MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES

www.mjhid.org ISSN 2035-3006

Mini-Review

Sickle Cell Anaemia and Malaria

Lucio Luzzatto

Honorary Professor of Haematology, University of Florence, Scientific Director, Istituto Toscano Tumori. Firenze.
Italy

Correspondence to: Prof. Lucio Luzzatto, Istituto Toscano Tumori. Via Taddeo Alderotti 26N, 50139, Firenze.
Italy. E-mail: lucio.luzzatto@ittumori.it

Competing interests: The author has declared that no competing interests exist.

Published: October 3, 2012

Received:August 31, 2012
Accepted: September 1, 2012
Citation: Mediterr J Hematol Infect Dis 2012, 4(1): e2012065, DOI 10.4084/MJHID.2012.065
This article is available from: http://www.mjhid.org/article/view/10928
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

Sickle cell anaemia is a major chapter within haemolytic anaemias; at the same time, its
epidemiology is a remarkable signature of the past and present world distribution of Plasmodium
falciparum malaria. In this brief review, in keeping with the theme of this journal, we focus on the
close and complex relationship betweeen this blood disease and this infectious disease. On one hand,
heterozygotes for the sickle gene (AS) are relatively protected against the danger of dying of
malaria, as now firmly established through a number of clinical field studies from different parts of
Africa. In addition, experimental work is consistent with a plausibile mechanism: namely, that in
AS heterozygotes P falciparum-infected red cells sickle preferentially and are then removed by
macrophages. On the other hand, patients who are homozygous for the sickle gene and therefore
suffer from sickle cell anaemia (SCA) are highly susceptible to the lethal effects of malaria. The
simplest explanation of this fact is that malaria makes the anaemia of SCA more severe; in
addition, in SCA there is often hyposplenism, which reduces clearance of parasites. From the point
of view of public health it is important that in malaria-endemic countries patients with SCA, and
particularly children, be protected from malaria by appropriate prophylaxis.

The history of sickle cell anaemia (SCA) lists being normal when oxygenated, but abnormal when
several gold medals. First, it was for SCA that the term deoxygenated.4,5 Fourth, once the globin genes
molecular disease was coined over half a century ago1, were cloned, the sickle mutation was found to be
and this led to the notion of haemoglobinopathies. in linkage disequilibrium with a polymorphic
Second, when the structural abnormality of DNA site,6 then called a restriction fragment
haemoglobin (Hb) S was pinpointed2, this was the first length polymorphism (RFLP), now called a SNP:
time that a single amino acid replacement in a protein
this was the seminal principle on which all of
was shown to cause a serious disease. Third, once the
today’s genome wide association studies (GWAS)
three-dimensional structure of Hb was solved3 it
became clear why Hb S had the unique characteristic of are based.
Thus, the entire field of human molecular genetics

