Malaria

PROF DR. HJ. WAN OMA

ABDULLAH, JSM
 MALARIA
• 40% of the world’s population live in endemic areas
• 300-500 million clinical cases per year
• 1.5-2.7 million deaths (90% Africa)
• increasing problem (re-emerging disease)
• resurgence in some areas
• drug resistance ( mortality)
• causative agent = Plasmodium species
• protozoan parasite
• member of Apicomplexa (sub-phylum)
• 4 species infecting human; P.falcifarum (malignant malaria), P.vivax
and P.ovale (benign tertian) and P malariae (quartan)
• transmitted by female anopheline mosquitoes
• In Malaysia: An.maculatus -most important vector in hills and mountains,
An.sundaicus: brackish water,
An. balabacensis & A. leucospyrus in deep jungles of Sabah
and Sarawak
Primate (Simian) Malaria or Monkey Malaria.

A number of Plasmodium species infect primates. Molecular analysis reveals P.

knowlesi of monkey does infect man. P. knowlesi is closely related to P.
malariae in term of genetic make up. Morphologically these two species are
indistinguishable. Microscopic misidentification as P. knowlesi as P. malariae
has led to misdiagnosis of many quartan malaria cases in the past.
Clinically, P. knowlesi in man causes symptoms similar with other species of
Plasmodium spp.
 Epidemiology
Endemic in most Southeast Asia,
Latin America and sub-Saharan
Africa (90% in Africa)
In Malaysia – interior parts of
Peninsular Malaysia (P.vivax = P.f),
rural areas of Sabah (P.falciparum)
and Sarawak (P.vivax)
Sporadic cases – “imported cases”,
foreign /immigrant workers
Most prevalence– forest areas, land
schemes (eg Felda)
P.f > P.v > mixed > P.m
P.falciparum more in Sabah
Cases in Malaysia Until 2001:

1997: 26 649 Rajah 1 : Taburan Penyakit Bawaan Vektor Utama di

Malaysia 1990-2001
1998 : 13 491
80000

1999 : 11 106 60000

BilanganKes

40000
20000
2000 : 12 705
0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
2001 : 11 604 Tahun

DENGUE FEVER DHF MALARIA

 Transmission
• sporozoites injected with
saliva when mosquitoes
feeds on human.
• enter circulation
• Blood transfusion
• Contaminated syringes
• From mother to fetus
(congenital)

Female Anopheles Mosquito

 Life Cycle in 2 Hosts:
• 1.Sporogony: the sporulating sexual
cycle in the mosquito
• 2.Schizogony : asexual cycle in
vertebrate host:
• Exoerythocytic cycle (hepatic cycle);
intraerythocytic cycle (erythrocytic
cycle)
• sporozoites injected during mosquito
feeding
• invade liver cells- SCHIZONT
• exoerythrocytic schizogony (merozoites)
• merozoites invade RBCs
• repeated erythrocytic schizogony
• gametocytes infective for mosquito
• fusion of gametes in gut
• sporogony on gut wall in hemocoel
• sporozoites invade salivary glands
Exoerythrocytic Schizogony
• hepatocyte invasion
• asexual replication
• 6-15 days
• 1000-10,000 merozoites
• no overt pathology
 Hyponozoite Forms
• some EE forms exhibit delayed replication
(i.e, dormant)
• merozoites produced weeks-to-months after
initial infection
• only P. vivax and P. ovale  Relapse
• Recrudesence : increase in parasite that has
persisited at low levels in the blood, e.g. P.
malariae

relapse = hypnozoite
recrudescence = subpatentt
 Erythrocytic
Schizogony
• intracellular parasite
undergoes trophic phase
• young trophozoite is ‘ring
P. falcifarum form’
• P.falcifarum infect RBC of all
ages, P.vivax/P.ovale infect
reticulocytes.
• Metabolize host hemoglobin
hemozoin (malarial
pigment)
P.vivax
Erythrocytic Schizogony
• nuclear division to
become an early
schizont stage
• 6-40 nuclei
• budding merozoites @
segmenter
• erythrocyte rupture to
release merozoites
pyrexia (fever)
erythrocytic schizogony
• 48 hr in Pf, Pv, Po
• 72 hr in Pm

gametocytes
Trophozoites transform
gametocytes
• induction is still unknown
• drug treatment  #'s
• immune response  #'s
• transformationgametogenesis
• Pf : ~10 days
• others: ~same as schizogony(3-4 days)
• sexual dimorphism
• Microgametocytes (male)
• Macrogametocytes (female)
• Do not cause pathology
• infective stage for mosquito
 Sporogony

• The sexual cycle

• occurs in mosquito (9-21 d); Microgamet
(Exflagelation)
• fusion of micro- and macrogametes
• zygote  ookinete (~24 hr)
• ookinete penetrate gut epithelium ('trans-
invasion')
• ookinete  oocyst
•between epithelium and basal lamina
• asexual replication  sporozoites
• Released sporozoites
• migrate through hemocoel
• sporozoites 'invade' salivary glands
EXFLAGELATION

