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Mini Review *Corresponding author Anuradha Chakraborti, Department of Experimental Medicine and Biotechnology, PGIMER, , Rheumatic Heart Disease , Tel: 0172-2755230; Fax: 0172-2746277; Email:

Submitted: 11 June 2016 (RHD) Prevention and Control Accepted: 12 October 2016 Published: 14 October 2016 in North India: Addressing the Copyright © 2016 Chakraborti et al. Challenges OPEN ACCESS Rastogi M1, Sagar V2, Kumar R2, and Chakraborti A1* Keywords 1Department of Experimental Medicine and Biotechnology, PGIMER, India • Rheumatic heart disease 2School of Public Health, PGIMER, India • GAS • Streptococcus

Abstract Rheumatic Heart disease (RHD) is one of the major causes of morbidity and mortality especially among 5-15-year-old children in developing countries like India. Globally, 15.6 million people suffer from RHD each year, and in India 600,000 children of less than 15 years suffer from this disease. Although incidence of RHD has come down with improvement in living conditions, but sporadic emergence in developed countries and continued persistence in developing countries is still an issue. RHD is preventable, yet there are many challenges which need to be addressed. In this review we have discussed key challenges which are hindering the efforts for prevention and control of this neglected disease.

INTRODUCTION in humans and RHD is one of them. Disease burden of GAS is high in lower, middle and high income countries with more than 600 Rheumatic heart disease (RHD) caused by Group A million cases worldwide [5]. Epidemiological distribution of GAS Streptococcus (GAS) infection, is the leading cause of mortality in cardiovascular disease group both in children and youth. Infact understood mechanism of pathogenesis. Streptococcus is the chain which links throat to heart valve [1]. and its associated diseases pose a significant threat due to less Globally, the prevalence of RHD is approximately 15.6 million Several epidemiological investigations, keeping in view the cases with 282,000 new cases and 233,000 deaths each year. prevention and control, have been done at our centre in the Post In India, approximately 600,000 children less than 15 years of Graduate Institute of Medical Education and Research (PGIMER), age suffer from RHD. However, due to the rise in socio-economic Chandigarh, India since many decades. Nandi et al. [6], conducted status in western countries, the incidence rate of RHD cases has a survey in school children in peri-urban slum area of Chandigarh come down, yet frequent sporadic cases are observed. On the (India) where incidence of GAS sore throat was found to be 0.95 other hand, high incidence and prevalence in Asian and African episodes per child per year. A clinical score card system was countries with high morbidity and mortality remains a challenge developed for early diagnosis of GAS infections. We observed [2-4]. that clinical score card along with the culture result may help the clinician to narrow down the patient population for antibiotic High incidence of RHD is attributed to GAS virulence treatment; this will further help in ruling out the viral etiology of factors, host genetic susceptibility, environmental factors and pharyngitis. Our observation is also in accordance with Infectious exaggerated immune response. Hence, it is the need of the hour Disease Society of America (IDSA) [7]. Many epidemiological that the challenges, which determine the higher burden of RHD studies were conducted over a period of about thirty years in in developing countries especially in India, should be addressed. rural areas of Raipur Rani Block in Haryana, India [8-10] and Herein, we highlight a string of issues which impair the efforts to in at in [11]. Enormous efforts have reduce the RHD burden by critical review of available information been made to understand the epidemiological aspect of the from the regions of North India. streptococcal infections, and over the period various policies Epidemiological challenges were also drafted to control RHD. Streptococcus pyogenes or Group a streptococcus is one of the A registry was started to enrol all the RHD patients residing most enigmatic bacteria capable of causing an array of diseases in Rupnagar district near Chandigarh (50 km from Chandigarh). Nearly 813 cases of RF/RHD were registered from 2002 to

Cite this article: Rastogi M, Sagar V, Kumar R, Chakraborti A (2016) Rheumatic Heart Disease (RHD) Prevention and Control in North India: Addressing the Challenges. Ann Cardiovasc Dis 1(3): 1015. Chakraborti et al. (2016) Email:

Central Bringing Excellence in Open Access 2009. Out of the 813 cases, 610 cases were RHD indicating the has also been documented in nutrition as well as in vaccination high prevalence of disease in the state [11]. Since 2008, under wherein male children were preferentially vaccinated and given the Rashtiya Bal Swasthya Karakarm (RBSK) or National Child nutritious food than the female child [23]. A recent study in the Care Programme as many as 3456 children having congenital area adjacent to Chandigarh region also highlights the gender heart disease and rheumatic heart disease have been referred bias in cardio vascular health in spite having the option of free to PGIMER, Chandigarh, India and other tertiary hospitals for treatment [24]. treatment where 2129 children have been operated [12]. Hence, it can be said that although improvement of living The challenge which still exists as far as epidemiology is conditions and awareness might have largely decreased the concerned is the huge strain heterogeneity which exists in Indian prevalence of RHD in urban settings however, poor living GAS strains in comparison to strains from western regions. S. condition, socio-economic bias in the rural areas of Chandigarh pyogenes has a range of virulence factors in its arsenal, of which increases the risk of GAS infection, ultimately leading to RHD. M protein in one of the most dominant antigen. The M-protein is coded by emm gene which has many subtypes, and a geographical Biological challenges area can have various GAS strains with different emm types. We Host pathogen interactions provide an insight in have reported many epidemiological studies where emm typing of comprehending the pathogenesis of the disease. However, in GAS strains was done and each of these studies from Chandigarh case of RHD the exact pathogenesis remains elusive which and its nearby areas indicated that our most prevalent types creates a gap between the diagnosis, treatment, prevention and are quite different from the ones in other countries [13-16]. control. One of the biological challenges is that no biomarker emm is clinically accepted till date for diagnosis of RHD in any of types respectively indicating huge heterogeneity among the GAS its stages (pharyngitis, ARF and RHD). In Chandigarh we did isolatesOur two [15,16]. main studies These prevalent too identified emm 37types and in 27 north different India were identify a HLA-DRB1*14 as a genetic susceptible marker in found to be different when compared to south India [17]. RHD patients [25]. We had also attempted to identify the stage Continuous emergence of new strains is also a burning (PCIP), anti-PARF (Peptide Associated with Rheumatic Fever) issue which needs an attention. In North India, emm 1, which is antibodyspecific marker and serum including cytokines by product level [26]. of collagen We found metabolism the high prevalent all over the world, was rare; instead a highly invasive level of anti- PARF antibody in serum of ARF patient but these emm1-2 strain prevalent in Chandigarh, India [18]. emm 1-2 were low in pharyngitis and RHD patients. Whereas, by product might have evolutionarily emerged from emm1. Therefore, designing preventive strategies based on vaccine would be an of collagen metabolism, C- terminal of type I collagen, was high uphill task with such wide and varied distribution of GAS strains. in RHD compared to other groups. However, serum cytokines Socio-economic challenges other than IL- 6 did not show any significant difference among There are plethora of evidences which support the surge anddisease endothelin and healthy -1 [26], population. plasma Numbergelsolin of[29] studies any anyhas identifiedmore but and decline of S. pyogenes infection depending upon the season, thesevarious have molecules failed tosuch get as wide fibroblast acceptance. growth Thus, factor-21 markers [27], which IL-10 nutritional status, and mode of cooking fuel used. Lamagni et al. determine the advancement of ARF to RHD or pharyngitis to ARF [19], noted change in lesser disease incidence in the autumn and remain obscure. This affects the development of prevention and then increasing in December through April. Similar study from treatment strategies, which increases the economic burden due our laboratory also reported incidence of sore throat correlated to the need for chronic medication and mitral valve replacement with age, season and also with living conditions of children. It surgery. was observed that incidence was higher in 11-year-olds, during winter and rainy season and among children who lived in the In addition, emergence of antibiotic resistant strains over houses where there were no separate kitchen [6]. a period of time is another challenge. The non adherence to antibiotics and positive selective pressure on prevalent Epidemiological studies have shown the occurrence of S. GAS types and subtypes may result in the emergence of drug pyogenes infection with higher predilection towards men than women. On the contrary, the post streptococcal autoimmune report on antibiotic resistance status of Indian GAS strains infection such as rheumatic fever and rheumatic heart disease resistance as seen in similar streptococci species [30]. Our first are higher in women than in men as observed with respect to are prevalent in North Indian community [16]. However, most other autoimmune diseases also. In a report submitted to Indian ofantibiotic the GAS resistance strains are confirmed still sensitive that antibioticto penicillin resistance but emergence strains Council of Medical Research (ICMR) it has been mentioned that of antibiotic resistant strains remains an imminent threat. Our although prevalence of RHD among boys and girls in school Study in Chandigarh region also highlighted that penicillin surveys was same however higher number of RHD cases were sensitivity (99%) in GAS strains. Besides, the GAS were registered in females of above 20 years of age [8]. Studies from resistant to tetracycline (25.5%), 7.8% to azithromycin, 4.9% to clarithromycin and 3.9% to both chloramphenicol and amikacin. the female sex. It was found that the “female” gender was the This study has also sheds light on resistant pattern to clindamycin, majorIndia highlight factor responsible the harsh realityfor not ofreceiving significant the gendermedical bias treatment, toward ampicillin, co-trimoxazole and gentamicin, wherein all the GAS which may be due personal and social discriminatory practices. strains were resistant to these antibiotics. Contrastingly group C Other factors which aggravated the gender bias were lower and Group G streptococci were sensitive to these antibiotics [16]. socioeconomic class and the cost of surgery [20-22]. Gender bias Variations in antibiotic sensitivity towards the site and disease

