MALARIA

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MALARIA

• Department of Infectious Diseases
• Third Affiliated Hospital
• Sun Yat-sen University
• Lin Yang

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Definition

• ? A parasitic diseases caused by plasmodium
• species.
• ? Transmitted by the bite of infected female
  
• anopheline mosquitoes.
• ? Characterized by periodic paroxysm with
• shaking chills, high fever, heavy sweating.
  
• ? Anemia and splenomegaly in cases suffering
• from several attack of paroxysm.

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• ? P. vivax and P.ovale-caused malaria often
• relapse.
• ? P.falcipraum-caused malaria often shows
• irregular fever, and may occur cerebral
  malaria.

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? History and now An old disease, and an
major health problems in the tropics today.
? 2000 years ago ?????????????????
Symptom and therapy about malaria were
described ? In 1880 Laveran found plasmodium
in blood of patient with malaria ? In
1897 Ross ---mosquitoes transmited malaria
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• ? Be epidemic in 92 countries and area
• ?New cases of malaria a year 300 to 500
  millions
• ?About two millions cases die a year
• ?About one million children die of malaria a year
• ?In China
• In 2000 25,520 cases
• 42 cases died

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• Etiology
• ? Four species of plasmodium cause malaria
• in human.
• P. vivax, P. ovale.
• P. malariae P. falciparum
• Each species has its own morphologic,
  biologic,
• pathogenic, and clinical characteristics.

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• ? P.vivax is the most common.
• ? P. falciparum--- the most strong pathogenicity
  
• causes the cerebral malaria,
• causes the chief mortality,
• presents the therapeutic problem of
  
• chloroquine resistance.

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? Life cycle of plasmodium ?Two hosts
female anopheles and humans ? Two types of
reproduction asexual reproduction in
human Humans as intermediate
host sexual reproduction in female
anopheles Female anopheles as
final host
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? Life cycle of plasmodium
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Infective sporozoite in female anopheles
(exoerythrocytic phase)
Schizont containing merozoites in human liver
cells (reproduce
asexualy)
(intraerythrocytic phase)
Mature schizont(merozoites) in human RBC
(reproduce asexualy)
Periodic paroxysm
RBC rupture release
merozoites parasite debris, pigments and
metabolites
gametocytes
anopheles
(reproduce sexualy)
paroxysm
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? Life cycle of plasmodium in human (In female
anopheles) infective sporozoite
blood circulation of human human liver
cells schizont containing merozoites
(tachysporozoites for 1-2 weeks,
bradysporozoites for 3- 6 months relapse,
exoerythrocytic phase) pour into blood
circulation by liver cell rupture
invade RBC merozoite ring form
trophozoite schizont containing
merozoites (intraerythrocytic phase)

gametocytes
female anopheles RBC rupture , release
merozoites parasite debris, pigments and
metabolites
Periodic paroxysm
clinical paroxysm
human body
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• ? Development of plasmodium in anopheles
• gametocytes in blood circulation of human
• female anopheles by bite, sexual reproduction
  
• (gametocytes zygote ookinete
  oocyst
• containing sporoblasts infective
  sporozoite )
• humans blood circulation by bite

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• ? life cycle in RBC and periodic paroxysm
• Clinical periodic paroxysm depend on life
  cycle
• of plasmodium in erythrocytes .
• Different plasmodium, the length of life
  cycle in
• RBC is different, so the interval of periodic
  
• paroxysm is different.
• P. vivax, and P. ovale 48hour
• P. malariae 72hour
• P. falciparum 36-48hrs, and irregular

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Anopheles mosquito
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Anopheles mosquito
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? Types of sporozoites and relapse Relapse
---Appear clinic signs of malaria about three
to six months or longer after
primary attack. P. vivax and P. ovale
two types of sporozoites
tachysporozoites---induce primary attack
bradysporozoites--- result in relapse P.
malariae and P. falciparum only
tachysporozoites ,without bradysporozoites,
No relapse in malaria caused by P. malariae
and P. falciparum.
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• Epidemiology
• ?Source of infection patients and carriers
• ? Route of transmission
• bite by infected female anopheles.
• occasionally, inoculation of blood, e.g.
  blood
• transfusion congenital infection .
• ? Susceptibility Universal, all ages and
  both sexes are susceptible to plasmodium.

