Rheumatic Heart Disease Worldwide

Rheumatic Heart Disease Worldwide

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 72, NO. 12, 2018 ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER T...

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 72, NO. 12, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE JACC SCIENTIFIC EXPERT PANEL

Rheumatic Heart Disease Worldwide JACC Scientific Expert Panel David A. Watkins, MD, MPH,a,b,c Andrea Z. Beaton, MD,d Jonathan R. Carapetis, MBBS, PHD,e,f Ganesan Karthikeyan, MD, DM,g Bongani M. Mayosi, MBCHB, DPHIL,b,h Rosemary Wyber, MBCHB, MPH,e,i Magdi H. Yacoub, MD,j Liesl J. Zühlke, MBCHB, MPH, PHDb,c

JACC JOURNAL CME/MOC/ECME This article has been selected as the month’s JACC CME/MOC/ECME activity, available online at http://www.acc.org/jacc-journals-cme by selecting the JACC Journals CME/MOC/ECME tab. Accreditation and Designation Statement

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The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.

CME/MOC/ECME Objective for This Article: Upon completion of this activity, the learner should be able to: 1) identify, within a global context, populations that remain at elevated risk of acute rheumatic fever and

Successful completion of this CME activity, which includes participation in

rheumatic heart disease; 2) summarize areas of consensus and the major

the evaluation component, enables the participant to earn up to 1 Medical

gaps in evidence regarding the prevention and medical management of

Knowledge MOC point in the American Board of Internal Medicine’s (ABIM)

rheumatic heart disease; and 3) describe indications for catheter-based or

Maintenance of Certification (MOC) program. Participants will earn MOC

surgical management of common rheumatic valvular lesions.

points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion

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vendra R. Baliga, MD, FACC, has reported that he has no financial relationships or interests to disclose.

Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel will be accredited by the European Board for Accreditation in Cardiology (EBAC)

Author Disclosures: Dr. Watkins has received support from the RHD Action

for 1 hour of External CME credits. Each participant should claim only

grant from Medtronic Foundation outside of the submitted work.

those hours of credit that have actually been spent in the educational

Dr. Carapetis has received funding from Novartis Institutes for Biomedical

activity. The Accreditation Council for Continuing Medical Education

Research. Dr. Wyber has received funding from the Postgraduate Scholar-

(ACCME) and the European Board for Accreditation in Cardiology (EBAC)

ship from the National Health and Medical Research Council (NHMRC),

have recognized each other’s accreditation systems as substantially

Australia, and from the Telethon Kids Institute. All other authors have

equivalent. Apply for credit through the post-course evaluation. While

reported that they have no relationships relevant to the contents of this

offering the credits noted above, this program is not intended to provide

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extensive training or certification in the field.

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Expiration Date: September 17, 2019

Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

From the aDivision of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington; b

Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa; cDepartment of Pae-

diatrics, University of Cape Town and Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; dChildren’s National Health System, Washington, DC; eTelethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia; f

Princess Margaret Hospital for Children, Perth, Western Australia, Australia; gDepartment of Cardiology, All India Institute of

Medical Sciences, New Delhi, India; hThe Deans Suite, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; iOffice of the Chief Scientist, The George Institute for Global Health, UNSW Sydney, Camperdown, New South Wales, Australia; and the jAswan Heart Centre, Aswan, Egypt. Dr. Watkins has received support from the RHD Action grant from Medtronic

ISSN 0735-1097/$36.00

https://doi.org/10.1016/j.jacc.2018.06.063

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JACC VOL. 72, NO. 12, 2018 SEPTEMBER 18, 2018:1397–416

Present Status of Rheumatic Heart Disease

Rheumatic Heart Disease Worldwide JACC Scientific Expert Panel David A. Watkins, MD, MPH,a,b,c Andrea Z. Beaton, MD,d Jonathan R. Carapetis, MBBS, PHD,e,f Ganesan Karthikeyan, MD, DM,g Bongani M. Mayosi, MBCHB, DPHIL,b,h Rosemary Wyber, MBCHB, MPH,e,i Magdi H. Yacoub, MD,j Liesl J. Zühlke, MBCHB, MPH, PHDb,c

ABSTRACT Rheumatic heart disease (RHD) is a preventable heart condition that remains endemic among vulnerable groups in many countries. After a period of relative neglect, there has been a resurging interest in RHD worldwide over the past decade. In this Scientific Expert Panel, the authors summarize recent advances in the science of RHD and sketch out priorities for current action and future research. Key questions for laboratory research into disease pathogenesis and epidemiological research on the burden of disease are identified. The authors present a variety of pressing clinical research questions on optimal RHD prevention and advanced care. In addition, they propose a policy and implementation research agenda that can help translate current evidence into tangible action. The authors maintain that, despite knowledge gaps, there is sufficient evidence for national and global action on RHD, and they argue that RHD is a model for strengthening health systems to address other cardiovascular diseases in limited-resource countries. (J Am Coll Cardiol 2018;72:1397–416) © 2018 by the American College of Cardiology Foundation.

O

ver the past decades, rheumatic heart dis-

Because of this renewed interest, the science of

ease (RHD) and its antecedent rheumatic

RHD has evolved rapidly. A number of new or

fever (RF) have largely disappeared from

ongoing studies aim to provide answers to key ques-

wealthy countries, and the clinical caseload of RHD

tions. This Scientific Expert Panel seeks to summarize

has shifted to older age groups. RHD has also been

recent research on RHD—from molecular mechanisms

dwarfed by ischemic heart disease. Additionally, RF/

to health systems—in one coherent, scientifically-

RHD control programs were successfully implemented

grounded vision for the future of science, clinical

in some low- and middle-income countries during the

medicine, and public health practice relating to RHD

latter part of the 20th century, prompting the World

(Central Illustration).

Health Organization (WHO) and others to downscale their RF/RHD activities by the early 2000s (1). Yet, RHD continues unabated in poor countries and

WHAT IS RHEUMATIC HEART DISEASE, AND HOW BIG IS THE PROBLEM?

among vulnerable groups in wealthy ones (2). A 2007 report on RHD among schoolchildren in Cambodia and

PATHOGENESIS. The major driver of acute RF is

Mozambique spawned a whole literature on echocar-

frequent group A beta-hemolytic streptococcal (GAS)

diography and RHD (3). The recent REMEDY study

infection.

(Global Rheumatic Heart Disease Registry) docu-

increased GAS exposure include household crowd-

mented high rates of disability and premature death

ing, poor hygiene, and low access to medical ser-

across African and Asian countries (4). In 2015, a civil

vices (7). Why only a minority of persons (<6%)

society movement, RHD Action, was launched to raise

living in GAS-endemic areas develop RF is less

awareness and support countries looking to address

understood.

RHD (5). In May 2018, the World Health Assembly

H o s t f a c t o r s . There are 2 theories of how GAS

adopted a resolution to reinvigorate global and na-

infection damages host tissues. The basis of the mo-

tional RF/RHD prevention and control efforts (6).

lecular mimicry theory is that molecules on the

Socioeconomic

conditions

Foundation outside of the submitted work. Dr. Carapetis has received funding from Novartis Institutes for Biomedical Research. Dr. Wyber has received funding from the Postgraduate Scholarship from the National Health and Medical Research Council (NHMRC), Australia, and from the Telethon Kids Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received March 22, 2018; revised manuscript received June 13, 2018, accepted June 15, 2018.

leading

to

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Present Status of Rheumatic Heart Disease

infecting organism are antigenically similar to mole-

recognize and activate valve endothelium to

ABBREVIATIONS

cules on host tissues. When the host immune

express adhesion molecules like vascular cell

AND ACRONYMS

response targets these molecules, both are damaged.

adhesion molecule 1, allowing CD4 T cells

In the case of acute RF, 2 main streptococcal antigens

(and others) activated by GAS to invade the

have been implicated: the surface M protein, and

heart valve, encounter antigens, and become

GlcNAc, the immunodominant epitope of the group A

further activated. Over time, tissue break-

carbohydrate (8). The “neo-antigen” theory, a more

down, partly involving autoantibodies and

recent development, suggests that the GAS organism

complement activation, releases additional

gains access to the subendothelial collagen matrix,

endogenous antigens such as collagen, lami-

where M proteins binds to the CB3 region of type IV

nin, myosin, and tropomyosin that may also

collagen, creating a neo-antigen that induces an

serve as autoantigens, stimulating more CD4 T cells,

autoimmune response against collagen (9).

which then produce Th1 and potentially Th17 cyto-

GAS = group A beta-hemolytic streptococcus

RF = rheumatic fever RHD = rheumatic heart disease WHF = World Heart Federation WHO = World Health Organization

In both theories, it is thought that the initial

kines, leading to further inflammation in the heart

damage to cardiac tissues is due mainly to antibodies,

valve. Over time, successive episodes coupled to

with cellular responses subsequently implicated as

resolution leads to neovascularization and fibrosis

the immunological cascade evolves. These antibodies

(Figure 1) (10).