Mediterr J Hematol Infect Dis 2012; 4; Open Journal System

is greatly indebted to SCA; at the same time, as far as Balanced Polymorphism. Many fundamental
haematology is concerned, SCA is a major chapter experiments in genetics have been carried out in micro-
within haemolytic anaemias. organisms, and biological selection is a good example.
Here we intend to discuss briefly one aspect of this Growing bacteria in a culture medium containing
condition that is eminently germane to the very name streptomycin is a very simple and certain way to select
of this journal: we focus on where SCA, a blood for the few bacteria, within the culture, that already had
disease, meets malaria, an infectious disease. The a gene – we can call it strr – that makes them resistant
relationship is complex. Here we will try to briefly to this antibiotic. If we now isolate one of the resistant
pinpoint what we know and what we don’t yet know bacteria we can grow up a new culture in which the
about this two-way relationship: malaria has influenced entire population will be streptomycin resistant. It
greatly the epidemiology of SCA, and SCA affects the happens that the streptomycin-resistant bacteria do not
clinical course of malaria. grow quite as fast as the streptomycin-sensitive ones:9
thus, in the presence of streptomycin the strr gene is a
The ‘Malaria Hypothesis’. That different persons great advantage; in the absence of streptomycin it is a
may differ in how they respond to an infectious disease disadvantage. Since bacteria are mostly haploid (i.e.
has been probably perceived for a long time. However, they have only one copy of each gene), each one of
the first to formulate this notion in terms of Darwinian them either has the strr gene or it doesn’t: there is
selection was J B S Haldane, who speculated that, nothing in between.
depending on their genetic makeup, people would have Since we humans, like most animals, are diploid,
a different risk of dying when they are confronted by a we have in this respect more options. SCA is a disease
parasitic organism: so much so, that even if a gene of homozygotes (SS) – this is why we call the disease
offering protection against that parasite were otherwise recessive – whereas heterozygotes (AS) are normal for
harmful, its frequency would increase when a most intents and purposes. The first test of Haldane’s
population was exposed to the parasite.7 Haldane hypothesis was carried out by A C Allison,10 when he
himself later hypothesized8 that one important example showed not only that the S gene was frequent in areas
could be thalassemia in the face of malaria, for several of high malaria transmission, but also that AS
reasons. First, one type of malaria, that caused by heterozygotes seemed to have less malaria. By the laws
Plasmodium falciparum, is highly lethal. Second, it is of population genetics it is to be expected that
estimated to have been around in many parts of the wherever the S gene is common there will be many
world for several thousands of years, i.e. for several patients suffering from SCA, a severe burden in the
hundreds of generations: thus, malaria as an agent of population; however, in the same population a much
natural selection seemed a better candidate than an larger number of heterozygotes (see Table 1) will have
infectious disease causing occasional epidemics even if the advantage of being, in first approximation,
associated with high mortality (such as plague or ‘malaria-resistant’. The disadvantage of homozygotes
influenza). Third, deaths from malaria take place coexisting with the advantage of heterozygotes –
mostly in children, i.e. before reproduction, a critical therefore called a balanced polymorphism – had been
criterion for effective selection. Last but not least, already well characterized in Drosophila11 and in other
Plasmodia take on different forms in the course of their model systems: with the S gene it became clear that
life cycle, but what causes disease are the intra- balanced polymorphism was a reality also in the human
erythrocytic parasites: therefore in principle it is not species.
surprising that if red cells are in any way abnormal (as
they, are, for instance, in thalassemia), this may affect
the chance of success of the parasite.

Table 1. Theoretical and real life examples in the epidemiology of the sickle cell trait and of sickle cell anaemia
Hypothetical region/country
A B C Nigeria
Population, millions 5 25 25 156a
S
Frequency of Hb allele 0.10 0.01 0.07 0.11 b
Number of AS heterozygotes, millions 0.9 0.495 3.255 30.5
Predicted frequency of SS patients, % c 1 .01 .49 1.21
Number of SS patients d 50,000 2,500 122,500 1,887,600
a
Population of Nigeria in year 2010 according to http://www.indexmundi.com/nigeria/population.html
b
Approximate average estimate from values in different parts of the country35
c
Calculated on the basis of Hardy-Weinberg equilibrium
d
Calculated from the data in the line above: figures are over-estimates in view of the considerable early mortality of SS patients

