Transcript Document

Malaria Pathogenesis and
Clinical Presentation
Gail Stennies, MD, MPH
Malaria Epidemiology Branch
May, 2002
Plasmodium species which
infect humans
Plasmodium vivax (tertian)
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartian)
Malaria Life
Cycle
Life Cycle
Sporogony
Oocyst
Sporozoites
Mosquito Salivary
Gland
Zygote
Exoerythrocytic
(hepatic) cycle
Gametocytes
Erythrocytic
Cycle
Schizogony
Hypnozoites
(for P. vivax
and P. ovale)
Malaria 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
MOSQUITO
Parasite undergoes
sexual reproduction in
the mosquito
HUMAN
Some merozoites
differentiate into male or
female gametocyctes
Dormant liver stages
(hypnozoites) of P.
vivax and P. ovale
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts
Components of the Malaria Life Cycle
Sporogonic cycle
Infective Period
Mosquito bites
uninfected
person
Mosquito bites
gametocytemic
person
Mosquito Vector
Parasites visible
Prepatent Period
Human Host
Symptom onset
Recovery
Incubation Period
Clinical Illness
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. vivax and P. ovale sporozoites form
parasites in the liver called hypnozoites
Exo-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
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
Malaria Life
Cycle
Life Cycle
Sporogony
Oocyst
Sporozoites
Mosquito Salivary
Gland
Zygote
Exoerythrocytic
(hepatic) cycle
Gametocytes
Erythrocytic
Cycle
Schizogony
Hypnozoites
(for P. vivax
and P. ovale)
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
Erythrocytic 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
Erythrocytic phase
stages of parasite in RBC
• Trophozoites are early stages with ring form the
youngest
• Tropohozoite nucleus and cytoplasm divide
forming a schizont
• Segmentation of schizont’s nucleus and
cytoplasm forms merozoites
• Schizogeny complete when schizont ruptures,
releasing merozoites into blood stream, causing
fever
• These are asexual forms
Erythrocytic phase
stages of parasite in RBC
• Merozoites invade other RBCs and
schizongeny is repeated
• Parasite density increases until host’s
immune response slows it down
• Merozoites may develop into gametocytes,
the sexual forms of the parasite
Schizogenic 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
Clinical presentation
• Early symptoms
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Headache
Malaise
Fatigue
Nausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent
• Could mistake for influenza or gastrointestinal
infection
Clinical 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
Clinical presentation
• Early symptoms
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Headache
Malaise
Fatigue
Nausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent
• Could mistake for influenza or gastrointestinal
infection
Clinical presentation
• Signs
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Anemia
Thrombocytopenia
Jaundice
Hepatosplenomegaly
respiratory distress syndrome
renal dysfunction
Hypoglycemia
Mental status changes
Tropical splenomegaly syndrome
Types 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
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
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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)
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 stage – Max temp can reach 40-41o C,
splenomegaly easily palpable
– Sweating stage
– Lasts 8-12 hours, start between midnight and midday
Malarial 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
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
Common 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
Common 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.
Common 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
Common 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
Common 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
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 of
blood donation or in cases of congenital
transmission
• Parasitemia rarely > 1%, all asexual stages can be
present
• Can cause nephrotic syndrome, prognosis is poor
Features 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 nonimmune patients
• Cerebral malaria can occur with P.f.
• Parasites can sequester in tissues, not detected on
peripheral smear
Some characteristics of infection with
four species of human Plasmodia
P.v.
P.o.
P.m.
P.f.
Preerythroctic
stage (days)
Pre-patent
period (days)
Incubation
period (days)
6-8
9
14-16
5.5-7
11-13
10-14
15-16
9-10
Erythrocytic
cycle (hours)
48 (about) 50
15 (12-17) 17 (16-18) 28 (18-40) 12 (9-14)
or up to 6- or longer or longer
12 months
72
48
Some characteristics of infection with
four species of human Plasmodia
P.v.
Paraitemia
per μl
Average
Maximum
Primary
attack*
Febrile
paroxysms
(hours)
P.o.
P.m.
20,000
9,000
6,000
50,000
Mildsevere
30,000
Mild
20,000
Mild
8-12
8-12
8-10
P.f.
20,00050,000
2,000,000
Severe in
nonimmunes
16-36 or
longer
Some characteristics of infection with
four species of human Plasmodia
Invasion
requirements
Relapses
Recrudescences
P.v.
P.o.
P.m.
P.f.
Duffy –ve
blood
group
++
?
?
?
++
-
-
+
+
-
-
Some characteristics of infection with
four species of human Plasmodia
P.v.
Period of
Variable
recurrence **
Duration of
1.5-5
untreated
infection
(years)
P.o.
P.m.
P.f.
Variable
Very long
short
Probably
same 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, 3rd rev ed. 1993
Congenital 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
Immunity
• Influenced by
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–
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–
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Genetics
Age
Health condition
Pregnancy status
Intensity of transmission in region
Length of exposure
Maintenance of exposure
Immunity
• Innate
– Red cell polymorphisms associated with some
protection
•
•
•
•
Hemoglobin S sickle cell trait or disease
Hemoglobin C and hemoglobin E
Thalessemia – α and β
Glucose – 6 – phosphate dehydrogenase deficiency
(G6PD)
– Red cell membrane changes
• Absence of certain Duffy coat antigens improves
resistance to P.v.
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 for
symptomatic disease as adults
Immunity
• 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