C ENTR AL I LL U STRA T I O N Framework for Rheumatic Heart Disease Control and Eventual Elimination

Prevention

Research

• Innovations in rheumatic fever/rheumatic heart disease diagnosis and risk prediction • Improved delivery of benzathine penicillin G • Raising public and health worker awareness • Comprehensive, community-based programs

Advanced care

Advocacy

Health policy

• Early echocardiographic diagnosis • Reproductive and antenatal services • Medical management of complications • Access to timely, high-quality surgical care

• “Diagonal” health system investments • Integration and cross-sector collaboration • Product development and research priorities (e.g., vaccines)

Implementation Watkins, D.A. et al. J Am Coll Cardiol. 2018;72(12):1397–416.

Global progress on rheumatic heart disease (RHD) will require a combination of advocacy efforts, implementation of existing evidence, and research in key areas. Priority areas for advocacy, implementation, and research are: 1) the prevention of rheumatic fever and RHD, typically through primary healthcare services in community settings; 2) advanced care, which includes tertiary cardiology and, critically, cardiac surgery services; and 3) health policy, including measures that should be taken by national health systems (mostly to deliver health care) and international collective action (mostly to support research, product development, and global stewardship and leadership).

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F I G U R E 1 Possible Pathogenic Mechanisms in Rheumatic Heart Disease

Fibrosis Inflammatory lesions Functional Antibodies

Complement

Neovasularization

Recruitment of cells activated by GAS infection

Anti-endothelial cell antibodies (AECA) generated by GAS infection

Pro-inflammatory cytokine production

AECA-induced adhesion molecule expression

Aschoff Nodule

Autoantibodies

VCAM-1

CD4+Tcell

B cell

Complement

Endogenous peptide loaded on MHCII

CD8+Tcell

Monocyte

Valvular dendritic cell Monocyte-derived dendritic cell

Myofibroblast Antigen Presentation

The schematic shows a cross-section of a heart valve leaflet. Autoreactive antibodies, including antiendothelial cell antibodies (AECA) and autoreactive T cells, are generated by infection with group A beta-hemolytic streptococcus (GAS) in the throat (pharyngitis) or possibly the skin (pyoderma, impetigo) through molecular mimicry and/or anticollagen responses. AECA have multiple effects, including the activation of endothelial cells leading to vascular cell adhesion molecule (VCAM) 1 expression, complement activation leading to cell death, and activation of neuronal cells leading to CaM kinase III signaling. Deposition of complement and immunoglobulin occurs. The presence of M protein in the subendothelial collagen matrix by GAS invasion of endothelial surfaces may lead to the generation of anticollagen type IV responses. Liberation of structural alpha helical coiled coil peptides, including collagen, laminin, keratin, and tropomyosin, occurs in areas of tissue damage such as valvular lesions. Liberated proteins are presented by antigen presenting cells (APC) either in situ or in the draining lymph node to induce autoreactive CD4þT cells. These APC are resident dendritic cells, recruited inflammatory monocytes that have differentiated into APC in the valve interstices or within ectopic Aschoff nodules, or valvular fibroblasts and cardiac endothelial cells that aberrantly express MHC II. The range of reactive T-cell and antibody specificities increases over time with epitope spreading. Th1 cytokines, such as IFNg, and chemokines including CXCL9 are generated in ARF and RHD. Prolonged and repeated cycles of inflammation facilitate ongoing tissue damage. In RHD, TGFb from interstitial cells may contribute not only to Th17 generation but also to new blood vessel growth, allowing greater access to the valve in successive episodes, as well as stimulating collagen deposition from myofibroblasts, leading to fibrosis. Reprinted with permission from Martin et al. (10).

The infrequency of RF/RHD relative to the frequency of childhood GAS infection raises the possi-

and B-cell alloantigens have been implicated (14), but most have not been replicated (15,16).

bility of genetic predisposition (11). Among children

Among genome-wide association studies, 2 had no

raised apart from their parents, those whose parents

significant findings, whereas another found that var-

had RHD had a 2.9-fold higher risk of RF compared

iants at the immunoglobulin heavy chain locus were

with peers whose parents did not have RHD (12). Twin

associated with RHD in 2 populations (17), but this

studies have estimated the heritability of RF at 60%

result was not replicated elsewhere (18). The latter

(13). Small candidate gene case-control studies have

study identified evidence for risk and protective

identified genetic variants associated with RF/RHD.

haplotypes across HLA-DQA/DQB Class II molecules,

Genes controlling the adaptive immune response

supporting molecular mimicry as the key pathogenic

(e.g., human leukocyte antigen [HLA] class II alleles),

mechanism. Although these studies differ in diag-

the innate immune response (e.g., toll-like receptor

nostic method, design, and population studied, they

2), cytokine genes (e.g., tumor necrosis factor alpha),

support the notion of autoimmune pathogenesis.

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T A B L E 1 Clinical Features Among 3,343 African, Yemeni, and

T A B L E 2 World Heart Federation Criteria for the Diagnosis of RHD

Indian Individuals With Symptomatic Rheumatic Heart Disease Median Age, yrs

New York Heart Association functional class III and IV

809 (24.6)

26

Medical history Acute rheumatic fever

1,340 (40.7)

Congestive heart failure

1,110 (33.4)

Pulmonary hypertension

25

957 (28.8)

26

Stroke

235 (7.1)

40

Infective endocarditis

133 (4.0)

25

Major bleeding

89 (2.7)

31

Peripheral embolism

25 (0.8)

43

Atrial fibrillation

586 (21.8)

Echocardiography Decreased LVEF in adults Decreased LVEF in children

661 (26.5) 168 (5.3)

Dilated LVEDD in adults

742 (23.0)

Dilated LVEDD in children

454 (14.1)

Left atrial thrombus

44 (1.4)

Previous percutaneous valvuloplasty

Definite RHD (A, B, C, D) Age >20 yrs

A. Pathological MR and at least 2 morphological features of RHD of the MV

A. Pathological MR and at least 2 morphological features of RHD of the MV

B. MS mean gradient $4 mm Hg*

B. MS with mean gradient $4 mm Hg*

C. Pathological AR and at least 2 morphological features of RHD of the AV

C. Pathological AR and at least 2 morphological features of RHD of the AV in those age <35 yrs

D. Borderline disease of both the AV and MV

D. Pathological AR and at least 2 morphological features of RHD of the MV Borderline Not Applicable to Those Age >20 yrs

Borderline RHD (A, B, C) A. At least 2 morphological features of RHD of the MV without pathological MR or MS B. Pathological MR C. Pathological AR Pathological Mitral Regurgitation

Pathological Aortic Regurgitation

Seen in 2 views

Seen in 2 views

715 (21.4)

In at least 1 view, jet length $2 cm†

In at least 1 view, jet length $1 cm†

135 (4.1)

Velocity $3 m/s for 1 complete envelope

Velocity $3 m/s in early diastole

Pan-systolic jet in at least 1 envelope

Pan-diastolic jet in at least 1 envelope

Surgical history Valve replacement or repair

Definite RHD (A, B, C, D) Age #20 yrs

Values are n (%) or n. Table presents authors’ own re-analysis of data from Zühlke et al. (4). LVEDD ¼ left ventricular end-diastolic diameter; LVEF ¼ left ventricular ejection fraction.

