Acute rheumatic fever (ARF) remains a major problem in resource-poor nations and in Indigenous populations of some resource-rich nations. Strikingly, the rates of ARF in Maori and Pacific children in New Zealand and aboriginal children in Australia are among the highest in the world.1,2 Group A Streptococcus (GAS) pharyngitis was long believed to be the sole precursor for ARF—a belief founded on laboratory and epidemiologic evidence collected from temperate settings some 70 years ago.3 However, contemporary epidemiologic data from settings where ARF persists today cast doubt over the role of GAS pharyngitis as the only etiologic agent of ARF. Notably, studies in aboriginal communities in the Northern territories of Australia and in Fiji where ARF rates are high have shown a relative lack of GAS pharyngitis, frequent GAS pyoderma and high carriage rates of Group C and G Streptococci (GCS/GGS).4–7 We present a case of ARF that developed after symptomatic GAS pyoderma and identification of GGS in the pharynx, but in the absence of GAS pharyngitis.
A 6-year-old Maori boy presented with symptoms consistent with ARF; fever, lethargy, arthralgia and inability to weight bear with pain and swelling over his left knee after being unwell for at least 24 hours. He was febrile 38.6°C, obese (weight 42 kg) and tachycardic at 120 bpm. He was given paracetamol and ibuprofen and transferred urgently to a secondary hospital. A cardiac murmur of mitral regurgitation was audible. An echocardiogram showed moderate carditis with mild to moderate mitral regurgitation and excessive leaflet motion of a thickened anterior mitral valve typical of acute rheumatic carditis.
He was diagnosed with definite ARF according to the New Zealand modification of the Jones criteria8 with 2 major (arthritis and carditis) and 2 minor (fever and polyarthralgia) criteria. The throat swab performed on admission was negative and serologic analysis provided evidence of a preceding GAS infection with raised anti-streptolysin-O (ASOT; 1600 IU/mL) and anti-deoxyribonulease B (anti-DNAseB; 680 U/mL) titers. He was hospitalized for 5 weeks with bed rest. Follow-up echocardiography after 1 month showed worsening mitral regurgitation to moderate-severe with normal left ventricle size and function and normal aortic valve structure and function. The child was given intramuscular benzathine penicillin as secondary prophylaxis to prevent further attacks of ARF. However, he subsequently refused treatment by injection so was then prescribed oral penicillin as prophylaxis.
The child has been seen in primary care for 33 days before ARF presentation with impetigo on his right knee that was GAS positive. This was treated with 5 days of cephalexin. The child attended a school with an active throat swabbing program, a primary prevention initiative for ARF in New Zealand.9 Six days after his presentation with GAS pyoderma (ie, 27 days before presentation with ARF), he self-identified as having a sore throat at school and his throat swab was positive for GGS. In both instances, the Streptococci isolates were grouped using the PathoDx Strep Grouping Universal Kit (ThermoFischer, Kent, United Kingdom), in laboratories that also perform species-level identification by MALDI-TOF MS Biotyper (Bruker, Germany) as required. No treatment was given for the GGS pharyngitis because this is considered a self-limiting condition and not associated with significant sequalae under the schools program.
This case developed ARF in the absence of symptomatic GAS pharyngitis; however, he had GAS pyoderma just over 4 weeks before developing ARF, and had GGS positive pharyngitis 6 days after his GAS pyoderma. This challenges the long held belief that ARF follows a GAS pharyngitis.
The evidence of prior GAS infection in the ARF diagnosis was provided by elevated ASOT and anti-DNAseB. However, there are caveats to interpreting these tests that are relevant to this case.10 False positives are associated with ASOT because streptolysin-O is expressed by both Group A and Group G Streptococci. It follows that the elevated ASOT could have been induced by either the GAS pyoderma or the GGS pharyngitis. The anti-DNAseB test is less prone to false-positives suggesting the raised anti-DNAseB titer resulted from the GAS pyoderma. If the serology from this case were considered in isolation, it would likely be assumed the elevated titers resulted from GAS pharyngitis. However, the well-documented-infection history, combined with the lack of GAS specificity for ASOT raises 2 possibilities. Either the elevated titers can be attributed to GAS pyoderma alone, or by a combination of GAS pyoderma and pharyngeal GGS.
