Malaria Pathogenesis and Clinical Presentation

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Malaria Pathogenesis and Clinical Presentation
Gail Stennies, MD, MPH Malaria Epidemiology
Branch May, 2002
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Plasmodium species which infect humans
Plasmodium vivax (tertian) Plasmodium ovale
(tertian) Plasmodium falciparum
(tertian) Plasmodium malariae (quartian)
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Malaria Life Cycle Life Cycle
Sporogony
Exo- erythrocytic (hepatic) cycle
Schizogony
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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
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
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Components 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
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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. vivax and P. ovale sporozoites form parasites
  in the liver called hypnozoites

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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

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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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Malaria Life Cycle Life Cycle
Sporogony
Exo- erythrocytic (hepatic) cycle
Schizogony
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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 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

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Erythrocytic 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

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Erythrocytic 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

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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

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Clinical presentation

• Early symptoms
• Headache
• Malaise
• Fatigue
• Nausea
• 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 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

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Clinical presentation

• Early symptoms
• Headache
• Malaise
• Fatigue
• Nausea
• 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, 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

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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 stage Max 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 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

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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 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

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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.

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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

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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

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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

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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 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

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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
  non-immune patients
• Cerebral malaria can occur with P.f.
• Parasites can sequester in tissues, not detected
  on peripheral smear

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Some characteristics of infection with four
species of human Plasmodia
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 human Plasmodia
P.v. P.o. P.m. P.f.
Paraitemia per µl 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 human Plasmodia
P.v. P.o. P.m. P.f.
Invasion requirements Duffy ve blood group ? ? ?
Relapses - -
Recrude-scences - -
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Some characteristics of infection with four
species of human Plasmodia
P.v. P.o. P.m. P.f.
Period of recurrence Variable Variable Very long short
Duration of untreated infection (years) 1.5-5 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
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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

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Immunity

• Influenced by
• Genetics
• Age
• 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 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.

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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 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

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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