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Malaria Pathogenesis and
Clinical Presentation
Gail Stennies, MD, MPH
Malaria Epidemiology Branch
May, 2002
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Plasmodiumspecies which
infect humans
Plasmodium vivax(tertian)
Plasmodium ovale(tertian)
Plasmodium falciparum(tertian)
Plasmodium malariae(quartian)
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Exo-erythrocytic(hepatic) cycle
Sporozoites
Mosquito SalivaryGland
Malaria LifeCycleLife Cycle
Gametocytes
Oocyst
ErythrocyticCycle
Zygote
Schizogony
Sporogony
Hypnozoites(for P. vivaxand P. ovale)
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Malaria Transmission Cycle
Parasite undergoes
sexual reproduction in
the mosquito
Some merozoites
differentiate into male or
female gametocyctes
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts
Dormant liver stages
(hypnozoites) of P.
viv ax and P. ovale
Exo-erythrocytic (hepatic) Cycle:
Sporozoites infect liver cells and
develop into schizonts, which release
merozoites into the blood
MOSQUITO HUMAN
Sporozoires injected
into human host during
blood meal
Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands
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Components of the Malaria Life Cycle
Mosquito Vector
Human Host
Sporogonic cycle
Infective Period
Mosquito bites
gametocytemic
person
Mosquito bites
uninfectedperson
Prepatent Period
Incubation Period
Clinical Illness
Parasites visible
Recovery
Symptom onset
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Exo-erythrocytic (tissue) phase
Blood is infected with sporozoites about 30
minutes after the mosquito bite
The sporozoites are eaten by macrophages
or enter the liver cells where they multiply
pre-erythrocytic schizogeny
P. vivaxandP. ovalesporozoites form
parasites in the liver called hypnozoites
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Exo-erythrocytic (tissue) phase
P. malariaeorP. falciparum sporozoites do
not form hypnozites, develop directly into
pre-erythrocytic schizonts in the liver
Pre-erythrocytic schizogeny takes 6-16 dayspost infection
Schizonts rupture, releasing merozoites
which invade red blood cells (RBC) in liver
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Relapsing malaria
P. vivax and P. ovale hypnozoites remain
dormant for months
They develop and undergoe pre-
erythrocytic sporogeny
The schizonts rupture, releasing merozoites
and produce clinical relapse
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Exo-erythrocytic(hepatic) cycle
Sporozoites
Mosquito SalivaryGland
Malaria LifeCycleLife Cycle
Gametocytes
Oocyst
ErythrocyticCycle
Zygote
Schizogony
Sporogony
Hypnozoites(for P. vivaxand P. ovale)
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Exo-erythrocytic (tissue) phase
P. vivax and P. ovale hypnozoites remain
dormant for months
They develop and undergoe pre-
erythrocytic sporogeny
The schizonts rupture, releasing merozoites
and producing clinical relapse
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Erythrocytic phase
Pre-patent periodinterval between date ofinfection and detection of parasites in peripheral
blood
Incubation periodtime between infection and
first appearance of clinical symptoms
Merozoites from liver invade peripheral (RBC)and develop causing changes in the RBC
There is variability in all 3 of these featuresdepending on species of malaria
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Erythrocytic phase
stages of parasite in RBC
Trophozoites are early stages with ring form theyoungest
Tropohozoite nucleus and cytoplasm divide
forming a schizont Segmentation of schizonts nucleus and
cytoplasm forms merozoites
Schizogeny complete when schizont ruptures,
releasing merozoites into blood stream, causingfever
These are asexual forms
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Erythrocytic phase
stages of parasite in RBC
Merozoites invade other RBCs and
schizongeny is repeated
Parasite density increases until hostsimmune response slows it down
Merozoites may develop into gametocytes,
the sexual forms of the parasite
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Schizogenic periodicity and fever
patterns
Schizogenic periodicity is length of asexualerythrocytic phase
48 hours inP.f.,P.v., andP.o.(tertian)
72 hours inP.m. (quartian) Initially may not see characteristic fever pattern if
schizogeny not synchronous
With synchrony, periods of fever or febrile
paroxsyms assume a more definite 3 (tertian)- or4 (quartian)- day pattern
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Clinical presentation
Early symptoms
Headache
Malaise
FatigueNausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent Could mistake for influenza or gastrointestinal
infection
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Clinical presentation
Acute febrile illness, may have periodic febrileparoxysms every 4872 hours with
Afebrile asymptomatic intervals
Tendency to recrudesce or relapse over months toyears
Anemia, thrombocytopenia, jaundice,hepatosplenomegaly, respiratory distress
syndrome, renal dysfunction, hypoglycemia,mental status changes, tropical splenomegalysyndrome
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Clinical presentation
Early symptoms
Headache
Malaise
FatigueNausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent Could mistake for influenza or gastrointestinal
infection
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Clinical presentation
Signs
Anemia
Thrombocytopenia
Jaundice Hepatosplenomegaly
respiratory distress syndrome
renal dysfunction
Hypoglycemia Mental status changes
Tropical splenomegaly syndrome
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Types of Infections
Recrudescence
exacerbation of persistent undetectable parasitemia, dueto survival of erythrocytic forms, no exo-erythrocyticcycle (P.f., P.m.)
