Differentiate stages of malaria life cycle, identify species of plasmodium, and list down signs, symptoms, and complications associated w/ malaria as well as treatment options and prophylaxis
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Has 2 hosts: vertebrate (intermediate) and mosquito (definitive)
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Definitive Host: Sporulating Cycle (Sporogony)
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Intermediate Host: Asexual Cycle (Schizogony)
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EXO-ERYTHROCYTIC CYCLE
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1. Anopheles mosquito (definitive host), inoculates sporozoites into human host (intermediate)
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Sporozoites are the infective stage to man
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2. Sporozoites infect liver parenchymal cells and mature into schizonts, which produce merozoites
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P. vivax and P. ovale assume a dormant stage (hypnozoites), and can persist in the liver
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3. Infected cell ruptures and releases merozoites
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ERYTHROCYTIC CYCLE
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4. Merozoites infect RBCs and become trophozoites (ring stage)
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Merozoites are the infective stage for RBCs
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5. Trophozoites mature into schizonts, which rupture and release merozoites
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Some differentiate into gametocytes, which are ingested by the mosquito looking for a blood meal
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6. Ruptured schizonts are responsible for the clinical manifestations of the disease
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SPOROGONIC CYCLE
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7. The gametocytes are ingested by an anopheles mosquito and make their way into the stomach of the mosquito
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8. While in the stomach, the microgametes (male) penetrate the macrogametes (female), which generate zygotes
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Microgametocyte exflagellates and produces 8 sperm-like microgametes
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9. The zygotes become motile and elongated
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These are called ookinetes
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10. The ookinetes invade the midgut wall of the mosquito, where they develop into oocysts
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11. The oocysts grow, rupture, and release sporozoites, which makes their way into the salivary glands of the mosquito
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12. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle
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Pathological process is the result of erythrocytic cycle
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1. Hemolysis
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RBC invasion by merozoites induces changes in cytoskeleton and decreases in deformability
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Increased capillary permeability, which allows fluid to lead into surrounding tissues, causing congestion in blood vessels and tissue infarction and necrosis
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2. Liberation of Metabolites
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Rupture of RBCs bring on malarial paroxysm and increased hemosiderin in the liver, spleen, and other organs, which become black in color
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Lysis of cells & phagocytosis of cell remnants, debris, and hemozoin congest the kupffer cells of the liver, resulting in hepatosplenomegaly. Tears of splenic capsule may occur due to trauma or coughing & may require surgery
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3. Immunologic Response
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Antigens of P. falciparum induces cytokines, which stimulate the release of TNF or Cachexin, which causes fever, paroxysms, HA, pains, and prostration
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TNF produces neurologic symptoms, which play a role in cerebral malaria
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Repeated attacks of malaria produce anemia
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Immune complexes are formed and may be deposited in the kidney
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4. Formation of Malarial Pigment
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In infected RBC, Hgb is digested forming the pigment hemozoin, which can get deposited to various organs
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Hemozoin formation depletes iron stores, which leads to anemia
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VIRULENCE FACTORS
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Knobs develop for adhesion to parasitized and non-parasitized cells and platelets
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P. falciparum erythrocyte membrane Pr1 (PfEMP1) is the most adhesive protein among the knobs
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Knobs contain Histidine-Rich Pr (HRP)
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In Falciparum, cytoadherence causes plugging of small vessels by masses of parasitized RBCs and RBCs sticking to endothelium causing: ischemia of the brain, heart, kidney, lungs, and GIT
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PREFERENCE
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Vivax and Ovale
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Only reticulocytes and young RBC
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Malariae
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Senescent cells
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infections with these 3 parasites (vivax, ovale, and malariae) limits number of RBCs that can be parasitized to less than 3% of all erythrocytes
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Falciparum and Knowlesi
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All ages of RBC
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Results in increased parasitemia, early anemia, and increased severity of complications and mortality
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Ring Form (Early Trophozoite)
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Earliest stage after invasion of RBC. The ring has a dot-like nucleus of red chromatin
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Falciparum ring: headphone type with a double chromatin dot.
