MISSION

“MABINI COLLEGES provides quality

VISION
MABINI COLLEGES INCORPORATED
“MABINI COLLEGES
shall cultivate a CULTURE COLLEGE OF NURSING
of EXCELLENCE in and MIDWIFERY
Education.”
Governor Panotes Avenue
Daet, Camarines Norte
Tel. no. (054) 721-1281 local 109
Email: mabinicollege@hotmail.com
instruction, research and extension service
programs at all educational levels as its
monumental contribution to national and global
growth and development.
Specifically, it transforms students into:
 God – fearing,
 Nation – loving,
 Law abiding
 Earth caring
 Productive,
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persons

A PATHOGENESIS
AND EVIDENCE BASED
ABOUT MALARIA

SUBMITTED BY:
DARYL S. ABRAHAM

SUBMITTED TO:
MODESTO P. FUCIO RN

NOVEMBER 19, 2020

 MISSION
“MABINI COLLEGES provides quality
VISION instruction, research and extension service
MABINI COLLEGES INCORPORATED programs at all educational levels as its
“MABINI COLLEGES
shall cultivate a CULTURE COLLEGE OF NURSING monumental contribution to national and global
growth and development.
of EXCELLENCE in and MIDWIFERY Specifically, it transforms students into:
Education.”  God – fearing,
Governor Panotes Avenue  Nation – loving,
Daet, Camarines Norte  Law abiding
 Earth caring
Tel. no. (054) 721-1281 local 109  Productive,
 and Locally and Globally competitive
Email: mabinicollege@hotmail.com persons

MALARIA
PATHOGENESIS

Malarial infection begins when a person is bitten by an infected female anopheles

mosquito and Plasmodium spp (species) parasites in the form of sporozoites are
injected into the bloodstream. The sporozoites travel to the liver, multiplying asexually
over the next 7–10 days. During this time there are no symptoms. The parasites, now in
the form of merozoites, emerge from the liver cells in vesicles and travel through the
heart to the capillaries of the lungs. The vesicles eventually disintegrate, releasing the
merozoites to enter the bloodstream where they invade and multiply in erythrocytes.
When the cells burst, the parasites invade more erythrocytes.
 MISSION
“MABINI COLLEGES provides quality
VISION instruction, research and extension service
MABINI COLLEGES INCORPORATED programs at all educational levels as its
“MABINI COLLEGES
shall cultivate a CULTURE COLLEGE OF NURSING monumental contribution to national and global
growth and development.
of EXCELLENCE in and MIDWIFERY Specifically, it transforms students into:
Education.”  God – fearing,
Governor Panotes Avenue  Nation – loving,
Daet, Camarines Norte  Law abiding
 Earth caring
Tel. no. (054) 721-1281 local 109  Productive,
 and Locally and Globally competitive
Email: mabinicollege@hotmail.com persons

Clinical symptoms, including fever, occur in synchrony with the rupture of

infected erythrocytes and the release of erythrocyte and parasite debris, including
malarial pigment (hemozoin) and glycophosphatidylinositol, the putative ‘malaria
toxin’.4,5 In some infected blood cells, instead of replicating asexually, the merozoites
develop into sexual forms (gametocytes), which circulate in the bloodstream and are
ingested during mosquito bites. The ingested gametocytes develop in the mosquito into
mature sex cells (gametes) which develop into ookinetes that actively burrow through
the mid-gut wall of the mosquito and form oocysts, in which develop thousands of active
sporozoites. The oocyst eventually bursts, releasing sporozoites that travel to the
salivary glands of the mosquito. The cycle of human infection begins again when the
mosquito bites another person.

The associated symptoms of malaria include severe anemia, fever,

thrombocytopenia, chills, headache, vomiting, muscle ache, anorexia, rigor, diarrhea,
abdominal discomfort, cough, seizures, respiratory distress, hypoglycemia, metabolic
acidosis, hyperlactemia, coma associated with increased intracranial pressure (cerebral
malaria), retinopathy, and complications of pregnancy, including preterm birth and low
birth weight due to fetal growth restriction (FGR). As noted, the symptoms are
associated with the rupture of the infected erythrocytes and the release of putative
malaria toxins, which activate peripheral blood mononuclear cells and stimulate the
release of cytokines. It is believed that the balance between pro-inflammatory and anti-
inflammatory cytokines, chemokines, growth factors, and effector molecules determines
disease severity.6 Studies have reported increased IL-1B, IL-6, IL-8, and TNF-alpha in
late-onset severe disease, and a low IL-10:TNF-alpha ratio. The role of cytokines,
however, remains contradictory and unclear.

Alterations in retinoids (vitamin A and its congeners) also occur in malaria, but the
precise role of retinoids in the disease may be different and even opposite to the
traditional focus on vitamin A deficiency and supplementation. This paper presents a
new theory on the pathogenesis of malaria, suggesting that an endogenous form of
 MISSION
“MABINI COLLEGES provides quality
VISION instruction, research and extension service
MABINI COLLEGES INCORPORATED programs at all educational levels as its
“MABINI COLLEGES
shall cultivate a CULTURE COLLEGE OF NURSING monumental contribution to national and global
growth and development.
of EXCELLENCE in and MIDWIFERY Specifically, it transforms students into:
Education.”  God – fearing,
Governor Panotes Avenue  Nation – loving,
Daet, Camarines Norte  Law abiding
 Earth caring
Tel. no. (054) 721-1281 local 109  Productive,
 and Locally and Globally competitive
Email: mabinicollege@hotmail.com persons

hypervitaminosis A induced by the parasite contributes significantly to the signs and

symptoms of the disease.

With 3.3 billion people at risk of infection, malaria remains one of the world’s
most significant health problems. Increasing resistance of the main causative parasite to
currently available drugs has created an urgent need to elucidate the pathogenesis of
the disease in order to develop new treatments. A possible clue to such an
understanding is that the malaria parasite Plasmodium falciparum selectively absorbs
vitamin A from the host and appears to use it for its metabolism; serum vitamin A levels
are also reduced in children with malaria. Although vitamin A is essential in low
concentration for numerous biological functions, higher concentrations are cytotoxic and
pro-oxidant, and potentially toxic quantities of the vitamin are stored in the liver. During
their life cycle in the host the parasites remain in the liver for several days before
invading the red blood cells (RBCs). The hypothesis proposed is that the parasites
emerge from the liver packed with vitamin A and use retinoic acid (RA), the main
biologically active metabolite of vitamin A, as a cell membrane destabilizer to invade the
RBCs throughout the body. The characteristic hemolysis and anemia of malaria and
other symptoms of the disease may thus be manifestations of an endogenous form of
vitamin A intoxication associated with high concentrations of RA but low concentrations
of retinol (ROL). Retinoic acid released from the parasites may also affect the fetus and
cause preterm birth and fetal growth restriction (FGR) as a function of the
membranolytic and growth inhibitory effects of these compounds, respectively. Subject
to testing, the hypothesis suggests that parasite vitamin A metabolism could become a
new target for the treatment and prevention of malaria.

EVIDENCE BASED

Public health strategies for malaria in endemic countries aim to prevent

transmission of the disease and control the vector. This historical analysis considers the
strategies for vector control developed during the first four decades of the twentieth
 MISSION
“MABINI COLLEGES provides quality
VISION instruction, research and extension service
MABINI COLLEGES INCORPORATED programs at all educational levels as its
“MABINI COLLEGES
shall cultivate a CULTURE COLLEGE OF NURSING monumental contribution to national and global
growth and development.
of EXCELLENCE in and MIDWIFERY Specifically, it transforms students into:
Education.”  God – fearing,
Governor Panotes Avenue  Nation – loving,
Daet, Camarines Norte  Law abiding
 Earth caring
Tel. no. (054) 721-1281 local 109  Productive,
 and Locally and Globally competitive
Email: mabinicollege@hotmail.com persons

century. In 1925, policies and technological advances were debated internationally for
the first time after the outbreak of malaria in Europe which followed World War I. This
dialogue had implications for policies in Europe, Russia and the Middle East, and
influenced the broader international control agenda. The analysis draws on the
advances made before 1930, and includes the effects of mosquito-proofing of houses;
the use of larvicides (Paris Green) and larvivorous fish (Gambusia); the role of large-
scale engineering works; and the emergence of biological approaches to malaria. The
importance of strong government and civil servant support was outlined. Despite best
efforts of public health authorities, it became clear that it was notoriously difficult to
interrupt transmission in areas of moderately high transmission. The importance of
combining a variety of measures to achieve control became clear and proved
successful in Palestine between 1923 and 1925, and improved education, economic
circumstances and sustained political commitment emerge as key factors in the longer
term control of malaria. The analysis shows that the principles for many of the present
public health strategies for malaria have nearly all been defined before 1930, apart from
large scale usage of pesticides, which came later at the end of the Second World War.
No single intervention provided an effective single answer to preventing transmission,
but certainly approaches taken that are locally relevant and applied in combination, are
relevant to today’s efforts at elimination.

Laveran in Algeria discovered the cause of malaria and the Plasmodium parasite
around 1880–1882. This was an important discovery, but did not at the time influence
the various treatments and prevention approaches that were already in use.
Nevertheless, understanding the biology of the diseases was clearly important to help
develop strategies to intervene, and some 15 years later (around 1895–1899), Ross
and Grassi defined the parasite’s life cycle and transmission by Anopheline mosquitoes.
This understanding paved the way for a science-based strategy to tackle malaria by
interrupting parasite transmission, or by tackling the insect vector, using tools already
available. Control of malaria, even its eradication, seemed a possibility at the turn of the
twentieth century.
 MISSION
“MABINI COLLEGES provides quality
VISION instruction, research and extension service
MABINI COLLEGES INCORPORATED programs at all educational levels as its
“MABINI COLLEGES
shall cultivate a CULTURE COLLEGE OF NURSING monumental contribution to national and global
growth and development.
of EXCELLENCE in and MIDWIFERY Specifically, it transforms students into:
Education.”  God – fearing,
Governor Panotes Avenue  Nation – loving,
Daet, Camarines Norte  Law abiding
 Earth caring
Tel. no. (054) 721-1281 local 109  Productive,
 and Locally and Globally competitive
Email: mabinicollege@hotmail.com persons

At the time, it was known that quinine could kill the Plasmodium parasite in
humans and it was a useful treatment. However, despite some promising initial results,
using quinine to prevent transmission in large populations of people exposed to the risk
of malaria was not successful at scale.

Knowing that preventing people from being exposed to the vector opened the
door to new strategies, such as reducing the vector through killing the larvae. From
1900 to 1925, success of local initiatives for malaria control were reported from a variety
of areas where malaria was common, including Brazil, India, Italy, Palestine, Panama
Canal and Spain, some of which are discussed later. Despite these apparent local
successes, policy makers acknowledged the difficulty of interrupting malaria
transmission, even in moderately high transmission areas. In the first comparative
analyses of results in 1925 carried out by the League of Nations (the Malaria
Commission of the League of Nations) and the First International Congress on Malaria,
the authors concluded that none of the methods so far tested had proved efficient and
stable enough to be confident that the answer to controlling malaria had been found.

Indeed, these conclusions were probably reasonable. In contrast to the clinical

use of quinine, it was not easy to make confident causal inferences about the effects of
most of these interventions to control and prevent malaria at the population level.
Multiple interventions were often poorly characterized and delivered without any formal
comparison groups. Even the apparent effects from carefully documented, integrated
interventions such as in the Canal Zone of Panama were not as clear as initially
thought. The Zone was placed under a strict control as for yellow fever, leading to a
marked reduction in the number of malaria cases (from 821/1000 in 1906 to 76/1000 in
1913 [5]); however, it appeared that this simply shifted the disease out of the area just
adjacent to the Canal Zone to other places and populations of Panama, so that the final
balance was not as positive as claimed. Indeed, medical entomologists showed that the
diffusion of malaria in the construction area was due to human activities and attitudes
[6]. On the whole, uncertainties and disputes around the effectiveness of the integrated
 MISSION
“MABINI COLLEGES provides quality
VISION instruction, research and extension service
MABINI COLLEGES INCORPORATED programs at all educational levels as its
“MABINI COLLEGES
shall cultivate a CULTURE COLLEGE OF NURSING monumental contribution to national and global
growth and development.
of EXCELLENCE in and MIDWIFERY Specifically, it transforms students into:
Education.”  God – fearing,
Governor Panotes Avenue  Nation – loving,
Daet, Camarines Norte  Law abiding
 Earth caring
Tel. no. (054) 721-1281 local 109  Productive,
 and Locally and Globally competitive
Email: mabinicollege@hotmail.com persons

interventions resulted from the lack of formal comparative studies, with inevitable
confusion about which anti-malarial policies to apply, particularly at a large-scale level.