Prevention and Control of Rheumatic Fever in India: An Achievable Health Target

INTRODUCTION

The blueprint of a pragmatic program on the prevention and control of acute rheumatic fever (ARF) in India presented by Khadar et al.,^[1] featured in the September issue of this journal is thought provoking and needs urgent consideration by the health authorities as an achievable health target. India is home to 40% of rheumatic heart disease (RHD) patients the world over.^[2] However, we do not have a nationwide registry or RHD control program.^[3] The Indian Council of Medical Research (ICMR) conducted a demonstration project from 2000 to 2010, which augmented and heralded the various registry-based secondary prevention programs in various states.^[4] Although similar efforts in many countries had success and some setbacks, we would like to put forward the available data with India in context, so that the blueprint gets prioritized as a health target with a time frame, similar to the sustainable development goals (SDGs) for the year 2030.^[5,6] The recent systematic review and meta-analysis of the available studies in India, in the at-risk age group of 5–15 years, reported a pooled prevalence of Group A streptococcal (GAS) pharyngitis to 2.79% and clinical echocardiographically diagnosed definite RHD 0.36% maintaining India in the high prevalence zone for ARF and RHD (all age prevalence of RHD >0.1%).^[7] Echocardiographic recognition of subclinical and latent cardiac involvement and initiation of penicillin prophylaxis is the best option to prevent the development of organic RHD in this high-risk population.^[8]

CONCEPT OF THE BLUEPRINT FOR PREVENTION OF RHEUMATIC FEVER IN INDIA AND GENDER ISSUES

The blueprint envisages the establishment of a health card, which documents a cardiac evaluation, including a Doppler echocardiographic study, at the time of school entry, again after 5 years, and approximately at the time of school exit.^[1] This needs the mobilization of the existing health facilities in India through public–private partnerships, considering the improvements in quality of life and social support measures that India has implemented.^[6] The Rashtriya Bal Swasthya Karyakram ensures free evaluation and treatment of children below the age of 18 years and could support the financial needs of the program with repeat echocardiographic evaluations.^[9] Over the next 5 years, it is expected that all children aged 0–15 years will be covered. School dropouts need to be evaluated by organizing targeted camps. Once this initiative is established, it should be continued, as the disease tends to fluctuate.^[5] Collecting comprehensive data is essential, and we need to demonstrate what works effectively in the Indian context.^[10,11] This documentation is highly relevant as younger individuals are likely to face challenges from both non-communicable and infectious diseases.^[12,13] In this context, the state of Kerala in India has made significant strides in controlling ARF and RHD.^[14] This progress is attributed to improvements in the quality of life, increased health awareness, and the widespread use of antibiotics. However, progress at the national level remains slow.^[2,3,14] The blueprint provided by Khadar et al., aligns the efforts with the World Heart Federation (WHF) advocacies on the prevention of ARF and RHD, with a focused approach on the high-risk age group, namely the children in the 5–15-year age group.^[15] Declaring rheumatic fever and RHD rheumatic heart disease as a notifiable disease, as was done in Australia,^[16] will make the registries comprehensive, given the Individual identity for every citizen, which India has achieved through the Aadhaar card.^[17]

The article is more relevant to the commitment of this journal since RHD has a higher prevalence in women and has an adverse obstetric outcome in mothers [Table 1].^[18] The blueprint emphasizes the importance of promptly recognizing streptococcal sore throat and using echocardiography to identify asymptomatic (subclinical) RHD.^[19] Getting at least one echo done for all children will also help to identify the “latent RHD” occurring in the community without an overt history of preceding pharyngitis or ARF, which is now very common in Indian studies.^[20,21] This approach provides an opportunity to eradicate streptococcal throat infections and ensures that those in need have access to ongoing prophylaxis, which prevents the onset and progression of RHD. Heart is the primarily the only organ chronically damaged by recurrent streptococcal infection.^[22] It is vital to thoroughly characterize early asymptomatic RHD identified through echocardiography to avoid unnecessary prolonged use of antibiotic prophylaxis.^[23] A recent review found that using echocardiographic evaluation for diagnosis, the prevalence of RHD increases at least threefold compared to clinical screening.^[21] During a follow-up period of 3–90 months, 11% of subjects with borderline RHD lesions identified by echocardiogram showed progression, whereas 74% of subjects with definite RHD progressed during the same follow-up period.^[24]