The notion that GAS pyoderma can precede ARF is based on the epidemiology of streptococcal infections in the Northern Territories of Australia and Fiji, where the high burden of GAS pyoderma5,7 is thought to contribute to high rates of ARF in these settings.11,12 Adding to this epidemiologic evidence, a recent study of ARF-associated GAS isolates from New Zealand that found a high proportion of the isolates had emm-types previously associated with pyoderma.13 However, the link between GAS pyoderma and ARF is not widely accepted outside the Pacific region,14 in part, due to a lack of well-described cases in the literature. Our review of the literature identified just 3 prior cases of ARF where GAS skin infections are documented.15–17 One is not relevant to the current debate because it describes a case that presented with acute poststreptococcal glomerulonephritis, necrotizing fasciitis and ARF.15 The other 2 cases occurred in the United Kingdom; 1 in a 17-year-old male, who developed ARF in the 1970’s after sustaining cuts on his hands that became infected with GAS16; and another in a 14-year-old female, who developed ARF in the 1990’s after lesions on her ankles became infected with GAS.17 The 17-year-old had both skin and throat swabs performed at admission but only the skin swab was positive for Streptococci, providing clear evidence that ARF developed after GAS pyoderma in this instance.16 The 14-year-old female was not throat swabbed at admission, and in the absence of this swab, the authors concluded that while the child developed ARF after symptomatic pyoderma, chronic pharyngeal carriage could not be discounted.17
The role of Group C and G Streptococci infection as a precursor for ARF was postulated after laboratory studies showed that antibodies against GCS/GGS cross-react with cardiac antigens.4 There is significant homology between the genomes of GCS/GGS and GAS such that GCS/GGS bacteria express major virulence factors implicated in the development of ARF, including the M-protein.18 Furthermore, pharyngeal carriage rates of GCS/GGS are greater than GAS in aboriginal communities5 and in other tropical settings where rheumatic fever is endemic, such as Fiji.6 While a role for GCS/GGS in the development of ARF is plausible, there has been a lack of reported cases directly linking symptomatic GCS/GGS pharyngitis with first episode ARF. Our review of the literature only identified as a single case of recurrent ARF where GGS was isolated from the throat of an aboriginal adolescent on presentation,18 and no cases of first episode ARF after GGS pharyngitis.
The case of ARF described in this report occurred in an Indigenous Maori child who was at high risk of developing the disease, as evidenced by his attendance at a school with an active throat swabbing program. The throat swabbing program is designed to detect and treat GAS pharyngitis in high-risk children to prevent ARF. However, this case clearly demonstrates that ARF can develop in the absence of GAS pharyngitis. The infection history of the patient and the streptococcal serology suggest an involvement of GAS pyoderma and/or GGS pharyngitis in triggering ARF. It has been hypothesized that repeated bacterial exposures are required to “prime” the immune system for ARF19 and that both GAS pyoderma and GCS/GGS could contribute to this “priming.”11 It is possible that the 2 streptococcal infections in quick succession triggered immune dysregulation in this case.
There are limitations associated with this case report. A throat swab was not performed when the child presented with GAS pyoderma so concurrent pharyngeal carriage of GAS at this time cannot be discounted. However, the throat swab performed 1 month later at hospital admission was negative for GAS, which suggests the child was not a chronic pharyngeal carrier of GAS. It is possible that the pharyngeal GGS isolate represents colonization with concurrent viral pharyngitis, rather than true, serologically confirmed, GGS pharyngitis but there is no way to confirm or refute this in the absence of appropriate blood samples. Given the high proportion of pharyngeal GGS/GGC detected in high-risk children in other ARF endemic settings,5,6 the presence of pharyngeal GGS should not be disregarded in this case. Moreover, within the school-based program operating in the region this child was domiciled, some 46.5% of all Streptococci positive throat swabs grew GGS/GGC (348 of 748 total positive swabs) in the same year.