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• ? Immunity
• ? species specific, strain specific,
• ? last for a short time only.
• ? No across protective immunity,
• For example immunity to P. falciparum does
  
• not protect from P.vivax.
• ?Immunity usually does not prevent from
• reinfection, but reduce the severity of the
  
• diseases or lead to an asymptomatic
  infection.

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• ? Distribution
• ? geographic distribution
• malaria is endemic in the tropics and
  subtropics,
• distribution in countries of Africa, Asia and
  Latin
• America
• ? In China several provinces
• ? P. vivax is the most common in epidemic area,
  
• and in China.

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• ? Seasonality
• Generally, malaria occurs in autumn and
  summer, but no seasonality,and malaria occur
  whole year in tropics and subtropics.

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• Pathogenesis and pathology
• ? Hepatocellular lesions, hepatomegaly,
• abnormal liver functions.
• ?Anemia and splenomegaly
• Continuous attack results in anemia and
• splenomegaly.

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• ?Anemia is caused by hemolysis of infected
  erythrocytes.
• Severe acute hemolytic anemia may occur in
  patients infected with very high parasitemia, or
  patients with G-6-PD deficiency.
• ? Splenomegaly and hepatomegaly
• Result from the marked mononuclear
• hyperplasia after the rupture of erythrocytes.

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Hepato-splenomegaly
survivors partially immune often with
splenomegaly
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• ? Necrosis of tissue cells, especially in the
  brain.
• Agglutination tendency of infected red
• blood cells and damage of vascular
• endothelial cells may cause thrombosis,
• and then result in necrosis of tissue cells.

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? Mechanism of paroxysm Erythrocytes
rupture (hemolysis), release parasite
debris, pigments and metabolites induce
periodic paroxysm with shaking chill, high
fever and heavy sweating.
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• ? Mechanism of severe malaria
• Most of severe malaria occur in falciparum
  malaria.
• The damage of vascular endothelium and
• agglutination of infected RBC obstacle
• in the microcirculation necrosis of
  tissue cells.
• P.vivax and P. ovale invade young RBC
• P. malariae invade old RBC
• P. falciparum invade all RBC

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• Clinical manifestations
• 1. Incubation period
• 2. Prodromal period
• 3. Clinical forms
• Typical form, Mild form,
• Cerebral malaria, Recrudescence,
• Relapse.

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• ? Incubation period
• P. vivax and P. ovale 1315 days
• P. malariae 2430 days
• P. falciparum 712 days

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• ? Prodromal period
• many patients experience a prodromal
• period, occur in several days before the
• onset of paroxysm.
• nonspecific symptoms, such as malaise,
• headache, myalgia, fatigue, poor appetite,
  etc.

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• ? Clinical forms
• 1gt Typical form
• Periodic attack of paroxysm with shaking
  chills-- high fever--heavy sweating.
• ? Shaking chills last for 20 min to 1 hrs,
• ? high fever T rise to or over 40?C for 2 to 6
  h,
• with severe headache, myalgia, and skin
• becomes warm and dry.
• ? heavy sweating last for 30 min to 1 h,
• anemia and moderate splenomegaly in cases
• with several paroxysms.

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• ? Intermittent period
• fatigue or being asymptomatic
• Intermittent period (interval of attack) is
  determined
• by the length of asexual erythrocytic cycle
• P. vivax and P. ovale , about 48 hrs---
• paroxysm attack every other
  day
• P. malariae, about 72 hours
• paroxysm attack every three
  days
• P. falciparum , 36-48 hours
• paroxysm attack every 36 to
  48 hrs
• In early stage of paroxysm, intermittent
  period may irregular.

