Hrev_master [page 12] [Dermatology Reports 2009; 1:e4] A case of rheumatic fever with acute post-streptococcal glomerulonephritis and nephrotic syndrome caused by a cutaneous infection with beta-hemolytic streptococci Carsten Sauer Mikkelsen,1 Allan Gelvan,1 Ahmad Ibrahim,2 Karin Ladefoged1 1Department of Medicine, Queen Ingrid’s Hospital, Nuuk, Greenland; 2Department of Nephrology, Copenhagen University Hospital (Rigshospitalet), Denmark Case Report A 44-year old woman of Greenlandic origin was referred to Queen Ingrid’s Hospital. She was previously healthy apart from excessive alcohol consumption and pulmonary tuberculo- sis diagnosed two years earlier for which she had received full antimycobacterial treatment. The patient initially complained of a painful traumatic skin lesion of the right lower extremity with a diameter of approximately 2 cm. A few days later, her temperature rose to 39.5°C and bullous erysipelas of the area of initial trauma was noted. Laboratory tests revealed a markedly elevated sedimentation rate of 111 mm/L hour [2-21], an elevated C reactive protein of 144 mg/L [<10], leukocyto- sis 18¥109/L [4.4-11] with neutrophilia and ¥109/L [150-450]. Intravenous dicloxacillin and phenoxymethylpenicillin were adminis- tered. Culture from the lesion of the right lower extremity was positive for group A β- hemolytic streptococci (GABHS). In spite of relevant antibiotic treatment, the clinical con- dition rapidly deteriorated with involvement of the deeper layers of the skin and subcutaneous tissue, spreading across the fascial planes of the subcutis (Figure 1). Necrotizing fasciitis (NF) was diagnosed. Based on positive skin cultures, this condition was considered to be due to GABHS. The patient had no other pre- disposing factors to NF, specifically no diabetes mellitus, no intravenous abuse and no daily intake of non-steroidal anti-inflammatory drugs (NSAID). Radiological examination of the right lower extremity and foot showed no signs of osseous involvement. Extensive surgi- cal revision of the NF-lesion was performed and meropenem, ciprofloxacin and clin- damycin were administered. Approximately three weeks after the initial presentation, impairment of renal function with azotemia and severe nephrotic syndrome with perior- bital and peripheral edema were noted. Laboratory tests showed an elevated creatinine of 386 umol/L [44-115], BUN: 23.6 mmol/L [2.5- 6.7], normochromic, normocytic anemia with hemoglobin: 4.9 mmol/L [7.5-9.0], as well as macroscopic hematuria, renal-creatinine clear- ance: 30 mL/min and U-protein: 5.8 g/24 h [<0.15]. Anti nuclear antibodies (ANA), anti- neutrophil cytoplasmic antibodies (ANCA), IgA, IgG, IgM and protein electrophoresis were all normal. Blood pressure was increased to 165/100. The hypertension was efficiently treat- ed by ACE-inhibitors and beta blockers. The patient was transferred to Rigshospitalet, Copenhagen where a renal biopsy was per- formed. The biopsy demonstrated endocapillary glomerulonephritis with proliferation of endo- thelial cells and infiltration of polymorphonu- clear cells. Using immunofluorescence tech- niques, granular deposits of IgG and C3 were identified as typically seen in acute post-strep- tococcal glomerulonephritis (APSGN) (Figure 2). During the same period, the patient com- plained of chest pain. Electrocardiogram (ECG) showed sinus rhythm with no signs of ischemia and no elevation of cardiac troponin I was found. Echocardiography showed moderate reduced left ventricular ejection fraction (LVEF): 35% [50-65%] and moderate mitral regurgitation (grade II). Pulmonary pressure was significantly increased > 60 mm Hg [18- 25]. Brain natriuretic peptide (BNP) was sig- nificantly increased >8000 pg/mL [<100]. There were complaints of arthralgia of the left elbow. There were no other signs of acute rheu- matic fever (ARF) and no signs of pharyngitis in the whole period. Chest X ray and HR-CT of the thorax showed changes in both lungs consistent with old tuberculosis. Two weeks after the first analysis, renal function had improved and U- protein had decreased to 2.6 g/24 h, creatinine 139 umol/L, BUN 9.5 mmol/L. Ultrasound of the kidneys was normal. Echocardiography still Dermatology Reports 2009; volume 1:e4 Correspondence: Carsten Sauer Mikkelsen, Department of Dermatology, Stavanger University Hospital, Arnauer Hansensvej 20, Postbox 8100 Postterminalen, 4068 Stavanger Norway. E-mail: c.s.mikkelsen@privat.dk and c.s.mikkelsen@hotmail.com Key words: rheumatic fever, acute post-strepto- coccal glomerulonephritis, nephrotic syndrome. Received for publication: 18 November 2009. Accepted for publication: 14 December 2009. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright C.S. Mikkelsen et al., 2009 Licensee PAGEPress, Italy Dermatology Reports 2009; 1:e4 doi:10.4081/dr.2009.e4 Figure 1. Group A b-hemolytic streptococci with involvement of the deeper layers of the skin and subcutaneous tissue, spreading across the fascial planes of the subcutis. Figure 2. Diffuse proliferative glomerulonephritis with approximately 40% halfmoons. Significant tubulus atrophy and interstitial fibrosis with inflammation. Endocapillary glomerulonephritis, with accu- mulation of endothelial cells and inflammatory cells in the capillary lumina. Changes compatible with acute post- streptococcal glomerulonephri- tis. No signs of systemic disease or vasculitis. No n- co mm er cia l regurgitation (grade II). Pulmonary pressure No n- co mm er cia l regurgitation (grade II). Pulmonary pressurewas significantly increased > 60 mm Hg [18- No n- co mm er cia l was significantly increased > 60 mm Hg [18-25]. Brain natriuretic peptide (BNP) was sig- No n- co mm er cia l 25]. Brain natriuretic peptide (BNP) was sig- No n- co mm er cia l and phenoxymethylpenicillin were adminis- No n- co mm er cia l and phenoxymethylpenicillin were adminis- tered. Culture from the lesion of the right No n- co mm er cia l tered. Culture from the lesion of the right lower extremity was positive for group A No n- co mm er cia l lower extremity was positive for group A β No n- co mm er cia l β- No n- co mm er cia l - hemolytic streptococci (GABHS). In spite of No n- co mm er cia l hemolytic streptococci (GABHS). In spite of relevant antibiotic treatment, the clinical con- No n- co mm er cia l relevant antibiotic treatment, the clinical con- dition rapidly deteriorated with involvement ofNo n- co mm er cia l dition rapidly deteriorated with involvement of the deeper layers of the skin and subcutaneousNo n- co mm er cia l the deeper layers of the skin and subcutaneousNo n- co mm er cia l u se found. Echocardiography showed moderate us e found. Echocardiography showed moderatereduced left ventricular ejection fraction us e reduced left ventricular ejection fraction (LVEF): 35% [50-65%] and moderate mitralus e (LVEF): 35% [50-65%] and moderate mitral regurgitation (grade II). Pulmonary pressureus e regurgitation (grade II). Pulmonary pressure was significantly increased > 60 mm Hg [18-us e was significantly increased > 60 mm Hg [18- the whole period. Chest X ray and HR-CT of the us e the whole period. Chest X ray and HR-CT of the thorax showed changes in both lungs consistent us e thorax showed changes in both lungs consistentwith old tuberculosis. Two weeks after the first us e with old tuberculosis. Two weeks after the firsto nly nificantly increased >8000 pg/mL [<100]. on lynificantly increased >8000 pg/mL [<100]. on lyThere were complaints of arthralgia of the left on lyThere were complaints of arthralgia of the leftelbow. There were no other signs of acute rheu- on lyelbow. There were no other signs of acute rheu- matic fever (ARF) and no signs of pharyngitis inon ly matic fever (ARF) and no signs of pharyngitis in the whole period. Chest X ray and HR-CT of theon ly the whole period. Chest X ray and HR-CT of the thorax showed changes in both lungs consistent on ly thorax showed changes in both lungs consistent on ly [Dermatology Reports 2009; 1:e4] [page 13] showed moderate reduced left ventricular ejec- tion fraction (LVEF): 35% with mild mitral regurgitation (grade I). Continued follow-up of