Bhupathiraju 1

Rheumatic Heart Disease in Underdeveloped Nations: ​An Endeavor

 Bhupathiraju 2

INTRODUCTION

Brothers, Mugisa and Mwesige, love running. There’s a power in running. A power that
makes the brown water look golden, a hut a palace, an emaciated young Ugandan boy a
superhero. But for Mugisa, before the cracks in the soles of his feet can touch the sandy Earth
below, there’s an agonizing crack maneuvering its way through the crevices of his chest. The
pain intensifies, beads of sweat cascade down the jagged curves of his face - but he doesn’t stop
running. In the native Tooro, Mugisa means “good fortune”. The good fortune in his name is
absent in the nine-year old’s body buried under the same sandy Earth his soles had once kissed.
In his brother’s absence, Mwesige never ran again.
There are hundreds of thousands like Mugisa. Hundreds of thousands that die without
ever knowing why. 20 cents...20 cents. The cost of a gumball. That’s the difference between
Mugisa’s soles bouncing on the soil or being six feet under. The bridge between life and death.
In our world today, rheumatic heart disease claims the lives of approximately 1.4 million
people (Talwar and Gupta, 2016). The consensus amongst the scientific and humanitarian
communities, however, is that these numbers are highly conservative (Sohn, 2019). The reality is
that the socio-economic inequities that are entrenched in the fabric of impoverished nations
conceals the deaths of people like Mugisa. In the United States, rheumatic heart disease ran its
course in the 1930’s with an astounding 8 percent frequency in autopsies conducted by the New
York Presbyterian Hospital (Sohn, 2019). The widespread employment and accessibility of
antibiotics has undermined the incidence of rheumatic heart disease and contributes to the lack of
recognition in developed nations. In addition, the FDA’s ban on the human testing of a
streptococcus A vaccine, a vaccine that would eliminate the potential to incur rheumatic fever
and consequent rheumatic heart disease, coupled with the inhibitions of the prolific American
pharmaceutical industry about a lack of market has diminished urgency pertaining to a vaccine
development (ibid). Furthermore, the globally disproportionate access to medical care has
inhibited the accumulation of robust data to establish the effectiveness of secondary prophylaxis
treatment (Chin, 2019).
As the culmination of my passion in cardiology and humanitarianism intertwined within
my ISM journey; I endeavor to investigate the mechanisms of the manifestation of rheumatic
heart disease, the effectiveness of current interventions in cohorts in underdeveloped nations
around the world, an analysis of systematic reviews oriented towards the impact of benzathine
penicillin in reducing incidence of rheumatic fever (RF), and a humanitarian outlook. My
methodology will be simple analyses of published and unpublished trials and reviews available
on scholarly databases such as PubMed, Embline, Cochrane, and Google Scholar. To promote
heterogeneity in perspective, my inclusion criteria is oriented towards underdeveloped nations,
single-blind cohort studies, and reviews with primary and secondary outcomes outlined by Jones
criteria. My passion for this endeavor is the Mugisas of the world.
 Bhupathiraju 3