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al. Prevalence and outcome of subclinical rheumatic heart disease where antibiotic awareness is minimal in rural areas, it will be in India. The RHEUMATIC (Rheumatic Heart Echo Utilisation and specific isolates were also observed. In clinical settings like India Monitoring Actuarial Tends in Indian Children) Study. Heart. 2011; challenge in war against RHD. Limited information is available on 97: 2018-2022. antibioticjustified to resistance, view antibiotic thus continuous policy and monitoring its awareness regarding as major the 4. Kingué S, Ba SA, Balde D, Diarra MB, Anzouan-Kacou JB, Working matter is required to control RHD. Group on Tropical Cardiology of the Société française de cardiologie, et al. The VALVAFRIC study: A registry of rheumatic heart disease in To lessen the burden of disease, vaccine against group A Western and Central Africa. Arch Cardiovasc Dis. 2016; 109: 321-329. streptococcus is needed, however it is still a dream to be realised. Few vaccines based on M protein (6, 26 and 30 valent) [31-33], 5. Sims Sanyahumbi A, Colquhoun S, Wyber R, Carapetis JR. Global Disease Burden of Group A Streptococcus. 2016 Feb 10. In: Ferretti JJ, Stevens DL, Fischetti VA,editors. Streptococcus pyogenes: Basic binding protein [36], streptococcal pyrogenic exotoxin A [37] Biology to Clinical Manifestations (Internet). Oklahoma City (OK): carbohydrate antigen [34], serum opacity factor [35], fibronectin etc. are at various stages of development. Various factors such University of Oklahoma Health Sciences Center. 2016. as prevalence of emm types in geographical area and also the lack of consensus for a pathway against which the vaccine shall 6. Nandi S, Kumar R, Ray P, Vohra H, Ganguly NK. Clinical score card for diagnosis of group A streptococcal sore throat. Indian J Pediatr. 2002; be developed are detrimental to vaccine development [38]. WHO 69: 471-475. report accurately terms GAS vaccines as impeded vaccine in spite of some major breakthrough [39]. 7. Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and management of group Greater challenge for vaccine development is the GAS A streptococcal pharyngitis: 2012 update by the Infectious Diseases strain heterogeneity. As discussed before, since our prevalent Society of America. Clin Infect Dis. 2012; 55: 1279-1282. emm types are quite different from the other countries, hence 8. Jai Vigyan Mission Mode Project on Rheumatic Fever and Rheumatic multivalent vaccine, which is currently under research, may Heart Disease, Comprehensive Project Report (2000-2010), Indian not be suitable for Indian subcontinent. The approach for the Council of Medical Research, New Delhi. development of indigenous vaccine needs to be explored further. We have two reports on vaccine development, where C terminal 9. Kumar R, Vohra H, Chakraborti A, Sharma YP, Bandhopadhya S, conserved region is targeted as a vaccine candidate [40,41]. As Dhanda V, et al. Epidemiology of Group A