Malaria is caused by Plasmodium parasites transmitted via mosquito bites. It has a complex life cycle alternating between human and mosquito hosts. The disease ranges from mild to severe depending on parasite species and host immune status. Common symptoms include fevers, chills, and flu-like illness. Severe malaria can involve cerebral symptoms, severe anemia, respiratory distress, and other complications without prompt treatment. Transmission is dependent on environmental factors permitting parasite and vector survival.

1. THEME: MALARIA.
Department of infectious diseasesDepartment of infectious diseases
Infectious diseasesInfectious diseases

2. Definition
Malaria is an infection caused by the coccidian
protozoan parasite of the genus Plasmodium carried by
female Anopheles spp. mosquitoes.
The clinical disease in humans may vary widely
according to the species of parasite — Plasmodium
falciparum, Plasmodium vivax, Plasmodium ovale or
Plasmodium malariae — and the genetics, immune status
and age of the host. These variables have a major influence
on all aspects of the disease, including epidemiology,
pathogenesis, clinical features and management.
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3. Before proceeding to study the parasites there are certain
terms which require definition.
Cycle.Cycle.
One speaks of an " asexual cycle " of development of the
parasite in man and a" sexual cycle" of development in
the mosquito.
Trophozoite.Trophozoite. The growing form of the parasite in the blood
of man; it includes the ring and all stages onwards, except
the fully grown gametocyte and the schizont.
Schizont.Schizont. A form which is in process of dividing asexually; it
is called "immature" when division has just begun and
"mature" when division is complete, and the parasitized
cell is just about to rupture.
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4. SchizogonySchizogony. A process of asexual reproduction by which
the nucleus and cytoplasm divide into many subsidiary
parts simultaneously, each part being a merozoite. The
process occurs in the liver cells and red blood corpuscles
of man.
Sporogony.Sporogony. A process or cycle of sexual reproduction,
which results in the formation of sporozoites; in the
mosquito.
Gametocyte.Gametocyte. The stage of the parasite containing the
gamete. The origin of these forms is not definitely
known; they are probably derived from merozoites
produced by schizogony in the blood stream.
Gametes.Gametes. The male gamete or spermatozoon, and the
female gamete or ovum before fertilization has taken
place.
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6. Zygote.Zygote. The fertilized ovum.
Ookinete. A zygote capable of moving.
Oocyst.Oocyst. An ookinete which has settled down, become
rounded and covered with a membranous cyst wall.
HemocoeleHemocoele. This is the body cavity functioning as the
blood vascular system in insects.
The species of parasites causing malaria in man differ from
each other in morphology, but the general course of their
life-history is similar. All of the parasites have an asexual
and a sexual cycle of development. The first known as the
endogenous cycle, is passed in man and the process of
reproduction during this cycle is called schizogony. The
second or sexual, known as the exogenous cycle, is
passed in some species of mosquito and the process of
reproduction during this cycle being called sporogony.
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7. Geographic distribution
Wherever temperatures are favorable and humans
and mosquitoes co-exist, there is the potential for malarial
transmission. Malaria certainly existed until the mid-20th
century in Europe, especially in Italy, as well as in northern
parts of Asia adjoining the former USSR. Almost 2 billion
people are at risk of malaria in endemic areas and each year
it is estimated that up to 250 million clinical cases occur and
over 1 million die, largely among infants and young children
in Africa.
Malaria occurs throughout the tropics and subtropics,
especially where the temperature exceeds the 60.8°F (16°C)
isotherm.
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8. The four species of malaria parasites that affect
humans differ in their geographic distributions:
P. falciparum is most common in sub-Saharan Africa
and Melanesia (Papua New Guinea and the Solomon
Islands);
P. vivax is found mainly in Central and South America,
North Africa, the Middle East and within the Indian
subcontinent;
P. ovale is found predominantly in West Africa but also
in Asia; and
P. malariae occurs worldwide, although most cases
occur in Africa.
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10. Malaria incidence is usually endemic, but hyperendemicity
is a distinct form, demanding for its production such an
intensity of transmission that a high degree of tolerance
to the effects of reinfection is induced in those who
experience its effects over a number of years, especially
as a result of repeated infections in early childhood.
The World Health Organization has proposed the following
classification:—
I Hypoendemic malaria with spleen rate in children 2-10
years of age 0-10 per cent.
II Mesoendemic malaria with spleen rate in children 2-10
years of age 11-50 per cent.
Ill Hyperendemic malaria with spleen rate in children 2-10
years of age constantly over 75 per cent. Spleen rate in
adults is also high.
IV Holoendemic malaria with spleen rate in children 2-10