PATHOPHYSIOLOGY PERSPECTIVE

The incidence of rheumatic fever in adolescents is rooted from the infection of the
pharynx by group A beta-hemolytic streptococcal bacteria (GAS) succeeded by an incubation
period of 2-4 days (Chin, 2019) and a latency period of 3 weeks (Sanghvi, 2009). As the exact
pathogenesis mechanisms of rheumatic heart disease remain unknown (Carpetis, 2011), there is
one extensively accepted theory on the late manifestation of rheumatic heart disease from
rheumatic fever (Watkins, 2018). In such theory, the molecular mimicry of GAS proteins and
human proteins is linked to the cross reactivity between GAS antigens and human heart antigens
(Cunningham, 2016). Such notions are corroborated by the identification of certain serotypes of
the M protein of GAS that have antigenic domains similar to human heart antigens
(Kimberlin,et.al, 2018). Molecular mimicry has been recognized for decades as contributing to
the immune response against foreign microbes and consequential cross-reactions with cardiac
antigens - thereby promoting autoimmunity and inflammation (Zabriske & Gibrofsky, 1986).
The consequent response of T cell recognition of self and foreign antigens triggers a prolific
autoimmune response (Nelson, 2015).
Thus, T-cell responses against M protein antigens are strongly connected to host
autoimmune responses against cardiac myosin due to the alpha-helical coiled coil structural
similarities (Sikhman, Greenspan, Cunningham, et. al, 1994). Furthermore, the role of
glycosylated proteins (laminin) and extracellular matrix proteins in trapping antibodies at valve
surfaces contribute to the upregulation of VCAM-1 (Galvin, Hemric, et. al, 2000). The
upregulation of vascular cell adhesion molecules (VCAM-1) promotes the infiltration of
streptococcal primed CD4+ T cells into the valve (Roberts, et.al, 2001). Subsequently, the
release of inflammatory cytokines, tumor necrosis factor alpha (TNF) and
interferon-gamma(IFN), promote persistent inflammation of the heart valve (Chin, 2019). The
cross-reactions of human mono antibodies and extracellular matrix proteins such as laminin and
collagen due to aforementioned alpha-helical structural similarities leads to the activation of the
valve endothelium (Martins, et. al, 2008). These antibodies against collagen and laminin act on
the collagen binding proteins of the group A streptococcus and promote autoimmunity against
the valve (Tandon, Sharma, et.al, 2013).
Thus, the initial cross-reactivity of anti-cardiac myosin antibodies (Chin,2019) due to
similarities in amino acid sequences with alpha-helical M protein antigens promotes
inflammation, edema, and fibrosis (Cunningham, 2016). Tissue scarring in the valve cusps
causes the development of mitral valve regurgitation (Watkins, et.al, 2018) and increases
susceptibility to future attack (Dudding and Ayoub, 1968). In that sense, future infections can
promote chronic valve insufficiency (Chin, 2019) with a poor prognosis (Dudding and Ayoub,
1968).
Valve insufficiency is typically seen between 2-10 years after acute RF episodes (Chin,
2019) and the most extensive complication is heart failure in endemic areas (Zuhlke,et.al, 2014 ).
 Bhupathiraju 4

TREATMENT PERSPECTIVE: ​Prophylaxis

The absence of a GAS vaccine coupled with the cost-barriers associated with tertiary
intervention in underdeveloped nations has led to the widespread understanding of primary and
secondary prophylaxis in treating acute rheumatic fever as the most optimal and feasible practice
(Kevat, Reeves,et.al, 2017). The widely accepted primary prophylaxis is the ten-day
administration of oral penicillin in response to GAS pharyngitis (Dajani, Ayoub, et.al, 1992).
The effectiveness of such undertaking, however, is largely vested in accurate diagnosis of GAS
pharyngitis through throat cultures and there is currently a lack of data validating the accuracy of
throat cultures in undeveloped nations (Irlam, Mayosi, 2013).
In secondary prophylaxis, intramuscular benzathine penicillin is recognized as the gold
standard in incidence of RF irrespective of RHD (Feldman, Bisno, et.al, 1987).The effectiveness
of intramuscular (IM) penicillin was corroborated by a 1958 meta-analysis conducted by
Robertson, et.al, that was oriented around the administration of therapeutic high doses vacillated
with continuous low doses in a military base demographic (Robertson, Volmink, Mayosi, 1958).
Despite limitations in design, the study cited a streptococcal infection rate of 22.7% in the
aforementioned oral regimen vs. 6.6% for IM benzathine penicillin; as well as a 0.6% recurrence
rate in IM benzathine penicillin vs 4.8% recurrence rate in PO penicillin (ibid). Some studies,
however, have consistently indicated a lack of statistical significance between the efficacy of IM
benzathine penicillin vs PO penicillin in treatment of RF (Markowitz, Ferencz, et.al, 1958). It is
of importance to note that patient adherence is typically higher in parenteral administration,
however, presumably due to lower frequency as noncompliance rates are substantial (Kevat,
Reeves, et.al, 2017). The importance of adhering to a secondary prophylaxis regimen is
accentuated by increased recurrence rates and severity in future episodes of RF, thereby
exacerbating ramifications in asymptomatic incidence of initial RF (Viesy, Wiedmesier, et.al,
1987).
In recognition of allergic responses to penicillin, a recent study reported incidence at 3.1% and
0.2% for allergic responses and anaphylactic reactions, respectively (Taubert, et.al, 2013). The
indication of azithromycin in cases of penicillin allergies has proven to be effective, while
cephalosporins are recognized as alternatives (Chin, et.al, 2019). Despite poor methodological
structure and reporting, systematic reviews have indicated a lower clinical relapse for
cephalosporins compared to penicillin (OR 0.42)(Driel, et.al,2016). In another systematic review
with poor methodological quality, only one trial out of three qualifying trials indicated that
penicillin reduced incidence of RF (RR 0.5,CI 95% 0.22-0.92)(Manyebi, et.al, 2002).
Furthermore, intriguingly, a longitudinal, pharmacokinetic study of adolescents receiving
secondary prophylaxis revealed that none of the study’s 18 participants had benzathine penicillin
concentrations >0.02 mg/l of blood serum (Hand, Salman, et.al, 1984). In that sense, the
culmination of these analyses coupled with the inconsistencies in duration reveal the blatant lack
of robust data on the efficacy of benzathine penicillin and its optimal duration.
 Bhupathiraju 5

