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MALARIA

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

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.

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

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

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.

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.

Life cycle of plasmodium


female anopheles and humans

Two hosts : 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

Infective sporozoite in female anopheles Schizont containing merozoites in human liver cells (reproduce asexualy)
(intraerythrocytic phase) (exoerythrocytic phase)

Mature schizont(merozoites) in human RBC


(reproduce asexualy) Periodic paroxysm gametocytes

RBC rupture
release merozoites
parasite debris, pigments and metabolites

(reproduce sexualy)

anopheles

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) Periodic paroxysm gametocytes female anopheles RBC rupture , release merozoites parasite debris, pigments and metabolites 11 clinical paroxysm human body

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 13~15 days P. malariae 24~30 days P. falciparum 7~12 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
1> 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 40C 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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2>.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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3>.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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4>.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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5>.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 Parasites Thin 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 Parasites Thin 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 Parasites Thin Blood Smears


1: Normal red cell 2-5: Young trophozoites 6-15: Trophozoites 16-23: Schizonts 24: Macrogametocytes (female) 25: Microgametocyte (male)

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Plasmodium malariae: Blood Stage Parasites Thin 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 antimalaria 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


1>.Drugs
chloroquine --first choice for sensitive plasmodia artesunate() first choice for cerebral malaria artemisinine()

pyromaridine phosphate()
mefloquine() quinine sulfate () arteflene() benflumethtolum()

naphthoquine phosphate()

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Artemisinine ()

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2>. chloroquine-sensitive plasmodia


a>.chloroquine phosphate
first choice

2.5g divided into three days, orally, 1.0g initially,


0.5g q12h for three times.

b>.artesunate
100mg bid orally for the first day, 100mg qd for the next 4 days, total amount is 600mg.

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3>. chloroquine -resistant plasmodia artesunate alone or combination with


benflumethtolum.

mefloquine alone or combination with TMP.

pyromaridine phosphate + pyrimethamine


() artemisinine

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4>. 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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