it is reasonable to suggest that the genetic predisposition of the individual plays an important role in the pathogenesis of the disease. In the 19th century, it was suggested that both RF and rheumatic heart disease were hereditary, possibly transmitted in autosomal recessive fashion. Further studies on the determinants of host susceptibility indicated that the immune response to streptococcal infection is genetically controlled. More recently, molecular biologic techniques have identified an association between the disease and some alleles of the major histocompatibility complex. These class II human leukocyte antigen molecules are expressed on the surface of antigen-presenting cells, such as macrophages, dendritic cells, and B cells. Together with the bound peptide antigen, they trigger the activation of T-lymphocytes. Several such alleles have been associated with RF in different countries ( Table 54.1 ). While DR7 is the allele most frequently associated with RF in Brazil, Turkey, and Latvia, the DR4 allele is found in American-Caucasian, Indian, and Saudi-Arabian patients. Recently, in Mexican and Brazilian patients with rheumatic heart disease, some alleles of the tumor necrosis factor alpha, also located in the region of the major histocompatibility complex, were described with increased frequency. A possible explanation for the frequent association of certain alleles with the development of RF and rheumatic heart disease is that these molecules might cause inappropriate activation of the T-cells, resulting in autoimmunity. Large future multiethnic genome studies shall provide more comprehensive understanding of the genetic susceptibility to RF.
| HLA Class II Allele | Country |
|---|---|
| DR1 | South Africa Martinique |
| DR2 | United States Mexico |
| DR3 | Turkey India |
| DR4 | United States Saudi Arabia India |
| DR5 | Turkey |
| DR6 | South Africa Egypt |
| DR7 | Brazil Turkey Latvia Egypt |
| DR9 | United States |
| DQA1*0104 | Japan |
| DQB1*05031 | Japan |
Interactions Between Host and Pathogens
It is well recognized that the molecular mimicry between some antigens present on the surface of GAS and specific human tissues triggers the autoimmune response causing acute RF. Structural similarities between streptococcal M protein and myosin are the key for the development of acute carditis. On the other hand, valvar lesions are triggered by immune reactions against human proteins such as laminin, an alpha-helical coiled-coil molecule present in the valvar subendothelium. Both the humoral and cellular arms of the immune response take part in the host response against these self-proteins sharing some homology with Streptococcus . Despite the strong evidence of the existence of a molecular mimicry between the host tissues and the microorganism, some authors have questioned the likelihood of such mimicry in RF based on the description of an autoantibody reaction against collagen IV in the disease.
Humoral Response
After the adherence of the bacteria to the host cells, the processes of colonization and invasion supervene, inducing the production of type-specific antibodies by B-derived mononuclear cells, leading to opsonization and phagocytosis. As pointed out recently, heart-reactive antibodies were first described by Calveti in 1945. The recognition of cross-reactive streptococcal epitopes and human antigens, mainly myosin and laminin, led to a great advance in the studies directed to the knowledge of the mechanism of the disease.
Cross-reaction between antibodies to cardiac valvar tissue and the N-acetyl glucosamine of the polysaccharide from GAS has been clearly demonstrated. Additionally, some studies have shown that the cross-reacting antibodies bind to the endocardial surface of valves, upregulating the local expression of adhesion molecules like vascular cell adhesion molecule-1, which facilitates infiltration of inflammatory cells inside the valvar leaflets, which are avascular, leading later to scarring ( Fig. 54.4 ). The pathogenic mechanism responsible for the Sydenham chorea present in some patients with acute RF is also dependent on the cross-recognition of neuronal tissue proteins by antibodies directed to the N-acetyl-glucosamine of Streptococcus . Such antibodies against the group A carbohydrate of Streptococcus spp. attack the neurons from basal ganglia, activating an altered cell signaling toward increased levels of dopamine, leading to abnormal movements and behaviors.
Cellular Response
T lymphocytes of subsets CD4 and CD8 are the main mediators of the myocardial and valvar lesions of RF and rheumatic heart disease, participating in a delayed-type hypersensitivity reaction (see Fig. 54.4 ). Cross-reactive antibodies upregulate the vascular cell adhesion molecule 1 (VCAM1) on the surface of the valvar endothelium, promoting infiltration of T cells into the valvar stroma. In the acute phase, the pathognomonic histologic feature is the Aschoff body, a granulomatous lesion found in both the myocardium and in valvar leaflets, and composed of T, B lymphocytes and macrophages, large mononuclear cells, and polymorphonuclear leukocytes. The presence of activated macrophages inside the bodies is consistent with an immune response of the CD4 + T helper 1 type.
Proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin-1, are overproduced by peripheral blood mononuclear cells in patients with RF. They are also predominantly expressed by mononuclear inflammatory cells inside the chronic valvar lesions, indicating their local role even in the chronic phase of the disease. Cytokines are considered important second signals after infections, triggering effective immune responses in most individuals, but in the context of autoimmune diseases they induce a deleterious response. T cell recruitment to the sites of inflammation is favored by specific chemokines and contribute to the maintenance of the rheumatic lesions. Differences in the pattern of cytokine production were observed between inflammatory cells derived from valvar and myocardial tissue from patients with RF. These findings reinforce the putative role of these regulatory cytokines in the myocardial healing, but not in valves, where the damage is progressive and permanent. The sparing of the right-sided cardiac valves in most cases of RF is usually attributed to the lower pressure and shear stress to which they are usually submitted compared to the left-sided valves. Quadrivalvar rheumatic disease has been reported only rarely, and usually then in patients with congenitally malformed hearts. The location of the acute valvar lesions along the lines of closure of the leaflets corroborates the hypothesis that lesions occur at places that are most liable to trauma.
Vaccine Development
Several efforts have been devoted in different centers to producing an effective vaccine against infection by the GAS, to avoid the occurrence of acute RF. A safe vaccine should evoke protective immune responses against Streptococcus , without eliciting tissue cross-reactive immunity. If the main mechanism of immunity generation against GAS infection is type-specific antibody protection, the challenge of a vaccine covering more than 200 emm types would be enormous. Different models of vaccines under development are based on the N- and the C-terminal regions of the surface-expressed M protein, while others focus on other streptococcal antigens. A promising antigen for a candidate vaccine is the C-terminal region of the M protein, which is conserved and common to most strains. Although some clinical trials are about to show the first results of vaccine development, global coordination and funding are among the main challenges to overcome for its production.
Morphology of the Acute Cardiac and Extracardiac Lesions
The sequence of immunologic events described above culminates in the development of acute RF, which presents as exudative and proliferative inflammatory reactions in the connective tissue of the affected organs. These lesions are more distinctive within the heart, but involve also the joints, subcutaneous tissue, brain, and vessels of the lung. Basically, they are characterized by mononuclear inflammatory cells around a focus of fibrinoid necrosis. In the heart, the pericardial, myocardial, endocardial layers are all affected; hence there is a pancarditis. The histologic landmark of acute RF is the Aschoff body, found underneath the valvar endocardium and in perivascular areas of the myocardium, to be described below.
Grossly, the pericarditis is characterized by the deposition of a serofibrinous exudate, giving the so-called “bread-and-butter” appearance. Acute valvar lesions are found as small vegetations of 1 to 2 mm along the lines of closure on the atrial aspect of the atrioventricular valves, and on the ventricular surface of the arterial valves ( Fig. 54.5 ). These small verrucous lesions may extend to the tendinous cords of the atrioventricular valves, and in rare instances, mainly in children, may be associated with chordal rupture, causing severe valvar regurgitation and cardiac failure. Microscopically, the vegetations are composed of fibrin thrombus overlying an area of fibrinoid necrosis of the valvar connective tissue. These areas of necrosis are surrounded by a dense inflammatory infiltrate, containing mononuclear cells and occasional giant cells. Presumably, the fibrin vegetations accumulate on the ulcerated endocardium in areas of extrusion of the damaged collagen ( Fig. 54.6 ). Although the typical Aschoff bodies, pathognomonic of the disease and most commonly seen in the myocardium, are not usually found in valvar tissues, the acute verrucous valvar lesion transforms with time, showing inflammatory cells arranged in palisade around the central necrotic core. These lesions eventually heal, producing local fibrosis. Moreover, the adjacent tissue of the valvar leaflets is edematous, and shows a diffuse nonspecific mononuclear infiltrate. Neovascularization is not a feature in this phase of the disease, but thin-walled blood vessels can be seen invading at the base of implantation of the leaflet.
In the case of a recurrent attack, the fibrin vegetations still appear on the same structures, but there are already valvar sequels, such as cordal fusion and thickening of the leaflets ( Fig. 54.7 ). The relative frequency of valvar involvement correlates to the hemodynamic closing pressures, the decreasing order being mitral, aortic, tricuspid, and pulmonary.
