Case Report

CASE REPORT Year : 2002 | Volume : 68 | Issue : 2 | Page : 107-108 Painless piezogenic pedal papules in a patient with rheumatic heart disease SK Singh, M Tehseen, A Kalam Department of Dermatology, J.N. Medical College, A.M.U., Aligarh, India Correspondence Address: Department of Dermatology, J.N. Medical College, A.M.U., Aligarh, India Abstract A 14-year - old female with rheumatic heart disease presented with multiple painless, non - itchy papules on her heel. Painless papules consisted of normal fat tissues. How to cite this article: Singh SK, Tehseen M, Kalam A. Painless piezogenic pedal papules in a patient with rheumatic heart disease. Indian J Dermatol Venereol Leprol 2002;68:107-8 How to cite this URL: Singh SK, Tehseen M, Kalam A. Painless piezogenic pedal papules in a patient with rheumatic heart disease. Indian J Dermatol Venereol Leprol [serial online] 2002 [cited 2009 Jul 17];68:1078. Available from: http://www.ijdvl.com/text.asp?2002/68/2/107/12617

Introduction Piezogenic pedal papules are soft, skin coloured papules and nodules, which appear on the side of the heel, usually the medial aspect, when the subject is standing and disappear when weight is taken off the foot.[1] Similar papules have also been noticed on the lateral edge of the hand and wrist.[2] Case Report A 14 - year -old girl came with multiple painless, soft, skin-coloured papules on both heels when standing, for 2 months duration. There was no change in size and number of papules within two months. Papules disappeared when weight was taken off. Papules were on medial, posterior and lateral aspect of both heels. There was no pain on standing. There was no history of such type of lesions in family members or relatives. Systemic examination showed features of rheumatic heart disease with mitral regurgitation and pulmonary hypertension. Routine investigations of blood and urine did not reveal any abnormality except mild anemia. Histopathological examination of papules showed normal fat tissue. [Figure - 1] Discussion

Piezogenic papules are a form of reaction to internal mechanical stress. They are mainly found on feet but can be found on hand and wrist. Papules appear when weight is put on that particular area. Papules may be painful when there is herniation of fat in to the dermis with a resultant reduction in dermal thickness.[3] Postulated reasons for this pain include a defect in septation of the adipose tissue and ischaemia due to extrusion of fat within its vascular supply and associated nerves. The frequency of the condition makes it difficult to assess the assertion that piezogenic pedal papules can be familial[4] and also that there is an increased frequency in Ehlers - Da nlos syndrome.[5] Since piezogenic pedal papule has not been reported in association with rheumatic heart disease, we report this case. References 1.

Cohen HJ, Gibbs RC, Minkin W, et al. Painful piezogenic pedal papules. Arch Dermatol

2.

1970;101:112-113. Laing VB, Fleischer AB. Piezogenic wrist papules: a common and asymptomatic finding. J

3.

Am Acad Dermatol 1991;24:415-17. Harman RRM, Mathews CNA. Painful piezogenic papules. Br J Dermatol 1974:90:573-

4.

574. Gibney MD, Glaber DA. Piezogenic pedal papules in two family members. Cutis

5.

1996;57:260-262. Kahana M, Feinstein A, Tabachnic E, et al. Painful piezogenic pedal papules in- patients with Ehlers - Danlos syndrome. J Am Acad Dermatol 1987;17:205-209.

http://www.ijdvl.com/article.asp?issn=03786323;year=2002;volume=68;issue=2;spage=107;epage=108;aulast=Singh

http://eurheartj.oxfordjournals.org/cgi/content/abstract/23/7/567

European Heart Journal 2002 23(7):567-573; doi:10.1053/euhj.2001.2837 Copyright © 2002 by the European Society of Cardiology.

Enterovirus replication in valvular tissue from patients with chronic rheumatic heart disease Y Lia, Z Panb, Y Jib, T Penga, L.C Archarda and H Zhanga,f1

Cell and Molecular Biology Section, Division of Biomedical Sciences, Imperial College School of Medicine, London, U.K. b Departments of General Practice and Pathology, Zhongshan Hospital, Shanghai Medical University, Shanghai, P. R. China a

revised June 15, 2001; accepted June 20, 2001

Abstract Aims To investigate the involvement of enterovirus infection in chronic, rheumatic heart disease. Methods and Results Formalin-fixed, paraffin-embedded, surgical samples of valve tissue were examined for the presence of enteroviral RNA and virus capsid protein VP1 by in situ hybridization and immunostaining. Of 53 cases, 33 were patients with chronic rheumatic heart disease and 20 had Marfan's syndrome or degenerative valve disease. Enterovirus RNA was detected in 8 (24·2%) of 33 patients with chronic rheumatic heart disease by in situ hybridization using strand-specific oligonucleotide probes, complementary to conserved sequences in enterovirus genomic (positive strand) RNA. The replication template (negative strand) RNA also was found in seven of these eight cases. The viral capsid protein VP1 was detected in 16 (48·5%) of 33 patients with chronic rheumatic heart disease by immunohistochemistry and correlated with viral RNA detection. Virus was localized generally to valvular tissue. Neither viral RNA nor capsid protein VP1 were found in valvular tissue from any of the 20 comparison cases. Conclusions This is the first demonstration of detection and localization of both enterovirus RNA and capsid protein in chronic rheumatic heart disease. The presence of negative strand RNA and VP1 indicates enteroviral RNA replication and protein synthesis and suggests an aetiological role of enterovirus in the pathogenesis of chronic rheumatic heart disease. Key Words: Rheumatic heart disease, valves, enteroviruses, hybridization, immunohistochemistry f1

Correspondence: Dr. Hongyi Zhang, Cell and Molecular Biology Section, Division of Biomedical Sciences, Sir Alexander Fleming Building, Imperial College School of Medicine, Exhibition Road, London SW7 2AZ, U.K.

http://americanheart.mediaroom.com/index.php?s=43&item=682 July 17, 2009 News Releases Diagnosing, treating strep throat key to preventing rheumatic heart disease Statement Highlights: • Rheumatic fever, though rare, can be prevented by accurate diagnosis and treatment of strep throat. • A certain type of strep causes rheumatic fever. Strep can be identified by a simple test at your doctor’s office. • Not all sore throats are strep – most are viral. DALLAS, Feb. 26, 2009 — Accurately diagnosing and treating strep throat is the key to preventing rheumatic fever and subsequent rheumatic heart disease, according to an updated

American Heart Association scientific statement published in Circulation: Journal of the American Heart Association. Rheumatic fever is an inflammatory disease that can affect many of the body’s connective tissues, especially those of the heart, joints, brain or skin. When the heart valves are damaged by rheumatic fever it leads to rheumatic heart disease which can last a lifetime. Rheumatic fever is caused when a particular strain of strep throat (group A β-hemolytic streptococcus, or GAS pharyngitis) is left untreated. Rheumatic fever/rheumatic heart disease continues to be the leading cause of cardiovascular death during the first five decades of life in the developing world. A throat culture, taken by swabbing the back of the throat, is considered the “gold standard” for identifying this strep infection. The culture and good clinical judgment are the best ways to diagnose strep throat, said Michael A. Gerber, M.D., lead author of the scientific statement. “It’s important to know that while strep throat is most common in children five to 15 years old, most sore throats in this age group are not caused by this particular type of strep,” said Gerber, Professor of Pediatrics in the Division of Infectious Diseases at Cincinnati Children’s Hospital Medical Center in Ohio. “In fact, most are caused by viruses which do not raise the risk of rheumatic fever and are not treatable with antibiotics.” The update of the American Heart Association’s 1995 scientific statement gives healthcare providers here and abroad the most recent evidence for preventing rheumatic fever, including specific diagnostic instructions and antibiotic treatment. Preventing initial episodes of rheumatic fever (primary prevention) requires accurate diagnosis and proper antibiotic treatment of GAS pharyngitis. Patients who have had an attack of rheumatic fever are at very high risk of developing recurrences if they have another case of strep throat. They need continuous antibiotics to prevent recurrences (secondary prevention). Patients who have had rheumatic carditis (inflammation of the heart or area around the heart) should also receive preventive antibiotic therapy well into adulthood and perhaps for life. Penicillin is the agent of choice for secondary prevention, but there are other antibiotics that are acceptable alternatives for people allergic to penicillin. Recurrent episodes of rheumatic fever can worsen rheumatic heart disease or, less frequently, cause rheumatic heart disease in people who didn’t develop it during their first infection. Signs of GAS pharyngitis include (but are not limited to): • sudden-onset of sore throat, • pain on swallowing, F,°• fever, usually 101-104 • headache; • abdominal pain, nausea, and vomiting may also occur, especially in children. These signs can occur with other upper respiratory tract infections, and it can be difficult even for an experienced healthcare provider to tell GAS pharyngitis from other types of pharyngitis, so the throat culture is important for accurate diagnosis. Symptoms of rheumatic fever vary widely, but may include: • fever, • painful, tender, red, swollen joints, • pain in one joint that migrates to another one, • heart palpitations, • chest pain,