Relapse
reactivation of hypnozoites forms of parasite in liver,separate from previous infection with same species(P.v. and P.o.)
Recurrence or reinfection
exo-erythrocytic forms infect erythrocytes, separatefrom previous infection (all species)
Can not always differentiate recrudescence fromreinfection
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Clinical presentation Varies in severity and course
Parasite factors Species and strain of parasite
Geographic origin of parasite
Size of inoculum of parasite
Host factors Age
Immune status
General health condition and nutritional status
Chemoprophylaxis or chemotherapy use Mode of transmission
Mosquito
Bloodborne, no hepatic phase (transplacental,
needlestick, transfusion, organ donation/transplant)
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Malarial Paroxysm
Can get prodrome 2-3 days before Malaise, fever,fatigue, muscle pains, nausea, anorexia
Can mistake for influenza or gastrointestinal infection
Slight fever may worsen just prior to paroxysm
Paroxysm Cold stage - rigors
Hot stageMax temp can reach 40-41o C,splenomegaly easily palpable
Sweating stage
Lasts 8-12 hours, start between midnight and midday
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Malarial Paroxysm
Periodicity
Days 1 and 3 forP.v.,P.o., (andP.f.) - tertian
Usually persistent fever or daily paroxyms forP.f.
Days 1 and 4 forP.m. - quartian
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Presentation of P.v.
Lack classical paroxysm followed by
asymptomatic period
Headache,dizziness, muscle pain, malaise,
anorexia, nausea, vague abdominal pain, vomiting Fever constant or remittent
Postural hypotension, jaundice, tender
hepatosplenomegaly
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Common features ofP.vivax
infections Incubation period in non-immunes 12-17 days but
can be 8-9 months or longer
Some strains from temperate zones show longerincubation periods, 250-637 days
First presentation of imported cases1 monthover 1 year post return from endemic area
Typical prodromal and acute symptoms Can be severe
However, acute mortality is very low
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Common features of
P.vivaxinfections Most people of West African descent are
resistant toP.v.
Lack Duffy blood group antigens needed forRBC invasion
Mildsevere anemia, thrombocytopenia,mild jaundice, tender hepatosplenomegaly
Splenic rupture carries high mortality
More common withP.v.than withP.f.
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Common features of
P.vivaxinfections Relapses
60% untreated or inadequately treated will
relapseTime from primary infection to relapse varies
by strain
Treat blood stages as well as give terminalprophylaxis for hypnozoites
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Common features of
P. ovale infections Clinical picture similar toP.v.but
Spontaneous recovery more common
Fewer relapses Anemia and splenic enlargement less severe
Lower risk of splenic rupture
Parasite often latent and easily suppressed by
more virulent species ofPlasmodia
Mixed infection withP.o.usually in those exposedin tropical Africa
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Common features of
P. malariae infections Clinical picture similar toP.v.but prodrome
may be more severe
Incubation period long18- 40 days Anemia less pronounced thanP.v.