If effectively implemented, the program will improve the health of children and adolescents not only by aiming to eliminate RHD but also by addressing a range of other health issues, particularly various other cardiac disorders identified at clinical evaluation and echocardiography. Therefore, it should be prioritized by reproductive and child health services as part of the SDGs for the year 2030.^[6] RHD contributes to a third of total cardiovascular morbidity and mortality in India.^[1] ARF is primarily an infectious disorder whereas chronic RHD is essentially a non-communicable entity.^[25] No other disease borders on both infectious disease and chronic disease epidemiology like streptococcal infections and their sequelae, where improvement in living standards contributed more to control than antibiotic prophylaxis.^[10,26] The state of Kerala with its high school enrolment and good access to health facilities are rightly poised to embark on the program, which other states in India can follow in the coming decades. The key suggestion of this blueprint is to get three serial echo evaluations over a period of 10 years to identify the early lesions of subclinical and latent RHD in the susceptible age group of children to prevent overt progression to valvar heart disease by regular Penicillin prophylaxis. The four main aspects of this concept need further elaboration to deliberate the implementation of this blueprint, namely (a) the role of penicillin for the prophylaxis of ARF/RHD, (b) the use of echocardiography for early identification of RHD, (c) the concept of elimination of ARF/RHD, and (d) the current control programs in India.

PENICILLIN AND THE PROMISE OF PREVENTION: RETHINKING RHD CONTROL IN THE MODERN ERA

Treatment with penicillin, to which Streptococci have remained universally sensitive,^[27] was demonstrated to prevent the onset of rheumatic fever by the landmark study published in 1950 which forms the main pillar for primary prevention.^[28] Stollerman in 1954 established the use of long acting penicillin in preventing recurrent streptococcal infection which evolved as the key secondary prevention strategy.^[29] Recent randomized data have confirmed the efficacy of parenteral long-acting penicillin in preventing the progression of established rheumatic valve lesions, though a very small percentage (0.8%) did continue to have progression.^[30] Although the effectiveness of the secondary prophylaxis could be debated, it remains the sole drug intervention in the prevention of ARF and RHD.^[31,32] The recent meta-analysis of 51 studies on secondary prophylaxis showed that good adherence to recommendation reduced the progression by 71% compared with the poorly compliant group.^[33] The other strategy on the horizon is the development of a streptococcal vaccine.^[34,35] However, the success of this cheap drug in preventing devastating heart disease depends on the adherence to guidelines which is poor in low-middle-income countries.^[36-38] In contrast, in the developed world, with the advent of penicillin prophylaxis, RHD evolved from the commonest heart disease of childhood to preventable heart disease with very low prevalence.^[39] There is widespread resistance to the use of benzathine penicillin for primary and secondary prophylaxis in India, for the fear of anaphylaxis, though parenteral injections are 10 times more effective.^[40] Many hospitals in India and developed countries lack benzathine penicillin in pharmacy, and compliance among established RHD patients is about 50%.^[34,41] Recently, subcutaneous administration was tested as a less painful alternative to Intramuscular injection.^[42] Hence, the blueprint published is timely reminder to streamline our health system toward an achievable target, focusing on the high-risk group, the children in the age group of 5–15 years. Success of this program essentially rests on identifying the children who will benefit maximally by the continued prophylaxis, for which echocardiography has evolved as the useful tool.^[43] The changing spectrum of ARF and RHD in India has highlighted that subclinical and latent cardiac involvement identified by echocardiography is often common.^[21,44] It is prudent to get an echocardiographic evaluation done before embarking on an long-term antibiotic prophylaxis, especially when the study can avoid, unnecessary prophylaxis in children who otherwise have a heart murmur unrelated to rheumatic involvement.^[45]