While, the infection history and streptococcal serology make it impossible to disentangle the contribution of GAS pyoderma and pharyngeal GGS to ARF in this case, it is clear that GAS pharyngitis was not the driving factor for disease. It is possible that the GAS pyoderma and pharyngeal GGS “primed” the immune system with both infections being causal. In New Zealand, there is a lack of robust incidence data for GAS pyoderma and GCS/GGS pharyngitis in high-risk children yet this case suggests these infections should not be dismissed in the context of rheumatic fever diagnosis and prevention. This case highlights the urgent need for further research to improve our understanding of ARF pathogenesis, with significant questions regarding the contribution of GAS pyoderma and non-Group A Streptococci to ARF remaining.
N.J.M. is a New Zealand Heart Foundation Senior Research Fellow. We thank the Maurice Wilkins Center for ongoing support.
1. Maguire GP, Carapetis JR, Walsh WF, et al. The future of acute rheumatic fever
and rheumatic heart disease in Australia. Med J Aust. 2012;197:133–134.
2. Milne RJ, Lennon DR, Stewart JM, et al. Incidence of acute rheumatic fever
in New Zealand children and youth. J Paediatr Child Health. 2012;48:685–691.
3. Wannamaker LW. The chain that links the heart to the throat. Circulation. 1973;48:9–18.
4. Haidan A, Talay SR, Rohde M, et al. Pharyngeal carriage of group C and group G streptococci and acute rheumatic fever
in an Aboriginal population. Lancet. 2000;356:1167–1169.
5. McDonald MI, Towers RJ, Andrews RM, et al. Low rates of streptococcal pharyngitis
and high rates of pyoderma
in Australian aboriginal communities where acute rheumatic fever
is hyperendemic. Clin Infect Dis. 2006;43:683–689.
6. Steer AC, Jenney AW, Kado J, et al. Prospective surveillance of streptococcal sore throat in a tropical country. Pediatr Infect Dis J. 2009;28:477–482.
7. Steer AC, Jenney AW, Kado J, et al. High burden of impetigo and scabies in a tropical country. PLoS Negl Trop Dis. 2009;3:e467.
8. Atatoa-Carr P, Lennon D, Wilson N; New Zealand Rheumatic Fever Guidelines Writing Group. Rheumatic fever diagnosis, management, and secondary prevention: a New Zealand guideline. N Z Med J. 2008;121:59–69.
9. Jack S, Williamson D, Galloway Y, et al. Interim Evaluation of the Sore Throat Management Component of the New Zealand Rheumatic Fever Prevention Programme. 2015:Porirua, New Zealand: The Institute of Environmental Science and Research Ltd; 1–175.
10. Steer AC, Smeesters PR, Curtis N. Streptococcal Serology: secrets for the Specialist. Pediatr Infect Dis J. 2015;34:1250–1252.
11. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever
: a chink in the chain that links the heart to the throat? Lancet Infect Dis. 2004;4:240–245.
12. Steer AC. Historical aspects of rheumatic fever. J Paediatr Child Health. 2015;51:21–27.
13. Williamson DA, Moreland NJ, Jack S. Invasive group A Streptococcal infections in indigenous New Zealanders with type 2 diabetes. Clin Infect Dis. 2016;63:1268–1269.
14. Kaplan EL, Bisno AL. Antecedent streptococcal infection in acute rheumatic fever
. Clin Infect Dis. 2006;43:690–692.
15. Mikkelsen CS, Gelvan A, Ibrahim A, et al. A case of rheumatic fever with acute post-streptococcal glomerulonephritis and nephrotic syndrome caused by a cutaneous infection with beta-hemolytic streptococci. Dermatol Reports. 2009;1:e4.
16. Popat KD, Riding WD. Acute rheumatic fever
following streptococcal wound infection. Postgrad Med J. 1976;52:165–170.
17. Vyse T. Rheumatic fever: changes in its incidence and presentation. BMJ. 1991;302:518–520.
18. Davies MR, Tran TN, McMillan DJ, et al. Inter-species genetic movement may blur the epidemiology of streptococcal diseases in endemic regions. Microbes Infect. 2005;7:1128–1138.
19. Raynes JM, Frost HR, Williamson DA, et al. Serological evidence of immune priming by group A Streptococci in patients with acute rheumatic fever
. Front Microbiol. 2016;7:1119.