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The erythrocyte hemoglobin is metabolized to produce a darkly staining pigment hemozoin
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Maurer's Clefts: P. falciparum infections containing older ring-form trophozoites and asexual stages
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Schüffner's Dots: seen in P. vivax and P. ovale
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Sexual form ingested by the mosquito (infective stage for mosquito)
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Macrogametocyte: nucleus is dense and compact
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Microgametocyte: nucleus is a pale, loose network
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MICROSCOPIC IDENTIFICATION
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Gold standard
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Specimens can be taken any time
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Giemsa stain is preferred for visualization of certain structures (ex. Maurer's Clefts)
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If high degree of synchrony exist, late developmental stages can be demonstrated in the repeated smears every 4-6hrs (not recommended for falciparum)
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Repeated testing is not recommended if parasites are not found initially
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Blood smears are obtained to monitor response to treatment
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Thick Film: reveals if parasite is present and is most efficient method of detection
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Thin Film: identification of species
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MALARIAL RDT
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Uses Immunochromatography to detect Plasmodium specific antigens in a finger prick blood sample
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Antigens utilized are: HRP II, pLDH, Plasmodium Aldolase
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HRP II: produced by trophozoites and young gametocytes of P. falciparum
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pLDH: produced by both sexual and asexual stages, and can distinguish between falciparum and non-falciparum. Sensitive for severe malaria
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Plasmodium Aldolase: PA + HRP II = PMA which has 90% specificity and can be performed in 30 minutes
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SEROLOGY
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Cannot differentiate past from current infection
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Indirect Hemagglutination (IHA)
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Indirect Fluorescent Antibody Test (IFAT)
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ELISA
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PCR
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low parasitemia or mixed infection
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MALIGNANT TERTIAN MALARIA
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Also known as subtertian or Aestivoautumnal Malaria
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Deadliest species of plasmodium
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Causes 50% of all malaria cases
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Erythrocytic cycle of 48hrs
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Found in tropics, subtropics, and sub saharan Africa
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Infected cell is same size as normal RBC
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Associated with the development of Burkitt's Lymphoma
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RING-FORM TROPHOZOITES
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Headphone Type: Rings may possess 1 or 2 chromatin dots
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They may be found on the periphery of the RBC (accolé, appliqué) and multiply-infected RBCs may be seen.
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Usually no enlargement of infected RBC
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Maurer's Clefts: can be seen in infections w/ older ring-form trophozoites, and resembles the Schüffner’s dots but are larger and coarser
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DEVELOPING AND OLDER TROPHOZOITES
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Remain in ring-form, but may become thicker and more compact
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Amount of pigment and chromatin may also increase
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SCHIZONTS
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Schizogony DOES NOT take place in the peripheral blood, but in capillaries of organs and muscles.
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The only stages seen in peripheral blood are rings and gametocytes
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Contain anywhere from 8-24 merozoites
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Mature schizont usually fills 2/3 of infected RBC
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GAMETOCYTES
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Crescent or sausage or banana shaped
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Pigment is more coarse and concentrated in macrogametocyte than microgametocyte
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Laveran's Bib: remnants of host RBC
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OVALE MALARIA
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Has an erythrocytic cycle of 48hrs
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Has a hypnozoite stage in the liver, which is the cause of relapse
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Infected RBC is slightly enlarged compared to normal RBC
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Found in Tropical Africa, West Africa, South America, and Asia
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RING-FORM TROPHOZOITES
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Contains single chromatin dot. Difficult to differentiate from vivax.
