Title: Malaria Pathogenesis and Clinical Presentation
1Malaria Pathogenesis and Clinical Presentation
Gail Stennies, MD, MPH Malaria Epidemiology
Branch May, 2002
2Plasmodium species which infect humans
Plasmodium vivax (tertian) Plasmodium ovale
(tertian) Plasmodium falciparum
(tertian) Plasmodium malariae (quartian)
3Malaria Life Cycle Life Cycle
Sporogony
Exo- erythrocytic (hepatic) cycle
Schizogony
4Malaria Transmission Cycle
Exo-erythrocytic (hepatic) Cycle Sporozoites
infect liver cells and develop into schizonts,
which release merozoites into the blood
Sporozoires injected into human host during blood
meal
Parasites mature in mosquito midgut and migrate
to salivary glands
Dormant liver stages (hypnozoites) of P. vivax
and P. ovale
HUMAN
MOSQUITO
Erythrocytic Cycle Merozoites infect red blood
cells to form schizonts
Some merozoites differentiate into male or female
gametocyctes
Parasite undergoes sexual reproduction in the
mosquito
5Components of the Malaria Life Cycle
Sporogonic cycle
Infective Period
Mosquito bites uninfected person
Mosquito Vector
Parasites visible
Human Host
Mosquito bites gametocytemic person
Symptom onset
Prepatent Period
Recovery
Incubation Period
Clinical Illness
6Exo-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. vivax and P. ovale sporozoites form parasites
in the liver called hypnozoites
7Exo-erythrocytic (tissue) phase
- P. malariae or P. falciparum sporozoites do not
form hypnozites, develop directly into
pre-erythrocytic schizonts in the liver - Pre-erythrocytic schizogeny takes 6-16 days post
infection - Schizonts rupture, releasing merozoites which
invade red blood cells (RBC) in liver
8Relapsing 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
9Malaria Life Cycle Life Cycle
Sporogony
Exo- erythrocytic (hepatic) cycle
Schizogony
10Exo-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
11Erythrocytic phase
- Pre-patent period interval between date of
infection and detection of parasites in
peripheral blood - Incubation period time 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 features
depending on species of malaria
12Erythrocytic phasestages of parasite in RBC
- Trophozoites are early stages with ring form the
youngest - 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, causing
fever - These are asexual forms
13Erythrocytic phasestages of parasite in RBC
- Merozoites invade other RBCs and schizongeny is
repeated - Parasite density increases until hosts immune
response slows it down - Merozoites may develop into gametocytes, the
sexual forms of the parasite
14Schizogenic periodicity and fever patterns
- Schizogenic periodicity is length of asexual
erythrocytic phase - 48 hours in P.f., P.v., and P.o. (tertian)
- 72 hours in P.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)- or
4 (quartian)- day pattern
15Clinical presentation
- Early symptoms
- Headache
- Malaise
- Fatigue
- Nausea
- Muscular pains
- Slight diarrhea
- Slight fever, usually not intermittent
- Could mistake for influenza or gastrointestinal
infection
16Clinical presentation
- Acute febrile illness, may have periodic febrile
paroxysms every 48 72 hours with - Afebrile asymptomatic intervals
- Tendency to recrudesce or relapse over months to
years - Anemia, thrombocytopenia, jaundice,
hepatosplenomegaly, respiratory distress
syndrome, renal dysfunction, hypoglycemia, mental
status changes, tropical splenomegaly syndrome
17Clinical presentation
- Early symptoms
- Headache
- Malaise
- Fatigue
- Nausea
- Muscular pains
- Slight diarrhea
- Slight fever, usually not intermittent
- Could mistake for influenza or gastrointestinal
infection
18Clinical presentation
- Signs
- Anemia
- Thrombocytopenia
- Jaundice
- Hepatosplenomegaly
- respiratory distress syndrome
- renal dysfunction
- Hypoglycemia
- Mental status changes
- Tropical splenomegaly syndrome
19Types of Infections
- Recrudescence
- exacerbation of persistent undetectable
parasitemia, due to survival of erythrocytic
forms, no exo-erythrocytic cycle (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,