• shortness of breath, • skin rashes, • small, painless nodules under the skin. Rheumatic fever is rare in children younger than 3 years of age in the U.S. Among adults, initial attacks of rheumatic fever are rare, but do occur. Overall, the progression from strep throat to rheumatic fever is rare in the United States, but a few localized acute rheumatic fever outbreaks in civilian and military populations were reported in the 1980s. “This reappearance of acute rheumatic fever reminds physicians, parents and others about the importance of continued attention to prevention of rheumatic fever in the United States and in other developed countries,” said Gerber. Co authors include: Robert Baltimore, M.D.; Charles Eaton, M.D.; Michael Gewitz, M.D.; Anne Rowley, M.D.; Stanford Shulman, M.D.; Kathryn Taubert, Ph.D.

http://eurjhf.oxfordjournals.org/cgi/content/full/4/5/593 European Journal of Heart Failure 2002 4(5):593-595; doi:10.1016/S1388-9842(02)00102-2 © 2002 European Society of Cardiology

Increased levels of high sensitive C-reactive protein in patients with chronic rheumatic valve disease: evidence of ongoing inflammation Zehra Gölbasia,*, Özgül Uçara, Telat Kelesa, Ahmet Sahinb, Kerim Çaglic, Ahmet Çamsaria, Erdem Dikera and Sinan Aydogdua Department of Cardiology, Ankara Numune Education and Research Hospital Yuva sok No 20/2, Küçükesat 06660, Ankara, Turkey b Düzen Laboratory Groups Ankara, Turkey c Yüksek Ihtisas Hospital, Department of Cardiovascular Surgery Ankara, Turkey a

Abstract The precise pathogenetic mechanism(s) of rheumatic fever and rheumatic heart disease have never been defined. C-reactive protein (CRP) is increased in patients with acute rheumatic fever, but it is not known whether plasma levels increase in patients with chronic rheumatic valve disease. The aim of this study was to determine the role of inflammation detected by high sensitivity CRP (hs-CRP) levels in the progression of chronic rheumatic valve disease. A total of

113 patients with chronic rheumatic valve disease (81 women, 32 men; mean age 40±14 years, range 13–70), 51 patients with prosthetic valve(s) (31 women, 20 men; mean age 48±13 years, range 21–71) and 102 healthy subjects (68 women, 34 men, mean age 41±12 years, range 25–73), as a control group, were assessed. Patients with acute rheumatic fever, acute infection, inflammatory disease, malignancy, acute myocardial infarction and trauma were excluded. hsCRP was determined using latex-enhanced immunonephelometric assays on a BN II analyzer (Behring). Transthoracic echocardiography was performed in all patients in order to evaluate valvular disease. Levels of hs-CRP were significantly higher in patients with chronic rheumatic heart disease than in patients with prosthetic valve(s) and healthy subjects (0.62±0.64 vs. 0.35±0.41 vs. 0.24±0.18 mg/l, P<0.01 and P<0.001 respectively). No correlation was observed between CRP and age, sex or functional capacity. We found that hs-CRP is increased in chronic rheumatic heart disease; this may indicate that inflammatory response still persists in the chronic phase. Key Words: Rheumatic valve disease • Acute rheumatic fever • C-reactive protein Received November 6, 2001; Revised February 6, 2002; Accepted April 22, 2002

1. Introduction The precise pathogenetic mechanism(s) of rheumatic fever and rheumatic heart disease have never been defined. It has been hypothesized that on exposure to group A streptococci during infection, ‘antigenic mimicry’ leads to autoimmune-like reaction within the human host and results in valvulitis, ultimately leading to rheumatic valvular heart disease [1]. It has been considered that chronic rheumatic valve disease is usually the result of repeated episodes of carditis alternating with healing and is characterized by the deposition of fibrous tissue. The debate continues about whether the anatomical changes in chronic rheumatic valve disease result from a smoldering rheumatic process or whether, once the valve has been deformed by turbulent flow, this leads to progressive fibrosis, thickening and calcification of the valve apparatus [2]. Creactive protein (CRP) is increased in patients with acute rheumatic fever, but it is not known whether plasma levels increase in patients with chronic rheumatic valve disease. The aim of this study was to determine the role of inflammation detected by hs-CRP levels in the progression of chronic rheumatic valve disease.

2. Methods A total of 131 patients with chronic rheumatic heart disease and 72 patients who had undergone valve replacement due to rheumatic etiology, all followed up on an out-patient basis, were included in the study. Patients with acute rheumatic fever, acute infection, inflammatory disease, malignancy, acute myocardial infarction and trauma were excluded. In addition, patients who had rheumatic valve involvement other than in the replaced valve(s), as detected on echocardiographic examination, were excluded from the study. After the initial evaluation, 113 patients with chronic rheumatic valve disease (81 women, 32 men; mean age 40±14 years, range

13–70), 51 patients with prosthetic valve(s) (31 women, 20 men; mean age 48±13 years, range 21–71) and 102 healthy subjects (68 women, 34 men; mean age 41±12 years, range 25–73), as a control group, were assessed. Of the patients with chronic rheumatic valve disease, 51 patients had mitral valve disease, 59 patients had combined mitral and aortic valve disease, and three patients had aortic valve disease; 49 patients were New York Heart Association (NYHA) functional class I, 49 were class II, and 15 were class III. Of the patients with prosthetic valve(s), 28 patients had mitral valve replacement, 12 patients had aortic valve replacement, and 11 patients had combined mitral and aortic valve replacement. Of these, 27 patients were NYHA class I, 23 patients were class II and one patient was class III. The mean time from valve replacement surgery to enrolment was 4.2±3 years in the prosthetic valve group. Levels of hsCRP were determined using latex-enhanced immunonephelometric assay on a BNP analyzer (Behring) [3]. Transthoracic echocardiography was performed in all patients in order to evaluate valvular disease (GE Vingmed System FiVe, 2.5-MHz transducer). The investigation conformed with the principles outlined in the Declaration of Helsinki. 2.1. Statistics Data were analyzed with the SPSS for Windows statistical package and are presented as mean±S.D. Differences between mean values were analyzed by Student's unpaired t-test. Univariate comparisons between groups were made with non-parametric tests: Kruskal–Wallis tests for multigroup comparisons and Mann–Whitney tests for two-group comparisons. The 2 test and Fischer's probability test were used to compare proportions. Differences were considered significant at P<0.05.

3. Results The levels of hs-CRP were significantly higher in patients with chronic rheumatic heart disease than in patients with prosthetic valve(s) and healthy subjects (0.62±0.64 vs. 0.35±0.41 vs. 0.24±0.18 mg/dl, P<0.01 and P<0.001, respectively) (Fig. 1). Although in the prosthetic valve group the hs-CRP level was higher than in healthy subjects, the difference was not statistically significant. In addition, compared with patients with one valve lesion, patients with multivalvular disease had significantly higher plasma hs-CRP levels (1.24±0.60 vs. 0.49±0.54 mg/dl, P<0.05). No correlation was observed between hs-CRP levels and age, sex or functional capacity.

Fig. 1 Individual values of levels of C-reactive protein (mg/dl) in patients and in healthy subjects.

