Malaria Pathogenesis

8/13/2019 Malaria Pathogenesis

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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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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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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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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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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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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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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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P.v. P.o. P.m. P.f.

Invasion

requirements

Duffyve

blood

group

? ? ?

Relapses ++ ++ - -

Recrude-

scences

+ + - -


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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

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Malaria Pathogenesis