Although myocardial involvement in acute RF is sometimes called myocarditis, direct myocytic injury as it is observed in the usual form of acute viral myocarditis is not a feature. Instead, the finding of multiple Aschoff bodies is the fingerprint of the disease. These granulomatous nodules are usually located in the connective tissue around small vessels ( Fig. 54.8 ). They show fibrinoid necrosis surrounded by lymphocytes, some plasma cells, and plump macrophages with abundant cytoplasm and a clear nucleus where a central wavy ribbon of condensed chromatin is observed. These are called Anitschkow cells, or “caterpillar cells,” the latter reflecting their appearance when cut longitudinally. Multinucleated macrophages may also be present, and receive the name of Aschoff giant cells. Aschoff bodies often appear in the myocardium about 4 weeks after the acute onset of RF, and may remain in the tissue for as long as 3 to 6 months. Although the earliest lesions show prominent fibrinoid necrosis and inflammation, as described above, the life cycle of the nodule continues with a gradual decrease in the cellular content. The complete healing of those lesions takes the form of a fibrous scar around small myocardial vessels.
The role of myocarditis in the failure of the heart in acute RF has recently been questioned, since levels of troponin I are typically within normal limits, which indicates absence of direct damage to cardiomyocytes as described above. Since most patients with heart failure have valvar dysfunction, mainly isolated mitral regurgitation, or combined mitral and aortic regurgitation, this in itself could explain the congestive symptoms. Even without direct damage to the contractile cells, nonetheless, the myocardium in the setting of acute RF is edematous and, besides the Aschoff bodies, an interstitial mononuclear inflammatory infiltrate of variable intensity is a common finding. The process has been referred to as interstitial carditis. Such features could disrupt the myocardial integrity, and possibly interfere with the cardiac function. Dilation of the mitral annulus is also a contentious topic. Some believe that valvar regurgitation precedes dilation of the chambers, while others argue that myocardial impairment comes first, since in the acute phase the leaflets are just mildly deformed by fibrin deposition. Since it is virtually impossible to be certain that a given episode of rheumatic carditis is the first, valvar regurgitation, when present in the context of an acute carditis, could always be the consequence of previous deformity of the leaflets. Another lesion considered characteristic of the acute phase is MacCallum patch. This is an endocardial lesion on the posteroinferior left atrial wall, frequently containing Aschoff bodies when examined histologically. This thickening, however, is more likely to be a “jet lesion” from mitral regurgitation than a specific rheumatic lesion. Although the diagnosis of acute RF is usually made on clinical grounds, the endomyocardial biopsy is said to have value in diagnosis. Histologic diagnosis, however, is based on the presence of Aschoff bodies. These structures were found, in one study, in less than one-third of patients with acute RF, and only two-fifths of those with recurrent attacks. This suggests that endomyocardial biopsy is not likely to add important diagnostic information.
Diagnosis
Clinical Manifestations
Since the description provided by Cheadle in 1889, no modifications have been incorporated into the clinical profile of RF. The disease is characterized by its uniformity as a syndrome and by its diversity as a multisystemic disease. The clinical presentation, with its variable patterns of symptoms and signs, is determined by the site of involvement, by the time of appearance along the course of the acute attack, and whether the manifestations occur alone or combined. Additionally, the clinical picture is also influenced by a wide range in severity of the individual manifestations.
The latent, or asymptomatic, period between streptococcal infection and the onset of RF lasts from 1 to 5 weeks, more frequently between 1 and 3 weeks. Sydenham chorea usually is a delayed manifestation and it may take longer to appear, between 1 and 6 months. The acute episode is time limited, ranging from 6 to 12 weeks, but sometimes as long as 6 months in patients with severe carditis. The duration of the latent period is similar in both, the first episode and recurrences. No single symptom or sign is pathognomonic, nor are there specific laboratory tests. The diagnosis is made on a clinical basis. The supportive microbiologic and serologic laboratorial data is then used to characterize the underlying streptococcal infection, besides establishing the presence or the resolution of the acute inflammatory process. The diagnostic criteria formulated by Jones in 1944 have been revised and modified over the past decades. The reviews have clarified the categorization of major and minor manifestations, and emphasized the importance of the laboratory evidence of a preceding infection by the GAS. As a consequence, overdiagnosis has been reduced and more detailed information about clinical findings has been provided resulting in improvement of specificity. In addition, exceptions to the criteria were highlighted aiming at diminishing the risks of underdiagnosis. The division between major and minor criteria was based on the specificity of the manifestations for the diagnosis, and not on their frequency or prognostic significance.
