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Indian Journal for the Practising Doctor

Rheumatic Heart Disease: Challenges and Opportunities

Author(s): Gaash B, Ahmad M, Bashir S

Vol. 4, No. 6 (2008-01 - 2008-02)

Gaash B, Ahmad M, Bashir S

ISSN: 0973-516X


Dr Muzaffar Ahmad, MD, a physician, is Director Health Services, Kashmir;
Dr Bashir Gaash, MD, is an epidemiologist and child health practitioner;
Dr Shabnam Bashir is a DNB scholar in Escorts-Fortis Hospiral & Medical Research Centre, Faridabad.

Correspondence: Shabnam Bashir, P O Box 673 (GPO), Srinagar, Kashmir.
Email: shabu-8171(at)gmail.com


Rheumatic fever is a serious inflammatory disease affecting mainly joints, heart, skin, and the central nervous system. The disease is of antiquity but its causation was explored only in the 19th Century and management strategy evolved as late as 2nd half of the 20th Century, when it was recognized that, the problem is common, has recurrence potential and the complications and sequelae are far more devastating than the disease itself. The public health significance of the disease is attributable to various characteristics of the disease or its management:

1) Complication of a common infection: Acute rheumatic fever follows streptococcal throat infection which is common in the school-age children. Studies performed on school children in 1960s showed that 0.3% of untreated patients with proved β-hemolytic streptococcal infection got acute rheumatic fever (ARF)1. However, 3% of US military personnel with untreated streptococcal infection developed ARF in the 1950s. It is held now that 1-3% of the most susceptible group (children aged 5-15 years) who suffer β-hemolytic streptococcal pharyngitis can be expected to proceed to ARF.

2) Dreadful sequelae: A sizeable proportion of ARF patients develop sequelae; carditis is the main and most devastating complication. The famous and favourite medical quote, attributed to Lasegue2, that ‘rheumatic fever licks the joints and bites the heart’ holds awfully true. In various American studies conducted before penicillin was used for prevention of rheumatic fever (1921-1930) showed that up to 73% of patients developed carditis3. The majority developed mitral insufficiency; approximately 50% had, in addition, aortic insufficiency4. The prognosis of carditis is ominous: the 20 year follow-up study by Bland and Jones confirmed that without proper treatment (secondary prevention programs, open heart surgery or use of prosthetic valves), patients with marked cardiomegaly, congestive carditis or pericarditis have 70-80% chance of dying within 10 years.

3) Poorman’s Disease: Rheumatic disease is primarily associated with poverty, illiteracy and disadvantaged socioeconomic status, though the relationship is not straightforward but reasonably complex. The disease which was widely prevalent in the developed world some 50 years ago is currently a disease of developing countries. There is no doubt that advent of penicillin and its subsequent use for primary and secondary prevention of RHD played its vital part but acute rheumatic fever had shown a drastic reduction in incidence and severity long before this intervention was widely adopted. From 1925 to 1950, ARF was the leading cause of death in American children and adolescents (5-19) yr5, and leading cause of heart disease below 40 yr, as it is today in developing countries. In the first quarter of the 20th Century, during spring season, up to 25% of pediatric beds were occupied by patients with ARF or its consequences6. Actually, hospitalization rates and death rates from ARF in USA exceeded those from pertussis, measles, diphtheria, scarlet fever, poliomyelitis, meningococcal meningitis and typhoid5. At that time, the annual incidence there was 100-200/100,000 population, ie equaling present day India’s.

Yugoslovian studies performed to determine the underlying factors in persistence of ARF among young population found associations with such diverse factors as home dampness, change of place of residence during the last 5 yrs, low maternal education, a bodyweight below normal, frequent incidents of sore throat, positive family history of rheumatic fever, etc – all found to be statistically significant7. Other contemporary and later studies found a higher incidence of ARF in children of families and communities with a lower socioeconomic status and sub-standard housing and living conditions. Thus it was hypothesized that ARF is closely linked to lower socioeconomic status and crowded living conditions.