Meta-analyses of thousands of well-characterized cases and controls will be required to identify reliable and reproducible genetic susceptibility and protective factors. Ultimately, genomic analyses could identify high-risk individuals to target for penicillin

Mitral Valve

Aortic Valve

AMVL thickening $3 mm (age #20 yrs), $4 mm (age 21 to 40 yrs), $5 mm (age >40 yrs)

Irregular or focal thickening

Chordal thickening

Coaptation defect

Restricted leaflet motion

Restricted leaflet motion

Excessive leaflet tip motion during systole

Prolapse

*Must rule out congenital anomalies of the mitral and aortic valve. †Jet to be measured from vena contracta to last pixel of color. Modified with permission from Remenyi et al. (24). AMVL ¼ anterior mitral valve leaflet; AR ¼ aortic regurgitation; AV ¼ aortic valve; MR ¼ mitral regurgitation; MS ¼ mitral stenosis; MV ¼ mitral valve; RHD ¼ rheumatic heart disease.

prophylaxis and vaccination against GAS. P a t h o g e n f a c t o r s . Outbreaks of rheumatic fever in North America in the mid-20th century were limited

regions of the M protein and include sequences

to GAS strains belonging to a subset of M types (based

homologous with human actin and cardiac myosin,

on the classical typing system; this has since been

although there are other cross-reactive antigens in

replaced by emm typing based on the genetic

GAS including the group A carbohydrate (10).

sequence of the M protein). Over the past 2 decades, it

While the recent growth in research on RHD path-

has become apparent that GAS strains from regions

ogenesis is promising and has challenged a variety of

where RHD is endemic are much more diverse than

historical paradigms, a number of key scientific

those in nonendemic areas, and that there is no as-

questions remain. Online Appendix Panel 1 suggests

sociation of particular emm types with RF/RHD (19).

priorities for future research.

This work has also suggested that RF-inducing strains

CLINICAL

may be associated with skin infection, supporting the

C l i n i c a l f e a t u r e s . Aside from a subset of children in

hypothesis that RF is not solely a consequence of GAS

whom RF leads to severe carditis and early RHD, RHD

pharyngitis (20–22).

is usually clinically silent (“latent”) until it manifests

AND

ECHOCARDIOGRAPHIC

ASPECTS.

Focus has shifted in recent years to better under-

during adulthood. Many individuals in RHD-endemic

standing the features of RF-associated GAS strains

countries present late in their disease process with 1

rather than emm types. Most attention has been paid

or more sequelae. The REMEDY study followed 3,343

to identifying surface or excreted antigens that have

individuals with symptomatic RHD presenting for

antigenic homology to human tissues and could

care at academic centers in 14 countries (Table 1) (4).

stimulate cross-reactivity. Most of the identified

Most individuals were 15 to 49 years of age, and

cross-reactive regions are in the A- and B-repeat

fewer than one-half recalled a history of RF. Heart

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F I G U R E 2 Parasternal Long-Axis Echocardiography Images of a Child With Borderline RHD

This echocardiogram demonstrates functional but not morphological changes of the mitral valve, including an anterior mitral valve (single arrow) thickness of 2.7 mm (criterion for definite rheumatic heart disease [RHD] is thickness $3 mm, or $4 mm if age >20 years) and jet length (double arrow) of 2.3 cm (criterion for definite RHD is >2 cm in at least 1 view). In addition, there is complete leaflet excursion without restriction. See Table 2 for full details of the WHF criteria for borderline and definite RHD. AAo ¼ aortic arch; LA ¼ left atrium; LV ¼ left ventricle.

failure, pulmonary hypertension, and atrial fibrillation

“Subclinical RHD” refers to RHD seen on echocardi-

were the most frequent medical complications. About

ography in a patient with a normal clinical cardiac

20% demonstrated decreased left ventricular ejection

examination. “Latent” RHD includes a broader spec-

fraction, and about one-third had increased left

trum of disease, including any RHD found on echo-

ventricular end-diastolic diameter—underscoring the

cardiographic screening in the absence of prior RF or

consequences of late presentation.

known RHD. Although latent RHD includes subclini-

Challenges in diagnosing acute RF are a major

cal RHD, one-third (Uganda) (25) to two-thirds (Fiji)

barrier to preventing RHD. Strong evidence of milder

(26) of children with latent definite RHD already have

presentation and the importance of subclinical car-

moderate-to-severe disease. Outcomes for these

ditis prompted revision of the Jones Criteria (the gold

children are poor (26). In Uganda, almost one-half of

standard for RF diagnosis) in 2015 to better account

children with moderate-to-severe RHD progressed (to

for differences in population risk (23). While these

worsening regurgitation, stenosis, or death) over a

criteria will likely increase case detection, barriers

median of 2.3 years, and only 9.5% showed any dis-

such as poor health seeking behavior, lack of pathol-

ease improvement (25).

ogy services, and clinical overlap with other endemic

By contrast, the clinical course of children with

diseases (such as malaria in sub-Saharan Africa) limit

borderline and mild definite RHD is enigmatic. Com-

the efficacy of a simple diagnostic shift within a

parison

clinical decision rule. Better RF diagnosis will require

cautiously: studies have used inconsistent definitions

the development of new (laboratory) technology tests

of progression, have used different outcomes, and in

that could augment or replace clinical decision rules.

some cases, have included children with advanced

R H D . The World Heart

RHD (25,27). Standardization is needed in reporting

Federation (WHF) published the first evidence-based,

outcomes (27). Although most children with border-

Echocardiography

and

across

cohorts

must

be

undertaken

standardized criteria for the echocardiographic diag-

line or mild definite RHD remain stable or show

nosis of RHD in 2012 (Table 2, Figure 2) (24). Since

improvement, 10% to 24% experience disease pro-

then, >2 dozen additional studies covering >100,000

gression (Figure 3). Outcomes are best for children

participants have been conducted. In parallel, studies

with borderline RHD and worst for those with

have investigated the practicalities of echocardio-

advanced RHD (25).

graphic screening in RHD-endemic countries, high-

There is no doubt that some overlap exists be-

lighting many challenges and exploring solutions

tween echocardiographic findings of borderline RHD

(Table 3).

and normal anatomic variation. Early RHD appears to

The vocabulary describing echocardiographically-

be a dynamic, heterogeneous entity with varied

detected RHD lacks precision in the published data.

outcomes (Figure 4). If subclinical RHD detected

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T A B L E 3 Research Progress and Remaining Questions Around Echocardiographic Screening for RHD

Rationale and Challenges

Progress

Next Step(s)

Simplified protocols

Category

 2012 WHF criteria were intended for RHD diagnosis by experts  In a screening environment, with its rapid pace, providers with varying experience, and suboptimal conditions, these criteria have proved less practical  Some portable devices lack spectral Doppler, which is required for the diagnosis of RHD according to the WHF criteria

 Simplified acquisition protocols, even a single view has reasonable sensitivity and specificity  Abbreviated screening criteria (vs. diagnosis) have good performance  Most focus exclusively on valve function; length of mitral regurgitation and presence of aortic insufficiency  Practical, but misses isolated morphological abnormalities that can occur in the absence of pathological regurgitation early in RHD

 Re-evaluate components of WHF criteria toward simplification of diagnosis  Standardize simplified protocols for screening

Handheld equipment

 Increased portability  Largely reliant on battery vs. need for reliable electricity  Less expensive  Lacks functionality (spectral Doppler, needed for WHF criteria)  Most research on a single system (GE VScan)/other systems increasingly available

 Experts show 79% sensitivity and 87% specificity for all latent RHD, improving to 98% sensitivity for definite RHD  May miss up to one-third of borderline RHD (even by experts)  Need for fully functional machine to meet 2012 WHF criteria increases overall costs

Task sharing

 Severe shortage of persons in LMICs trained in echocardiography  Severe shortage of physicians in LMICs outside of major metropolitan areas

 Nonexpert diagnostic performance following brief training has been promising  Performance, even within individual studies, has varied substantially between learners

Standardized training

 WHO guidelines recommend continuous monitoring and evaluation during implementation of task sharing  Standardized training is central to this endeavor

 Freely available online modules in 3 languages developed (WiRED International)  Modules show good performance and acceptability among nurses and other health providers  Telemedicine shows promise as an adjunct to training and mentorship

 Determine best strategies for scaling up training (such as trainthe-trainer, and so on)  Development of standardized competency assessments/ accreditation processes

Effect on children and communities

 Need to understand the effect of a screening test on a community, on those who test positive, and on those who test negative

 Strong support for screening from parents of screened children in New Zealand and screened children and teachers in Uganda  Negative screening has no effect on quality of life, but positive result can cause anxiety and decreased physical activity, and can decrease parental and child quality of life  Peer support groups may be able to normalize QOL in children with positive screen and to improve social connectedness

 Community-engaged research to minimize negative effects of RHD screening on children and communities

Outcomes

 It remains unclear at what rate latent RHD progresses and if early detection leads to improved outcomes

 Ten longitudinal cohorts, 2 to 7 yrs of follow-up  Heterogeneous diagnosis with varied outcomes  Outcomes best for borderline RHD, followed by mild definite RHD, and worst for those with moderate/severe RHD at screening  Progression rates are challenging to compare— inconsistent definitions of progression, use of different binomial outcomes (stable þ progression), and inclusion of children with advanced RHD