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4. Discussion In this cross-sectional study of patients with rheumatic valve disease, hs-CRP was found to be significantly higher in the chronic phase. In addition, we observed that, in patients with prosthetic valve(s), hs-CRP levels were no longer high. One current hypothesis, so-called ‘antigenic mimicry’, to explain the valvular damage in acute rheumatic fever, is based upon an antigenic similarity between human heart valves and group A streptococci [1,4]. It has been postulated that an abnormal antibody response leads to an ‘autoimmune’ process, which causes continuing or smoldering damage to the heart valves. This hypothesis is based upon an earlier study, in which the prolonged persistence of group A streptococcal carbohydrate antibody and the reduction of humoral antibody levels to the group A carbohydrate after surgical removal of the involved valve were shown [5]. The findings in our study indicating an increase in hs-CRP levels in patients with rheumatic heart disease in chronic phase, and hs-CRP levels after surgical removal of the involved valve(s) comparable with the healthy subjects, may support this hypothesis. High levels of hs-CRP in patients with chronic rheumatic valve disease indicate the persistence of inflammation in the chronic phase. In a previous study, it was shown that myocarditis associated with acute rheumatic fever itself may remain ‘active’ months after the clinical disease has entered a quiescent period [6]. We might expect this to be a similar case with progressive valvular damage in rheumatic heart disease. C-reactive protein is not only an indicator of the acute phase response to the primary underlying process, but can also exacerbate existing tissue damage itself. In chronic rheumatic valve disease, involvement is either univalvular or multivalvular. In our study, compared with the patients who had a single valve lesion, patients with multivalvular disease showed significantly higher plasma hs-CRP levels. This finding may have two meanings: one is that high CRP levels can cause multiple valve involvement, and the other is that the severity of the underlying process can cause an augmented CRP production. In our study, hs-CRP levels in patients with replaced valve(s) were significantly lower than those without valve replacement. This may be due to attenuation of the antigenic stimulus after the removal of the involved valve(s) carrying antigenic similarity. Pepys and Berger have suggested that it will only be possible to test CRP as a pathogenic factor in coronary artery disease when drugs are developed that can selectively inhibit CRP production or binding [7]. The same assumption may be valid regarding chronic rheumatic heart disease. If the presence of CRP could be demonstrated on surgically removed valve(s), this would denote the contribution of CRP to valvular damage. The results of this study may have implications in the management of chronic rheumatic valve disease. Although corticosteroids and salicylates can provide symptomatic improvement in acute rheumatic fever, they do not alter the long-term outcome of rheumatic heart disease. Currently the treatment of chronic rheumatic heart disease mainly involves the prevention of acute attacks of rheumatic fever, and no specific treatment is defined to prevent the progression of valvular

damage. The high level of CRP in the chronic phase brings the use of anti-inflammatory therapy, such as aspirin, into question. In addition, it has been suggested that statins may also inhibit the inflammatory or non-inflammatory process that induces the acute-phase response and can reduce CRP levels [8]. The biochemical mechanism of their anti-inflammatory effect is uncertain [9]. Chronic degenerative aortic valvular stenosis is another valvular disease that shows signs of local and systemic inflammation, and in a recent study CRP levels were found to be increased in this condition [10]. Furthermore, it was reported that statins could reduce the progression of aortic stenosis in patients with chronic degenerative aortic valvular stenosis and that their mechanism of action is believed to be anti-inflammatory [11]. It can be speculated that statins may be useful in the management of chronic rheumatic heart disease. However, randomized controlled trials are required to determine the value of anti-inflammatory therapy in the chronic phase.

References 1. Goldstein I., Halpern B., Robert L. Immunologic relationship between streptococcus A

polysaccharide and the structural glycoprotein of heart valve. Nature (1967) 213:44– 47.[CrossRef][Web of Science] 1. Dalen JE, Alpert JS, editors. Valvular Heart Disease. 2nd ed. Boston: Little, Brown and Co, 1987, 600 pp. 1. Rifai N., Tracy R.P., Ridker P.M. Clinical efficacy of an automated high-sensitivity C-

reactive protein assay. Clin Chem (1999) 45:2136–2141.[Abstract/Free Full Text] 1. Dudding B.A., Ayoub E.M. Persistence of streptococcal group A antibody in patients

with rheumatic valvular disease. J Exp Med (1968) 128:1081–1087.[Abstract] 1. Ayoub E.M., Taranta A., Bartley T.D. Effect of valvular surgery on antibody to the group

A streptococcal carbohydrate. Circulation (1974) 50:144–150.[Abstract/Free Full Text] 1. Narula J., Chopra P., Reddy K.S., et al. Endomyocardial biopsies in acute rheumatic fever. In: Proceedings of the Third World Congress on Pediatric Cardiology, Bangkok, Thailand, November (1989) Abstract no F226. 1. Pepys M.B., Berger A. The renaissance of C-reactive protein. Br Med J (2001)

322(7277):4–5.[Free Full Text] 1. Jialal I., Stein D., Balis D., Grundy S.M., Adams-Huet B., Devaraj S. Effects of

hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive Creactive protein levels. Circulation (2001) 103:1933–1935.[Abstract/Free Full Text] 1. Sparrow C.P., Burton C.A., Hernandez M., et al. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arter Throm Vasc Biol (2001) 21:115–121. 1. Galante A., Pietroiusti A., Vellini M., et al. C-reactive protein is increased in patients with

degenerative aortic valvular stenosis. J Am Coll Cardiol (2001) 38:1078– 1082.[Abstract/Free Full Text]

1. Novaro G.M., Tiong I.Y., Pearce G.L., et al. Effect of hydroxymethylglutaryl coenzyme A

reductase inhibitors on the progression of calcific aortic stenosis. Circulation (2001) 104:2205–2209.[Abstract/Free Full Text]

http://www.clinicalcorrelations.org/?p=823

Class Act: Pathogenesis of Rheumatic Heart Disease Class act is a feature of Clinical Correlations written by NYU 3rd and 4th year medical students. Prior to publication, each commentary is thoroughly reviewed for content by a faculty member. Commentary by Matt Stein MS-4; Reviewed by Harold Horowitz MD, Professor, NYU Division of Infectious Diseases and Immunology

In general, acute rheumatic fever (ARF) is a delayed sequela of a group A streptococcus (GAS) pharyngeal infection. Following an initial throat infection, which is often either untreated or incompletely treated, there exists a latent period of two to three weeks before the first signs of acute rheumatic fever become apparent. Weeks after the initial symptoms, patients may present with any of the characteristic manifestations of acute rheumatic fever, including arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum. (1,2) Knowledge of the specific microbiology of ARF is crucial to understanding the pathophysiology of this disease. GAS is a gram-positive, extracellular bacterial pathogen that typically colonizes the throat or skin. GAS is an organism that has developed many complex virulence mechanisms; it has become the most common cause of bacterial pharyngitis, scarlet fever, and impetigo. There are distinct GAS strains, or serotypes, that have a particularly strong tendency to cause either throat or skin infections. Moreover, streptococci have been further characterized based on the presence of particular M protein structures. There are more than eighty different M protein types of GAS currently described. The M protein has numerous functions in the bacterium, among which is protection from host immune response. More specifically, it has been shown to inhibit antibody binding and complement-derived opsonin deposition, thereby protecting GAS against phagocytosis by polymorphic neutrophils. (3) The importance of the GAS M protein in the pathogenesis of rheumatic heart disease extends beyond its value in avoiding host immune response. It has been demonstrated that molecular mimicry, associated with the structure of the M protein, induces cross-reactivity with the host immune system that results in the destruction of cardiac myosin. It has been shown that crossreactive auto-antibodies against GAS M protein antigens and heart tissue are present in the sera of rheumatic fever patients. The production of mouse and human monoclonal antibodies against GAS confirmed these cross-reactions and identified myosin, tropomyosin, and vimentin as heart auto-antigens cross-reactive with GAS M protein. (4) Although advances have been made regarding the pathogenesis of rheumatic heart disease (RHD), the specific method by which cross-reacting antibodies lead to myocarditis, endocarditis, and pericarditis is incompletely understood. One model linking humoral and cellular immune responses hypothesizes that the cross-reactive antibodies may bind to the valvular endothelium, leading to inflammation, cellular infiltration, and valvular scarring. Once activated, increased expression of various adhesive molecules by the valvular endothelium facilitates the binding of T cells and a subsequent cycle of scarring neo-vascularization and re-infiltration by lymphocytes. In addition, the particular role of anti-myosin antibodies was studied in a classic experiment in which anti-myosin antibodies from rheumatic fever patient sera were applied to neonatal rat cardiac myocytes. These antibodies caused increased calcium uptake and retention, leading to eventual myocyte dysfunction and death. (5) It appears that cardiac myosin is very involved in the pathogenesis of RHD. It seems counterintuitive, therefore, that the most prominent long-term sequela of rheumatic heart disease would be valvular dysfunction, as opposed to myocardial abnormalities. However, myosin is an intracellular protein found in small amounts in valvular tissue. Recent studies have demonstrated that the majority of peptides recognized by the infiltrating T cell clones were exclusively from valvular tissue. (6) Following the initial valvular insult, the recognition process described above initiates a cascade by which myocyte destruction leads to T-cell recognition of additional myosin epitopes, which allow for more severe valvular damage. Additionally, valvular destruction may expose more valvular epitopes that lead to more specific and localized valvular disease. This hypothesis is also