years of age constantly over 75 per cent. Spleen rate in
adults low; it is in this type of endemicity that the
strongest adult tolerance is found.
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11. With modern air travel, individuals with malaria can be
rapidly transported within hours to any part of the world and
malaria is the single most common imported infection
occurring in travelers.
There have been occasional reports of 'airport malaria'
where infected mosquitoes have been imported on board
aircraft into a nonendemic area of the world where they infect
local inhabitants who have not traveled.
A few outbreaks have also been documented in
nonendemic areas where environmental conditions have
become optimal for the transmission of disease by local
susceptible mosquitoes becoming infected after biting
individuals who have obtained their infection elsewhere. In
addition, there is now the threat of a global climate change. If
the predictions of a 3.6°F (2°C) rise by the year 2100 become
a reality, this might lead to the spread of malaria back into
areas previously affected by malaria.
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12. Epidemiology
Malaria can also be transmitted by blood and blood
products. The epidemiology of malaria depends upon a
complex interplay between the:
host (humans),
vector (mosquito), and
malarial parasite.
Population density and prevalence of infection among
children are important factors because children tend to have
both high parasitemias and rates of carriage of the sexual
forms of the parasite (gametocytes), which are necessary for
transmission of the infection. Paradoxically, in the 2 weeks
after effective treatment of P. falciparum malaria, the
numbers of gametocytes in the blood rises, so that while the
patient improves clinically, mosquitoes biting the patient
during this time are more likely to transmit infection.
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13. Epidemiology
The longevity of the mosquito is also crucial because it
needs to be of sufficient duration to allow for full development
of the parasite. Ambient temperatures have a major impact,
because higher temperatures significantly shorten this period
of maturation in the mosquito (the extrinsic incubation period)
and increase transmission. Seasonal rainfall dramatically
increases the breeding of mosquitoes.
Where malaria prospers, human societies prosper the
least and there is a striking correlation between malaria and
poverty. The effects of malaria are felt on diverse areas
including fertility, population growth, savings and investment,
worker productivity, absenteeism, premature mortality and
medical costs.
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14. Pathogenesis
Malaria is one of the few infective agents of humans
that invades red cells. All four species of malarial parasites
that infect humans have a similar life cycle that alternates
between human and mosquito. The clinical symptoms and
signs are produced by the asexual forms of the parasite,
which invade and destroy red cells, localize in critical organs
and tissues in the body, and induce the release of many
proinflammatory cytokines, of which tumor necrosis factor
(TNF)-α is thought to be the most important.
The sporozoites injected by the bite of the infected
mosquito, the exoerythrocytic parasites, which subsequently
develop in the liver, and the sexual forms of the parasite
(macro- and microgametocytes), which arise from the
asexual forms do not cause clinical disease.
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16. Invasion of red cells
Merozoites in the peripheral blood invade red cells (and
occasionally platelets) and the rate and degree to which the
parasite multiplies appear to relate to disease severity in
nonimmune individuals. Invasion is a highly specific, ordered
and sequential process in which the invasive form, the
merozoite, attaches to a susceptible red cell, reorients itself so
that its apical end is apposed to the red cell membrane, and
then slowly moves into a localized invagination. The entire
process of invasion is completed within 30 seconds. In
falciparum malaria the erythrocyte binding antigen and/or
merozoite surface proteins appear to interact with the red cell
sialoglycoproteins, whereas in P. vivax infection, the red cell
Duffy antigen on the uninfected red cell is involved. There is
surprising redundancy in the invasion pathways of P. falciparum
and a number of sialoglycoprotein and nonsialoglycoprotein
pathways have been identified.
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17. Attachment and orientation is followed by
interiorization accompanied by deformation of the red cell
membrane. Although each merozoite of P. falciparum can
theoretically produce from 16 to 32 new merozoites every 48
hours, a more realistic figure in vivo is between three and 10.
It is only recently (largely because of technical difficulties)
that parasite multiplicative ability within red cells (i.e. the
ability to invade) has been shown to relate to disease
severity.
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19. Plasmodium vivax
lifestyle. It starts
when an infected
mosquito feeds,
inoculating the
sporozoite form of
the parasite,
which infects the
hepatocytes. The
parasite cells then
multiply (liver
schizonts) and are
liberated into the
circulation to
invade red cells
where they grow
(trophozoites) and
divide (schizonts).
Some
trophozoites
differentiate into
gametocytes
infective for
mosquito.

20. CLINICAL FEATURES
The most frequent presentation of malaria is that of a
pronounced febrile illness with rigors. However, the clinical
features of malaria can be extremely diverse because the
parasitized red cell circulates to every organ and tissue within
the body and therefore has the potential for producing a wide
variety of pathology.
The incubation period for malaria is variable, but under
optimal conditions may be as short as 7 days and in
exceptional cases up to 20 years, as in the case of P.
malariae infections. The majority (>90%) of P. falciparum
infections in travelers occur within 6 weeks of leaving an
endemic area.
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21. Mild malaria
The incubation period for malaria is variable, but under
optimal conditions may be as short as 7 days and in
exceptional cases up to 20 years, as in the case of P.
malariae infections. The majority (>90%) of P. falciparum
infections in travelers occur within 6 weeks of leaving an
endemic area.
The clinical presentation of mild malaria with rigors is well
known. There is usually a history of travel to or residence
within an endemic area. A history of even the best
compliance with the most effective antimalarial
chemoprophylaxis cannot exclude the diagnosis. There may
be a prodromal period of tiredness and aching. The features
of a classic paroxysm are:
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22. The features of a classic paroxysm are:
Premonitory stagePremonitory stage.—For several days before the actual
attack the patient may be conscious of headache, lassitude,
a desire to stretch or yawn, aching in the bones, anorexia,
sometimes vomiting.
Cold stageCold stage.—This usually lasts one to two hours, and is
the rigor, or "ague." The feeling of cold is intense and
universal. The teeth chatter; - the patient shivers from head
to foot and wraps himself up in any garment he can lay his
hands upon. Vomiting may be most distressing. The features
are pinched, the fingers shrivelled and the skin blue like
"goose-skin" (cutis anserina). The feeling of cold is purely
subjective, because the temperature is rapidly rising.
Children usually have convulsive fits.
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23. Hot stageHot stage.—The hot stage may last from three to four
hours. The shivering abates and gives place to, or alternates
with, sensations of great heat. The clothes are thrown off.
The face is flushed ; pulse full, bounding and usually dicrotic;
headache intense ; vomiting usual; respiration hurried ; skin
dry and burning; the temperature rising to 40° C, sometimes
41,1° C, rarely higher.
Sweating stageSweating stage.—This usually lasts from two to four
hours. The patient breaks out into profuse perspiration with
sweat literally running off him in streams, saturating clothes
and bedding. With sweating the fever rapidly declines.
Headache, thirst and distress give place to a feeling of relief
and tranquillity. When it has ceased the patient may feel
exhausted, but quite well and able to go about. The body
temperature is now subnormal and remains so until the
approach of the next paroxysm, one or two days later.
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24. Such a paroxysm may last 6–10 hours and a prolonged
asymptomatic period may follow and last 38–42 hours in the
case of P. vivax and P. ovale infections and 62–66 hours in
P. malariae infections. In P. falciparum infections the
periodicity of fever tends to be less predictable and the fever
may be continuous. There may be an accompanying
headache, cough, myalgia (flu-like symptoms), diarrhea and
mild jaundice.
Malaria is rarely, if ever, the cause of lymphadenopathy,
pharyngitis or a rash, and alternative explanations need to be
considered for these specific symptoms.
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25. Severe malariaSevere malaria
Definitions of the clinical manifestations of severe
falciparum malaria are included in table. However, many of
these definitions are for study purposes in order to compare
data from different parts of the world, especially for the
standardization of clinical trials, and must be taken in context.
For example, any degree of impairment of consciousness,
prostration, jaundice or evidence of renal impairment,
especially in a nonimmune individual, should be taken
seriously. Furthermore, parenteral therapy is regarded by
many as necessary for a parasitemia of 2% or above in a
nonimmune patient and in the presence of vomiting.
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26. Manifestations of severe malaria requiring special managementManifestations of severe malaria requiring special management
Manifestation Comment
Cerebral malaria Coma with peripheral parasitemia and other causes
of encephalopathy excluded
Severe anemia Normocytic anemia with hemoglobin <50g/l (5gm/dl)
(<15% hematocrit) in presence of parasitemia
>10,000/µl
Respiratory distress Pulmonary edema or adult respiratory distress
syndrome
Renal failure Urine output of less than 400ml/24h (or less than
12ml/kg in children) and a serum creatinine
>3.0mg/dl (265µmol/l)
Hypoglycemia Whole blood glucose <40mg/dl (2.2mmol/l)
Circulatory collapse (shock) Systolic blood pressure less than 70mmHg or core
skin temperature difference >18°F (10°C)
Coagulation failure Spontaneous bleeding or laboratory evidence of
disseminated intravascular coagulation
Impaired consciousness of any
degree, prostration, jaundice,
intractable vomiting,
parasitemia =2%
In nonimmune individuals should be managed as
severe malaria (i.e. with parenteral antimalarials)

27. Cerebral malariaCerebral malaria
Cerebral malaria in which the patient passes from
drowsiness into coma may develop insidiously over a few
days or abruptly within 1–2 hours and is often heralded by a
convulsion. The majority of patients have no focal neurologic
signs, but there may be a wide variety of neurologic
manifestations such as a cranial nerve palsy, monoplegia or
hemiplegia, extensor posturing, decerebrate or decorticate
rigidity, conjugate or even dysconjugate eye movements,
grinding of the teeth (bruxism) or hiccoughs.
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28. Some patients have retinal
hemorrhages, sometimes with
extramacular whitening of the fundus
and retinal vessel changes where they
turn white in isolated segments,
particularly at branch points.
Coma in malaria may not only
be due to primary neurologic
involvement, but may also be part of a
prolonged postictal state, status
epilepticus or a severe metabolic
disorder such as acidosis or
hypoglycemia. Thus drowsiness and
coma may be the result of a number
of different pathological processes.
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29. DIAGNOSISDIAGNOSIS
The definitive diagnosis of malaria is made by prompt
microscopic examination of thick and thin blood films. There
is no need to wait for a fever peak before carrying out a blood
film as parasites are often present throughout the red cell
cycle. Malarial chemoprophylaxis should be withheld during
investigation for malaria as antimalarials can suppress
peripheral parasitemia.
The most common abnormality on full blood count is
thrombocytopenia, especially in the nonimmune. This is
thought to be largely splenic pooling of platelets but also
platelet activation. The total white count is usually in the
normal range but often there is a lymphopenia on
presentation due to lymphocyte redistribution and more
recently, apoptosis of lymphocytes has been identified in
falciparum malaria.
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30. Thick blood filmsThick blood films
One or two drops of blood from a fingerprick are stirred in a
circle on a glass slide, allowed to air dry and then stained
with Giemsa or Field's stain. With this method, the red cells
lyse whereas the white cells and parasites remain intact.
Parasites are identified by recognizing both the eosinophilic
nucleus and the basophilic cytoplasm of the malarial parasite.
Parasite density can be related to the number of white cells
present. This method has far greater sensitivity than the thin
blood film.
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31. Thick blood filmsThick blood films
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32. Thin blood filmsThin blood films
A thin film is produced by spreading a small drop of blood
across a slide using the edge of a second slide, thereby
producing a monolayer of red cells. Fixation is usually with
methanol and the staining technique is as for the thick blood
film (optimally at pH 7.2). The red cells remain intact. The thin
blood film allows accurate speciation of the parasite and
quantitation, in which the number of parasites is related to the
number of red cells present. It is important that parasites are
accurately recognized, as platelets or debris can often be
mistaken for parasites. The size, shape and stippling of the
red cell cytoplasm help in the speciation of the parasite.
Examples of the four species are shown in Figures.
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33. Thin blood film from patient with malaria. Delicate small ring forms of
Plasmodium falciparum showing multiply infected red cells and a
characteristic 'applique' form in the uppermost parasite in the central
red cell where the parasite appears as if it is applied to the surface,
rather than within the red cell.

34. Thin blood film from patient with malaria. Ring forms of P. falciparum in
a heavy infection and where the pH of the stain is 7.2 rather than 6.7
showing the irregular, basophilic Maurer's clefts in the cytoplasm of
infected cells characteristic of P. falciparum.

35. Thin blood film from patient with malaria. Very early trophozoites of P.
falciparum in the peripheral blood film of a patient with severe disease.
The relative size and presence of pigment indicates the greater
maturity of the parasite and may indicate a poorer prognosis.

36. Thin blood film from patient with malaria. Peripheral blood film from a
patient with vivax malaria showing mixed ring and schizont forms. The
ring forms are far more fleshy and ameboid and the cytoplasm of the
infected cell shows the characteristic regular and eosinophilic
Schьffner's dots, which help in diagnosis.

37. Thin blood film from patient with malaria. Peripheral blood film from a
patient with ovale malaria showing a small ring form on the left, which
could quite easily be mistaken for P. falciparum. The larger central
parasite has enlarged the cell into an oval shape and has also formed
a fimbriated fringe at the upper pole of the cell.

38. Thin blood film from patient with malaria. Peripheral blood film from a
patient with malariae malaria showing the characteristic rosette
schizont with daughter merozoites (usually eight) around a central
piece of pigment. The ring forms of this species characteristically form
a band stretching across the width of the red cell.

39. Treatment
Once a definitive diagnosis of malaria has been made
treatment with specific antimalarial drugs can be initiated.[29]
Non-falciparum malaria
Malaria due to P. vivax, P. ovale or P. malariae requires a
standard course of treatment with chloroquine, which usually
leads to defervescence. Chloroquine-resistant asexual forms
of P. vivax have recently been documented and may require
quinine treatment. In the case of P. vivax and P. ovale
malaria treatment with an 8-aminoquinoline (primaquine) is
given to eradicate the exoerythrocytic forms, especially the
hypnozoites responsible for relapses.
Treatment with primaquine should be delayed until after
delivery and/or breastfeeding in pregnant women.
Primaquine-resistant vivax hypnozoites have been identified
which require more prolonged (often 3 weeks) and higher
dose (22.5mg/day) therapy.
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40. Falciparum malaria
Mild falciparum malaria
In endemic areas the treatment of malaria in children
involves the use of drugs that are locally affordable and
appropriate. For this reason mild falciparum malaria in many
parts of Africa is still treated with chloroquine as for non-
falciparum malaria and recrudescences are treated with
pyrimethamine/sulfadoxine (Fansidar). For travelers and in
areas where there is resistance to chloroquine and
pyrimethamine/sulfadoxine, followed by the use of
pyrimethamine/sulfadoxine or doxycycline to eradicate
remaining asexual forms of the parasite. Mefloquine may be
used and more recently drug combinations such as
atovaquone with proguanil (Malarone) and
artemether/lumefantrine (Coartemether) have been
successfully used. Whichever drug is used, parasitemia may
paradoxically rise in the first 24–36 hours and is not generally
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41. Severe falciparum malariaSevere falciparum malaria
The management of severe falciparum malaria constitutes a
medical emergency.[29] The diagnosis needs to be confirmed
microscopically and intravenous access obtained as soon as
possible. Depending upon the clinical manifestations, the
investigations detailed in Table 166.5 should be carried out.
Patients with severe malaria should be transferred to the highest
possible level of clinical care (e.g. a high-dependency or intensive
therapy unit). Measurement of glucose and where possible lactate
and arterial blood gases should be performed in the initial
assessment. An effective antimalarial, at present quinine in most
cases, should be given intravenously by slow infusion. Meticulous
care must be given to fluid balance as both dehydration and
overhydration can occur as a result of the disease or treatment.
Convulsions should be treated with intravenous diazepam and
attention paid to hypoglycemia and hyponatremia. The routine use
of prophylactic anticonvulsants is unwarranted.
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42. There are a number of points
in the malaria parasite's life
cycle where the infection can be
interrupted. This mainly involves
reduced mosquito contact and
the use of antimalarial
chemoprophylaxis.
Vaccination against malaria is
currently not a reality.
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PREVENTION

43. Antimosquito measuresAntimosquito measures
In endemic areas those at risk should:
sleep in properly screened rooms;
use mosquito nets without holes and impregnated with
permethrin and tucked in carefully under the mattress before
nightfall;
wear long-sleeved clothing and long trousers when
outdoors after sunset; and
use other adjuncts — insect spray (usually containing
permethrin) and mosquito coils or repellents such as
diethyltoluamide, DEET or citronella.
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44. For those living in highly endemic areas, the use of
permethrin-impregnated bednets has been found to reduce
both malarial morbidity and mortality. However, problems
remain regarding cost, state of repair of the net, regular
impregnation and how the bednets might change the rate of
acquisition of immunity and consequently the pattern of
disease, especially relating to severity. By protecting the
very young against the severe manifestations of malaria, it is
argued that severe complications may be deferred until they
are older, but this remains a theoretic possibility only.
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45. Malarial chemoprophylaxisMalarial chemoprophylaxis
The spread of drug-resistant P. falciparum malaria and
awareness that some of the more effective combination
drugs, such as pyrime-thamine with sulfadoxine (Fansidar)
and pyrimethamine with dapsone (Maloprim) and
amodiaquine (Camoquin), may rarely have severe and
sometimes fatal side-effects have complicated malarial
chemoprophylaxis. The risk of contracting malaria in any
given country or situation needs to be weighed constantly
against the risk of a serious adverse reaction to any drug
used. In the absence of adequate data, this becomes
difficult. Compliance is of extreme importance because,
although those who comply poorly have a similar attack rate,
their risk of death is much greater than that of individuals on
no prophylaxis.
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46. Brief guidelines for the chemoprophylaxis of malaria
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47. Chemoprophylaxis should start 1 week before
entering an endemic area (to ensure adequate blood levels
and to evaluate any potential side-effects), and continue
while within such an area and for 4 weeks after return
except in the use of Malarone which can be commenced on
the day before entry into a malarious area and continue for a
week after leaving. Chloroquine, two tablets (300mg base)
once a week, together with proguanil, two tablets (200mg)
daily, is one of the safest and most inexpensive regimens,
but is of diminishing efficacy. These drugs have only minor
side-effects, the commonest being difficulty in visual
accommodation in the case of chloroquine and mouth ulcers
with proguanil.
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48. There is increasing use of mefloquine one tablet
(250mg) weekly, doxycycline one tablet (100mg) daily and
Malarone one tablet daily, by travelers to sub-Saharan
Africa, Papua New Guinea and the Solomon Islands
because of chloroquine resistance. The main side effects of
mefloquine are neuropsychiatric and are of varying severity.
Doxycycline can lead to light sensitization and
Malarone can cause gastroenterological upset.
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