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iWHO Technical Report Series923RHEUMATIC FEVER ANDRHEUMATIC HEART DISEASEReport of a WHO Expert ConsultationGeneva, 29 October 1 November 2001World Health OrganizationGeneva 2004iiWHO Library Cataloguing-in-Publication DataWHO Expert Consultation on Rheumatic Fever and Rheumatic Heart Disease(2001 : Geneva, Switzerland)Rheumatic fever and rheumatic heart disease : report of a WHO Expert Consultation,Geneva, 29 October 1 November 2001.(WHO technical report series ; 923) fever heart disease of illness 92 4 120923 2(NLM classification: WC 220)ISSN 0512-3054 World Health Organization 2004All rights reserved. Publications of the World Health Organization can be obtained from Marketing andDissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22791 2476; fax: +41 22 791 4857; email: Requests for permission to reproduce ortranslate WHO publications whether for sale or for noncommercial distribution should be addressedto Publications, at the above address (fax: +41 22 791 4806; email: designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the World Health Organization concerning the legalstatus of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiersor boundaries. Dotted lines on maps represent approximate border lines for which there may not yet befull mention of specific companies or of certain manufacturers products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital World Health Organization does not warrant that the information contained in this publication iscomplete and correct and shall not be liable for any damages incurred as a result of its publication contains the collective views of an international group of experts and does not necessarilyrepresent the decisions or the stated policy of the World Health in Hong KongPrinted in Singapore2003 of group A streptococci, rheumatic fever and rheumaticheart disease3Group A streptococcal infections3Rheumatic fever and rheumatic heart disease5Determinants of the disease burden of rheumatic fever and rheumaticheart of rheumatic fever13Introduction13Streptococcal M-protein14Streptococcal superantigens14The role of the human host in the development of rheumatic fever andrheumatic heart disease15Host-pathogen interaction16The role of environmental factors in RF and of rheumatic fever20Jones criteria for the diagnosis of rheumatic fever202002 2003 WHO criteria for the diagnosis of rheumatic fever andrheumatic heart disease (based on the revised Jones criteria)22Diagnosis of rheumatic carditis24Valvulitis/endocarditis24Myoca rditis25Pericarditis26Diagnosis of extracarditic manifestations of RF26Major manifestations26Arthritis26Sydenham s chorea31Subcutaneous nodules34Erythema marginatum35Minor manifestations36New diagnostic techniques for rheumatic carditis36Echocardiography36Endomyocardi al biopsy36Radionuclide of rheumatic fever and assessment of valvular diseaseusing echocardiography41The advent of echocardiography41Echocardiography and physiological valvular regurgitation41ivThe role of echocardiography in the diagnosis of acute rheumaticcarditis and in assessing valvular regurgitation42Clinical rheumatic carditis42Classification of the severity of valvular regurgitation usingechocardiography42Diagnosis of rheumatic carditis of insidious onset43The use of echocardiography to assess chronic valvular heartdisease43Diagnosis of recurrent rheumatic carditis43Diagnosis of subclinical rheumatic carditis44Conclusions: the advantages and disadvantages of role of the microbiology laboratory in the diagnosis of streptococcalinfections and rheumatic fever50Diagnosis of streptococcal infection50Laboratory tests that support a diagnosis of RF51The role of the microbiology laboratory in RF prevention programmes53References54Appendix. WHO collaborating centres for reference and research rheumatic heart disease56Mitral stenosis56Mitral regurgitation60Mixed mitral stenosis/regurgitation61Aortic stenosis61Aortic regurgitation62Mixed aortic stenosis/regurgitation64Multivalvular heart disease64References65Pregnancy in patients with rheumatic heart management of rheumatic fever69General measures69Antimicrobial therapy69Suppression of the inflammatory process69Management of heart failure70Management of for rheumatic heart disease73Indications for surgery in chronic valve disease73Mitral stenosis (MS)74Mitral regurgitation (MR)74Aortic stenosis (AS)74Aortic regurgitation (AR)74Contra-indications to surgery75vTreatment options76Balloon valvotomy (commissurotomy)76Surgical treatment76Long-term complications77Long-term postoperative management77The role of surgery in active rheumatic prevention of rheumatic fever82Epidemiology of group A streptococcal upper respiratory tract infection 82Diagnosis of group A streptococcal pharyngitis82Laboratory diagnosis83Antibiotic therapy of group A streptococcal pharyngitis85Special situations87Other primary prevention prevention of rheumatic fever91Definition of secondary prevention91Antibiotics used for secondary prophylaxis: general principles91Benzathine benzylpenicillin91Oral penicillin92Oral sulfadiazine or sulfasoxazole93Duration of secondary prophylaxis93Special situations93Penicillin allergy and penicillin skin endocarditis97Introduction97Pathogenesis of infective endocarditis97Microbial agents causing infective endocarditis198Clinical and laboratory diagnosis of infective endocarditis98Medical and surgical management of infective endocarditis100Prophylaxis for the prevention of infective endocarditis in patients withrheumatic valvular heart for a streptococcal vaccine106Early attempts at human immunization106M-protein vaccines in the era of molecular biology106Immunization approaches not based on streptococcal M-protein107Epidemiological socioeconomic burden of rheumatic fever111The socioeconomic burden of rheumatic fever111Cost-effectiveness of control and implementation of national programmes for theprevention and control of rheumatic fever and rheumatic heart disease115Secondary prevention activities116Primary prevention activities116Health education activities116Training health-care providers117Epidemiological surveillance117Community and school and recommendations120viiWHO Expert Consultation on Rheumatic Fever andRheumatic Heart DiseaseGeneva, 29 October 1 November 2001MembersAlan Bisno, Department of Medicine, Veterans Administration Medical Center,Miami, Florida, G Butchart, Director, Cardiothoracic Surgery, University Hospital, Cardiff,Wales, Ganguly, Director-General, Indian Council of Medical Research, New Delhi, Ghebrehiwet, Consultant, Nursing & Health Policy, International Coun-cil of Nurses, Geneva, Lue, Professor of Pediatrics, National Taiwan University Hospital, Taipei, L Kaplan, Department of Pediatrics, University of Minnesota MedicalSchool, Minneapolis, MN, USA. (Co-Chair).Nawal Kordofani, Programme Coordinator, RF/RHD Prevention Programme, ShaabTeaching Hospital, Khartoum, Martin, Principal Scientist, Institute of Environmental Science & Research,Kenepuro Science Centre, Porirua, New Millard, Consultant Paediatrician, Paediatrics & Paediatric Cardiology,Kingston, Narula, Hahnemann University School of Medicine, Philadelphia, USA. (Co-Rapporteur).Diego Vanuzzo, Servizio di Prevenzione Cardiovascolari, Centro per la Lotta alleMalattie Cardiovascolari, P. le Santa Maria Misericordia, Udine, RA Zaher, Assistant Professor of Pediatrics, University of Alexandria, Alexan-dria, Egypt. (Co-Rapporteur).WHO SecretariatDerek Yach, Executive Director, Noncommunicable and Mental Health Cluster(NMH).Rafael Bengoa, Director, Management of Noncommunicable Diseases (MNC).Shanthi Mendis, Coordinator, Cardiovascular Disease (CVD). (Co-Chair).Porfirio Nordet, Cardiovascular Disease (CVD).Dele Abegunde, Cardiovascular Disease (CVD).Francesca Celletti, Cardiovascular Disease (CVD).Claus Heuck, Blood Safety and Clinical Technology, Diagnostic Imaging andLaboratory Technology (BCT/DIL). WHO Expert Consultation on Rheumatic Fever (RF) and Rheu-matic Heart Disease (RHD) met in WHO/HQ, Geneva from 29October to 1 November 2001 to update the WHO Technical Report764 on Rheumatic Fever and Rheumatic Heart Disease, first pub-lished in 1988 (1). Dr. Rafael Bengoa, Director Division of Manage-ment Noncommunicable Diseases, opened the meeting on behalf ofthe and RHD remain significant causes of cardiovascular diseases inthe world today. Despite a documented decrease in the incidence ofacute RF and a similar documented decrease in the prevalence ofRHD in industrialized countries during the past five decades, thesenon-suppurative cardiovascular sequel of group A streptococcalpharyngitis remain medical and public health problems in both indus-trialized and industrializing countries even at the beginning of the 21stcentury. The most devastating effects are on children and youngadults in their most productive at least five decades this unique non-suppurative sequel to groupA streptococcal infections has been a concern of the World HealthOrganization and its member countries. Sentinel studies conductedunder the auspices of the WHO during the last four decades clearlydocumented that the control of the preceding infections and theirsequelae is both cost effective and inexpensive. Without doubt,appropriate public health control programs and optimal medicalcare reduce the burden of disease (1 6).Although the responsible pathogenic mechanism(s) still remain in-completely defined, methods for optimal prevention and manage-ment have changed during the past fifteen years (5 8). To make thisinformation available to physicians and public health authorities,WHO convened this expert consultation to both update and to ex-pand the 1988 document. RF and RHD remain to be conquered, butuntil that can be accomplished, optimal methods of prevention andmanagement are required. The recommendations in this documentare based upon current medical literature. Every attempt has beenmade to make this a practically useful document and at the same timeto furnish appropriate references with additional information for fever and rheumatic heart disease. Report of a WHO StudyGroup. World Health Organization, Geneva, 1988 (Technical Report SeriesNo. 764). of rheumatic fever. Report of a WHO Expert Committee. WorldHealth Organization, Geneva, 1966 (Technical Report Series No. 342). T et al. The community control of rheumatic fever and rheumaticheart disease: report of a WHO international cooperative project. Bulletin ofthe World Health Organization, 1981, 59(2):285 WHO/CVD unit and principal investigators. WHO programme for theprevention of rheumatic fever/rheumatic heart disease in sixteen developingcountries: report from Phase I (1986 1990). Bulletin of the World HealthOrganization, 1992, 70(2):213 WHO/ISFC meeting on rheumatic fever/rheumatic heart disease controlwith emphasis on primary prevention, Geneva, 7 9 September , World Health Organization, 1994 (WHO/CVD ). WHO global programme for the prevention of RF/RHD. Report of aconsultation to review progress and develop future activities. Geneva, WorldHealth Organization, 2000 (WHO/ ). J et al. Rheumatic fever. Washington, DC, American Registry ofPathology Publisher, D, Kaplan E. Streptococcal infections. Clinical aspects,microbiology, and molecular pathogenesis. New York, Oxford UniversityPress, of group A streptococci,rheumatic fever and rheumatic heart diseaseRheumatic fever (RF) and rheumatic heart disease (RHD) arenonsuppurative complications of Group A streptococcal pharyngitisdue to a delayed immune response. Although RF and RHD are rarein developed countries, they are still major public health problemsamong children and young adults in developing countries (1 6). Theeconomic effects of the disability and premature death caused bythese diseases are felt at both the individual and national levelsthrough higher direct and indirect health-care A streptococcal infectionsBeta-haemolytic streptococci can be divided into a number of sero-logical groups on the basis of their cell-wall polysaccharide in serological group A (Streptococcus pyogenes) can be furthersubdivided into more than 130 distinct M types, and are responsiblefor the vast majority of infections in humans (7 9). Furthermore, onlypharyngitis caused by group A streptococci has been linked with theetiopathogenesis of RF and RHD. Other streptococcal groups ( B,C, G and F) have been isolated from human subjects and are some-times associated with infection; and streptococci in groups C and Gcan produce extracellular antigens (including streptolysin-O) withsimilar characteristics to that produced by group A streptococci (7 9).Nevertheless, the available evidence does not link streptococci innon-group A types with the pathogenesis of RF and RHD, althoughfurther studies are warranted into the role of groups C and G in thepathogenesis of RF (1, 2, 7 9).In both developing and developed countries, pharyngitis and skininfection (impetigo) are the most common infections caused by groupA streptococci. Group A streptococci are the most common bacterialcause of pharyngitis, with a peak incidence in children 5 15 years ofage (3, 5, 7, 9). Streptococcal pharyngitis is less frequent among chil-dren in the first three years of life and among adults. It has beenestimated that most children develop at least one episode of pharyn-gitis per year, 15 20% of which are caused by group A streptococciand nearly 80% by viral pathogens (1, 5, 7, 9). The incidence ofpharyngeal beta-haemolytic streptococcal infections can vary be-tween countries and within the same country, depending upon season,age group, socioeconomic conditions, environmental factors and thequality of health care (1 3, 5, 10, 11). Surveys of healthy schoolchil-dren 6 10 years of age, for example, found anti-streptolysin-O titres>200 Todd units in 15 70% of the children (2), while other studies4reported beta-haemolytic streptococci carrier rates of 10 50% forasymptomatic schoolchildren (1, 2). In temperate countries, 50 60%of streptococci isolated from asymptomatic children belong to sero-logical group A, while streptococci in serological groups C and Gtogether occur in less than 30% of the children. Conversely, in manytropical countries, groups C and G streptococci occur with rates ashigh as 60 70% in asymptomatic carriers (1 3, 5, 11).The presence of group A streptococci in the upper respiratory tract(URT) may reflect either true infection or a carrier state. In eitherstate, the patient harbours the organism, but only in the case of a trueinfection does the patient show a rising antibody response. In thecarrier state there is no rising antibody response. It is thought that apatient with a true infection is at risk of developing RF and of spread-ing the organism to close contacts, while this is not thought to be thecase with carriers (1, 5, 10). Therefore, many professionals feel thatonly patients with true infections need to be given antibiotics. (Foralternative characterizations of the streptococcal carrier state seereference 10).Under endemic conditions, group A streptococci have been isolatedfrom patients with symptomatic pharyngitis. Recovery rates variedfrom in Northern India, to 33% in Utrecht, Netherlands, andto 44% in Zagreb, Croatia (Table ; 12 18). Group A streptococciare highly transmissible and spread rapidly in families and communi-ties, with the predominant M types constantly changing. However, inpublications about RF outbreaks, including recent ones in the UnitedTable of presence of group A beta-haemolytic streptococci in children withsymptomatic pharyngitisSourceYearCity/countryPatient s withGAbHSpharyngitispositive(N)(%)a14198 0sRhode Island, USA8668 (5 19 years old) , , , , , positive = patients positive for group A beta-haemolytic with clinical features of streptococcal pharyngitis (fever > 38 C; tonsilar exudate,anterior cervical lymphadenopathiy and absence of cough, rhinorrhea and of America (USA), it was reported that only a limited numberof streptococcal stereotypes ( M serotypes 1, 3, 5, 6, 18, 19, 24) wereobtained from the throat cultures of children in the affected commu-nities (2, 3, 5, 7, 19 23).Although no longitudinal studies have examined trends in group Astreptococcal pharyngitis, nor in the asymptomatic carrier rates, avail-able data suggest that pharyngitis and asymptomatic carrier rateshave remained more-or-less stable in most countries (3, 5). However,in the last 20 years, some countries have reported changes in the Mtypes, severity and other characteristics of group A strains have re-emerged, for example, and non-M typestreptococci have been detected (1 3, 5, 7, 11, 22). In the USA,despite a remarkable reduction in the incidence of RF since the 1950s,the incidence of URT infections caused by group A streptococci hasnot declined (1 3, 5, 20, 23). In the mid-1980s, the virulence, severityand sequelae of these infections also appear to have changed remark-ably. Outbreaks of acute RF have been described from widely sepa-rated areas of the country, and complications of streptococcalinfections have been reported, including necrotising fascitis, strepto-coccal myositis, streptococcal bacteremia and streptococcal toxicshock syndrome (3, 20, 22, 23). These outbreaks have not been con-fined to socially and economically disadvantaged populationsRheumatic fever and rheumatic heart diseaseIn 1994, it was estimated that 12 million individuals suffered from RFand RHD worldwide (6), and at least 3 million had congestive heartfailure (CHF) that required repeated hospitalisation (24). A largeproportion of the individuals with CHF required cardiac valve sur-gery within 5 10 years (4, 6, 24). The mortality rate for RHD variedfrom per 100 000 population in Denmark, to per 100 000 popu-lation in China (25), and the estimated annual number of deaths fromRHD for 2000 was 332 000 worldwide (26). The mortality rate per100 000 population varied from in the WHO Region of the Ameri-cas, to in WHO South-East Asia Region. The disability-adjustedlife years (DALYs)1 lost to RHD ranged from DALYs per100 000 population in the WHO Region of the Americas, to per100 000 population in the WHO South-East Asia Region. An esti-mated million DALYs are lost per year worldwide (Table ).Data from developing countries suggest that mortality due to RF and1Disability-adjusted life years (DALYs) lost is the sum of years of life lost owing topremature death, plus the years lived with disability adjusted for the severity of thedisability (24).6RHD remains a problem and that children and young adults still diefrom acute RF (4 6, 14, 24 26).Reliable data on the incidence of RF are scarce. In some countries,however, local data obtained from RF registers of schoolchildrenprovide useful information on trends. The annual incidence of RF indeveloped countries began to decrease in the 20th century, with amarked decrease after the 1950s; it is now below per 100 000 (6). Afew studies conducted in developing countries report incidence ratesranging from per 100 000 school-age children in Costa Rica (27), per 100 000 in French Polynesia, 100 per 100 000 in Sudan, to 150per 100 000 in China (6).The prevalence of RHD has also been estimated in surveys, mainly ofschool-age children. The surveys results showed there was wide varia-tion between countries, ranging from per 1000 schoolchildren inHavana, Cuba, to per 1000 in Samoa (Table ; 1, 28 45). Theprevalence of RF and RHD and the mortality rates varied widelybetween countries and between population groups in the same coun-try, such as between Maoris and non-Maoris in New Zealand, Samo-ans and Chinese in Hawaii, and Aboriginals and non-Aboriginals inNorthern Australia (1, 2, 5, 6, 12, 17).Although it is known that hospital morbidity data often give biasedinformation about the magnitude of diseases, they are the onlydata available in many developing countries. Based on such data,RHD accounts for 12 65% of hospital admissions related to cardio-vascular disease, and for of all hospital discharges in someTable deaths and DALYs lost to rheumatic heart disease in 2000, by WHORegionaWHO RegionDeathsDALYsb lostNRatenRate( 103)(per 100 000( 106)(per 100 000population)population) : = disability-adjusted life countries (5, 6, 46). There has been a marked decrease inthe mortality, incidence, prevalence, hospital morbidity and severityof RF and RHD in some places that have implemented preventionprogrammes, such as; Havana, Cuba; Costa Rica; Cairo, Egypt; andMartinique and Guadeloupe (2, 5, 6, 27, 44, 47 54).Determinants of the disease burden of rheumatic fever andrheumatic heart diseaseIt is well known that socioeconomic and environmental factors playan indirect, but important, role in the magnitude and severity of RFand RHD. Factors such as a shortage of resources for providingquality health care, inadequate expertise of health-care providers,Table of reported prevalence of rheumatic heart disease in schoolchildrenSourceWHO Region (country, city)YearRate(per 1000population)Africa28Kenya (Nairobi) (Lusaka) (Addis Ababa) (Republic of Guinea) Congo (Kinshasa) (Havana, Santiago, P. del Rio) (La Paz)1986 (Cairo)1986 (Khartoum)1986 Asia38Northern India1992 (Kathmandu) Lanka19986Western Pacific1Cook Zealand (Hamilton) (Maoris) (non-Maoris) (Northern Territory)1989 a low level of awareness of the disease in the community can allimpact the expression of the disease in populations. Crowdingadversely affects rheumatic fever incidence (1 7, 14, 22, 23) ( ). fever and rheumatic heart disease. Report of a WHO StudyGroup. Geneva, World Health Organization, 1988 (Technical Report Series,No. 764). A, Markowitz M. Rheumatic fever. Boston, Kluwer AcademicPublishers, 1989:1 E. Recent epidemiology of Group A streptococcal infections inNorth America and abroad: an overview. Pediatrics, 1996, 97(6):S945 and indirect results of environmental and health-system determinants onrheumatic fever and rheumatic heart diseaseDeterminantsEffectsImpact on RF and RHDburdenSocioeconomic andRapid spread of group AHigher incidence of acuteenvironmental factors:streptococcal (poverty, undernutrition,Difficulties in accessingand suppurativeovercrowding, poorhealth ).Higher incidence of acute rates of relatedInadequate diagnosisHigher incidence of acute RFfactors:and treatment ofand its recurrence. shortage of resourcesstreptococcalfor health care;pharyngitis. inadequate expertiseMisdiagnosis or latePatients unaware of the firstof health-carediagnosis of acuteRF ; severe evolution of low-level the disease in theUntimely initiation or lack secondaryHigher rates of recurrentprophylaxis and/orattacks with more frequentnon-compliance withand severe heart valvesecondary , and higherrates of repeated hospitaladmissions and expensivesurgical World Health Report. Conquering suffering. Enriching humanity. Geneva,World Health Organization, 1997:43 R et al. Epidemiology of streptococcal pharyngitis, rheumaticfever and rheumatic heart disease. In: Narula J et al., eds. Rheumaticfever. Washington, DC, American Registry of Pathology Publisher,1999:41 WHO/ISFC meeting on RF/RHD control with emphasis on primaryprevention, Geneva, 7 9 September 1994. Geneva, World HealthOrganization, 1994 (WHO Document WHO/CVD ). AL. Acute pharyngitis: etiology and diagnosis. Pediatrics, 1996,97(6):S949 JR et al. Epidemiology and prevention of group A streptococcalinfection: acute respiratory tract infections, skin infections, and theirsequelae at the close of the twentieth century. Clinical Infectious Diseases,1999, 28:205 ST et al. Streptococcal infections. In: Stevens D, Kaplan E, aspects, microbiology, and molecular pathogenesis. New York,Oxford University Press, 2000:76 EL. The group A streptococcal upper respiratory tract carrier state:an enigma. Journal of Pediatrics, 1980, 97(3):337 S et al. Epidemiological analysis of non-M-typeable group AStreptococcus isolates from a Thai population in Northern Thailand. Journalof Clinical Microbiology, 2000, 38(3):1250 S et al. Group A streptococcal sore throat in a periurban populationof Northern India: a one-year prospective study. Bulletin of the World HealthOrganization, 2001, 79:528 J et al. Asymptomatic pharyngeal carriage of beta-haemolyticstreptococci and streptococcal pharyngitis among patients at an urbanhospital in Croatia. European Journal of Epidemiology, 1993, 9(4):405 GE. A review of the epidemiology and prevention of rheumatic Heartdisease: Part II. Features and epidemiology of streptococci. CardiovascularReview and Report, 1996, 17(4):7 P et al. Amigdalofaringitis aguda. Estudio clinico-bacteriologico yterapeutico. [Acute tonsilo-pharyngitis. Clinical, bacteriological andtherapeutic study.] Revista Cubana Pediatria, [Cuban Journal of Pediatrics,]1989, 61(6):821 MC et al. Effectiveness of clinical guidelines for the presumptivetreatment of streptococcal pharyngitis in Egyptian children. The Lancet,1997, 350:918 CF et al. Bacterial flora in patients presenting with sore throat inDutch general practice. British Journal of General Practice, 1998, 427:959 R et al. Towards a better diagnosis of throat infections (with group Abeta haemolytic streptococcus) in general practice. British Journal ofGeneral Practice, 1998, 427:959 BF et al. The dynamics of streptococcal infections in adefined population of children: serotypes associated with skin andrespiratory infections. American Journal of Epidemiology, 1976,104:652 EL et al. Group A streptococcal serotypes isolated from patientsand siblings contact during the resurgence of rheumatic fever in the UnitedStates in the mid-80s. Journal of Infectious Diseases, 1989, 159:101 LG et al. Persistence of acute rheumatic fever in the intermountainarea of the United States. Journal of Pediatrics, 1994, 124:9 MS, Dale JB. The re-emergence of serious group A streptococcalinfections and acute rheumatic fever. American Journal of Medical Science,1996, 311(1):41 WHO Programme on Streptococcal Disease Complex. Report of aConsultation. Geneva, 16 19 February 1998. Geneva, World HealthOrganization, 1998 (WHO document EMC/ ). CJ, Lopez AD, eds. In: Global health statistics. Cambridge, HarvardUniversity Press, 1996:64 67. (See also: Murray CJ, Lopez AD, eds. In:Global burden of disease and injury series. Cambridge, Harvard UniversityPress, 1996:643 645). Health Statistical Annual 1990 2000. Geneva, World Health system: improving performance. In: The World Health Report , World Health Organization, 2001:144 A, Mohs E. Prevention of rheumatic fever in Costa Rica. Journal ofPediatrics, 1992, 121(4):569 GM et al. Prevalence of heart disease in school children in ruralKenya using colour-flow echocardiograph. East African Medical Journal,1996, 73(4):215 K et al. Rheumatic heart disease in a sub-Saharan African city:epidemiology, prophylaxis and health education. Cardiologie Tropicale,[Tropical Cardiology] 2000, 26(102):25 K et al. Prevalence of rheumatic heart disease among school children inAddis Ababa. East African Medical Journal, 1999, 76(11):601 S et al. Enqu te sur les cardiopaties en mielieu scolaire etuniversitaire Conakry, R. de Guin e. [Prevalence of cardiopathies inprimary school, secondary school and university in Conakri, R. Guin a.]Cardiologie Tropicale, [Tropical Cardiology] 1992, 18(72):205 et al. Survey of rheumatic heart disease in schoolchildren ofKinshasa town. International Journal of Cardiology, 1998, 63(3):287 P. et al. Fiebre reum tica en Cuba: incidencia, prevalencia,mortalidad y caracteristicas clinicas. [Rheumatic fever and rheumatichear disease in Cuba: incidence, prevalence mortality and clinicalcharacteristics.] Revista Cubana de Cardiologia y Cirugia Cardiovascular,[Cuban Journal of Cardiology and Cardiovascular Surgery] 1991, 5(1):25 WHO/CVD Unit. WHO programme for the prevention of rheumatic fever/rheumatic heart disease in 16 developing countries (AGFUND). Report fromPhase I (1986 1990). Bulletin of the World Health Organization, 1982,70(2):213 rhumatisme articulaire aigu: r alit s et perspectives au Maroc. L Objectifm dical, Edition Maroc. Num ro sp cial et hors s rie, MA et al. Rheumatic fever and chronic rheumatic heart disease inschoolchildren in Saudi Arabia. Saudi Medical Journal, 1991, 12:407 A et al. Acute rheumatic fever in Tunisia. In: Horoued et al., and the host. New York, Plenum Press Publishers, 1997:121 JS et al. Epidemiological survey of rheumatic heart disease amongschool children in the Shimla Hills of northern India: prevalence and riskfactors. Journal of Epidemiology and Community Health, 1996, 50(1):62 S. Rheumatic heart disease: prevalence and preventivemeasures in the Indian subcontinent. Heart, 2001, 86 RR et al. Prevalence of rheumatic fever and rheumatic heartdisease in school children of Kathmandu city. Indian Heart Journal, 1997,49:518 S, Nasser M, Perera K. A study of rheumatic heart disease andrheumatic fever in a defined population in Sri Lanka. The Ceylon Journal ofMedical Science, 1998, 40(2):31 RG. Rheumatic fever and rheumatic heart disease in the Hamiltonhealth district: an epidemiological survey. New Zealand Medical Journal,1984, 97:630 JR et al. Acute rheumatic fever and rheumatic heart disease inthe top end of Australia s Northern Territory. Medical Journal of Australia,1996, 164(3):146 P. et al. Fiebre reumatica in Ciudad de la Habana. Prevalencia ycaracteristicas, 1972 1987. [Rheumatic fever in Havana. Prevalence andcharacteristics, 1972 1987.] Revista Cubana Pediatria, [Cuban Journal ofPediatrics,] 1989, 61(2):228 A. Rheumatic heart disease in school children in Samoa. Archives ofDisease in Childhood, 1999, 81(4):373 E. Morbidit Cardiovasculaire en Afrique Subsaharienne en 1990 2000. [Cardiovascular morbidity in sub-Saharan Africa between 1990 2000.]Cardiologie Tropicale, [Tropical Cardiology,] 2000, 26(104):88 The WHO Global Programme for the prevention of RF/RHD. Report of aconsultation to review progress and develop future activities. Geneva, WorldHealth Organization, 2000 (WHO document WHO/ ). L. The virtual disappearance of rheumatic fever in the United States:lessons in the rise and fall of disease. Circulation, 1985, 72(6):1155 T et al. The community control of rheumatic fever and rheumaticheart disease: report of a WHO international cooperative project. Bulletin ofthe World Health Organization, 1981, 59(2):285 RJ. The Northland rheumatic fever register. New Zealand MedicalJournal, 1984, 97:671 JF et al. Ten-year educational programme aimed at rheumatic fever intwo French Caribbean islands. The Lancet, 1996, 347:644 G et al. Rheumatic fever and chronic rheumatic heart disease inYarrabah aboriginal community, North Queensland. Establishment of aprophylactic program. Medical Journal of Australia, 1993, 158:316 , HA et al. The natural history of acute rheumatic fever in Kuwait: aprospective six-year follow-up report. Journal of Chronic Diseases, 1986,39(5):361 FF et al. Rheumatic fever in children: a 15-year experience in adeveloping country. Pediatric Cardiology, 2000, 21(2):119 of rheumatic feverIntroductionThe epidemiological association between group A b-haemolyticstreptococcal infections and the subsequent development of acuterheumatic fever (RF) has been well established. RF is a delayedautoimmune response to Group A streptococcal pharyngitis, and theclinical manifestation of the response and its severity in an individualis determined by host genetic susceptibility, the virulence of theinfecting organism, and a conducive environment (1 3). Althoughstreptococci from serogroups B, C, G and F can cause pharyngitis andtrigger a host immune response, they have not been linked to theetiology of RF or rheumatic heart disease (RHD). There is consider-able geographical variation in the prevalence of all serogroups ofb-haemolytic streptococci. In many tropical countries, up to 60 70%of isolates from the throats of asymptomatic children fall intoserogroups C and G. Conversely, in temperate regions, serogroup Ais the predominant isolate (50 60%), with serogroups C and G to-gether accounting for less than 30% of isolates. Nonsuppurative se-quel, such as RF and RHD, are seen only after group A streptococcalinfection of the upper respiratory tract. Post-streptococcal glomerulo-nephritis may occur after an infection of either the throat or skin bynephritogenic strains of group A streptococci (1, 2). It is presumedthat chronic streptococcal carrier states do not trigger the develop-ment of RF (1 5).Although substantial progress has been made in the understandingof RF as an autoimmune disease, the precise pathogenetic mechanismof RF has not been defined. Major histocompatibiltiy antigens, poten-tial tissue-specific antigens, and antibodies developed during andimmediately after a streptococcal infection are being investigated aspotential risk factors in the pathogenesis of the disease. Recentevidence suggests that T-cell lymphocytes play an important role inthe pathogenesis of rheumatic carditis. It has also been postulatedthat particular M types of group A streptococci have rheumato-genic potential. Such serotypes are usually heavily encapsulated, andform large, mucoid colonies that are rich in M-protein. These charac-teristics enhance the ability of the bacteria to adhere to tissue, as wellas their ability to resist phagocytosis in the human host. Howeverencapsulation is not exclusive to these strains and much of the datasupporting the idea of selective rheumatogenicity is anecdotal(1, 5).14Streptococcal M-proteinM-protein is one of the best-defined determinants of bacterial viru-lence. The streptococcal M-protein extends from the surface of thestreptococcal cell as an alpha helical coiled coil dimer, and sharesstructural homology with cardiac myosin and other alpha-helicalcoiled coil molecules, such as tropomyosin, keratin and laminin. It hasbeen suggested that this homology is responsible for the pathologicalfindings in acute rheumatic carditis. Laminin, for example, is an extra-cellular matrix protein secreted