supported by the cross-reactivity that has been demonstrated between myosin and valvular protein, myosin, and M protein, and the three cross-reactive proteins at once. (6) With this knowledge in mind, a fairly detailed hypothesis has been developed to explain the way in which a GAS infection leads to RHD. Initially, when GAS pharyngitis goes untreated there is a latent phase which often deceives patients into believing they are cured. The GAS then infects the heart, utilizing a surface M protein with structural similarities to numerous cardiac proteins, including myosin, to trigger an aberrant immune response. This host response leads to autoimmune destruction of myocardium and valvular structures. This begins a cascade in which infiltration and destruction of cardiac valves leads to exposure of additional epitopes, which also cross-react, thereby amplifying the pathogenicity of GAS and furthering valvular disease. References: 1. Kaplan EL. Rheumatic fever. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JR, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGrawHill;2005:1977-79. 2. www. uptodate. com (multiple articles), November 2007. 3. Cunningham MW, McCormack JM, Talaber LR, et al. Human monoclonal antibodies reactive with antigens of the group A Streptococcus and human heart. J Immunol 1988;141:2760-66. 4. Dale JB, Beachey EH. Epitopes of streptococcal M proteins shared with cardiac myosin. J Exp Med 1985;162:583-91. 5. Fae, KC, da Silva, DD, Oshiro, SE, et al. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J Immunol 2006;176:5662-70. 6. Cunningham, MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000;13:470-511. admin @ August 14, 2008

http://www.pedrheumonlinejournal.org/july-august/RHEUMATIC%20FEVER.htm REVIEW FOR THE PRIMARY CARE PHYSICIAN RHEUMATIC FEVER

Sheila Knupp Feitosa de Oliveira and Marcia Ribeiro Keywords: arthritis, chorea, rash, nodules

Contact: Sheila Knupp Pediatric Rheumatology Universidade Federal do Rio de Janeiro Av. Sernambetiba 2940, Bl.F202 Rio de Janeiro, Brazil 22620-172 e-mail: [email protected]

INTRODUCTION

In spite of the dramatic decline of acute rheumatic fever (RF) and rheumatic heart disease (RHD) in developed nations, there is still a significant morbidity and mortality in developing countries. Although accurate data on the incidence of RF are lacking in developing countries, estimates range from 100 to 200 per 100,000 school aged children per year while in developed nations the mean annual incidence is 0.5/100,000 in children of the same age (1). Over 12 million people are affected by rheumatic fever worldwide and approximately 40,000 deaths result from rheumatic heart disease annually, mainly among children and young adults. It is estimated that two million patients now require heart surgery due to RF and one million more will require heart surgery in the next 5 to 20 years (2). EPIDEMIOLOGY Risk factors pertaining to the 3 components of classical epidemiologic triad – agent, host and environment – have been identified as important determinants of disease distribution in the population. The etiologic agent – To initiate acute RF, the site of infection caused by a strain of group A beta hemolytic streptococcus (GABHS) must be pharyngeal. Yet, not all strains that infect the pharynx cause acute RF. All age groups can be infected by streptococcus, but RF usually occurs among school-age children, where the prevalence of group A streptococci isolated from sporadic pharyngitis varies from 20 to 35%. The infection is asymptomatic in half of the patients and the diagnosis can be documented only retrospectively by a rise of antistreptococcal antibodies. It is important to differentiate the carrier state from actual infection. Detection of GABHS from the throat does not necessarily indicate a recent active infection and a rise of an immune response to the bacteria is an additional prerequisite (3). Attack rates of RF are related to the virulence of the infecting strains and possibly by the capacity of the immune response of the host. In the 1950’s, it was reported that 3% of untreated epidemic streptococcal pharyngitis in military recruits in the US resulted in RF (4, 5). In civilians and in children the rates were about 0 and 3%, respectively (6-10). The risk of recurrences of RF is still high in patients following repeated episodes of GABHS pharyngitis and in the pre-antibiotic era, 50% or more of patients had one or more recurrent attacks of RF during their lifetime (11, 12). Epidemiologic observations during epidemics of streptococcal infections associated with RF outbreaks suggest that the “rheumatogenic” potential could be closely linked to the streptococcal virulence. The virulence appears to be linked to the protein M present in the streptococcal cell wall. The protein M has the ability to resist phagocytosis by neutrophils (13, 14) and may also be an attachment factor providing the bacterium with an adherence

advantage (15). Although there are approximately one hundred different serotypes of streptococcus based on the protein M, only a limited number of streptococcal M-types have been isolated or have been associated with one or more outbreaks of RF. Other extracellular and cell-associated products of streptococcus could play a role in the virulence. These products include the presence of hyaluronate capsules that may make strains more resistant to phagocytosis and lipoteichoic acid on the streptococcal surface that is responsible for the ability to adhere to pharyngeal mucosa. The host - RF affects mainly children between 6 and 15 years, is uncommon in children under 5 years, and rare in children younger than 3 years. The frequency of the disease declines after puberty and is rare in adulthood. Both sexes are equally affected although there is a slight predominance of chorea in females. RF is reported in all ethnic groups although living conditions, socioeconomic status, and access to health care may be more important and represent potential confounders. The first evidences of genetic predisposition for the disease were based on a higher predisposition to RF in certain families (16,17) as well as the higher incidence of concordance of RHD among monozygotic twins (18.7% of 56 twin pairs) compared to dizygotic twins (2.5% of 40 pairs) (18). More recently a variety of genetic markers such as class II HLA haplotypes and a specific B-cell alloantigen (D8/17) were noted to be associated with a higher incidence of RF in certain populations. In fact, significant associations were encountered for the class II HLA-DR alleles, but these differences were related to the ethnicity of the populations studied. The diversity of these associations raised a number of questions regarding the absence of a clear association between susceptibility to RF and a specific HLA-DR (19-22). The specific Bcell alloantigen (D8/17) has been identified in a high percentage of B cells in most RF patients, but a commercial test for this alloantigen is not yet available to the clinician. Furthermore, the costs of these tests and the low specificity and sensitivity do not allow their use as a preventive strategy directed towards individuals predisposed to RF (23). The environment – Overcrowding and poor access to health care, both linked to socioeconomic development, seem to be the most important determinants of disease distribution. Seasonal variations in RF are not pronounced in the tropics (24), although in temperate climates, streptococcal infections have a peak in late winter and early spring.

PATHOGENESIS A complete understanding of the pathogenesis of RF remains elusive. The etiologic agent is the GABHS and the site infected is the throat. However, how and why a small percentage of patients develop RF is still under investigation. The latent period between the streptococcal infection and the clinical manifestation of rheumatic fever associated with the evidence of molecular mimicry between streptococcus structures and human tissues favor the hypothesis of a cross reaction between the streptococcus and the host (25,26). In fact, it is believed that the pathogenicity is related to development of autoimmunity as several humoral and cellular immune responses can be observed in patients with RF (27). Some streptococcal antigens, such as protein M, can cross-react with human tissues and this could induce a specific immunological response in some genetically predisposed patients. Besides the well studied humoral immunity related to the presence of cross-reaction antibodies in patients with rheumatic fever (myocardium, valves, cartilage, nervous system), attention has recently been drawn to the involvement of cellular immunity in RF. The contribution of cellular immunity has been suggested by changes in the number and function of lymphocytes in the peripherical blood in different phases of the disease (28). The presence of several markers of cellular immunity activation, including a higher production of cytokines, has been observed in some RF patients (29). However, the most direct evidence linking cell mediated immune response against streptococcal proteins to the pathogenesis of RHD came from the studies of Guilherme et al (30). They generated T cells clones from rheumatic valvular tissues and demonstrated that these clones recognized specific epitopes of the M5 type protein. More recently, the role of superantigens in the pathogenesis of RF has been suggested. In fact, some structures of GABHS, including protein M, have superantigen properties (31-33). CLINICAL MANIFESTATIONS RF is a multisystemic disease affecting multiple organs: heart, joints, central nervous system and skin (1). The beginning of the symptoms usually occurs after a latent period from 1 to 3 weeks (mean 18 days) after a streptococcal pharyngitis caused by GABHS and does not become shorter in repeated attacks. Onset may be acute or insidious. Usually acute attacks are associated with arthritis or carditis with pericardial effusion. Insidious onset of RF is seen in some cases of carditis and chorea, in which early behaviour changes may be misinterpreted. Arthritis- Arthritis is the commonest mode of onset and tends to occur early in the disease. In the first attack of RF, approximately 60 to 75% of children have arthritis as the major sign.