 Standardization of reporting outcomes for children with latent RHD is of high priority  Randomized controlled trial of secondary prophylaxis in children diagnosed with latent RHD (GOAL trial, planned to start June 2018)

Cost effectiveness

 It is not yet known if screening for RHD is cost-effective  It is likely that the downstream costs of screening (additional health system burden, impact on patient and family quality of life, and so on) will be significant

 3 studies assessing the cost effectiveness of screening  Broad assumptions leading to hypothetical conclusions—the impact of secondary prophylaxis on latent RHD (see above) is not fully understood

 Reassessment as more data is gathered around outcomes for latent RHD and the impact of secondary prophylaxis, which can more precisely inform the investment case for RHD screening

LMICs ¼ low- and middle-income countries; QOL ¼ quality of life; RHD ¼ rheumatic heart disease; WHF ¼ World Heart Federation.

through echocardiographic screening is indeed part

secondary prevention for early-stage disease (see

of same disease process as RF-associated carditis—as

Part 2 of this review).

suggest

The published echocardiography data has taught

(28,29)—then a high rate of resolution does not

us that latent RHD is neither homogeneously malig-

necessarily cast doubt on RHD diagnosis. It does,

nant

however, raise questions about the added benefits of

screening has played a pivotal role in reinvigorating

studies

in

low-risk

populations

largely

nor

uniformly

benign.

Echocardiographic

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Present Status of Rheumatic Heart Disease

F I G U R E 3 Progression of Borderline RHD

(Top) A 2-cm mitral regurgitant jet is seen in at least 1 view, mitral regurgitation is seen in 2 or more views, and a pan-systolic jet is seen and measures >3 m/s. (Bottom) Two years later, the same features are noted, but in addition there are new signs of restricted posterior leaflet motion and anterior mitral valve leaflet thickness >3 mm. This echocardiogram meets the criteria for definite rheumatic heart disease (RHD) (pathological mitral regurgitation with 2 morphological criteria).

global research and helping to modernize our

followed by stroke or transient ischemic attack (8.5

understanding

In

per 1,000 patient-years) and infective endocarditis

Online Appendix Panel 2, we provide recommenda-

(3.7 per 1,000 patient-years). The incidence of recur-

tions for echocardiography-based RHD research.

rent RF in this cohort was 3.5 per 1,000 patient-years,

DISEASE EPIDEMIOLOGY. Relatively more is known

and regular use of secondary prevention was not

of

disease

pathogenesis.

about the prevalence of RHD compared with other

associated with better outcomes (32). The median age

epidemiological parameters. A systematic review

at death was 28 years, and case-fatality at 24 months

undertaken for the Global Burden of Disease 2015

was highest in low-income countries (21%) and

study identified prevalence data from 59 countries

significantly lower in middle-income countries (12%

(2). Using epidemiological modeling techniques, this

to 17%).

study estimated about 33 million individuals (0.4% of

Less is known about mortality from RHD in the

the global population) currently live with RHD. The

general population. In many countries, RHD is

disease is most common in sub-Saharan Africa, South

captured in nationally-representative vital or sample

Asia, and Oceania. Most prevalence studies have been

registration systems. Using these datasets, the Global

conducted in children attending school; relatively

Burden of Disease 2015 study estimated about

little

children

320,000 deaths from RHD in 2015, or about 0.6% of all

not attending school and among adults. Emerging

deaths. The highest death rates were in the highest-

data suggest that RHD is more common in adults

prevalence regions, and no significant decline in

and

mortality over 1990 to 2015 was detected in a number

is

known

among

about

children

RHD

in

among

community

settings

(compared with children well enough to attend

of countries, whereas other countries—mostly of

school) (30,31).

middle or high income—demonstrated dramatic re-

Hospital-based studies have provided insights into

ductions in mortality (2). The limitations of these

complications of and case-fatality from RHD. REM-

estimates include incomplete vital registration sys-

EDY estimated the incidence of RHD complications

tems in some (predominately African) countries and

over 24 months of follow-up. The most frequent was

the potential for misclassifying RHD deaths as deaths

new-onset heart failure (38 per 1,000 patient-years),

from other causes, for example, stroke (33).

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Present Status of Rheumatic Heart Disease

Online Appendix Panel 3 summarizes priorities for research on the descriptive epidemiology of RHD.

F I G U R E 4 The Spectrum of RHD

HOW SHOULD RHEUMATIC HEART DISEASE

Death due to RHD

BE MANAGED? PREVENTION. We generally endorse current guide-

lines on primary and secondary prevention of

Symptomatic RHD (active disease)

RHD (34). The following section highlights gaps in

P r i m a r y p r e v e n t i o n . Primary prevention of RHD focuses on the prompt recognition and treatment of

RHD causing sequelae* RHD causing cardiac failure

knowledge and needs for research in RHD-endemic countries.

RHD requiring surgery

Asymptomatic RHD (latent disease)

Clinical definite RHD (i.e., murmur present) Subclinical definite RHD (i.e., no murmur)

GAS pharyngitis to decrease the risk of RF in high-risk populations. Research is needed to clarify whether

Borderline echocardiographic findings suggestive of RHD

other Lancefield groups (35) and skin infections (36) can cause RF. Intramuscular benzathine penicillin G (BPG) remains the most widely-used antibiotic for GAS pharyngitis (37). Trials among American military recruits conducted

This model illustrates the distinctions between symptomatic and asymptomatic (or latent) disease and between definite and borderline rheumatic heart disease (RHD).

in the 1950s demonstrated that treating GAS pharyn-

*Sequelae of RHD include heart failure, atrial fibrillation/stroke, and infective endo-

gitis reduced the risk of acute RF by about 80%. A

carditis, among others. Reprinted with permission from Zühlke L, Steer A. Estimates of

meta-analysis summarized the main limitations of

the global burden of rheumatic heart disease. Glob Heart 2013;8:189–95.

the primary prevention trials (38). Most studies were of low quality compared to current standards, and little comparative evidence exists to quantify effects

of recurrence with repeated GAS infection may be as

among females or diverse populations.

high as 50%. Secondary prevention involves contin-

Accurate diagnosis of GAS pharyngitis remains

uous antibiotic chemoprophylaxis to prevent recur-

challenging in resource-limited countries. While

rent RF and reduce progression to RHD (34). Four-

throat culture is the gold standard for diagnosis,

weekly intramuscular BPG remains the standard of

access

often

care in most settings, and contemporary studies have

cost-prohibitive (39). Rapid diagnostic tests offer high

found low rates of RF recurrence (0.07 per 100

sensitivity and specificity, but their performance may

patient-years) with this regimen (44).

to

microbiology

is

limited

and

vary across settings, requiring validation studies prior

A systematic review summarized the findings and

to local adoption (40). Low-cost, portable systems for

limitations of the existing clinical trials on secondary

rapid GAS diagnosis are urgently needed. In the

prevention (45). Compared with doing nothing,

absence of confirmatory testing, clinical decision

providing penicillin appears to confer a 55% relative

rules may be used and may even be more cost-

reduction in risk of RF. Injectable penicillin is

effective (39). There is no consensus clinical deci-

significantly more effective than oral penicillin;

sion rule; most have been developed and tested in

however, the studied formulations of penicillin are no

single populations, with further testing needed to

longer in widespread use. Although secondary pre-

confirm generalizability. The issue of GAS carriage in

vention clearly reduces recurrent RF, less is known

the pharynx also requires further research.

about its effect on RHD. Newer data suggest

Poor health-seeking behavior and lack of community awareness regarding pharyngitis and RHD are

reductions in valvular pathology (46) and possibly mortality (47).

also barriers to primary prevention (41). Successful

The optimal duration of secondary prevention is

RHD programs in the Caribbean emphasized com-

controversial. Current recommendations are based on

munity education (42), and the WHO recommends, as

expert opinion, and no trial has recruited individuals

a pillar of RHD programs, community-based cam-

aged >25 years. Although the risk of GAS (and thus RF)

paigns that emphasize the link between pharyngitis

generally falls with age, this may not be true in certain

and RHD (43).

life stages (e.g., parenthood), among certain pro-

S e c o n d a r y p r e v e n t i o n . Recurrent RF can be trig-

fessions exposed to GAS (e.g., teachers, nurses, mili-

gered by asymptomatic and even appropriately-

tary), and in highly GAS-endemic areas (34). More

treated GAS infection. After the first attack, the risk

rigorous study of this issue is needed given the

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Present Status of Rheumatic Heart Disease

resource implications and risks of long-term antibiotic

who develop severe tricuspid insufficiency late after

use (34).

surgical correction of other valve disease.