by endothelial cells that line the heartvalves and is an integral part of the valve structure. It is also a targetfor a polyreactive antibody that recognizes M-protein, myosin M-protein molecule has a hypervariable N-terminal region, aconserved C-terminal region, and is divided into A, B and C repeatregions on the basis of peptide sequence periodicity (5 7). Epitopesthat are cross-reactive in myocardium, synovia and brain are locatedbetween the B and C repeat regions, away from the type-specificepitopes in the N-terminal region. The C repeat regions containhighly conserved epitopes, and streptococci are often classified intoClass I or II, based on whether their M-protein reacts with a mono-clonal antibody (10B6) that targets epitopes in the C repeat region ofthe M6 molecule. The majority of Class I strains (with reactive M-protein) are implicated in RF. Of the more than 130 M-protein typesidentified, M types such as 1, 3, 5, 6, 14, 18, 19 and 24 have beenassociated with RF. However, not all M-protein serotypes are associ-ated with RF and serotypes 2, 49, 57, 59, 60 and 61, for example, havebeen associated with pyoderma and acute glomerulonephritis (4, 5).Class II strains, on the other hand, have nonreactive M-proteins andproduce an apolipoproteinase called opacity factor (7, 8). Individualsmay have multiple streptococcal infections throughout their lifetime,but reinfections with the same serological M type are relatively lesscommon because individuals acquire circulating homologous anti-Mantibodies following an superantigensSuperantigens are a unique group of glycoproteins synthesized bybacteria and viruses that can bridge Class II major histocompatibilitycomplex molecules to nonpolymorphic V b-chains of the T-cell recep-tors, simulating antigen binding. The T-cells bearing the appropriateV b-chain are activated (to release cytokines or become cytotoxic),regardless of their antigenic specificity. Some T-cells activated in thismanner can have autoreactive specificities, since previously anergizedT-cell subsets are susceptible to superantigenic stimulation. In the15case of streptococci, much work has focused on the role of thesuperantigen-like activity of M-protein fragments (PeP M5, in par-ticular), as well as the streptococcal pyrogenic exotoxin, in the patho-genesis of RF (4, 5, 9, 10).Superantigenic activation is not limited to the T-cell compartmentalone. Streptococcal erythrogenic toxin may behave like a super-antigen for the B-cell, leading to the production of autoreactive anti-bodies, but as noted above, much of the evidence is still in genetic studies, and the identification of extracellularproducts and cell-wall components represent advances in knowledgeabout the virulence of group A streptococci. The role of GRAB (analpha-2 macroglobulin-binding protein expressed by Streptococcuspyogenes), streptococcal fibronectin-binding protein 1 (sfb1), whichmediates streptococcal adherence and invasion into human epithelialcells, and streptococcal C5a peptidase (SCPA), which inactivatescomplement chemotaxin C5a and allows streptococci to adhere totissues, are all subjects of active research in the pathogenesis of strep-tococcal infections. These studies have also facilitated the genotypicand phenotypic characterization of group A streptococcal strains (3 8, 11 19).The role of the human host in the development of rheumatic feverand rheumatic heart diseaseThere is strong evidence that an autoimmune response to streptococ-cal antigens mediates the development of RF and RHD in a sus-ceptible host. Genetically-programmed determinants of hostsusceptibility to RF have been studied extensively, in an attempt todetermine why only 3% of individuals with acute streptococcalpharyngitis go on to develop RF (1 3). Pedigree studies suggestedthat this immune response is genetically controlled, with high respon-siveness to the streptococcal cell-wall antigen being expressedthrough a single recessive gene, and low responsiveness through asingle dominant gene. Further data indicate that the gene controllingthe low-level response to streptococcal antigen is closely linked to theClass II human leukocyte antigen, HLA (20). However, studies ofdifferent HLA-DR loci and ethnicity further suggested that the linkbetween susceptibility to RF and Class II HLA was highly diverse andnot linked to one particular allele, but to a susceptibility gene presentat, or nearby, the HLA-DR locus. For example, DR4 was presentmore frequently in Caucasian RF patients; DR2 more frequently inAfrican-American populations (21); DR1 and DRw6 in RF patientsfrom South Africa (10); and HLA-DR3 was present more frequentlyin RF patients in India (who also had a low frequency of DR2). In16addition, DQW2 was present more frequently in Asian RF , it was reported that a B-lymphocyte alloantigen, recog-nized by the monoclonal antibody, D8/17, and another 70-kD mol-ecule, may be genetically innate markers of an altered immuneresponse to unidentified streptococcal antigens in susceptible sub-jects. The implication of an alloantigen on B-cells of patients with RFis currently being studied (1).Host-pathogen interactionInfection by streptococci begins with the binding of bacterial surfaceligands to specific receptors on host cells, and subsequently involvesspecific processes of adherence, colonization and invasion. The bind-ing of bacterial surface ligands to host surface receptors is the mostcrucial event in the colonization of the host, and it is initiated byfibronectin and by streptococcal fibronectin-binding proteins (17).Streptococcal lipoteichoic acid and M-protein also play a major rolein bacterial adherence (9). The host responses to streptococcal infec-tion include type-specific antibody production, opsonization role of environmental factors in RF and RHDSecular trends in RF and RHD over the last one-and-a-half centuries,in both the developed and developing countries, all point towardsenvironmental factors such as poor living conditions, overcrowdingand access to health care as the most significant determinants ofdisease distribution (1 5). Indeed, the global distributions of RF andRHD are still influenced by socioeconomic indices, and the recentoutbreak of RF in the USA is an aberration to this otherwise validmaxim. Crowded living conditions, with close interpersonal contacts,contribute to the rapid spread and persistence of virulent streptococ-cal strains. Seasonal variations in the incidence of RF ( high inci-dences in early fall, late winter and early spring) closely mimicvariations in streptococcal infections. These variations are particu-larly pronounced in temperate climates, but are not significant in is evident from the preceding discussion that the pathogenesis ofRF and RHD is a complex maze of events that are immunologicallyintricate, pathologically significant, and clinically devastating for thepatients. It is ironic that a rather innocuous sore throat shouldextract such a high price from the host. As scientific research evolves,it is hoped that the gaps in our understanding will be filled, and better17strategies for prophylaxis and treatment will become available. Thefollowing is a summary of our current understanding of the pathoge-netic maze of rheumatic streptococcal infection in a genetically predisposed host in asusceptible environment leads to the activation of T-cell and B-celllymphocytes by streptococcal antigens and superantigens, which re-sults in the production of cytokines and antibodies directed againststreptococcal carbohydrate and myosin. It has been proposed thatinjury to the valvular endothelium by the anti-carbohydrate antibod-ies leads to an up-regulation of VCAM1 and other adhesion mol-ecules (10). VCAM1 expression is a hallmark of inflammation and itheralds cellular infiltration. VCAM1 interacts with VLA4 on acti-vated lymphocytes and leads to an influx of activated CD4+ andCD8+ T-cells. A break in the endothelial continuity of a heart valvewould expose subendothelial structures (vimentin, laminin and valvu-lar interstitial cells) and lead to a chain reaction of valvular destruc-tion. Once valve leaflets are inflamed through the valvular surfaceendothelium and new vascularization occurs, the newly formed mi-crovasculature allows T-cells to infiltrate and perpetuate the cycle ofvalvular damage. The presence of T-cell infiltration, even in old min-eralized lesions, is indicative of persistent and progressive disease inthe valves. Valvular interstitial cells and other valvular constituentsunder the influence of inflammatory cytokines perpetuate the foregoing offers a very feasible explanation of the ex-perimental data, questions remain that have significant implicationsfor choosing streptococcal vaccines (22 24). For example, there is nodirect and conclusive evidence for a pathogenetic role of cross-reac-tive antibodies in vivo and there is no exact animal model of rheu-matic fever for study. The need for a better understanding of theepidemiology of streptococci is underscored by a report that onegroup A streptococcal serotype can be rapidly and completely re-placed by another serotype in a stable population with adequateaccess to health care (25). This serotype change still has not beenadequately explained and it raises questions about the efficacy of anytype-specific streptococcal vaccine that is synthesized by combiningM-protein sequences from virulent streptococcal serotypes. Further-more, the ability of streptococci to infect the host after a prior infec-tion by a different M serotype strain, suggests there is no broad,non-type-specific immunity directed against conserved M-proteinepitopes or their extracellular products, which complicates the devel-opment of a RF vaccine aimed at conserved M-protein pathogenesis of RF will continue to perplex clinicians until suchquestions are fever and rheumatic heart disease. Report of a WHO StudyGroup. Geneva, World Health Organization, 1988 (Technical Report SeriesNo. 764). EL. The group A streptococcal upper respiratory tract carrier state:an enigma. Journal of Pediatrics, 1980, 97:337 A, Markowitz M. Rheumatic fever. Boston, Kluwer AcademicPublishers, 1989:19 J et al. Rheumatic fever. Washington, the American Registry ofPathology Publisher, 1999:48 68 and 103 D, Kaplan E. Streptococcal infections. Clinical aspects,microbiology and molecular pathogenesis. New York, Oxford UniversityPress, 2000:102 T et al. Identification and characterization of novel superantigens fromStreptococcus pyogenes. Journal of Experimental Medicine, 1999, 189:89 G, Widdowson JP. The relationship between opacity factor and Mprotein in Streptococcus pyogenes. Journal of Medical Microbiology, 1983,16(1):13 JP et al. The relationship between M-antigen and opacity factorin group A streptococci. Journal of General Microbiology, 1971, 65(1):69 M, Watanabe-Ohnishi R, Wang B. Analysis of the TCR V betaspecificities of bacterial superantigens using PCR. Immunomethods, 1993,2:33 S et al. Pathogenic mechanisms in rheumatic carditis: focus onvalvular endothelium. Journal of Infectious Diseases, 2001, 183(3):507 JE, Hsu KC, Gotschlich EC. Electron microscopic studies onstreptococci IM antigen. Journal of Experimental Medicine, 1969, 130:1063 JE. Streptococcal toxins (streptolysin O, streptolysin S, erythrogenictoxin). Pharmacology and Therapeutics, 1980, 11:661 N et al. Rapid molecular genetic subtyping of serotype M1 groupA streptococcus strains. Emerging Infectious Diseases, 1999,5(2):254 EL. The resurgence of group A streptococcal Journal of Clinical Microbiology and Infectious Diseases, 1991,10:55 SE et al. Aspects of pathogenesis of serious group A streptococcalinfections in Sweden. Journal of Infectious Diseases, 1988 1999, 166:31 C, Bormann N, Cleary PP. VirR and Mry are homologous trans-actingregulators of M protein and C5a peptidase expression in group Astreptococci. Molecular and General Genetics, 1993, 241(5 6):685 WA, Courtney HS, Ofek I. Interactions of fibronectin withstreptococci: the role of fibronectin as a receptor for Streptococcuspyogenes. Reviews of Infectious Diseases, 1987, 9(Suppl 4):S351 A, Krebs B, Kaufhold A. Genetic variability of the emm-relatedgene of the large vir regulon of group A streptococci: potential intra- andintergenomic recombination events. Molecular and General Genetics, 1994,243(6):691 JJ et al. Complete genome sequence of an M1 strain ofStreptococcus pyogenes. Proceedings of the National Academy of Sciences(USA), 2001, 98(8):4658 T et al. An HLA-linked immune suppression gene in man. Journalof Experimental Medicine, 1980, 152(2 Pt 2):297s EM et al. Association of class II human histocompatibility leukocyteantigens with rheumatic fever. Journal of Clinical Investigation, 1986,77(6):2019 D, Fischetti VA. Synthetic peptide vaccine against mucosalcolonization by group A streptococci. I. Protection against a heterologous Mserotype with shared C repeat region epitopes. Journal of Immunology,1990, 145(4):1251 M, Gerber MA, Kaplan EL. Treatment of streptococcalpharyngotonsillitis: reports of penicillin s demise are premature. Journal ofPediatrics, 1993, 123(5):679 L et al. Antibody-mediated autoimmune myocarditis depends ongenetically determined target organ sensitivity. Journal of ExperimentalMedicine, 1995, 181(3):1123 EL, Wotton JT, Johnson DR. Dynamic epidemiology of group Astreptococcal serotypes associated with pharyngitis. Lancet, 2001,358(9290):1334 of rheumatic feverJones criteria for the diagnosis of rheumatic feverThe Jones criteria were introduced in 1944 as a set of clinical guide-lines for the diagnosis of rheumatic fever (RF) and carditis (1). Theclinical features of RF were divided into major and minor categories,based on the prevalence and specificity of manifestations (Figure 1).Major manifestations were least likely to lead to an improper diagno-sis and included carditis, joint symptoms, subcutaneous nodules, andchorea. A history of RF or preexisting rheumatic heart disease(RHD) was considered to be a major criterion since RF tends torecur. Minor manifestations were considered to be suggestive, but notsufficient, for a diagnosis of RF. The minor manifestations comprisedclinical findings (such as fever and erythema marginatum, abdominalpain, epistaxis and pulmonary findings), and laboratory markers ofacute inflammation, such as leukocytosis (WBC), and elevated eryth-rocyte sedimentation rate (ESR) or C-reactive protein (CRP) (Figure1). It was proposed that the presence of two major, or one major andFigure 1Changes in the Jones criteria following reviews from AHA and WHOOriginalJones critera 1944AHAModified1956AHARevised1965(1984)A HAUpdate1992WHO1988WHO2003Manifestations CarditisLong PRaArthritisArthralgiaSubcutaneous nodulesChoreaErythenamarginaturnPre-exis tingRF/RHDFeverWBC, ESR, CRP aEpistaxis, abdominalpain, anemia,pulmonary findingsRecent streptococoalinfectionEssentialMajorMino rSpecialconsiderationa PR = PR interval in the electrocardiogram; WBC = leukcoytosis; ESR = erythrocyteseyimontation rate; CRP = C-reactive protein. Modified in part from reference (45)21two minor, manifestations offered reasonable clinical evidence ofrheumatic activity. Since a previous history of definite RF or RHDwas considered a major criterion, diagnosis of a recurrence of RF didnot require strict application of these guidelines, and minor manifes-tations were considered sufficient for the importance of the Jones criteria was soon realized, especially asobjective guidelines that allowed RF to be diagnosed uniformly inmulticenter studies of RF. The Jones criteria were subsequently re-viewed by the American Heart Association (AHA) and the WorldHealth Organization (WHO) (2 6) and were modified to encompassvexing clinical issues and to improve the specificity (Figure 1).Although the Jones criteria have been revised repeatedly, the modi-fications were often made without prospective studies and were basedon the perceived effects of previous revision(s).The importance of a preceding streptococcal infection has beenemphasized in subsequent revisions of the Jones criteria, in which adiagnosis of RF required the demonstration of streptococcal etiology(2, 3). Although the inclusion of this criterion helped to improvediagnostic specificity, it impaired sensitivity when evidence of ante-cedent streptococcal infection had already subsided (such as withinsidious and chronic carditis), or if manifestations of RF weredelayed (such as with chorea) (7). Therefore, late manifestations ofRF were subsequently exempted from the requirement to demon-strate streptococcal etiology (4, 5).Carditis is the single most important prognostic factor in RF; onlyvalvulitis leads to permanent damage and its presence determinesthe prophylactic strategy (8). The prophylactic and prognostic stakesclearly underscore the importance of correctly identifying clinical diagnosis of carditis in an index attack of RF is based onthe presence of significant murmurs (suggestive of mitral and/oraortic regurgitation), pericardial rub, or an unexplained cardiomegalywith CHF. Rheumatic cardiac involvement almost invariably occursin an RF recurrence, if the initial episode involved the heart (9, 10). Adiagnosis of recurring carditis requires the demonstration of valvulardamage or involvement, with or without pericardial or myocardialinvolvement (11). Such clinical findings include a documented changein a previous murmur to a new murmur or pericardial rub, or anobvious radiographic increase in cardiac size, respectively. The clini-cal diagnosis of rheumatic carditis by the Jones criteria occasionallybecomes difficult (9, 12, 13), such as during RF recurrence, especiallywhen carditis is the sole manifestation of rheumatic activity. During arecurrence of rheumatic activity in a patient with preexisting RHD,22the carditis may result in florid CHF, but it may not be possible todiagnose carditis from an interval change in valvular regurgitationowing to a lack of previous cardiac findings. This is in contrast to theprimary RF episode, where unexplained CHF is considered sufficientfor the diagnosis of active rheumatic carditis by the revised Jonescriteria. It is important to differentiate between the recurrence ofcarditis as the cause of CHF, and the decompensation of chronicprogressive valvular disease, because the use of steroids may be life-saving in active carditis, but of no benefit in valvular disease. Therecurrent carditis is likely to remain subclinical in the absence of CHFand its diagnosis becomes even more difficult when previous cardiacfindings are not majority of RF cases are observed in developing countries (14).Further, recurrences of the disease are common in developing coun-tries, owing to gaps in the detection and secondary prevention ofdisease caused by a lack of health-care facilities. In such countries, themajority of active RF patients present with a recurrence of disease atleast in the tertiary care 2003 WHO criteria for the diagnosis of rheumatic fever andrheumatic heart disease (based on the revised Jones criteria3,4)These revised WHO criteria (Table ) facilitate the diagnosis of: a primary episode of RF recurrent attacks of RF in patients without RHD recurrent attacks of RF in patients with RHD rheumatic chorea insidious onset rheumatic carditis chronic the diagnosis of a primary episode of RF, it is recommended thatthe major and minor clinical manifestations of RF, the laboratorymanifestations, and evidence of a preceding streptococcal infectionshould all continue according to the 1988 WHO recommendations(6). In the context of a preceding streptococcal infection, two majormanifestations, or a combination of one major and two minor mani-festations, provide reasonable evidence for a diagnosis of RF. WHOhas continued to maintain that a diagnosis of a recurrence of RF ina patient with established RHD should be permitted on the basisof minor manifestations plus evidence of a recent should use their clinical judgment to diagnose carditis in anepisode of RF, especially during a recurrence of RF, and shoulduse the above recommendations as guidelines for the , clinical examination remains the basis of a diagnosis of RFand carditis, and the role of echocardiography should be consideredsupportive. However, an echo-Doppler examination should be per-formed if the facilities are available. The other invasive andnoninvasive diagnostic modalities for RF, such as endomyocardialbiopsy and radionuclide imaging, should be considered research 2003 WHO criteria for the diagnosis of rheumatic fever and rheumatic heartdisease (based on the revised Jones criteria3,4)Diagnostic categoriesCriteriaPrimary episode of major *or one major and two minor**manifestations plus evidence of apreceding group A streptococcalinfection***.Recurrent attack of RF in a patient withoutTwo major or one major and two minorestablished rheumatic heart plus evidence of apreceding group A streptococcal attack of RF in a patient withTwo minor manifestations plus evidence ofestablished rheumatic heart preceding group A major manifestations or evidence ofInsidious onset rheumatic A streptococcal infection valve lesions of RHD (patientsDo not require any other criteria to bepresenting for the first time with purediagnosed as having rheumatic heartmitral stenosis or mixed mitral and/or aortic valve disease).d* Major manifestations carditis polyarthritis chorea erythema marginatum subcutaneous nodules** Minor manifestations clinical: fever, polyarthralgia laboratory: elevated acute phasereactants (erythrocyte sedimentation rateor leukocyte count)*** Supporting evidence of a preceding electrocardiogram: prolonged P-R intervalstreptococcal infection within the last elevated or rising antistreptolysin-O or45 daysother streptococcal antibody, or a positive throat culture, or rapid antigen test for group Astreptococci, or recent scarlet may present with polyarthritis (or with only polyarthralgia or monoarthritis) and with several(3 or more) other minor manifestations, together with evidence of recent group A streptococcalinfection. Some of these cases may later turnout to be rheumatic fever. It is prudent to consider themas cases of probable rheumatic fever (once other diagnoses are excluded) and advise regularsecondary prophylaxis. Such patients require close follow up and regular examination of the cautious approach is particularly suitable for patients in vulnerable age groups in highincidence endocarditis should be patients with recurrent attacks may not fulfil these heart disease should be recommendations are in keeping with the original intent of theJones criteria, which were established as a universal standard for thediagnosis of , chorea, erythema marginatum, and subcutaneous nodulesare among the noncarditic manifestations considered to be majordiagnostic features of acute RF. Subcutaneous nodules are almostalways associated with cardiac involvement and are found morecommonly in patients with severe carditis. Unlike rheumatic carditis,noncarditic manifestations of RF do not lead to permanent major noncarditic manifestations occur in varying combinations,with or without carditis, during the evolution of the disease. Arthritisis the most common manifestation of RF and usually draws attentionto the disease. When arthritis appears as the sole major manifestationthe clinical diagnosis of RF is difficult, because many infectious,immunological and vasculitic disorders may present with polyarthri-tis. The presence of noncarditic manifestations facilitates the detec-tion of rheumatic carditis and their identification is particularlyimportant in recurrences of disease, when the diagnosis of carditis , techniques for detecting pericardial, myocardial and valvu-lar involvement in RF have been studied (15), and WHO carefullyreviewed their role in the diagnosis of RF, with special emphasis ontheir applicability in developing of rheumatic carditisAlthough the endocardium, myocardium and pericardium are allaffected to varying degrees, rheumatic carditis is almost always asso-ciated with a murmur of valvulitis (Table ). Accordingly, myocardi-tis and pericarditis, by themselves, should not be labeled rheumatic inorigin, when not associated with a murmur and other etiologies mustbe first episode of rheumatic carditis should be suspected in a patientwho does not have a history suggestive of previous RF or RHD, andwho develops a new apical systolic murmur of mitral regurgitation(with or without an apical mid-diastolic murmur), and/or the basalearly diastolic murmur of aortic regurgitation. On the other hand, inan individual with previous RHD, a definite change in the character ofany of these murmurs or the appearance of a new significant murmurindicates the presence of (alone) in the absence of valvulitis is unlikely to be ofrheumatic origin and by itself should not be used as a basis for such adiagnosis. It should always be associated with an apical systolic orbasal diastolic murmur. Clinically apparent CHF and radiographiccardiac enlargement indicate that the myocardium is likely to beinvolved in the primary episode of RF, although the role of unex-plained CHF in the diagnosis of a recurrence of rheumatic carditis hasbeen questioned. It seems safe to recommend that an unexplainedworsening of CHF in a suspected case of recurrent RF indicates thepresence of active carditis, if supported by adequate minor manifesta-tions and evidence of a preceding streptococcal infection. If previousclinical findings are known, they can be compared with current data myocardial involvement is likely to result in a sudden cardiacenlargement that will be detectable radiographically. Infective en-docarditis may also masquerade as a recurrence of rheumatic with CHF are considered to suffer from severe carditis. Al-though CHF has always been directly linked with myocardial involve-ment in RF, the impairment in left ventricular systolic function doesTable features of rheumatic carditisPericarditis: Audible friction rub; can be supported by echocardiographic evidenceof pericardial effusion. Simultaneous demonstration of valvular involvementgenerally considered essential. Pericarditis is equally diagnostic in primary episode,or a recurrence of : Unexplained CHF or cardiomegaly, almost always associated withvalvular involvement. Left ventricular function is rarely affected. In presence of RHD,CHF and minor manifestations, and elevated streptococcal antibody titers providereasonable evidence of rheumatic : Presence of apical holosystolic murmur of mitral regurgitation(with or without apical mid-diastolic murmur, Carey Coombs), or basal earlydiastolic murmur in patients who do not have a history of the other hand, in an individual with previous RHD, a definite change in thecharacter of any of these murmurs or the appearance of a new significant murmurindicates the presence of can provide early evidence of valvular involvement, can confirmsuspected valvular regurgitation, and can exclude non-rheumatic causes of demonstration of valvular regurgitation is not a prerequisite for thediagnosis of rheumatic carditis and should not be considered a limitation where the facilitiesare not available. The strict application of diagnostic criteria is mandatory to demonstratepathological valvular regurgitation. Currently, data do not allow subclinical valvularregurgitation detected by echocardiography to be included in the Jones criteria, as evidenceof a major manifestation of carditis. Echocardiography can only play a limited role in cases ofrecurring RF, unless a previous echocardiographic study is available for occur in RF, and the signs and symptoms of CHF may result fromsevere valvular incompetence (16, 17).PericarditisPericardial involvement in RF may result in distant heart sounds, afriction rub, and chest pain. At times, however, the friction rub canmask the mitral regurgitation murmur, which becomes evident onlyafter the pericarditis subsides. Since isolated pericarditis is not goodevidence of rheumatic carditis without supporting evidence of avalvular regurgitant murmur, it may be helpful to have Dopplerechocardiography available in such circumstances to look for signsof mitral regurgitation. Echocardiography could also corroboratethe mild-to-moderate pericardial effusion likely to be associated withpericarditis; large effusions and tamponade are rare (18). Althoughnot specific, the electrocardiogram may show low-voltage QRS com-plexes and ST-T changes, and the heart may appear enlarged in an X-ray silhouette. Patients with this form of pericarditis are usuallytreated as cases of severe of extra cardiac manifestations of RFAlthough the cardiac manifestations of RF are most important interms of immediate and long-term prognoses, the generalized inflam-matory process in RF, as defined in the 1988 WHO revision of theJones Criteria (6), may occur in extra cardiac target sites ( skin,joints, brain) during the evolution of the disease. Noncardiac manifes-tations may be the best guide for a diagnosis of rheumatic carditis. Aswith previous editions of the Jones Criteria, the presence of two majorcriteria, or of one major and two minor criteria, indicates a highprobability of RF, if supported by evidence of a prior Group Astreptococcal infection. Absence of the latter always makes a diagno-sis of RF doubtful, except for specific situations (Table ).Major manifestationsArthritisArthritis is the most frequent major manifestation of RF, occurring inup to 75% of patients in the first attack of RF (19, 20). It occurs earlyin the course of the disease, as the presenting complaint. Arthritis isoften the only major manifestation in adolescents, as well as in adults,where carditis and chorea become less common in older age involvement of joints in RF may present as arthralgia, to dis-abling arthritis. Joint pain without objective findings does not qualifyas a major disease manifestation because of its nonspecificity. The27articular manifestations in RF typically present as migratory poly-arthritis, most often in the larger joints (commonly in the knees andankles); the wrists, elbows, shoulders and hips are less frequentlyinvolved; and the small joints of the hands, feet and neck are rarelyaffected (20). Inflamed joints are characteristically warm, red andswollen, and an aspirated sample of synovial fluid may reveal a highaverage leukocyte count (29 000 mm-3, range 2000 96 000 mm-3) (21).Tenderness in rheumatic arthritis may be out of proportion to theobjective findings and severe enough to result in excruciating pain ontouch. The term migratory reflects the sequential involvement ofjoints, with each completing a cycle of inflammation and resolution,so that some joint inflammation may be resolving while others all cases of rheumatic arthritis conform to this characteristicdescription. Monoarthritis may occur, for example, and its frequencyincreases when anti-inflammatory therapy is initiated before RF isfully expressed. Frequently, several joints may be affected simulta-neously, or the arthritis may be additive rather than migratory. In-flammation in a particular joint usually resolves within two weeks andthe entire bout of polyarthritis in about a month if to other manifestations. Polyarthritis and Sydenham s choreavirtually never occur simultaneously due to the disparity in the la-tency period following the antecedent streptococcal infection. Choreamay, however, occur after arthritis has subsided. Carditis and arthritisfrequently coexist during an RF episode, and demonstrate an inverserelationship between the severity of arthritis and carditis. One study,for example, found severe cardiac involvement in 10% of those witharthritis, 33% of those with arthralgia, and 50% of those with no jointsymptoms (19).Poststreptococcal reactive arthritis. Following a streptococcal infec-tion, some patients develop arthropathy that differs from acute rheu-matic arthritis. This entity, poststreptococcal arthritis, occurs after arelatively short latency period of about a week, may be persistent orrelapsing (22, 23), may not respond dramatically to anti-inflammatoryagents, and is not associated with other major manifestations of RF. Itremains unclear whether it represents a form of reactive arthritisdistinct from true RF, which may have important implications regard-ing prognosis and the need for antistreptococcal prophylaxis. A num-ber of patients presenting initially as poststreptococcal arthritis havelater manifested RHD (24). Given our inability to differentiate be-tween a benign poststreptococcal arthritis and RF, patients witharthritis following a streptococcal upper respiratory infection shouldbe considered to have RF if they fulfill the Jones diagnosis. Polyarthritis unaccompanied by other majormanifestations of RF deserves differential diagnosis from many clini-cal entities (Tables and ) (25). Septic arthritis should be ruledout by microbiological studies. Gonococcal arthritis can present aproblem because it occurs frequently in adolescents who do not havelocalized gonococcal disease, and whose blood and joint fluid culturesare negative in microbiological tests. The diagnosis can be helped byan epidemiological history and characteristic gonococcal skin lesions(if present), in addition to gonococcal cultures of urethra, cervix,rectum and diagnosis of polyarthritis and feveraDiagnosisConfirmatory studyInfectious arthritisBacterial infectionsSeptic arthritisSynovial fluid and blood cultureBacterial endocarditisBlood cultureLyme diseaseSerological studiesMycobacterial and fungal arthritisCulture or biopsyViral arthritisSerological studiesPostinfectious or reactive arthritisEnteric infectionCulture or serological studiesUrogenital infection (Reiter s syndrome)CultureRFClinical findingsInflammatory bowel diseaseClinical findingsRheumatoid arthritis and Still s diseaseClinical findingsSystemic rheumatic illnessesSystemic vasculitisBiopsy or angiographySystemic lupus