The classic pattern is migratory polyarthritis with overlap of joint involvement. Pain is more marked than swelling and frequently leads to functional impairment. In general, arthritis starts in large joints but it can also affect the small ones. The most common sites of involvement are knees (75%) and ankles (50%), followed by elbows, wrists, hips and small joints of feet (12-15%). Shoulders and small joints of the hands are the least involved (7-8%). Rarely, spine and temporomandibular joints are involved. Arthritis is usually self-limited: each joint swelling lasts from few days to one week and the total episode rarely lasts more than one month. The therapeutic response to anti-inflammatory doses of aspirin or other NSAID’s is considered an important clue to the diagnosis as it stops pain in 24 hours and the other inflammatory signs in 2 or 3 days. Some patients can exhibit a different pattern of arthritis adding some difficulty to the diagnosis, mainly when there is no other major sign of RF. They can show an additive and more prolonged duration of arthritis and a weak response to NSAID’s, in the same way as it has been described in poststreptococcal reactive arthritis (34-35). Monoarthritis can occur but it is usually related to the early use of nonsteroidal anti-inflammatory drugs before the disease is fully expressed in its migratory pattern. Carditis - Heart involvement occurs in 40-50% cases of initial attack. It is the most serious manifestation as it can cause a permanent damage - rheumatic heart disease (RHD) or can be fatal.

All cardiac structures such as endocardium, myocardium and pericardium may be involved but the lesion that defines carditis is mitral regurgitation in 98% (being the only involved valve in 70 to 75% of the patients) or isolated aortic regurgitation in 2%. Carditis onset is quite variable. Its severity may range from asymptomatic to severe. It can be diagnosed as an isolated manifestation or together with other major signs. Asymptomatic carditis often is detected in patients who present with arthritis or develop chorea. In general, older patients present more with carditis associated with arthritis. The articular pain often brings the patient to the doctor who then makes the diagnosis of carditis as well. In these cases, usually carditis appears in the first 2 weeks of arthritis onset. After the first two weeks, the chance of developing carditis is reduced. However, younger patients often have an insidious onset of isolated carditis, and 50% of all patients diagnosed with RHD don’t recall any past history of joint pain. Auscultatory findings are the most indicative findings of carditis. Tachycardia and murmur are the commonest clinical manifestations of carditis. Tachycardia is not related to fever and basal pulse rate is high. Mitral regurgitation is manifested by an apical, high

pitched, blowing, holosystolic murmur. It may be accompanied by a low-pitched, short, middiastolic murmur (Carey-Coomb’s murmur) which does not have a presystolic accentuation typical of mitral stenosis and disappears on follow-up. The severity of mitral regurgitation is of prognostic significance, as in the majority of patients with mild or moderate mitral regurgitation, the lesion disappears on follow-up (36). Aortic regurgitation is present in 20 to 25% of the patients and is manifested by a high-pitched, soft, decrescendo murmur. Tricuspid valve and pulmonary valve lesions are rarely clinically significant (37). If the valvular insufficiency persists or later on evolves to stenosis, rheumatic heart disease (RHD) is the accepted terminology.

Pericarditis is associated with small to moderate effusions but never produces cardiac tamponade. Clinically it is present in 6 to 15% of the patients and is usually suspected in the presence of precordial discomfort or pain or a pericardial rub (scratchy, leathery sound altered by varying pressure of stethoscope) heard in both phases of cardiac cycle. Myocarditis is confined to the interstitium and does not usually result in significant myocyte damage, consistent with the preserved left ventricular ejection phase indices seen in patients with active rheumatic activity. Severe carditis comes with cardiac failure and may be fatal in the acute stage. In cases of severe carditis, cardiomegaly, a third heart sound and symptoms of cardiac failure may be present. It is now believed that rheumatic myocarditis is not the primary cause congestive heart failure in patients with acute carditis. It is important to note that pathologic data show little damage in the myocardium in patients dying from RF (38) and cardiac failure does not occur in the absence of significant valvular lesions (39). The diagnosis of a new flare of carditis in a patient with an established RHD may be difficult. Cardiac manifestation such as pericardial friction rub, a new murmur or worsening of a pre-existent one, increasing heart size, unexplained congestive cardiac failure in the presence of evidence of recent streptococcal infection should be considered highly suspicious for the diagnosis of recurrence of active rheumatic carditis. Silent carditis is a term used to define patients with subclinic carditis, without murmur but in whom valve regurgitation is detected by Doppler echocardiography. However, according to the last revision of Jones’ criteria in 1992, this exam by itself

can not be considered as evidence of carditis. The use of echocardiography to document carditis without auscultatory findings remains controversial. Chorea - Chorea occurs in approximately one-third of the patients with RF. It is characterized by an array of neuropsychiatric symptoms that vary in severity, timing and character (40). The latent period can be long, as much as 9 months, so that no evidence of previous streptococcal infection can be found. The onset can be associated to other RF manifestations, mainly carditis, during an acute episode or as an isolated form characterizing the “pure” chorea in 35%. Follow up of patients with pure rheumatic chorea has shown RHD in 23 % in a 20-year period (41). Thus, chorea may be a good marker for future occurrence of valvar heart disease. Clinically, the main features are involuntary movements, diffuse hypotonia, dysartria, emotional disorders and less frequently by other neuropsychiatric manifestations (42). Emotional lability precedes the onset of chorea movements. Most reported are impatience, irritability and inattention to school-work. However, in the last decade, more severe neuropsychiatric abnormalities, such as obsessive compulsive and tics disorders, have been associated with chorea. Incoordination and involuntary movements are initially perceived as clumsiness and as a tendency to drop objects. Then, purposeless, unilateral (hemichorea) or bilateral movements become evident. All voluntary muscles may be involved although they can be suppressed voluntarily for short time. During the physical examination, the physician should observe involuntary movements in face, tongue, hands, where they are more evident. Some tests to detect them include: quality of handwriting, slurred speech when counting from 1 to ten, milking sign when gripping the examiner hand, spooning or dishing of hands (flexion of wrist and hyperextension of MCP) when extending hands and pronator sign (pronation of hand) when raising hands above the head. The difficulties can become more evident when asking to perform 2 or more motor functions, one after another.

Subcutaneous Nodules - They are infrequent as they occur in less than 10% of the patients and their presence usually suggests an underlying carditis. They are rare in adults. Usually they appear after some weeks after the first few weeks of cardiac findings. Subcutaneous nodules are small (few mm to 1-2 cm in size), round, firm, painless, multiple on bony prominences or extensor tendons without signs of skin inflammation. They are better felt than seen. Erythema Marginatum - This is an infrequent manifestation of RF (less than 5%) and due to its evanescent nature and lack of associated symptoms, it can often be missed in patients

with dark skin. It is nearly always indicative of underlying carditis. It is an early manifestation of RF but may reappear at later stages. It is seen on the trunk and proximal limbs, but the face is spared. It is a non-pruritic, transient rash, 1-3 cm in size with a slightly raised periphery and clear central skin. Other manifestations: Arthralgia and fever are not rare but are not specific of RF, being considered minor signs according to Jones’ criteria. Arthralgia can be present for days or weeks and should be considered as a minor sign only in patients without arthritis. Fever usually occurs in all patients with arthritis, can be low in carditis and never occurs in isolated chorea. There is no characteristic pattern and often lasts only 1 week. LABORATORY INVESTIGATIONS There is no specific diagnostic laboratory test for RF. Lab exams can only demonstrate a recent streptococcal infection, the presence of inflammation, and the presence and severity of heart disease. Other tests can be performed initially to exclude other diseases in the differential diagnosis.