JAI VIGYAN MISSION MODE PROJECT: ​ANALYSIS

In recognition of the endemic nature of rheumatic heart disease (RHD) as contributing to

25-40% of acquired cardiovascular disease in India coupled with the Indian Council of Medical
Research dire estimates of incidence in approximately 6 out of 1,000 children aged 5-16, fostered
a substantial rationale for initiative in community prevention (Rastogi, Zahid, et.al, 2016). One
such endeavor culminated in the comprehensive Jai Vigyan Mission Mode Project that
encompasses objectives of determining prevalence in 5-14 year olds, monitoring and sensitizing
community secondary prophylaxis, and establishing a registry in selected communities. The
public health undertaking spanned ten centres across India : Jammu, Rupnagar, Shimla, Vellore,
Kochi, Wayanad, Indore, Dibrugarh, Jodhpur, and Mumbai over a period between 2000-2010.
The analysis of this research surveillance will be oriented around the findings of one centre
chosen randomly: Jodhpur 2007-10, and a discussion of the published comprehensive project
report spanning all ten centres.
The parameters of the Jodhpur centre surveillance were delineated by three community
development blocks: Osian, Bilara, and Bhopalgarh. The methodology encompassed the
implementation of intial screening programs in schools and subsequent referrals to cardiologist
Dr.Sanjeev Sanghvi for free echocardiography, where confirmed cases were documented in a
registry and results communicated to the nodal center in PGIMER, Chandigarh. The initial
school health survey saw the team of microbiologists, sociologists, and research officers oversee
the inoculation of throat swabs in blood agar for GAS bacterial culture in 201 schools. The
process for identifying schools was obtaining a government list from the education department
and selecting every fifth school to undermine any external bias. Further, 50 students from each
respective school were randomly selected from a classroom for the documentation of name, age,
sex, height, weight, hip cicrcumference, etc. Symptomatic students presented with sore throat as
well as every third student in the group had throat swabs performed and immediately inoculated
in blood agar. Suspected cases via clinical examination were referred for echocardiography by
distributing referral cards and communication with patients encouraging consultation with
Dr.Sanghvi every Monday and Thursday. To promote primary awareness, the field team
distributed educational posters as well as presented to classrooms and school staff pertaining to
the symptoms of RF/RHD.
Over the span of three years, the team was able to examine 10,011 students aged 5-14
with 3,151 students from the urban Bilara block and 6,860 students from the rural Osian and
Bhopalgarh blocks. Through the examination of these students, 110 children (1.1%) were
referred to the outpatient department on the basis of abnormal heart murmurs or known history
of rheumatic fever. Of the 110 referred children, 90 children (82%) underwent
echocardiography, throat swab cultures, and antistreptolysin O titers; of which 8 children had a
diagnosis of rheumatic heart disease. Thus, through active screening, the study indicated the low
prevalence of 0.8/1000 children aged 5-14 with RHD. Unsurprisingly 7 children (87.5%) had
 Bhupathiraju 6

