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

Zygote

Mosquito Salivary Gland

Gametocytes

Exoerythrocytic (hepatic) cycle

Hypnozoites (for P. vivax and P. ovale)

Erythrocytic Cycle

Schizogony

Malaria Transmission Cycle

Sporozoires injected into human host during blood meal Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood

Parasites mature in mosquito midgut and migrate to salivary glands

MOSQUITO

HUMAN

Dormant liver stages (hypnozoites) of P. vivax and P. ovale

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

Components of the Malaria Life Cycle

Sporogonic cycle

Infective Period
Mosquito bites uninfected person Mosquito bites gametocytemic person Parasites visible Prepatent Period Symptom onset Recovery

Mosquito Vector Human Host

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 preerythrocytic sporogeny The schizonts rupture, releasing merozoites and produce clinical relapse

Malaria Life Cycle Life Cycle

Sporogony
Oocyst
Sporozoites

Zygote

Mosquito Salivary Gland

Gametocytes

Exoerythrocytic (hepatic) cycle

Hypnozoites (for P. vivax and P. ovale)

Erythrocytic Cycle

Schizogony

Exo-erythrocytic (tissue) phase

P. vivax and P. ovale hypnozoites remain dormant for months They develop and undergoe preerythrocytic 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 schizonts 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 hosts 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
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
Headache Malaise Fatigue Nausea Muscular pains Slight diarrhea Slight fever, usually not intermittent

Could mistake for influenza or gastrointestinal infection

Clinical presentation
Signs
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
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. Preerythroctic stage (days) 6-8 P.o. 9 P.m. 14-16 P.f. 5.5-7

Pre-patent period (days) Incubation period (days)

Erythrocytic cycle (hours)

11-13

10-14

15-16

9-10

15 (12-17) 17 (16-18) 28 (18-40) 12 (9-14) or up to 6- or longer or longer 12 months 48 (about) 50 72 48

Some characteristics of infection with four species of human Plasmodia

P.v. Paraitemia per l Average Maximum Primary attack* Febrile paroxysms (hours) P.o. P.m. P.f.

20,000 50,000 Mildsevere 8-12

9,000 30,000 Mild

6,000 20,000 Mild

20,00050,000 2,000,000 Severe in nonimmunes 16-36 or longer

8-12

8-10

Some characteristics of infection with four species of human Plasmodia

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

Invasion requirements
Relapses Recrudescences

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. Variable Probably same as P.v. P.m. Very long 3-50 P.f. short 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
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 and 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