Ensuring adherence to secondary prevention has

There is no RHD-specific evidence on optimal drug

proven challenging in limited-resource settings,

therapy for heart failure. Digoxin is widely used

usually reflecting socioeconomic deprivation and

among those who have atrial fibrillation or heart fail-

health

are

ure (4), although its effect on clinical outcomes is not

considered best practice to improve the delivery of

known. Individuals with mitral stenosis in sinus

secondary prevention (49). Improvements in BPG

rhythm awaiting intervention or surgery may gain

formulation could support adherence (50). Therapy-

some symptom relief with heart rate control using

related adherence barriers include fear of adverse

beta-adrenergic blockers, calcium-channel blockers,

drug reactions to BPG (51). Reported risks of allergy

or ivabradine (58,59). It may be reasonable to recom-

and anaphylaxis are 3.2% and 0.2%, respectively; yet,

mend vasodilator therapy with nondihydropyridine

anecdotal experiences suggest higher rates (52). Cre-

calcium blockers, angiotensin-converting enzyme

ation of a global reporting system for BPG adverse

inhibitors or angiotensin receptor blockers, and beta-

events has been proposed to track these risks (53).

blockers for symptomatic patients with severe aortic

system

weaknesses

(48).

Registries

Longitudinal studies provide little evidence that

regurgitation (57). Although there are fewer data

secondary prevention improves outcomes for chil-

supporting the use of these approaches in severe

dren with echocardiographically-detected early and

mitral regurgitation, it is generally accepted that

borderline RHD. In fact, an Australian cohort found

individuals with congestive symptoms and signs

increased risk of progression with penicillin (54), with

should receive these medications. Diuretics can also

similar findings in Uganda (25). Currently, most chil-

be used as needed for symptom relief.

dren presenting with mild definite RHD receive sec-

A t r i a l fi b r i l l a t i o n a n d s t r o k e . About 1 in 5 persons

ondary prevention, whereas most with borderline

with symptomatic RHD are in atrial fibrillation (4).

RHD do not. We recommend at least yearly clinical

Atrial inflammation and chronically elevated left

follow-up and counseling on the signs and symptoms

atrial pressure leading to atrial remodeling are

of GAS infection and RF. The presence of equipoise

important causal factors. Older age and the presence

has prompted a 2-year randomized controlled trial,

of mitral valve disease (especially stenosis) are

beginning in June 2018, of 4-weekly BPG for latent

strongly associated with incident atrial fibrillation. In

RHD (Determining the Impact of Penicillin in Latent

REMEDY, older persons living in upper-middle-

RHD: The GOAL Trial; NCT03346525).

income countries had a higher prevalence of atrial and

fibrillation than younger persons from low-income

research in the area of primary and secondary pre-

countries (28% vs. 18%) despite having milder dis-

vention are provided in Online Appendix Panel 4.

ease (32). From 40% to 75% of individuals with mitral

Recommendations

for

clinical

practice

f a i l u r e . Onset of

stenosis have atrial fibrillation (60). As with heart

heart failure is often associated with advanced RHD

failure, the development of atrial fibrillation gener-

that may not be amenable to corrective surgery. Heart

ally portends a poor prognosis. Among individuals

failure doubles the risk of death independent of other

with symptomatic disease, atrial fibrillation is asso-

prognostic variables (32), and in patients with aortic

ciated with a 40% higher mortality independent of

stenosis or dominant regurgitant lesions portends a

other prognostic markers, and risk of stroke increases

particularly poor prognosis (55). By contrast, the he-

2-fold (2.4% vs. 1.2% at 24 months) (32).

MEDICAL MANAGEMENT. H e a r t

modynamic consequences of mitral stenosis are

Treatment of atrial fibrillation in RHD is directed at

relieved by percutaneous balloon or surgical mitral

the underlying valve disease. Restoration and main-

valvuloplasty.

tenance of sinus rhythm is preferred for younger

Based on studies of nonrheumatic valve disease

persons (61). Although this may be possible using

(55,56), it is recommended that surgical correction be

balloon valvuloplasty in some cases of mitral stenosis

performed before the onset of symptoms in patients

(62), it may not be possible in cases of long-standing

with severe mitral and aortic regurgitation, guided by

disease and very large left atria. In a small random-

echocardiographic indexes of left ventricular func-

ized study, amiodarone following electrical cardio-

tion (57). Likewise, individuals with severe aortic

version for maintenance of sinus rhythm was shown

stenosis should undergo intervention following the

to be superior to placebo in the short-term (63), but

onset of symptoms (57). Medical therapy is reserved

given its toxicity, the value of long-term amiodarone

for those awaiting surgery or deemed unsuitable for

is debatable. Likewise, radiofrequency ablation was

surgery. One subset of individuals with intractable

successful in restoring sinus rhythm in a small case

heart failure who require aggressive therapy are those

series (64), but cannot be recommended for most

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Present Status of Rheumatic Heart Disease

F I G U R E 5 Effect of Percutaneous Transvenous Mitral Commissurotomy

Simultaneous left atrial and left ventricular tracings in a patient with mitral stenosis undergoing percutaneous transvenous mitral commissurotomy. The left atrial pressure normalizes after successful valve opening, with no residual gradient between the left atrium and the left ventricle in diastole.

patients. Some individuals undergoing mitral valve

disease in endemic countries (67). Pregnancy is a

replacement may be suitable candidates for intra-

high-risk period, often resulting in clinical deterio-

operative catheter ablation, but there are limited data

ration and adverse events (68). Most pregnant women

on long-term efficacy (65). Consequently, rate control

with RHD become symptomatic after 24 weeks when

with beta-blockers and nondihydropyridine calcium-

hemodynamic changes peak. The modified WHO

channel blockers remains the mainstay of pharma-

classification IV identifies those with severe mitral

cotherapy for atrial fibrillation in RHD.

stenosis, severe aortic stenosis, and severe pulmo-

There are limited prospective data to assess the risk

of

stroke

from

RHD.

No

validated

nary hypertension as having the highest possible risk

risk-

(69). In these women, perinatal outcomes (stillbirth,

stratification tools or randomized trials evaluating

prematurity, low birthweight, and neonatal mortal-

the efficacy and safety of oral anticoagulation are

ity) are poor. A total of 34% of pregnant Senegalese

available to guide anticoagulation decisions. Never-

women with RHD died, and rates of stillbirth and

theless, nearly all individuals with atrial fibrillation

pregnancy termination were high (70), prompting

are prescribed oral anticoagulation in clinical prac-

calls to screen pregnant women for RHD (71).

tice. The risk of stroke is highest with atrial fibrilla-

Optimal care for RHD-affected women involves

tion from mitral stenosis (about 4%/year), so these

pre-conception counseling (72), and among those

persons probably derive the greatest benefit from

pregnant, a comprehensive risk assessment and

anticoagulation. Among older individuals with RHD,

management plan that includes replacing contra-

the CHADS2 score may be used (66). However, the

indicated medications, optimizing loading condi-

quality of oral anticoagulation with vitamin K antag-

tions, and monitoring and addressing exacerbating

onists in limited-resource countries is poor due to

factors (e.g., anemia). When needed, surgery or

barriers to regular international normalized ratio

percutaneous transvenous mitral commissurotomy

monitoring (4). Direct anticoagulants may prove to be

(see the following text) is best performed after

more effective than vitamin K antagonists. A ran-

24 weeks to minimize radiation risk and improve fetal

domized trial comparing rivaroxaban with vitamin K

survival if early labor occurs (73). Among individuals

antagonists in patients with RHD is underway to test

with complex pathology (e.g., multivalve disease,

this hypothesis (INVICTUS [INVestIgation of rheu-

calcified valves), conservative management is often

matiC AF Treatment Using Vitamin K Antagonists,

preferable because the risk of fetal loss is high with

Rivaroxaban or Aspirin Studies, Non-Inferiority]

cardiopulmonary bypass.

noninferiority trial; NCT02832544).

For individuals with prosthetic heart valves, anti-

Management of RHD in women of reproductive

coagulation during pregnancy is challenging (74,75).

a g e . RHD accounts for the majority of antenatal heart

Current standard practice is “sequential treatment,”

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Present Status of Rheumatic Heart Disease

highest fetal losses; 2) sequential treatment is asso-

F I G U R E 6 Effect of Rheumatic Heart Disease on the

ciated with higher maternal thrombotic/bleeding

Mitral Valve

events then single therapy with vitamin K antagonists; and 3) low-molecular weight heparin is associated with the lowest rate of fetal or neonatal loss but higher risk of valve thrombosis (76,77). Safe, affordable anticoagulation options during pregnancy are needed. The optimal delivery of antenatal care for women with RHD is through a multidisciplinary specialized management team; these are rarely encountered in RHD-endemic

regions

(78).