Evidence of a recent streptococcal infection Throat cultures – Only 20% of throat cultures are positive for GABHS in patients with RF. This low rate occurs because of the latent period between the infection and symptoms onset and sometimes due to previous use of antibiotics. Rapid antigen detection – The specificity of this test is high (over 95%) but not the sensitivity (43). Its positivity is equivalent to a positive culture throat. Streptococcal antibody tests – GABHS have many antigens and antibodies directed towards some of them have been utilized to identify a previous streptococcal infection even in asymptomatic cases. The most utilized is anti-streptolysin O (ASO). When the first symptoms of RF present, titers generally are high due to the latency period. ASO antibodies start to appear 7 to 10 days after onset of the infection, reach the maximum between the second and third weeks, and maintain this plateau for 3 to 6 months and then decline (44). As chorea has a long latency period, many times there is no evidence of streptococcal infection at the time of diagnosis. If a test is positive in a patient with arthritis, it does not mean that the diagnosis is RF but only that the patient had a previous streptococcus infection. Unfortunately, in approximately 20% of patients with RF, the ASO titer may be normal. In these cases, this test should be repeated after 2 or 4 weeks to check if the titer increases. If

it continues to be negative, other antibodies, such as anti-DNaseB and anti-hialuronidase, should be performed in order to improve the capacity to confirm a previous infection. All three tests together establish the diagnosis of previous streptococcal infection in 95% of the patients (45). However, in most of developing countries, where the incidence of RF is high and resources are limited, the only test available is ASO and sometimes it seems better to treat a suspected case of RF despite a normal ASO titer result.

Tests for systemic inflammation Acute phase reactants are non-specific and only indicate the presence of an inflammatory process. They help to confirm and monitor the acute phase of the inflammation. Erythrocyte sedimentation rate (ESR) and C-reactive protein are the main tests used in RF as both are often abnormal during the period of carditis and arthritis. Neither is specific but both are very sensitive and reflect the magnitude of the inflammatory process (rheumatic activity). C-reactive protein is better than ESR because it is should be negative in healthy subjects whereas false positive elevations of ESR may occur.

Tests for recent carditis: Electrocardiographic abnormalities can occur during an episode of acute rheumatic carditis. The most important finding, although non-specific, is the increased PR interval, present in 28-40% cases with carditis. Currently, chest radiographs are not important in the diagnosis of rheumatic fever as Doppler echocardiography is the best non-invasive method to evaluate and follow cardiac changes. It can evaluate chamber size, systolic ventricular function, detect presence of pericardial effusion and demonstrate absence or presence of valve lesions and abnormal regurgitation. Doppler echocardiography is able to identify subclinical carditis in patients with RF who do not have audible murmurs. PATHOLOGY Arthritis - Histologically, there is swelling of the articular and periarticular surfaces, but there is no erosion of the articular surface. Synovial fluid may be turbid but non-purulent. Initially there is a predominance of neutrophils but later on, mononuclear cells predominate. Fibrin may be enmeshed with the exudative cells. Swelling and fibrinoid degeneration of the connective tissue occurs.

Carditis - The morphologic hallmark of cardiac involvement in RF is the Aschoff body which is not described in any other cardiovascular disorder. Typically it is a granulomatous lesion, round to oval, usually less than 1 mm in size and found almost always in the endocardium, subendocardium or perivascular regions of myocardial interstitium. Aschoff bodies may be seen years after the initial illness and do not correlate with the activity of the disease. Usually pericarditis with myocardial damage predominates in severe cases. Pericarditis is accompanied by a serofibrinous effusion, but does not cause constriction at any time. Myocardium is flabby, edematous or pale. Chambers are enlarged. Heart enlarges due to dilatation of chambers or hypertrophy of the heart musculature. Within the muscle there is an exudative inflammatory response with lymphocytosis and plasma cells in the interstitium. Aschoff bodies are much less frequent in the myocardium (5% of cases) compared to the endocardium (72%) (39). Endocarditis is always present. Acute inflammation of valves is characterized by tiny translucent vegetations of 1 to 2 mm in diameter on the atrial surface at sites of the valve closure and on chordae tendinae. The valves have inflammatory infiltrate, edema and vascularization. Repeated fibrin deposits on the valve cusp results in fibrosis of the valvular ring causing stenosis (e.g. mitral stenosis). Later, commissures may be fused and chordae tendinae may be retracted and fused. Valve lesions are often responsible for cardiac failure. Calcification of valve leaflets occurs over a time. The most frequent valves involved are mitral and aortic valves, while right sided valves are rarely involved. The endocardium and subendocardium regions away from the valves are often inflamed and Aschoff bodies are frequently present. Chorea - The main histological features were described in the cortex, cerebellum and basal ganglia. They consist mainly in perivascular infiltration, petechial hemorrhages, and hyalinisation of small blood vessels. Subcutaneous Nodules - Histologically, a nodule consists of fibrinoid material in strands with clear space in between. There is much edema with very few cells- fibroblasts or histocytes and occasional lymphocytes. There is no palisading characteristically seen in rheumatoid nodules. DIAGNOSIS

In spite of significant advances, there is no single laboratory test to establish a diagnosis of RF. It is still based on Jones’ criteria, proposed initially in 1944 and reviewed and modified four times, in order to avoid missed diagnosis or overdiagnosis. The most important items are the identification of at least one major sign (polyarthritis, carditis, chorea, erythema marginatum and subcutaneous nodules) and the detection of a previous streptococcal infection. In the last revision of Jones’ criteria (1992) (46) (Table. 1), the basic rule for the diagnosis - presence of two major or one major and two minor signs together with an evidence of streptococcal infection - was not altered but, for the first time, this formula was to apply only to the initial attack of RF. They also recognized and accepted three exceptions where diagnosis could be done without strict adherence to the criteria: recurrent attacks in which signs and symptoms could be less apparent, insidious or late onset carditis or chorea as the only manifestation of RF (pure chorea). In these patients, the diagnosis should be presumptive until other causes have been excluded. Table I: Modified Jones' Criteria for diagnosis of RF: MAJOR MANIFESTATIONS

MINOR MANIFESTATIONS

Carditis

Fever

Polyarthritis

Arthralgia

Chorea

Elevated acute phase reactants: erythrocyte sedimentation rate, Creactive protein

Erythema marginatum

Prolonged PR interval on ECG

Subcutaneous nodules SUPPORTING EVIDENCE OF ANTECEDENT GROUP A STREPTOCOCCAL INFECTION:

Positive throat culture or rapid streptococcal antigen test or an elevated or rising streptococcal antibody titer

TREATMENT

Treatment of RF should be directed toward suppressing the ongoing inflammatory process in its different presentations, eradicating GABHS still present in the throat, and preventing new recurrences that could cause more damage in the future. Treatment of the clinical manifestations

Arthritis Acetylsalicylic acid was the first anti-inflammatory drug to be used in the treatment of RF. In arthritis, anti-inflammatory doses usually are used as a diagnostic test as the response is often dramatic. Pain ceases in one day and the other inflammatory signs in two days, a pattern that is not observed in several other causes of polyarthritis. An initial dose of 80 mg per kilogram per day, in 4 or 5 divided doses is usually well tolerated and does not cause important hepatotoxicity. It is recommended to give this dose during the first two weeks and then taper it over the next 3 or 4 weeks. Nowadays, other nonsteroidal antiinflammatory drugs have been used with the same efficacy. Rest is only necessary during the acute phase. Carditis Bed rest is advisable for all patients and should be proportional to the severity of the disease and continue as long as necessary. Steroids are more potent antiinflammatory drugs than salycilates as they can cause a more rapid improvement of acute manifestations of carditis, although they do not alter the course of rheumatic fever and subsequent development of rheumatic heart disease. There is still some controversy as to whether steroids are better than salycilates for mild carditis, but according to the guidelines for treatment of patients with RF (47), the use of corticosteroids should be reserved for patients with severe rheumatic carditis. Many experts in developing countries prefer to treat all cases of carditis (mild to severe) with steroids and do not feel that it is necessary to add salycilates at the end of the treatment. They suggest starting with an initial high dose (2 mg/kg / day – maximum 60 mg/day) during the first 3 weeks and then decreasing the dose by 20% every week. This treatment will be completed, on average, in 6 to 8 weeks and it will be not necessary to add acetylsalicylic acid. Some authors recommend the use of intravenous methylprednisolone in severe cases of heart failure (48), but occasionally, surgical intervention will be indicated in patients with refractory congestive heart failure (39). Immunological mechanisms appear to be involved in the pathogenesis of acute rheumatic fever but intravenous immunoglobulin did not alter the natural history of acute RF. There was no evidence of reduction in the extent and severity of carditis, more rapid resolution of inflammatory activity, or decreased chronic morbidity (49). In established

rheumatic heart disease, recurrence of carditis may present as congestive heart failure. Both the carditis as well as congestive failure need to be treated.

