Rheumatic fever (RF), or acute rheumatic fever (ARF), is an autoimmune complication caused by the human-specific bacterial pathogen group A (B-hemolytic) streptococcus (GAS), Streptococcus pyogenes. S. pyogenes is a Gram-positive aerobic bacterium that is coccoid or spherical in shape and usually occurs in pairs or chains. It produces hemolysin that forms a clear zone around the colonies when grown on blood agar. It has been designated as part of group A via Lancefield serotyping because it displays the carbohydrate antigen A on its cell wall. It is non acid-fast, non-spore forming, and may or may not have capsules. It has generally been considered non-motile but a study by Mora et al. (2005) revealed a pilus-like structure on the bacterial cell surface. Moreover, S. pyogenes is catalase negative (as are all streptococci) and pyrrolidonearylamidase (PYR) positive (Carapetis et al., 2006; Tortora, Funke, and Case, 2010; Henningham et al., 2012).
Although the exact mechanisms of pathogenesis of S. pyogenes (GAS) are still unclear, it is widely accepted that the most important and well-defined virulence factor involved is the M protein on the bacterial surface. This protein is utilized by the bacterium to avoid phagocytosis. Other factors that affect the severity of infection include conduciveness of the environment, virulence of the infecting strain, and inherent (genetic) host susceptibility (Carapetis et al., 2006; Tortora et al., 2010).
Streptococcal infections can lead to superficial diseases such as pharyngitis (sore throat), impetigo (skin infection), erysipelas, and vaginitis, as well as post-partum infections. GAS can be spread by person-to-person contact, presumably via airborne spray droplets from nasal secretions or saliva (especially when sneezing). Acute rheumatic fever (ARF) occurs about 10 days to 6 weeks after an episode of GAS infection and could occur even in the absence of the bacterium. The exact pathogenetic mechanism of RF is not well defined, but the autoimmune response could be explained by the inability of the immune system to differentiate epitopes of the bacterial pathogen from host cells after the infection has cleared, thereby attacking residual antigens in the skin, joints, brain, and heart (World Health Organization [WHO], 2004; Tortora et al., 2010; Henningham et al., 2012).
Rheumatic fever (RF) is considered a notifiable disease by the Center of Disease Control and Prevention (CDC) but only during local outbreaks to prevent widespread epidemic. RF was last mentioned in a 1993 (or at least the latest date the author of this article has found through research) statistical summary for CDC (CDC, 1993). Rheumatic fever occurs primarily in young children aged 4 to 18, but all ages are susceptible to this disease. RF is usually first expressed as a short period of arthritis and fever, and is usually accompanied by subcutaneous nodules at the joints. A misdirected immune reaction against streptococcal M protein can damage the heart valves which can further result in congestive heart failure, strokes, endocarditis, and even death. Lasting damage to the mitral or aortic valves of the heart leads to rheumatic heart disease (RHD). People who have had RF are at risk for subsequent recurrence of episodes or infections (Smith et al., 2012; Henningham et al., 2012).
Invasive infection of GAS requires significant changes in gene expression to evade the immune system and to further disseminate into deeper tissues. Many of the differentially expressed genes in invasive isolates are used to resist polymorphonuclear leukocytes (as well as phagocytosis, opsonisation, and antimicrobial peptides), inhibit neutrophil recruitment, and escape from neutrophil extracellular traps. Invasive GAS also produces increased levels of certain toxins, such as cytotoxins and superantigens, which could destroy immune cells and dysregulate the host’s immune response (WHO, 2004; Henningham et al., 2012).
Other proposed explanations for the persistence and virulence of GAS are biofilm formation and the presence of pilus-like structures on the bacterial cell wall. Formation of biofilm within the host’s cells and tissues helps the bacterium avoid the immune system and antibiotics. The existence of pili in GAS is unusual because Gram-positive bacteria generally do not have pili. Pili in Gram-negative bacteria aids in their virulence because they are used to attach to target cells. Pili of GAS seem to be used in a similar fashion, as they were found to contain extracellular matrix-binding proteins (Mora et al., 2005; Baldassarri et al., 2006).