Mediterr J Hematol Infect Dis 2012; 4: Open Journal System

How the S Gene Affects Malaria. Allison’s seminal studies that the rate of sickling of AS red cells that had
work has been abundantly confirmed by numerous been parasitized in vivo was significantly higher than
studies on much larger population samples validated by that of non-parasitized red cells within the very same
rigorous statistical analysis;12 and they have indicated blood sample.16 It seemed reasonable to surmise and it
that for AS heterozygotes the phrase ‘malaria-resistant’ was shown subsequently (see Figure 1) that once the
ought to be regarded as shorthand for ‘relatively parasite has triggered sickling the sickled cells would
protected from dying of malaria’. In essence, the be removed by macrophages17.
following points have emerged. (a) AS heterozygotes This mechanism is consistent with in vitro culture
do get malaria. (b) AS heterozygotes with malaria tend studies that have shown normal growth of P falciparum
to have lower numbers of parasitized red cells in their in AS red cells and even in SS red cells,17,18 clearly
blood. (c) AS heterozygotes have a decreased indicating that it is not Hb S per se that hinders parasite
incidence of the two forms of severe malaria development: it must be something downstream of the
recognized as immediately life-threatening: namely, parasite cycle, such as phagocytosis of sickled cells.
cerebral malaria and malaria with severe anaemia. (d) In fact, although it is often stated that the
Very rarely do AS heterozygotes die of malaria, even mechanism of protection against malaria of AS
in the rare cases when they do develop cerebral heterozygotes is not clear, over the past 40 years there
malaria.13 It stands to reason that (d) is a consequence has not been any evidence contrary to the sickling-
of (c), and (c) is at least to some extent the result of (b). phagocytosis model; and increased phagocytosis of AS
These data from clinical epidemiology14 are parasitized red cells has been confirmed.19 The
consistent with increased fitness of AS heterozygotes clinically relevant consequence of this process is to
in an environment with malaria (there would be no keep parasitemia relatively low in AS heterozygotes,
advantage in an environment without malaria); at the and this has been also abundantly confirmed in many
same time, they tell us clearly that Hb S is not an studies.14,20-23 Of course there may be other protective
absolute impediment to the malaria parasite. Therefore, mechanisms at work: for instance, it has been found
the mechanism for the increased fitness of AS that AS parasitized red cells have impaired adherence
heterozygotes is not failure of invading red cells (see to endothelial cells, which could decrease the risk of
Table 2): rather, it must be based in something that cerebral malaria.
takes place subsequently. Beet15 first suggested that the The impaired cytoadherence seems to result from
phenomenon of sickling may be responsible; and altered display on the red cell surface of the P
subsequently it was shown by quantitative in vitro falciparum erythrocyte membrane protein 1 (PfEMP-

Table 2. Protective mechanisms against malaria deployed by polymorphic genes expressed in red cells

Basic Mechanisms Example Comments References

P vivax in Duffy-negative red P vivax not found in West Africa where almost all
1. Failure of invasion 36
cells people are Fy-/-
2. Impaired intra- Haemoglobin C interferes with ability of parasite
P fal in Hb CC red cells 25; 37; 38
erythrocytic growth to remodel host cell cytoskeleton
Hb AS red cells sickle Suicidal infection39: parasitised sickled cells are
3. Enhanced removal of
preferentially when they are P phagocytosed (see Fig. 2). Probably applies also 16; 40; 41
parasitized red cells
fal infected to parasitized G6PD deficient red cells

Figure 1. Cartoon illustration of how AS heterozygotes are

relatively protected from severe P falciparum malaria. The upper
part of the cartoon is a schematic diagram of what happens in red
cells in a normal (Hb AA) person with malaria: after invasion of a
red cell by a merozoite, this becomes a ring form, and this starts
multiplying (schizogony) ; when a schizont is mature the infected
red cell essentially bursts and releases new merozoites, each one of
which can invade a new red cell. The lower part of the cartoon is a
schematic diagram of what happens in red cells in an AS
heterozygote with malaria: the red cell, which appears normal at the
time of invasion, once infected undergoes sickling (probably as a
result of deoxygenation and lowering pH caused by the parasite),
and thus it falls easy prey to macrophages in the spleen, in other
organs and even in the peripheral blood42. Phagocytosis of a
parasitized red cells clearly interrupts the schizogonic cycle and
thus the parasitaemia can be kept under control.

