Rheumatic fever (RF) is an inflammatory disease that affects various systems such as the skin, brain, cardiovascular system, and many mucosal membranes, that is, the pericardium, the pleura and the peritoneum. The joints are involved to a great extent. However, although the peripheral joints produce the most noticeable symptoms, it is the cardiovascular system that suffers the most long-lasting influences. It remains the most common pathogenic cause of acquired heart disease in children and young adults, because although in developed countries its incidence has decreased very sharply, it remains a major problem in the developing world.
The etiologic agent is the group A streptococcus (GAS), causing untreated tonsillopharyngitis. It is believed that skin infections (impetigo) do not cause RF. However, Carapetis et al. point out that in areas with high rates of acute RF, skin infections may represent an important reservoir of all strains of GAS.
As already stressed, not all GAS are causative of RF. The common strains M2, 4 and 12 do not cause RF. Homology has been shown to exist between the M protein of the surface of the streptococcus and the human heart myosin and tropomyosin. This M protein is characterized by an epitope that differs between those causing or not causing RF.
In heart tissue, antigen-driven oligoclonal T-cell expansions probably cause the rheumatic heart lesions. These cells are CD4 + and produce inflammatory cytokines (tumor necrosis factor [TNF] alpha and interferon [IFN] gamma). IL-4+ cells are found in the myocardium; however, these cells are very scarce in the valve lesions of rheumatic heart disease (RHD) patients. Interleukin (IL)-4 is a Th2-type cytokine and plays a regulatory role in the inflammatory response mediated by Th1 cytokines. These findings indicate that the Th1/Th2 cytokine balance has a role in healing myocarditis while the low numbers of IL-4-producing cells in the valves probably induced the progressive and permanent valve damage.
As already mentioned, the human leukocyte antigen (HLA) system may be responsible for the propensity of certain individuals to develop RF; susceptibility has been liked to HLA-DR haplotypes.
In Turkish patients with RHD, a higher percentage of the D8/17 expressing B lymphocytes in the patient group compared with control was found. In the patient group the DRB4 expression was lower, but the HLA DR 1∗15 and the DRB5 were higher.
The propensity to develop RF after streptococcal involvement depends on characteristics of both the infecting organism and the host:
The infecting organism: The strains belonging to types M1,3,5,6 and 18 have been more frequently involved in the appearance of RF. All these strains have a long terminal antigenic domain. Moreover, they share epitopes with human cardiac tissue.
The incidence of RF is much higher in patients with a previous episode of RF (50% vs. 3%).
Recurrences of acute RF episodes play an important role in valve disease progression because of the inflammatory process, which involves the reactivation of autoreactive T cells. In RHD, CD4 + infiltrating T cells cross-reactively recognize bacterial and human proteins and produce Th1 inflammatory cytokines, such as TNF-α and IFN-γ. So, RHD develops as autoimmune reactions in the valvar tissue, in the absence of Streptococcus pyogenes , because of a previous throat infection by the bacterium.
Genetic susceptibility is an important feature for the development of RHD. Several gene polymorphisms have been implicated, most of which are involved in the activation of the immune response.
The incidence of acute RF varies from 2/100,000 in the United States up to 100/100,000 in the developing countries. In New Zealand the incidence is 2.5 per total 100,000 population; it is much higher in Maori and Pacific Island children, between 50 and 70 per 100,000. Tibazarwa et al. give an excellent recent review. Roughly, they state that incidence is less than 10/10,000 per year in America and Western Europe; however, in areas with higher rates (20 to 30/100,000) the rates are steadily falling. Mortality due to RF RHD declined 42% between 1994 and 2004 in the United States.
The incidence of RHD in school-age children varies from 0.6/1000 in the United States to 15 to 19/1000 in South Africa and South America. Interesting data have emerged from the global use of echocardiography in areas where prevalence of RF is still high. Thus in Cambodia RHD was detected clinically in 8 of 3677 children but in 79 with echocardiographic screening. However, cases of RF are still being underreported. Also, unfortunately, register-based programs are waning mostly due to underfunding.
Brazil is another country that gives abundant data. In 2012, 4731 hospitalizations due to acute RF were registered.