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• ? Physical examination
• Anemia and splenomegaly in patients after
• several paroxysms.
• Tender hepatomegaly in less frequently.
• Other physical findings
• Jaundice, urticaria, petechial, rash,
  etc.
• may be seen in less frequently.

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• 2gt.Mild form
• Often seen in patients living in endemic
  region of malaria.
• Clinical manifestations of paroxysm are not so
  typical. Symptoms are milder, and persistent time
  is shorter.

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• 3gt.Cerebral malaria
• ? The most serious type of malaria.
• ? generally caused by P. falciparum.
• ? Clinical manifestations including High fever,
• headache, vomiting, delirium, convulsion,
• coma, positive pathological reflexes.
• Examination of CSF usually show normal.

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• 4gt.Recrudescence
• Appear clinic signs of malaria a short time
  after primary paroxysm.
• Induced by non-standard pathogenic therapy or
  drug resistant plasmodium (merozoites ).
• Parasites in red blood cells were suppressed
  by specific drugs, or immunity, but not
  eradicated, and proliferated again after a short
  time, and induce clinical manifestations.

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• 5gt.Relapse
• appear clinic signs of malaria about three
• to six months or longer after primary attack.
  
• caused by bradysporozoites of P. vivax
• and P. ovale.

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• Relapse Recrudescence
• three to six months or longer short
  time
• after primary attack after
  primary attack
• Caused by bradysporozoites non-eradicated
  parasite
• P. vivax and P. ovale. Four
  species of
  
• 
  plasmodium
• 
  non-standard therapy
• 
  or drug resistance

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• Complications
• ? Hemolytic urinemic syndrome
• (Black water fever)
• Often occur in patients with G-6-PD
  deficiency,
• may be induced by primaquine treatment or by
  
• heavy infection(high parasitemia) with P.
  falciparum or an atypical immune response during
  reinfection.
• Massive RBC rupture and hemolysis.
• Shows hyperhemoglobinemia lumbago,
  malarial hemoglobinuria, anemia, jaundice, acute
  renal failure.

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• ? Nephropathic syndrome
• usually occurs in cases of p. malariae
  infection. Patients with hypertension, edema,
  massive protein in urine, etc.

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• Diagnosis
• ? Epidemiological data
• ? Clinical manifestations
• ? Laboratory findings

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• ? Epidemiological data
• History of living in or traveling to
  epidemic areas. History of blood transfusion.
• Neonates was born by malaria mothers.
• ? Clinical manifestations
• Periodic paroxysms with shaking chills, high
  fever, sweating. Anemia and splenomegaly may
  present.
• Fever patterns may be irregular in some cases

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• ? Laboratory findings
• ? WBC, RBC, Hb.
• Normal white blood cell count, decreased
  red blood
• cell count and hemoglobin level.
• ? Thick and thin blood smear (Giemsa stain)
• Plasmodium species are found in thick and
  thin
• blood smear, or bone marrow smear.
• --------Definitive diagnosis
  
• Thick and thin blood smear are very simple
  and
• important

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Malaria Thick Smear
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Plasmodium falciparum Blood Stage ParasitesThin
Blood Smears
1 Normal red cell 2-18 Trophozoites ( 2-10
ring-stage trophozoites)  19-26 Schizonts ( 26
is a ruptured schizont)  27, 28
Mature macrogametocytes (female)
29, 30 Mature microgametocytes
(male)
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Plasmodium vivax Blood Stage ParasitesThin
Blood Smears
1  Normal red cell  2-6  Young trophozoites
(ring stage parasites)  7-18 
Trophozoites 19-27  Schizonts 28,29 
Macrogametocytes (female) 30
 Microgametocyte (male)
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Plasmodium ovale Blood Stage ParasitesThin
Blood Smears
1  Normal red cell 2-5 Young trophozoites
6-15  Trophozoites  16-23  Schizonts 24 Macrog
ametocytes (female) 25 Microgametocyte
(male)
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Plasmodium malariae Blood Stage ParasitesThin
Blood Smears
1 Normal red cell 2-5 Young trophozoites
(rings) 6-13  Trophozoites  14-22 
Schizonts 23 Developing gametocyte  24
Macrogametocyte (female) 25 
Microgametocyte (male)
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• ? Serologic tests not so important
• Test antibody against plasmodium
• ? Test DNA of plasmodium by PCR
• high sensitivity
• ? Therapeutic trial is not advocated
• because of the side effects of
• chloroquine and primaquine.