renal and cardiac function is planned. Discussion This case illustrates the simultaneous development of carditis, arthralgia and endo- capillary glomerulonephritis with severe nephrotic syndrome preceded by a cutaneous GABHS in the lower right leg. The patient ful- fils the revised and updated Jones criteria for classification of ARF based on fever, arthralgia, carditis, increased acute phase reactants (CRP, ESR) and a positive culture of GABHS. ARF develops after group A streptococcal pharyngi- tis1,2 and is only seldom described after GABHS skin infections.3-5 Our patient had no signs of pharyngitis but developed NF presumably from a traumatic skin lesion. Culture from the ini- tial lesion of the right lower extremity was pos- itive for GABHS.We propose that our patient developed ARF from her skin infection. We are aware of no history of sore throat described in the literature in cases of ARF.6 Also throat swab will be positive in only a third of patients infected with group A streptococcus before antibiotic treatment and in only a tenth of patients afterwards.7 GAS pyoderma rather than pharyngitis as a driving force behind ARF has been described in aboriginal communities in Northern Australia.8,9 Repeated exposure to GABHS can play a central role in the develop- ment of ARF10 as a sort of immune priming.8 In our case there was no previous history of pharyngitis or other focus of GABHS infec- tions. ARF and APSGN, two important sequelae of streptococcal throat or skin infections, according to current concepts may be elicited by autoimmune mechanisms due to molecular mimicry between GABHS and human tissue.11 APSGN follows infection with a limited number of GABHS serotypes. Type 12 is the most fre- quent M serotype causing APSGN after pharyn- gitis or tonsillitis, whereas M-49 is the type most frequently related to pyoderma-associat- ed nephritis.12 The patient had no earlier symp- toms of heart disease and so we strongly sus- pect the high BNP and and moderate mitral regurgitation to be carditis related to ARF. In affluent societies where GABHS disease is uncommon apart from pharyngitis in child- hood, increasing numbers of NF and strepto- coccal toxic shock syndrome (STSS) have been seen, as well as an upsurge of acute rheumat- ic fever apparently restricted to parts of the United States.13-16 In some of these locations, a virulent M1 serotype GABHS clone has been found.17 We suggest a possible relation between a virulent GABHS clone causing NF and ARF. References 1. Wannamaker L. The chain that links the heart to the throat. Circulation 1973;48:9- 18. 2. Wannamaker L. Differences between streptococcal infections of the throat and of the skin. N Engl J Med 1970;282:78-85 3. Popat K. Riding W. Acute rheumatic fever following streptococcal wound infection. Postgrad Med J 1976;52:165-70. 4. McDonald MI, Towers RJ, Andrews R, et al. The dynamic nature of group A streptococ- cal epidemiology in tropical communities with high rates of rheumatic heart dis- ease. Epidemiol Infect 2008;136:529-39. 5. McDonald MI, Towers RJ, Andrews R, et al. Molecular typing of Streptococcus pyo- genes from remote Aboriginal communi- ties where rheumatic fever is common and pyoderma is the predominant streptococ- cal infection. Epidemiol Infect 2007; 135:1398-405. 6. Wilson NJ, Neutze JM. Echocardiographic diagnosis of subclinical carditis in acute rheumatic fever. Int J Cardiol 1995;50:1-6 7. Jansen TLThA, Janssen M, Van Reil PLCM. Acute rheumatic fever or post-streptococc- cal reactive arthritis: a clinical problem revisited. Br J Rheumatol 1998;37:335-40. 8. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat. Lancet Infect Dis 2004:4:240-5. 9. Currie BJ, Carapetis JR. Skin infections and infestations in Aboriginal communi- ties in northern Australia. Australas J Dermatol 2000;41:139-43. 10. Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000;13:470-511 11. Burova AL, Nagornev VA, Pigarevsky PV, Gladilina MM, Seliverstova, et al. Myo- cardial tissue damage in rabbits injected with group A streptococci, types M1 and M22. Role of bacterial immunoglobulin G- binding surface proteins. APMIS 2005; 113:21-30. 