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CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
about the outcome of the mild lesions found in community-based
studies on asymptomatic children. In Western countries, marked
reduction in RHD prevalence occurred with improvement in
health systems (education of health professionals for quicker
diagnosis and correct management with antibiotics) and socio-
economic status (less overcrowding, education of the population).
RHD was the leading cause of death 100 years ago in
people aged five to 20 years in the United States but, as in other
developed countries, its incidence has declined.
4
This reduction
is related to the adequate treatment of streptococcal pharyngitis
with penicillin, as well as less overcrowding, better sanitation
and improvement in general living conditions. The incidence of
ARF has dropped dramatically since the 1960s; a few localised
outbreaks of GAS occurred in civilian and military populations
in the 1980s.
4
The reported increase in RHD prevalence
2
is likely
to be related to increased survival due to advances in diagnosis,
and medical and surgical treatments for RHD.
RHD remains the most common cardiovascular disease
in people under 25 years and is the leading cause of valve
disease in developing countries.
5,6
The African continent has the
highest prevalence in the world,
2
and RHD represents the most
common form of acquired cardiovascular disease in children and
adolescents.
7
RHD affects between 15.6 and 19.6 million people
worldwide and causes 233 000 to 492 000 deaths annually,
8
imposing a substantial burden on the families, health systems
and communities in many low-income settings.
Screening with portable echocardiography has uncovered a
large burden of latent RHD among asymptomatic children in
endemic regions of Africa,
9,10
the significance of which remains
unclear.
11
In marked contrast, there are almost no data on ARF,
probably related to low access to healthcare, inadequate resources
for diagnosis of throat and skin streptococcal infection, lack of
awareness of the importance of correct treatment of bacterial
pharyngitis, and overall, to the absence of national prevention
and control programmes. These usually allow notification of the
disease and the institution of long-term secondary prophylaxis
to those at risk of developing RHD.
The reduction in the burden of ARF and RHD among the
less than 20% of the world’s population living in high-income
countries has led to a decrease in research on rheumatic fever
(RF) and RHD.
12
Despite being a major cause of premature death
and disability, the pathogenesis is still incompletely understood,
the natural history is not fully explained, phenotypes have been
only partially described, and some aspects of management
remain debatable.
Pathogenesis of ARF and RHD
Throat infection by GAS is the common trigger for RF/RHD. In
resource-limited tropical settings however, where both impetigo
and rheumatic disease are endemic, there is a growing body of
opinion implicating impetigo in the pathogenesis of rheumatic
fever and rheumatic heart disease.
13
Repeated GAS infection is
necessary for the first episode of ARF to occur, and similarly,
RHD usually develops due to cumulative damage to the heart
valves secondary to recurrent episodes of ARF.
14
Molecular mimicry explains the triggering of RF, but
an intense and sustained inflammation is needed to cause
sequelae.
15,16
Antigens in the cell wall and cell membrane of GAS
are immunologically similar to molecules in human myosin,
tropomyosin, actin, laminin and other common proteins.
GAS carbohydrate epitope (N-acetyl glucosamine) and the
α
-helical coiled-coil streptococcal M protein structurally mimic
cardiac myosin.
17
When GAS antigens reach the blood, they are
recognised by B cells in the spleen; they may also enter the lymph
and be recognised by B cells in local lymph nodes.
B cells specific for GAS antigens become activated and begin
to proliferate and secrete antibodies, activate complement and
promote the opsonisation and phagocytosis of the bacteria.
16,18
An autoimmune response is triggered in susceptible children,
in whom antibodies against streptococcal antigens (mainly the
M protein) cross-react with heart tissue proteins such as cardiac
myosin (in the myocardium) and laminin (on valve endothelium
and basement membrane).
17
At the same time, antigens taken
up at the site of infection by antigen-presenting cells become
activated and migrate to local lymph nodes where they present
the antigens to T cells. Activated T cells begin to proliferate and
additionally stimulate B cells to produce antibodies against the
GAS antigens. It is believed that both T cell and antibody cross-
reactions occur between GAS and host proteins.
19
In rheumatic carditis, attachment of anti-GAS antibodies to
the myocardium and valve endothelium leads to the release of
inflammatory cytokines that up-regulate vascular cell adhesion
molecule-1 (VCAM-1) on the valve surface endothelium; this
up-regulation of VCAM-1 promotes lymphocyte adhesion to
the endothelium and subsequent infiltration of lymphocytes
into the valve. Both inflammatory (transforming necrosis factor-
alpha: TNF-
α
, and interferon-gama: IFN-
γ
) and regulatory
(interleukin: IL-4) cytokines are produced, increasing local
inflammatory reactions in both the myocardium and the
valves. Granulomatous lesions containing lymphocytes and
macrophages are formed, the so-called Aschoff nodules, which
are identifiable and regarded as pathognomonic for rheumatic
carditis.
20
The initial attack with ARF increases vulnerability
to reactivation of the disease, with subsequent pharyngeal
infection.
21
Exposure of the valve surface to inflammation
ensures further binding of cross-reactive antibodies to the valve,
leading to endocarditis, which is on the basis of rheumatic heart
valve disease (RHVD),
16
and the lack of production of regulatory
cytokines may contribute to permanent valve damage.
18.
Chronic
RHVD can result from a single episode of ARF, but usually
follows repeated episodes of ARF, with cumulative valve damage
occurring due to fibrotic healing of acute inflammatory lesions
and turbulent flow induced by ongoing valve damage.
22
The
major morphological changes of the valves include commissural
fusion, shortening and fusion of the chordae tendinae, and
leaflet thickening.
23
Gaps in knowledge and management
Although the diagnosis of GAS pharyngitis may be suspected
on clinical examination, several procedures are involved in
its confirmation, because clinical presentation performance
as a diagnostic test is low. Laboratory test availability is
important, especially culture, virulence test, antibiotic sensitivity,
C-reactive protein and erythrosedimentation rate.
24
Because these
examinations are expensive and time consuming, rapid antigen
testing is a more attractive solution for Africa.
25
Therefore the
diagnosis of ARF relies on a high index of suspicion from