Gross splenomegaly but risk of rupture less
common than inP.v. No relapseno hepatic phase or persisting
hepatic cycle
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Common features of
P. malariae infections Undetectable parasitemia may persist with
symptomatic recrudescences
Frequent during first year
Then longer intervals up to 52 years
Asymptomatic carriers may be detected at time ofblood donation or in cases of congenitaltransmission
Parasitemia rarely > 1%, all asexual stages can bepresent
Can cause nephrotic syndrome, prognosis is poor
f f l
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Features ofP.falciparumcases
Lack classical paroxysm followed by
asymptomatic period Headache,dizziness, muscle pain, malaise,
anorexia, nausea, vague abdominal pain, vomiting
Fever constant or remittent
Postural hypotension, jaundice, tenderhepatosplenomegaly
Can progress to severe malaria rapidly in non-immune patients
Cerebral malaria can occur withP.f.
Parasites can sequester in tissues, not detected onperipheral smear
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Some characteristics of infection with
four species of humanPlasmodia
P.v. P.o. P.m. P.f.
Pre-
erythroctic
stage (days)
6-8 9 14-16 5.5-7
Pre-patent
period (days)
11-13 10-14 15-16 9-10
Incubation
period (days)
15 (12-17)
or up to 6-12 months
17 (16-18)
or longer
28 (18-40)
or longer
12 (9-14)
Erythrocytic
cycle (hours)
48 (about) 50 72 48
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Some characteristics of infection with
four species of humanPlasmodia
P.v. P.o. P.m. P.f.
Paraitemia
per l
Average
Maximum
20,000
50,000
9,000
30,000
6,000
20,000
20,000-50,000
2,000,000
Primary
attack*
Mild-
severe
Mild Mild Severe in
non-
immunes
Febrile
paroxysms
(hours)
8-12 8-12 8-10 16-36 or
longer
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Some characteristics of infection with
four species of humanPlasmodia
P.v. P.o. P.m. P.f.
Invasion
requirements
Duffyve
blood
group
? ? ?
Relapses ++ ++ - -
Recrude-
scences
+ + - -
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Some characteristics of infection with
four species of humanPlasmodia
P.v. P.o. P.m. P.f.
Period of
recurrence **
Variable Variable Very long short
Duration ofuntreated
infection
(years)
1.5-5 Probablysame as
P.v.
3-50 1-2
*The severity of infection and the degree of parasitemia are greatly influenced by the immune response. Chemoprphylaxis
May suppress an initial attack for weeks or months.
** Patterns of infection and of relapses vary greatly in different strains.
Bruce-Chwatt Essential Malariology, 3rdrev ed. 1993
C i l l i
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Congenital malaria
Transplacental infection
Can be all 4 species CommonlyP.v.andP.f.in endemic areas
P.m.infections in nonendemic areas due to longpersistence of species
Neonate can be diagnosed with parasitemia within7 days of birth or longer if no other risk factors formalaria (mosquito exposure, blood transfusion)
Fever, irritability, feeding problems, anemia,
hepatosplenomegaly, and jaundice Be mindful of this problem even if mother has not
been in malarious area for years before delivery
I i
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Immunity
Influenced by
GeneticsAge
Health condition
Pregnancy status
Intensity of transmission in region
Length of exposure
Maintenance of exposure
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Immunity
Innate
Red cell polymorphisms associated with someprotection
Hemoglobin S sickle cell trait or disease
Hemoglobin C and hemoglobin E
Thalessemia and
Glucose6phosphate dehydrogenase deficiency(G6PD)
Red cell membrane changes Absence of certain Duffy coat antigens improves
resistance toP.v.
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Immunity
Acquired
Transferred from mother to child
3-6 months protection
Then children have increased susceptibility
Increased susceptibility during early childhood
Hyper- and holoendemic areas
By age 5 attacks usually < frequent and severe
Can have > parasite densities with fewer symptoms
Meso- or hypoendemic areas Less transmission and repeated attacks
May acquire partial immunity and be at higher risk forsymptomatic disease as adults
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Immunity
AcquiredNo complete immunity
Can be parasitemic without clinical disease
Need long period of exposure for induction
May need continued exposure for maintenance
Immunity can be unstable
Can wane as one spends time outside endemic area
Can change with movement to area with different
endemicity Decreases during pregnancy, risk improves with
increasing gravidity