• ‘exflagellation’ occurs in
mosquito gut, whereby
Microgametocyte undergo
• 3X nuclear replication
• 8 microgametes formed
Invasive Stages:
Merozoite
• erythrocytes
Sporozoite
• salivary glands
• hepatocytes
Ookinete
• epithelium
 Clinical Features
• characterized by acute febrile attacks (malaria
paroxysms)
• periodic episodes of fever alternating with
symptom-free periods
• manifestations and severity depend on species and
host’s status
• immunity, general health, nutritional state,
genetics
• Recrudescence and relapse signify increase in
parasites persisted at low level in blood &
parasitemia develops from EE stages in liver.
• Malaria causes severe complications especially P.
falciparum; cerebral malaria fatal in young
children.
 Malaria
Paroxysm
• The classic periodic fever paroxysm
consists : 1. Prodromal : malaise,
myalgias, viral like syndrome.2.
Cold (chill) stage – shivering stage
3. Hot stage : 102-104 0F 4.
sweating stage : resolution of fever,
severe fatigue and patient go to sleep
• paroxysms associated with
synchrony (cycle) of merozoite
release
• temperature is normal between
paroxysms and patient feels well
• P. falciparum may not exhibit
classical paroxysms (continuous
fever)
Chills
Rigors
Fever
Perspiration
Fatigue
Headache
Delirium
Confusion
Coma
Shortness of
breath
Anemia
Splenomegaly
Black urine
 Disease Severity
Pv Po Pm Pf
Paroxysm moderate mild to
mild severe
Severity to severe moderate
Average 50,000-
20,000 9,000 6,000
(per mm3) 500,000
Maximum
50,000 30,000 20,000 2,500,000
(per mm3)
Anemia ++ + ++ ++++
Duration
Disease 3-8 w 2-3 w 3-24 w 2-3 w
Infection 5-8 y* 12-20 m* >20 y 6-17 m
Complications renal cerebral**
*true relapses ( recrudescence) due to dormant hypnozoite
stage in liver **plus many other organs
Treatment
 Choose the appropriate blood/tissue
schizonticide; need to expect resistance
pattern of the organism, severity of infection,
and patient’s background eg. immune status.
 In severe cases, patient will need to be closely
monitored for complications such as
hypoglycemia, anemia, seizures, septicemia,
renal failure, acidosis and respiratory failure.
 Indication of blood transfusions, hemodialysis,
mechanical ventilation and antibiotics.
Antimalarial Drugs
 Treatment: to clear  Prophylaxis: to
parasitemia
 Chloroquine protect from
 Fansidar (Sulfadoxine/ infection
pyrimetamine)
 Quinine  Chloroquine
 Artesunate  Daraprim
 Doxycycline
 Malarone  Proguanil
 Primaquine
 Artemesinin derivatives;
artesunate, artemether and
arte-ether
Chloroquine Resistance
 Frequent in P.falcifarum in most parts of
world outside of Central America and the
Caribbean
 P.vivax resistance in SEA and Amazon
 Multiple drug resistant strains exist
especially in Thailand and border areas.
 Summary on Antimalaria Chemotherapy

1. Chloroquine phosphate- Treatment of uncomplicated attacks

(except resistant P. falciparum).
2. Alternatively, Amodiaquine dihydrochloride
3. Prevention of relapses – Primaquine phosphate; Primaquine is
the only drug effective against persisting EE liver stages.
6. Infections of P. f resistant to chloroquine are treated by
combined therapy:
a. Quinine sulfate  pyrimethaminesulfadiazine or
b. Quininetetracycline/clindamycin.
7. Mefloquine is effective against P..f that is resistant to all known
drugs, including quinine
 Laboratory Diagnosis
 Thin and thick blood film;
 shape and size of trophozoite,
schizont, gametocyte,
 size of RBCs which contain
parasites ;P.vivax and P. ovale
(infect younger RBC,
enlargement of RBC)
 Metabolic debris in RBC around
the parasites (Schuffner’s dot in
P.vivax infection)
 QBC-flourescence
microscopy
 P. malariae trophozoite (band form) and P. ovale
 Indirect Diagnosis
 Serological: antibody/antigen detection assay;
ELISA, IFAT
 Molecular Bio.Techniques; PCR, DNA probe
(mainly as research tools)
Control and Prevention
 Personal protection against vectors
 Evening and night behavior (bite at night)
 Mosquito nets
 Mosquito repellants
Vector Control
 Biological control
Bacteria: Bacillus thuringiensis, Bacillus sphaericus
 Chemical control
Larvicidal
 Organophosphates-temephos,Abate 500E
Adulticidal
 DDT residual spraying once in 6 month,endemic area once
in 3 month, nowadays DDT has been banned in many
countries
 Malathion
 Phyrethroids; impregnated bednets
 Thermal fogging or ultra-low-volume (ULV)
Chemoprophylaxis: for those
entering malarious areas.
 Should be given 1-2 weeks before
traveling to endemic areas.
 Should be continued during travel and
after leaving endemic areas.
 Chloroquine
 Doxycycline
 Mefloquine
 REVIEW QUESTIONS
MCQ (T & F)

1. The following are invasive stages of human malarial parasites

A. Ookinete
B. Sprozoite
C. Merozoite
D. Trophozoite
E. Gametocytes

2. The following are clinical symptoms of malaria

A. Anemia
B. Splenomegaly
C. Fever
D. Keratitis
E. Adenolymphagitis
3. The following are routinely performed diagnostic procedures for malaria.
A. Polymerase Chain Reaction
B. DNA probe
C. Immunosassay
D. Microscopic detection in blood smears
E. Liver biopsy

4. Regarding malarial parasites:

A. Febrile paroxysm in quartan malaria is every 48 hours interval.
B. Accurate identification of species is by morphological features.
C. P. knowlesi, a monkey malaria was misdiagnosed as P. malariae in the past.
D. Malignant tertian malaria is caused by P. vivax.
E. Chloroquin phosphate is effective against liver schizont.
 OSPE

An American tourist returned to USA after a vacation in Sarawak. Few months

later he experienced severe febrile attacks and was admitted to ICU of Mayo
Clinic. Microscopic examination of his blood smear
revealed infected RBC as shown.

a. Identify the parasite (genus and species)

b. Explain the pathogenesis of fever in this
patient.
c. List two clinical complications that could
arise from infection with this parasite.