cases of mitral valve regurgitation to varying degree and the other child was presented with
mitral valve stenosis, consistent with recent data of the mitral valve being affected most
frequently in RHD (Naghavi, et.al, 2013). The screening also yielded the confirmed diagnosis of
26 cases of congenital heart disease (28.8%) and a significantly greater frequency of congenital
heart disease at 3.2/1000 school children aged 5-14 in the study area.
In that sense, the prevalence of congenital heart disease in referrals corroborates clinical
effectiveness of detecting abnormalities by the field research team during initial screening.
Simultaneously, however, it is important to note that throat swabs were only conducted on
symptomatic school children and every third school child, thereby potentially restricting
asymptomatic pools. The effects of this restriction are evidenced by the growth of GAS bacteria
in 25 throat swabs (3.25%) out of 768 asymptomatic school children. Furthermore, as students
were chosen from the same classroom, transmission is likely to be greatly facilitated within that
classroom if one student were to have rheumatic fever due to physical proximity. In addition, a
potential limitation of the study is that no GAS bacteria was grown in cultures up till December
2007 and thereby omitted from statistical calculations. On that account, it is noteworthy that the
presence of blood agar plates at the site of throat swabbing beginning January 2008 yielded GAS
bacterial growth. To further explain the relatively low frequency of RHD in the Jodhpur study
group with respect to IMC estimates, it is noteworthy that the study is conducted amongst school
children in an area of an approximate literacy rate of 47.7%. In that sense, the study is not
representative of the entire demographic of the given area due to the potential for unenrolled
children aged 5-14. Another potential limitation in the study is the 20 referred school children
(18.1%) who did not report to the outpatient department.
Irrespective of limitations in design, the Jodhpur initiative showcases the ramifications of
reduced incidence with respect to prior cross-sectional studies amongst rural communities in
Aligarh, Uttar Pradesh that indicated a frequency of 6.4/1000 (ICM). Further, the study
strengthens the correlation between socio-economic inequity and incidence of RHD/RF through
the documentation of weight and hip circumference measurements that are significantly lower
than the WHO respective medians. In endeavors of promoting primary intervention, pamphlets,
educational posters, and referral cards were distributed in primary health centers, and physicians
in the designated area were instructed to refer suspected cases to Dr.Sanghvi. Thus, over the 3
year span, independent of the field school study, physician referrals in the designated area of
approximately 1 million in population yielded 220 cases of RHD/RF. Of the 220 cases, 127 were
severe RHD (57.7%) and 52 moderately severe (23.6 %) with respect to the Jones criteria of
evaluation. Intriguingly, only 36 cases (16.3%) were between the age group of 5-14 -
conventionally recognized as the most susceptible group (Rastogi, 2015). Within this referral
group, it is interesting that 44 patients (20 %) were advised to not be administered benzathine
penicillin and 25 patients (11.4%) had never undergone secondary prophylaxis. On that account,
the need for greater monitoring of secondary prophylaxis as well as availability of alternative
medications is underscored.
 Bhupathiraju 7

Analysis of all ten centres reveals relative consistency with the low frequency exhibited
at the Jodhpur centre with a cumulative incidence of approximately 1.1/1000 in the school health
survey. Of particular interest with respect to the inclusion criteria is the prevalence of GAS in
415/3,357 (12.3%) of the Vellore cohort study compared to 44/3,385 (1.3%) in the Chandigarh
counterpart. Further, the relative low incidence of GAS in 74/657 (11.3%) in those with a clinical
presentation of sore throat in the same Vellore cohort indirectly provides potential insight into
the development of research suggesting the acquisition of virulence factors such as fibronectin
binding proteins and M-proteins in Group C and Group G streptococcal bacteria (Walker, et.al,
2014). The data from the Vellore cohort consistently indicated the highest frequency of GAS
prevalence in cases presented with impetigo through a prolific incidence of 236/938 (25.2%)
throat swabs inoculated. In that sense, the subtropical geography of Vellore provides substantial
rationale for the unparalleled incidence of impetigo across other centres. However, the
geographical classification of subtropical extends to Wayand and Cochin, despite limited GAS
prevalence in impetigo at the respective centres. Thus, it is important to note that inequities in
socioeconomic conditions and deviations in duration may have contributed to discrepancy.
The emm typing of 567 GAS isolates and subsequent identification of 98 emm types is a
testament to the substantial heterogeneity of M-protein in underdeveloped nations. On that
account, the study revealed irrefutable regional diversity as the common emm types of the
southern centers were emm 112, emm 11, emm 82, and emm 110 compared to the predominant
emm types of emm 77, emm 81, emm 11, and emm 71 in the northern counterparts. Of further
contribution to this heterogeneity is the discovery of the distinct emm 4 for the first time in the
Indian community. From that perspective, the ICMR study has elucidated a cumulative
distinction between the prevalence of emm types commonly found in the Indian community vs.
targeted emm types in the development of the 26-valent and 30-valent vaccines undergoing
clinical trials (Steer, et.al, 2009). The presumable inefficacy of the aforementioned vaccines is
corroborated, to some extent, by research indicating merely 39% and 24% strain coverage of the
26-valent vaccine in African and Pacific demographics, respectively (Steer, et.al, 2009).
However, the ramifications of this research may be undermined by increasing momentum
towards cross-immunity amongst strains through susceptibility of heterologous emm-types
(Dale, 2013) and the identification of proposed cross-protection within 48 emm-clusters (Smith,
2014). Regardless, the identification of emm types from GAS isolates in the Jai Vigyan
surveillance may prove to be beneficial in future studies evaluating the effectiveness of potential
vaccines and furthers the correlation between socio-economic status and serotype diversity.
Although the parameters of the study did not accommodate the measurement of the
effectiveness of secondary prophylaxis, it is intriguing to recognize the differences in regional
administration. To expound upon, the ban on intramuscular injections of benzathine penicillin,
conventionally recognized as the most effective treatment to undermine incidence of RHD
(Feldman 1987), in the states of Tamil Nadu and Kerala wholly prevented administration in the
Kochi, Wayanad, and Vellore centres. The ban on intramuscular benzathine penicillin coupled
 Bhupathiraju 8