erythematosusSerological studiesCrystal-induced arthritisGout and pseudogoutPolarizing microscopy of synovial fluid ortophiOther diseasesFamilial Mediterranean feverClinical findingsCancersBiopsySarcoidosisBiopsyMu cocutaneous disordersBiopsy or clinical findingsdermatomyositisBechcet s diseaseHenoch-Schonlein purpuraKawasaki s disease (mucocutaneouslymph node syndrome)erythema nodosumerythema multiformepyoderma gangrenosumaSource: (25).29Table features in patients presenting with polyarthritis and feveraSymptom or signPossible diagnosisTemperature of 40 CStill s diseaseBacterial arthritisSystemic lupus eythematosusFever preceding arthritisViral arthritisLyme diseaseReactive arthritisStills diseaseBacterial endocarditisMigratory arthritisRFGonococcemiaMeningococcermiaV iral arthritisSystemic lupus erythematosusAcute leukemiaWhipple s diseaseEffusion disproportionately greater than painTuberculosis arthritisBacterial endocarditisInflammatory bowel diseaseGiant cell arthritisLyme diseasePain disproportionately greater than effusionRFFamilial Mediterranean feverAcute leukemiaAIDSPositive test for rheumatoid factorRheumatoid arthritisViral arthritisTuberculous arthritisBacterial endocarditisSystemic lupus erythematosusSarcoidosisSystemic vasculitisMorning stiffnessRheumatoid arthritisPolymyalgia rheumaticaStill s diseaseSome viral and reactive arthritidesSymmetric small joint synovitisRheumatoid arthritisSystemic lupus erythematosusViral arthritisLeukocytosis (15 000 per mm3)Bacterial arthritisBacterial endocarditisStill s diseaseSystemic vasculitisAcute leukemiaLeukopeniaSystemic lupus erythematosusViral arthritis30Arthritis may also occur in infective endocarditis, and it may bedifficult to differentiate this disease from RF, particularly when theendocarditis occurs in a patient with known RHD. The epidemiologi-cal features, history, physical examination, results of blood cultures,echocardiographic studies, and antistreptococcal antibody assays mayall help to differentiate between infective endocarditis and RF. Lymedisease, which presents with arthritis, cardiac involvement, and skinlesions, may at times suggest RF; even the skin lesions of erythemachronicum migrans may resemble erythema marginatum. A diagnosisof Lyme disease should take into account the season of the year,geographical locale, and history of tick bites. The diagnosis can beconfirmed by serological studies and the patient response to anti-microbial , some of which are associated with immune complex forma-tion, may also mimic rheumatic polyarthritis. Examples include hepa-titis B and C, and rubella. Rheumatological manifestations of otherimmune complex diseases such as serum sickness may be confusing,particularly when they occur in a patient who has recently receivedantibiotics for an upper respiratory tract , collagen vascular diseases, such as rheumatoid arthritis andsystemic lupus erythematosus (SLE) may, at their onset, mimic RF. Injuvenile rheumatoid arthritis certain associated findings, such as rash,lymphadenopathy and splenomegaly, may suggest the diagnosis. Thecervical spine may also be involved in this disease, but is unusualin RF. At times, the only way to arrive at a definite diagnosis is toobserve the clinical course. In addition, Henoch-Schonlein purpura,sickle-cell anemia, acute leukemia and gout at times mimic the arthri-tis of or signPossible diagnosisEpisodic recurrencesLyme diseaseCrystal-induced arthritisInflammatory bowel diseaseWhipple s diseaseMediterranean feverStill s diseaseJuvenil Rheumatoid arthritisSystemic lupus erythematosusaSource: (25).31Prognosis. Arthritis heals completely, unlike carditis, and leaves nopathological or functional residua. The one possible exception isJoccoud chronic postrheumatic arthritis. This rare condition is not atrue synovitis, but rather is a periarticular fibrosis of the metacar-pophalangeal joints. It usually occurs in patients with severe RHD,but is not associated with evidence of RF (26).Sydenham s choreaChorea occurs primarily in children and is rare after the age of 20years. It occurs primarily in females, and almost never occurs inpostpubertal males. The prevalence of chorea in RF patients variedfrom 5 36% in different reports (27). The reasons for the variationwere not apparent, but might be related to differences in susceptibil-ity to chorea in the host population, or to differences in case-findingmethods. It is unknown whether particular strains of group A strepto-cocci vary in their propensity to elicit s chorea is characterized by emotional lability, uncoordi-nated movements, and muscular weakness (28, 29). The onset mayoften be difficult to determine, as initially the child may becomefretful, irritable, inattentive to schoolwork, fidgety, or even severelydisturbed. Physical uncoordination soon becomes apparent, perhapsmanifested as clumsiness and a tendency to drop objects, whichprogresses to spasmodic, uncoordinated movements. On physical ex-amination, the movements are abrupt and erratic. All muscle groupsmay be affected, but erratic movements of the hands, feet and face aremost evident. Facial movements include grimaces, grins and the tongue is protruded it resembles a bag of worms, andspeech is jerky and staccato. Handwriting becomes illegible, and thepatient may stumble when attempting to walk. When the hands areextended, the dorsum assumes a spoon or dish configuration dueto flexion of the wrist and hyperextension of the metacarpopha-langeal joints. When raising the hands above the head, the patientmay pronate one or both hands ( pronator sign ). Patients with cho-rea are unable to sustain a titanic contraction; therefore, when askedto grip the examiner s hand, their irregular, repetitive squeezes havebeen termed milkmaid grip . Although the choreiform movementsare usually bilateral, they may be unilateral (hemichorea) (30). Thechoreiform movements disappear during sleep, decrease with rest andsedation, and can be suppressed by volition for few movements. Theymay be accentuated by asking the patient to perform several volun-tary movements at once. Neither sensory deficits nor pyramidal tractinvolvement are to other manifestations of RF. Chorea may occur alone( pure chorea), or in association with other manifestations of relationship of chorea to polyarthritis and carditis was clarified bythe recognition that chorea has a longer latency period after anteced-ent group A streptococcal infection, as long as 1 7 months. As aresult, polyarthritis and Sydenham s chorea do not occur together;and indeed the onset of chorea often calls attention to subclinicalcarditis. Another consequence of the long latency period is that strep-tococcal antibody titres and laboratory measures of inflammationmay have resolved by the time choreiform movements recurrences. Recurrent attacks of acute RF tend to be mi-metic, and recurrences of chorea are not uncommon. As discussedabove, when patients experience recurrent attacks of pure chorea, apreceding streptococcal infection may be difficult to establish. Fre-quently, patients with chorea gravidarum, or with oral contraceptive-induced chorea, have a past history of chorea (including Sydenham schorea), suggesting that certain individuals may have an innate chore-iform diathesis, or that a first attack confers an enhanced susceptibil-ity to subsequent et al. (31) observed 17 recurrences of pure chorea in 10patients over a 51/2-year period. All patients were highly compliantwith the prophylactic regimen and were followed prospectively, withmonthly throat cultures and serum antistreptococcal antibody deter-minations every three months. In most cases, a recent streptococcalinfection was confirmed by serological evidence, although titre in-creases were often quite modest. In four recurrences it was possible torule out an immunologically significant streptococcal infection withinthe six months preceding the episode. It was concluded either thatsome recurrences of Sydenham s chorea in patients on optimal pro-phylaxis were triggered by streptococcal infections too weak andtransient to be detected, or that stimuli other than streptococcal infec-tions triggered the diagnosis. In only approximately two-thirds of cases ofpure chorea can a recent streptococcal infection be documented,which makes differential diagnosis more difficult. Non-cardiac choreacan occur owing to other collagen vascular, endocrine, metabolic,neoplastic, genetic, and infectious disorders (Table ), perhaps themost common of which is SLE. It is not unusual for the centralnervous system to be involved in SLE, and less than 2% of patientsmanifest chorea (32). The differentiation of SLE and RF is compli-cated by the occurrence of fever, arthritis, carditis, and skin lesions inboth to the differential diagnosis of chorea in children and adolescentsaDiagnosisDiagnostic cluesAtypical seizureElectroencephalographic in level of accidentsMRIb or CT evidence of vascular diseaseHistory and physical examination.( SLE, periarteritis nodosa)Laboratory evidence ( , decreased complementlevels, positive ANA titers). (Note: ANA can beelevated following infection and therefore maybe positive in acute RF).Drug intoxicationDrug screen, especially for phenytoin,amitriptyline, metoclopramide, and choreaThe prototype is Huntington s disease, but thediagnosis also includes benign familial chorea,familial paroxysmal dystonic choreoathetosis,familial paroxysmal kinesigenic choreoathetosis,familial chorea with canthocytosis (check bloodsmear for acanthocytes), familial calcification ofbasal ganglia (MRI or CT scan may be helpful),ataxia telangiectasia, and induced choreaUse of oral (choreagravidarum)HyperthyroidismAbnorma l thyroid function test serum calcium and magnesium serum phosphorus levelLyme diseaseHistory and accompanying examination findings( rash)Titres against BorreliaburgdorferiSydneyham s choreaOther signs of of precedingstreptococcal infectionWilson s diseaseDecreased serum ceruloplasmin urinary copperexcretionKayser-Fleischer ringsAnemia, hepatitisFamily historyaSource: (73).bAbbreviations: ANA = antinuclear antibody; CT = computed tomography; MRI = magneticresonance imaging; SLE = systemic lupus occurrence of chorea during pregnancy, or chorea gravidarum,may remit prior to delivery or soon after. Because many of the pa-tients have a history or prior attacks of chorea, it has been postulatedthat chorea gravidarum might represent a recurrence of RF duringpregnancy. It is more likely, however, that in most cases the disorderis related to hormonal alterations. The role of hormonal factors in thepathogenesis of chorea is further exemplified by the association ofchoreic disorder associated with oral contraceptive use (33, 34). Cho-rea usually begins soon after the patient has started taking oral con-traceptives and stops within a few weeks after they are manifestations are usually asymmetric or unilateral. Nearly halfthe patients have a history of previous chorea, which may have beenassociated with a rheumatic attack or with nonrheumatic conditions( chorea gravidarum, Henoch-Schonlein purpura). Interestingly,patients with oral contraceptive-induced chorea who later becamepregnant do not necessarily develop chorea gravidarum. The patho-genesis of oral contraceptive-induced chorea remains addition to the above-mentioned causes of choreiform movements,simple motor tics in children or the involuntary jerks of Tourette ssyndrome may be confused with chorea. However, the confoundingfeature is that many such disorders may also be secondary to theantecedent streptococcal infection, and collectively they have beenreferred to as PANDAS syndrome. However, at the present time, thePANDAS syndrome remains only an hypothesis and is not a The duration of chorea is quite variable, ranging from oneweek to more than two years; the median duration of an attack was 15weeks in hospitalized patients. Three-quarters of the patients recoverwithin six months. The manifestations of chorea may wax and waneduring its course. A number of long-term neurological and psycho-logical sequelae have been described, including convulsions, de-creased learning ability, behavior problems, and psychosis. The exactrelationship, if any, of these conditions to chorea is nodulesThe incidence of subcutaneous nodules in patients with RF varieswidely in different studies and from country to country. The lesionshave been reported in up to 20% of cases (35). The subcutaneousnodules are round, firm, freely movable, painless lesions varying insize from cm. Because the skin over them is not inflamed, theymay easily be missed if not carefully sought on physical occur in corps over bony prominences or extensor locations are the elbows, wrists, knees, ankles and Achilles35tendons. They may also be found over the scalp, especially theocciput, and the spinous processes of the vertebrae. The number ofnodules varies from one to a few dozen, but usually three or persist from days to 1 2 weeks to, rarely, more than a nodules are not pathognomonic of RF; similar lesions occur inSLE and rheumatoid arthritis. The nodules in the latter conditiontend to be larger than those seen in to other manifestations of RF. Subcutaneous nodules rarelyoccur as an isolated manifestation of RF. In most cases, they areassociated with the presence of carditis, usually appearing severalweeks after the onset of cardiac findings. Nodules are found morefrequently in patients with severe carditis and may appear in recur-rent corps (36).Erythema marginatumErythema marginatum occurs in up to 15% of RF patients, althoughit was seen in only 4% of 274 patients admitted to the PrimaryChildren s Medical Center in Salt Lake City, Utah, between 1985 1992 (37), and in 4% of 73 RF patients studied at the King KhalidUniversity Hospital in Riyadh, Saudi Arabia, between 1985 1989(38). In view of the evanescent nature of the lesions and the lack ofassociated symptoms, however, erythema marginatum may be missedif not specifically sought, particularly in dark-skinned lesions of erythema marginatum appear first as a bright pinkmacule or papule that spreads outward in a circular or seripiginouspattern. The lesions are multiple, appearing on the trunk or proximalextremities, rarely on the distal extremities, and never on the are nonpruritic and nonpainful, blanch under pressure, and areonly rarely raised. Individual lesions may come and go in minutes tohours, at times changing shape before the observer s eye or coalescingwith adjacent lesions to form varying patterns. Indeed, they havebeen described as appearing like smoke rings beneath the marginatum usually occurs early in the course of a rheu-matic attack. It may, however, persist or recur for months or evenyears, continuing after other manifestations of the disease have sub-sided, and it is not influenced by anti-inflammatory therapy. Thiscutaneous phenomenon is associated with carditis but, unlike subcu-taneous nodules, not necessarily with severe carditis. Nodules anderythema marginatum tend to occur diagnosis. Erythema marginatum is not unique to RF andhas also been reported during sepsis, drug reactions, and glomerulo-nephritis, and in children in whom no etiology is evident. It must be36differentiated from other toxic erythemas in febrile patients and therash of juvenile rheumatoid arthritis. The circinate rash of Lymedisease (erythema chronicum migrans) may resemble manifestationsArthralgia and fever are termed minor clinical manifestations ofRF in the Jones diagnostic criteria, not necessarily because they occurless frequently than the five recognized major criteria, but ratherbecause they lack diagnostic specificity. Fever occurs in almost allrheumatic attacks at the onset, usually ranging from 101 F to 104 F( C). Diurnal variations are common, but there is no charac-teristic fever pattern. Children who present only with mild carditiswithout arthritis may have a low-grade fever, and patients with purechorea are afebrile. Fever rarely lasts more than several weeks. Ar-thralgia without objective findings is common in RF. The pain usuallyinvolves large joints, may be mild or incapacitating, and may bepresent for days to weeks, often varying in abdominal pain and epistaxis may occur in only about 5%of patients with RF, they have not been considered a part of the Jonescriteria owing to the lack of specificity of these symptoms. However,they may be of considerable clinical importance because they oftenappear hours or days before major manifestations of the disease andmay mimic a variety of other acute abdominal conditions. The pain isusually epigastric or periumbilical, but may be accompanied by guard-ing and at times can be virtually indistinguishable from acute appen-dicitis. Both the temperature and sedimentation rate tends to behigher than in appendicitis, but if the latter cannot be excluded,surgery may be diagnostic techniques for rheumatic carditisEchocardiographyThe use of echocardiography to detect rheumatic carditis is discussedin the following Chapter 4, entitled, Diagnosis of rheumatic fever andassessment of valvular disease using biopsySince myocarditis is an obligatory component of cardiac involvementin RF (8), the value of endomyocardial biopsy has been investigatedfor diagnosing rheumatic carditis (39). To establish the histologicalcharacteristics of carditis, endomyocardial biopsies from patients pre-senting with a first episode of RF were compared to biopsies from37patients with quiescent chronic RHD. The results demonstrated thatmyocarditis was virtually absent (defined by the Dallas criteria to befocal or diffuse myocytic necrosis associated with cellular infiltrationof mononuclear lymphocytes). Instead, there was evidence of intersti-tial inflammation that ranged from perivascular mononuclear cellularinfiltration, to histiocytic aggregates and Aschoff nodule aggregates and Aschoff nodules were identified in only30% of patients. On the other hand, Aschoff nodules were seen in40% of the endomyocardial biopsies taken from patients with preex-isting RHD and who developed a possible recurrence of rheumaticcarditis with CHF. These results suggested that an endomyocardialbiopsy is not likely to provide additional diagnostic information forpatients with clinical carditis in a primary episode of RF. The resultsalso suggested that an onset of unexplained CHF in patients withestablished RHD, and who presented with only minor manifestationsof RF and elevated antistreptolysin-O titers, would indicate a highprobability of rheumatic carditis, and that an invasive test may not beneeded for the imagingRadionuclide techniques are simple, noninvasive modalities thathave been commonly used to evaluate a variety of cardiovasculardisorders. The pathology of rheumatic myocarditis is characterizedpredominantly by the presence of myocardial inflammation, withsome damage to myocardial cells (39, 40). Gallium-67 (41), radiola-belled leukocytes (42, 43), and radiolabelled antimyosin antibody(44) have all been used to image myocardial inflammation. Althoughradionuclide imaging has been used successfully to identify rheumaticcarditis by non-invasive means, there is not enough experience withsuch methods to allow them to be used for the routine diagnosis ofRF. However, the results of these studies have revealed that gallium-67 imaging has better diagnostic characteristics than antimyosin scin-tigraphy; and the results also confirmed that rheumatic carditis ispredominantly infiltrative, rather than degenerative, in TD. Diagnosis of rheumatic fever. Journal of the American Medicalassociation, 1944, 126:481 DD et al. Report of the Committee on Standards and Criteria forPrograms of Care of the Council of Rheumatic Fever and Congenital HeartDisease of American Heart Association. Jones Criteria (modified) forguidance in the diagnosis of rheumatic fever. Circulation, 1956, 13:617 GH et al. Report of the ad hoc Committee on Rheumatic Feverand Congenital Heart Disease of American Heart Association: Jones Criteria(Revised) for guidance in the diagnosis of rheumatic fever. Circulation,1965, 32:664 ST et al. Committee on Rheumatic Fever, Endocarditis andKawasaki Disease of the American Heart Association. Jones Criteria(Revised) for guidance in the diagnosis of rheumatic fever. Circulation,1984, 70:204A AS et al. Special writing group of the Committee on Rheumatic fever,Endocarditis and Kawasaki disease of the Council of Cardiovasculardisease in the young of the American Heart Association. Guidelines for thediagnosis of rheumatic fever: Jones criteria 1992 Update. Journal of theAmerican Medical Association, 1992, 268:2069 fever and rheumatic heart disease. Report of a WHO studygroup. Geneva, World Health Organization, 1988 (Technical Report Series,No. 764). M. Problems in clinical application of revised Jones diagnostic criteriafor rheumatic fever. Japanese Heart Journal, 1971, 12:436 BF, Narula J. Rheumatic fever and rheumatic carditis. In: BraunwaldE, Abelman WH, eds. The atlas of heart diseases. Philadelphia, CurrentMedicine, 1994 AR, Stern EK. Clinical effects of recurrent attacks of acuterheumatic fever: a prospective epidemiologic study of 105 of Chronic Diseases, 1967, 20:13 AG, Meyer FE. Carditis during second attack of rheumatic fever: itsincidence in patients without clinical evidence of cardiac involvement intheir initial rheumatic fever episode. New England Journal of Medicine,1963, 268:1259 J et al. Can Antimyosin scintigraphy supplement the Jones Criteria inthe diagnosis of active rheumatic carditis? American Journal of Cardiology,1999, 84:746 AR, Spagnuolo M. Mimetic features of rheumatic feverrecurrences. New England Journal of Medicine, 1960, 262:533 M. Evolution and critique of changes in Jones criteria fordiagnosis of acute rheumatic fever. New Zealand Medical Journal, 1988,101:392 R et al. Epidemiology of streptococcal pharyngitis, rheumaticfever and rheumatic heart disease. In: Narula J et al., eds. Rheumatic , DC, American Registry of Pathology, 1999:41 EL, Narula J. Echocardiographic diagnosis of rheumatic , 2001, 358(9297) MR, Wisenbaugh T, Sareli P. Evidence against a myocardial factoras the cause of left ventricular dilation in active rheumatic carditis. Journalof the American College of Cardiology, 1993, 22:826 BS, Edwards JE. Congestive heart failure in rheumatic carditis:valvular or myocardial origin. Journal of the American College of Cardiology,1993, 22:830 AT, Mah PK, Chia BL. Cardiac tamponade in acute rheumatic of the Rheumatic Diseases, 1983, 42:699 AR et al. Rheumatic fever in children and adolescents. A long-term epidemiologic study of subsequent prophylaxis, streptococcalinfections, and clinical sequelae. VI. Clinical features of streptococcalinfection and rheumatic recurrences. Annals of Internal Medicine, 1964,60(Suppl. 5):68 SL et al. Sequelae of the initial attack of acute rheumatic fever inchildren from North India: a prospective 5-year follow-up study. Circulation,1982, 65:375 M et al. Immunoglobulins and complement components insynovial fluid of patients with acute rheumatic fever. The Journal of ClinicalInvestigation, 1975, 56:111 WN, Hughes GR. Streptococci and reactive arthritis. Annals of theRheumatic Diseases, 1982, 41 C. Beta haemolytic streptococci and reactive arthritis in of the Rheumatic Diseases, 1993, 52:475 FM et al. Poststreptococcal reactive arthritis and silent carditis: acase report and review of the literature. Pediatrics, 1994, 93:837 RS. Polyarthritis and fever. New England Journal of Medicine, 1994,330:769 NJ. Chronic postrheumatic-fever (Jaccoud s) arthritis. New EnglandJournal of Medicine, 1962, 267:10 A. Noncardiac manifestations of rheumatic fever. In: Narula et al.,eds. Rheumatic fever. Washington, DC, American Registry of Pathology,1994:245 AM, Freeman JM, Carter S. The natural history of Sydenham s chorea:review of the literature and long-term evaluation with emphasis on cardiacsequelae. American Journal of Medicine, 1965, 38:83 M, Gordis L. Rheumatic fever, 2nd ed. Philadelphia, WBSaunders Co., A. Sydenham s chorea: a new look at an old disease. BritishJournal of Clinical Practice, 1993, 47:14 X et al. Are all recurrences of pure Sydenham s chorea truerecurrences of acute rheumatic fever? Journal of Pediatrics, 1985, 107:867 RA et al. Chorea in system lupus erythematosus and lupus-like disease: association with antiphospholipid antibodies. Seminars in Arthritisand Rheumatology, 1987, 16:253 DJ, Maciel BC. Physiological valvular regurgitation: Dopplerechocardiography and potential for iatrogenic heart disease. Circulation,1988, 78:1075 DG et al. Long term prognosis of rheumatic fever patientsreceiving regular intramuscular benzathine penicillin. Circulation, 1972,45:543 United Kingdom and United States Joint Report on Rheumatic HeartDisease. The natural history of rheumatic fever and rheumatic heart report of a cooperative clinical trial of ACTH, cortisone, andaspirin. Circulation, 1965, 32:457 BF, Fyler DC, Roy SB. The clinical picture of rheumatic fever:diagnosis, immediate prognosis, course and therapeutic Journal of Cardiology, 1958, 1:436 LG, Tani LY, Hill HR. Persistence of acute rheumatic fever in theintermountain area of the United States. Journal of Pediatrics, 1994,125:673 YA. Acute rheumatic fever during childhood in Saudi of Tropical Paediatrics, 1991, 11:225 J et al. Endomyocardial biopsies in acute rheumatic , 1993, 88:2198 J et al. Acute myocarditis masquerading as myocardial England Journal of Medicine, 1993, 328(2):100 JU et al. Galio-67 na febre rheumatica: experiencia preliminary.[Gallium-67 in rheumatic fever: preliminary experience.] Arquivos Brasileirosde Cardiologia, [Brazilian Archives of Cardiology] 1991, 56:487 CH, Wang SJ, Yeh SH. Detection of myocarditis in dilatedcardiomyopathy by Tc-99m HMPAO WBC myocardial imaging in a Nuclear Medicine, 1992, 17:678 CH et al. Comparison of Tc-99 m HMPAO labeled white blood scanningfor the detection of carditis in the differentiation of rheumatic fever andinactive rheumatic heart disease in children. Nuclear MedicineCommunications, 1992, 1:478 J, Chandrashekhar Y, Rahimtoola SH. Echoes of change: diagnosisof active rheumatic carditis. Circulation, 1999, 100:1576 M. Evolution of the Jones criteria for the diagnosis of acuterheumatic fever. In: Narula J et al., eds. Rheumatic fever. Washington, DC,American Registry of Pathology, 1999:299 of rheumatic fever and assessment ofvalvular disease using echocardiographyThe advent of echocardiographyEchocardiography is an imaging technique that rapidly evolved andmatured, and currently it is a key component in the diagnosis of heartdisease. The technique includes transthoracic, transesophageal andintracardiac echocardiography (1 3). Three-dimensional and evenfour-dimensional echocardiography have also been developed (4). Todiagnose rheumatic carditis and assess valvular disease, however,M-mode, two-dimensional (2D), 2D echo-Doppler and colour flowDoppler echocardiography are sufficiently sensitive and providespecific information not previously available. Of these, M-modeechocardiography provides parameters for assessing ventricular func-tion, while 2D echocardiography provides a realistic real-time imageof anatomical structure. Two-dimensional echo-Doppler and colourflow Doppler echocardiography are most sensitive for detectingabnormal blood flow and valvular use of 2D echo-Doppler and colour flow Doppler echo-cardiography may prevent the overdiagnosis of a functional murmuras valvular heart disease (5). Similarly, the overinterpretation ofphysiological or trivial valvular regurgitation may result in a misdiag-nosis of iatrogenic valvular disease (6, 7). Accurate interpretation ofthe echocardiographic signals is therefore and physiological valvular regurgitationTwo-dimensional echo-Doppler and colour flow Doppler echo-cardiography have permitted all audible valvular regurgitation to bedetected, even the physiological, functional, trivial or so-called nor-mal flow disturbance that may occur when normal valves close (7 11). Utilizing colour flow Doppler echocardiography, physiologicalregurgitation is characteristically localized at the region immediatelybelow or above the plane of valve leaflets (or within cm), and thesignals are short and the maximum regurgitant area small. The ap-pearance of physiological valvular regurgitation in healthy subjectswith structurally normal hearts varies with the devices, sensitivity,penetration power and techniques used, with changes in systemic andpulmonary vascular resistance and pressure, and with body habitusand age (3, 6, 7, 9, 12). The prevalence of physiological valvularregurgitation in normal people varied by valve: mitral regurgitationwas present in 45% of normal individuals (7, 9), aortic regurgita-tion in 0 33% (9, 12), tricuspid regurgitation in 95% (9, 13), andpulmonary regurgitation in 92% of normal individuals (9, 12).42The role of echocardiography in the diagnosis of acute rheumaticcarditis and in assessing valvular regurgitationClinical rheumatic carditisEchocardiographic images provide information about the size of atriaand ventricles, valvular thickening, leaflet prolapse, coaptation fail-ure, restriction of leaflet motility, and ventricular dysfunction (8, 14 18). In 25% of patients with acute rheumatic carditis, focal noduleswere found on the bodies and tips of the valve leaflets, but the nodulesdisappeared on follow-up (17).Congestive heart failure in patients with rheumatic carditis appears tobe invariably associated with severe mitral and/or aortic valve insuffi-ciency (16, 17). Myocardial factor or myocardial dysfunction ap-peared not to be the main cause of congestive heart failure, as thepercent fractional shortening of the left ventricle in such patients withheart failure has been found to be normal, and they improved rapidlyafter surgery (16, 17, 19). The pathogenesis of severe mitral regurgita-tion has been found to be owing to a combination of valvulitis, mitralannular dilatation and leaflet prolapse, with or without chordal elon-gation (16, 17). Chordal rupture occurs in some patients with rheu-matic carditis requiring an emergency mitral valve repair (14, 20).Echo-Doppler and colour flow Doppler imaging may also providesupporting evidence for a diagnosis of rheumatic carditis in patientswith equivocal murmur, or with polyarthritis and equivocal minormanifestations (10, 17).Classification of the severity of valvular regurgitationusing echocardiographyTraditionally, the severity of valvular regurgitation has been classifiedaccording to a five-point scale (0+, 1+, 2+, 3+ and 4+), based on theechocardiographic findings with angiocardiographic correlations (21 24). But based on colour flow Doppler mapping, it has been suggestedthat the severity of mitral and aortic valvular regurgitation may beclassified into a six-point scale as follows (21 24):0:Nil, including physiological or trivial regurgitant jet < cm, nar-row, small, of short duration, early systolic at mitral valve or earlydiastolic at aortic +: Very mild regurgitant jet, more than cm, wider, localized im-mediately above or below the valve, throughout systole at themitral valve or diastole at the aortic valve (clinically, no murmuraudible).1+: Mild regurgitant +: Moderate regurgitant jet, longer and at a wider +: Moderately severe regurgitant jet, reaching the entire left atrium(mitral regurgitation) or left ventricle (aortic regurgitation).4+: Severe regurgitant jet, diffusely into the enlarged left atrium,with systolic backward flow into pulmonary veins (mitral valve);markedly enlarged left ventricle filled with regurgitant jets (aorticvalve).Diagnosis of rheumatic carditis of insidious onsetIn patients with rheumatic carditis of insidious onset, or indolentcarditis, as defined in the 1992 update of the Jones criteria (25),echocardiography serves to establish the diagnosis of mitral and/oraortic insufficiency, after excluding the non-rheumatic causes, such ascongenital mitral valve cleft and/or anomalies, degenerative floppymitral valve, bicuspid aortic valve; and acquired valvular diseasesdue to infective endocarditis, systemic disease and others. Silent, butsignificant, very mild (grade 0+) mitral and/or aortic valvular regurgi-tation may be transient or persistent, even for years (26). It is recom-mended that such significant mitral and/or aortic regurgitation belabelled as probable rheumatic heart disease (RHD) until provenotherwise, and that the patients have long-term follow-up studies andbe placed on secondary rheumatic fever (RF) prophylaxis. In cases ofindolent rheumatic carditis, the cardiomegaly and valvular regurgita-tion may improve, and valve competency may even be restored (26,27).The use of echocardiography to assess chronic valvular heart diseaseTwo-dimensional echocardiography can display the anatomicalpathology of the mitral, aortic, tricuspid and (less well) pulmonaryvalves, and the valvular annulus and apparatus can be flow Doppler imaging has gained wide acceptance for qualita-tively and quantitatively evaluating the flow characteristics across thevalve, as well as for evaluating the severity of the flow pathology (11,22, 28, 29). Congenital, as well as acquired, valvular disease of non-rheumatic origin has to be excluded. Echocardiography may assistphysicians to decide the timing of surgical intervention for diseasedvalves (29).Diagnosis of recurrent rheumatic carditisIn patients with preexisting RHD, recurrence of RF is almost invari-ably associated with carditis, manifested as pericarditis; new valvularregurgitation and/or aggravation of the existing valve lesions;increased cardiac enlargement; and congestive heart failure. Thesefindings are easily and accurately detected and displayed of subclinical rheumatic carditisDiagnosis of rheumatic carditis traditionally depends on detectingtypical mitral murmurs and/or aortic valvular regurgitation. Two-dimensional echo-Doppler and