Chorea

Bed rest is required only for severe attacks to prevent injury. Several drugs have been used to treat chorea with varying success. Since choreiform movements are known to be influenced by emotional stress, there has been some success with sedative drugs especially phenobarbital, diazepam, and chlorpromazine. Other drugs used successfully are haloperidol and valproic acid. (49-51). Recently, in a double blind study using prednisone and placebo in 37 children with chorea, the authors could demonstrate a significant reduction of symptoms in the first week of treatment, and this response was maintained until the end of the study (p<0.001) (52). Medication should be given until chorea is controlled and then gradually tapered. Erythema marginatum and subcutaneous nodules These manifestations do not require specific medication. Treatment of streptococcal pharyngitis and prophylaxis It is difficulty to be sure if there is still streptococcal infection in the throat of a patient with RF at the diagnosis. Therefore, all patients should receive antistreptococcal antibiotics. In developing countries, benzathine penicillin is the preferred drug, followed by oral penicillin or erythromycin for penicillin allergic patients (Table 2). Table 2: Streptococcal eradication Benzathine Penicillin •

Patients > 27 Kg: 600.000 U, IM

•

Patients < 27 Kg: 1.200.000 U, IM

Oral penicillin for 10 days Erythromycin •

20 mg to 40 mg/kg in 2 to 4 divided doses for 10 days

To prevent recurrent RF, it is essential to start a secondary prophylaxis as soon as the diagnosis is established. Preferentially it should be done with benzathine penicillin in the same

doses used to eradicate streptococci given every 3 weeks. Other options are oral penicillin or sulfadiazine (1 g once a day) or erythromycin for allergic patients. There is no agreement about the duration of secondary prophylaxis. In some developing countries, for patients without carditis, it can be withdrawn at the age of 18 since the patient has received the prophylaxis for a minimum of 5 years. In patients with carditis, it is advisable to continue prophylaxis until at least the age of 35. There is even less evidence-based medicine and agreement in prophylaxis of children with rheumatic fever without carditis or for post-streptococcal arthritis (Table 3).

Table 3: Secondary prophylaxis Benzathine Penicillin each 21 days • Patients < 27 Kg: 600,000 U , IM • Patients > 27 Kg: 1,200,000 U, IM Benoxymethylpenicillin • 250 mg twice a day Sulfadiazine • Patients < 27 Kg: 0,5 g/day • Patients > 27 Kg: 1g /day Duration: • No carditis: until 18 years old (and minimum of 5 years) • With carditis: until at least 35 years old (or life long) OUTCOME Recurrences of RF often have the same clinical pattern as the previous attack. Patients with chorea or arthritis have the best prognosis. The prognosis is usually good with a full recovery. Patients with chorea generally have good prognosis with a full recovery. However, rheumatic heart disease can be diagnosed years after the initial attack of chorea and this possibility should be considered carefully in respect to maintaining secondary prophylaxis. Chorea can rarely recur after an intercurrent illness, drug exposure or pregnancy. The outcome of carditis has a wide range of possibilities - from total recovery (with risk of recurrences) to death due to cardiac failure. Between these two ends of the spectrum are various kinds of chronic RHD. Approximately 58-74% lose evidence of cardiac involvement. This occurs mainly in patients with a single valve (mostly mitral) involvement without cardiomegaly. However, it rarely occurs in patients who present with multiple valve involvement, cardiomegaly and cardiac failure. Mitral stenosis develops later but it is more

precocious in developing countries. Chances of recurrence are higher (50%) within the first 6 months of the initial attack and lessen to only 10% after 5 years. Death is rare during the first attack but the chances increase during recurrences, especially in patients with pre-existing heart involvement. If the heart is spared in the first attack, it is likely to be spared in subsequent occurrences. Patients with valvular disease should be educated on how to avoid infective endocarditis. Specific prophylaxis should be given before any minor or major surgical procedure, including minor suturing and removal of tartar from teeth. (Table 4) (53).

Table 4: Infective Endocarditis Prophylaxis For almost all patients, the drug is given one hour before the procedure unless mentioned otherwise. 1. Oral Amoxicillin 50mg/kg, it may be given IM or IV. Adults: 2 gms. 2. For patients with Amoxicillin/ Ampicillin allergy: • Oral Clindamycin 20 mg/kg. Adults: 600mg. •

OR Oral Cephelexin or Cefadroxil 50mg/kg. Adults: 2.0gm

•

OR Oral Azithromycin or Clarithromycin 15 mg/kg. Adults: 500 mg

•

OR IV Clindamycin 20mg/kg. Adults: 600 mg

•

OR IV Cefazolin 2.5 mg/kg. Adults: 1.0 gm

3. If gastrointestinal or genitourinary surgery is contemplated, then the following drugs can be given: High risk procedure: • IV Ampicillin/ Amoxicillin 50 mg/ kg + Gentamycin 1.5 mg/kg 30 minutes • •

before the procedure and 6 hours after the procedure. High risk procedure in patients with Amoxicillin allergy: IV Vancomycin 20 mg/kg (Adults 1gm) over 1-2 hours + IV Gentamycin 1.5 mg/kg 30 minutes before the procedure.

•

Moderate risk surgery: Only IV or IM Amoxicillin 50 mg/kg (Adults: 1gm)

Moderate risk surgery in patients with Amoxicillin allergy: • Vancomycin 20 mg/kg (Adults: 1gm) over 1-2 hours.

In summary, rheumatic fever is still a major health problem in many developing countries and still occurs in developed countries. It is a systemic illness whose effects, particularly cardiac, can be devastating. Its cause is well-known but the immune mechanisms remain poorly understood. Prevention awaits a better understanding of who is susceptible and how to prevent the triggering streptococcal infections in a practical and cost-effective manner.

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ORIGINAL CONTRIBUTION

Role of Lymphocyte Subsets in Pathogenesis of Chronic Rheumatic Heart Disease Rajendar K Suri, MS, Neerod K Jha, MCh, Harpreet Vohra, PhD1, Ratna S Manjari, MCh, Rajam Venkateshwaran, MS2, Madhulika Sharma, MSc1, Shyam KS Thingnam, MCh, Nirmal K Ganguly, PhD1

Department of Cardiovascular and Thoracic Surgery 1 Department of Experimental Medicine 2 Department of General Surgery Postgraduate Institute of Medical Education and Research Chandigarh, India For reprint information contact: Rajendar K Suri, MS Department of Cardiovascular and Thoracic Surgery Postgraduate Institute of Medical Education and Research Chandigarh 160012, India Tel: 91 172 54 1031 Ext. 302 Fax: 91 172 54 0401

ABSTRACT Analyses of lymphocyte subsets using flow cytometry were conducted to determine the significance of these cells in the pathogenesis of chronic rheumatic heart disease. Lymphocytes (B cells, T cells, CD4 cells, CD8 suppressor or cytotoxic T cells, activated T cells, and natural killer cells) were measured in blood and left atrial appendage samples of 30 patients with rheumatic heart disease and 10 patients with acyanotic congenital heart disease. Monoclonal fluorescent-labeled antibodies were used to identify various cells by flow cytometry. There was a significant increase in CD4 cells and activated T cells with a significant decrease in B cells in the left atrial appendage tissue of patients with rheumatic heart disease compared to those in the control group. There was no significant difference between the two groups in the distribution pattern of T lymphocytes in peripheral blood. These changes in rheumatic heart disease reflect an abnormal immunoregulatory mechanism with an ongoing enhanced immunological process continuing into the chronic phase of the disease. In our opinion, this persistent T cell response may lead to fresh damage to the myocardium and deformation of the heart valves.