Nonetheless, a single set of diagnostic criteria has become insufficient to encompass the variability in the clinical profile of acute episodes related to different populations in diverse geographic settings. Additionally, the concept of cardiac involvement in the absence of auscultatory findings, the so-called subclinical carditis, has emerged from the widespread use of Doppler echocardiography. Taking into account the technological advances and new evidence from epidemiologic data, the Jones criteria were last reviewed and updated in the year 2015 ( Table 54.2 ). First, subclinical carditis was incorporated as a major manifestation for all patient populations. Second, with the introduction of two different sets of diagnostic criteria based on population risk, monoarthritis or polyarthralgia was considered a major criterion for arthritis, and low-grade fever was included as a minor manifestation, both conditions applied only for moderate- and high-risk populations. Moderate–high risk is defined as coming from a population with an RF incidence of 2 or more per 100,000 school-aged children (usually 5 to 14 years old) per year or an all-age rheumatic heart disease prevalence of more than 1 per 1000 people per year.
| A. FOR ALL PATIENT POPULATIONS WITH EVIDENCE PRECEDING GAS INFECTION | |
| Diagnosis: initial ARF | 2 Major manifestations or 1 major plus 2 minor manifestations |
| Diagnosis: recurrent ARF | 2 Major or 1 major and 2 minor or 3 minor manifestations |
| B. MAJOR CRITERIA | |
| Low-risk populations (ARF incidence ≤2/100,000 school-aged children or all-age rheumatic heart disease prevalence of ≤1/1000 population per year) | Moderate- and high-risk populations (all populations that are not low risk) |
Carditis
Arthritis
Chorea Erythema marginatum Subcutaneous nodules | Carditis
Arthritis
Chorea Erythema marginatum Subcutaneous nodules |
| C. MINOR CRITERIA | |
| Low-risk populations | Moderate- and high-risk populations |
| Polyarthralgia Fever (≥38.5°C) ESR ≥60 mm in the first hour and/or CRP ≥3.0 mg/dL Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion) | Monoarthralgia Fever (≥38°C) ESR ≥30 mm in the first hour and/or CRP ≥3.0 mg/dL Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion) |
The five most characteristic clinical features constitute the major manifestations, namely carditis, arthritis, chorea, subcutaneous nodules, and erythema marginatum, independent of their severity. Classically, arthritis and carditis isolated or combined are seen most frequently. Chorea is less common, and the other major manifestations are rare ( Fig. 54.9 ). The minor manifestations are frequent and mostly related to the underlying systemic inflammation. These clinical and laboratorial findings are nonspecific but supportive of the diagnosis when accompanying a major manifestation. In addition to the Jones criteria, other nonspecific clinical findings may also be present during the course of the acute episodes.
The diagnosis of a first episode of RF includes the combination of two major, or one major and two minor manifestations, supported by evidence of a preceding infection with the GAS. When clinical or subclinical carditis is considered as a major manifestation, a prolonged P-R interval cannot be included as a minor manifestation in the same patient. Similarly, in the presence of arthritis, monoarthralgia, or polyarthralgia cannot be considered as a minor manifestation. Once other diagnoses are excluded, Sydenham chorea and indolent carditis are exceptions to the strict adherence to the Jones criteria. Since Sydenham chorea usually occurs as a late manifestation of the disease, evidences of the inflammatory process and of the preceding streptococcal infection could have already subsided when the major manifestation becomes evident. Similarly, evidence of a streptococcal infection is not required for patients with indolent carditis. This subacute condition is more frequently seen in young children and shows insidious onset and slow progression over several weeks or months. By the time of evaluation, the acute-phase reactants and levels of antistreptococcal antibodies may be normal. For the diagnosis of a recurrent attack, the complete set of Jones criteria is not needed when faced with a reliable history of a previous episode of RF, or an established chronic rheumatic heart disease. The diagnostic requirements are two major or one major and two minor or at least three minor manifestations, along with supporting evidence of a recent streptococcal infection. Diagnostic categories described as “possible” and “probable” RF have been used to include patients who did not meet the Jones criteria for a definitive diagnosis of an acute episode, although RF is the most likely diagnosis.
Major Manifestations
Carditis
The cardiac involvement is variable ranging from subclinical to severe presentation with heart failure and fulminating evolution ( Box 54.1 ). The severity of carditis is the most important prognostic factor. Only the lesions in the heart are potential causes of sequels and death during the acute attack or later. Cardiac failure is more common in recurrences and has been reported in around less than one-tenth of patients during the first episodes. The cardiac failure is characterized by pancarditis. The determinants of morbidity and mortality, nonetheless, are the degree and extent of endocarditis, represented by the damage in the cardiac valves. The pericardial and myocardial damages carry no long-term morbidity. The cardiac involvement tends to appear early, and is usually diagnosed within the first 3 weeks of the acute episode. Carditis is reported to be seen in up to three-fifths of first attacks although more recent series of patients have shown higher rates when echocardiography is included in the evaluation. Nonetheless, a prevalence of 28%, much lower than expected, has been documented in the Northern Territory of Australia.
a According to the protocol of the Rheumatic Fever Outpatients Clinic, Division of Pediatric Cardiology/Department of Pediatrics/Hospital das Clínicas/Federal University of Minas Gerais, Brazil.