colour flow Doppler echocardiogra-phy can detect silent, but significant, mitral and aortic regurgitation inpatients with acute RF (30 36). Echocardiographic images reveal: (i)a regurgitant jet >1 cm in length; (ii) a regurgitant jet in at least twoplanes; (iii) a mosaic colour jet with a peak velocity > m/s; and (iv)the jet persists throughout systole (mitral valve) and diastole (aorticvalve) (30, 32, 37 40).Based on the presence of very mild silent but significant valvularregurgitation, a new category of subclinical carditis , echocarditis or asymptomatic carditis has been proposed in patients with choreaand polyarthritis (30 35, 37, 41, 42). In such cases of subclinical rheu-matic carditis, annular dilatation, leaflet prolapse, and elongation ofthe anterior mitral chordae were observed, indicating that the valvemight have been sensitized or damaged (30, 33). Patients with sub-clinical valvular regurgitation may develop an audible murmur in twoweeks (31), may continue without audible murmur for 18 months tofive years (35 37), or may progress to irreversible sequelae, such asmitral stenosis (35). Although other studies do not support thesefindings (10, 43, 44), 2D echo-Doppler echocardiography detectedtrivial-to-mild mitral valvular regurgitation in 38 45% of normal/healthy children (7, 9, 10), and in even higher proportions of febrilepatients (10).These results confirm the usefulness of 2D echo-Doppler and colourflow Doppler echocardiography for diagnosing subclinical rheumaticcarditis. However, the use of echocardiography to detect left-sidevalvular regurgitation and confirm a diagnosis of subclinical rheu-matic carditis remains controversial. As such, until the results of long-term encompassing prospective studies are available to substantiatethe therapeutic and prognostic importance of subclinical rheumaticcarditis, the addition of this criterion to the Jones criteria cannot bejustified (10, 43 47). However, the acute management of such patientsand the duration of secondary prophylaxis would not changesignificantly, even if a diagnosis of subclinical carditis were made(10, 43, 44).It is also important to recognize that technical expertise with colourflow Doppler echocardiography is necessary to make an accuratediagnosis of subclinical carditis and to avoid overdiagnosis. In devel-oping countries, where the majority of RF cases occur, such expertiseand facilities are available in only a limited number of centres. As a45result, the impact of erroneous diagnoses of rheumatic carditis basedon subclinical echocardiographic findings should not be underesti-mated, nor should the potentially adverse consequences to patientsand health systems in such settings (10, 44).Conclusions: the advantages and disadvantages ofDoppler echocardiographyThere are significant advantages in using echocardiography to detectvalvulitis. Foremost, is its superior sensitivity in detecting rheumaticcarditis, which should prevent patients with carditis from beingmisclassified as noncarditic and placed on abbreviated secondary pro-phylaxis, in line with the more benign prognosis. It is reasonable toaccept that valvular regurgitation may not always be detected byroutine clinical auscultation. Even in the Irvington House reports, anumber of patients in with no audible murmurs in the first attack ofRF developed RHD on follow up (48, 49). This suggests that carditiswas missed by clinical examination, even in the golden era of clinicalauscultation. The likelihood of misclassification is higher now, sinceclinical auscultatory skills of training physicians are suboptimal, atleast in countries where RF is declining (50, 51). A second advantageof echocardiography is that it should allow the valve structure to bedetected, as well as nonrheumatic causes of valvular dysfunction ( valve prolapse, bicuspid aortic valve), and may preventpatients from being mislabeled as cases of rheumatic the other hand, there are logistical problems with the universaluse of echocardiography to detect RF, including the likelihood ofdetecting carditis in a large proportion of RF patients. This could beascribed either to the high sensitivity of Doppler echocardiographyfor diagnosing valvular regurgitation, or to the overdiagnosis ofphysiological valvular regurgitation as an organic dysfunction, orto both. Another logistical problem with universally applyingechocardiography stems from the observation that the use of echo-Doppler echocardiography resulted in a diagnosis of carditis in 90 100% of RF patients. This prevalence of carditis in RF patients issignificantly higher than that reported clinically, and the utility of atest that diagnoses a disease characteristic (such as carditis in RF) inalmost every patient with RF is , in developing countries, which bear the brunt of RF disease,it is unlikely that echocardiographic facilities will be widely available(52). Moreover, most of the RF episodes in developing countries arerecurrences in patients with established RHD, and the ability of echo-Doppler echocardiography to detect the recurrence of subclinical46carditis remains unclear, unless there is an interval change in echo-Doppler findings from a previous echocardiogram. But in manydeveloping countries, it is unreasonable to expect that previousechocardiograms or records will be available for H, Zaky A, Waldhausen JA. Use of ultrasound in the diagnosisof pericardial effusion. Annals of Internal Medicine, 1966, 65:443 JB et al. Transesophageal echocardiography: technique, anatomiccorrelations, implementation, and clinical applications. Mayo ClinicProceedings, 1988, 63:649 LL et al. Role of echocardiography in the diagnosis and follow-upevaluation of rheumatic carditis. In: Narula et al., eds. Rheumatic , DC, American Registry of Pathology, 1994:307 DJ. Directions for the use of intracardiac high-frequency ultrasoundscanning for monitoring pediatric interventional catheterization , 1990, 7:465 NG et al. Three-dimensional and four-dimensional transesophagealechocardiographic imaging of the heart and aorta in humans using acomputed tomographic imaging probe. Echocardiography, 1992, 9:677 PR, Pandey MR. Prevalence of rheumatic fever and rheumatic heartdisease in school children of Kathmandu city. Indian Heart Journal, 1997,49:518 PM. Quantitative assessment of mitral regurgitation. Journal of theAmerican College of Cardiology, 1989, 13:591 K et al. Colour Doppler evaluation of valvular regurgitation innormal subjects. Circulation, 1988, 78:840 NJ et al. Mitral valve prolapse in patients with prior rheumatic , 1988, 77:830 A, Dollberg S, Keren A. The prevalence of valvular regurgitation inchildren with structurally normal hearts: a colour Doppler echocardiographicstudy. American Heart Journal, 1992, 123:177 J, Chandrasekhar Y, Rohimtoola S. Diagnosis of acute rheumaticcarditis: the echoes of change. Circulation, 1999, 100:1576 PM. Quantitative assessment of mitral regurgitation. Journal of theAmerican College of Cardiology, 1989, 13:591 W et al. Pulsed Doppler regurgitant flow patterns of normal Journal of Cardiology, 1986, 58:309 PG, Schnittger I, Popp RL. Is continuous wave Doppler too sensitivein diagnosing pathologic valvular regurgitation? Circulation, 1984,70(II) RH et al. Functional anatomy of severe mitral regurgitation in activerheumatic carditis. American Journal of Cardiology, 1989, 63:577 MR, Wisenbaugh T, Sareli P. Evidence against a myocardial factoras the cause of left ventricular dilation in active rheumatic carditis. Journalof the American College of Cardiology, 1993, 22:826 RS et al. Echocardiographic evaluation of patients with acuterheumatic fever and rheumatic carditis. Circulation, 1996, 94:73 LY, Lu K. Inflammatory valvular prolapse produced by acuterheumatic carditis: echocardiographic analysis of 66 cases of acuterheumatic carditis. International Journal of Cardiology, 1997, 58:175 BS, Edwards JE. Congestive heart failure in rheumatic carditis:valvular or myocardial origin? Journal of the American College ofCardiology, 1993, 22:830 YN et al. Rupture of chordae tendineae in acute rheumatic carditis:report of one case. Acta Paediatrica Sinica, 1992, 33:376 F et al. Colour Doppler assessment of mitral regurgitation withorthogonal planes. Circulation, 1987, 75:175 MG et al. Quantitative assessment of mitral regurgitation by Dopplercolour flow imaging: angiographic and hemodynamic correlations. Journalof the American College of Cardiology, 1989, 13:585 YT, Chang AC, Chin AJ. Semiquantitative assessment of mitralregurgitation by Doppler colour flow imaging in patients aged <20 Journal of Cardiology, 1993, 71:727 S et al. Noninvasive estimation of left ventricular end-diastolicpressure using transthoracic Doppler-determined pulmonary venous atrialflow reversal. American Journal of Cardiology, 1994, 73:1017 American Heart Association guidelines for the diagnosis of rheumatic fever:Jones criteria, 1992 update. Journal of the American Medical Association,1992, 268:2069 HC et al. Long-term outcome of patients with rheumatic fever receivingbenzathine penicillin G prophylaxis every three weeks versus every fourweeks. Journal of Pediatrics, 1994, 125:812 HC et al. Three-versus four-week administration of benzathine penicillinG: effects on incidence of streptococcal infections and recurrences ofrheumatic fever. Pediatrics, 1996, 97:984 L et al. Validation of the proximal flow convergence of orifice area in patients with mitral stenosis. Circulation, 1993,88:1157 CL, Starling MR. Role of echocardiography in the timing ofsurgical intervention for chronic mitral and aortic regurgitation. In: Otto CM,ed. The practice of clinical echocardiography. Philadelphia, PA, WBSaunders Co., 1997:327 GM, Hajar R. Doppler echocardiographic findings of mitral and aorticvalvular regurgitation in children manifesting only rheumatic Journal of Cardiology, 1989, 63:1278 M et al. Doppler echocardiography and the early diagnosis ofacute rheumatic fever. Australian and New Zealand Journal of Medicine,1994, 24:530 NJ, Neutze JM. Echocardiographic diagnosis of subclinical carditisin acute rheumatic fever (editorial). International Journal of Cardiology,1995, 50:1 PK et al. Usefulness of echocardiography in detection ofsubclinical carditis in acute rheumatic polyarthritis and rheumatic of the Association of Physicians of India, 1998, 46:937 HB, Guzman SV. Advocacy for echocardiography in Jones criteriafor the diagnosis of rheumatic fever. In: Calleja HB, Guzman SV, fever and rheumatic heart disease. Manila, Philippine Foundationfor the Prevention and Control of Rheumatic Fever and Rheumatic HeartDisease, 2001:27 FE et al. Prospective comparison of clinical andechocardiographic diagnosis of rheumatic carditis: long term follow up ofpatients with subclinical disease. Heart, 2001, 85:407 LM et al. Intravenous immunoglobulin in acute rheumatic fever: arandomized controlled trial. Circulation, 2001, 103:401 GM et al. Occurrence of valvular heart disease in acute rheumaticfever without evident carditis: colour flow Doppler identification. British HeartJournal, 1992, 67:434 N et al. A common colour flow Doppler finding in the mitralregurgitation of acute rheumatic fever. Echocardiography, 1991, 8:627 C et al. O ecocardiograma no primeiro surto de fibre reum tica nacrianca. [The echocardiogram in the first attack of rheumatic fever inchildhood.] Revista Portuguesa do Cardiologia, [Portuguese Journal ofCardiology,] 1994, 13:581 LL et al. Doppler echocardiography distinguishes betweenphysiologic and pathologic silent mitral regurgitation in patients withrheumatic fever. Clinical Cardiology, 1997, 11:924 LG, Tani LY, Hill HR. Persistence of acute rheumatic fever in theintermountain area of the United States. Journal of Pediatrics, 1994, 124:9 MO et al. The value of echocardiography in the diagnosis and followup of rheumatic carditis in children and adolescents: a 2 years prospectivestudy. Journal of Rheumatology, 2000, 27:1082 RS et al. Echocardiographic evaluation of patients with acuterheumatic fever and rheumatic carditis. Circulation, 1996, 94:73 J, Kaplan EL. Echocardiogrphic diagnosis of rheumatic , 2001, 358(9297) AS et al. American Heart Association guidelines for the diagnosis ofrheumatic fever: Jones criteria, updated 1992. Circulation, 87(1):302 WHO/ISFC meeting on RF/RHD control with emphasis on primaryprevention. Geneva, 7 9 September 1994. Geneva, World HealthOrganization, 1994 (WHO/CVD ). P. AHA scientific statement: proceedings of the Jones CriteriaWorking Group. Circulation, 2002, 106:2521 A et al. Rheumatic fever in children and adolescents. A long-termepidemiologic study of subsequent prophylaxis, streptococcal infections,and clinical sequelae. V. Relation of the rheumatic fever recurrence rate perstreptococcal infection to preexisting clinical features of the patients. Annalsof Internal Medicine, 1964, 60(Suppl 5):58 AR et al. Rheumatic fever in children and adolescents. A long-term epidemiologic study of subsequent prophylaxis, streptococcalinfections, and clinical sequelae. VI. Clinical features of streptococcalinfection and rheumatic recurrences. Annals of Internal Medicine, 1964,60(Suppl 5):68 S et al. The teaching and practice of cardiac auscultation duringinternal medicine and cardiology training. Annals of Internal Medicine, 1993,119:47 JA. Cardiac auscultation: a cost-effective diagnostic skill. CurrentProblems in Cardiology, 1995, 20:441 M et al. Incidence of rheumatic fever and prevalence ofrheumatic heart disease in India. International Journal of Cardiology, 1994,43:221 role of the microbiology laboratory in thediagnosis of streptococcal infections andrheumatic feverGroup A streptococci commonly cause pharyngitis/tonsillitis thatneed treatment with antibiotics, and it is important that streptococcalpharyngitis be promptly diagnosed and treated to prevent rheumaticfever (RF), particularly for high-risk populations (1). The microbiol-ogy laboratory plays an important role in ensuring that the documen-tation of group A streptococcal infections is accurate. It does so byusing scientific methods both to determine whether group A strepto-cocci (Streptococcus pyogenes) are present on swabs from suspectedstreptococcal throat infections, and to measure streptococcal serumantibody titres for documenting previous infection. An adequatelaboratory system is also vital for RF prevention programmes, and thecapabilities of microbiology laboratories should extend beyond diag-nostic testing, to providing information about the disease and identi-fying the streptococcal types causing it (1, 2). The conventionalmethods and procedures for serologically identifying group A strep-tococcal infections are described elsewhere (3).Diagnosis of streptococcal infectionGroup A streptococci can be subdivided into more than 130 distincttypes, based upon a characterization of the M protein of the cell wall,opacity factors antigens produced by the organism, and by molecularsequencing of the emm gene that codes for M protein. A less-specificmethod is to determine the T-antigen pattern, but similar T antigensmay be shared by several different M types (4 7). Nevertheless, allgroup A streptococci produce hemolysis on blood agar, and have anoptimum growth temperature in the range 35 37 gold standard for detecting Streptococcus pyogenes remains athroat swab cultured on blood agar, although it takes 24 48 hours toproduce a result, with the consequent delay in starting antibiotictherapy. If possible, throat swabs should be examined for all patientswith clinically suspected streptococcal upper respiratory tract infec-tion. The correct procedure for taking a throat swab is to directlyobserve the tonsillar-pharyngeal area while vigorously swabbingthe tonsils or tonsillar crypts and the posterior pharyngeal wall (2, 4,8 10). If the swabs have to be transported to a laboratory, care shouldbe taken to avoid conditions that are suboptimal for the survival ofstreptococci, such as high temperatures and swabs that remain moistfor long periods (10). On the growth media in commercial swabs,51however, beta haemolytic streptococci can remain viable for up to 48hours (9). Cultures negative for S. pyogenes after an overnight incuba-tion should be incubated for another 24 hours. S. pyogenes can bepresumptively identified using a IU bacitracin differential disc ona purity plate (4), although erroneous results will be obtained if thebacitracin discs are placed on primary some countries a number of kits are commercially available forrapidly detecting group A streptococci on throat swabs, either in a near-patient situation or in a laboratory. Most of these tests use animmunological method to detect a carbohydrate cell-wall antigenspecific to group A streptococci in material from throat swabs, and donot require expert laboratory skills. Detecting the antigen is the mostspecific method for confirming the presence of group A streptococciand the kits have reported specificities in the range 85 100%, com-pared with blood agar cultures (8, 11). False-positive results areunusual and therapeutic decisions can be made with confidence. How-ever, different kits can vary in sensitivity from 31 95% and hence theycannot be used to replace standard blood agar cultures, particularly inpopulations at high risk for RF. In such circumstances, it is recom-mended that negative kit results should be confirmed by culturing (2,8). Neither culturing nor rapid testing can reliably distinguish be-tween an acute streptococcal infection, and a streptococcal carrier(12) with a concomitant viral infection (13). Serological examinationfor streptococcal antibodies (antistreptolysin-O, antideoxyri-bonuclease B) is not required for cases of uncomplicated streptococ-cal upper respiratory tract infection, except in specific cases ( of uncertain etiology). Rather, this method is used to estab-lish a diagnosis of a previous streptococcal infection in acute RFpatients (4, 7, 8).Laboratory tests that support a diagnosis of RFThe diagnosis of RF requires evidence of a prior streptococcal infec-tion (see Jones criteria section). If throat swabs are taken from indi-viduals suspected of acute RF there is no certainty that any isolaterecovered is the etiology agent triggering the episode of RF or if thepatient could be a streptococcal serum antibody tests should be undertaken for all sus-pected cases of acute RF (9), since these provide evidence for ante-cedent streptococcal infection and fulfil the clinical criteria for adiagnosis of RF. Although a single elevated antibody titre may beuseful for documenting a previous streptococcal infection, it is recom-mended that an additional test be performed 3 4 weeks after the52onset of RF. The most commonly performed and commercially avail-able tests are the antistreptolysin-O test, and the antideoxyri-bonclease B test (12, 14). Kits for the antihyaluronidase test are nolonger marketed, and an alternative test that uses the simultaneousdetection of several antibodies has been reported to be unreliable(15).The blood titres of antistreptolysin-O, antideoxyribonuclease B andother antibodies raised against extracellular antigens of streptococcireach a peak 3 4 weeks after the acute infection, and usually aremaintained for 2 3 months before declining (12). In most cases ofacute RF, when two antibody tests are used, elevated titres will befound in both tests. But about 20% of individuals with a first attack ofRF, and most patients with chorea alone, have low antistreptolysin-Otitres (16). At least one anti-streptococcal antibody titre should beelevated for a diagnosis of acute RF. A serum antibody is judged to beelevated if the titre exceeds the upper limit of the normal titre rangefor a community, where upper limit is defined as the titre exceeded byno more than 20% of the population. The range of normal values foreach test is variable and depends upon the age of the patient, geo-graphical locale and the season of the year (see Table ; 5, 17 19).The upper limit of normal can be determined by measuring antibodytitres in a subset of sera from individuals without a recent streptococ-cal infection and who belong to the appropriate age group. An anti-body standard, or reference serum with a known titre, should be usedas a control with each set of antibody in normal antibody titres with age and/or geographyAge groupCountryULN (test)aSubjects (N)ReferenceAdults (military)USA400 (ASO)600162 4 years120 160 (ASO)15917USA60 240 (anti-DNase)5 9 years160 240 (ASO)695320 640 (anti-DNase)10 12 years240 320 (ASO)277480 640 (anti-DNase)2 5 yearsNew Zealand141 (ASO)18120 (anti-DNase)6 10 years282 (ASO)400 (anti-DNase)26011 14 years282 (ASO)600 (anti-DNase)aASO = antistreptolysin-O test; anti-Dnase = antideoxyribonuclease B microbiological testing is used, precise guidelines and stan-dards should be followed. This applies to taking throat swabs, trans-porting swabs to the laboratory, culturing and identifying themicrobes, as well as to the procedures used for the antibody test (1, 2,8 10). It is relatively simple to maintain standards by continuing totrain laboratory staff (3), and this is achievable by most role of the microbiology laboratory in RFprevention programmesThe microbiology laboratory plays important roles in RF preventionprogrammes at several levels (20, 21). Both primary and secondaryprevention programmes require laboratory support to detect andmeasure group A streptococci, and to understand the epidemiology ofRF in the population. The epidemiology of RF, in particular, cannotbe defined using demographic detail alone: it also requires a knowl-edge of the behaviour and types of streptococci in the population. Themicrobiology laboratory also contributes to the study and control ofactual outbreaks of group A beta-haemolytic streptococci, and allowsany suspected outbreaks to be evaluated following three levels of laboratory expertise are recommended,to meet most needs for diagnostic and reference streptococcalservices: Peripheral laboratories handle immediate routine diagnostic tests,such as throat cultures, and also antibody tests. These laboratoriesshould work closely with clinicians. In certain cases, diagnostictesting may be referred to an intermediate laboratory or to anational streptococcal reference laboratory. Intermediate laboratories are more centralized and should havegreater technical skills or instrumentation than peripheral laborato-ries. They should be able to handle more specimens and carry outmore sophisticated testing. National streptococcal reference laboratories. All countries shouldbe serviced, either nationally or internationally, by such laborato-ries that can provide reference strains and expert advice on labora-tory standards and training, as well as carry out typing (molecularand traditional) of the streptococcal strains. Laboratories shouldwork closely with WHO collaborating centres for reference andresearch on streptococci (see Appendix 1) or with national refer-ence laboratory to exchange information and to discuss progress instreptococcal microbiology and epidemiology (20, 21). F et al. Prevention of rheumatic fever. Treatment of the precedingstreptococcal infection. Journal of the American Medical Association, 1950,143:151 A et al. Treatment of acute streptococcal pharyngitis and preventionof rheumatic fever: a statement for health professionals. Pediatrics, 1995,96:758 Diagnosis of group A streptococcal infections. Geneva, WorldHealth Organization, DR, Kaplan EL. A review of the correlation of T-agglutinationpatterns and M-protein typing and opacity factor production in theidentification of group A streptococci. Journal of medical microbiology 1993May;38(5):311 A, Kaplan EL. Clinical use and interpretation of group A streptococcalantibody tests: a practical approach for the pediatrician or primary carephysician. Pediatric Infectious Disease Journal, 2002, 21(5):420 EL, Wooton JT, Johnson DR. Dynamic epidemiology of group Astreptococcal serotypes. Lancet, 2002, 359(9323):2115 EL et al. Dynamic epidemiology of Group A streptococcal serotypesassociated with pharingitis. Lancet, 2001, 358:1334 AL et al. Practice guidelines for the diagnosis and management ofgroup A streptococcal pharyngitis. Infectious Diseases Society of Infectious Diseases, 2002, 35(2):113 JA. Suitability of throat culture procedures for detection of groupA streptococci and as reference standards for evaluation of streptococcalantigen detection kits. Journal of Clinical Microbiology, 1990, 28:165 JJ, Hibbard EW, Borman EK. Improved dry-swab transportation forstreptococcal specimens. Public Health Reports, 1968, 83:143 MA et al. Antigen detection test for streptococcal pharyngitis;evaluation of sensitivity with respect to true infections. Journal of Pediatrics,1986, 108:654 EM. Streptococcal antibody tests in rheumatic fever. ClinicalImmunology Newsletter, 1982, 3:107 , EL. The group A streptococcal upper respiratory tract carrier state:An enigma. Journal of Pediatrics, 1980, 97(3):337 EM, Wannamaker LW. Evaluation of the streptococcaldeoxyribonuclease B and diphosphopyridine nucleotidase antibody tests inacute rheumatic fever and acute glomerulonephritis. Pediatrics, 1962,29:527 Evaluation of the streptozyme test for strepococcal antibodies. Bulletin ofthe World Health Organization, 1986, 64 LW, Ayoub EM. Antibody titers in acute rheumatic , 1960, XXI:598 GC et al. Interpreting a single antistreptolysin O test; a comparison ofthe upper limit of normal and likelihood ratio methods. Journal of ClinicalEpidemiology, 1993, 46:1181 EL, Rothermal CD, Johnson DR. Antistreptolysin O and anti-deoxyribonuclease B titers: Normal values for children ages 2 to 12 in theUnited States. Pediatrics, 1998, 101:86 KP, Martin DR. Streptococcal involvement in childhood acuteglomerulonephritis: a review of 20 cases at admission. New ZealandMedical Journal, 1982, 95(709):373 fever and rheumatic heart disease. Report of a WHO StudyGroup. Geneva, World Health Organization, 1988 (WHO Technical ReportSeries, No. 764). WHO Programme on Streptococcal Disease Complex. Report of aconsultation, Geneva, 16 19 February, 1998. Geneva, World HealthOrganization (unpublished document EMC/ ).Appendix 1WHO collaborating centres for reference andresearch on streptococci (21) Department of Paediatric, University of Minnesota MedicalSchool, Minneapolis, Minnesota 55455, USA. Streptococcus & Diphtheria Reference Unit, Respiratory &Systemic Infection Laboratory, Central Public Health Labora-tory, London NW9 5HT, UK. Laboratoire de Bact riologie et Mycologie M dicale, InstitutSup rieur de la Sant , Minist re de la Sant , I-00144 Roma, Italy. National Institute of Public Health, Centre of Epidemiology andMicrobiology 100 42 Prague 10, Czech Republic. Department of Molecular Microbiology, Research Institute ofExperimental Science, St. Petersburg, Russian rheumatic heart diseaseIt is important to emphasize that medical management of chronicrheumatic heart disease (RHD) must defer to operative interventionwhen clinical or echocardiographic criteria are met, and when surgeryis both accessible and feasible. In many cases, the development ofheart failure, particularly when attributable to left ventricular systolicdysfunction, implies that surgery has been inappropriately stenosisThe natural history of mitral stenosis varies across geographical North America, for example, it is most commonly an indolent andslowly progressive disease, with a latency period as long as 20 40years between the initial infection and the onset of clinical symptoms(1, 2). In developing countries, on the other hand, mitral stenosisprogresses much more rapidly, perhaps because of more severe orrepeated streptococcal infections, genetic influences, or economicconditions, and may lead to symptoms in the late teens and earlytwenties (3). Survival is >80% at 10 years for untreated patients whoare asymptomatic or minimally symptomatic (New York Heart Asso-ciation (NYHA) Functional Class I/II) at time of diagnosis; 60% ofsuch patients may not experience any progression of symptoms overthis time frame (4). Once limiting symptoms (Functional Class III/IV)develop, however, survival without intervention predictably worsensand has been estimated at 0 15% over the ensuing 10 years (4, 5).Mean survival time falls to less than three years if severe pulmonaryhypertension has intervened (6). The mortality of untreated patientswith mitral stenosis is attributable to progressive heart failure in 60 70% of patients, systemic embolism in 20 30%, pulmonary embolismin 10%, and infection in 1 5% (7, 8).The development of symptoms in patients with mitral stenosis isattributable to either a critical increase in transmitral flow, or a de-crease in the diastolic filling period, either or both of which can leadto an increase in left atrial and pulmonary venous pressures and theexpression of dyspnea. The initial presentation of patients with evenmild-to-moderate mitral stenosis (mitral valve area cm2) maybe precipitated by exercise, emotional upset, fever, pregnancy, oratrial fibrillation, especially with a rapid ventricular response. Duringthe late stages of mitral stenosis, as pulmonary vascular resistancerises and cardiac output falls, fatigue or effort intolerance may playa dominant role. Alternatively, patients may adapt to thehaemodynamic impairment and inadvertently curtail their activitiesto the extent that symptoms are minimized despite progressive57disease. Severe mitral stenosis is usually defined by a mitral valve areaof cm2 (9).There is no medical therapy available to reverse the mechanical ob-struction to mitral inflow. Because the left ventricle is protected fromany volume or pressure load, there is no indication for empiricaltreatment in the asymptomatic patient with mild-to-moderate mitralstenosis and normal sinus rhythm. Symptoms of congestion can betreated with diuretics and salt restriction, though care is needed toavoid a critical fall in filling pressures, to the extent that cardiacoutput and peripheral perfusion suffer. The intermittent use of diuret-ics may suffice. Digoxin is of no proven benefit in patients withnormal sinus rhythm and preserved left ventricular systolic and rate-slowing calcium channel antagonists may beof benefit in some patients by slowing the heart response to treatment of haemoptysis must be directed at the root cause,which can vary from pulmonary edema to bronchitis; measures toreduce left atrial and pulmonary venous pressures may be appro-priate. Patients with severe stenosis or symptoms of such should beadvised against strenuous physical activities (9).Patients with mitral stenosis are particularly susceptible to the devel-opment of atrial fibrillation (AF), because of left atrial dilatation inresponse to valve obstruction, and because of the inflammatory andfibrotic changes caused by the rheumatic process (10, 11). Althoughepisodic and paroxysmal at first, AF tends to become persistent overtime. With the onset of AF, there is an abrupt loss of the atrialcontribution to ventricular filling and as much as a 30% reduction incardiac output. Under such conditions, there is the potential for asudden increase in left atrial pressure, especially with rapid ventricu-lar rates due to a critical decrease in diastolic filling times, and thepotential for a significant increase in the associated risk of throm-boembolism. AF is more common among older patients and, in somestudies, has been related to the severity of the stenosis and to the leftatrial pressure (10).Among the acquired heart valve lesions, mitral stenosis is associatedwith the highest risk of systemic thromboembolism. The incidence ofsystemic embolization, including stroke, among patients with rheu-matic mitral valve disease has been estimated at per incidence increases markedly following the onset of AF, and isconsiderably higher for patients with mitral stenosis, rather than iso-lated mitral regurgitation (12). Patients who suffer a first embolus areat increased risk for a second, particularly within the next six claims to the contrary, there are no prospective data to58support the contention that successful valvuloplasty (surgical or bal-loon) obviates the need for long-term anticoagulation therapy in pa-tients who have had an embolus (9). Observational studies havereported significant reductions in the incidence of recurrent emboliamong patients treated long-term with warfarin anticoagulation, fromrates of approximately 5% per year in untreated patients, to year in those receiving warfarin (13, 14). In addition, evidence tosupport the efficacy of anticoagulation for preventing thromboembo-lism in mitral valve disease can be extrapolated from four large,randomized prospective trials in patients with nonvalvular AF (15 18). In each of these studies, the patients who benefited most fromanticoagulant treatment were those at highest risk for embolic with mitral stenosis at highest risk for embolic events arethose with paroxysmal or persistent AF, or a history of prior , warfarin anticoagulation to an international normalizedratio (INR) of is recommended for these patients. If emboliza-tion occurs despite such treatment, an INR of and/or theaddition of low dose aspirin (75 100 mg per day) is recommended(9, 19).The management of AF must be tailored to the clinical context inwhich it occurs. In all instances, a precipitating cause (fever, anemia,thyrotoxicosis) should be identified and treated. Slowing the ventri-cular response and providing a diuretic can often restore clinicalstability. Agents useful for slowing the ventricular response includebeta-blockers, the non-dihydropyridine calcium channel antagonists(diltiazem, verapamil), and digoxin. Beta-blockers and diuretics canbe used in pregnant women with little risk to the fetus. With newonset AF of no more than 24 48 hours duration, particularly whenrapid and accompanied by symptoms, consideration should be givento direct