Streptococcal Pharyngitis and Impetigo: A Cross Sectional and Follow-up Study in a Rural far as N terminal multivalent vaccine is concerned, based on Community of Northern India. Indian J Med Res. 2009; 130: 765-771. strain heterogeneity, different emm types needs to be selected. The prevalence of emm types in particular region and variation 10. Kumar R, Chakraborti A, Aggarwal AK, Vohra H, Sagar V, Dhanda et in emm al. Streptococcus pyogenes pharyngitis and impetigo in a rural area other issues include safety concerns, and minimal development of Panchkula district in Haryana, India. Indian J Med Res. 2012; 135: 133-136. of combination gene will antigen determine vaccines the vaccine (WHO designreport). and Thus, efficacy; it is imperative to understand the enigmatic pathogenesis of RHD for 11. Kumar R, Sharma YP, Thakur JS, Patro BK, Bhatia A, Singh IP, et al. diagnosis, treatment and prevention. Streptococcal pharyngitis, rheumatic fever and rheumatic heart disease: Eight-year prospective surveillance in Rupnagar district of CONCLUSIONS Punjab, India. Natl Med J India. 2014; 27: 70-75. Although, RHD remains a neglected disease nationally 12. https://punjabgovtindia.wordpress.com/2016/02/ however, a lot has been done in the rural settings of north Indian 13. Dey N, McMillan DJ, Yarwood PJ, Joshi RM, Kumar R, Good MF, et community for control of the disease. As quoted by Ramakrishna al. High diversity of group A Streptococcal emm types in an Indian S [42] that RHD is “buried alive”, and it requires many steps community: the need to tailor multivalent vaccines. Clin Infect Dis. for the RHD control such as social awareness, free distribution 2005; 40: 46-51. of antibiotics and annual check up of school going children. 14. Sagar V, Bakshi DK, Nandi S, Ganguly NK, Kumar R and Chakraborti There is an urgent need to keep a check on GAS-RF-RHD nexus A. Molecular heterogeneity among North Indian isolates of Group A but continuous emergence of strains, antibiotic resistance, lack Streptococcus. Lett Appl Microbiol. 2004; 39: 84-88. of diagnostic/susceptibility makers and vaccine development are still huge challenges which need to be tackled. However, in 15. Sagar V, Kumar R, Ganguly NK, Chakraborti A. Comparative analysis Chandigarh and in its neighbouring , we are conducting of emm type pattern of Group A Streptococcus throat and skin isolates from India and their association with closely related SIC, a regular school check-up and maintaining registry on RHD and streptococcal virulence factor. BMC Microbiol. 2008: 16; 8: 150. providing RHD prevention and control services to save the precious life of children and young adults. 16. Dhanda V, Chaudhary P, Toor D, Kumar R, Chakraborti A. 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Cite this article Rastogi M, Sagar V, Kumar R, Chakraborti A (2016) Rheumatic Heart Disease (RHD) Prevention and Control in North India: Addressing the Challenges. Ann Cardiovasc Dis 1(3): 1015.

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