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• Differential diagnosis
• ? septicemia
• ? leptospirosis
• ? typhoid fever
• ? bile duct infection
• ? Japanese encephalitis
• ? toxic form of shigellosis

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• ? Septicemia
• Severe toxemia symptoms, with
• primary inflammation focus
• Positive blood bacterial culture.
• Without periodic paroxysm and
• intermittent period.

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• ? Leptospirosis
• The history of contacting contaminated
• water or wet soil,
• enlargement of lymph nodes, persistent
• high fever, myalgia of the calf muscle.
• Positive agglutination-lyse test for
• antibodies against leptospira species.

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• ? Typhoid fever
• Insidious onset, sustained fever, relative
• bradycardia, rose spots, positive Widals
• reaction and positive blood culture for
• salmonella typhi.
• ? Biliary ducts inflammation
• sudden onset, with high fever, colic pain
  in
• right upper part of abdomen, jaundice.
• Utrasonography will be very helpful for
• making the diagnosis.

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• ? Japanese encephalitis and toxic form of
• shigellosis
• should be considered in differential
• diagnosis of cerebral malaria.

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• Prognosis
• Good in ordinary cases.
• Poor in cerebral malaria and Black Water
• Fever.

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• Treatment
• 1. Symptomatic and supportive treatment
• 2. Etiologic treatment
• A.Control paroxysm treatment
• B. Prevent relapse
• C. Prevent transmission

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• ? Symptomatic and supportive treatment
• High fever, convulsion, cerebral edema,
• black water fever, etc.
• ? Keep warm for shaking chill
• ? Physical and chemical defervescent methods
• for high fever, such as ice bag, air
  condition.
• Corticosteroid may be given , if necessary.
  
• ? diazepam and wintermin for convulsion.

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• ? 20 Mannitol injection fluid intravenous
• quickly for cerebral edema Dextran also
• is useful for cerebral malaria.
• ? For black water fever, withdraw all anti-
• malaria drug, and giving dexamethason,
• small amount of blood transfusion. Giving
• sodium bicarbonate, and must keep more
• than 2000ml urine output per day.

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• ?Etiologic treatment
• ? Treatment principle
• 1.Combination anti-paroxysm treatment with
• preventing from relapse and transmission
  
• treatment
• 2. Ordinary examining G-6-PD before giving
• primaquine.
• primaquine only is given in these patients
  
• without G-6-PD deficiency

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• ? Anti-paroxysm
• kill reproducting plasmodia in RBC
• ? Prevent relapse kill bradysporozoite
• primaquine, for 8 days
• ? Prevent transmission kill gametocyte
• primaquine for 3days

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? For P. vivax and P. ovale malaria Anti-
paroxysm drugs and primaquine ( for 8 days)
must be given to control paroxysm, prevent
from relapse and transmission.
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• ? For P.falciparum and P. malariae-caused malaria
• Anti-paroxysm drugs and primaguine (for 2-4
• days) must be given to control paroxysm and
• to kill gametocyte for prevent from
• transmmision although prevent from relapse
• is not necessary.

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• ? It is necessary to examine G-6-PD before
  giving primaquine because primaquine may induce
  acute intravascular hemolysis in patients with
  G-6-PD deficiency.

primaquine only is given in these patients
without G-6-PD deficiency.
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• ? Control paroxysm drugs and treatment
• 1gt.Drugs
• chloroquine --first choice for sensitive
  plasmodia
• artesunate(????) first choice for cerebral
  malaria
• artemisinine(???)
• pyromaridine phosphate(?????)
• mefloquine(???) quinine sulfate (????)
• benflumethtolum(???) arteflene(???)
• naphthoquine phosphate(?????)

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Artemisinine (???)
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2gt. chloroquine-sensitive plasmodia
agt.chloroquine phosphate first choice
2.5g divided into three days, orally, 1.0g
initially, 0.5g q12h for three times.
bgt.artesunate 100mg bid orally for the
first day, 100mg qd for the next 4 days,
total amount is 600mg.
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• 3gt. chloroquine -resistant plasmodia
• ?artesunate alone or combination with
• benflumethtolum.
• ? mefloquine alone or combination with TMP.
• ? pyromaridine phosphate pyrimethamine
• (????)
• artemisinine

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• 4gt. Control paroxysm for cerebral malaria
• ? artesunate first choice
• 60mg 5 sodium bicarbonate solution,
• First, slowly intravenous drip, then, given
  orally for
• 2-3 days after recovering from unconscious.
• ? chloroquine (sensitive plasmodia)
• ? pyromaridine phosphate quinine

slowly intravenous drip, then given orally
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• ? Prevent relapse kill bradysporozoite
• primaquine 39.6mg(22.5mg base) qd, orally, for
  8
• days for P. vivax and P. ovale caused malaria
  to
• prevent replase.
• For P.falciparum and P.malariae-malaria,
• prevent replase is not necessary, but
  primaquine
• still must be given for 3 days to kill
  gametocytes
• for preventing transmission.

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• ? Prevent transmission
• primaquine 39.6mg(22.5mg base), qd, orally,
• for 3 days, for interrupting transmission of
• P. falciparum malaria and P. malariae
• malaria by kill gametocytes.
• Another drug tafenoquine ??? shows to kill
• bradysporozoite and gametocyte.
• 0.3 /day for 7 days.

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Summary for etiologic treatment
? First, giving a kind of drugs to kill
reproducting plasmodia to control paroxysm,
then, examining G-6-PD. If G-6-PD is normal,
the drug primaquine killing bradysporozoite
and gametocyte must be given to prevent
relapse and transmission.
? primaguine is given in these patients without
G-6-PD deficiency .
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• Prophylaxis
• 1.Treatment of patients and carriers
• 2.Control mosquito vectors
• 3. Individual protection
• Avoid mosquito bite
• chemoprophylaxis with drug
• chloroquine phosphate 0.5 qw
• pyrimethamine 0.25 qw
• doxycycline(????) 0.2 qw

No vaccine is available
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Summary

• ?Malaria is a parasitic diseases caused by
  plasmodium species, and transmitted by the bite
  of infected female anopheline mosquitoes.
• ? Be caused by four species of plasmodium
• P. vivax, P. ovale. P. malariae P.
  falciparum
• ? Occur major in tropic and subtropic area
• ? All person are susceptible, and no last
  immunity
• ? Life cycle of plasmodium
• two hosts, two types of reproduction

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• ? The clinical features
• periodic paroxysm with shaking chills, high
  fever,
• heavy sweating. Anemia and splenomegaly
  in
• some of cases . Cerebral malaria.
• ? Relapse and Recrudescence
• ? Definite diagnosis Plasmodium species is
  found in
• thick and thin blood smear, or bone marrow
  smear.

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? Etiologic treatment principle
1.Combination anti-paroxysm with prevent
replase and transmission treatment 2.
Examining G-6-PD before giving primaquine. ?
Control paroxysm treatment,
1.chloroquine-sensitive plasmodia first
choice chloroquine 2.chloroquine -resistant
plasmodia 3. Control paroxysm for cerebral
malaria artesunate, first choice
chloroquine (sensitive plasmodia)
slowly intravenous drip ,then orally
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? Prevent relapse kill bradysporozoite
primaquine, for 8 days ? Prevent
transmission kill gametocyte primaquine
for 3days primaguine only is given in these
patients without G-6-PD deficiency .
Prophylaxis No vaccine is available
1.Treatment of patients and carriers
2.Control mosquito vectors 3. Individual
protection Avoid mosquito bite
chemoprophylaxis
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