current cardioversion (when available) to restore sinusrhythm quickly. For AF of more than 48 hours, or of uncertain dura-tion, one of two strategies is recommended, assuming anticoagulationcan be administered and monitored, and echocardiography is avail-able (9, 20, 21). The strategies are: (i) control the ventricular rate anduse warfarin anticoagulation targeted to a therapeutic INR for threeweeks, followed by direct current cardioversion; and (ii) control theventricular rate, use intravenous unfractionated heparin, trans-oesophageal echocardiography to exclude left atrial thrombus, anddirect current cardioversion if negative. If a left atrial thrombus isidentified, patients should receive at least three weeks of therapeuticwarfarin anticoagulation and undergo repeat trans-oesophagealechocardiography before cardioversion. With either of these twostrategies, warfarin anticoagulation is recommended indefinitely59thereafter (when feasible), as would also be the case for any patientwith a history of prior embolization independent of rhythm. If indefi-nite anticoagulation is not feasible, a 3 4 week post-cardioversioncourse is advised (when feasible) to decrease the incidence of embo-lization during the delayed recovery of the left atrial mechanicalfunction. Although individual exceptions do occur, the success rate ofcardioversion falls significantly as a function of left atrial size and thelength of time in AF. The empirical use of warfarin as prophylaxisagainst a first embolus in patients with moderate or severe mitralstenosis, left atrial enlargement (> cm), and sinus rhythm, is contro-versial (22).There are several anti-arrhythmic agents available for the mainte-nance of sinus rhythm in patients with frequent paroxysms of are usually given prior to a second or third cardioversion, buttheir efficacy in patients with mitral valve disease, as measured bytheir ability both to restore and maintain sinus rhythm, can be difficultto predict given the structural changes in left atrial architecture thatunderlie the AF. The choice of an individual agent, usually fromamong the Vaughan-Williams classes IA (quinidine, procainamide,disopyramide), IC (flecainide, propafenone), or III (amiodarone,sotalol), is dictated by the relative safety profile for any given patient,drug-drug interactions, and physician familiarity. These drugs are notreadily available in many areas and their electrophysiological effectscan be very difficult to monitor. Use of the class IA and class ICagents, for example, may often necessitate the concomitant use of anatrioventricular nodal blocking specialized centres, several nonpharmacological interventionshave been employed for the treatment of AF, including catheter-delivered radio-frequency ablation, dual-site atrial pacing, atrialcardioverters/defibrillators, and the surgical (Cox) maze procedure(23).The late stages of uncorrected, severe mitral stenosis may be compli-cated by the development of pulmonary hypertension, and by failureof the right side of the heart, with edema and ascites. Tricuspidregurgitation commonly co-exists and is more often secondary toright ventricular dilatation, than to primary rheumatic this stage, AF is invariably present and the risk of venous throm-boembolic disease is greatly increased. Treatment is directed at opti-mization of fluid status with diuretics and salt/fluid restriction, ratecontrol of AF, anticoagulation, and inotropic support of right ven-tricular function (if needed). Digoxin is the preferred agent to controlventricular rate; beta-blockers and rate-slowing calcium channel60antagonists have negative inotropic effects that could be deleteriousin this setting. Nutritional efforts to protect against hypoalbuminemiaand the use of graduated compression stockings are also regurgitationThe volume load of chronic mitral regurgitation can be well toleratedfor several years. Indeed, the favourable loading conditions may ob-scure the recognition of left ventricular contractile dysfunction untilrelatively late in the natural history. Symptoms and/or signs of leftventricular systolic dysfunction (defined by an ejection fraction < ,or an end-systolic dimension cm) are indications for surgery (9).The long-term results of mitral valve surgery are influenced by age,the severity of symptoms, coexistent coronary artery disease, pre-operative left ventricular function, the type of surgery (repair ), and the presence of AF (9). The onset of symptomsmay correlate with the development of AF. Compared with patientswith predominant stenosis, patients with isolated mitral regurgitationare less susceptible to thromboembolism with AF, but are more proneto infective endocarditis (10, 24).A few small-scale studies have suggested that patients with rheu-matic (fixed orifice) mitral regurgitation might actually experiencehaemodynamic worsening following exposure to vasodilators (25 27). These agents, particularly angiotensin converting enzyme inhibi-tors, are certainly indicated for the treatment of coexistent systemichypertension or established left ventricular systolic dysfunction,whether or not symptoms are present. Beta-blockers (metoprolol,bisoprolol, carvedilol) and digoxin can be used to manage chronicheart failure owing to left ventricular systolic dysfunction, as currentlyrecommended by consensus guidelines (28). Diuretics should beemployed to treat pulmonary or systemic venous congestion. A singletrial has suggested that spironolactone may provide additional benefitto NYHA Class III/IV patients, but only a minority of the studyparticipants were receiving beta-blockers and the applicability ofthese findings to patients with chronic valvular heart disease is uncer-tain (29).Atrial fibrillation is managed according to the principles enumeratedabove for mitral stenosis. In chronic, severe mitral regurgitation, theleft atrium can dilate to massive proportions ( giant left atrium),thus hindering the chances for successful restoration and maintenanceof sinus rhythm. Warfarin anticoagulation is recommended when fea-sible. Pulmonary hypertension and failure of the right side of theheart can occur, but are usually less prominent features of the naturalhistory of mitral regurgitation than they are with mitral mitral stenosis/regurgitationMany patients with rheumatic mitral valve disease have importantstenotic and regurgitant components owing to commissural fusionand the fish mouth deformity imparted by the pathological lesion may predominate, or the components may be more closelybalanced, creating a hybrid natural history. Treatment must respectthe inherent risks of AF and thromboembolism with mitral stenosis,as well as the chronic left ventricular volume overload of mitralregurgitation. The combined use of diuretics and vasodilators insymptomatic patients may prove challenging, given the more difficult-to-predict effects on filling pressures and systemic perfusion, althoughthe former agents are well tolerated in patients with pulmonary con-gestion. The indications for anticoagulation, cardioversion, or ratecontrol of AF are the same as would pertain for either lesion stenosisThe well-known natural history of aortic stenosis has long dictatedthat surgery be undertaken once symptoms appear. Indeed, survivalwithout valve replacement after the onset of angina, syncope, or heartfailure is generally measured at five, three, and two years, respectively(30). For patients with severe aortic stenosis (valve area cm2) whodevelop heart failure and who are not candidates for surgery, diuret-ics can be provided to alleviate congestion, but special care must betaken to avoid a critical fall in left ventricular preload. Once leftventricular systolic dysfunction intervenes, digoxin can be added;beta-blockers and other drugs with negative inotropic effects shouldbe avoided. Angiotensin converting enzyme inhibitors must also begiven with great care in this setting, but may on occasion be helpful incontrolling or ameliorating symptoms. AF is an uncommon complica-tion of isolated aortic stenosis, but the associated fall in cardiac outputfrom loss of atrial pump function can be quite deleterious and promptcardioversion may be necessary. Patients with heart failure and aorticstenosis with low gradient/low output should undergo referral andadditional testing to determine if the depressed left ventricular func-tion is due to severe, uncorrected aortic stenosis (afterload mismatch)or to a primary cardiomyopathy (31).Asymptomatic patients with aortic stenosis may require treatment forother, acquired cardiovascular diseases, such as hypertension andcoronary artery disease. In the presence of normal left ventricularsystolic function, standard doses of angiotensin converting enzymeinhibitors, beta-blockers, and long-acting nitrate preparationsare usually well tolerated, though caution is always advised when62instituting these medications. Low starting doses are recent studies in patients with degenerative, calcific aorticstenosis have identified smoking, hyperlipidaemia, elevated creati-nine, and hypocalcaemia as risk factors for the progression of disease(32 34). Aggressive prevention strategies would seem appropriate forpatients with rheumatic disease as well, if only to reduce the incidenceof coronary heart disease events, although specific data are activity need not be restricted in patients with mild aorticstenosis (valve area > cm2). Patients with moderate aortic stenosis(valve area cm2) should be advised to avoid strenuous activityand competitive sports. Severe aortic stenosis usually mandates areduction in physical activities to low levels (9).Aortic regurgitationPatients with chronic, severe aortic regurgitation usually enjoy a long,yet variable compensated phase characterized by an increase in leftventricular end-diastolic volume, an increase in chamber compliance,and a combination of both eccentric and concentric reserve is maintained, ejection performance remains normal,and the enormous increase in stroke volume allows preservation offorward output (9). In contrast to the haemodynamic state associatedwith mitral regurgitation, however, left ventricular afterload progres-sively increases. Aortic regurgitation thus leads both to volume andpressure overload (9, 24). Vasodilators can favorably alter these load-ing conditions and may extend the compensated phase of aortic regur-gitation prior to the development of symptoms or left ventricularsystolic dysfunction (defined as a subnormal resting ejection fraction)that would prompt valve replacement. Preoperative left ventricularfunction is the most important predictor of postoperative natural history of asymptomatic patients with normal systolicfunction has been well characterized. The rate of progression tosymptoms and/or systolic dysfunction has been estimated at less than6% per year. Thus, these patients can be safely and expectantly fol-lowed. Asymptomatic patients with left ventricular dysfunction, how-ever, develop symptoms (angina, heart failure) at a rate of >25% peryear, and symptomatic patients with severe aortic regurgitation havean expected mortality that exceeds 10% per year (9). Clinical andnoninvasive variables associated with poor outcomes include age, thecoexistence of coronary artery disease, the severity of symptoms,resting ejection fraction, end-systolic dimension, end-diastolic dimen-sion, and AF. Asymptomatic patients with normal left ventricularsystolic function should avoid isometric exercises, but can otherwisepursue all forms of physical activities including, in some instances,63competitive sports. Symptoms or left ventricular dysfunction shouldprompt a limitation of agents are recommended for the treatment of patientswith severe (3 4+/4+) aortic regurgitation under one of three circum-stances (9): (i) short-term administration in preparation for aorticvalve replacement in patients with severe heart failure symptoms, orsignificant left ventricular systolic dysfunction; (ii) long-term adminis-tration in patients with symptoms or left ventricular systolic dysfunc-tion who are not considered candidates for valve replacement surgerybecause of medical comorbidities or patient preference; (iii) long-term administration in asymptomatic patients with normal left ven-tricular systolic function to extend the compensated phase of aorticregurgitation prior to the need for valve replacement surgery. Vasodi-lator therapy is generally not recommended for asymptomaticpatients with mild-to-moderate aortic regurgitation unless systemichypertension is also present, as these patients generally do well foryears without medical intervention. The goal of long-term therapy inappropriate candidates is to reduce the systolic pressure (afterload),though it is usually difficult to achieve low-to-normal values owing tothe augmented stroke volume and preserved contractile function atthis small studies have demonstrated haemodynamically benefi-cial effects with a variety of vasodilators, including nitroprusside,hydralazine, nifedipine, enalapril and quinapril (27). These agentsgenerally reduce left ventricular volumes and regurgitant fraction,with or without a concomitant increase in ejection fraction. Onlyone study, which compared long-acting nifedipine (60 mg bid) withdigoxin in 143 patients followed for six years, has demonstrated thatvasodilator therapy can favorably influence the natural history ofasymptomatic severe aortic regurgitation (35). The use of nifedipinein this study was associated with a reduction in the need for aorticvalve surgery from 34% to 15% over six years. Whether angiotensinconverting enzyme inhibitors can provide similar long-term effectshas not been conclusively demonstrated in large numbers of , it is important to note that vasodilator therapy is not a substi-tute for surgery once symptoms and/or left ventricular systolic func-tion intervene, unless there are independent reasons not to pursueaortic valve replacement. Diuretics are recommended to relievesymptoms of pulmonary congestion (dyspnea, orthopnea). Extrapo-lating from studies of patients with dilated cardiomyopathy, digoxinand spironolactone may be of symptomatic and survival benefit whenadded to diuretics and angiotensin converting enzyme inhibitors, al-though data from prospective studies in patients with valvular heart64disease are lacking. As noted previously for patients with acute severeaortic regurgitation, beta-blockers, which can slow the heart rateand thus allow greater time for diastolic regurgitation, are contra-indicated. The loss of the atrial contribution to ventricular filling withthe onset of fibrillation, as well as a rapid ventricular rate, can resultin sudden and significant haemodynamic deterioration. Cardiover-sion is advised whenever feasible, with the same caveats regardinganticoagulation for thromboembolic prophylaxis, as reviewed aortic stenosis/regurgitationManagement of patients with mixed aortic valve disease can be quitechallenging and depends, in part, on the dominant lesion. Clinicalassessment requires integration of both physical examination andechocardiographic data. Symptoms may develop and indicationsfor surgery may be met before the traditional anatomic (valve area)and haemodynamic (ejection fraction) thresholds are nondominant lesion may exacerbate the pathophysiology im-posed by the dominant lesion. Diuretic and/or vasodilator therapiesmay alter loading conditions in favorable or unfavorable ways, thoughthe former is usually well tolerated in patients with pulmonary con-gestion. Beta-blockers should be avoided; digoxin may be of benefitonce left ventricular systolic function has declined, though its useremains largely heart diseaseIn many patients with chronic RHD both the mitral and aortic valvesmay be involved, often with mixed lesions in one or both locations. Ingeneral, management should be predicated on the identification ofthe dominant valve lesion and location, though it is recognized thatthe proximal valve lesion(s) may mask the presence and significanceof the more distal valve lesion(s). Thus, the signs of left ventricularvolume overload with aortic regurgitation may be attenuated by thepresence of significant mitral stenosis, as obstruction to left ventricu-lar inflow restricts filling. Other common combinations include mitralstenosis with tricuspid regurgitation (usually secondary to pulmonaryhypertension and right ventricular dilatation), and aortic stenosis withmitral regurgitation. Intermittent or chronic diuretic use to treatsymptoms of pulmonary or systemic venous congestion is usually welltolerated. The use of vasodilators must be individualized and dependson the dominant valve lesion, as well as on the expected contributionof the nondominant lesion(s). As is true for the individual lesions, theonset of AF is typically a signal event in the natural history ofmultivalve disease, is often a clue to the coexistence of mitral involve-65ment in patients followed for aortic disease, and mandates anticoagu-lation, cardioversion, or rate control as discussed JC, Bland EF, Sprague HB. The course of mitral stenosis withoutsurgery: ten and twenty year perspectives. Annals of Internal Medicine,1960, 52:741 JD, Feldman T. Percutaneous mitral balloon valvotomy and thenew demographics of mitral stenosis. Journal of the American MedicalAssociation, 1993, 270:1731 BC et al. Contrasting progression of mitral stenosis in Malayansversus American-born Caucasians. American Heart Journal, 1982,104 A, Cohn KE. Natural history of mitral stenosis: a review. Circulation,1972, 45:878 S et al. Influence of surgery on the natural history of rheumatic mitraland aortic valve disease. American Journal of Cardiology, 1975, 35:234 C, Hancock BW. Extreme pulmonary hypertension caused by mitralvalve disease: natural history and results of surgery. British Heart Journal,1975, 37:74 KH. The natural history of 271 patients with mitral stenosis undermedical treatment. British Heart Journal, 1962, 24:349 WC, Perloff JK. Mitral valvular disease: a clinicopathologic surveyof the conditions causing the mitral valve to function abnormally. Annals ofInternal Medicine, 1972, 77:939 RO et al. ACC/AHA guidelines for the management of patients withvalvular heart disease. Journal of the American College of Cardiologists,1998, 32:1486 AE et al. Factors associated with atrial fibrillation in patients withmitral stenosis. A cardiac catheterization study. American Heart Journal,1998, 135:138 G et al. Atrial fibrillation and atrial enlargement in patients with mitralstenosis. American Heart Journal, 1987, 114 PB et al. Incidence of stenosis embolism before and after mitralvalvotomy. Thorax, 1968, 23:530 HA, Bailey SM. Mitral valve disease, systemic embolism, andanticoagulants. Postgraduate Medical Journal, 1971, 47:599 D et al. Usefulness of anticoagulant therapy in the prevention ofembolic complications of atrial fibrillation. American Heart Journal, 1986,112:1039 P et al. Placebo controlled, randomized trial of warfarin andaspirin for prevention of thromboembolic complications in chronic atrialfibrillation. Lancet, 1989, 8631:175 Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminaryreport of the stroke prevention in atrial fibrillation study. New EnglandJournal of Medicine, 1990, 322(12):863 The Boston Area Anticoagulation Trial for Atrial Fibrillation effect of low dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. New England Journal of Medicine, 1990,323:1505 MD et al. Warfarin in the prevention of stroke associated withnonrheumatic atrial fibrillation. New England Journal of Medicine, 1992,327(20):1406 DN et al. Antithrombotic therapy in valvular heart disease. Chest,2001, 119(Suppl): 207S WJ et al. Transesophageal echocardiographically facilitated earlycardioversion from atrial fibrillation using short term anticoagulation: finalresults of a prospective year study. Journal of the American College ofCardiologists, 1995, 25:1354 AL et al. Use of transesophageal echocardiography to guidecardioversion in patients with atrial fibrillation. New England Journal ofMedicine, 2001, 344:1411 CW, Fuster V, Cheseboro HJ. Systemic thromboembolism invalvular heart disease and prosthetic heart valves. Modern Concepts inCardiovascular Disease, 1982, 51:131 V et al. ACC/AHA/ESC guidelines for the management of patientswith atrial fibrillation. Journal of the American College of Cardiologists, 2001,38 E. Valvular heart disease. In: Braunwald E, Zipes D,Libby P, eds. Heart Disease, 6th ed. New York, WB Saunders, 2001:1643 T et al. Effects of a single oral dose of captopril on leftventricular performance in severe mitral regurgitation. American Journal ofCardiology, 1992, 69:348 C, Sareli P, Weisenbaugh T. Comparison of single dosenifedipine and captopril for chronic severe mitral regurgitation. AmericanJournal of Cardiology, 1994, 73:978 H, Gaasch W. Vasoactive drugs in chronic regurgitant lesions of themitral and aortic valves. Journal of the American College of Cardiologists,1996, 28:1083 SA et al. ACC/AHA guidelines for the evaluation and management ofheart failure in the adult. Circulation, 2001, 104(24): 2998 B et al. The effect of spironolactone on morbidity and mortality inpatients with severe heart failure. New England Journal of Medicine, 1999,341:709 J Jr, Braunwald E. Aortic stenosis. Circulation, 1968, 38:61 B. Aortic stenosis. New England Journal of Medicine, 2002,346:677 CM et al. Association of aortic valve sclerosis mortality and morbidity inthe elderly. New England Journal of Medicine, 1999, 341 PT et al. A case control investigation of the relationship betweenhyperlipidemia and aortic valve stenosis. Heart, 1997, 78 BF et al. Clinical factors associated with calcific aortic valvedisease. Journal of the American College of Cardiologists, 1997, 29 R et al. Nifedipine in asymptomatic patients with severe aorticregurgitation and normal left ventricular function. New England Journal ofMedicine, 1994, 331:689 in patients with rheumatic heart diseaseThe haemodynamic changes that occur during pregnancy presenta challenge to the cardiovascular system in women with RHD andmay threaten the well-being and survival of the patient and changes can worsen prior haemodynamic alterations and thissituation poses a special therapeutic problem. The relevanthaemodynamic changes are an increasing heart rate, instability inarterial blood pressure and in systemic and pulmonary resistance,and increased cardiac output. During labour, delivery and the post-partum, these haemodynamic alterations suffer sudden and severechanges that can cause life-threatening complication in these , subclinical RHD becomes apparent for the first timeduring pregnancy (1 3).The management of RHD patients depends on the type and severityof valvular disease. To make a timely decision on the optimal treat-ment for such patients, it is mandatory that the haemodynamic statusof the patient be evaluated, and follow-up evaluations be carried include: Following general recommendations that apply to all pregnantRHD patients, including restricting physical activity and salt intake;administering appropriate secondary prophylaxis and avoiding in-tercurrent infectious diseases; monitoring haemodynamics (mainlyfor the symptomatic patients). Following the status of patients with mitral regurgitation, aorticregurgitation and mild-to-moderate mitral stenosis (NYHA Func-tional classification Class I and II) and giving medical care as nec-essary. Patients can be supported with diuretics, digoxin and others,as needed. Angiotensin-converting enzyme inhibitors should not beused during pregnancy. Giving special attention to patients with: moderate-to-severe RHD(NYHA Class III and IV, symptomatic heart failure, left ventricu-lar dysfunction, or pulmonary hypertension); mainly mitral steno-sis; aortic stenosis; plurivalvular disease and AF; prosthetic heart68valves; and to those under anticoagulant therapy. These patientsare at high risk of life-threatening complications during pregnancyand delivery, and in most cases physicians should advise that preg-nancy be avoided. However, given the advances in cardiovasculardiagnostic and therapeutic techniques, including percutaneous bal-loon mitral valvotomy and surgical commissurotomy performedduring pregnancy, pregnancy could be allowed if the appropriatefacilities are available (1 9). Warfarin is contraindicated during pregnancy because of teratoge-nic effects on the E. Pregnancy in patients with rheumatic cardiopathy. ArchivosCardiologia de Mexico, [Mexican Archives of Cardiology,] 2001, 71:S160 HB, Guzman SV. Pregnancy and rheumatic valvular heart disease. In:Calleja HB, Guzman SV, eds. Rheumatic fever and rheumatic heart disease:epidemiology, clinical aspects, management and prevention, 1st ed. PasigCity, Philippines, Medicomm Pacific Inc., 2001:323 E. Heart disease. A textbook of cardiovascular medicine, 4th , USA, WB Saunders Company, 1992:1796 SC, Colman JM. Heart disease and pregnancy. Heart, 2001, 85:710 PJ et al. Prognostic factors of rheumatic mitral stenosis duringpregnancy and puerperium. Arqivos Brasileiros de Cardiologia, [BrazilianArchives of Cardiology,] 2000, 75(3):215 J, Lin Q, Hong S. Retrospective analysis of 266 cases of pregnancycomplicated by heart disease. Zhonghua Fu Chan Ke Za Zhi, 2000,35(6):338 Andrade J et al. The role of mitral valve balloon valvuloplasty in thetreatment of rheumatic mitral valve stenosis during pregnancy. RevistaEspa ola de Cardiologia, [Spanish Journal of Cardiology,] 2001, 54(5):573 L et al. Pregnancy outcomes and cardiac complications in womenwith mechanical, bioprosthetic and homograft valves. British Journal ofObstetrics and Gynaecology, 2000, 107(2):245 A et al. Balloon mitral valvotomy in pregnancy: maternal and fetaloutcomes. Journal of the American College of Surgeons, 1998, 187(4):409 management of rheumatic feverGeneral measuresHospital admission may be helpful for confirming a diagnosis of rheu-matic fever (RF), for instituting treatment and for educating thepatients and family. Initial tests should include a throat culture (or insome circunstances rapid streptococcal detection test), a measure-ment of streptococcal antibody titres (eg ASO or anti DNase B), anassessment of acute-phase reactants (eg ESR or CRP), a chest X-ray,an electrocardiogram, and an echocardiogram (if facilities are avail-able). A blood culture may help to exclude infective endocarditis (1).All patients with acute RF should be placed on bed chair rest andmonitored closely for the onset of carditis. In patients with carditis, arest period of at least four weeks is recommended (2), althoughphysicians should make this decision on an individual basis. Ambula-tory restrictions may be relaxed when there is no carditis and whenarthritis has subsided (1). Patients with chorea must be placed in aprotective environment so they do not injure therapyEradication of the pharyngeal streptococcal infection is mandatoryto avoid chronic repetitive exposure to streptococcal antigens (2).Ideally, two throat cultures should be performed before starting anti-biotics. However, antibiotic therapy is warranted even if the throatcultures are negative. Antibiotic therapy does not alter the course,frequency and severity of cardiac involvement (3). The eradication ofpharyngeal streptococci should be followed by long-term secondaryprophylaxis to guard against recurrent pharyngeal of the inflammatory processIt is advisable to avoid premature administration of salicylates orcorticosteroids until the diagnosis of RF is confirmed. Aspirin,100 mg/kg-day divided into 4 5 doses, is the first line of therapy and isgenerally adequate for achieving a clinical response. In children, thedose may be increased to 125 mg/kg-day, and to 6 8 g/day in adults(4). The optimal aspirin dose should ensure an adequate response butavoid toxicity. If symptoms of toxicity are present, they may subsideafter a few days despite continuation of the medication, but salicylateblood levels could be monitored if facilities are available (4, 5). Afterachieving the desired initial steady-state concentration for two weeks,the dosage can be decreased to 60 70 mg/kg-day for an additional703 6 weeks (2, 4, 5). No controlled trials comparing aspirin and nonste-roidal anti-inflammatory agents have been conducted. However, inpatients who are intolerant or allergic to aspirin, naproxen (10 20 mg/kg-day) has been used (6). One of the most common errors made byphysicians is the early administration of anti-inflammatory therapybefore the diagnosis has been finally a recent meta-analysis of salicylates and steroids, no differenceswere observed in the long-term outcomes of these treatments fordecreasing the frequency of late rheumatic valvular disease (7). How-ever, since one large study in the meta-analysis favoured the use ofsteroids, it remains unclear whether one treatment is superior to theother. Patients with pericarditis or heart failure respond favorably tocorticosteroids; corticosteroids are also advisable in patients who donot respond to salicylates and who continue to worsen and developheart failure despite anti-inflammatory therapy (1). Prednisone (1 2 mg/kg-day, to a maximum of 80 mg/day given once daily, or individed doses) is usually the drug of choice. In life-threatening cir-cumstances, therapy may be initiated with intravenous methyl pred-nisolone (8). After 2 3 weeks of therapy the dosage may be decreasedby 20 25% each week (2, 5). While reducing the steroid dosage, aperiod of overlap with aspirin is recommended to prevent rebound ofdisease activity (1, 9).Since there is no evidence that aspirin or corticosteroid therapy af-fects the course of carditis or reduces the incidence of subsequentheart disease, the duration of anti-inflammatory therapy is basedupon the clinical response to therapy and normalization of acutephase reactants (1, 4, 5). Five per cent of patients continue to demon-strate evidence of rheumatic activity for six months or more, and mayrequire a longer course of anti-inflammatory treatment (4). Infre-quently, laboratory and clinical evidence of a rebound in diseaseactivity may be noticed 2 3 weeks after stopping anti-inflammatorytherapy (4). This usually resolves spontaneously and only severesymptoms require reinstitution of therapy (4).Management of heart failureHeart failure in RF generally responds to bed rest and steroids, but inpatients with severe symptoms, diuretics, angiotensin converting en-zyme inhibitors, and digoxin may be used (4, 5, 10). Initially, patientsshould follow a restricted sodium diet and diuretics should be admin-istered. Angiotensin converting enzyme inhibitors and/or digoxinmay be introduced if these measures are not effective, particularly inpatients with advanced rheumatic valvular heart disease (4). No data71exist on the use of angiotensin converting enzyme inhibitors to treatcardiac failure in children with RF. Their benefit has been extrapo-lated from trials in adults with congestive heart failure due to multipleetiologies (10).Management of choreaChorea has traditionally been considered to be a self-limiting benigndisease, requiring no therapy. However, there are recent reports thata protracted course can lead to disability and/or social isolation (11).The signs and symptoms of chorea generally do not respond well toanti-inflammatory agents. Neuroleptics, benzodiazepines and anti-epileptics are indicated, in combination with supportive measuressuch as rest in a quiet room. Haloperidol, diazepam, carbamazepinehave all been reported to be effective in the treatment of chorea (12 14). There is no convincing evidence in the literature that steroids arebeneficial for the therapy of the chorea associated with Rheumatic fever and rheumatic heart disease. Report of a WHO ExpertCommittee. Geneva, World Health Organization, 1988 (WHO TechnicalReport Series, No. 764). NA, Pereira BA. Acute rheumatic fever: still a challenge. RheumaticDisease Clinic of North America, 1997, 23(3):545 DG, Boxerbaum B, Liebman J. Long-term prognosis of RFpatients receiving regular intramuscular benzathine penicillin. Circulation,1972, 45:543 D, Turi ZG. Current guidelines for the treatment of patients withrheumatic fever. Drugs, 1999, 57(4):545 AS. Rheumatic fever. In: Braunwald E, Zipes DP, Libby P, eds. HeartDisease, 6th edition, 2001:2192 Y et al. The use of naproxen in the treatment of children withrheumatic fever. Journal of Pediatrics, 2000, 137:269 A et al. The treatment of rheumatic carditis: a review and meta-analyis. Medicine, 1995, 74(1):1 GV et al. Pulse therapy (high dose of venous methylprednisolone) inchildren with rheumatic carditis. Prospective study of 40 episodes. ArquivosBrasileiros de Cardiologia, 1993, 60(6):377 AR, Spagnuolo M, Gill FA. Rebound phenomenon in acuterheumatic fever. I. Incidence and significance. Yale Journal of BiologicalMedicine, 1961, 33:259 RO, Carabello B, de Leon AC Jr. ACC/AHA guidelines for themanagement of patients with valvular heart disease. Journal of the AmericanCollege of Cardiology, 1998, 32:1486 SE et al. Sydenham s chorea: physical and psychological symptomsof St Vitus dance. Pediatrics, 1993, 91:706 M et al. Effectiveness of haloperidol in the treatment of choreaminor. Brain Development, 1995, 27:191 HL et al. Successful treatment of rheumatic chorea withcarbamazepine. Pediatric Neurology, 2000, 23(2):147 MV et al. The use of haloperidol and valproate in children withSydenham chorea. Indian Pediatrics, 1998, 35(12):1215 for rheumatic heart diseaseSurgery is usually performed for chronic rheumatic valve disease. It israrely required during acute rheumatic fever (RF). In general terms,the necessity for surgical treatment is determined by the severity ofthe patient s symptoms and/or evidence that cardiac function is sig-nificantly impaired. It is particularly important to prevent irreversibledamage to the left ventricle and irreversible pulmonary hypertension,since