Subclinical Carditis
Without symptoms or murmur of valvar regurgitation; normal radiographic and electrocardiologic exams; mild regurgitation of mitral and/or aortic valves with pathologic characteristics on echocardiography (see Table 54.4 ).
Mild Carditis
Rapid sleeping pulse, tachycardia out of proportion to fever, decrease in the intensity of the first sound may be found, systolic murmur of mild mitral regurgitation; no cardiac enlargement on chest radiography; normal radiographic and electrocardiologic exams, except for the presence of prolonged PR interval may be present on ECG; mild mitral regurgitation, isolated or in combination with mild aortic regurgitation and normal chamber size on echocardiography.
Moderate Carditis
The clinical signs are more evident than mild carditis with persistent tachycardia and a more intense murmur of mitral regurgitation, but without thrill, as an isolated lesion or associated to aortic diastolic murmur. Carey-Coombs murmur, besides findings of incipient heart failure; a mild or mild-to-moderate degree of cardiac enlargement in the chest radiography due to left-sided chambers and, if present, the pulmonary congestion is discreet; premature beats, ST segment and T wave changes, low voltage, prolongation of QTc or PR intervals may be observed on ECG; mitral and/or aortic regurgitation (one must be moderate) and mild to moderate enlargement of the left-side chambers on echocardiography.
Severe Carditis
In addition to the findings of moderate carditis, symptoms and signs of congestive heart failure; valvitis is expressed by murmurs related to more severe degrees of mitral and/or aortic regurgitation and can be associated with pericarditis and arrhythmias; significant cardiomegaly with prominent vascular markings in the chest radiography; in addition to findings of moderate carditis, left ventricular hypertrophy is sometimes associated to right ventricular hypertrophy. Moderate to severe or severe mitral and/or aortic regurgitation and the left cardiac chambers show at least a moderate enlargement on echocardiography.
Different clinical patterns of carditis can be found and are related to the severity, association with other manifestations, and ultimate outcome. Abrupt onset of clinical presentation is observed in older children with fever and arthritis, complaints that bring the patients to medical attention. If there is evidence of carditis, the involvement of the heart can be noted simultaneously with the articular presentation or becomes more apparent later over the first 2 to 3 weeks of the disease. A second pattern is mostly seen in young children. The cardiac involvement may begin more insidiously, with vague symptoms, slight fever, and mild arthritic complaints over a period of several weeks. Cardiac findings are commonly marked, and tend to progress to congestive cardiac failure. Another type of presentation is the subclinical carditis. Mild cardiac involvement may not be clinically recognized as the valvitis is identified only by Doppler echocardiography.
Pericarditis is not common, as it is found in only one-tenth or less of the patients. As with the myocardial participation, it is part of the active pancarditis, and is not found as a sole manifestation. When present, it is invariably associated with valvar damage, so other causes should be investigated if valvar dysfunction is not recognized. Pericardial involvement is diagnosed by the presence of pericardial friction rub, effusion, distant heart sounds, and chest discomfort or chest pain. The rub is heard as a scratching or grating sound over the precordium, especially along the sternal border, and is heard in both phases of the cardiac cycle, having a to-and-fro character. It is less transient in RF than in pyogenic infections. In the early stages, the friction rub may obscure the murmur of an underlying valvar dysfunction, and the murmur becomes apparent only when the rub subsides. In mild cases, the pericardial injury is sometimes an exclusive echocardiographic finding. Significant effusion is rarely found, and the rheumatic pericarditis does not result in constriction. Despite its low frequency, pericarditis has diagnostic value by providing evidence of an active disease.
Myocarditis has been diagnosed on the basis of signs such as a soft first sound, protodiastolic gallop, cardiomegaly, and congestive cardiac failure. Nevertheless, in spite of histologic evidence of the myocardial participation in the acute inflammatory process of RF, a more accurate assessment has provided new insights into the role played by the presence and degree of valvulitis in the presentation of heart failure. Markers of injury to the myocytes are not found to be above normal limits in rheumatic carditis. Patients with congestive cardiac failure unresponsive to clinical treatment throughout the acute phase have shown rapid recovery after valvar surgery. Observations have supported that mechanical factors are the most important contributors to myocardial damage. In conclusion, congestive heart failure in RF is not due to primary myocarditis but results from significant valvar dysfunction secondary to valvitis.