Subsequent studies suggested that a steady decline in the incidence of ARF in USA and Europe in the 20th Century was associated with improved socioeconomic conditions with better nutrition, improved sanitation and less crowding1,4. Consequently, overcrowding living conditions got firmly associated with incidence of ARF8.

It is not unreasonable to expect overcrowding to be an underlying factor in rheumatic fever. Streptococcal throat infection is more readily spread in overcrowded circumstances, and a seasonal flare up of ARF in late winter and spring seasons can be linked to overcrowding during these months, especially in colder, temperate regions. However, overcrowding long believed to be at the bottom, failed to be substantiated as an important risk factor by conditional logistic regression in a modern day study7,9. The recent (1974-1985) US outbreaks also lacked the classic association with lower SES10.

Experts believe that some other socioeconomically determined factor closely paralleling crowding could be the actual determinant of rheumatic fever. In the 1974 Utah and Tennessee outbreaks, the families of affected people were larger than the State average10,11. Other reports showed a higher incidence in members of extended families12.

4) Availability of Health Care: Although many socioeconomic factors and environmental factors are important in reduction of incidence and severity of ARF, the importance of widespread use of antibiotics and improved availability of health care, can not be undermined. In 1950, Denny and his colleagues showed the possibility of preventing initial attacks with injectable pencillin in military camps. Their discovery is considered to be one of the most important research contributions in the past 50 yrs. For the first time it was apparent that rheumatic fever could be prevented if preceding beta-hemolytic streptococcal infection was treated adequately13,14. The universal realization that eradication of streptococcus was essential for prevention of ARF15, which led to a spectacular reduction in the incidence of severity of rheumatic fever all over the world, particularly in the developed world. Thus in the USA, the incidence of ARF declined by 60% over a decade in areas covered by a comprehensive rheumatic fever prevention program. Also, it witnessed a steady fall in carditis, from 73% in 1922-1930 to 51% in 1951-19603,4. The policy implication was that appropriate medical intervention could help reduce the number of initial attacks of ARF in the mainland USA16 – thereby relating availability of healthcare to reduction of ARF. Similar results were seen among Native American17,18 and Alaskan populations12,19.

5) Role of genetics: Studies suggest that rheumatic fever also may have some genetic predisposition1; a higher concordance has been seen in monozygotic twins than the dizygotic ones1. Some specific HLA markers20 and non-HLA B-cell alloantigen21 have been found related with susceptibility to rheumatic fever.

6) Racial predilection: ARF has shown a clear racial predilection. In the USA, where the incidence in mainland children has fallen below 1/100,000 population (currently it is at 0.5), unexplained high incidence persists in Hawaii and NZ in Polynesian children12. High endemic rates still prevail in poor urban blacks22 and Hispanic children23.

Differences among ethnic and non-ethnic populations are more vivid in Australia, where aborigines have almost 100 times more incidence than the non-aboriginal.(Table 1). Among aboriginal people of northern Australia, acute rheumatic fever develops in 0.2 to 0.5% of schoolage children each year, and more than 2% of people of all ages have rheumatic heart disease. In New Zealand, Maori population has a 4 times higher incidence than the non-Maoris. (Table 1).

Table 1: Comparative incidence of ARF in the ethnic and non-ethnic populations of Australia and New Zealand1

Country Incidence of
ARF/100,000
population
New Zealand
Non-Maori 9
Maori 37
Australia
Aboriginal 3
Non-aboriginal 282

Racial and ethnic minorities in other countries are also unusually susceptible to rheumatic fever24-26. Thus, unexpectedly higher incidence is seen among Malays in Singapore, Arabs in Israel and Bantus in South Africa. Although generally such minorities have a lower socioeconomic status than their majority counterparts, studies on Maori and Pacific Islander population of New Zealand, have shown that ethnicity is an independent risk factor for development of ARF22,25.

7) Duration of Disease/Treament: Rheumatic fever is a protracted disease. The average duration of ARF is approximately 3 months27. Carditis, which occurs in 50-60% cases of ARF, appears within first 2 wks28 and not only persists lifelong but progresses without treatment. Treatment also is prolonged; the minimum recommended is 5 years secondary prophylaxis. As validated by a recent study in Chile29, lifelong prophylaxis may be required30.