Standard

practices

include measures to shorten the second stage of labor. In most cases, Cesarean section is not required. Outcomes beyond 42 days postpartum reveal ongoing risk (79). Although recent reviews have found low maternal mortality rates, these do not capture the Pre-operative photograph of a stenotic, regurgitant mitral

highest-risk regions, and even with ideal care,

valve, showing fused commissures and thickened cusps.

morbidity remains high. The Registry of Pregnancy and Cardiac Disease

which

involves

unfractionated

heparin

before

conception if planned or as soon as pregnancy is detected,

vitamin

K

antagonists

from

second

trimester until delivery, then unfractionated heparin in the peripartum period. Two systematic reviews concluded that: 1) vitamin K antagonists are associated with the better maternal outcomes but the

recently reported on the outcomes of 390 pregnant women with RHD and mitral valve disease. Women with moderate and severe mitral stenosis and mixed moderate to severe regurgitation with stenosis had the highest complication rates (80). Mitral stenosis remains an independent risk factor for adverse neonatal outcomes. Aside from valvular pathology, maternal age, body mass index above 28 kg/m 2, New York Heart Association functional class III to IV symptoms, significant pulmonary

F I G U R E 7 Country Performance on Rheumatic Heart Disease Mortality Targets

Percent Reduction in Mortality by 2030 (SDG3 Target)

hypertension,

reduced

ejection

fraction,

and

development of heart failure during pregnancy are

40

strong Georgia

Guam

20 Meeting WHF but not SDG3 target

Underperforming on both targets

Northern Mariana Islands

0

Guinea

India

South Africa China

of

4%

of

Staphylococci, Streptococci, Enterococci, Brucella

Namibia Rwanda

–80

total

fetal

pregnancy (84). The most common pathogens are

Indonesia

–60

endocarditis. A

and

endocarditis cases overall and 12% of cases during

Fiji

–40

maternal

for 15% (China) (82) to 55% (Pakistan) (83) of infective

Egypt Bolivia

poor

endocarditis at initial presentation (4). RHD accounts

Kiribati Lesotho

–20

of

REMEDY participants had native-valve infective

Federated States of Micronesia Niger

predictors

outcome (81). Native-valve

species, Candida albicans, and Stenotrophomonas Meeting SDG3 but not WHF target

Syria

maltophilia (85). Culture positivity ranges from 30% to 65%. A Chilean study that included 22% of

–100

participants with RHD reported a 10-year survival of –100

–80

–60

–40

–20

0

20

40

Percent Reduction in Mortality by 2025 (WHF Target)

49%; Staphylococcus aureus infection, sepsis, heart or renal failure, and lack of surgical treatment during infection were associated with increased mortality

Projected reduction in age-specific mortality from rheumatic heart disease based on country trends 2000 to 2015. The x-axis shows the total percentage reduction in deaths for those age <25 years (World Heart Federation [WHF] target) between 2013 and 2025 if 2000 to 2015 trends continue. The y-axis shows the total percent reduction in deaths

(86). In limited-resource settings, infective endocarditis is often first diagnosed at autopsy (87). These data reflect the need for laboratory diagnostic

for those age 30 to 69 years (Sustainable Development Goal 3 [SDG3] target) between

services, access to antibiotics for medium-term regi-

2015 and 2030 if 2000 to 2015 trends continue. See Online Appendix for details.

mens, and access to interventions or surgery to ameliorate outcomes.

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Present Status of Rheumatic Heart Disease

T A B L E 4 Proposed Indicators for Countries Tracking Progress on the 2018 Global RHD Resolution

Inputs

Outputs and Outcomes

Indicator

/

Measurement Units

Indicator

Measurement Units

National Assessment A1. National RF/RHD strategy

Presence of strategy* and yr of last update

A4. Mortality from RHD§

Deaths per 100,000 population/yr†

A2. Number of persons living with RHD

Prevalent cases per 100,000 population†

B2. Delivery of specialized cardiac services

Number of percutaneous and surgical procedures performed per yr‡

A3. Local guidelines for pharyngitis, RF, and RHD

Presence of guidelines and yr(s) of last update

B1. Access to specialized cardiology services

Presence of national program; density of interventionalists and surgeons per 100,000 population

B3. Outcomes of specialized cardiac services

Proportion dead and/or reoperated on within 90 days‡

C1. RF/RHD registry

Proportion of districts with functioning registry in place

C5. Incidence of acute RF

Number of new cases per 100,000 population/yrk

C2. Availability of BPG

Proportion of health facilities with BPG currently in stock

D1. Adherence to secondary prevention

Proportion receiving >80% of scheduled injections/yrk

C3. In-service training on RF/RHD (relevant to clinical role/ qualification)

Proportion of workforce (re)trained over the past 24 months

D2. Adverse BPG events

Number of events/yr

D3. Acute RF recurrences§

Number of recurrences per registry patient per yr

C4. Availability of echocardiography services

Proportion of districts with functional ultrasound machine

D4. Priority-based follow-up for individuals with RHD

Proportion of new moderate-to-severe cases referredk

Subnational (District or Province/State) Assessment

Indicators were measured as follows: category A ¼ desk review by ministry of health; category B ¼ audit of tertiary healthcare facilities; category C ¼ facility surveys conducted in a random sample of districts stratified according to known geographical variations in access to care; and category D ¼ audit of RF/RHD registries in districts sampled according to category C. *Strategy can be a stand-alone document or embedded in noncommunicable disease or general health sector strategy; however, it must be specific that RHD is a priority condition that requires specific activities, targets, and budget. †Local data are preferred; however, default estimates can be obtained from the Global Burden of Disease Study. ‡Also disaggregates by approach and by lesion (e.g., mitral valve repair, dual valve replacement, and so on). kQuantitative indicators of the quality of care should ideally be supplemented by semi-structured interviews of samples of registry enrollees to assess user experience and trust in the health care system. §Ideally assessed using population-based rather than hospital-based samples. BPG ¼ benzathine penicillin G; PTMC ¼ percutaneous transvenous mitral commissurotomy; RF ¼ rheumatic fever; RHD ¼ rheumatic heart disease.

Recommendations for medical management of

subvalvular fusion and calcification reduce the

RHD and future research priorities are provided in

chances of a durable outcome. Several echocardio-

Online Appendix Panel 5.

graphic scores (90) and more complex multifactorial

PERCUTANEOUS AND OPEN INTERVENTIONS. We

scores that use a combination of demographic, clin-

generally endorse the current ACC/AHA guidelines

ical, and echocardiographic variables (91) are used to

for the interventional and surgical management of

assess suitability for PTMC. Individuals with mitral

RHD (57). However, it should be stressed that most of

stenosis are younger in countries where RHD is

the evidence informing these guidelines is based on

endemic and may have a lower prevalence of age-

nonrheumatic valve disease. The discussion in the

related morphological changes like calcification,

following text highlights some particular issues

making them somewhat more suitable candidates for

related to RHD and challenges delivering these

PTMC. On the contrary, RHD may follow a more

procedures in limited-resource settings.

aggressive course in endemic countries, resulting in with

severe morphological abnormalities including sub-

severe mitral stenosis and suitable valve morphology

valvular disease. Still, PTMC provides acceptable

Interventional

m a n a g e m e n t . Individuals

benefit most from catheter-based interventions,

immediate and medium-term outcomes (Figure 5) and

especially percutaneous transvenous mitral commis-

remains the initial treatment of choice in most

surotomy (PTMC). Although there have been hard-

individuals without unfavorable demographic or

ware improvements over the past 3 decades, the basic

clinical features (91).

procedure is relatively unchanged. Pivotal studies

The main complications associated with PTMC are

established the percutaneous approach to the treat-

severe mitral regurgitation needing urgent surgery

ment of mitral stenosis using single or double con-

(1% to 3%), cardiac tamponade (1% to 2%), systemic

ventional

the

embolism (<1%), and death (<1%) (92). A meta-

self-centering Inoue balloon (Toray, Tokyo, Japan)

analysis of the small randomized studies comparing

has superseded these in clinical practice. Subsequent

PTMC with surgical commissurotomy suggests that

trials comparing PTMC with surgical approaches used

PTMC produces a slightly smaller valve area, a higher

the Inoue balloon and technique (89).