It is estimated that GAS causes around 700 million human infections annually, and causes about 500,000 deaths. Although the prevalence and incidence of ARF and RHD have been declining in developed nations since the early 1900s, they still contribute to morbidity and mortality in developing nations (particularly in poor and indigenous communities), especially among young people, and often persist at endemic levels (WHO, 2004; Henningham et al., 2012). Reported prevalence rates of RHD (per 1000 persons) in some countries were 20.6 in Minnesota, USA (years 1935-64), 6.7 in Colorado, USA (years 1949-1951), 4.6 in Japan (1958-61), 10-30 in USSR (1961), and 1.8 in Karachi, Pakistan (1964-65) (Seckeler and Hoke, 2011). Meanwhile, morbidity is influenced by socio-environmental factors. In 1994, mortality rate (per 100,000 people) for RHD was 0.5 in Denmark, 8.2 in China, 1.8 in the WHO Region of the Americas, 7.6 in WHO Southeast Asia Region (WHO, 2004; Henningham et al., 2012).
The decline of RF and other GAS related diseases in developed nations can be attributed to some loss of virulence in the streptococci in circulation. Also, the improvement of public health and the use of antibiotics during the 20th century may have also influenced the decline in disease incidence in industrialized countries (Madden and Kelly, 2009; Henningham et al., 2012).
However, there has been global resurgence of RF infections in developed countries from time to time. These localized outbreaks can be related to certain M-protein serotypes that had been prevalent during epidemics in earlier times but had almost disappeared from circulation, or to the emergence of GAS strains that have been fortified through the horizontal exchange of novel and extremely virulent mobile elements. There is no commercially available vaccine to prevent GAS infection (Tortora et al., 2010; Henningham et al., 2012).
There is currently no diagnostic laboratory test for RF, as objective measurements vary greatly due to multiple factors such as location, ethnicity, strain virulence, and host susceptibility. Thus, diagnosis is still a clinical decision made by certified health professionals using accepted guidelines. One such set of guidelines is the Jones criteria (Carapetis et al., 2006; Smith et al., 2012).
The Jones criteria for the diagnosis of rheumatic fever, introduced in 1944, separated the clinical features of RF into minor and major manifestations, based on their specificity and prevalence. Major manifestations are those more specific to RF and make diagnosis more likely and include carditis, joint symptoms, subcutaneous nodules, and chorea. Prior history of RF or RHD was considered to be a major manifestation due to the recurrent property of RF. Minor manifestations are more suggestive but insufficient on their own. These include clinical findings such as fever, erythema marginatum, abdominal pain, epistaxis and pulmonary findings; and laboratory markers of acute inflammation, such as leukocytosis and elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Two major manifestations, or one major and two minor manifestations were considered sufficient to diagnose RF. For those with previous history of RF and RHD, minor manifestations seemed to be sufficient. Sometimes, when facilities are available, throat swab cultures, rapid streptococcal detection tests, or serum antibody tests are also used to verify GAS and used to support the diagnosis as prior evidence. Electrocardiogram (ECG), echocardiograms, and chest X-rays are also used to evaluate valvular damage especially for RHD. Blood cultures are also used to rule out infective carditis (WHO, 2004; Carapetis et al., 2006; Smith et al. 2012).
The most widely used version of the Jones criteria is the 1992 update. However, this version (and other modifications) may not be applicable or sensitive enough to use in high-incidence populations, which could risk under-diagnosis. An expert group convened by WHO provided additional guidelines for the application of the Jones criteria in primary and recurrent episodes. Because of the difficulty of using generalized criteria, different organizations and communities around the world have varying guidelines on RF diagnosis, especially for areas with both high and low risk populations (WHO, 2004; Carapetis et al., 2006; Smith et al. 2012).
For the specific guidelines of the 2002-2003 WHO criteria (based on the revised Jones criteria), see appendix A. For the 2005 Australian guidelines, see appendix B.
When properly treated and managed, RF should cause no permanent damage to the skin, brain, joint, or heart. Acute RF is usually treated with intramuscular benzathine benzylpenicillin to eradicate the pathogenic GAS bacterium. For those allergic to penicillin, erythromycin is usually prescribed. Symptoms such as joint and muscle pain are managed using salicylates or other non-steroidal anti-inflammatory drugs (NSAIDs). Chorea usually goes away on its own and is not usually medicated because anti-chorea drugs can be toxic. In extreme cases wherein self-injury seems imminent, mild sedatives can be used. For those with carditis or heart failure, glucocorticoids and other anti-inflammatory medications are prescribed. For those with severe damage, acute cardiac surgery might be necessary. Low-grade fever usually gets better with the salicylates or other NSAIDs and does not require specific treatment. Also, rest is an important therapy in getting better, although strict bed-rest for prolonged periods of time is not usually necessary (Carapetis et al., 2006; Tortora et al., 2010; Smith et al, 2012).