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Multiply-Infected RBC may be see
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MATURE TROPHOZOITES
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As trophozoite matures, infected RBCs may exhibit fimbriation and Schüffner’s dots
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SCHIZONTS
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Similar to P. vivax, though tend to contain fewer merozoites (4-16, on average 8)
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Elongation to an oval shape and fimbriation are common
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Schüffner’s dots can be observed with proper staining
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GAMETOCYTES
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Difficult to distinguish from P. vivax
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Slight enlargement of infected RBC
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BENIGN TERTIAN MALARIA
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Erythrocytic cycle of 48 hours
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Hypnozoite: persistant dormant stage in the liver, which is the cause of relapse
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Predominant malarial species
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Infected RBC is enlarged due to affinity for young RBCs or reticulocytes
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RING-FORM TROPHOZOITES
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Has a thick cytoplasm w/ single, large chromatin dot. Difficult to distinguish from P. ovale
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Cytoplasm becomes ameboid and Schüffner’s dots may appear as trophozoites mature
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LATE TROPHOZOITES
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Developing trophozoites become amoeboid, with pseudopodial processes and large vacuoles. Schüffner’s dots are visible with proper staining
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band-form appearance of trophozoite may occur
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May be mistaken for P. Malariae or P. knowlesi
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SCHIZONTS
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Pigment is organized in 1-2 clumps
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Mature schizonts contain 12-24 merozoites, each of which contains a dot of chromatin and a mass of cytoplasm
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GAMETOCYTE
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Macrogametocyte: round to oval and usually fill host cell. Infected RBC is larger and cytoplasm is usually a darker blue with fine brown pigments throughout
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Microgametocyte: usually the size of an uninfected RBC and has a paler blue, pink or grey cytoplasm
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KNOWLESI MALARIA
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Vector is A. balabacensis & A. maculatus
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Primate malaria in macaques in South East Asia
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Infects ALL stages of RBC, and causes severe malaria
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Erythrocytic cycle has quotidian pattern (every 24hrs)
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Non-relapsing due to absence of hynozoites
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Microscopically indistinguishable from P. malariae (Use PCR to distinguish)
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Quotidian pattern results in high levels of parasitemia and severe disease with fatal consequence
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TREATMENT
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Chloroquine
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Primaquine
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Should be treated aggressively and urgently
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RING-FORM TROPHOZOITES
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Normal to 0.75x smaller than uninfected RBC
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Rings may show double chromatin dots
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Appliqué forms may be seen as well as rectangular rings harboring one or more accessory chromatin dots
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RBC may be Multiply-infected
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OLDER, DEVELOPING TROPHOZOITES
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Band forms may appear similar to P. malariae
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Sinton and Mulligan's stippling may appear
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SCHIZONTS
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Sinton and Mulligan's stippling may appear
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10-16 merozoites
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Gametocytes
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Mature Macrogametocyte: usually spherical and fill the host RBC. Cytoplasm stains blue and eccentric nucleus stains red
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Microgametocyte: smaller and cytoplasm stains pale pink, while nucleus stains a darker red
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QUARTAN MALARIA
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Erythrocytic cycle of 72hrs
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Found in subtropical and temperate areas
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Infected cells are normal to smaller in size than most RBCs
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Old cells are preferentially infected**
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RING-FORM TROPHOZOITES
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Have 1 chromatin dot and a cytoplasm ring that is thicker than P. falciparum.
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Infected RBC is normal to smaller
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Bird's-eye forms may appear
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MATURE TROPHOZOITES
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Rounded chromatin and compact cytoplasm
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As the trophozoite matures, the cytoplasm may elongate across the host RBC, forming a band-form
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Pigment granules become larger and tend to have a more peripheral arrangement
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Zeimann's stippling may be present
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SCHIZONTS
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6-12 merozoites, often arranged in a rosette or irregular cluster
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Mature schizonts nearly fill the normal-sized host
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GAMETOCYTES
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Compact and fills* host RBC
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Sometimes, there is a reduction in size of the infected RBC
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Cytoplasm stains blue and the chromatin is pink to red.
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Abundant dark pigment may be scattered throughout the cytoplasm
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PRE-PATENT PERIOD
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Interval from sporozoite injection to detection of parasites in blood
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P.falciparum: 11-14 days
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vivax: 11-15 days
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ovale: 14-26 days
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malariae: 3-4 weeks
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knowlesi: 9-12 days
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INCUBATION PERIOD
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time between sporozoite injection and appearance of clinical symptoms (8-40)
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falciparum: 8-15 days
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vivax: 12-20 days
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ovale: 11-16 days
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malariae: 18-40 days
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knowlesi: 5 days- few weeks
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PRODROMAL SYMPTOMS
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Weakness, exhaustion, aching bones, limbs, and back; loss of appetite; nausea; vomiting
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malaise, backache, diarrhea, and epigastric discomfort
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MALARIAL PAROXYSM
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1. Cold Stage
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Sudden feelings of coldness and apprehension
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Mild shivering quickly turns to violent teeth chattering and shaking of entire body
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Vomiting may occur
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Rigors last for 15min-1hr, then stops
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2. Hot Stage or Flush Phase
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Patient becomes hot (41° C ), with headache, palpitations, tachypnea, epigastric discomfort, thirst, nausea, and vomiting
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Skin is hot and flushed, patient is confused and delerious
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Lasts 2-6hrs
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3. Sweating Stage
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Defervesence and diaphoresis or profuse sweating occurs
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Temperature lowers in the next 2-4hrs and symptoms diminish accordingly
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Total duration is 8-12hrs
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Periodicity of attack only occurs if patient is left untreated
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Interval length is determined by length of erythrocytic cycle
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falciparum, vivax and ovale – 48 hours
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malariae – 72 hours
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knowlesi – 24 hours
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COMPLICATIONS
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Vivax, ovale and quartan malaria are relatively benign
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Knowlesi
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Severe thrombocytopenia, jaundice, deranged liver enzymes.
