Download malaria - Sun Yat

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.
2
▲ P. vivax and P.ovale-caused malaria often
relapse.
▲ P.falcipraum-caused malaria often shows
irregular fever, and may occur cerebral malaria.
3
▲ History
and now
An old disease, and an major health problems
in the tropics today.
 2000 years ago:
《黄帝内经·素问》有《疟论篇》和《刺论篇》等专篇:
Symptom and therapy about malaria were described
 In 1880: Laveran: found plasmodium in blood of
patient with malaria
 In 1897: Ross ---mosquitoes transmited malaria
4
 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
5
■ 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.
6
 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.
7
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
8
 Life cycle of plasmodium
9
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)
gametocytes
Periodic
paroxysm
RBC rupture
release merozoites
anopheles
(reproduce sexualy)
parasite debris, pigments and
metabolites
10
paroxysm
 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
12
 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
13
14
15
16
Anopheles mosquito
17
Anopheles mosquito
18
 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.
19
■ 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.
20
▲ 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.
21
▲ 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.
22
▲ Seasonality
Generally, malaria occurs in autumn and
summer, but no seasonality,and malaria
occur whole year in tropics and subtropics.
23
■ Pathogenesis and pathology
▲ Hepatocellular lesions, hepatomegaly,
abnormal liver functions.
▲Anemia and splenomegaly
Continuous attack results in anemia and
splenomegaly.
24
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.
25
Hepato-splenomegaly
survivors partially immune
often with splenomegaly
26
▲ 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.
27
▲ Mechanism of paroxysm
Erythrocytes rupture (hemolysis), release
parasite debris, pigments and metabolites
induce periodic paroxysm with shaking
chill, high fever and heavy sweating.
28
▲ 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
29
■ Clinical manifestations
1. Incubation period
2. Prodromal period
3. Clinical forms
Typical form, Mild form,
Cerebral malaria, Recrudescence,
Relapse.
30
▲ Incubation period
P. vivax and P. ovale 13~15 days
P. malariae 24~30 days
P. falciparum 7~12 days
31
▲ 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.
32
▲ 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 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.
33
 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.
34
 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.
35
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.
36
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.
37
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.
38
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.
39
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
40
■ 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.
41
▲ Nephropathic syndrome
usually occurs in cases of p. malariae
infection. Patients with hypertension,
edema, massive protein in urine, etc.
42
■ Diagnosis
▲ Epidemiological data
▲ Clinical manifestations
▲ Laboratory findings
43
▲ 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
44
▲ 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
45
Malaria – Thick Smear
46
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)
47
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)
48
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)
49
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)
50
 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.
51
■
Differential diagnosis
▲ septicemia
▲ leptospirosis
▲ typhoid fever
▲ bile duct infection
▲ Japanese encephalitis
▲ toxic form of shigellosis
52
▲ Septicemia
•Severe toxemia symptoms, with
primary inflammation focus
• Positive blood bacterial culture.
• Without periodic paroxysm and
intermittent period.
53
▲ 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.
54
▲ Typhoid fever:
Insidious onset, sustained fever, relative
bradycardia, rose spots, positive Widal’s
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.
55
▲ Japanese encephalitis and toxic form of
shigellosis:
should be considered in differential
diagnosis of cerebral malaria.
56
■
Prognosis
Good in ordinary cases.
Poor in cerebral malaria and Black Water
Fever.
57
■ Treatment
1. Symptomatic and supportive treatment
2. Etiologic treatment:
A.Control paroxysm treatment
B. Prevent relapse
C. Prevent transmission
58
▲ 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.
59
 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.
60
▲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
61
 Anti-paroxysm
kill reproducting plasmodia in RBC
 Prevent relapse:
kill bradysporozoite
primaquine, for 8 days
 Prevent transmission: kill gametocyte
primaquine for 3days
62
 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.
63
 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.
64
 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.
65
 Control paroxysm drugs and treatment
1>.Drugs
chloroquine --first choice for sensitive plasmodia
artesunate(青蒿琥酯) first choice for cerebral malaria
artemisinine(青蒿素)
pyromaridine phosphate(磷酸咯萘啶)
mefloquine(甲氟喹)
quinine sulfate (磷酸奎宁)
benflumethtolum(本勿醇)
arteflene(常山素)
naphthoquine phosphate(磷酸萘酚喹)
66
Artemisinine
(青蒿素)
67
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.
68
3>. chloroquine -resistant plasmodia
artesunate alone or combination with
benflumethtolum.
 mefloquine alone or combination with TMP.
 pyromaridine phosphate + pyrimethamine
(乙胺嘧啶)
artemisinine
69
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
70
▲ 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.
71
▲ 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 特芬喹 shows to kill
bradysporozoite and gametocyte.
0.3 /day for 7 days.
72
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 .
73
■ 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(多西环素) 0.2 qw
No vaccine is available
74
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
75
 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.
76
 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
77
 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
78