12. Bisno AL, Brito MO, Collins CM. Molecular basis of group A streptococcal virulence. Lancet Infect Dis 2003:3:191-200. 13. Stevens DL. The flesh-eating bacterium: what`s next? J Infect Dis 1999;179:S366- 74. 14. Chelsom J, Halstensen A, Haga T, Højby EA. Necrotising fasciitis due to group A Streptococci in western Norway: incidence and clinical features. Lancet 1994;344: 1111-15. 15. Kaul R, McGeer A, Low DE, Gren K, Schwartz B. Population based surveillance for Group A streptococcal necrotizing fasciitis: Clinical features, prognostic indi- cators, and microbiologic analysis of sev- enty cases. Am J Med 1997;103:18-24. 16. Haywood C, McGeer A, Low D. Clinical experience with 20 cases of Group A strep- tococcus necrotizing fasciitis and myo necrosis: 1995-1997. Plast Reconst. Surg 1999, 103: 1567-73 17. Cleary PP, Kaplan EL, Handley JP, et al. Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980`s. Lancet 1992;339:518-21. Case Report No n- co mm er cia l 3. Popat K. Riding W. Acute rheumatic fever No n- co mm er cia l 3. Popat K. Riding W. Acute rheumatic feverfollowing streptococcal wound infection. No n- co mm er cia l following streptococcal wound infection. Postgrad Med J 1976;52:165-70. No n- co mm er cia l Postgrad Med J 1976;52:165-70. No n- co mm er cia l pharyngitis or other focus of GABHS infec- No n- co mm er cia l pharyngitis or other focus of GABHS infec- tions. ARF and APSGN, two important sequelae No n- co mm er cia l tions. ARF and APSGN, two important sequelae of streptococcal throat or skin infections, No n- co mm er cia l of streptococcal throat or skin infections, according to current concepts may be elicited No n- co mm er cia l according to current concepts may be elicited by autoimmune mechanisms due to molecular No n- co mm er cia l by autoimmune mechanisms due to molecular mimicry between GABHS and human tissue. No n- co mm er cia l mimicry between GABHS and human tissue. APSGN follows infection with a limited numberNo n- co mm er cia l APSGN follows infection with a limited number of GABHS serotypes. Type 12 is the most fre-No n- co mm er cia l of GABHS serotypes. Type 12 is the most fre- 4. McDonald MI, Towers RJ, Andrews R, et al. No n- co mm er cia l 4. McDonald MI, Towers RJ, Andrews R, et al. The dynamic nature of group A streptococ- No n- co mm er cia l The dynamic nature of group A streptococ- cal epidemiology in tropical communities No n- co mm er cia l cal epidemiology in tropical communities with high rates of rheumatic heart dis- No n- co mm er cia l with high rates of rheumatic heart dis- ease. Epidemiol Infect 2008;136:529-39. No n- co mm er cia l ease. Epidemiol Infect 2008;136:529-39. 5. McDonald MI, Towers RJ, Andrews R, et al. No n- co mm er cia l 5. McDonald MI, Towers RJ, Andrews R, et al. Molecular typing of Streptococcus pyo- No n- co mm er cia l Molecular typing of Streptococcus pyo- genes from remote Aboriginal communi- No n- co mm er cia l genes from remote Aboriginal communi- ties where rheumatic fever is common and No n- co mm er cia l ties where rheumatic fever is common and us e 2. Wannamaker L. Differences between us e 2. Wannamaker L. Differences betweenstreptococcal infections of the throat and us e streptococcal infections of the throat and of the skin. N Engl J Med 1970;282:78-85us e of the skin. N Engl J Med 1970;282:78-85 3. Popat K. Riding W. Acute rheumatic feverus e 3. Popat K. Riding W. Acute rheumatic fever on ly heart to the throat. Circulation 1973;48:9- on ly heart to the throat. Circulation 1973;48:9- binding surface proteins. APMIS 2005; on ly binding surface proteins. APMIS 2005; 113:21-30. on ly113:21-30.12. Bisno AL, Brito MO, Collins CM. Molecular on ly12. Bisno AL, Brito MO, Collins CM. Molecularbasis of group A streptococcal virulence. on lybasis of group A streptococcal virulence. Lancet Infect Dis 2003:3:191-200.on ly Lancet Infect Dis 2003:3:191-200.on ly 13. Stevens DL. The flesh-eating bacterium:on ly 13. Stevens DL. The flesh-eating bacterium: