Malaria basics Paul R. Earl Facultad de Ciencias Biolgicas Universidad Autnoma de Nuevo Len San Nico

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Malaria basicsPaul R. EarlFacultad de Ciencias
BiológicasUniversidad Autónoma de Nuevo LeónSan
Nicolás, NL, Mexico
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The main points. The protozoan genus
Plasmodium is responsible for malaria and has
four medically important species Plasmodium
falciparum, P. vivax, P. malariae and P. ovale.
The most vicious of these is P. falciparum
because it is rapidly fatal and is responsible
for most malaria related deaths.
Mosquito-transmitted malaria is the greatest
public health problem in large parts of the world
with more than 500 million clinical cases and
over 3 million deaths every year, mostly in
African children under five years.
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Malaria occurs in most of the tropics of the
world with P. falciparum predominating in
subSaharan Africa through to New Guinea. P. vivax
is more common on the Indian subcontinent, in
Mexico in Central America with the prevalence
of falciparum and vivax malarias being about the
same in Asia, Oceania and South America.
Infrequent P. malariae is found in most endemic
areas, especially subSaharan Africa that has also
90 of the deaths. P. ovale is unusual outside
Africa, although it can be found in southern
India. Also, malaria can be a travelers disease
and imported into any country.
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By 1970 malaria eradication had succeeded with
DDT in all Europe. Malaria used to be prevalent
in Russia, USA Canada. It was prevalent around
the Mediterranean, Italy, Greece, Yugoslavia,
Bulgaria, Turkey and southern Britain. It had
also been eradicated in USSR, North America,
several middle eastern countries, large parts of
South America, the Caribbean, Australia, Japan
and Taiwan. See the map.
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In India 75 million cases in 1950 were down to
100,000 cases by 1970. Transmission rates in
Africa and India were severely reduced. Malaria
had been almost eliminated in Sri-Lanka. All of
this progress was lost because of DDT hysteria.
The enormous penalty for hysteria and mendacity
includes losing control of filariasis. Still, the
WHO did know what would happen if DDT was
suspended. Mendacity is exhibited by crying about
drug resistance, while not honestly discussing or
otherwise even mentioning lifesaving DDT.
Affluent countries without malaria decided to ban
DDT whose main features are low cost and
efficient residual effect.
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Clinical symptoms include the following
cough, fatigue, malaise, arthralgia, myalgia, and
paroxysm of shaking chills and sweats. The
classic paroxysm begins with a period of
shivering and chills, which lasts for 1-2 hours
followed by high fever. Paroxyms of varying 48
hours belong to vivax, ovale and falciparum
malaria, whereas 72 hours belongs to malariae
infections.
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As many as 30 of nonimmune adults infected with
P falciparum suffer acute renal failure, some
with seizures. Blackwater fever is hemoglobinuria
with the passage of dark-colored urine
Noncardiogenic pulmonary edema is most common in
pregnant women and results in death in 80 of
patients. Profound hypoglycemia often occurs in
young children and pregnant women. The most
prominent symptoms all relate to loss of RBCs a)
tachycardia, b) anemia, c) fever, d) hypotension
and e) splenomegaly.
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Malaria has always had a greater impact on humans
than any other parasite or infectious agent.
Malaria is a rural disease due to the presence of
the female Anopheles mosquito vector. Can
mosquito vector transmission be lowered? How? In
1956 the World Health Organization (WHO) began a
global malaria eradication program, mainly
because of the effectiveness of DTT in killing
the mosquito vectors. This is an incredibly good
pesticide, cheap to make, long-lasting and
apparently harmless to humans.
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One biological reason for the defeat was the
development of some resistance to pesticides by
the vectors, and another was the development of
some drug resistance by the parasite itself. But
. . . When health authorities do not have the
money or have the will to spend it on vector
control, they often lie and promote
underestimates of the threat.Transgenic
mosquitoes incompetent to transmit the
sporozoites are a bright shiny hope.
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How is global malaria to be managed? Who pays
the bill? Political will, public health education
and similar social factors sometimes centering on
poverty shape the WHO campaign for eradication.
Global eradication as an ideal may be impossible
for fault of gigantic financing, yet the
eradication of malaria is long overdue in
countries like Mexico that have fallen very far
behind the position they had in their DDT days,
not willing to spend the money. Many populations
across the world have no idea of the health
threats that they live under.
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What does relapse mean? An infected person who
has recovered functions normally for a long time
then becomes ill, i. e., has a relapse. Let us
say that his town is malaria-free. By 2-3 weeks
an outbreak of malaria occurs and public health
officials face a new series of infection cycles
in local mosquitoes. Universally, the mosquito
vectors are not infected as a rule. A single case
of relapse is likely to cause a disaster. Before
relapse, transmission was not occurring. Acute
hospitalized cases display many parasites in red
blood cells (RBC), whereas cases in recovery do
not, therefore some way has to be found to
concentrate RBCs, especially in vivax malaria.
This is the thick.
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Symptoms. Malaria is
characterized by severe undulating fever
(paroxyms) occurring every 48 or 72 hours,
depending on the species, varying from 48 hours
in P.vivax, P. ovale, and P. falciparum malaria,
to 72 hours in P. malariae infections. The 48
hour fever is called tertian because it occurs
every third day fever on day 1, no fever on day
2, fever on day 3 and so on. The 72 hour fever is
called quartan, because it returns on every
fourth day.The erythrocytic schizogony cycle
(vegetative) becomes synchronized, and the
febrile paroxysms become consistent.
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Table1. Clinical Features of Malaria
P. vivax, P.
falciparum P. MalariaeP. ovale .
Incubation 8-24 d 8-24 d
15-30 daysType of fever Tertian
Aperiodic Quartan
quotidianExoerythrocytic cycle
Yes No No Relapse
Common Recrudescence Recrudescence
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The principal signs of cerebral malaria are
seizures and unconsciousness, usually preceded by
a severe headache. Neurologic examination may
include contracted or unequal pupils, a Babinski
sign, and absent or exaggerated deep tendon
reflexes. Cerebrospinal fluid examination shows
increased pressure, increased protein, and
minimal or no pleocytosis. High fever, 41 to
42C (106 to 108F), with hot, dry skin may
occur.
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Often fatal, acute pulmonary edema can develop
rapidly and is associated with excessive
intravenous fluid therapy. Fast, labored
respiration, with shortness of breath, a
non-productive cough, and physical findings of
moist rales and rhonchi are usually present.
Chest X-rays usually show increased
bronchovascular markings. Most patients with
falciparum malaria complain of loss of appetite
and nausea. However, in some patients (especially
young children), additional symptoms including
vomiting, abdominal pain, watery diarrhea, and
jaundice.
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Treatment of Malaria. 1) P. vivax, P.
ovale Oral chloroquine 10 mg/kg (max. 600 mg)
followed by 5 mg/kg (max. 300 mg) after 6, 24 and
48 hours Oral primaquine 15 mg/kg / day x 14 days
to prevent relapse 2) P. falciparum Chloroquine
sensitive As above. Chloroquine resistant -
Pyrimethamine 25 mg sulphadoxine 500 mg tablets
- 3 tablets single dose for adults OR - Quinine
sulphate 650 mg (10 mg/kg) salt orally TDS times
7 days, plus Tetracycline 250 mg QDS times 7 days
- Multidrug resistant - Mefloquine 15-25 mg/kg
(max 1.5 g) single dose orally OR - Artesunate
200 mg on first day followed by 100 mg daily
times 4 days.
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The vector life cycle. All four species are
transmitted through the bite of an infected
female Anopheles species mosquito. Malaria also
can be transmitted via a blood transfusion or
congenitally between mother and fetus.
Malaria-carrying Anopheles mosquitoes tend to
bite only near dusk and dawn. The vector, the
Anopheles species mosquito, passes plasmodia,
which are contained in its saliva, into its host
while obtaining a blood meal. Plasmodia enter
circulating RBCs and feed on the hemoglobin,
other proteins and glucose within the cells.
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Insect life cycles are well known eggs, pupas,
larvas and adults. Anopheles mosquitoes feeding
on infected hosts ingest sexual forms developing
in RBCs. The female macrogametocytes and male
microgametocytes mature in the mosquitos stomach
and combine forming a zygote. The products of
this fertilization are ookinetes, which force
themselves between the epithelial cells to the
outer surface of the mosquito stomach, and form
into small spheres called oocysts. The oocysts
enlarge as the nucleus divides, eventually
rupturing and releasing thousands of motile
sporozoites into the body cavity. The sporozoites
migrate to the salivary glands, making the female
mosquito infective. The vector phase of the life
cycle, called sporogony, is complete in 8 to 35
days depending on species and environmental
conditions.
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The mammalian life cycle. Plasmodia replicate
inside the RBC. This replication induces RBC
cytolysis and causes the release of toxic
metabolic byproducts into the bloodstream. These
symptoms include chills, headache, myalgias and
malaise, occurring in cycles. The parasite also
may cause splenomegaly, jaundice and anemia. The
symptoms relate to blood cell destruction. P
falciparum may induce kidney failure, coma and
death.
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The sexual cycle.Fertilization of the
macro- by the microgamete to form a karyosome
called a sporogonia in the mosquito stomach is a
good place to start the life cycle, but by
tradition it starts with the mosquito bite of the
mammal, bird or other vertebrate host. The
injection of sporozooites caused infection.
Sporo-zoites, the infective stage of plasmodia,
are injected from the salivary glands of
mosquitoes during a blood meal. The sporozoites
disappear from the blood within a half hour, most
destroyed by white blood cells, but some enter
liver cells. Sporozoites that enter liver cells
multiply asexually in a process called
exoerythrocytic schizogony.
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Merozoite is the traditional term for vegetative
or nonsexual state trophozoite schizont. A
hepatic schizont contains many thousands of tiny,
invasive merozo-ites, created in a single
segmentation. These asexual merozoites are the
smallest and shortest lived form of the life
cycle. Within a few minutes, they invade RBCs.
The apical complex of the merozite is specialized
to recognise and attach to epitopes on the
RBCsOver 5-10 hours, the zygote in the mosquito
differentiates into a cigar-shaped invasive
ookinete. During the differentiation of the
ookinete the diploid set of chromosomes divides
as the first step in a two stage meiosis, the
second stage takes place at the start of
sporogony.
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All infected liver cells parasitized with P.
falciparum and P. malariae rupture and release
merozoites at about the same time. In contrast,
P. vivax and P. ovale have two exoerythrocytic
forms. The primary type develops, causes liver
cell rupture, and releases merozoites just as in
P. falciparum and P. malariae. The other form,
which develops concurrently, is known as the
hypnozoite. Sporozoites that enter liver cells
differentiate into nonsexual hypnozoites that
remain dormant for weeks, or even years. The
hypnozoites activate and undergo exoerythrocytic
schizogony, forming a wave of merozoites that
cause a relapse.
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Anopheles species.North America, from
Great Lakes to southern Mexico A. freeborni, A.
quadrimaculatus, A. hermsi Central
America, southwestern Mexico, Caribbean islands,
north of South American coast A.
albimanus, A. argyritarsis,
A. pseudopunctipennis, A.
aquasalis, A. darlingi South America A.
pseudopunctipennis, A.
punctimaculus, A. albimanus, A. albitaris,
A. aquasalis, A. darlingi North Eurasia,
Europe and west Asia, excluding Mediterranean
coast Mediterrane-an South coast of Europe,
North coast of Africa A. atroparvus,
A. labranchiae, A. sacharovi, A. superpictus
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Defective globin genes. About 250 million
people, 4.5 of the world population, are
carriers of a defective globulin gene. Each year
about 300,000 homozygotes are born about equally
divided between sickle cell disorders and
thalassemia syndromes. Malarial parasites feed on
RBCs. Then clinical symptoms like plain anemia
and just about everything else are strongly
affected by RBC destruction. Are there mutant
hemoglobin molecules unsuitable to mosquitoes?
Yes. One causes sickle cell anemia, and others
cause ?- and ?-thalassemias.
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Another associated genetic blood disease is
glucose-6-phosphate dehydrogenase deficiency in
RBCs. Only men are affected as this is an
X-chromosome linked trait. Glucose-6-phosphate
dehydrogenase is involved in protecting RBCs from
damage by free radicals and in particular
reactive oxygen intermediates.
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In sickle cell anemia, normal hemoglobin is
replaced by hemoglobin S (HbS). HbS is much less
soluble than normal hemoglobin when in the
deoxygenated state and may precipitate,
distorting the RBCs. This is caused by a single
amino acid substitution where a glutamic acid in
the gene sequence is replaced by a valine.
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A heterozygous person has HbA/HbS. Their blood
appears normal unless exposed to low oxygen when
reversible sickling occurs. However, the
homozygotes with HbS/HbS become ill, and most die
in infancy. Children who are heterozygous are
more likely to survive than those having normal
hemoglobin. Is selection of the fittest in
operation?
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Hemoglobin consists of two subunits, 2-? and 2-?.
In thalassemia, one of the two subunits is not
made. The persons lack either the ?- or
?-subgroups. This causes abnormal RBCs that again
confer resistance to malaria.One homozygote dies
of malaria, the other of a globin gene defect,
and the heterozygotic person is protected.
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Laboratory identifications with Giemsa. Again,
the heart of an eradication campaign is the
thick. Interest focuses on good Geimsa staining.
You must be able to identify the gametocytes of
the 4 species, but first find out if malaria
parasites are present. Examine a thick Giemsa
slide, especially if from a field survey. The
hospital slide from a patient already diagnosed
needs to be identified to the species level.
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Vaccination and control. In general,
vaccination, yet to be truely developed for
malaria, prevents high-risk diseases. High risk
can relate to lack of vector control, and
involves millions of people. Next, the cost of
any procedure is paramount. Diagnosis by the
polymerase chain reaction (PCR) can become
routine in some laboratories, whereas in most the
cost is prohibitive. Dipsticks for histidine-rich
protein (HRP2) of P. falciparum are accurate,
fast and cheap. Other simple immunological
highlights may develop. Present rapid dipstick
methods stand out.
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The first requirement for the classic
malariologist is to differentiate the 4 malaria
species with Giemsa stain at the microscope.
Diagnosis, medical treatment, epidemiology,
vector control and vaccination (hardly mentioned
here) and other concerns all follow the
identifications of infections from asymtomatic to
fatal. In eradication campaigns, emphasis might
be placed on rooting out silent or relapsed
cases. The prevalence of malaria in some
districts points to the failure of vector
control.
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Roll Back Malaria. The campaign Roll
Back Malaria in Africa involving the manufacture
of insecticide impregnated sleeping nets began in
October 1998, supported by the World Health
Organization (WHO). Regardless, the way to rid
the world of malaria and some other insect-borne
diseases like dengue fever is by spraying
residual insecticides like DDT inside houses. The
establishment of the Global Fund to Fight AIDS,
Tuberculosis and Malaria (GFATM) is providing
significant new grants to help countries
accelerate implementation of their plans to roll
back malaria.
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Malaria morbidity and mortality a) Hospital
deaths due to malaria the percentage of recorded
inpatient deaths that are attributed to malaria
derived from Ministry of Health reports where
data are available, b) Malaria admissions the
percentage of recorded health facility admissions
that are attributed to malaria, c) Malaria
outpatient attendance the percentage of recorded
outpatient visits to health facilities that are
attributed to malaria.