In Greece, in one of the two main pediatric hospitals in Athens, during the years 1980–1997 the diagnosis of RF was made in 66 children: Carditis and arthritis were the major manifestations in 70% and 68% of the cases, respectively.
Altogether, acute RF and RHD are estimated to affect nearly 20 million people and remain leading causes of cardiovascular death during the first five decades of life.
Specific clinical manifestations exist which will establish the diagnosis as will be described later.
The Jones criteria have been used for many years. It should be stressed that they concern the first attack of RF and not the recurrences. The major Jones criteria are carditis, polyarthritis, erythema marginatum, subcutaneous nodules and chorea. Minor criteria are arthralgia, fever, erythrocyte sedimentation rate (ESR) elevation, C reactive protein (CRP) elevation and PR prolongation. If evidence of antecedent group A streptococcal infection exists, the presence of two major or one major and two minor criteria render the diagnosis of RF very highly likely. The supporting evidence of antecedent group A streptococcal infection is a positive throat culture or a rapid streptococcal antigen test or elevated streptococcal antibody titers (ASO).
Carapetis et al. in a seminal review in 2005, point out that the World Health Organization (WHO) proposed criteria in 2002–2003 may have somewhat different functions according to their epidemiologic setting. Thus in regions of high prevalence, sensitivity may be more important. They believe that the 1992 Jones criteria may not be sensitive enough in this milieu, and the 2002–2003 WHO criteria are more appropriate.
The ESR and CRP are invariably increased during the acute stage of RF. However they may have returned to normal when chorea develops. The CRP is more specific because it is not affected by anemia or heart failure.
The PR interval prolongation is a nonspecific finding. It is not associated with carditis or long-term valvular lesions.
As regards evidence of antecedent group A streptococcal infection, it must be remembered that because RF develops approximately 3 weeks after the streptococcal infection, throat cultures are rarely positive at this time for streptococci. The rapid streptococcal antigen detection tests have high specificity but low sensitivity. The antibody tests are used more widely. The prevalent ones are antistreptolysin O (ASO) and antideoxyribonuclease B (anti DNAase B). The former is performed first and only if negative is the latter performed. However, elevated ASO or anti-DNA B titers may persist for months after a previous streptococcal infection. A rapid antigen detection test has been found to have high sensibility and specificity.
Special Clinical Manifestations
It has been described as a pancarditis (endo-, myo- and pericarditis). Its incidence is approximately 50%. In a study by Voss et al. the incidence was 39/59 (66%).
It may range from mild to severe, leading to death. In the latter case the murmur of valvulitis signifying endocardial involvement can be missed by auscultation.
The mitral and aortic valves are the ones predominantly affected, in order of frequency. Myo- or pericarditis in the absence of valvulitis is unlikely.
Essentially, the carditis is clinically diagnosed by valvar regurgitation. Some authors have described diffuse and focal thickening by echocardiographic examination. The changing picture by the use of American Heart Association echocardiographic criteria has already been discussed. The 1995 guidelines require valvular involvement either by clinical or echocardiographic criteria.
Echocardiographic criteria for the confirmation of subclinical rheumatic carditis :
Mitral Regurgitation—Jet Characteristics
Extension 1 cm back into the left atrium
Seen in two planes
Mosaic pattern indicative of chaotic flow
Holosystolic flow as confirmed by Doppler
Mitral Stenosis—Jet Characteristics
Extension 1 cm into left ventricle
Veasy points out that these criteria should also be used for the follow-up management of patients with RF. In this context, Ozkutlu et al. followed 26 consecutive patients with silent valvulitis without clinical sign of carditis for 4.5 months. They concluded that RF with silent carditis is not a benign entity.
In a study performed by Marijon et al. , in Maputo, Mozambique, 2170 randomly selected school children aged 6 to 17 were screened clinically and by a portable ultrasound system. Two different echocardiographic sets of criteria for RHD were assessed: “WHO” (exclusively Doppler based) and “combined” (Doppler and morphology-based) criteria. Independent investigators reviewed all suspected RHD cases using a higher-resolution, nonportable ultrasound system. On-site echocardiography identified 18 and 124 children with suspected RHD according to WHO and combined criteria, respectively. After consensus review, 17 were finally considered to have definite RHD according to WHO criteria, and 66 had definite RHD according to combined criteria, giving prevalence rates of 7.8 (95% confidence interval, 4.6 to 12.5) and 30.4 (95% confidence interval, 23.6 to 38.5) per 1000 children, respectively ( P = .0001). The authors concluded that “currently recommended WHO criteria risk missing up to three quarters of cases of subclinically affected and therefore potentially treatable children with RHD”.