8) Recurrences: It was none other than Sir William Osler who noted the propensity of rheumatic fever to recurrence as early as 189231. Every recurrence of ARF further damages the heart and worsens carditis. Thus, while carditis occurs in approximately half of the initial cases, recurrent attacks of ARF are associated with very high rates of carditis, leading to chronic progressive valvular disease – especially stenosis – necessitating valve replacement and predisposing to bacterial endocarditis. Risk of ARF rises dramatically from the 1st (1-3%) to subsequent attacks (25-75%)13. Studies have shown that patients who get carditis in the initial attack of ARF are at risk of further aggravation, while those who don’t get it with the 1st attack have much less risk of cardiac involvement after a recurrences32.

9) Outbreaks in developed world: During the past 40 years, there has been a spectacular fall in the incidence and severity of rheumatic disease in all the developed countries and some prosperous Asian countries24. Rheumatic disease which was a reportable disease in Denmark for many years registered a steady decline since 190012. In the USA, mortality rates and hospital discharge rates have shown a steady decline particularly since 195012. By 1980s, very low rates (<1 case/100,000) of ARF were seen in the 5-19 yr old American population33. The severity of disease also decreased; carditis rates fell from 73% in 1922-30 to 51% over the 1951-60 period3,4. The 5-year morality rates declined from 24% to 3% between 1921 and 195112.

The striking reduction in incidence and severity of rheumatic fever in the developed world made researchers complacent about it, and they even forgot that the ‘dog’ continues to bite the children in developing countries as before. However, the contented siesta was shortlived. There was an unexpected upsurge of ARF in USA in the late 1980s and 1990s, with increasing number of ARF cases in different parts of the country. The shocking resurgence, which began from 1985-86, affected mostly the intermountain region of Salt Lake City12, and the military installations10. All these were found to be focal outbreaks, because of highly rheumatogenic strains of group A (M1,M3,M5,M6,M18) circulating in the particular region12,34.

The clinical profile proved to be more severe than anticipated. In the investigated outbreaks in USA, severity of disease was higher: 68% of pts had carditis (19% severe carditis with CCF, 3% requiring mitral valve replacement) while 37% developed chorea34. Earlier US reports (1951-1965) had documented clinical carditis in initial attacks in 40-51% and chorea in 9-17%27. Because of the appearance of the rheumatogenic strains in selected communities, the areas where focal outbreak were reported still continue to report increased incidence of ARF1.

The role of prevention is paramount, since no specific treatment is available, while prevention of initial (primary prevention) and recurrent attacks (secondary prevention) is possible and the only measure available for control of rheumatic fever.

Impact of drastic reduction in developed world

As discussed above, the burden of rheumatic fever has registered a drastic reduction in the developed world over the last 4-5 decades. This was sadly accompanied by loss of interest in the disease by medical writers, authors and researchers in the developed world. While an average of 516 articles on rheumatic fever per year were published in Medline-indexed journals between 1967 and 1976, only 172 papers on rheumatic fever (and related problems) appeared between 1997 and 200635. This waning interest was foreseeable since rheumatic fever ceased to be a public health problem in almost all wealthy countries. Most of the practitioners there are unlikely ever to see a case of acute rheumatic fever, and their experience with rheumatic heart disease may be limited to heart-valve lesions in older patients who had rheumatic fever in their youth.

However, the affluent countries experiencing near elimination of rheumatic fever form a mere 20% of the globe. Elsewhere, rheumatic fever and rheumatic heart disease have, instead, assumed a greater significance. Currently, some 15.6 million people have rheumatic heart disease worldwide, with 470,000 new cases of rheumatic fever occurring each single year35. At the same time, rheumatic fever or its complications particularly, rheumatic heart disease, kill approximately 233,000 people each year35. These are, however, conservative estimates — the actual figures are likely to be substantially higher. The tragic part is that almost all these cases and deaths occur in developing countries, where poverty rules and most people do not have reasonable access to quality health care.

Globally, rheumatic heart disease continues to be the most common form of acquired heart diseases in all age groups36,37, and accounts as much as 50-60% of all CVS disease1.