with the Indian government's price control on the drug has contributed to the severe shortages of
benzathine penicillin as pharmaceutical companies reduce production in light of low margins
(Saxena, 2018). The flailing supply market and presumable fears over anaphylactic reactions
irrefutably contributed to the administration of oral penicillin in 75% and 95% of cases with
identified GAS colonization in Vellore and Chandigarh, respectively.
The prevalence of RF/RHD across the 10 centres is likely a severe underestimate
attributed primarily to clinical underdiagnosis. In the Utah,U.S cohort study conducted from
1985-94, clinically identifiable carditis was reported in 16% of cases (Kumar and Tandon, 2013).
Similarly subclinical carditis with respect to all carditis cases ranged from 19-44% in the Jai
Vigyan surveillance. Thus, the influence of asymptomatic carditis is likely the most extensive in
the centres reporting the greatest number of cases of carditis such as Jammu, Shimla, and
Jodhpur with a cumulative incidence of 58.5%. The non-ideal conditions for auscultation of heart
murmurs in a presumably loud school setting may have further accentuated low referrals to
echocardiography and doppler. Further explanation of the low incidence is the
acknowledgement of abnormally low registry based prevalence in the designated study areas due
to the absence of an unspecified amount of cases in government hospital registries. The lack of
registration is likely reflective of lack of patient turn-out in clinical settings as a whole as
economic statistics rule out the potential for reliance on private health institutions. In addition,
the retention of registered cases evidently posed a substantial challenge in study design. In
Mumbai, for example, 201/406 (49.5%) of registered cases were unable to be monitored due to
various reasons such as migration, absence at follow-up, financial inhibitions, etc. Migration
consistently posed the greatest challenge in monitoring secondary prophylaxis as evidenced by
the loss of 75/813 (9.2%) and 42/503 (8.3%) of registered cases in Chandigarh and Vellore,
respectively. Similar factors influenced lack of intervention in cases requiring intervention. In
Indore, poor financial condition limited intervention to 84/233 (36%) of cases requiring
intervention.
In comparison with prior ICMR studies conducted in 1984-1987 and 1984-1990 with
respective prevalences of 2.2/1000 and 2.9/1000 (Negi, Sondhi, et.al, 2019), the cumulative
incidence of 1.1/1000 in the Jai Vigyan Mission Mode initiative indisputably represents
statistical progression. It is unclear, however, if the results elucidate a progressive decline in
RHD in India (ibid). In that sense, the necessity of expanding the parameters of the study into
historically impoverished areas such as Orissa, Bihar, etc. is underscored. With respect to the
major diagnostic criteria of the Jones criteria, the high prevalence of polyarthritis in the Indian
case (39.9%-75.9%) corroborates the efficacy of such evaluation. Furthermore, the incredible
heterogeneity of emm types amidst the northern and southern centres advances speculation that
the development of a vaccine is highly unlikely in the near future. In that respect, the inefficacy
of primary prevention is delineated by the lack of distinction in administration as it pertains to
cases of sore throat or those solely with identified GAS isolates. Thus, secondary treatment and
effective registration remains India’s most viable avenue within the current health infrastructure.
 Bhupathiraju 9

NICARAGUA CASE: ​ANALYSIS

In light of increased research suggesting a lack of sensitivity of clinical examination of