TARGETING PROPHYLAXIS: ECHOCARDIOGRAPHY AS A GATEKEEPER FOR PENICILLIN USE IN CHILDREN

Clinical recognition of heart disease in rheumatic fever happened with the discovery of the stethoscope and clinical auscultation for heart murmurs.^[46] In 1889 Cheadle, the United Kingdom correlated the heart murmurs with the occurrence of acute rheumatism which led to the description of events by which the chain of organism infecting the throat damages the heart.^[47] The high prevalence of the disease in temperate climates facilitated Duckett Jones, from United States in 1944 to put down the observed clinical and laboratory features as the criteria for the diagnosis.^[48] It was Veasy et al. in 1987 for the 1^st time described asymptomatic echo detected rheumatic heart valve involvement in ARF when he documented the resurgence of ARF in the United States.^[49] In 1996, Anabwani and Bonhoeffer undertook an echocardiographic screening of 1,115 Kenyan children with surprising findings: While only three out of every 1000 showed auscultatory findings of RHD 62/1000 had echocardiographic findings that suggested early RHD.^[50] With increasing evidence across the globe on subclinical and latent RHD, over two decades American Heart Association accepted the echocardiographic criteria as a major criteria for the diagnosis of rheumatic fever which is now endorsed by various stakeholders including the World Health Organization.^[51] Both the American Society of Echocardiography have published recommendations for echo diagnosis of RHD, and the evidence-based echo scoring system developed in India will help to minimize the false-positive studies.^[52,53] WHF guidelines re-classify the borderline and definite diagnosis based on echo to A–D categories and give guidelines for echo screening of at-risk populations.^[54] Further innovations with hand-held echocardiography, training of paramedics, utilizing telemedicine, artificial intelligence, and single parasternal-long-axis-view-sweep of the heart, community screening is now a reality.^[55,56] Recent study from Uganda, using a hand-held echo device in the acute care setting identified a group of febrile children with echo identified valve involvement as the sole manifestation of “silent ARF.”^[57] Similarly follow-up of children with echocardiographic diagnosis showed that children with echo-diagnosed definite ARF had twice the risk for progression of heart disease, compared to echo-negative children, though the heart lesions remained stable or regressed in the 1^st year.^[8,58] Auscultatory diagnosis, which was crucial in the diagnosis of rheumatic fever, is now supplemented by echocardiographic diagnosis of subclinical and latent heart disease, which is crucial for preventing the progression by identifying early asymptomatic valve lesions.^[59] Given the huge population at risk in India, with large disparity in health facilities, cost effective analysis essentially highlights the utility of secondary prophylaxis as a national strategy.^[60] The repeat echocardiographic scanning factored every 5 years in the blueprint will help to document the natural history of the valve lesions and offer an opportunity for withdrawal of the prophylaxis if the valve lesion remains static or show regression, at least by 18 years of age.

Major bottleneck for this blueprint is the need for 3 echo evaluations for all children at 5 years interval starting with their school entry. As per the data available in the public domain in Kerala, 2.5 lakh students get enrolled for school entry every year and hence will need an equal number of health cards and color Doppler evaluation. This could be well within the reach of the health system in Kerala, which needs to be expanded to 7.5 lakh students to cover the students at 10 years and 15 years of age. This will result in at least 0.58% of the school children in this age group receiving long-acting penicillin prophylaxis, once all the children in the age group are covered given the current data on echo diagnosed RHD from Kerala.^[14,61] In that study on community screening of school children from Kerala, half the rheumatic group were classified as borderline RHD cases.^[14] These children need to be kept on more frequent follow-ups rather than the five yearly review, to take them out of the unnecessary continuation of prophylaxis, either by expert referral especially when the serial echo shows static nature or regression of the valve lesion.

It is interesting to note that in Kerala, over the past four decades, the use of long-acting penicillin injections has declined to be replaced by oral penicillin tablets (though the decline in ARF and RHD is substantial) with the state ranking fifth position in the national antibiotic use.^[62] 3.3% of the Kerala population use antibiotic self-medication in the state, commonly for throat infections using azithromycin.^[63] Among the antibiotics cephalosporins and fluoroquinolones were purchased thrice more often than penicillin in outpatient prescriptions.^[64] Recent review on streptococcal infections suggests some superiority of cephalosporins in eradicating GAS infections since they reduce penicillinase-generating pharyngeal flora, which are implicated in GAS carrier state.^[65] This context role of normal pharyngeal flora in modulating the rheumatic response and their contribution to carrier state needs further exploration.^[66,67] The decline in rheumatic fever in Kerala correlated with the evolution of Kawasaki disease, where post-infectious inflammatory phenomena are implicated.^[68] Changing lifestyles, increase in vaccination coverage, and declining infectious diseases are discussed as contributors to this transition.^[69] Whether this transition is an illustration of the epigenetic inflammatory modulation or alternation in indoor atmospheric pollution could be an aspect of future research.^[70-72] The feasibility of prophylactic treatment of school children based on echo-diagnosed RHD, in India, is now published from Bikaner.^[73] The study from India which reported the highest prevalence of echocardiographically recognized RHD is from Bikaner in 2010.^[74] Here, 5.1% of echocardiographically detected RHD were reported in school children, whereas the clinical recognition was only 0.1%.^[75] Subsequent school survey from Bikaner in 2016 adopting the WHF echocardiographic criteria reported a prevalence of 3.52%.^[73] In the study published in 2020, 115 children with subclinical valvular lesions were offered prophylaxis of which only 57 adopted the same.^[73] 14 children adopted benzathine injections whereas 37 opted for oral penicillin and six were on oral erythromycin. On 2-year follow-up, 45 children underwent repeat echocardiography. In 29 study children, the valve lesions were considered static, and in 14 (29%), the valve lesions disappeared or decreased. Only two children showed echocardiographic progression (3.6%) and on analysis, their prophylaxis was considered suboptimal. The study suggests that only 50% of the families adopt prophylaxis for their children and improvement does occur on oral penicillin prophylaxis as well. Those who improved did so early on initiation of prophylaxis.