Currently, some 15.6 million people have rheumatic heart disease worldwide35.

Annual global incidence of rheumatic fever is up to 280/100,000 population; 470,000 new cases occur each single year35.

Rheumatic fever and RHD kill approximately 233,000 people each year35.

RHD is the most common form of acquired HD in all age groups.

Table 2: Comparative incidence of ARF1

Location/population group Incidence/100,000
Sweden 0.2
USA 0.5
Australia 3
New Zealand 9
China 20
Kuwait 29
India 44
Turkey 46
Iran 80
Sri Lanka 140

Rheumatic fever, like tuberculosis, leprosy and malaria, has disappeared from the developed world mainly attributed to improved living conditions. Better housing, less overcrowding, better personal and environmental hygiene, coupled with highly efficient modern health care have all played their role in liberating affluent countries from these diseases of poverty. Rising standard of life brings with it a higher literacy, better nutrition, improved health seeking behaviour, and a voice that is heard.

Now rheumatic disease, previously ravaging whole world, has got pushed to be another disease of the global 80% poor, deprived citizens. An unfortunate accompaniment of the dramatic decline in the developed world has been a parallel reduction in rheumatic fever-related research there. Scrutiny of the progress made in the last 40-50 years shows that the only real advances during the past half a century have been in the treatment of severe rheumatic heart disease — treatment that is largely palliative and neither accessible nor affordable to the majority of the affected patients. The mainstay of the control of rheumatic fever remains the primary prophylaxis (penicillin treatment of group A streptococcal pharyngitis with penicillin) and secondary prophylaxis (benzathine penicilin injections every 3 to 4 weeks) for almost lifetime. Both the control strategies are based on findings from studies conducted in the US published as early as the 1950s13,38. Benzathine penicillin is a painful experience for the recipient, generally a child or adolescent, yet no viable or feasible alternative is available there. Oral penicillin for secondary prophylaxis is not recommended, since its ability to eradicate streptococci in throats is not equal to the ability of injectable penicillin to do so39. This 50-year old treatment is apt to continue for long since no viable alternative is anywhere apparent in the foreseeable future. Study supports the use of 1% lidocaine HCl as a diluent for benzathine penicillin G to increase tolerability40; however, there are other considerations also. Recurrence rates with the attendant increased risk of carditis reported after some recent outbreaks41,42 have forced experts to have a careful secondary look at secondary prevention and its delivery12.

It is not surprising, though, that no significant progress has been made in primary and secondary prophylaxis of rheumatic fever during the last 40-50 years. Clinical research, particularly developing a new drug, entails huge costs which should be returned with profit. There is no great hope of good returns from poor countries, therefore, hardly any multinational pharmaceutical company has ever played the gamble of developing new drugs for tropical diseases and various diseases of poverty. After all, who is going to invest in poor people? Research in developed world is generally sponsored by pharmaceutical companies; that partly accounts for loss of interest in trying new modalities of treatment among researchers there.

Parenteral secondary prophylaxis (despite the criticism) is the only one strategy of control that has proved to be cost-effective and practical even in the poorest countries. Therefore, WHO has continued to recommended this strategy for the last 2 decades, most effectively delivered within a coordinated program using a registry of patients, as the first priority for the control of rheumatic heart disease.(WHO). Yet, most developing countries still do not have effective secondary-prophylaxis programs. India, too, does not have a national programme and there is no rheumatic disease registry anywhere. While policy-makers, planners, health administrators, and practitioners are vehemently talking about ischemic heart disease, diabetes, and cancers, no one seems to be bothered by rheumatic fever and its sequelae.

In conclusion:

India is an endemic country as regards rheumatic fever; studies in different parts show a prevalence of rheumatic heart diseases in school children between 1 and 5.4 cases/1000 (Padmavati et al). Despite the fact that living conditions have improved in urban areas, the incidence of rheumatic fever between 1966 and 1980 remained stable in India during the period of rapid decline in the US and other developed countries24.