Endocarditis is the diagnostic hallmark of carditis, being expressed by valvitis. The inflammatory process affects the mitral and aortic valves. In primary episodes, mitral regurgitation is the predominant valvar dysfunction and can be identified in more than 90% of patients as a single valvar lesion or in combination with aortic regurgitation. On the other hand, isolated aortic regurgitation is a rare feature and accounts for less than 5%. Valvar regurgitation at primary episodes is more often of a mild degree. Severe involvement of the left-sided cardiac valves has been seen in one-tenth of patients. Obstructive lesions become established during the chronic phase since the process of cicatrization takes time to develop. If stenotic lesions are found in the acute phase, this favors the diagnosis of recurrence.
Three murmurs are characteristic of the first acute episode, and they do not represent definitive valvar dysfunction. The apical murmur of mitral regurgitation is pansystolic, regurgitant, beginning with the first sound, and is transmitted to the left axilla. It has a high-pitched blowing quality, with its loudness roughly proportional to the degree of valvar regurgitation. The murmur is heard maximally at the apex, at end-expiration, and with the patient in the left lateral decubitus position. The Carey Coombs murmur is a low-pitched mid-diastolic murmur, beginning immediately after the third sound, finishing before the first sound, and usually of low intensity. The murmur is best heard at the apex, or just above it, by using the bell of the stethoscope applied lightly against the chest wall with the patient lying in left lateral decubitus position. This murmur occurs when there is significant mitral regurgitation and is thought to be related to the consequences of the inflammatory process on the mitral apparatus. It has been attributed to the increased diastolic flow across the mitral valve besides its high velocity into the dilated and overloaded left ventricle. Characteristically, it is transient, and tends to disappear during the recovery from the acute episode. The third murmur, the basal diastolic murmur of aortic regurgitation, has a soft, high-pitched, decrescendo quality, and may be found early in the course of the disease. It is difficult to detect, and sometimes has an intermittent character. It is an early diastolic murmur, best heard with the diaphragm of the stethoscope, and is usually loudest at the third space on the left border of the sternum with the patient in the upright position, leaning forward, and after deep expiration.
Subclinical Valvitis.
Until the advent of Doppler echocardiography, the diagnosis of rheumatic valvitis had been exclusively based on the presence of auscultatory findings, supported by radiographic and electrocardiographic abnormalities. By the late 1980s, it proved possible positively to identify subclinical valvitis. Such silent carditis, accepted as part of the spectrum of rheumatic carditis, is found in patients with isolated arthritis and/or pure chorea, without auscultatory findings of valvar dysfunction, but with a pathologic pattern of valvar regurgitation revealed by Doppler echocardiographic interrogation ( Box 54.2 ). Minor thickening of the valvar leaflets has also been described in patients with subclinical carditis. The presence of mitral and aortic subclinical regurgitant jets has been observed with a wide variation of prevalence, ranging from 0% to 53% probably due to the heterogeneity in the methodologic approaches. In 2007, a systematic review estimated the prevalence of subclinical carditis as 16.8%. Nonetheless, in some patients without auscultatory findings in the early stage of the disease, the murmurs of valvar lesions can be identified later. Patients therefore require serial clinical evaluation during the acute phase, aimed at detecting late evidence of clinical carditis. In addition, physiologic insufficiency can be detected in up to nine-tenths of the normal population, and its prevalence was found to increase with increasing age. As trivial valvar leaks are commonly identified by Doppler echocardiographic investigation in normal subjects at all ages, it is essential to use strict criteria to differentiate pathologic from physiologic regurgitation. Aortic leaks, however, have rarely been considered physiologic.
Mitral Regurgitation a
a Thickening of valve leaflets is an additional finding to support the diagnosis.
(All Four Criteria Met)- 1.
Seen in at least two views
- 2.
Regurgitant jet length >2 cm in at least one view
- 3.
Peak velocity ≥3 m/s
- 4.
Pansystolic regurgitant jet in at least one envelope
Aortic Regurgitation a (All Four Criteria Met)
- 1.
Seen in at least two views
- 2.
Regurgitant jet length >1 cm in at least one view
- 3.
Peak velocity ≥3 m/s
- 4.
Pandiastolic regurgitant jet in at least one envelope
As mild valvar dysfunctions are most frequently seen in subclinical valvitis, favorable outcomes are expected for the great majority of patients, with anticipated spontaneous healing of the valvar lesions without sequels. The valvar lesions can remain subclinical in the chronic phase, characterizing subclinical chronic rheumatic heart disease. Considering the propensity of recurrences to mimic clinical manifestations of the first episode, the increased risk of more severe involvement of the heart must be borne in mind should there be subsequent attacks. The predictors for deterioration, persistence or improvement of subclinical valvar damage are unknown. Major questions remain regarding the natural history, the late outcome, the best approach, and its impact on the prognosis. Considering the data now available, it is reasonable to give the same importance to the detected acute subclinical lesions as to those diagnosed clinically, especially in settings where the risk of recurrences is high.