both considerably increase the risk of surgical treatment, impairlong-term results and render surgery for surgery in chronic valve diseaseEchocardiography is essential for an assessment and follow-up ofvalvular disease. If echocardiography is not available, a diagnosis ofvalvular disease must rely on careful clinical examination supple-mented by an electrocardiogram (ECG) and chest X-ray before thepatient is referred to a cardiac surgical centre. Referrals for furtherassessment should be considered under the following circumstances(1, 2): Symptoms have progressed beyond New York Heart Association(NYHA) Class II. Note: with aortic stenosis (AS), all symptomaticpatients should be referred. Patients who are asymptomatic, or mildly symptomatic, with pro-gressive left ventricular enlargement on clinical or radiological ex-amination (> cm/year). Cardiac failure due to the valve lesion itself, rather than to anepisode of rheumatic carditis. Pulmonary hypertension, with physical signs and ECG evidence ofchanges in right ventricular hypertrophy, and chest X-ray evidenceof pulmonary artery dilatation. Tricuspid regurgitation that complicates mitral valve disease. Development of atrial fibrillation. Thromboembolism. Endocarditis is suspected to contribute to cardiac facilities for echocardiography are available, regular assess-ments (at least once per year) should be undertaken. The followingechocardiographic criteria should also be considered as indicationsfor further assessment at a surgical centre, regardless of the patient ssymptoms (1, 2):74Mitral stenosis (MS) Mitral valve area < cm2 or valve area index < cm2/m2. The occurrence of dense, spontaneous echo contrast in the leftatrium, because of the increased risk of thromboembolism. The presence of thrombus in the left atrial appendage or body ofthe left atrium. Pulmonary hypertension?Mitral regurgitation (MR) Severe regurgitation on colour flow imaging. Left ventricular ejection fraction <50%. Left ventricular end-systolic dimension >55 mm. Pulmonary stenosis (AS) Valve area < cm2 or valve area index < cm2/m2. Maximum jet velocity > m/sec. Left ventricular ejection fraction <50%.Aortic regurgitation (AR) Severe regurgitation. Left ventricular ejection fraction <50%. Left ventricular end-systolic dimension >55 patients with mitral and aortic valve disease, the threshold forreferring symptomatic patients should be lower than each individuallesion would results of surgical treatment depend on: the severity of thedisease process at the time of surgery; left ventricular function;nutritional status; and on long-term post-operative management, par-ticularly anticoagulation management. Advanced NYHA functionalclass, impaired left ventricular function, atrial fibrillation, diabetesand other co-morbidities all have an adverse effect on hospital mor-tality rates and long-term survival rates (3). Operative mortality forelective, first-time single valve repair or replacement without anyconcomitant procedure is in the range of 2 5%. Further incrementalincreases in risk occur with emergency operations, re-operations, con-comitant procedures such as coronary surgery, and operations forendocarditis (3, 4).The indications for surgical treatment are as follows (1): In the presence of MS, patients with moderate or severe MS (mitralvalve area cm2) and NYHA class II/IV In the presence of MR, patients with NYHA functional class symp-toms II/III/IV with: normal left ventricular (LV) function (ejection fraction >60%and end-systolic dimension <45 mm); mild dysfunction (ejection fraction 50 60% and end-systolicdimension 45 50 mm); moderate dysfunction (ejection fraction 30 50% and end-systolic dimension 50 55 mm); severe LV dysfunction and chordal preservation, or normal LVfunction and pulmonary hypertension. In the presence of AS, symptomatic patients with severe AS or inthe presence of LV dysfunction, ventricular tachycardia, >15 mmLV hypertrophy, valve area < cm2. In the presence of AR, with NYHA functional class symptoms II/III/IV with: NYHA functional class III/IV and preserved LV function(ejection fraction >50%); preserved LV function (ejection fraction >50%), but LVdilation or declining ejection fraction at rest or at functionalstudies; mild dysfunction (ejection fraction 50 60% and end-systolicdimension 45 50 mm); moderate dysfunction (ejection fraction 30 50% and end-systolic dimension 50 55 mm).Contra-indications to surgeryThere are few absolute contra-indications to valve surgery. Mostare relative contra-indications and involve a risk/benefit contra-indications include manifestations of end-stage valvedisease, such as very poor LV function in association with a regur-gitant lesion, severe fixed pulmonary hypertension or extensive extra-annular tissue destruction due to uncontrolled endocarditis. Poor LVfunction in association with isolated severe AS is rarely a contra-indication, as considerable improvement can be expected followingrelief of the obstruction. Judgment is often more difficult when severeAS coexists with extensive coronary disease and the cause of the LVdysfunction is age of the patient and the presence of co-morbidities also affectrisk/benefit calculations. Young patients often have a remarkablecapacity for recovery, even from end-stage valve disease. Conversely,adverse risk factors have a much more pronounced effect in olderpatients. Co-morbidities that require consideration include:76 renal failure (particularly if local facilities for haemofiltration orhaemodialysis are scarce); advanced pulmonary disease; severe haemolytic anaemia which can not be controlled medically; severe generalized arteriopathy; malignant diseases; extreme overweight (leading to pulmonary complications); serious infections until they can be nutritional status improves post-operative chances of survival,while severe cachexia due to cardiac or other causes greatly reducesthe chances of optionsBalloon valvotomy (commissurotomy)This technique is reserved almost entirely for stenosis of the mitralvalve. Overall, the incidence of re-stenosis is reported to be about40% after seven years (5), although this may vary according to thepopulation studied (6). In some cases, it is feasible to repeat theprocedure if re-stenosis is confined to commissural fusion only. In lowresource settings, the cost of the procedure means it is not an treatmentSurgical procedures performed include closed mitral commissuro-tomy, valve repair and valve replacement. Valve repair techniquesand valve replacement require open-heart surgery using cardiopul-monary bypass. Valve repair to prevent progression of rheumaticvalvular disease is not indicated (7). Also, although a bioprostheticvalve may be appealing for young women who wish to become preg-nant, it may deteriorate more rapidly during pregnancy, particularlywith multiple pregnancies (8, 9). In many developing countries, theuse of biological and bioprosthetic valves has almost been abandoned,and mechanical valves represent the best compromise for young andmiddle-aged patients with rheumatic valve disease, despite the needfor long-term anticoagulation treatment (10). In fact, the risk ofthromboembolism in young active patients in sinus rhythm with goodLV function is much lower than that of the typical older middle-agedand elderly valve patients with associated risk factors such as diabe-tes, hypertension and arterial disease (11, 12). It is important that theleast thrombogenic prostheses be implanted, since it can be difficult tomanage long-term anticoaugulation therapy in low-resource general, mechanical valves with a bileaflet design seem more proneto valve thrombosis if anticoagulation is not used, or if the treatment77is suboptimal, compared to valves with a modern tilting disc design(11 13).Long-term complicationsLong-term complications of valve replacement include (13): structural valve deterioration (this is only a concern for biologicaland bioprosthetic valves and the deterioration is time-dependent); valve thrombosis ( per year); thromboembolism (2 5% per year); prosthetic endocarditis ( per year); major bleeding (conventionally attributed to anticoagulation),1 4% per year; paravalvular leak ( per year).Many of these complications, particularly valve thrombosis, throm-boembolism, endocarditis and bleeding, are related more to patientand management factors than to the prosthesis itself. The need toreplace prosthetic valves tends to be higher in developing countriesbecause of difficulties in post-operative management, and becauseprosthetic valves need to be replaced in growing postoperative managementAll patients who have undergone intervention treatment for rheu-matic valve disease will require regular long-term follow-up (1). Ide-ally, this should be done in a centre equipped with who have had conservative valve procedures, such as valvo-tomy or valve repair, require close observation to detect re-stenosis ora recurrence of valve regurgitation, and to ensure secondary prophy-laxis. It is also important to monitor LV function and echocardiography is not available, patients should be referred backto the surgical centre if they develop any of the following: recurrent symptoms evidence of cardiac failure muffled prosthetic heart sounds a new regurgitant murmur any thromboembolic episode symptoms and signs suggestive of of the above conditions may indicate a complication related tothe prosthesis, and all require further investigation (14). If only onevalve has been repaired or replaced, progression of valve disease atanother site may also be a cause of patient patients with mechanical valves, anticoagulation control is themost important, independent determinant of long-term survival(14, 15), and is perhaps the most important aspect of post-operativemanagement. Good anticoagulation management has three principalcomponents (16):1. Standardized anticoagulation measurement, using the Interna-tional Normalised Ratio (INR).2. Prosthesis-specific and patient-specific anticoagulation general terms, a patient with a low-thrombogenicity prosthesisin the aortic position, who is in sinus rhythm and has good LVfunction can be managed with an INR in the range ,whereas a patient with a low-thrombogenicity prosthesis in themitral position, or who is in atrial fibrillation, or has impaired LVfunction, will need a higher INR (in the range ). Patientswith more-thrombogenic prostheses may require an INR in therange However, it must emphasized that ideal INR rangeshave yet to be determined for all currently available Regular monitoring of the INR and maintaining it within thetherapeutic range. In developing countries, small portable devicesfor monitoring INR may have a role in remote communities, wherean experienced health worker can monitor the INR of many pa-tients within a particular community (17).Long-term management also involves regular penicillin prophylaxisin high-risk patients, to prevent further episodes of RF (18). En-docarditis prophylaxis is also necessary to cover any dental or surgicalprocedure. It is essential that patients and their relatives are fullyinformed about the importance of endocarditis prophylaxis, as manystudies report a mortality rate from prosthetic endocarditis of >50%(19). Refer to Chapter 11, Infective endocarditis, for a discussion ofendocarditis role of surgery in active rheumatic carditisTraditional belief has discouraged the surgical option in acute RF,given the profound inflammatory state. An earlier study series (20)showed that repair or replacement surgery was possible in mitralvalve disease (stenotic or regurgitant), albeit with a high rate of in-hospital mortality. Of 304 instances of mitral valve replacement orrepair in patients with mitral valve disease of rheumatic etiology, thetotal hospital mortality rate was , but was as high as ifvalve replacement was performed after a failed attempt at repair. Ofthe 26 reoperations, 24 needed the second procedure owing to mitral79valve dysfunction, and 8 of 24 patients had active rheumatic actuarial total survival at 30 months was 72% for valve replace-ment and 94% for valve repair. The authors stressed the need forbetter preoperative identification of valvular lesions, using techniquessuch as echocardiography (21) to prevent unsuccessful attempts atvalvular repair. Details of the rheumatic carditis patients were notavailable from this study, and other studies reporting less-favorableoutcomes are only , after the series published by Essop and co-workers (22),there was a change in how the surgical option was viewed. In theseries, 32 patients with medically refractory acute carditis and conges-tive heart failure (CHF) underwent mitral or mitral and aortic valvereplacement. There was no operative mortality and there was a sig-nificant decrease in the heart size and resolution of heart contractile function was preserved, and there was nomortality or decline in ventricular function during the follow-up pe-riod. This study established that surgery was a preferred option overthe long-term use of high-dose corticosteroids for severe refractoryacute carditis, and also disproved that a myocardial factor played arole in the pathogenesis of acute RF. Since contractility parameterswere preserved and returned to the normal range after the valvularlesion was corrected (even in the most severe cases), this discountedany notion of a significant myocardial component to the clinicalpicture. This was also borne out by echocardiographic studies thatevaluated ventricular mechanics during acute RF, and which foundthat cardiac function remained stable throughout the course of thedisease, despite the presence of CHF (23). Endomyocardial biopsiesperformed during the acute phase of the disease failed to demonstrateevidence of myocardial damage, and inflammatory activity was con-fined to the interstitial compartment only (24). The resolution of CHFafter valvular surgery also suggested that the pathophysiologicalderangement seen in acute RF was caused by valvular regurgitationsecondary to a subsequent study, 254 patients (aged 6 52 years) with pure rheu-matic regurgitant lesion and CHF (96% in NYHA class III or IV)were enrolled in a study to examine the efficacy of repairing the mitralvalve surgically (25). Of the 254 patients, 76 showed acute rheumaticactivity. The patients were followed for 60 35 months after acute mortality rate for the patients was and the five-yearmortality rate was 15%. There was a high incidence of valve failure,which necessitated reoperation (27%). The presence of acute carditiscorrelated with reoperations, and patients undergoing early reoperations were more likely to have rheumatic activity (47%)80compared to those with late reoperations. The mean event freesurvival at five years was 73%. Thus, surgical valve repair duringactive carditis was associated with an acceptable survival rate, butreoperations were the available studies, the following observations can bemade(20 25): Surgery can be safely performed during active carditis and, in re-fractory cases of active carditis, may be preferable to the long-termuse of corticosteroids. Myocardial inflammation plays no significant role in the clinicalpathology of active carditis. Valve repair during active carditis may not constitute the bestsurgical option if there is macroscopic evidence of valvularinflammation, because valve repair is associated with significantreoperation RO et al. ACC/AHA guidelines for the management of patients withvalvular heart disease. Journal of the American College of Cardiology, 1998,32:1486 WRE et al. Risk stratification for cardiac valve Cardiac Surgery Database. Annals of Thoracic Surgery, 1999,67:943 D et al. Long-term relative survival rates after heart valvereplacement. Journal of the American College of Cardiology, 1990, 15:566 B et al. Surgery for rheumatic mitral regurgitation below twentyyears of age. An analysis of failures. Journal of Heart Valve Disease, 1996,5:294 Ben F et al. Percutaneous balloon versus surgical closed andopen mitral commissurotomy: seven year follow-up results of a randomizedtrail. Circulation, 1998, 971:245 TM et al. Mitral valve repair and replacement for rheumatic of Thoracic and Cardiovascular Surgery, 2000, 119:53 E, Oakley CM. Outcome of pregnancy in women with valveprostheses. British Heart Journal, 1994, 71:196 RA et al. Long-term survival and valve-related complications inyoung women with cardiac valve replacement. Circulation, 1999,99:2669 K et al. Outcomes 15 years after valve replacement with amechanical versus a bioprosthetic valve: final report of the Veteran Affairsrandomised trial. Journal of the American College of Cardiology, 2000,36:1152 EG et al. The role of risk factors and trigger factors incerebrovascular events after mitral valve replacement. Journal of CardiacSurgery, 1994, 9(Suppl.):228 EG. Prosthetic heart valves. In: Cardiovascular thrombosis, 2nd M, Fuster V, Topol EJ, eds. Philadelphia, Lippincott-Raven,1998:399 EG et al. Arterial risk factors and cerebrovascular events followingaortic valve replacement. Journal of Heart Valve Disease, 1995, 4:1 GL et al. Long-term performance of prosthetic heart Problems in Cardiology, 2000, 25:73 EG et al. Better anticoagulation control improves survival aftervalve replacement. Journal of Thoracic and Cardiovascular Surgery. (Inpress). rwolf C et al. Guidelines for prevention of thromboembolic eventsin valvular heart disease. Study Group of the Working Group on ValvularHeart Disease of the European Society of Cardiology. European HeartJournal, 1995, 16:1320 U, M ller-Berghaus G. State-of-the-art patient self-management forcontrol of oral anticoagulation. Seminars in Thrombosis and Hemostatics,1999, 25:43 AS et al. Prevention of bacterial endocarditis: recommendations ofthe American Heart Association. Circulation, 1997, 96:358 AS et al. Diagnosis and management of infective endocarditis and itscomplications. Circulation, 1998, 98:2936 MR et al. Surgical treatment of endocarditis. Progress inCardiovascular Disease, 1997, 40:239 CM, Gometza B, de Vol EB. Valve repair in rheumatic mitral , 1991, 84(5 Suppl.):III125 RS et al. Echocardiographic evaluation of patients with acuterheumatic fever and rheumatic carditis. Circulation, 1996, 94(1):73 MR, Wisenbaugh T, Sareli P. Evidence against a myocardial factoras the cause of left ventricular dilation in active rheumatic carditis. Journalof the American College of Cardiology, 1993, 22(3):826 TL et al. Left ventricular mechanics during and after acuterheumatic fever: contractile dysfunction is closely related to valveregurgitation. Journal of the American College of Cardiology, 2001,37(1):201 J et al. Does endomyocardial biopsy aid in the diagnosis of activerheumatic carditis. Circulation, 1993, 88(5 Pt. 1):2198 J et al. Evaluation of the long-term results of mitral valve repairin 254 young patients with rheumatic mitral regurgitation. Circulation, 1994,90(5 Pt 2):II167 prevention of rheumatic feverThe primary prevention of rheumatic fever (RF) is defined as theadequate antibiotic therapy of group A streptococcal upper respira-tory tract (URT) infections to prevent an initial attack of acute RF (1 9). Primary prevention is administered only when there is group Astreptococcal URT infection. The therapy is therefore intermittent, incontrast to the therapy used for the secondary prevention of RF,where antibiotics are administered continuously (see table ).Epidemiology of group A streptococcal upper respiratorytract infectionGroup A streptococcal infection is endemic throughout the world, butsporadic epidemics are common, particularly among schoolchildren,in residential facilities for the elderly, and in other unique populationssuch as military personnel. Although group A streptococcal coloniza-tion and infection of the URT is common and can occur in people ofany age, streptococcal pharyngitis/tonsillitis primarily affects childrenbetween the ages of 5 15 years. It is thought that natural immunitycan be conferred by the surface M-protein of specific group A strep-tococci (M-types), but since more than 130 different M-proteins havebeen described, it is common for individuals throughout their lifetimeto have multiple infections by different M-type A streptococcal URT infections can lead to RF and acute post-streptococcal glomerulonephritis. In contrast, although some haveproposed otherwise, group A streptococcal skin infections do notappear to predispose to acute RF, but can lead to of group A streptococcal pharyngitisTo treat patients effectively and prevent suppurative and non-suppurative sequelae, it is important that group A streptococcal phar-yngitis be diagnosed promptly and accurately. An accurate andprompt diagnosis will not only help to control the spread of infection,it will also minimize the inappropriate use of antibiotics. The inappro-priate use of antibiotics is a consideration because most cases ofpharyngitis are caused by viruses, and of the many bacterial patho-gens that cause pharyngitis (Table ), antibiotic therapy is onlyrecommended for group A streptococcal infection (with rare excep-tions). Indeed, cases of group A streptococcal pharingytis representonly 20% of all pharyngitis cases (9).It is often difficult to diagnose streptococcal URT infection, even forexperienced clinicians, despite the fact that the clinical symptoms83associated with such an infection occur frequently. The complex ofsymptoms include a sudden onset of high fever, very sore throat withdysphagia, a scarlatiniform rash and abdominal pain. Numerous at-tempts have been made to devise algorithms to make the clinicaldiagnosis easier (especially in areas where a microbiology laboratoryis not available), but in general these algorithms lack accuracy and arenot universally helpful. Part of the difficulty in devising an algorithmderives from the fact most common clinical findings associated withgroup A streptococcal URT infection can differ by age of the of the most frequently observed clinical findings, signs andsymptoms are shown for different age groups in Table single element of history taking or physical examination is accu-rate enough to exclude or diagnose streptococcal throat factors such as age younger than 15 years, history of fever,tonsillar swelling or exudate, tender anterior cervical lymphadenopa-thy and absence of cough should all be taken into consideration inarriving at a diagnosis. If four or five of the factors are present, thelikelihood ratio of streptococcal infection is (approximately 50%of cases); if 3 factors are present the ratio decreases to (approxi-mately 25%); and if only 2 are present, to (approximately 10%)(12).Laboratory diagnosisSince the clinical diagnosis of acute streptococcal pharyngitis is oftenimprecise, laboratory confirmation is needed, although in many partsof the world clinical laboratory facilities are not available (7, 8, 11,12). A major function of a clinical laboratory in the diagnosis andmanagement of group A streptococcal URT infections are to culturethroat samples and, when available, to perform rapid antigen detec-tion tests. The throat culture is optimal for confirming whether thereare group A streptococci in the URT of patients with acute pharyngi-tis. If carried out properly, the sensitivity and specificity of this assayTable most common bacterial causes of pharyngitisaOrganismIllnessStreptococcus pyogenes (Group A)Pharyngitis and tonsillitisStreptococcus pyogenes (Group C or G)Pharyngitis and tonsillitisNeisseria gonorrheaePharyngitisCorynebacterium diphtheriaDiphtheriaArcanobacterium hemolyticumPharyngitisaModified from (10).84are excellent (see Chapter 5, The role of the microbiology laboratoryin the diagnosis of streptococcal infections and rheumatic fever). Rapidantigen detection tests are available in some parts of the world, andalmost exclusively use antibodies directed against the group A carbo-hydrate of the streptococcal cell wall. The specificity of the immu-noassays most often exceeds their sensitivity. In general, they aremore expensive than blood agar plates, and like culture plates theyneed refrigeration, which can be a problem in some parts of the world,especially those with tropical A streptococcal antibodies to extracellular antigens such asstreptolysin-O (antistreptolysin-O) or deoxyribonuclease B (anti-DNase B) have little or no use in diagnosing acute group A strepto-coccal pharyngitis or tonsillitis, since they can be accuratelyinterpreted only in retrospect. This should not detract from theirimportance in assisting with the diagnosis of acute RF, however,which requires evidence of a preceding group A streptococcal infec-Table signs and symptoms of group A streptococcal upper respiratory tractinfection, by patient age groupaClinical signs and/orInfantsSchool-ageAdolescentssympto mschildrenand adultsAnterior cervical++++b++++++++lymphadenitis(tende r nodes)Close contact with++++++++++++an infected personScarlatiniform rashUnusual++++++++Excoriated nares++++UnusualUnusualTonsillar or pharyngealUncommon in infants++++++++exudateyounger than threeyears of agePositive throat culture++++++++++++Fever++ (Not specific)++ (Not specific)++ (Not specific)Acute onset of+ (Unusual)++ (Not specific)++ (Not specific)symptomsAbdominal pain+++++ (Unusual)Coryza++UnusualUnusualErythema of theNot specificNot specificNot specificpharynxHoarsenessUnusualUnusualU nusualCoughUnusualUnusualUnusualaModifie d from (11).bThe symptoms are classified semiquantitatively as being: less typical (+); more typical andfrequent/moderately suggestive (++); and almost always present in patients with streptococcalpharyngitis/very suggestive (++++).85tion (see the Jones Criteria in Chapter 3, Diagnosis of rheumaticfever). If laboratory facilities are not available, a diagnosis of strepto-coccal pharyngitis has to be made on the basis of clinical findings (7,8, 11 13).Antibiotic therapy of group A streptococcal pharyngitisEffective antibiotic therapy eradicates group A streptococci from theURT and can prevent RF if therapy is started within nine days afterthe onset of symptoms (1, 3, 9, 13). Table shows the most com-monly used antibiotics to treat group A streptococcal URT date, no clinical isolate of group A beta-hemolytic streptococcus(Streptococcus pyogenes) has been shown to be resistant to this reason, and because penicillin is inexpensive and available inmost countries, it remains the drug of choice for treating group Astreptococcal URT infections (14 24). To eradicate a group A strep-tococcal infection, oral penicillin (penicillin V or penicillin G) shouldbe given for a full 10 days (25 29). A single intramuscular injection ofbenzathine benzylpenicillin can be used to treat the infection if it isanticipated that the patient will not adhere to a treatment regimen oforal antibiotics. First-generation cephalosporins have also been usedsuccessfully. In contrast, tetracyclines and sulfa drugs are contraindi-cated for the primary prevention of RF because many group A strep-tococci are patients with allergies to penicillin, the macrolide erythromycinhas been the recommended antibiotic of choice for many years. How-ever, in the 1960s and 1970s, the prevalence of macrolide-resistantgroup A streptococci began to increase in areas where macrolideswere widely used, to the point that it became a clinically significantproblem ( in several countries in Europe) (30 32). In many coun-tries, resistance to macrolide antibiotics has reached more than 15%.This must be taken into account when considering a macrolide fortherapy of group A streptococcal URT infection. In some cases, theincrease in resistance has been related to the introduction of newmacrolide drugs that frequently are recommended only for abbrevi-ated therapy. Shortened courses of antibiotic therapy remain contro-versial since there is a paucity of carefully conducted studies toconfirm that this form of therapy is fully effective in eradicating groupA streptococci from the URT (24, 32, 33).Most authorities do not believe that routine culturing of the patient sthroat after completing antibiotic therapy is indicated, except inunique epidemiological situations such as a patient known to have RFor rheumatic heart disease (9).86Table prevention of rheumatic fever: recommended treatment for streptococcal pharyngitisa,bAntibioticAdministrationDo seCommentsBenzathineSingle intramuscular injection1 200 000 units intramuscularly;Preferable to oral penicillin because ofbenzylpenicillin600 000 units for childrenpatient adherence <27 penicillinOrally 2 4 times/day for 10Children: 250 mg bid or resistance by group A(Penicillin V)full daysAdolescents or adults: 250mg tidstreptococci has never been qid, or 500 mg 2 3 times/day for 1025 50 mg/kg/day in three alternative to oral penicillinfull daysTotal adult dose isbecause of the 1500 2 3 times/day for 10Varies with alternative for oralcephalosporinscfull 4 times/day for 10 fullVaries with formulation. AvailableAlternative drug for patients allergic toethylsuccinatedaysas the stearate, ethylsuccinate,penicillin. Should not be used in areasestolate or group A streptococci have highrates of macrolide in part from (24).bIn some countries, macrolides have been approved for an abbreviated course of therapy (shorter than 10 days), but the efficacy of this treatment iscontroversial and it cannot be recommended at present. Also, trimethoprim, sulfonamides and tetracyclines are not effective antibiotics for eradicatingGroup A streptococci and are not indicated for the primary prevention of agents should not be used in patients who have had immediate-type hypersensitivity to beta-lactam has been used in some patients who have either a poorly documented history of penicillin allergy, but should not be used for patients with immediatehypersensitivity reactions to penicillin ( anaphylaxis or hives). About 5% of those who have even a mild allergic reaction to penicillin may also have areaction to situationsIf pharyngitis recurs after antibiotic therapy has been completed itwill be necessary to perform a throat culture to confirm that group Astreptococci are responsible. M-typing of strains when possible maybe necessary to establish whether the recurrence was because oftreatment failure or because of a new infection. The same antibioticused to treat the infection initially should be administered, especiallyif a new infection is suspected. If oral penicillin had been used ini-tially, then a single intramuscular injection is recommended. If it issuspected that the streptococci are penicillinase producers it is advis-able to administer clindamycin or amoxycillin/clavulanate (9, 26,34 36).Antibiotics should not be administered to group A streptococcalcarriers, because they are unlikely to spread the microorganism tocontacts and they are at a low risk, if any, of developing RF (9, 37).Other primary prevention approachesAlthough a cost-effective vaccine for group A streptococci wouldbe the ideal solution, scientific problems have prevented the de-velopment of such a vaccine (see Chapter 13, Prospects for a strepto-coccal vaccine). There have been no controlled studies showingthat tonsillectomy is effective in reducing the incidence of RF, andit is not recommended for the primary prevention of RF (24, 28,38 40). F et al. Prevention of rheumatic fever. Treatment of the precedingstreptococcal infection. Journal of the American Medical Association, 1950,143:151 LW et al. Prophylaxis of acute rheumatic fever by treatment ofthe preceding streptococcal infection with various amount of depotpenicillin. American Journal of Medicine, 1951, 10:673 L. The virtual disappearance of rheumatic fever in the United States:lessons in the rise and fall of disease. Circulation, 1985, 72(6) M, Kaplan EL. Reappearance of rheumatic fever. Advances inPediatrics, 1989, 36:39 EL, Hill HR. Return of rheumatic fever: consequences, implications,and needs. Journal of Pediatrics, 1987, 111(2):244 SRA, Bothig S. Rheumatic fever and rheumatic heart disease indeveloping countries. World Health Forum, 1989, 10(2):203 WHO/ISFC meeting on RF/RHD control with emphasis on primaryprevention, Geneva, 7 9 September 1994. Geneva, World HealthOrganization, 1994 (WHO Document WHO/CVD ). WHO Global Programme for the prevention of RF/RHD. Report of aconsultation to review progress and develop future activities. Geneva, WorldHealth Organization, 2000 (WHO document WHO/ ). AL et al. Practice guidelines for the diagnosis and management ofgroup A streptococcal pharyngitis. Clinical Infectious Diseases, 2002,35(2):113 AL. Acute pharyngitis: etiology and diagnosis. Pediatrics, 1996,97(6 Pt 2):949 LW. Perplexity and precision in the diagnosis of streptococcalpharyngitis. American Journal of Diseases of Children, 1972, 124(3):352 MH et al. The rational clinical examination. Does this patient havestrep throat? Journal of the American Medical Association, 2000,284(22):2912 A, Kaplan EL. Clinical use and interpretation of group Astreptococcal antibody tests: a practical approach for the pediatrician orprimary care physician. Pediatric Infectious Disease Journal, 2002,21(5):420 GH. Penicillin for streptococcal pharyngitis: has anythingchanged? Hospital Practice, 1995, 30(3):80 RM. Prevention of streptococcal sequelae by penicillin prophylaxis:a reassessment. Journal of Infectious Diseases, 1975, 131(5):592 AS. Rheumatic fever prevention revisited. Pediatric InfectiousDisease Journal, 1989, 8(5):266 M. Benzathine penicillin G after thirty years. Clinical therapeutics,1980, 3(1):49 ME. Eradication of group A streptococci. Pediatrics, 2000, 106(2Pt 1):380 Kholy A. A controlled study of penicillin therapy of group A streptococcalacquisitions in Egyptian families. Journal of Infectious Diseases, 1980,141(6):759 JW. A review of the rationale and advantages of various mixtures ofbenzathine penicillin G. Pediatrics, 1996, 97(6 Pt 2):960 JW et al. Streptococcal pharyngitis in children. A