ARF AND RHD: ELIMINATION WITHIN REACH, ERADICATION BEYOND?

While eliminating ARF and RHD could be an achievable goal, full eradication of these post-streptococcal sequelae would remain an elusive target at present, given the streptococcal biology, pathogenesis, and the lack of an effective vaccine against streptococcal infections.^[32,31,76] Three factors are critical in the genesis of rheumatic fever, namely infection by a rheumatogenic strain, a susceptible individual, and an abnormal immune response.^[77,78] GAS is an exclusive human pathogen having co-evolved with Homo Sapiens and exists in a carrier state in the throat and skin in about 20% of the children.^[79,80] The genus Homo lost the ability to synthesize Vitamin C corresponding with the evolution of color vision.^[81] Streptococcus got adapted to infect species that have a limited ability to synthesize vitamin C, such as humans and guinea pigs as well.^[82] These human adaptation of GAS has prevented the establishment of an animal model except in rats, where the valvular lesions could be generated without streptococcal infection but with immunization.^[83] The role of normal microbial flora and epigenetics in the modulation of rheumatic lesions has also been explored.^[59,66] Another reason for the exclusive human specificity of streptococci could be the glycoprotein biology peculiar to humans.^[84-86] Earlier studies categorically differentiated the nephritogenic and rheumatogenic strains, but this concept was displaced in recent studies suggesting that both mucosal and skin infection with GAS can lead to long-term cardiac sequelae.^[87,88] Although there are about 600 million throat infections due to GAS worldwide every year, only 0.05 % develop RHD.^[89] Furthermore, only two-thirds of the subjects with ARF recollect a preceding pharyngitis, and only 60% of the subjects with RHD recollect an prior episode of Rheumatic fever.^[90] Family history increases the risk of developing rheumatic fever from a throat infection by 3 times, although the specific genetic factors involved are not yet well understood.^[91] During endemics of streptococcal throat infections, the average incidence of ARF is around 0.3% which may increase by tenfold to 3% in marginalized population and in army barracks and during epidemics with a novel strain.^[92] The disease has shown a rise and fall throughout the world corresponding with mutations and possible development of virulence factors by the Streptococci.^[5] The efforts to develop a streptococcal vaccine were initiated in 1923, and 100 years down the line, the vaccines are just entering clinical trials.^[93] There is more to learn about the agent, host, and environmental factors and their interaction to clarify the pathogenesis of ARF and RHD and strategize its eradication.^[94,95]

CURRENT PRACTICE ON PREVENTION AND CONTROL OF ARF/RHD IN INDIA

India does not have a National Program for Prevention and Control of ARF and RHD. Hence, it is considered integrated with the existing health services. At present, clinicians (pediatricians, otolaryngologists, dermatologists, and cardiologists) dealing with children with streptococcal infection, routinely follow the recommendations of various professional organizations.^[96] Various academic centers have adopted community interventions as well.^[97] The Jay Vigyan mission mode project on control of rheumatic fever and RHD initiated by ICMR piloted the current practices across various centers in India, from 2000 to 2010. In addition, it established registries in various centers, developed teaching modules, trained health workers, and serotyped GAS.^[4] The current efforts on the prevention of RHD globally and nationally are directed at strengthening the secondary prevention program, delegating primary prevention to individual level.^[98] There are good studies highlighting success of a primary prevention program, where as many recommendations across the world avoid antibiotic therapy short of costly point of care molecular diagnostics.^[99-102] In India, the primary prevention strategy is left to the individual decision of the treating physician, given the chance that more than two thirds of the GAS sore throats are subclinical, and latent RHD substantiates that probability.^[103] Although some studies show a declining trend in RHD, an overview of available data highlights the overall static nature of the problem in India over the past five decades.^[104] Hence, the need for a focused augmentation of the secondary preventive strategies in the high risk age group as the initial step to achieve the targets defined by the WHF in its road map.^[15] Elimination of rheumatic fever and RHD is an achievable target, which needs to be prioritized, given the current epidemiology of the disease in India. The simplified concepts of the blueprint are summarized in Table 2.

CONCLUSION

The editorial on the Global burden of diseases in 2017 aptly described India as the RHD capital of the world. The current focused review substantiates the options published in the blueprint, to enable the health system in India step down from this podium.