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Acute Respiratory Distress Syndrome with tachypnea, hypoxemia, and pulmonary infiltrates on CXR.
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Acute Renal Failure with elevated serum creatinine
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Hypotension
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Acidosis
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Chronic Malariae
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immune-complex deposition on the glomerular walls, leading to nephrotic syndrome in children
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Falciparum
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Cerebral Malaria (requires prompt administration of quinidine IV and then quinine PO)
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Anemia
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Acute Renal Failure (tubular necrosis and nephrotic syndrome)
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Blackwater fever: from massive intravascular hemolysis and hemoglobinuria
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Dysenteric Malaria
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Algid Malaria: rapid development of hypotension and impairment of vascular perfusion
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Pulmonary Edema
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Tropical Splenomegaly Syndrome
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Hyperparasitemia (>10-20% of RBC mean high mortality rate)
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Hypoglycemia
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Proper use of the antimalarial drugs is based on knowledge of their effects on the parasite at various stages of the life cycle
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Suppressive therapy:
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destroy the parasites as they enter the bloodstream; effective against the erythrocytic stages.
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Clinical Cure:
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full and rapid elimination of plasmodiumfrom the blood to prevent complications
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Radical cure:
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elimination of not only the bloodstream infection but the tissue stages in the liver as well.
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BLOOD SCHIZONTICIDES
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Clinical cure of an acute attack, no effect on pre-erythrocytic and gametocyte stage
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1. Quinine
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blood schizonticide against all five species of human malarial parasites. Side effects of treatment include tinnitus and headache, vertigo
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2. Quinidine
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3. Chloroquine
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4. Amodiaquine
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5. Mefloquine
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effective against both chloroquine-sensitive and –resistant strains of P. falciparum and P. vivax. It is also effective against P. malariae and P. ovale
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6. Doxycycline
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7. Proguanil
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Prevents development of oocysts in mosquito
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8. Halofantrine
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9. Artemisinin
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effective against P. falciparum , P. knowlesi and P. vivax, and in patients with cerebral malaria
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TISSUE SCHIZONTICIDES
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destroy the developmental stages in the liver
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1. Primaquine
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effective against the hypnozoites of P. vivax and P. ovale.
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*GAMETOCYTICIDES
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1. Primaquine
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gametocyticidal for all five species of malaria parasites and acts to render the patient noninfectious to the mosquito
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UNCOMPLICATED P. FALCIPARUM
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1. Atovaquone-Proguanil
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(Malarone™) 4 adult tabs po qd x 3 days
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2. Artemether-Lumefantrine
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(Coartem™) 1 tablet = 20mg artemether and 120 mg lumefantrine . 4 tabs initial dose, followed by 4 tabs as second dose 8 hours later, then 4 tabs po bid for the following 2 days.
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3. Quinine Sulfate
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plus one of the following: Doxycycline, Tetracycline, or Clindamycin (for pregnant)
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4. Mefloquine
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CHLOROQUINE-SENSITIVE FALCIPARUM OR UNCOMPLICATED P. MALARIAE
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1. Chloroquine phosphate
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UNCOMPLICATED P. VIVAX OR OVALE
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1. Chloroquine phosphate plus Primaquine phosphate
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CHLOROQUINE RESISTANT VIVAX
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1. Quinine sulfate plus either Doxycycline or Tetracycline plus Primaquine phosphate
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SEVERE MALARIA
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1. Quinidine gluconate plus one of the following: Doxycycline, Tetracycline, or Clindamycin
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2. Exchange transfusion has been recommended for very severe falciparum malaria associated with high parasitemia ( >10% of RBCs )
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P. KNOWLESI
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Uncomplicated
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1. Chloroquine
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2. Primaquine
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Severe
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1. Quinine
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2. Artemether-Lumefantrine
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MALARIA PROPHYLAXIS
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1.Atovaquone/Proguanil
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2. Doxycycline
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3. Chloroquine
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4. Mefloquine
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5. Primaquine
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Cheatography n. The art of mapping complex subjects into clear, instantly navigable reference guides.
