Malaria Pathogenesis and Clinical Presentation Plasmodium species which

Malaria Pathogenesis and Clinical Presentation Plasmodium species which

Malaria Pathogenesis and Clinical Presentation Plasmodium species which infect humans Plasmodium vivax (tertian) Plasmodium ovale (tertian) Plasmodium falciparum (tertian) Plasmodium malariae (quartian) Malaria Life Cycle Life Cycle Sporogony Oocys t

Sporozoite s Mosquito Salivary Gland Zygot e Exoerythrocytic (hepatic) cycle Gametocyte s Erythrocyti c Cycle

Schizogony Hypnozoite s (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 Oocys t Sporozoite s Mosquito Salivary Gland Zygot e Exoerythrocytic

(hepatic) cycle Gametocyte s Erythrocyti c Cycle Schizogony Hypnozoite s (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 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 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. 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 ll 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 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

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