Secondary prophylaxis or prevention of RF is usually the continued administration of specific antibiotics to prevent colonization or subsequent infection of the upper respiratory tract by GAS. Secondary prophylaxis was said to be the most efficient and effective control strategy at the community or population level. IM injection of benzathine benzylpenicillin every three or four weeks is recommended for management of RF and RHD. Oral antibiotics (such as phenoxymethylpenicillin, sulfa drugs, or erythromycin) can also be used but it raises the risk of non-compliance to a set routine (Carapetis et al., 2006; Beggs, Peterson, and Tompson, 2008).
Rheumatic fever (RF) is an autoimmune complication of streptococcal (GAS) infections that attacks the skin, brain, joints, and the heart. Damage to the mitral or aortic valves of the heart can result to rheumatic heart disease and can be permanent, even fatal. Antibodies against GAS react with bacterial antigens deposited in joints or heart valves, or may cross-react with the heart muscle. RF usually follows a GAS infection and may occur without the presence of the bacterium. Prompt treatment of streptococcal infections can reduce the risk of rheumatic fever. GAS has generally remained sensitive to penicillin, which is also administered as a preventive measure against recurrent infections. Secondary prevention is effective in keeping RF and RFD at bay and preventing recurrent attacks or complications.
WHO guidelines for the diagnosis of rheumatic fever (based on revised Jones criteria)
Australian guidelines for the diagnosis of RF (adjusted for high- and low-risk populations)
Baldassarri, L., Creti, R., Recchia, S., Imperi, M., Facinelli, B., Giovanetti, E., Pataracchia, M., Alfarone, G., and Orefici, G. (2006). Therapeutic Failures of Antibiotics Used to Treat Macrolide-Susceptible Streptococcus pyogenes Infections May Be Due to Biofilm Formation. Journal of Clinical Microbiology 44(8): 2721-2727.
Beggs, S., Peterson, G., and Tompson, A. (2008). Antibiotic use for the Prevention and Treatment of Rheumatic Fever and Rheumatic Heart Disease in Children. Report for the 2nd meeting of World Health Organization’s subcommittee of the Expert Committee of the Selection and Use of Essential Medicines, Geneva, 29 October to 3 September 2008. WHO.
Carapetis, J.C., et al. (2006). Diagnosis and management of acute rheumatic fever and rheumatic heart disease in Australia – an evidence-based review. Australia: National Heart Foundation of Australia.
Centers for Disease Control and Prevention (1994). Summary of Notifiable Diseases, United States 1993. Morbidity and Mortality Weekly Report 42(53): [inclusive page numbers].
Henningham, A., Barnett, T.C., Maamary, P.G., and Walker, M.J. (2012). Pathogenesis of Group A Streptococcal Infections. Discovery Medicine 13(72): 329-42.
Madden, S., and Kelly, Len. (2009). Update on acute rheumatic fever: it still exists in remote communities. Canadian Family Physician 55(5): 475-478.
Mora, M., G. Bensi, S. Capo, F. Falugi, C. Zingaretti, A. G. Manetti, T. Maggi, A. R. Taddei, G. Grandi, and Telford, J.L. (2005). Group A streptococcus produce pilus-like structures containing protective antigens and Lancefield T antigens. Proceedings of the National Academy of Sciences of the USA 102(34): 15641-15646.
Seckeler, M.D., and Hoke, T.R. (2011). The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clinical Epidemiology 3(1): 67-84.
Smith, M.T., Zurynski, Y., Smith, D.L., Elliott, E., and Carapetis, J. (2012). Rheumatic fever: identification, management and secondary prevention. Australian Family Physician 42(1-2): 31-35.
Tortora, G.J., Funke, B.R., and Case, C.L. (2010). Microbiology: An Introduction (10th Ed.). CA: Pearson Education, Inc.
World Health Organization (2004). Rheumatic Fever and Rheumatic Heart Disease. WHO Technical Report Series 923. Singapore: WHO.