risk of mitral regurgitation, and a nearly 3-fold risk of

valvuloplasty

balloons

(88),

but

The success of PTMC depends to a great extent on

reintervention compared with surgery (93). Never-

the morphology of the mitral valve. The presence of

theless, because of increasing familiarity, ease of use

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Present Status of Rheumatic Heart Disease

T A B L E 5 Product Development Priorities for RHD Prevention and Control

Product

GAS vaccine Reformulation of BPG

Progress

Comments

Phase 2 clinical trials

Substantial benefit in reduced antibiotic use, reduced invasive GAS disease

Candidate identification

Improved rational use of antibiotics, improved acceptability and adherence likely to lead to better clinical outcomes

Rapid antigen detection tests

On market; need local testing and trials

Assists in rational use of antibiotics; not being used in endemic countries

RF diagnostic

Academic research

Syndromic diagnosis means opportunities to initiate disease altering secondary prophylaxis are missed

Handheld echocardiography devices

On market

Affordability and durability of prolonged use in remote settings are the major barriers to use

Point of care INR testing

On market

Not being used in endemic countries; production of cheaper alternatives would be an important short-term advance

Alternatives to current mechanical and bioprosthetic valves

Academic research

Lower-cost mechanical prosthesis, in themselves, would be a critical shortterm advance; in the longer term, percutaneously-delivered mechanical or tissue-engineered valves would be more likely to meet the total need for surgical care at reasonable cost

BPG ¼ benzathine penicillin G; GAS ¼ group A beta-hemolytic streptococcus; INR ¼ international normalized ratio; RF ¼ rheumatic fever; RHD ¼ rheumatic heart disease.

the presence of valve thickening, variable degrees of commissural fusion, and subvalvular disease. Transcatheter treatment of severe tricuspid regurgitation may be more promising (97). S u r g i c a l m a n a g e m e n t . Severe, chronic structural changes in the valves are the major cause of mortality from RHD. Ensuring timely access to definitive surgical care is a key aspect of addressing the current disease burden. Unfortunately, many individuals present too late to benefit from surgery, so early detection efforts (98), accompanied by priority-based follow-up (99), are required to ensure that

surgical

programs

have

maximal

impact.

Although valve replacement provides good early results, long-term outcomes are poorer as the cumulative risk of valve-related complications increases (100). Hence, valve-conserving restorative operations are now the preferred first-line approach. One unanswered question is the timing of surgery for regurgitant lesions; most recommendations are based on extrapolation from nonrheumatic valve disease (56). RHD usually affects all components of the mitral valve (Figure 6), and these should be systematically

of the procedure, improvement in operator experi-

dealt with during surgery. Commissural fusion is

ence, and perhaps the lower direct and opportunity

dealt with by sharp dissection extending into the

costs compared with surgical treatment, PTMC (using

fused papillary muscles while preserving chordal

an Inoue or Inoue-like balloon) remains the treatment

attachment and, if necessary, creating intercostal

of choice for rheumatic mitral stenosis.

spaces and/or inserting artificial chords. The anterior

Catheter-based treatment of rheumatic aortic ste-

and posterior leaflets are then mobilized using a

nosis has not been well-studied, perhaps because of

process of decalcification and peeling to enhance

the rarity of isolated aortic stenosis in RHD and its

mobility, increasing surface area and extent of cusp

tendency to manifest later in life when valve calcifi-

coaptation (101). These techniques are possible

cation is common (4). There is good rationale for

because the disease process spares the elastica and

using balloon dilatation to treat noncalcific rheumatic

part of the fibrosa. Changes in mitral annular shape,

aortic stenosis. In vitro studies have shown that

size, and dynamism can be characterized by modern

balloon dilatation reliably splits the fused commis-

imaging techniques and need to be addressed during

sures in a rheumatic aortic valve (94). Balloon

operative

dilatation has an 86% immediate success rate, with

evolving, and the efficacy of current practices needs

only 14% of patients needing valve replacement at

to be validated in studies involving larger numbers of

repair.

Surgical

techniques

are

still

5-year follow-up (95). Moderate or severe aortic

participants followed for sufficiently long periods,

regurgitation occurs in about 14% of patients as an

specifically focusing on ventricular function and

immediate complication. Transcatheter aortic valve

quality of life, the latter of which is often significantly

replacement is unlikely to be useful in RHD due to the

impaired (102).

rarity of isolated aortic stenosis and the relatively young age of patients with RHD. Rheumatic tricuspid stenosis is rare and almost

Dysfunction of the tricuspid valve can be secondary to mitral valve disease or be affected by the rheumatogenic

process

itself.

Most

changes,

always occurs in association with mitral valve disease,

including annular dilation and cusp fusion, can be

particularly stenosis. A small case series suggested

addressed through repair techniques. Failing to repair

that tricuspid valvuloplasty may be as successful and

the tricuspid valve when affected can result in

durable as PTMC (96). A large-sized Inoue balloon (28

chronic disability and possibly death (103). Aortic

to 30 mm) is usually used for dilation. Mitral regurgi-

valve disease is less common than mitral valve dis-

tation is unlikely to be amenable to the transcatheter

ease, but has a more serious effect on left ventricular

techniques used for nonrheumatic disease because of

function, quality of life, and overall prognosis (104).

Watkins et al.

JACC VOL. 72, NO. 12, 2018 SEPTEMBER 18, 2018:1397–416

Unlike the mitral and tricuspid valves, aortic pathology is infrequently suitable for valve-conserving operations.

Additionally,

currently

available

F I G U R E 8 Rapid Scale-Up of Specialized Cardiac Surgical Services in a

Middle-Income Country

valve

substitutes—with the exception of the Ross opera-

900

tion—are not suitable for use in the relatively young

800

population with RHD (105). of

patches

or

entire

valves

(106).

Although not currently in use, such technologies will hopefully will be available in the near future and could significantly increase access to surgery and at a lower cost. Tissue-engineered products could also be delivered through percutaneous techniques, making them even more attractive in settings where access to open procedures is limited. An important consideration for surgical programs

700 Number of Patients

An emerging area of surgical research is in tissue engineering

600 500 400 300 200 100 0 2009

2010

2011

Increasingly robust standards for post-operative outcome recording have been developed for congenital heart disease surgery for children in these set(107).

Because

patient

demographics

2012

2013

easily be extended to individuals requiring surgery for RHD. More research is needed on ensuring quality

Mitral Valve Repair Mitral Valve Replacement Percutaneous Balloon Mitral Commissurotomy

Between 2010 and 2015, the Aswan Heart Centre in Aswan, Egypt dramatically increased the total number of procedures performed for rheumatic mitral valve disease. Over time, the mix of procedures shifted toward more conservative approaches (i.e., valve repairs and percutaneous interventions). Reprinted with permission from Remenyi et al. (104).

of post-surgical care, including anticoagulation, for those living in remote or deprived areas; some have even argued that younger individuals with RHD should be offered tissue valves (108).

(Online Appendix Panel 7) (6). The resolution man-

A summary of recommendations for practice and

dates Member States to take action on RF/RHD and

research on interventional and surgical care is pro-

resources WHO to provide support to country pro-

vided in Online Appendix Panel 6.

grams. Several tools have recently been published that can assist in technical support of programs

WHAT IS NEEDED TO ERADICATE

(49,111). Drawing on these tools, we propose a set of

RHD WORLDWIDE?

indicators for countries to use in tracking imple-

THE GLOBAL AGENDA. R H D p o l i c y t a r g e t s a n d

mentation of the resolution (Table 4).

s t a t e m e n t s . In 2013, the WHF called for a 25%

I n t e r n a t i o n a l c o l l e c t i v e a c t i o n o n R H D . Ensuring

reduction

individuals

global leadership in RHD has been challenging. RHD

aged <25 years by the year 2025 (109). More recently,

has been neglected by policymakers and civil society

the United Nations Sustainable Development Goal

because it does not sit in a single department (e.g., at

3 (SDG3) proposed a one-third reduction in premature

WHO) nor is it amenable to single-intervention stra-

deaths from noncommunicable diseases by 2030

tegies. Advocacy and engagement are needed to build

RHD

mortality

among

2015

and

providers overlap significantly, these practices could

in

2014

Year

in limited-resource settings is ensuring quality.

tings

1411

Present Status of Rheumatic Heart Disease

(110). Assuming that trends in mortality over the past

relationships with other disciplines—such as maternal

15 years hold, many endemic countries are on track to

and child health—that have larger, more visible con-

achieve either 1 or both of the targets (Figure 7).

stituencies and audiences with decision-makers.