The difficult challenges in rheumatic fever control are:

1. How to know that a child complaining of sore throat has streptococcal infection? Vast majority of schoolage children suffer sore throat many times a year, and which episode is streptococcal can be said with certainty only if throat culture is done. However, such facilities in India exist only in teaching hospitals, which generally cater to urban or semi-urban population. Giving penicillin empirically for 10 days to all school-goers for all episodes of sore throat is a tall order, indeed for a developing country. The World Health Organization is not sure whether a community primary prophylaxis program can be a practical and cost-effective public health measure in developing countries, and how to ensure that limited health care funds are spent most effectively — which may entail diverting some funding from the tertiary care (provision of expensive cardiac surgery for severe rheumatic heart disease) to the development of robust secondary prophylaxis program.

The golden standard of diagnosis for streptococcal throat infection has been culture. Unavailability of culture facilities in almost all rural areas of India, where 80% of the Indians live, speaks for itself. Rapid diagnostic test (rapid antigen-detection kit test) are available; though some are highly specific, others need to be confirmed by throat culture.

Sensitivity too is not very high; in one study, in one third of persons with false negative rapid test, streptococcal antibody titres rose subsequently, thus suggesting presence of infection43. This implies that, practically, we will have to rely on throat culture for detection or confirmation of streptococcal pharyngitis and initiating primary penicillin prophylaxis. A –ve culture avoids unnecessary antibiotics in the 70-80% of children with a sore throat attributable to viral pharyngitis44. Primary preventive treatment is effective even if started as late as 9 days after the infection develops; thus experts suggest that physicians can wait 24-48 hrs for verification of infection by throat culture.15

2. How to diagnose rheumatic fever?The diagnosis of rheumatic fever is not easy. There is no pathognomic symptom or sign which can be elicited easily. The hallmark of diagnosis for ARF has been the Jone’s criteria, which are revised regularly indicating their incompleteness.

Jones Criteria, Updated 199245

  • A) Major criteria
    • Carditis
    • Polyarthritis
    • Chorea
    • Erythema matginatum
    • SC nodules
  • B) Minor criteria
    • Clinical findings –Arthralgia/fever
    • Lab findings-Elevated acute phase reactants/elevated ESR/elevated CRP
    • Prolonged PR interval
  • C) Supporing evidence of antecedent Group A streptococcal inf
    • Positive throat culture or rapid streptococcal antigen test
    • Elevated or rising strep antibody titre

If supported by evidence of preceding group A streptococcal infection, the presence of 2 major manifestation or one major and 2 minor manifestations indicates a high probability of ARF.

As obvious, evidence of previous group A beta-hemolytic streptococci is essential for diagnosis of probable ARF. It is not an overemphasis to remind that diagnosing a patient as having rheumatic fever may mean condemning him to a lifetime of painful injections, with the ever present risk of allergic reactions. RHD may remain undiagnosed. When found, carditis is generally diagnosed clinically; clinical data suggests that 40-50% of patients with the first attack of ARF develop carditis. However, researchers in developed as well as developing countries have shown that carditis diagnosed clinically grossly underestimates the problem. Marijon et al46 found that 2-3% of school-age children in Cambodia and Mozambique had rheumatic heart disease, almost all of it previously undiagnosed!! In sharp contrast to clinical examination alone which showed a prevalence of mere 2.2-2.3/1000, echocardiography detected a prevalence of 21.5-30.4/1000 (ie 2-3%). In other words, the actual prevalence was 10 times more than generally perceived. This may be the mere tip of the iceberg, since cases in children 5-15 year old represent only 15- 20% of all cases in the population47. Many other studies, using echocardiography, have found subclinical carditis in ARF10,41,48.49. In Utah outbreak, Doppler echo raised carditis rates to 85% (up from around 70% diagnosed clinically)34 These data confirm that rheumatic fever and rheumatic heart disease are of sufficient importance to warrant the urgent attention of the international public health and research communities.