The finding of a subclinical carditis has been included in the most recent revision of Jones criteria for diagnosis of RF. This finding can increase the confidence in the diagnosis of patients with polyarthritis, monoarthritis, or chorea and it reinforces the importance of secondary prophylaxis.
Recurrent Carditis.
Carditis is rarely present for the first time in recurrences. The term mimetic carditis was proposed, considering the heart almost always is involved in the subsequent attacks in patients exhibiting carditis in the primary episode. The diagnosis of recurrent carditis in patients with an established rheumatic valvar disease is often difficult. The clinical presentation includes changes in the character of the murmur, reappearance of a previous murmur, or detection of a new one as the result of the involvement of an additional valve. In addition, detection of a pericardial friction rub or effusion, and a significant increase in the size of the heart, may also be present. Congestive failure is more common in recurrent carditis. Although the heart is involved in recurrences of patients suffering carditis in the first attack, cardiac failure in the chronic phase could also reflect mechanical stress due to valvar dysfunction, being related to the extent of hemodynamic effects. The epidemiologic and clinical context, as well as the evidence of a recent streptococcal infection, therefore, must be considered when making the diagnosis of recurrent carditis.
Polyarthritis
Polyarthritis is the most frequent major manifestation seen in older children, adolescents, and adults, but is the least specific clinical finding of RF. When arthritis is present as a sole manifestation, other alternative diagnoses should carefully be excluded. Its frequency increases with age, being seen in up to three-quarters of patients as an isolated presentation, or in association with other manifestations of the disease. The articular involvement usually occurs early in the illness, with duration and severity greater in adults than in children. Polyarthritis is rarely simultaneous with active chorea, the severity of the articular symptoms and signs being inversely proportional to the degree of carditis and its sequels. Polyarthritis is nonsuppurative, asymmetric, migratory, and self-limited. The classical migratory pattern refers to the sequential involvement of joints. While the process is resolving in one joint, another becomes involved, resulting in an overlapping in time with the participation of more than one joint. There is a marked preference to involve the peripheral large joints, particularly of the legs. The small joints of the hands and feet, the shoulders, and hips are less commonly affected. The spine is rarely involved. Tenderness and severe pain, out of proportion to the findings of the physical examination, are the most prominent features. The pain occurs in both active and passive movements, is usually diffuse, can show radiation to periarticular areas, and is associated with limitation of motion. Other characteristics of inflammation, such as heat, redness, and swelling, although present, are usually less marked. A pronounced and prompt relief of the symptoms and signs follows the use of salicylates and nonsteroidal antiinflammatory agents. If untreated, the inflammatory findings last from 1 to 5 days in each joint, reach the higher intensity in the first 2 days, with the entire process subsiding over 2 to 4 weeks.
Atypical presentations of articular involvement in RF such as monoarthritis and additive and symmetric polyarthritis have been reported. Involvement of only one joint is often observed if the antiinflammatory therapy is administered before the migratory pattern has been established; however, in some parts of the world monoarthritis is a common presentation. In the Aboriginal population of Australia, 23% to 32% of the cases presented with features of aseptic monoarthritis.
Usually the arthritis heals without anatomic deformities or functional abnormalities. Jaccoud arthritis is considered a rare sequel of recurrent attacks of RF, and is a possible exception for residual articular deformity. In this situation, periarticular fibrosis of the metacarpophalangeal joint results in marked ulnar deviation and hyperextension of the proximal interphalangeal joints. Poststreptococcal reactive arthritis is related as an acute and nonsuppurative arthritic condition following a documented GAS infection. Its characteristics are not typical of RF, and do not meet the Jones criteria. There is a latent period, usually shorter than 10 days, and persistence of mono- or polyarthritis for several months with atypical presentation. Clinical findings include an additive and symmetric rather a migratory pattern and involvement of small and axial joints, besides a poor response to antiinflammatory therapy. An association with mitral valvar dysfunction has been described in one-twentieth of the patients. Doubts remain if poststreptococcal reactive arthritis is a different condition from RF, or if the two entities represent a diverse expression of the same disease.
