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)

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

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. vivax 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

Components of the Malaria Life Cycle Mosquito Vector Human Host Sporogonic cycle Infective Period Mosquito bites gametocytemic person Mosquito bites uninfected person Prepatent Period Incubation Period Clinical Illness Parasites visible Recovery Symptom onset

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 pre- erythrocytic sporogeny The schizonts rupture, releasing merozoites and produce clinical relapse

Exo- erythrocytic (hepatic) cycle Sporozoites Mosquito Salivary Gland Malaria Life Cycle Life Cycle Gametocytes Oocyst Erythrocytic Cycle Zygote Schizogony Sporogony 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 pre- erythrocytic 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 o 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 days but can be 8-9 months or longer Some strains from temperate zones show longer incubation periods, 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 – 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 non- immune 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. Pre- erythroctic stage (days) Pre-patent period (days) Incubation period (days) 15 (12-17) or up to months 17 (16-18) or longer 28 (18-40) or longer 12 (9-14) Erythrocytic cycle (hours) 48 (about)507248

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 2,000,000 Primary attack* Mild- severe Mild Severe in non- immunes Febrile paroxysms (hours) or longer

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 ++--

Some characteristics of infection with four species of human Plasmodia P.v.P.o.P.m.P.f. Period of recurrence ** Variable Very longshort Duration of untreated infection (years) 1.5-5Probably same as P.v *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, 3 rd 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