RHD, the León, Nicaragua 2006-2009 observational study (Paar, Barrios, et.al, 2010) aspired to
establish RHD prevalence in a geographical parameter with historically high incidence by
employing echo-Doppler criteria (Minich, Pagotta, et.al, 1997). The methodology of the study
consisted of the identification of dwellings from the government demographic surveillance
system (CIDS) that formed the cluster sampling of the León population and consequent clinical
examination by a cardiologist and performance of echo-Doppler on all subjects. The emphasis on
the sensitivity of the echo-Doppler created diagnostic criteria distinct from the Jones criteria and
stratified into definite, probable, and possible RHD. The basis of the stratification is primarily
oriented around the identification of significant mitral stenosis with potential valvular lesions as
confirmation of diagnosis, with a lack of thereof, classified inferiorly. The subjects classified as
probable and possible were consequently followed-up within 4-12 months for re-evaluation of
adherence to respective strata and review by independent cardiologists.
The study of 3,150 children aged between 5-15 years yielded a prevalence of 48/1000 in
initial examination amongst the definite, probable, and possible strata. It is of significance to
acknowledge, however, that the vast majority of the identified cases were classified as possible
137/150 (91.3%) and consequent re-examination yielded highly variable results particularly in
oscillation between probable and possible cases. The variability is manifested in the
re-evaluation of the 8 probable cases (5.3%) that yielded the reversion of 4 probable subjects
(50%) to no audible murmurs and 2 probable subjects (25%) to no audible murmur nor structural
abnormalities justifying maintenance of probable designation. The volatility of the classifications
coupled with an approximate 20% rate of lack of retention in follow-up fostered an impetus for
the inclusion of adult subjects to evaluate the chronic progression of RHD. The prevalence of the
young adult demographic aged 20-35 was reported as 22/1000. An increased stringency was
applied to the diagnosis of the young adult subjects to accomodate for the exclusion of
non-rheumatic etiologies by assessing the presence of structural abnormalities of the mitral valve
and valvular murmurs.
Intriguingly, rural incidence was significantly greater than urban incidence in the
children’s study, 77/1000 vs. 38/1000, respectively. Although it is unclear whether the prolific
prevalence of the rural demographic is attributed to a relatively small proportion of the sample
size 944/3,150 (30%), it is presumably that a lower frequency of clinical settings has hindered
prophylaxis endeavors. In that sense, however, the findings are inconsistent with the young adult
study indicating a modest distinction in prevalence of 25/1000 vs. 17/1000 in urban and rural
settings, respectively. Of further interest, none of the subjects of the young adult study with
confirmed diagnosis of RHD reported a history of ARF, thereby implying potential
inaccessibility to clinical settings as ARF is consistently neglected in communities. In essence,
the lack of infrastructure for diagnosing GAS pharyngitis may have effectively inhibited the
 Bhupathiraju 10

administration of oral penicillin to undermine the progression of RHD. Thus, in future study
design, it may be beneficial to assess the burden of RF and the surveillance of prophylaxis to
understand the efficacy of current health infrastructure. Furthemore, the maintenance of
registries prescribed by Kevat, Reeves, et.al, may increase the rates of adherence to initial oral
regimens.
A potential limitation of the study, cumulatively, lies in the restriction of diagnostic
criteria through the developed stratification that is oriented solely towards anatomic and
haemodynamic abnormalities of RHD. The high sensitivity of the echo-Doppler may have
contributed to the high incidence, although warranted in a historically prevalent parameter.
Although the employment of the color Doppler criteria is highly effective in the diagnosis of
mitral regurgitation (Minich, Pagotta, et.al, 1997), the criteria is exclusive to clinical
presentations of ARF prescribed in the Jones criteria such as subcutaneous nodules, erythema,
and polyarthritis. In addition, the reported incidence of 48/1000 is misleading, to an extent, as
subsequent re-evaluation yielded 20 possible cases (14.6%) without structural or hemodynamic
abnormalities and 21 possible cases (15.3%) that no longer met the regurgitant jet requirements
of the echo-Doppler criterion. The consequent results of the young adult demographic revealed a
highly disproportionate incidence in female subjects (90.9%) that was attributed to lack of male
compliance and absence in dwellings during the period of the study. From that perspective,
expansion of the study to accommodate community burden may be achievable by expanding
surveillance throughout clinics in the geographic parameter and establishing a more accurate
representation of incidence in male subjects.
The study indisputably is a highly commendable initiative in the face of new momentum
suggesting lack of sensitivity in clinical examination as great as 4 fold (Anabwani, Bonhoeffer,
1996). Furthermore, it is consistent with data reported in echo-Doppler studies reporting
prevalences of 27/1000 and 30/1000 in Kenya and Mozambique, respectively ( (Anabwani,
Bonhoeffer, 1996)(Marijon, Celermajer, et.al, 2007). The design of the study is particularly
effective in accommodating inclusivity of children unenrolled in school and thereby increases the
accuracy of establishing burden. In addition, the considerable incidence of RHD in the adult
demographics typically not associated with high-risk of RHD epitomizes the chronic progression
and compensates, to some degree, for the infeasibility and unethicality of longitudinal studies.
In terms of applicability, the discussion of lack of adherence to prophylaxis reduces the
feasibility of the initial treatment of RF and increases the dependence on vaccine development.
In that sense, future studies should aim to extract GAS isolates to determine the heterogeneity of
emm types present in Nicaragua with respect to other underdeveloped countries. The increased
emphasis on establishing the diversity of the M-protein serotypes may contribute to the
assessment of the feasibility of the applicability of a potential 26-valent or 30-valent vaccine.
Therefore, it is essential to preserve prophylaxis administration in the interim for the Nicaragua
case to reduce incidence of RF and control recurrence of RF in propagating RHD. All in all, it is
 Bhupathiraju 11