comparison of fourtreatment schedules with intramuscular penicillin G benzathine. Journal ofthe American Medical Association, 1976, 235(11):1112 S et al. Efficacy of benzathine penicillin G in group Astreptococcal pharyngitis: reevaluation. Journal of Pediatrics, 1987,110(5):783 BF. Prevention of rheumatic fever. Journal of the American MedicalAssociation, 1972, 221(4):410 model prescribing information. Drugs used in the treatment ofstreptococcal pharyngitis and prevention of rheumatic fever. Geneva, WorldHealth Organization, 1999 (WHO/EDM/ ). ME et al. Variables influencing penicillin treatment outcome instreptococcal tonsillopharyngitis. Archives of Pediatrics and AdolescentMedicine, 1999, 153(6):565 TD et al. Efficacy of beta-lactamase-resistant penicillin and influenceof penicillin tolerance in eradicating streptococci from the pharynx afterfailure of penicillin therapy for group A streptococcal pharyngitis. Journal ofPediatrics, 1987, 110(5):777 EL, Johnson J. Eradication of group A streptococci from the upperrespiratory tract by amoxicillin with clavulanate after oral penicillin Vtreatment failure. Journal of Pediatrics, 1988, 113(2):400 GM et al. Epidemiology of streptococcal infections in rheumaticand non-rheumatic families. IV. The effect of tonsillectomy on streptococcalinfections. American Journal of Epidemiology, 1968, 87(1):226 A et al. Azithromycin compared with clarithromycin for the treatmentof streptococcal pharyngitis in children. Journal of International MedicalResearch, 1998, 26(3):152 MA et al. Potemtial mechanisms for failure to eradicate group Astreptococci from the pharynx. Pediatrics, 1999, 104(4):911 EL, Johnson DR. Unexplained reduced microbiological efficacy ofintramuscular benzathine penicillin G and oral penicillin V in eradication ofgroup A streptococci from children with acute pharyngitis. Pediatrics, 2001,108(5):1180 ST. Evaluation of penicillins, cephalosporins and macrolides fortherapy of streptococcal pharyngitis. Pediatrics, 1996, 97:955 S et al. Penicillin for acute sore throat: randomized double blind trialof seven days versus three days treatment or placebo in adults. BritishMedical Journal, 2000, 320:150 S et al. Penicillin V and rifampin for the treatment of group Astreptococcal pharyngitis: a randomized trial of 10 days penicillin vs 10days penicillin with rifampin during the final 4 days of therapy. Journal ofPediatrics, 1985, 106(3):481 A et al. Clindamycin in persisting streptococcal pharyngotonsillitisafter penicillin treatment. Scandinavian Journal of Infectious Diseases, 1994,26(5):535 RR et al. Penicillin plus rifampin eradicates pharyngeal carriage ofgroup A streptococci. Journal of Pediatrics, 1985, 106(6):876 EJ et al. Azithromycin versus cefaclor in the treatment of pediatricpatients with acute group A beta-hemolytic streptococcal Journal of Clinical Microbiology and Infectious Diseases, 1998,17(4):235 GM. The role of the tonsils in streptococcal infections: acomparison of tonsillectomized children and sibling controls. AmericanJournal of Epidemiology, 1972, 95(3):278 JL et al. Efficacy of tonsillectomy for recurrent throat infectionin severely affected children. Results of parallel randomized and90nonrandomized clinical trials. New England Journal of Medicine, 1984,310(11):674 H, Dowd B. Tonsillectomy and rheumatic fever. Medical Journal ofAustralia, 1967, 2(25):1121 prevention of rheumatic feverDefinition of secondary preventionSecondary prevention of rheumatic fever (RF) is defined as the con-tinuous administration of specific antibiotics to patients with a previ-ous attack of RF, or a well-documented rheumatic heart disease(RHD). The purpose is to prevent colonization or infection of theupper respiratory tract (URT) with group A beta-hemolytic strepto-cocci and the development of recurrent attacks of RF. Secondaryprophylaxis is mandatory for all patients who have had an attack ofRF, whether or not they have residual rheumatic valvular used for secondary prophylaxis: general principlesIntramuscular injection of benzathine benzylpenicillin every threeweeks (every four weeks in low-risk areas or low risk patients) is themost effective strategy for preventing recurrent attacks of RF (1).Oral penicillin may also be used as an alternative in secondary pro-phylaxis, but the greatest concern with oral administration is non-compliance, since patients often find it difficult to adhere to a dailyregimen of antibiotics for many years (2). Even for patients whostrictly adhere to the regimen, serum penicillin levels are less predict-able with this method, and RF recurs more frequently in patients onan oral regimen than in comparable patients receiving intramuscularbenzathine benzylpenicillin (3). Situations in which an oral regimenmay be used include patients who are at a relatively low risk for arecurrence of RF, and those who refuse to accept the regular remains the antibiotic of choice (4). For those patients whoare known to be, or are suspected of being, allergic to penicillin, oralsulfadiazine or oral sulfasoxazole represent optimal second choices(5). In the rare instance where patients are allergic both to penicillinand the sulfa drugs, or if these drugs are not available, oral erythro-mycin may be used (5). Note that while the sulfa drugs should not beused for primary prophylaxis, they are acceptable for secondary pro-phylaxis. A complete list of antibiotics and appropriate dosage sched-ules for the secondary prophylaxis of recurrent RF is provided inTable benzylpenicillinBenzathine benzylpenicillin is a repository form of penicillin G de-signed to provide a sustained bactericidal serum concentration. Earlystudies indicated that serum levels of penicillin remained above the92minimum inhibitory concentration for group A streptococci for 3 4weeks (6). Vials of the antibiotic usually contain million units,equivalent to 720 mg of benzyl penicillin G. The reconstituted orlyophilized penicillin should be stored at temperatures not exceeding30 C and be protected from moisture. Although the activity ofbenzathine benzylpenicillin remains stable in the vial for several yearsif appropriately stored, the activity may be affected by the presence ofpreservatives (4). The physical properties of the solution, if not opti-mal, may also affect its degree of solubility and hence its absorptionfrom the injection site, which can affect its bioavailability (7). Sincepreparations of benzathine benzylpenicillin are available from phar-maceutical manufacturers around the world, quality control proce-dures are necessary to ensure that the preparations have optimalabsorption characteristics and that effective serum levels of penicillinwill be maintained between deep intramuscular injection, peak serum concentrations areusually reached within 12 24 hours and effective concentrations areusually detectable for approximately three weeks in most patients andfor four weeks in a smaller proportion (8). The usual dose for second-ary RF prophylaxis is million units given intramuscularly, mostoften administered in the upper outer quadrant of the buttock, or inthe anterior lateral penicillinAlthough published data indicate that intramuscular benzathine ben-zylpenicillin is superior to oral penicillin for preventing acquisition ofgroup A beta-hemolytic streptococci in the URT, and for preventingsubsequent recurrences of acute RF, oral regimens can be used in secondary prophylaxis of RFAntibioticMode ofDoseadministrationBenzathineSingle intramuscularFor adults and children 30 kg inbenzylpenicillininjection every 3 4weight: 1 200 000 children <30 kg in weight:600 000 mg twice adults and children 30 kg in( sulfadiazine,weight: 1 gram ,For children <30 kg in weight:sulfisoxazole).500 mg mg twice in part from (5)93Originally, oral regimens utilized penicillin G, but this is more suscep-tible to gastric hydrolysis than penicillin V. Since penicillin V is nowas inexpensive as penicillin G, and since penicillin V is available inmost countries, it is the preferred form of oral penicillin. The usualdose is 250 mg taken twice daily (Table ).Oral sulfadiazine or sulfasoxazoleFor a patient allergic to penicillin, oral sulfadiazine or sulfasoxazoleare acceptable substitutes, unless the patient is also sensitive to sulfadrugs (5). These drugs are also contraindicated in pregnancy. Al-though sulfa drugs are effective in preventing colonization of theURT with group A beta-hemolytic streptococci, they cannot be usedfor the primary prevention of established streptococcal dose is either one gram daily or 500 mg daily, depending on theweight of the patient (Table ).Duration of secondary prophylaxisIt is difficult to formulate blanket guidelines for the duration ofsecondary prophylaxis. The duration of prophylaxis for a patient witha questionable history of RF and no evidence of valvular heart dis-ease, for example, may be different than that for a patient with signifi-cant residual heart disease and documented recurrent attacks ofRF. Consequently, the duration of secondary prophylaxis must beadapted to each patient, depending on the risk of RF factors can influence the risk of RF recurrence, including: the age of the patient the presence of RHD the time elapsed from the last attack the number of previous attacks the degree of crowding in the family a family history of RF/RHD the socioeconomic and educational status of the individual the risk of streptococcal infection in the area whether a patient is willing to receive injections the occupation and place of employment of the patient (schoolteachers, physicians, employees in crowded areas).Such decisions can be facilitated using the general recommendationsin Table situationsPenicillin prophylaxis for recurrent attacks of RF should be continuedduring pregnancy. There is no evidence of teratogenicity associated94with benzathine benzylpenicillin. The sulfa drugs are not recom-mended because of the potential risk to the fetus. The teenage yearspresent a special problem with adherence to any prophylactic regime;special efforts should be made at this crucial period when the risk ofrecurrence remains relatively high. Special regimens for patients withRHD must be used for bacterial endocarditis prophylaxis, as second-ary RF prevention regimens are not appropriate for preventing en-docarditis (see Chapter 12, Infective endocarditis). Finally, it shouldbe remembered that even though patients have a prosthetic heartvalve they remain susceptible to recurrences of rheumatic fever, butcaution must be taken in recommending intramuscular benzathinepenicillin G for patients with a prosthetic valve receiving warfarin oranother form of allergy and penicillin skin testingThe incidences of allergic and anaphylactic reactions to monthlybenzathine penicillin injections are and respectively; fatalreactions are rare (9, 10). The risk of a serious reaction is reduced inchildren under the age of 12 years, and the duration of prophylaxisdoes not appear to increase the risk of an allergic reaction (1 3). Thelong-term benefits of benzathine penicillin therapy in preventing RFfar outweigh the risk of a serious allergic reaction (1 5).The overall incidence of hypersensitivity reactions has been estimatedto be 2 5% (10). The most common allergic reactions are manifest asskin rashes. Anaphylaxis is rare and occurs in only about ofcases (11). It should be emphasized that what appear to be clinical anaphylactic reactions have been reported most often in patientswith severe RHD. Because of poor cardiac function these patients aremore susceptible to vaso-vagal reactions and are at high risk of life-threatening arrhythmias (9). Resuscitation can be difficult. Yet suchTable duration of secondary prophylaxis*Category of patientDuration of prophylaxisPatient without proven 5 years after the last attack, or until 18 yearsof age (whichever is longer).Patient with carditisFor 10 years after the last attack, or at least until 25(mild mitral regurgitation oryears of age (whichever is longer).healed carditis).More severe valvular valve * See Text. These are only recommendations and must be modified by individual circumstancesas warranted95instances do not represent true anaphylaxis. While true anaphylacticreactions can occur in individuals without RHD, the risk is low (9, 10).It has been suggested that the risk of true anaphylaxis is less than therisk of recurrence of RF in some populations (9).Penicillin skin testing is an acceptable and usually accurate method todetermine whether a person is at risk of having an immediate reactionto penicillin (10, 12, 13). Only 10 20% of patients reporting penicillinallergy are truly allergic when assessed by skin testing (10, 12, 14).Acute allergic reactions are rare in patients with negative skin testsand virtually all patients with a negative skin test can receive penicil-lin prophylaxis without serious sequelae (10 13). However, penicillinskin testing also has an adverse reaction rate of It is gener-ally considered safe when performed properly, although rare in-stances of anaphylactic shock have been reported (14, 15).Health-care providers should take a careful history regarding previ-ous allergic reaction, not only to benzathine penicillin, but also toother beta-lactam antibiotics (such as ampicillin, amoxicillin, cepha-losporins, etc.). If a patient has a convincing history of a severeimmediate allergic reaction to penicillin (oral or intramuscular), skintesting is not advocated and a non-beta-lactam antimicrobial shouldbe used ( erythromycin, sulfa drugs) (5, 10, 12).An emergency kit for treating anaphylaxis should be available in anyclinical setting where intramuscular penicillin is administered. Al-though a positive history of penicillin allergy may not always bereliable, it is nevertheless recommended that all patients who are toreceive secondary prophylaxis are carefully questioned as to whetherthey are allergic to penicillin. All health workers dispensing second-ary prophylaxis should also be trained in performing the penicillinskin test (15 17) and in treating anaphylaxis. If a hypersensitivityreaction of any degree develops during prophylaxis a different anti-biotic should be used in the HC et al. Rheumatic fever recurrences: controlled study of 3-weekversus 4-week benzathine penicillin prevention programs. Journal ofPediatrics, 1986, 108:299 AS. Adherence to physicians instructions as a factor in managingstreptococcal pharyngitis. Pediatrics, 1996, 97(6 Pt 2):976 HF et al. Rheumatic fever in children and adolescents. A long termepidemiological study of subsequent prophylaxis, streptococcal infections,and clinical sequelae. III. Comparative effectiveness of three prophylaxisregimens in preventing streptococcal infections and rheumatic of Internal Medicine, 1964, 60(2) Suppl 5:31 American Heart Association. Treatment of acute streptococcal pharyngitisand prevention of rheumatic fever: a statement for health , 1995, 96(4 Pt 1):758 model prescribing information. Drugs used in the treatment ofstreptococcal pharyngitis and prevention of rheumatic fever. Geneva, WorldHealth Organization, 1999 (WHO/EDM/ ). GH, Russoff JH, Hirschfield I. Prophylaxis against group Astreptococci in rheumatic fever. The use of single monthly injection ofbenzathine penicillin G. New England Journal of Medicine, 1955, 252:787 JW et al. Serum levels of penicillin in basic trainees in the US Armywho received intramuscular penicillin G benzathine. Clinical InfectiousDiseases, 1996, 22(4):727 EL et al. Pharmacokinetics of benzathine penicillin G: serum levelsduring the 28 days after intramuscular injection of 1 200 000 units. Journal ofPediatrics, 1989, 115:146 International Rheumatic Fever Study Group. Allergic reactions to long-termbenzathine penicillin prophylaxis for rheumatic fever. Lancet, 1991,337:1308 M, Lue HC. Allergic reactions in rheumatic fever patients on long-term benzathine penicillin G: the role of skin testing for penicillin , 1996, 97(S):981 O et al. Nature and extent of penicillin reactions, with particularreference to fatalities from anaphylactic shock. Bulletin of the World HealthOrganization, 1968, 38:159 AR et al. Is this patient allergic to penicillin? An evidence-basedanalysis of the likelihood of penicillin allergy. Journal of the AmericanMedical Association, 2001, 285(19):2498 DA, Sox HC. The role of skin testing for penicillin of Internal Medicine, 1990, 150(9):1939 RJ et al. The value of skin testing for penicillin allergy ininpatient population: analisis of the subsequent patient management. AllergyAsthma Procedings, 2000, 21(5):297 DM et al. Introduction of a practice guidelines for penicillin skintesting improves the appropriateness of antibiotic therapy. Clinical InfectiousDiseases, 2001, 32(12):1685 NF. Tests for immunological drug reactions. In: Rose NR,Friedman H, eds. Manual of clinical immunology. Washington, DC, AmericanSociety of Microbiology, 1980:822 C, Mendelson L. Skin test for diagnosis of penicillin allergy: currentstatus. Annals of Allergy, 1987, 59:167 endocarditisIntroductionInfective endocarditis poses a special threat for individuals withchronic rheumatic valvular disease, or who have had prosthetic valvesimplanted because of rheumatic heart disease (RHD). Superimposedupon chronic RHD, infective endocarditis can significantly increasethe morbidity and mortality rates in either of these categories ofpatients. For these patients, prophylaxis for the infective endocarditisis thus recommended. However, individuals who have had rheumaticfever (RF), but who have no evidence of damage to heart valves, donot require endocarditis prophylaxis (1 4).Infective endocarditis rarely occurs without underlying cardiac pa-thology, either congenital or acquired. An example of an acquiredpathology is seen in intravenous drug users. Even though these indi-viduals usually have normal valvular anatomy, infective endocarditisis not uncommon in this group, particularly of the tricuspid with congenital heart disease also have a higher risk of devel-oping endocarditis. Although a discussion of the risks of infectiveendocarditis in individuals with congenital heart disease is beyond thescope of this discussion, one principle is that fluid turbulence resultsin endothelial damage, whether the congenital lesion is valvular, as incongenital bicuspid aortic valves, or a ventricular septal defect. Inpatients with rheumatic valvular heart disease, infective endocarditisusually occurs in the mitral or aortic valves since these are the mostcommonly damaged heart of infective endocarditis1For the vast majority of patients who develop infective endocarditis(either with bacteria or with fungi), normal laminar blood flow isconverted into turbulent flow across the defect. This occurs in patientswith rheumatic valvular damage, for example. Although the right-sideheart valve is less commonly involved, right-side endocarditis couldpose a threat to a patient with either tricuspid or pulmonary valvedamage that resulted from with animal models suggest that turbulent flow may lead toinjury and/or disruption of the vascular endothelium or a consequence, a matrix of platelets and fibrin is laid down to forma sterile vegetation. If significant bacteremia then occurs, and bacter-emia is common in humans, circulating microorganisms become1Source: (3).98enmeshed in the initially sterile vegetation and form a nidus of infec-tion. One of the most important factors determining whether bacteriainfect sterile vegetation may be the concentration of bacteria circulat-ing through the bloodstream during bacteremia. Early studies alsosuggested that Gram-positive oral flora, such as viridans group strep-tococci, had a greater affinity for the vascular endothelium and en-docardium than did Gram-negative organisms. This correlated wellwith clinical observations that Gram-negative organisms frequentlycause urinary tract infections, yet rarely cause infective , investigators caution that understanding of the infectiveprocess is incomplete, and point to studies demonstrating that detailsof the intercellular interactions are agents causing infective endocarditis1In the first half of the twentieth century, the most common organismsrecovered from individuals with documented infective endocarditiswere the alpha-hemolytic streptococci normally found in the oralcavity and upper respiratory tract. This pattern changed in the latterhalf of that century, with an increase in the number of episodes ofinfective endocarditis associated with staphylococci, particularly inindustrialized countries. Increasingly, Staphylococcus aureus and co-agulase-negative staphylococci were recovered from infective en-docarditis patients, probably because the patients had undergonemedical or surgical procedures that required extended hospitaliza-tions. In immunocompromised patients, whether from tumor chemo-therapy or from acquired conditions like HIV/AIDS, infectiveendocarditis has also been associated with other unusual most published studies, staphylococci and viridans streptococciwere found in more than 50% of the cases, but other organisms arebeing recovered from patients more frequently, including group Denterococci, gram-negative organisms, and the HACEK organisms(Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, andKingella). Similarly, yeast and fungi are also more common for rea-sons previously mentioned. In developing countries, the continuingpredominance of viridans streptococci in patients with endocarditishas been attributed to the poor dental hygiene among children andadults in socially and economically disadvantaged and laboratory diagnosis of infective endocarditis1Even in industrialized countries, it has been estimated that a primary-care physician may see only one patient with endocarditis during his/1Sources: (1 7).99her career. Since the clinical signs and symptoms commonly associ-ated with infective endocarditis are often nonspecific and overlapwith many other illnesses, a diagnosis of infective endocarditis can bedifficult using clinical observations alone. In 1994, to facilitate patientevaluation, more objective clinical criteria were published for assess-ing infective endocarditis (6). It is beyond the scope of this documentto discuss the use of these criteria in detail. However, as with theJones Criteria for RF, using clinical criteria to diagnose infectiveendocarditis is fraught with thus important to confirm clinical suspicions of endocarditis withdata from the microbiology laboratory. If there are no supportingmicrobiology laboratory facilities, or if existing ones are substandard,this makes a diagnosis of endocarditis especially difficult. A compli-cating factor is that patients with nonspecific symptoms at the onset ofinfective endocarditis are often given antibiotics or take antibiotics ontheir own. Consequently, even with microbiology laboratory facilities,it can be difficult to confirm a suspected infection. Laboratory studiesfor assisting the clinician can be divided into two major , the blood culture is a sine qua non for confirming a diagnosis ofinfective endocarditis. Since the bacteremia associated with en-docarditis is thought to be qualitatively continuous, there is no needfor the clinician to wait for temperature elevations to obtain bloodcultures. It is important to obtain more than a single blood culture (ithas been proposed that three samples are sufficient) before any anti-biotic therapy is initiated. The volume of blood taken for laboratoryculture evaluation can be important even in is more difficult for the clinician to manage a patient with infectiveendocarditis if the underlying organism has not been identified. Thisis a problem in locations where there are no fully operational micro-biology laboratories. There is a consensus that, at least in local orregional referral hospitals, it is important that the laboratories beequipped for this important task. Other laboratory tests, such asmeasuring the erythrocyte sedimentation rate or levels of C-reactiveprotein or other acute-phase reactants, are often helpful for followingthe clinical course of patients, but are nonspecific measures of inflam-mation and are not pathognomonic of infective endocarditis. Thesame is true for the white blood count and differential. Haematuria,casts (or other signs of nephritis) and even small numbers of bacteria(especially staphylococci) in the urine are also helpful adjuncts inmaking a diagnosis of infective technique of echocardiography is potentially the most useful laboratory examination in the diagnosis and management of100individuals with infective endocarditis. In adults, the resolution andsensitivity of echocardiography can be considerably improved by em-ploying transoesophageal echocardiography. In children, or very thinadults, transthoracic echocardiography may suffice. It is beyond thescope of this document to completely discuss the advantages anddisadvantages of this important diagnostic tool. While the identifica-tion of a vegetation can be most helpful in establishing the diagnosis,the failure to demonstrate the vegetation by echocardiography doesnot eliminate the disease from is not uncommon for individuals with endocarditis to present withembolic phenomena. There may be either massive emboli or smallemboli producing vague and nonspecific complaints over a period oftime. Therefore, the clinician must investigate other organ systems forevidence of embolic and surgical management of infective endocarditis1The most important aspects of the medical management of patientswith infective endocarditis are a correct diagnosis and the eradicationof the causative microorganism. For these reasons, a positive bloodculture remains the gold standard for assisting clinicians to planantibiotic therapy. Although it is possible to make an educatedguess about the identity of the causative organism, the antibioticsensitivities of these organisms can vary, not only between countriesand cities, but even between hospitals within the same city. Conse-quently, the antibiotic susceptibility of a causative organism should betested in a laboratory. Although such laboratories may not always bepresent in local clinics, a regional referral hospital should be able toperform the tests. Such tests are important to the outcome and canindirectly reduce morbidity and mortality. The importance of per-forming antibiotic susceptibility tests is underscored by the continuingincrease in antibiotic resistance among even the most commonlyisolated pathogens associated with infectious endocarditis ( resistant Staphylococcus aureus (MRSA) and vancomycinresistant enterococci (VRE)).The medical treatment of endocarditis with antibiotics depends uponthe microorganism, its sensitivity, and the extent of the example, individuals who have myocardial abscess formation willrequire different considerations than those who have only valvularinvolvement. The duration of therapy must be sufficiently long toensure the bacterial infection is cured. Many national cardiac societies1Sources: (2, 3, 6).101have published recommendations for therapy of infective endocardi-tis and duration of the treatment. Treatment is essentially alwaysparenteral; oral therapy is less desirable because of the potential forsuboptimal patient compliance and the distinct possibility of irregularabsorption from the gastrointestinal tract. In addition to antimicro-bial therapy, supportive care for complications such as heart failure medical management is not effective, surgery must be consideredwhenever possible. Assuming surgical facilities are accessible, thereare several indications for considering prompt surgical intervention,including: the persistence of bacteremia by blood culture after four or fivedays of what should be adequate antibiotic therapy; the occurrence of major or multiple continuing embolicphenomena; in individuals with valvular heart disease, the presence ofsignificantly increasing valvular dysfunction ( more regurgita-tion), leading to heart individuals with prosthetic valve endocarditis, the criteria are con-siderably different as this situation is more difficult to treat withantibiotics alone, particularly if there is an annular abscess, for ex-ample. The need for surgery is more obvious in these speaking, surgery is not contra-indicated in active infec-tion, and may be the sole life-saving procedure for the prevention of infective endocarditis in patientswith rheumatic valvular heart disease1No controlled study has adequately demonstrated that antibiotic pro-phylaxis prior to dental or surgical procedures is efficacious in pre-venting endocarditis. However, numerous reports do confirm thatantibiotic prophylaxis reduces the occurrence of bacteremia. Sincebacteremia necessarily precedes actual endocarditis, it has been as-sumed that reducing the occurrence of bacteremia reduces the risk ofdeveloping infective endocarditis. Accordingly, while specifics maydiffer, prophylaxis for infective endocarditis is widely recommendedby national cardiac societies around the for preventing endocarditis has become less years ago, three or four days of antibiotic prophylaxis was rec-ommended in advance of a dental or surgical procedure, whereas1Sources: (1 5).102current recommendations are for only one or two doses prior to theprocedure. It should recognized that individuals who have had RF,but have no evidence of valvular heart disease, do not require prophy-laxis to prevent infective endocarditis. On the other hand, individualswith rheumatic valvular disease should be given prophylaxis for den-tal procedures and for surgery of infected or contaminated studies have shown that the use of oral antiseptic solutions( phenolated oral mouth wash, Betadine mouth wash) can reduceoral flora and reduce bacteremia following dental extraction. Whilethis can be used as an adjunct just prior to dental procedures, it shouldnever replace the use of antibiotics for appropriate indications procedures for which endocarditis prophylaxis is recommendeda dental extractions periodontal procedures ( surgery, scaling, etc.) dental implant placement or replacement gingival surgery initial placement of orthodontic appliances, but not routine adjustments dental cleaning when gingival bleeding is expected endodontic instrumentation intraligamentary local anesthetic : (1).Table procedures for which endocarditis prophylaxis is not recommendeda restorative dentistry (filling cavities) procedures associated with shedding primary teeth adjusting orthodontic appliances taking oral radiographs removing post-operative : (1).Table procedures for which endocarditis prophylaxis is recommendeda surgical procedures that involve respiratory tract mucosa ( tonsillectomy) bronchoscopy with a rigid bronchoscope sclerotherapy for esophageal varices oesophageal stricture dilatation surgical procedures on intestinal mucosa or biliary tract prostate surgery cystoscopy and urethral : (1).103A list of dental and other procedures for which endocarditis prophy-laxis is, or is not, recommended is given in Tables Com-monly proposed antibiotic prophylaxis regimens are given in and As shown in Table , individuals already receivingsecondary RF prophylaxis with oral penicillin should not be givenpenicillin for their dental or upper respiratory tract procedures. ThisTable procedures for which endocarditis prophylaxis is not routinely neededa endotracheal intubation bronchoscopy with flexible bronchoscope tympanostomy tube insertion trans-oesophageal echocardiography vaginal delivery or hysterectomy caesarian-section delivery if not infected: urethral catheterization, uterine dilatation and curettage, therapeuticabortion, sterilization procedures, insertion or removal of intrauterine devices cardiac catheterization or angioplasty circumcision biopsy of surgically scrubbed : (1).Table prophylactic antibiotic regimens for dental, oral, respiratory tract andoesophageal proceduresaSituationAntibioticDosebStand ard oralAmoxicillinOne doseParenteralAmpicillinOne dose (IM or IV)Penicillin allergyClindamycinOne doseOralCephalexin/CefadroxilOne doseParenteralCefazolinOne doseaModified from sources: (1, 2).bChildrens doses should never exceed the adult antibiotic prophylaxis regimens for gastrointestinal and genitourinarytract proceduresaSituationAntibioticDosebHigh riskAmpicillin plus gentamicin2 dosesHigh risk/allergy to penicillinVancomycin plus gentamicin1 doseModerate riskAmoxicillin or ampicillin1 doseModerate risk/allergy to penicillinVancomycin alone1 doseaModified from sources: (1, 2).bChildrens doses should never exceed the adult of antibiotic prophylaxis for rheumatic fever and bacterial endocarditisProphylaxisPrimary rheumatic feverSecondary rheumatic feverBacterial endocarditisPurposeTo treat group A streptococcalTo prevent colonization and/orTo prevent or minimize bacteremia inupper respiratory tract infectionsinfection in patients who havepatients with heart disease, toand eradicate the organism, tohad a previous attack of RF;prevent the development ofprevent an initial attack of acuteprevents a recurrence of given?Intermittently: only when there isContinuously: duration variesIntermittently: shortly before dental orgroup A streptococcal individual circumstancessurgical procedures that could(age, sequelae, etc.).result in commonlyPenicillin (oral or intramuscularOral penicillin twice daily, orThose antibiotics directed towardusedbenzathine). Erythromycin forintramuscular benzathineorganisms likely to enter thethose allergic to penicillin. Notpenicillin G once every 3 4bloodstream from the surgical orsulfa drugs and not May also use oraldental site; also dependent on thesulfadiazine or oral erythromycinsusceptibilities of bacteria toif the patient is allergic toantibiotics in the local because of the likely presence of penicillin-resistant microorgan-isms, particularly in the upper respiratory tract and oral cavity ofpatients receiving oral penicillin. The