Mediterr J Hematol Infect Dis 2012; 4: Open Journal System

1).24 Very recently, through elegant cryoelectron at least as effective in SS homozygotes, i.e. in patients
tomography microscopic techniques it has been shown with SCA: however, the mechanism is not failure of
that PfEMP-1 display depends on remodeling by the infection, and therefore it may not necessarily apply to
parasite of the red cells cytoskeleton; and that this homozyogotes SCA patients. They have a prototype
process is defective in CC and SC red cells25 (AS red congenital haemolytic anaemia and are susceptible to
cells have not yet been tested). Protection against malaria, which is a prototype acquired haemolytic
malaria by the S gene has been also demonstrated in a anaemia. Clinical experience has shown that, not
mouse model, and attributed to accelerated breakdown surprisingly, this combination is highly dangerous.31
of haeme by haeme oxygenase26 however, the One obvious reason is that malaria will make the
pathophysiology of P berghei malaria in mouse is very anemia of SCA worse, to the point of it becoming life-
different from that of P falciparum in humans, and threatening; another reason is that malaria, like any
therefore it is difficult to know whether this interesting other acute infection, can trigger in a patient with SCA
phenomenon observed in the former is relevant to the a pain crisis or a sequestration crisis. Of special note is
latter. the fact that normally the spleen plays an important
Acquired immunity is a major determinant of the role in filtering and removing parasitized red cells: but
clinical outcome of malarial infection. Several studies patients with SCA regularly have an impaired splenic
have suggested that AS heterozygotes have accelerated function: often to the extent of functional asplenia, and
acquisition of immunity,27,28 although the matter is still sometimes the functional asplenia evolves to
controversial.29 A recent study carried out in Uganda anatomical atrophy of the spleen from multiple infarcts
has shown that AS heterozygous children (age 1-10) (so-called auto-splenectomy).32 A recent population
are protected from (i) the establishment of blood-stage study carried out in Kenya has shown that malaria is no
infection, (ii) the development of high densities of more common in SCA children than in controls:
parasites, (iii) the progression of infection to however, the mortality of SCA children who had
symptomatic malaria.30 From an analysis of data as a malaria was about 10 times higher than in controls.33
function of age the authors infer that both innate and We can infer that in Africa malaria contributes
acquired mechanisms of protection come into play. substantially to the early mortality of patients with
This confirms the notion 20 that the main advantage of SCA, which makes it imperative that they ought to be
AS heterozygotes in areas with heavy malaria protected by life-long antimalarial prophylaxis.
endemicity consists in their increased probability of
surviving until acquired immunity is sufficient to Conclusion. In an era of evidence-based medicine it is
protect them, as well as others, regardless of their still not uncommon that hypothetical propositions are
haemoglobin type (Figure 2). stated as facts. By contrast, it is quite remarkable that
the protective effect of the Hb S gene against malaria is
still portrayed as a hypothesis when it is, in fact, one of
the best documented examples in the human species of
balanced polymorphism, in which the severe disease of
homozygotes (SS or SCA) is balanced by the
advantage of AS heterozygotes.
Malaria and sickle cell anaemia are still major
challenges to infectious disease medicine and to
haematology respectively, and both are also major
public health problems. One might have hoped that
what we have learnt about the of advantage of AS
heterozygotes with respect to malaria would enable us
to protect from malaria mortality other people as well.
Figure 2. In an area of heavy malaria (Abeokuta, SW Nigeria) the That this has not yet happened is disappointing but
P falciparum parasite density is significantly reduced in AS versus perhaps not surprising, because the key is sickling of
AA children, specifically between the age of 3 and 5. Protection red cells, and this is a unique phenomenon. It cannot be
from life-threatening levels of parasitaemia is crucially important in a straightforward task to mimic sickling by a
this age group for the survival of AS heterozygotes, because
subsequently acquired immunity can protect AA subjects as well.
pharmacological approach in subjects who do not have
From.20 Hb S, and in a way that would act selectively only on
parasitized red cells. We can still hope that human
How Malaria Affects Patients with SCA. If AS imagination will evolve novel approaches that can
heterozygotes were protected from malaria through match the power of mutation and selection in
failure of infection, one might expect protection to be biological evolution. In the meantime SCA remains a

Mediterr J Hematol Infect Dis 2012; 4: Open Journal System

source of great suffering to patients, especially in those helped human populations to survive in malaria-
developing countries where the numbers are staggering endemic regions of the world.
(see Table 1). It is urgent that more is done in order to
offer to these patients a better way of life: this ought to Acknowledgement. I am taking this opportunity to
include optimal management of pain, often thank all patients with sickle cell anemia from whom I
hydroxyurea and, especially in Africa,34 protection have learnt about the disease through their Hospital and
against the potentially fatal threat of P falciparum Clinic visits in Ibadan, London, New York and
malaria. If, as doctors, we have a professional Firenze. I also thank all my colleagues in the respective
obligation towards all of our patients, for those with Haematology departments: particularly G J F Esan, O
SCA we have an added human obligation, if we Sodeinde, A Olujohungbe, and the late E S Nwachuku-
consider that they carry the genetic burden that has Jarrett.

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