evident that there is an impetus for increased equipping of public health to maintain registries
and an established framework designated to improve adherence to prophylaxis regimens.
CONCLUSION

The overarching theme permeating approaches to RHD have encompassed the

acknowledgement of initial assessment of ARF, but the consequent lack of clinical visitation and
retention to undermine progression through prophylaxis administration has substantially
hindered surveillance endeavors (Roberts, Colquhoun, et.al, 2012). In addition, there are
conflicting views regarding the extensivity of a developmental vaccine due to the tremendous
scope of M-protein heterogeneity (Steer, Law, et.al, 2009). Furthermore, as evidenced by the
Indian case, the lack of substantial margin markets for a potential vaccine further contributes to
ambiguity of feasibility (Sohn, 2019). However, the considerable momentum pertaining to
identification of highly conserved regions of the M-protein across serotypes (Pruksakorn, Brandt,
et.al, 1994) coupled with the development of emm-cluster systems ( Sanderson-Smith, De
Oliveira, et.al, 2014) have substantiated notions of cross-protection (Dale, Penfound, et.al, 2013).
In that sense cross-protection between emm-types identified in developed nations and those
found in underdeveloped nations would provide impetus for vaccine development.
Intriguingly, the WHO’s delineation of disproportionate incidence amongst women,
citing almost a two-fold discrepancy between males and females, was largely not experienced in
the Indian and Nicaragua cases. In addition, the respective incidences of the cases reveal a lack
of sensitivity in clinical examination in the Indian case and a potential hyper-sensitivity in
detecting structural abnormalities in the Nicaragua case. Although the maintenance of registries
is consistently represented as the gold-standard, the high migratory populations had severely
inhibited such adherence in both studies and is potentially reflective of its infeasibility in parallel
demographics. In that sense, the role of increased government allocation of funding for public
health surveillance is accentuated to validate the applicability of registries. The inhibitions to
penicillin administration is again reflected in the lack of manufacturing incentivization through
rigid price control that contributes to a vicious cycle of deteriorating supply chains. From that
perspective, the necessity of reviews establishing the efficacy of cephalosporins and
azithromycin is pronounced. By accumulating robust data through longitudinal studies, our
understanding of pathogenesis mechanisms pertaining to specificity in cross-reactivity may be
amplified (Watkins, 2018). The proliferation of studies establishing the burden of RHD in
respective countries are integral to our understanding that RHD is chronically underdiagnosed
and foster an impetus for increased assessment of chronic progressions. Furthermore, as many
studies have been confined to school-enrolled children, there must be increased inclusitity to
vulnerable un-enrolled children in identified high-risk populations.
Indisputably, the global fight against RF/RHD has made monumental strides from initial
apprehension of vaccine development as propagating the incidence of RF (Massil, Honikman,
Amezcua, 1969) to the current status of a 30-valent vaccine (Dale, Penfound, Tamboura, 2013).
 Bhupathiraju 12

However, much more needs to be done to erode the wall of negligence we constructed. In the
same native Tooro that Mugisa belonged to, Mwesige means trust. And it's time to build trust.
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