In the REMEDY study a total of 3343 participants with RHD were enrolled. Atrial fibrillation was documented in 586/2688 (21.8%) of patients with electrocardiograms performed. Children in the first decade of life presented predominantly with pure mitral regurgitation, while in the second decade of life mixed mitral and mixed aortic valve disease emerged as a dominant valve lesion. The frequency of pure mitral stenosis, isolated aortic valve disease (ie, aortic stenosis or aortic regurgitation) and mixed aortic valve disease without mitral disease was low in early life, and increased with age. The majority of cases of mitral stenosis (1119/1535, 72.9%), mitral regurgitation (1479/2464, 60.4%), pulmonary stenosis (19/32, 59.4%), tricuspid stenosis (58/107, 54.2%), and aortic stenosis (187/302, 61.9%) had moderate-to-severe disease, whereas the majority of cases of aortic regurgitation (922/1671, 55.2%) were mild.
Its incidence is approximately 55%. It is characterized by asymmetric and migratory involvement of the large joints (knees, elbows, ankles, wrists). Involvement is always transient with permanent residua. Its duration is limited (as long as 2 to 3 weeks). It responds very readily to salicylates.
It occurs in about 20% of cases. It is ascribed to an autoimmune inflammatory response involving primarily the basal ganglia and caudate nuclei.
Although Sydenham chorea has been known as the neurological manifestation of RF for decades, the combination of autoimmunity and behavior is a relatively new concept linking brain, behavior, and neuropsychiatric disorders with streptococcal infections. In Sydenham chorea, human monoclonal antibodies (mAbs) and their expression in transgenic mice have linked autoimmunity to central dopamine pathways as well as dopamine receptors and dopaminergic neurons in basal ganglia.
The latent period of appearance is around 3 months. Accordingly, in its presence the diagnosis of RF can be made even if the other Jones criteria are lacking. It resolves in 1 to 2 weeks. The first line of treatment is valproic acid; risperidone and haloperidol may also prove useful.
It is rare (<5%) and present only in severe cases. The size is highly variable. It involves mostly the trunk and proximal extremities.
They are also seen infrequently (3%), mostly in severe cases, especially in the extensor joint surfaces and the scalp.
However, one should be aware that just as the incidence has changed, so have the clinical manifestations of RF. Thus Carapetis and Currie found monoarthritis in only 17% of confirmed nonchorea cases and fever greater than 39°C in only 25%.
The diagnosis of streptococcal pharyngeal tonsillitis is essential. The main symptoms are sore throat, fever above 38°C, headache, abdominal pain, nausea, and vomiting.
The tonsils are reddened with or without exudate, and lymphadenitis is common. The differential diagnosis from viral involvement is not always easy. Findings not common in streptococcal infection are conjunctivitis, stomatitis, and ulcerative pharyngeal lesions. Viruses causing pharyngitis are adenoviruses, enteroviruses, herpes viruses. Neisseria gonorrhoeae , Mycoplasma pneumoniae, Chlamydia pneumoniae, and arcanobacterium hemolyticum have been reported. The best diagnostic modality is swab culture of both tonsils and posterior pharynges. However culture cannot always differentiate true pharyngeal tonsillitis from viral infection because many individuals chronically harbor streptococci. A negative culture allows the physician not to start antibiotic therapy. Bisno gave a very thorough description of this entity. He stresses the importance of the tonsillopharyngeal exudate and the anterior cervical lymphadenitis. The absence of fever and pharyngeal erythema diminishes the likelihood. He also states that a correctly carried out and interpreted throat culture has a sensitivity greater than 90%. Definitive results are obtained at 24 to 48 hours. He also believes that a positive rapid test can be considered equivalent to a positive throat culture; however, its sensitivity, in comparison with the throat culture, is only 80% to 90%.