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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 preerythrocytic 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 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 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 – – – – – – –

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.

P.o.

P.m.

P.f.

Preerythroctic 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) 17 (16-18) 28 (18-40) 12 (9-14) or up to 6- or longer or longer 12 months

Erythrocytic cycle (hours)

48 (about) 50

72

48


Some characteristics of infection with four species of human Plasmodia P.v. Paraitemia per Îźl Average

P.o.

P.m.

P.f.

20,000

9,000

6,000

50,000

30,000

20,000

Primary attack*

Mildsevere

Mild

Mild

Severe in nonimmunes

Febrile paroxysms (hours)

8-12

8-12

8-10

16-36 or longer

Maximum

20,00050,000 2,000,000


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

++

++

-

-

Recrudescences

+

+

-

-


Some characteristics of infection with four species of human Plasmodia P.v.

P.o.

P.m.

P.f.

Period of Variable recurrence **

Variable

Very long

short

Duration of untreated infection (years)

Probably same as P.v.

3-50

1-2

1.5-5

*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 – 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

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