development of resistance isless likely in individuals receiving intramuscular benzathine penicillinG for secondary RF prophylaxis. However, some authorities believethat a change to a macrolide or clindamycin is more effective forendocarditis endocarditis remains a significant cause (many times unsus-pected) of cardiovascular morbidity and mortality. Although thereare no data from controlled studies to support the use of antibioticprophylaxis to prevent infective endocarditis, it remains the acceptedmedical/dental standard of care. Clearly, antibiotics have been shownto be able to prevent bacteraemia following dental extraction. Fur-thermore, proper laboratory facilities and clinical acumen are re-quired to reduce the occurrence of this complication of rheumaticheart American Heart Association Committee on the Prevention of RheumaticFever, Endocarditis and Kawasaki Disease. Prevention of bacterialendocarditis. Journal of the American Medical Association, 1997, 277:1794 European Society of Cardiology Task Force on Infective for prevention, diagnosis and treatment of infectiveendocarditis. Unpublished L, Brusch JL. Infective endocarditis. New York, USA and Oxford,UK, Oxford University Press, fever and rheumatic heart disease. Report of a WHO StudyGroup. Geneva, World Health Organization, 1988 (WHO Technical ReportSeries, No. 764). DT. Prevention of infective endocarditis. New England Journal ofMedicine, 1995, 332:38 RS. Infective endocarditis in children. Pediatric Infectious DiseaseJournal, 1992, 11:907 DT, Lukes AS, Bright DK. New criteria for diagnosis of infectiveendocarditis: utilization of specific echocardiographic findings. DukeEndocarditis Service. American Journal of Medicine, 1994, 96:200 for a streptococcal vaccineEarly attempts at human immunizationAttempts to prevent group A streptococcal infections by immuniza-tion date back to the early years of the twentieth century (1 4).However, the vaccines did not appear to prevent primary or recurrentattacks of rheumatic fever (RF), despite the injection of largeamounts of crude streptococcal toxins and killed organisms into thou-sands of subjects. Efforts to develop a vaccine against group A strep-tococci were placed on a firmer scientific footing with the recognitionthat the principal virulence factor of group A streptococci was M-protein, a streptococcal wall constituent (5), and that opsonic anti-bodies to M-protein protected animals from lethal challenge. Suchantibodies persisted for many years in humans (6) and appeared to bethe basis of acquired type-specific immunity (7). Nevertheless, at-tempts to develop a safe and effective M-protein vaccine encounteredconsiderable difficulties because of the multiplicity of M-protein sero-types (and genotypes), the toxicity of early M-protein preparations,and the immunological cross-reactivity between M-protein and hu-man tissues, including heart tissue (8) and synovium (9). Cross-reactivity with synovial tissue is of particular concern, because anti-genic mimicry is thought to play a central role in the pathogenesisof RF (10).M-protein vaccines in the era of molecular biologyAlthough our knowledge of the structure and function of M-proteinhas advanced considerably in recent years (11 15), M-protein pre-parations used in vaccines are still not free of epitopes that elicitimmunological cross-reactivity with other human tissues. Antibodiesagainst M-proteins, for example, cross-react with alpha-helical humanproteins, such as tropomyosin, myosin and vimentin. Primary struc-ture data have revealed that M-proteins of rheumatogenic streptococ-cal serotypes, such as serotypes 5, 6, 18 and 19, share similarsequences within their B-repeats, and it is likely that such sequencesare responsible for eliciting antibodies that cross-react with epitopesin the heart, brain and joints (16). Most of the cross-reactive M-protein epitopes appear to be located in the B-repeats, the A-Bflanking regions, or the B-C flanking regions, all of which are somedistance from the type-specific N-terminal epitopes (16 18).In contrast, antibodies raised against synthetic N-terminal peptidesthat correspond to the hypervariable portions of M-protein serotypes5, 6 and 24 are opsonic, but do not cross-react with human tissue (17 19). Further studies have shown that peptide fragments of M-107proteins, incorporated into multivalent constructs as hybrid proteinsor as individual peptides linked in tandem to unrelated carrier pro-teins, elicited opsonic and mouse-protective antibodies against mul-tiple serotypes, but did not evoke heart-reactive antibodies (20, 21).Phase I human trials with such vaccines are now in a limited number of streptococcal strains (serotypes) are re-sponsible for most human disease, it has been estimated that a sero-type-specific octavalent vaccine would prevent 77% of infectionscausing RF, 52% of those causing severe infections, and 40% ofuncomplicated infections (16). These estimates were based on sero-type distribution data from economically developed western coun-tries, and such a vaccine might need to be reconstituted, based onprevalent local strains. Current studies are directed toward utilizingcommensal gram-positive bacteria as vaccine vectors (22 23).Immunization approaches not based on streptococcal M-proteinTargets other than streptococcal M-protein have been proposed as abasis for immunization against RF. One of these is C5a peptidase, anenzyme that cleaves the human chemotactic factor, C5a, and thusinterferes with the influx of polymorphonuclear neutrophils at thesites of inflammation (24). Intranasal immunization of mice with adefective form of the streptococcal C5a peptidase reduced the colo-nizing potential of several different streptococcal M-serotypes (25). Asecond potential vaccine target is streptococcal pyrogenic exotoxin B(SpeB), a cysteine protease that is present in virtually all group Astreptococci. Mice passively or actively immunized with the cysteineprotease lived longer than non-immunized animals after infectionwith group A streptococci (26).Epidemiological considerationsOnce a safe and effective streptococcal vaccine is available manypractical issues would need to be addressed. With few exceptions, thehighest rates of RF tend to occur in areas with limited resources andpublic health infrastructure, and ways of delivering a vaccine undersuch conditions need to be examined. Other issues, such as cost, routeof administration, number and frequency of required doses, potentialside-effects, stability of the material under field conditions, and dura-bility of immunity, would all influence the usefulness of any mucosal vaccine would obviously be preferable to one requiringinjections, and it is likely that multivalent vaccines would need to bereformulated to account for the epidemiology of the local streptococ-cal strains associated with RF (27, 28). These and other questionsawait the advent of effective current efforts to develop a safe and effective group A strep-tococcus vaccine succeed, the rational application of the vaccine willrequire knowledge of the clinical, epidemiological and microbiologi-cal characteristics of streptococcal disease in many areas of the research into these issues should be given a high persistence of RF in many developing countries of the world, theapparent increase in life-threatening invasive group A streptococcusinfections in North America and Europe, and the revolution inmolecular biology have all spurred attempts to achieve a safe andeffective vaccine against group A streptococci. The most promisingapproaches are M-protein-based, including those using multivalenttype-specific vaccines, and those directed at non-type-specific, highlyconserved portions of the molecule. Success in developing vaccinesmay be achieved in the next 5 10 years, but this success would have tocontend with important questions about the safest, most economicaland most efficacious way in which to employ them, as well as theircost-effectiveness in a variety of epidemilogic and LA, Randall E, Rantz HH. Immunization of human beings with groupA hemolytic streptococci. The American Journal of Medicine, 1949, 6:424 FA. A review of past attempts and present concepts of producingstreptococcal immunity in humans. Quarterly Bulletin of NorthwesternMedical School, 1960, 34:326 VP, Brown EE. Immunization against rheumatic fever. Journal ofPediatrics, 1943, 23:24 MG, Swift HF. Intravenous vaccination with hemolytic streptococci:its influence on the incidence of rheumatic fever in children. AmericanJournal of Diseases of Children, 1931, 42:42 RC. Current knowledge of type-specific M antigens of group Astreptococci. Journal of Immunology, 1962, 89:307 RC. Persistence of type-specific antibodies in man followinginfection with group A streptococci. Journal of Experimental Medicine, 1959,110:271 LW et al. Studies on immunity to streptococcal infections inMan. American Journal of Diseases of Children, 1953, 86:347 JB, Beachey EH. Multiple, heart-cross-reactive epitopes ofstreptococcal M proteins. Journal of Experimental Medicine, 1985, 161:113 RW et al. Epitopes of group A streptococcal M protein shared withantigens of articular cartilage and synovium. Journal of Immunology, 1991,146:3132 JB. Rheumatic fever: a model for the pathological consequencesof microbial-host mimicry. Clinical and Experimental Rheumatology, 1986,4:65 GN Jr. et al. Streptococcal M protein: alpha-helical coiled-coilstructure and arrangement on the cell surface. Proceedings of the NationalAcademy of Sciences (USA), 1981, 78:4689 VA et al. Streptococcal M protein: an antiphagocytic moleculeassembled on the cell wall. Journal of Infectious Diseases, 1977,136(Suppl):S222 AL. Alternate complement pathway activation by group Astreptococci: role of M-protein. Infection and Immunity, 1979, 26:1172 RE, Schultz DR, Bisno AL. M-proteins of group G streptococci:mechanisms of resistance to phagocytosis. Journal of Infectious Diseases,1995, 171(3):601 PK et al. Inhibition of alternative complement pathwayopsonization by group A streptococcal M protein. Journal of InfectiousDiseases, 1979, 139:575 JB. Multivalent group A streptococcal vaccines. In: Stevens DL,Kaplan EL, eds. Streptococcal infections: clinical aspects, microbiology,and molecular pathogenesis. New York, Oxford University Press, 2000:390 JB, Seyer JM, Beachey EH. Type-specific immunogenicity of achemically synthesized peptide fragment of type 5 streptococcal M of Experimental Medicine, 1983, 158:1727 EH, Seyer JM. Protective and nonprotective epitopes of chemicallysynthesized peptides of the NH2-terminal region of type 6 streptococcal Mprotein. Journal of Immunology, 1986, 136:2287 EH et al. Protective and autoimmune epitopes of streptococcal Nprotein. Vaccine, 1988, 6(2):192 JB. Multivalent group A streptococcal vaccine designed to optimizethe immunogenicity of six tandem M protein fragments. Vaccine, 1999,17(2):193 JB et al. Recombinant, octavalent group A streptococcal M proteinvaccine. Vaccine, 1996, 14(10):944 VA. Vaccine approaches to protect against group A streptococcalpharyngitis. In: Fischetti VA et al., eds. Gram-positive , DC, American Society for Microbiology, 2000:96 VA, Hodges WM, Hruby DE. Protection against streptococcalpharyngeal colonization with a vaccinia:M protein recombinant. Science,1989, 244:1487 PP et al. Streptococcal C5a peptidase is a highly specificendopeptidase. Infection and Immunity, 1992, 60:5219 Y et al. Intranasal immunization with C5a peptidase preventsnasopharyngeal colonization of mice by the group A and Immunity, 1997, 65(6):2080 V et al. Vaccination with streptococcal extracellular cysteine protease(interleukin-1 beta convertase) protects mice against challenge withheterologous group A streptococci. Microbial Pathogenesis, 1994, 16:443 DR et al. Acute rheumatic fever in Auckland, New Zealand: spectrumof associated group A streptococci different from expected. The PediatricInfectious Disease Journal, 1994, 13(4):264 EL et al. A comparison of group A streptococcal serotypes isolatedfrom the upper respiratory tract in the USA and Thailand: of the World Health Organization, 1992, 70(4):433 socioeconomic burden of rheumatic feverThe socioeconomic burden of rheumatic feverAlthough rheumatic fever (RF) and its most important sequel, rheu-matic heart disease (RHD), are worldwide problems, they are mostprevalent in developing countries. In these countries, RF accounts forup to 60% of all cardiovascular disease in children and young adults,and it has the potential to undermine national productivity, sinceyoung adults are the most productive segment of the population inthese countries (1, 2). In addition, 67% of school aged patients dropout of school due to RF, which stifles their ability to realize their fullpotential (3).Moreover, the burden of managing RHD puts additional pressure onthe economies of these countries, which are often characterized by alow Gross Domestic Product and Gross National Product. In coun-tries of the African region, for example, the direct medical cost ofmanaging one patient with RHD for six years was estimated to beUS$ 17 375 in 1987, increasing to US$ 31 661 with surgical procedures(4, 5). And in Nigeria, it was estimated that the cost of treating onepatient with RF was equivalent to the cost of preventing cases (3).Adding to the burden on health systems of developing countries arethe costs of outside referrals that are often required during the courseof results of a study of RF and RHD in 100 low-income patients inSao Paulo, Brazil, underscored the socioeconomic costs of thesediseases (6). With a mean follow-up time of years (range, 1 10years), the patients had a total of 1657 medical consultations, 22hospital admissions and 4 admissions to an intensive care unit. It wasalso estimated that RF and RHD patients had a 22% failure rate inschool. The socioeconomic costs were also borne by the parents ofthe patients, with 22% exhibiting absenteeism from work, and about5% losing their jobs. There are also intangible costs associated withRF and RHD, resulting from premature disability and death, as wellas from the loss of intellectual opportunities, with its adverse effectson the socioeconomic development of the family and society. InBrazil, the annual cost of RF to society was estimated to beUS$ 51 144 347, approximately equivalent to of the averagefamily the more immediate costs of RF and RHD documented bysuch studies, these diseases could also have distal effects. Already,there are inherent inequities in health-care access and delivery forless-advantaged people in developing countries, and the additional112burdens that RF and RHD place on the economies of these countriescould exacerbate these inequities. Potentially, the most cost-effectivestrategy for ameliorating the impact of RF and RHD on the econo-mies and health-care systems of developing countries is the secondaryprevention of of control programmesIn low-income and middle-income countries with a high prevalence ofRF and RHD, prevention and control programmes must compete forlimited resources, and it is therefore crucial that available resourcesbe committed efficiently to guarantee the success and sustainability ofsuch programmes. As a programme design strategy, it is advisable toattempt small-scale pilot programmes before initiating large-scalenational control programmes, as the lessons learnt from pilot schemescan, in addition to many other benefits, prevent the waste of scarceresources (2, 7).The available empirical evidence underscores the intuitive notion thatsecondary prevention programmes are the most cost-effective, whencompared with primary prevention programmes and programmes fo-cusing on managing the cardiovascular complications of RF. For ex-ample, the cost of averting one death and gaining 37 DALYs1 thatwould have been lost was estimated to be US$ 40 920 using primaryprophylaxis alone, US$ 12 750 using tertiary prevention strategies(including cardiac surgeries), but only US$ 5520 using secondaryprophylaxis (8). In New Zealand, the average hospital costs for treat-ing RHD (which included the cost of surgery) accounted for 87% oftotal expenditures for RF and RHD in 1985, whereas the ambulatorycomponent of care accounted for only 13% of total expenditure share(9). Management of chronic RHD alone can take as much as 71% ofthe total national allocation for treating RF and RHD (10), and muchof this expenditure could be prevented with vigorous efforts atcheaper secondary prevention studies emphasize that national prevention programmes basedon secondary prophylaxis have the potential for considerable costsavings, which could be used to improve the spread and gains of aprogramme. National control programmes should therefore focus onreducing the need for hospitalization, averting the need for surgery,and improving the quality of life (when RF has been established).1The disability-adjusted life years (DALYs) lost is the sum of the number of years of lifelost due to premature death, plus the number of years lived with disability, adjusted forthe severity of programmes, which are integrated within existing primaryhealth-care systems, have the further potential to reduce the costburden on patients (7).No control programme would be complete without strategies fortreating acute pharyngitis and acute episodes of RF in endemic, andparticularly epidemic, situations. Strategies should be tailored to-wards local circumstances, however. Evidence has been presentedfrom a simulation study suggested that the most cost-effective strat-egy was to treat all pharyngitis patients with penicillin (particularlythose within an at-risk group), without a strict policy of waiting for thedisease to be confirmed by bacterial culture (7, 11). However, thisapproach has not been confirmed and cannot be advocated until morethorough studies are carried out. In hospital settings where facilitiesare available, the culture and treat strategy has been shown to becost-effective (12). a D. Rheumatic heart disease (editorial comment). East AfricanMedical Journal, 1999, 76(11):599 WHO/ISFC meeting on RF/RHD control with emphasis on primaryprevention, Geneva, 7 9 September 1994. Geneva, World HealthOrganization, 1994 (document WHO/CVD ). F. Chronic rheumatic heart disease in childhood: its cost andeconomic implications. Tropical Cardiology, 1982, 8(30):55 JOB. Acute rheumatic fever in Africa. Africa Health, 1994,16(5):32 A, Bertrand E. Rheumatic heart disease in Africa. World Health Forum,1992, 13(4):331 MT et al. Resource utilization and cost of rheumatic fever. Journal ofRheumatology, 2001, 28(6):1394 WHO Global Programme for the prevention of RF/RHD. Report of aconsultation to review progress and develop future activities. Geneva, WorldHealth Organization, 2000 (document WHO/ ). CJ et al. Rheumatic heart disease. In: Jamison DT et al., control priorities in developing countries. New York, OxfordUniversity Press, 1993:221 JM. Rheumatic fever and rheumatic heart disease in theWestern Pacific Region. New Zealand Medical Journal, 1988, 101:404 DA et al. Analysis of costs of acute rheumatic fever and rheumaticheart disease in Auckland. New Zealand Medical Journal, 1993, 106:400 RT, Burnes DC, Cables WC. Analysis of the cost-effectiveness ofpharyngitis management and acute rheumatic fever prevention. Annals ofInternal Medicine, 1977, 86(4):481 J, Kotagal UR. Management of sore throats in children: a cost-effectiveness analysis. Archives of Pediatric and Adolescent Medicine,1999, 153:681 and implementation of nationalprogrammes for the prevention and control ofrheumatic fever and rheumatic heart diseaseThe establishment of a national prevention programme is essential incountries where rheumatic fever (RF) and rheumatic heart disease(RHD) remain significant health problems. Both primary and second-ary prevention of RF and RHD have been proven to be safe, feasibleand effective in both developed and developing countries (1 12). Theoverall goal of a national programme should be to reduce morbidity,disabilities and mortality from RF and country level, the planning phase of the programme should includean assessment of the prevalence of RF and RHD and a plan ofoperation with objectives and approaches adapted to local needs andcircumstances. It is important to implement such programmesthrough the existing national infrastructure of the ministry of healthand the ministry of education without building a new administrativemechanism. This would minimize additional costs and prevent unsus-tainable monolithic programmes (2, 3, 6, 11, 12). Based upon previousexperience (1, 2, 11, 12), planning and implementation of nationalprogrammes should be based on the following principles: There should be a strong commitment at policy level, particularly inthe ministries of health and education. A national advisory committee should be formed, under the aus-pices of the ministry of health, with broad representation from allstakeholders, including representatives from a wide spectrum ofprofessional organizations ( cardiologists, paediatricians, familyphysicians, internal medicine specialists, epidemiologists andnurses). Programme implementation should be stepwise. For example, startin one or more defined areas to test whether the methods andprocedures are appropriate for the local situation (Phase I), andthen gradually extend the programme to provincial (Phase II)and national coverage (Phase III). The programme should be service-oriented and emphasize activesecondary prevention, and be integrated into the existing health-care systems, particularly primary health care. Support from the microbiology laboratory should be optimized atperipheral, intermediate and national levels. Suspected outbreaks of group A beta-haemolytic streptococcalinfection should be controlled and main components of a national programme are:116 secondary prevention activities aimed at preventing the recur-rence of acute RF and severe RHD; primary prevention activities aimed at preventing the first attackof acute RF; health education activities; training of health-care providers; epidemiological surveillance; community prevention activitiesSecondary prevention is based on case finding, referral, registration,surveillance, follow-up and regular secondary prophylaxis for RF andRHD patients. A central or a local referral or registration centreshould be established in participating areas. Once detected, patientswith a history of RF or with RHD are referred to the central or localcentre for medical care, follow-up and long-term secondary prophy-laxis. Attention should be given to patients who have difficulties inadhering to long-term secondary prophylaxis regimes, or who dropout of the prevention regime ( they miss more than two consecu-tive injections). For more details see Chapter 11, Secondary preven-tion of rheumatic prevention activitiesPrimary prevention is based on the early detection, correct diagnosisand appropriate treatment of individual patients with Group A strep-tococcal pharyngitis. Vertical programmes for the primary preventionof RF and RHD are not cost effective in developing countries. Suchprogrammes need to part of the routine medical care available andshould be integrated in to the existing health infrastructure. Healtheducation to the public, teachers and health personnel would enhancethe impact of a primary prevention programme. For more details seeChapter 10, Primary prevention of rheumatic education activitiesHealth education activities should address both primary and second-ary prevention. The activities may be organized by trained doctors,nurses or teachers and should be directed at the public, teachers andparents of school-age children. Health education activities shouldfocus on the importance of recognizing and reporting sore throatsearly; on methods that minimize and avoid the spread of infection; onthe benefits of treating sore throats properly; and on the importanceof complying with prescribed treatment education campaigns in schools and in the community areeffective methods for communicating health messages and for in-creasing awareness in schoolchildren and parents. Health messagescould be transmitted to parents indirectly by targeting involvement of the print and electronic media (radio, TV, news-letters, posters) is vital to the success of such programmes. Patientgroup meetings are also a potent means of transmitting and network-ing health information. The commitment of the school and schoolhealth service (when available) to the health education of children isof tremendous importance when implementing RF/RHD health-care providersMembers of the health team at all levels have clearly identified rolesand responsibilities in running RF/RHD prevention programmes, andthey should receive appropriate training at regular intervals. Trainingshould be given to physicians, as well as to non-physician health-careproviders who are involved in primary or secondary preventionactivities. Training programmes should stress the importance of earlydetection, diagnosis and appropriate treatment of streptococcal phar-yngitis, as well as the importance of detecting, treating RF/RHD andmonitoring compliance to secondary prophylaxis. Training coursesshould also include procedures for penicillin skin testing and fortreating anaphylactic health nurses are essential for running RF/RHD preventionprogrammes in developing countries, particularly in planning, coordi-nating and implementing such programmes where there is a shortageof available surveillanceSurveillance of acute RF and RHD, if incorporated in to the nationalstatistical report, would provide useful information on the epidemio-logical trends of the disease. Regular analysis and evaluation of theRF and RHD registers would also provide useful information ontrends and characteristics of the disease in defined locations. Whereresources permit, surveys in school-age children may be conducted todetermine prevalence of RF/RHD, the seasonal frequency and distri-bution of streptococcal pharyngitis, and the levels of antistreptolysin-O titres in the school-age and school involvementThe success of a prevention programme depends on the cooperation,effectiveness and dedication of health personnel at all levels, as well118as of other members of the community ( health administrators,educational administrators, teachers and community leaders). Mostimportantly, potential patients themselves and their families must beinvolved in the control strategies adopted by schools play a large part in spreading streptococcal infection, theycan also play a large role in its control. Where school health servicesexists, they should be used to identify children with signs suggestive ofRF. Screening schoolchildren for RF is worthwhile in areas with ahigh prevalence of RHD, and such screening may be carried out bycommunity health workers who have been specially trained for thepurpose. Teachers and pupils should also be involved in efforts toimprove patient adherence to secondary prophylaxis, as well as infollow-up manual with detailed recommendations for preparing a plan ofoperation for RF and RHD prevention has been published by theWHO/CVD programme (2). fever and rheumatic heart disease. Report of a WHO StudyGroup. Geneva, World Health Organization, 1988 (Technical Report Series,No. 764). WHO Global Programme for the prevention of RF/RHD. Report of aconsultation to review progress and develop future activities. Geneva, WorldHealth Organization, 2000 (document WHO/ ). L. The virtual disappearance of rheumatic fever in the United States:lessons in the rise and fall of disease. Circulation, 1985, 72(6):1155 A, Mohs E. Prevention of rheumatic fever in Costa Rica. Journal ofPediatrics, 1992, 121(4):569 RJ. The Northland rheumatic fever register. New Zealand MedicalJournal, 1984, 97:671 JF et al. 10-year educational programme aimed at rheumatic fever intwo French Caribbean islands. Lancet, 1996, 347:644 G et al. Rheumatic fever and chronic rheumatic heart disease inYarrabah aboriginal community, North Queensland. Establishment of aprophylactic program. Medical Journal of Australia, 1993, 158:316 P et al. Fiebre reumatica in Ciudad de la Habana, 1972 y caracteristicas. [Rheumatic fever in Havana, 1972 and characteristics.] Revista Cubana de Pediatria, [CubanJournal of Pediatrics] 1988, 60(2):32 P et al. Fiebre reumatica in Ciudad de la Habana, 1972 y caracteristicas. [Rheumatic fever in Havana, 1972 and characteristics.] Revista Cubana de Pediatria, [CubanJournal of Pediatrics] 1989, 61(2):228 HA et al. The natural history of acute rheumatic fever in Kuwait: aprospective six-year follow-up report. Journal of Chronic Diseases, 1986,39(5):361 T et al. The community control of rheumatic fever and rheumaticheart disease: report of a WHO international cooperative project. Bulletin ofthe World Health Organization, 1981, 59(2):285 WHO programme for the prevention of rheumatic fever/rheumatic heartdisease in 16 developing countries: report from Phase I (1986 1990).Bulletin of the World Health Organization, 1992, 70(2):213 and recommendations1. Although proven inexpensive cost-effective strategies for theprevention and control of streptococcal infections and their non-suppurative sequelae, acute rheumatic fever and rheumatic heartdisease, are available, these diseases remain significant public-health problems in the world today, particularly in Available data suggest that the incidence of group A streptococ-cal pharyngitis and other infections as well as the prevalence ofthe asymptomatic carrier state have remained unchanged in bothdeveloped and developing The largely ineffective control of RF and RHD in developingcountries is associated with poverty, and its associated conditionssuch as substandard nutrition and overcrowding, and inadequatehousing. In addition, weak infrastructure and limited resourcesfor health care also contribute to the poor status of Although progress has been made in the understanding of pos-sible pathogenic mechanism(s) responsible for the epidemiologyand the development of these non-suppurative sequelae of strep-tococcal infections, the precise pathogenic mechanism(s) are notidentified or The diagnostic criteria for RF and RHD have been reviewed andmodifications have been recommended based upon new informa-tion and upon the need to offer practical guidelines for diagnosisand management for physicians and for public health 2002 2003 World Health Organization criteria for the diag-nosis of RF and RHD specifically address: Primary attacks of rheumatic fever Recurrent attacks of rheumatic fever in patients without evidenceof rheumatic heart disease Recurrent attacks of rheumatic fever in patients with pre-existingrheumatic heart disease. Rheumatic (Sydenham) chorea Insidious onset carditis associated with rheumatic fever Chronic rheumatic heart disease6. Clinical history and physical examination remain the mainstay fordiagnosing RF and rheumatic valvular heart disease particularlyin resource-poor settings. Two-dimensional echo-Doppler andcolour flow Doppler echocardiography have a role to play inestablishing and clinically following rheumatic carditis and rheu-matic valvular heart The clinical microbiology laboratory plays an essential role inrheumatic fever control programs, by facilitating the iden-tification of group A streptococcal infections and providing infor-mation of streptococcal types causing the disease. National andregional streptococcal reference laboratories are lacking in manyparts of the world and attention needs to be given to establishsuch laboratories and to assure quality Patients with rheumatic valvular disease need timely referral foroperative intervention when clinical or echocardiographic criteriaare met. Management of RHD in pregnancy depends on the typeand severity of valvular disease, and regular followed up andevaluation are mandatory for this Primary prevention of rheumatic fever consists of the effectivetreatment of group A beta-hemolytic streptococcal pharyngitis,with the goal of preventing the first attack of rheumatic it is not always feasible to implement broad-based primaryprevention programs in most developing countries, a provisionfor the prompt diagnosis and effective therapy of streptococcalpharyngitis should be integrated into the existing Secondary prevention of rheumatic fever is defined as regularadministration of antibiotics (usually benzathine penicillin Ggiven intramuscularly) to patients with a previous history of rheu-matic fever/rheumatic heart disease in order to prevent group Astreptococcal pharyngitis and a recurrence of acute rheumaticfever. Establishment of registries of known patients has proveneffective in reducing morbidity and Infective endocarditis remains a major threat for individuals withchronic rheumatic valvular disease and also for patients withprosthetic valves. Individuals with rheumatic valvular diseaseshould be given prophylaxis for dental procedures and for surgeryof infected or contaminated The establishment of a national RF prevention program is essen-tial in countries where RF and RHD remain significant healthproblems. It is important to include such programs in nationalhealth development plans, and to implement them through theexisting national infrastructure of ministries of health and ofeducation without requiring a new administrative framework orhealth care delivery Well planned and encompassing research studies are required togather epidemiological data on group A streptococcal infections,122RF and RHD. This can result in the targeting of high risk indi-viduals and populations to make more effective use of often lim-ited financial and human resources. Basic research studies arealso needed to further elucidate the pathogenesis mechanismsresponsible for the development of the disease process and fordevelopment of a cost-effective vaccine.

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