separate from previous infection (all species) - Can not always differentiate recrudescence from
reinfection
20Clinical 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)
21Malarial 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 stage Max temp can reach 40-41o C,
splenomegaly easily palpable - Sweating stage
- Lasts 8-12 hours, start between midnight and
midday
22Malarial Paroxysm
- Periodicity
- Days 1 and 3 for P.v., P.o., (and P.f.) - tertian
- Usually persistent fever or daily paroxyms for
P.f. - Days 1 and 4 for P.m. - quartian
23Presentation 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
24Common features of P.vivax infections
- Incubation period in non-immunes 12-17 days but
can be 8-9 months or longer - Some strains from temperate zones show longer
incubation periods, 250-637 days - First presentation of imported cases 1 month
over 1 year post return from endemic area - Typical prodromal and acute symptoms
- Can be severe
- However, acute mortality is very low
25Common features of P.vivax infections
- Most people of West African descent are resistant
to P.v. - Lack Duffy blood group antigens needed for RBC
invasion - Mild severe anemia, thrombocytopenia, mild
jaundice, tender hepatosplenomegaly - Splenic rupture carries high mortality
- More common with P.v. than with P.f.
26Common features of P.vivax infections
- Relapses
- 60 untreated or inadequately treated will
relapse - Time from primary infection to relapse varies by
strain - Treat blood stages as well as give terminal
prophylaxis for hypnozoites
27Common features of P. ovale infections
- Clinical picture similar to P.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 of Plasmodia - Mixed infection with P.o. usually in those
exposed in tropical Africa
28Common features of P. malariae infections
- Clinical picture similar to P.v. but prodrome may
be more severe - Incubation period long 18- 40 days
- Anemia less pronounced than P.v.
- Gross splenomegaly but risk of rupture less
common than in P.v. - No relapse no hepatic phase or persisting
hepatic cycle
29Common 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 of
blood donation or in cases of congenital
transmission - Parasitemia rarely gt 1, all asexual stages can
be present - Can cause nephrotic syndrome, prognosis is poor
30Features of P.falciparum cases
- 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 - Can progress to severe malaria rapidly in
non-immune patients - Cerebral malaria can occur with P.f.
- Parasites can sequester in tissues, not detected
on peripheral smear
31Some characteristics of infection with four
species of human Plasmodia
32Some characteristics of infection with four
species of human Plasmodia
33Some characteristics of infection with four
species of human Plasmodia
34Some characteristics of infection with four
species of human Plasmodia
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, 3rd rev ed. 1993
35Congenital malaria
- Transplacental infection
- Can be all 4 species
- Commonly P.v. and P.f. in endemic areas
- P.m. infections in nonendemic areas due to long
persistence of species - Neonate can be diagnosed with parasitemia within
7 days of birth or longer if no other risk
factors for malaria (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
36Immunity
- Influenced by
- Genetics
- Age
- Health condition
- Pregnancy status
- Intensity of transmission in region
- Length of exposure
- Maintenance of exposure
37Immunity
- Innate
- Red cell polymorphisms associated with some
protection - Hemoglobin S sickle cell trait or disease
- Hemoglobin C and hemoglobin E
- Thalessemia a and ß
- Glucose 6 phosphate dehydrogenase deficiency
(G6PD) - Red cell membrane changes
- Absence of certain Duffy coat antigens improves
resistance to P.v.
38Immunity
- 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 lt frequent and severe
- Can have gt parasite densities with fewer symptoms
- Meso- or hypoendemic areas
- Less transmission and repeated attacks
- May acquire partial immunity and be at higher
risk for symptomatic disease as adults
39Immunity
- Acquired
- No 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