Malaria Pathogenesis and Clinical Presentation

1. Malaria Pathogenesis and Clinical Presentation Gail Stennies, MD, MPH Malaria Epidemiology Branch May, 2002

2. Plasmodium species which infect humans Plasmodium vivax (tertian) Plasmodium ovale (tertian) Plasmodium falciparum (tertian) Plasmodium malariae (quartian)

3. Oocyst Sporozoites Mosquito Salivary Gland Zygote Hypnozoites (for P. vivax and P. ovale) Gametocytes Erythrocytic Cycle Malaria Life Cycle Life Cycle Sporogony Exo- erythrocytic (hepatic) cycle Schizogony

4. 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

5. 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

6. 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

7. 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

8. 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

9. Oocyst Sporozoites Mosquito Salivary Gland Zygote Hypnozoites (for P. vivax and P. ovale) Gametocytes Erythrocytic Cycle Malaria Life Cycle Life Cycle Sporogony Exo- erythrocytic (hepatic) cycle Schizogony

10. 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

11. 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

12. 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 schizont’s nucleus and cytoplasm forms merozoites • Schizogeny complete when schizont ruptures, releasing merozoites into blood stream, causing fever • These are asexual forms

13. Erythrocytic phasestages 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

14. 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

15. Clinical presentation • Early symptoms • Headache • Malaise • Fatigue • Nausea • Muscular pains • Slight diarrhea • Slight fever, usually not intermittent • Could mistake for influenza or gastrointestinal infection

16. 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

17. Clinical presentation • Early symptoms • Headache • Malaise • Fatigue • Nausea • Muscular pains • Slight diarrhea • Slight fever, usually not intermittent • Could mistake for influenza or gastrointestinal infection

18. Clinical presentation • Signs • Anemia • Thrombocytopenia • Jaundice • Hepatosplenomegaly • respiratory distress syndrome • renal dysfunction • Hypoglycemia • Mental status changes • Tropical splenomegaly syndrome

19. 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

20. 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)

21. 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

22. 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

23. 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

24. 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

25. 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.

26. 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

27. 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

28. 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

29. 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

30. 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

31. Some characteristics of infection with four species of human Plasmodia

32. Some characteristics of infection with four species of human Plasmodia

33. Some characteristics of infection with four species of human Plasmodia

34. Some characteristics of infection with four species of human Plasmodia *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

35. 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

36. Immunity • Influenced by • Genetics • Age • Health condition • Pregnancy status • Intensity of transmission in region • Length of exposure • Maintenance of exposure

37. 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.

38. 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

39. 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