Notable high-performing countries include China,

Additionally, people living with RHD are often

Bangladesh, and Rwanda. A number of Pacific

socially vulnerable and have few opportunities to

Island nations are struggling to meet these targets

share their lived experiences. The Listen to My Heart

(Online Appendix).

program is one promising model of patient engage-

Since the mid-2000s, several policy statements

ment and empowerment (112).

have been issued on RHD. Notable recent statements

This review has provided recommendations for a

include the Addis Ababa communique (2015) and the

number of global public goods, including scientific

WHF roadmap on RHD (2017). A resolution on RHD

research, that warrant investment. Greater public and

was adopted at the 71st World Health Assembly

private funding is needed to support laboratory,

1412

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JACC VOL. 72, NO. 12, 2018 SEPTEMBER 18, 2018:1397–416

Present Status of Rheumatic Heart Disease

clinical/translational,

and

policy/implementation

research to address the basic and applied scientific

leveraging the strengths of RHD-specific activities to build overall health system capacity (114).

questions posed throughout this review. In addition,

Workforce challenges in RHD care parallel the

there are a number of urgent RHD product develop-

workforce challenges in other health areas (115). In

ment priorities (Table 5).

the short-term, strengthening primary and secondary

RHD has important links to the global health se-

prevention should be prioritized, for example, using

curity agenda in the area of antimicrobial resistance.

nurse-led primary care (including school-based plat-

Development and enforcement of guidelines on

forms) and community health workers, although

pharyngitis management, including rational use of

further research is needed on these models (44,116). A

antibiotics, are needed in all countries. Better supply

pressing issue for most countries will be to create

and more consistent use of BPG as a first-line anti-

incentives to train and retain cardiovascular special-

biotic for GAS, and eventually the roll-out of a GAS

ists. These providers could care for a wide range of

vaccine, will probably be the most effective long-term

conditions, so while the initial rationale might be to

strategies for curbing antimicrobial resistance risk

address RHD and support the global resolution,

from pharyngitis.

increasing the cardiovascular workforce will have programs.

broader benefits. Cardiac surgery deserves special

The notion that RF can be eliminated is supported by

emphasis given its importance in RHD. The experi-

studies of country control programs conducted dur-

ence of the Aswan Heart Centre has demonstrated

ing the 1970s and 1980s. The largest was a multi-

that, with political and financial commitment, surgi-

country study emphasizing secondary prevention

cal care can be rapidly scaled up and at high quality

(113), and the last study was from Brazil (46). Expe-

(Figure 8) (104).

THE

NATIONAL

AGENDA. Disease

control

rience with primary prevention programs has also

Much has been written on the need for better in-

been favorable, and the WHO recommends combined

formation systems for tracking RHD. Disease registers

primary and secondary prevention efforts delivered

have been recommended since the 1950s, but few

in community settings (43). These programs can

RHD-endemic countries have made significant prog-

achieve the vast majority of their impact within about

ress on expanding registers beyond single centers,

a decade or so (42).

which suggests that novel approaches are needed.

A number of unknowns remain. Most countries

One recent initiative is the smartphone-based Pan

that implemented RF programs were relatively

African Society of Cardiology eRegister (117). How to

economically advanced, limiting their applicability

integrate registers and eRegisters into local health

to current RHD-endemic countries. No program

information systems is less clear and warrants further

used an active case-finding approach, which could

consideration.

in theory lead to a more rapid decline in RF,

Disease notification and surveillance systems pro-

although the appropriateness of screening echocar-

vide opportunities for RHD integration. There is good

diography remains unclear. Finally, the role of sur-

rationale for classifying RF as a notifiable condition

gery

been

because of its outbreak potential, although weak-

established. Cardiac surgery was available in some

nesses in RF notification systems have been described

of

it

(99). Improving RF notification efforts and public

most

health action could have spillover benefits and

in

the

remains

RHD-control

programs

countries

mentioned

largely

unavailable

has

not

previously, today

RHD-endemic countries. Integration of RHD programs

but

in

contribute to global health security. (RF is one of the country

few conditions that involves clinician-based rather

h e a l t h s y s t e m s . There is currently little appetite

than laboratory-based notification. Notification for

among health planners for developing targeted

emerging

programs, especially for chronic noncommunicable

nonlaboratory-based pathway, so strengthening sys-

diseases (114). Yet, historical case studies of RF/RHD

tems for syndromic reporting would have benefits

control frequently used vertical approaches. Conse-

beyond RF/RHD.) Last, improving the quality of death

quently, there is little evidence upon which to make

certification for RHD (33), although important for

technical recommendations for integrating RHD-

obtaining better mortality data, could also be inte-

related

grated into efforts to improve the overall quality of

activities

into

existing

into

health

systems.

Across several health system “building blocks,” discussed in the following text, we find important opportunities overarching

for

integration

approach

of

would

would

need

to

follow

a

vital registration. A final opportunity for RHD integration is health

The

financing. The vast majority of health care in many

“diagonal,”

low- and middle-income countries is financed out-of-

RF/RHD. be

pandemics

Watkins et al.

JACC VOL. 72, NO. 12, 2018 SEPTEMBER 18, 2018:1397–416

Present Status of Rheumatic Heart Disease

“diagonal”

pocket, especially for noncommunicable diseases like

vulnerable.

RHD. Consequently, poor households tend to forgo

lead to rapid progress on RF/RHD and strengthen

health care or borrow money or sell assets to pay for

health systems to address other noncommunicable

care, increasing the so-called “poverty trap” (118).

diseases.

A

approach

could

both

Charitable programs exist for RHD surgery in some

While scientific questions remain, the evidence

countries, but they are neither sufficient to meet the

base is sound for tackling RHD now. Across a wide

populations’ needs nor fiscally sustainable (119).

range of global health interventions, primary and

Increasingly, surgical skills and knowledge will need

secondary prevention of RHD stand out as providing

to be transferred to local health systems to sustain-

excellent value for money (122). Challenges in scale-

ably meet the large unmet need for cardiac surgery,

up of advanced care for RHD are nuanced and

and governments will need to increase budgets for

complex, but it is evident from historical trends that

advanced cardiovascular services.

all countries will eventually require advanced car-

The goal of universal health coverage, which all

diovascular services—not just for RHD—and must

countries have endorsed as part of United Nations

start training the next generation of the cardiovas-

Sustainable Development Goal 3, holds promise for

cular workforce, putting in place incentives to

improving access to and the affordability of RHD-

ensure that these individuals work where needs are

related care. The challenge is mobilizing sufficient

greatest.

domestic resources to finance (relatively inexpensive)

Complementing the national agenda is an agenda

prevention services as well as costly surgical care

for the global community. International agencies,

without displacing other health priorities. Integrated

civil society, and donors will play a critical role in

financing models are needed. Over time, the scale and

the elimination of RHD. Support is needed for

scope of covered services could progressively expand.

research, advocacy, and implementation. Armed

One modeling study suggested that universal coverage

with scientific, economic, and ethical arguments,

of primary prevention would be the first priority

the RHD community can establish links and part-

for most African countries, followed by secondary

nerships across sectors and health areas. The inte-

prevention, then referral and tertiary services (120).

gration of RHD into the broader global health agenda will ensure that the future generations grow

SUMMARY AND CONCLUSIONS

up free from the scourge of this eminently pre-

This Scientific Expert Panel has summarized recent advances in the science and practice of RHD, from laboratory science to population health. We identify a number of pressing issues requiring immediate action and propose a research agenda for the coming years. But, why invest in RHD research and care when there

ventable disease. ACKNOWLEDGMENTS This paper is dedicated to the

memory of Professor Bongani Mayosi, a pre-eminent scientist and visionary who inspired us all to work toward the “eradication of rheumatic fever in our lifetime.”

are many other important health concerns? RHD is a disease of poverty that affects chil-

ADDRESS FOR CORRESPONDENCE: Dr. David A.

dren and working-age adults. The global economic

Watkins, Division of General Internal Medicine,

impact of early death from RHD was about $65

Department of Medicine, University of Washington,

billion in 2015 (121). RHD provides an unparal-

325 9th Avenue, Box 359780, Seattle, Washington 98104.

leled opportunity to advance the global cardio-

E-mail: [email protected]. Twitter: @davidawatkins,

vascular agenda by giving priority to the most

@UW.

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KEY WORDS cardiac surgery, echocardiography, health services, pathogenesis, prevention, rheumatic heart disease

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