Use of colour or pulsed doppler has other advantages also. It can differentiate pathologic leftsided regurgitation from physiologic regurgitation50. Doppler is particularly of use in patients with polyarthalritis as the sole manifestation, when diagnosing rheumatic fever is difficult4,12,51, or in patients without any major criterion12 or when only echocardiographic evidence of mitral/aortic regurgitation is present.12

Missing a case of carditis implies that the patient will get recurrent attacks of carditis in absence of secondary prophylaxis. Marijon and his colleagues report that, in the absence of echocardiography 9 out of 10 cases of RHD may be missed. This makes a strong case for the use of Doppler for detection of all cases of sub-clinical and clinical rheumatic carditis. However, for any developing country relying mainly on primary and secondary health care Doppler is a far fetched idea unless an organized well-knit referral system is established.

2. How to ensure that secondary prophylaxis is delivered to those who need it? Most cases of rheumatic fever in developing countries go unnoticed, and a patient is recognized as a case only after rheumatic fever has damaged the valves or after the first episode of subacute bacterial endocarditis (SABE). Secondary penicillin prophylaxis, parenteral and delivered within a coordinated program using a community registry of patients, is recommended as the first priority for the control of rheumatic heart disease by the World Health Organization. Despite very high incidence of rheumatic fever and RHD among children and young adults, India does not have an official programme for secondary prophylaxis. This is because the more important killes (diarrhoea, ARI, TB, HBV, malaria, etc) are still at large. Also, because non-communicable, high profile, diseases like IHD and diabetes are also pushing through. Possibly, our policymakers and planners will not have time to think about rheumatic diseases for a long time to come. Thus, we will have to go on with ARF and RHD as we are doing now, ie a hospital-based approach to the individual patient who lands somehow in a pediatric hospital.

The burden of rheumatic fever and rheumatic heart disease is largely unappreciated in India or else gets eclipsed by frequent outbreaks of diarhhoea, hepatitis, typhoid, HBV, HIV, malaria, tuberculosis, and pneumonia. Frequent outbreaks of these diseases drain the resources and lead to fatigue among the staff.

In the low risk areas, parenteral depot penicillin is given ever 28 days. In high risk areas, WHO recommends giving benzathine penicillin G every 21 days. Studies have found this dosing to be more efficacious on longterm basis (Lue et al), since serum levels toward end of time can be unreliable (69 and not sufficient to offer protection (Kaplan et). This recommemdation may be sound for an individual patient presenting for secondary prophylaxis, but for a national programme in a developing country, it can have tremendous managerial and financial implications. WHO recommends that before adopting the 3-wk strategy, practicability, cost, and other probable complications need to be considered.

3. Tertiary prevention (rehabilitation) is quite expensive, and generally not accessible to the large majority who need it. It is available only in a few selected tertiary care centres in developing countries, and costs are prohibitive.

4. Development of a vaccine against rheumatic fever is a burning issue. A number of vaccines are in different stages of development, and a safe and effective vaccine may well be available within one or two decades. However, experience with other relatively recent vaccines, including conjugate pneumococcal and Haemophilus influenzae type B vaccines, suggests that there may be many barriers to the funding, acceptance, and use of new vaccines in the places that need them most.

There is no doubt that the much needed research in epidemiology, pathogenesis and treatment of rheumatic fever can be undertaken in many developing countries, which have the necessary expertise and resources. China and India could take the lead. Other developing countries which have scattered and scant resources could pool their resources. Sadly no such initiative is being taken by any developing country. Since epidemiologically-relevant and clinicallyapplicable research in a disease can be done in a population with a high incidence of that disease, developing countries – despite their limitations of illiteracy, the lack of skilled staff, limited finances, and inadequate technology, should come forward to this common objective.

Such collaboration is also possible between developed and developing countries. Marijon et al report a partnership among researchers in Mozambique, Cambodia, France, and Australia, with the aim of finding out ways to conduct screening for rheumatic heart disease among school-age children in developing countries. The study presents a compelling argument for the use of echocardiographic screening. There is no doubt that the use of such expensive technology is neither feasible nor affordable in the countries with the highest disease burden. Unfortunately, pure clinical diagnosis misses approximately 90% of echocardiographically-detected cases! It is not acceptable to leave these cases undiagnosed and at risk for recurrence of rheumatic fever. Instead of rejecting echocardiography as an inappropriate screening tool for rheumatic carditis in developing world, we need to go further in defining models of echocardiographic screening that are practical, affordable, and widely applicable.

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