Sydenham Chorea
Sydenham chorea, chorea minor, or St. Vitus’ dance affects children and adolescents, more frequently females. It is uncommon after puberty and rarely seen in postpubertal males. It has been reported in up to one-third of patients, with a peak incidence at around 8 to 9 years of age. The latent period, after streptococcal infection, is longer than for arthritis and carditis, varying from 1 to 7 months. Chorea may occur as an isolated manifestation, the so-called pure chorea, or less frequently in association with carditis or arthritis. Considering the longer latency period, simultaneous occurrence with arthritis is rare. But chorea may coexist with clinical or subclinical carditis in up to two-fifths of patients. Chronic rheumatic heart disease has been described in around one-quarter of patients 20 years after the presentation of isolated chorea.
It is usually a self-limited disorder, and diagnosis is based exclusively on clinical examination. It is a manifestation of the central nervous system characterized by muscular weakness, hypotonia, and emotional instability, besides involuntary and purposeless but conscious movements of the skeletal muscles. Although the face, tongue, and the arms and legs are more often involved, any voluntary muscle may be affected. The presentation of facial grimacing is frequent, besides abrupt but not repetitive movements of the limbs, mainly the hands. The uncoordinated movements are mostly evident when the patient is awake, particularly under stress, excitement, or effort. Oculomotor problems have also been reported, which go into remission in most patients after the improvement of the choreiform movements.
More frequently, the onset is insidious. Chorea as the first and sole manifestation of RF may not be recognized in the early stages as the signs could be attributed to behavioral or emotional problems. The child shows attention-deficit, inappropriate behavior, and becomes irritable, restless, and clumsy. Fine muscular incoordination is noted, and voluntary movements, such as unbuttoning clothes or tying shoes laces, are difficult to execute. The manifestations become progressively more evident, with disturbances in the speech and handwriting. The signs of muscular weakness and choreiform movements are mostly generalized, sometimes asymmetric. One-fifth of patients have hemichorea, with the manifestations limited to one side of the body. The so-called chorea paralytica or chorea mollis is an expression of generalized and severe presentation characterized by a profound hypotonia and severe disability, albeit very rare. Certain maneuvers are helpful to bring out the choreiform movements. When the patient is asked to extend the arms forward, the hands assume the shape of a spoon or dish as a result of wrist flexion and hyperextension of the fingers. The milking sign is demonstrated by alternate increase and decrease in tension when the patient grips the examiner’s hand. If the arms are raised above the head, the hands are involuntarily turned outwards. Undulating movements can be observed when the tongue is protruded, resembling a “bag of worms.” Motor impersistence can also be displayed by patients during ocular fixation.
Recurrent chorea is not uncommon and may be associated with oral contraceptive use or pregnancy. The severity and the evolution of the disorder up to its resolution are variable. In mild cases, the choreiform movements may subside in few weeks, but most frequently the recovery takes up to 6 months, although in severe case the manifestations may persist up to more than 2 years. Behavioral abnormalities occur in up to one-third of patients with Sydenham chorea. Obsessive–compulsive features have been seen in the long-term follow-up. A broad spectrum of poststreptococcal movement conditions associated with emotional and behavior disorders have been identified using the acronym PANDAS—pediatric autoimmune neuropsychiatric disorders associated to Streptococcus. This entity shows a distinctively neuropsychiatric profile. The onset is usually abrupt, symptoms of obsessions and/or compulsions are predominant, and neurologic abnormalities may include choreiform movements. Association with cardiac involvement has not been reported. Considering the overlapping of neurobehavioral symptoms and signs between PANDAS and Sydenham chorea, clinicians should be cautious in making diagnosis of PANDAS in high-risk populations.
Subcutaneous Nodules
Subcutaneous nodules are one of the most characteristic major criteria, but they are not pathognomonic. They have also been found in other diseases like rheumatoid arthritis and systemic lupus erythematosus. Almost invariably the subcutaneous nodules are associated with severe carditis. Other than being useful for diagnosis, subcutaneous nodules have a limited value due to their lower frequency as they are seen in only up to one-tenth of patients. Their frequency seems to have been reduced over the last decades. The nodules are small, varying in size from millimeters to 2 cm, and are firm, painless, and freely movable under the skin. They are encountered in clusters, on the extensor surface of the joints and overlying bone prominences, mainly in the large joints of limbs, knuckles, scalp, and along the spine in the paravertebral areas ( Figs. 54.10 to 54.12 ). On many occasions, the nodules are not noticed by the patients and sometimes they are found only following careful investigation. They are almost never seen in the first stages of the disease but can be found earlier in recurrences. The subcutaneous nodules usually appear several weeks after the onset of the acute episode, persist from days to weeks, and rarely last longer than 1 month.
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