INTRODUCTION Rheumatic heart disease (RHD) is a poststreptococcal nonsuppurative inflammatory disease with an abnormal cellular and humoral autoimmune response caused by the products of type A beta hemolytic streptococci. Type A beta hemolytic streptococci cross-react with connective tissues glycoproteins of various organs, with the greatest damage occurring in the heart.1 The incidence of rheumatic fever in India is 100 per 100,000 school children.2 Although the incidence of RHD has decreased in developed countries, it is the leading cause of death in the 5-year to 24-year age group in developing countries.3 Increased infiltration of T lymphocytes in heart valves has been well documented and these lymphocytes were found to be toxic to cultured heart cells.1 This cytotoxicity was not enhanced by plasma or serum, suggesting the nonparticipation of complement or antibodies.4 It has also been suggested that helper lymphocytes have a role in contracture and fibrosis of heart valves.1 Flow cytometry is a technique for measuring single particles or cells as they flow in a stream through a detection point transected by a laser beam.5 It is used increasingly to analyse T cell subsets with fluorescent-labeled monoclonal antibodies directed against cell surface antigenic glycoproteins involved in the immune response of RHD. Patients undergoing surgery for chronic rheumatic valvular disease may not show serological evidence of rheumatic activity (C-reactive protein, anti-streptolysin O) or histopathologic markers (Aschoff's bodies). The purpose of this

study was to determine the significance of various T cell subsets in the pathogenesis of chronic RHD.

MATERIAL AND METHODS Forty patients with heart disease who were admitted to the cardiothoracic surgery department of our institute were randomly selected and divided into 2 groups. The study group consisted of 30 patients with incapacitating chronic rheumatic valvular heart disease who required mitral valve surgery, while the control group comprised 10 patients with acyanotic congenital heart disease (atrial or ventricular septal defects) with no history of rheumatic fever or other inflammatory connective tissue disease. Peripheral venous blood (2 mL) and a tissue specimen of the left atrial appendage (LAA) were obtained from each of the 40 patients. Patients who received steroids and those with increased anti-streptolysin O and C-reactive protein titers suggestive of active RHD were not included in the study. Lymphocytes from LAA and blood samples were processed and labeled with monoclonal antibodies (Table 1 ).

CELL ANALYSIS OF LEFT ATRIAL APPENDAGE The LAA specimen was collected in a plastic vial containing normal saline and transferred to the laboratory for immediate analysis. A modification of the method of Davies and Parrott6 was used for separation of the lymphocytes. The tissue was minced with a surgical knife and washed 3 times for 10 minutes each with Hank's basal salt solution pH 7.2. They were then washed once for 10 minutes with Hank's basal salt solution containing 5 mM ethylenediaminetetraacetic acid (EDTA). The washed tissues were incubated with 0.08% (w/v) collagenase in an incubator shaker at 37°C for 45 minutes. The tissue debris was discarded and the cell suspension was removed. The separated cells were washed and suspended in RPMI 1640 (Rossel Park Medical Institute medium no. 1640; Gibco-BRL Products, Grand Island, NY, USA) containing 10% (v/v) fetal calf serum. The cells were layered on a metrizoate gradient and centrifuged for 15 minutes at 1800 rpm. The cell monolayer was aspirated and washed. Viability of cells was checked by trypan blue exclusion. Cell concentration was adjusted to 1 x 106 per mL. Cell samples were stained and incubated with 6 types of specific monoclonal labeled antibodies (Table 1 ). After incubation at 37°C for 30 minutes, the cells were washed in phosphate-buffered saline pH 7.2 and 0.5 mL of 0.5% (v/v) paraformaldehyde was added as a fixative before storing at 4°C. The control was gamma1 fluorescein isothiocynate gamma2 phycoerythrosin. Samples were analyzed with LYSUS II software (FACSCAN Immunocytometry System; Becton-Dickinson, San Jose, CA, USA). PERIPHERAL BLOOD CELL ANALYSIS The samples (2 mL) of venous blood collected from the 40 patients were transferred to the laboratory in fresh ethylenediaminetetraacetic acid vials. A sample (0.1 µL) of whole blood was added to each of 6 tubes containing specific monoclonal labeled antibodies, incubated at 37°C for 30 minutes, and washed with phosphate-buffered saline pH 7.2. The cells were lysed with a blood cell lysing solution (FACS lysing solution; Becton-Dickinson, San Jose, CA, USA), kept at room temperature for 10 minutes, and washed again with phosphate-buffered saline. They were fixed with 0.5 mL of 0.5% (v/v) paraformaldehyde and stored at 4°C. Analysis was performed

with SIMULSET software (FACSCAN Immunocytometry System; Becton-Dickinson, San Jose, CA, USA).

RESULTS The data were statistically analyzed using the unpaired Student t test and expressed as mean ± standard deviation. The mean age of patients in the study group was 25 ± 7 years. The male to female ratio was 1:2. In the control group, the mean age was 17.5 ± 5 years and the male to female ratio was 3:7. There was an increase in total T cells in the LAA samples from the study group as shown in Table 2 , although this was not significant (p > 0.05). There was a significant increase in the mean percentage of CD4 cells and activated T cells in the patients with RHD. The B cells and natural killer cells were decreased in the study group compared to the control group but in the case of natural killer cells this was not significant. The decrease in CD8 cells in RHD patients was also not significant. The CD4:CD8 ratio in the LAA samples of the study group was significantly higher than that of the control group. In the peripheral blood samples, there was no significant difference in the mean percentages of total T cells, CD4, or CD8 cells. However, the percentage of B cells and activated T cells was higher in the RHD patients who showed a decrease in natural killer cells (Table 2 ).

DISCUSSION The exact pathogenesis of chronic RHD remains unclear although the available literature suggests an aberrant immunologic process with antibodies of the streptococcal antigens cross-reacting with connective tissue of the target organs.1,2 The role of CD4 lymphocytes in the development of contracture and fibrosis of heart valves has been established, while that of other T cell subsets remains controversial.1 Automated flow cytometry, often referred to as fluorescent activated cell sorter analysis, is a specialized research tool being more frequently used because of the greater availability of monoclonal antibodies made possible by hybridoma technology.5

There was no significant difference in the mean percentage of T cells or T cell subsets in the peripheral blood samples from either group in our study, reflecting the chronic nature of the disease process in these RHD patients. Several studies have reported a decrease in T cells and CD4 cells and a relative increase in the CD8 and B lymphocytes in the peripheral blood of patients with acute RHD. This can be attributed to the acute nature of the disease process and to the effect of steroids used to treat these patients because these values generally returned to normal after the acute phase.7–9 However, the percentage of T cells, CD4, and helper T cells increased in the LAA samples of our study group. CD4 cells help in collagen deposition and act as an ancillary factor in the genesis of contracture and fibrosis in a deformed cardiac valve. Their increase in the chronic phase of RHD indicates an ongoing immunological process leading to

fibrotic deformation of the cardiac valves, thus emphasizing the role of the helper T cells in the pathogenesis of chronic RHD, which corroborates other studies.1,3,10,11 The mean percentage of CD8 cells in the study group LAA samples was not significantly lower than in the controls but suggests a lack of immunoregluatory or suppressor control on the disease process and may be due to the presence of circulating immune complexes, antilymphocytic antibodies, or antigenic cross-reactivity between lymphocytes. Other reports have suggested that the decrease in CD8 cells may lead to unchecked helper cell (CD4) activity and tissue damage.1,11 In the LAA samples, the percentage of B cells in the RHD patients was significantly lower than that of the controls. This indicates that the B cells may not have a role in the pathogenesis of chronic RHD. Raizada and colleagues1 found that the interstitial infiltrates in heart valves were predominantly T cells. The activated T cells in the LAA samples from our patients with chronic RHD were significantly elevated. This increase in activated T cells possibly leads to production of interleukin-2, a lymphokine produced by activated T cells. The release of interleukin-2 triggers the accumulation of CD4 cells, resulting in an undamped T cell response.12 There was no age difference between the two groups of patients in our study. In our country, many patients present with congenital acyanotic heart disease in middle age, thus affording us the opportunity to select comparable groups and avoid any differences in T cell changes related to age. The left atrial appendage was selected as the sample site because biopsies of this tissue in patients with rheumatic heart disease have shown the persistence of focal inflammatory lesions in those who no longer have other evidence of rheumatic activity.13 In addition, samples of the LAA can be removed easily in patients undergoing cardiac surgery without increased risk of morbidity or mortality. We postulate that the sequence of events responsible for cellular damage in chronic RHD might be stimulation of T lymphocytes by streptococcal antigens, leading to an increase in activated T cells with secretion of interleukin-2. This in turn results in increased natural killer cell cytotoxicity and the pathological changes leading to fibrosis of the cardiac valves and ultimately to incapacitating hemodynamic changes.

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