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AFRICA
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CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
health workers, a high level of awareness of the community, and
laboratory criteria of recent infection or previous ARF.
Some symptoms and signs included on the Jones criteria
are unspecific and may be present in various febrile conditions
affecting children in Africa. Moreover, the time gap between
GAS infection and the occurrence of ARF is variable, and
therefore many patients do not recall having had pharyngitis.
Therefore ARF is usually underdiagnosed in developing
countries.
26
Additionally, many patients are not correctly treated,
secondary prophylaxis is not instituted and progression to RHD
occurs, explaining the high incidence of newly diagnosed RHD
in adults.
27
Subclinical disease is commonly found in Africa when
echocardiographic screening is used.
9-11
The advent of portable
battery-powered ultrasound machines has allowed access to the
communities and recognition of the need for an update of the
WHO criteria for echocardiographic diagnosis of subclinical
RHD. It has been suggested that in endemic areas the diagnosis
can be based on the presence of pathological valve regurgitation
without considering the morphological features of the valves.
28
African scientists were also part of the World Heart
Federation panel of experts that created a set of screening
criteria using morphological and Doppler features, aimed at
standardising the diagnosis across different areas of the world.
29
Therefore, although echocardiographic diagnosis of RHD is not
yet readily available in some parts of Africa, its use has allowed
better characterisation of cardiac abnormalities, definition of
the natural history of the disease and assessment of the current
practice in managing these patients on the continent. The Global
Registry of RHD
30
confirmed the extremely virulent forms of
chronic RHVD in Africa.
RHD in Africa is encountered in young people, showing a
much faster and malignant progression of cardiac involvement
than that seen in Europe or North America.
31
Severe disease
and rapid progression to complications such as mitral stenosis,
heart failure and atrial fibrillation occur at younger ages.
30-32
It
is believed that this pattern results from environmental factors
such as higher occurrence of skin and pharyngeal streptococcal
infections in these settings, recurrent GAS infections early in
life, inadequate treatment of GAS infections, and inappropriate
secondary prophylaxis after the first episode of RF, but the role
of host specificity in determining the malignant course of the
disease in Africa cannot be excluded.
Benzathine penicillin G (BPG), the gold standard for
secondary prophylaxis of RF/RHD, is usually administered
every three or four weeks. Occurrence of ARF in patients on
adequate secondary prophylaxis with BPG has been attributed to
the low quality of the product, inadequate storage, inappropriate
technique for injection, and incorrect dosage for the patient’s
weight.
33
Knowing that HLA-DRA variants were found to predict
penicillin allergy in genome-wide fine-mapping genotyping,
one may speculate on the need to explore whether genetic
polymorphisms determine differences in pharmacokinetics and/
or pharmacodynamics of penicillin in African individuals. This is
of particular relevance considering that the correct management
of GAS pharyngitis and secondary prophylaxis of RF with
penicillin prevent the occurrence of RHD. Currently, there are
no data to support a higher occurrence of penicillin allergy in
Africa than is seen in other parts of the globe. However, of
importance for the implementation of control programmes
in Africa, it has been suggested that analysis of gene variants
of HLA-DRA and the HLA-DRA|HLA-DRB5 inter-region,
which may be significant predictors of allergy to penicillin,
should occur in African populations.
34
The role of genetic studies
ARF and RHD are caused by a combination of immune,
environmental and genetic factors. While the role of GAS
and social conditions that determine progression to RHD is
well understood,
35,36
there is a major gap in knowledge of the
mechanisms of host susceptibility to the disease.
28
Familial
aggregation, similarity of disease patterns between siblings,
concordance of disease in identical twins, and HLA correlation
studies are evidence for a genetic influence on RF susceptibility.
37
A systematic review and meta-analysis of 435 twin pairs from six
independent studies concluded that ARF has high heritability,
estimated at 60% across all the studies; the pooled proband-wise
concordance risk for ARF was 44% in monozygotic twins and
12% in dizygotic twins.
38
Only 0.4 to 3.0% of patients with untreated GAS pharyngitis
develop ARF, but higher attack rates occur when a stronger host
immune response occurs, approaching 50% in patients with a
prior episode of ARF. In patients with the first episode of ARF,
the rate of progression to RHD will differ, probably being related
not only to environmental factors such as the high recurrence of
GAS and different virulence of the circulating GAS, but also to
a particular immune response geared by genetic susceptibility.
37
Similarly, the genetic background directing the immune response
towards a predominantly Th1 or Th2 pattern may contribute
to explain variations in RF clinical phenotype by modulating
the intense and sustained inflammation that is needed to cause
sequelae such as RHD.
17,37
Inherited susceptibility to ARF was initially studied around
the major histocompatibility class II human leucocyte antigens
(HLA). Several genes associated with RHD have been described,
most of them involved with immune responses.
39
Given the
current state of the literature, it is hard to make generalisations
Table 1. RHD genetic susceptibility; HLA class II alleles found
in studies in patients from different regions of the globe
(adapted from Guillerme
et al
.
39
and updated).
Continent Country, reference HLA class II alleles
Africa South Africa
DR1, DR6
Uganda
DR1, DR11
Egypt
DRB1*0701, DQA1*0201, DRB1*13,
QA1*0501/0301
Americas United States of
America
DR2 (Africans); DR4, DR6, DR9
(Caucasians)
Mexico
DRB1*1602, DQB1*0301, DQA1*0501
Martinique
DR1
South Brazil
DR7, DR53
India
DR3
Kashmir
DR4
Japan
DQB1*05031, DQA1*0104
South China
DQA1*0101
Saudi Arabia
DR4
Asia
Turkey
DR3, DR7, DR11
Europe Latvia
DRB1*0701, DQB1*0302, DQB1*0401-2