MALARIA Overview - Protozoan disease (Plasmodium) - Transmitted by Anopheles mosquitoes - Causing 1-3 million deaths each yr - Has been

eliminated from US, Canada, Europe, Russia. But has resurged in many part of tropics Etiology and Pathogenesis Life Cycle 1. Mosquito Stage - Female Anopheles mosquito bites human and transmits sporozoites into the bloodstream
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Human Stage a. Exo Erythrocytic Stage asymptomatic - Sporozoites migrate through blood to liver - Invade hepatocytes and divide to form Multinucleated Schizonts * Atovaquone-proguanil and primaquine against hepatic stage schizonts * P. Vivax and P. Ovale form latent hypnozoites in hepatocytes, which cause relapses of malaria long after initial infection Primaquine is effective - Schizonts rupture and release merozoites into circulation where invade RBC Erythrocytic Stage - Merozoites Early trophozoite (ring forms) Trophozoite Multinucleated Schizonts cause rupture of RBC releasing merozoites back into circulation and infect other RBC *Artemisins, atovaquone-proguanil, doxycycline, mefloquine, choloroquine interrupt this process within RBC * Primaquine active against schizonts of P. Vivax, but not P. falciparum - Some merozoites differentiate into male or female gametocytes taken up by mosquito infect another host
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Within RBC parasites digest Hb breakdown is hemozoin (formed in food vacuole) Parasites inside RBC also derive energy from anaerobic glycolysis to glucose to lactic acid hypoglycaemia and lactic acidosis Parasites also cause RBC membrane less deformable hemolysis and haemolytic anemia by spleen. Enlarged spleen also cause thrombocytopenia Hemozoin & remnants of cell membrane phagocytised by circulating macrophages stimulating immune cascade Free heme also released into peripheral bood endothelial activation Immune stimulated Release TNF suppresses hematopoiesis

Species of Plasmodium

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Plasmodium Falciparum Tertian fever (every 48 hrs). But in P. Falciparum almost continuous Deadliest of all (malignant). Why? a. P. Falciparum able to infect RBC of any age high parasite burdens and profound anemia. The other only infect new & old RBC b. P. Falciparum produces PfEMPI (P. Falciparum Erythrocyte Membrane Protein) form knobs on surface of RBC. PfEMP I binds to ligands on endothelial cells, including CD36, thrombospondin, VCAM-1, ICAM-1 and E-selectin. This causes infected RBC to clump together (rosetting) and stick to endothelial cells lining small blood vessels (sequestration) block blood flow. Brain: Poor perfusion ischemia cerebral malaria main cause of death in children Kidneys: ATN + renal failure Intestines: Ischemia + ulceration Placenta: Intrauterine growth retardation

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P. Falciparum stimulates production of high levels of cytokines TNF, IFN-, IL-1 suppress hematopoiesis (anemia), increase fever, increase NO, induce expression of endothelial receptors for PfEMP1 (increasing sequestration)

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Plasmodium Vivax Benign tertian malaria (48 hr fever cycle) Has hypnozites dormant, can cause relapse Mortality rate low P. Vivax is major cause of morbidity in early infancy Splenic rupture is rare complication

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Plasmodium Ovale Benign tertian malaria (48 hr fever cycle) Also have the dormant hypnozites stage Plasmodium Malariae Quartan malaria (72 hr cycle) Can be chronic. Parasitemia can exist years or more with or without symptoms (recurrence can happen more than 40 yrs after known exposure) Chronic P. Malariae in children has mixed IgM and IgG basement membrane immune complex nephropathy nephrotic syndrome most die within 2 yrs can be cured with early recognition & tx

Epidemiology - Occurs throughout most of tropical regions - P. Falciparum causing largest burden of disease followed by P. Vivax - P. Falciparum predominates in Africa, New Guinea, Hispaniola (Haiti & Dominican Republic) - P. Vivax is more common in Americas and Western Pacific - Both equal in Indian subcontinent, Eastern Asia, and Oceania - P. Malaria uncommon sub Saharan Africa - P. Ovale less common and unusual outside Africa Determinants of epidemiology - Number (density), human biting habits (indoor or outdoor) and longevity of the Female Anopheline mosquito - Eg. An. Gambiae in Africa effective as vector as long lived, occur in high densities in tropical climates, breed readily, rest and bite within dwellings, and bite human in preference to other animals

Clinical presentation of Malaria 1. After Anopheles female bite sphorozites go to liver within 1 to 2 hrs Asymptomatic for 12 35 days (exo erythrocytic stage) 2. Symptoms manifest when merozoites released from ruptured RBC - 3 successive stages: a. 15-60 Minute Cold Stage shivering + feeling of cold b. 2-6 hr Hot Stage Fever Flushed, dry skin Headache Nausea/vomiting c. 24 Hr Sweating Stage Fever drops rapidly Rapid thready pulse Polyuria Poor Px if: Altered consciousness with or without seizures Respiratory distress Circulatory collapse Metabolic acidosis Renal failure, hemoglobinuria (blackwater fever intravascular hemolysis leading to Hburia) Hepatic failure Coagulopathy with or without disseminated intravascular coagulation Severe anemia Hypoglycemia Physical findings: Pallor, petechiae, jaundice, hepatosplenomegaly Lab findings: - parasitemia > 5-10% of neutrophil contain malaria pigment - Normochromic normocytic Anemia - Thrombocytopenia - Coagulopathy - Elevated transaminases (ALT or AST) liver damage - Elevated BUN/creatinine - Acidosis - Hypoglycemia Thick & Thin Blood Films

Thin films are similar to usual blood films and allow species identification, because the parasite's appearance is best preserved in this preparation. Thick screen a larger volume of blood and are about eleven times more sensitive than the thin film picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult

MALARIA DRUGS Drugs that kill parasite in blood Schizonticides - For acute attack act on erythrocytic stage 1. Quinine MOA: - Inhibit Plasmodiums Haem Polymerase (wh/ breaks down Hb to haemozoin. Free Haem is also toxic to plasmodium) - Interferes with DNA or RNA syntheses - Increase intravascular pH AE: Cinchonism (tinnitus, headache, nausea, vomiting, blurry vision)
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Mefloquine MOA: Forms toxic complexes with free haem damages membranes AE: Neuropsychiatric disorders (avoid in depressed, schizophrenic, psychological ill), GIT, giddiness, confusion, insomnia Chloroquine widespread resistance, still remains effective for P. Ovale, P. Malariae, and in most regions P. Vivax

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Drugs for radical cure (to remove hypnozoites) Tissue Schizonticide - Act on parasites in liver in P. Ovale and P. Vivax eliminating hypnozoites - Also destroy gametocytes in P. Falciparum - Drugs: Primaquine and Tafenoquine Drugs that prevent transmission Gametocides - Primaquine, Proguanil, Pyrimethamine, Artermisinin all have additional action of destroying gametocytes preventing transmission Prophylactic drugs - Block link between pre-erythrocytic and erythrocytic by killing parasites when out from liver

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Doxycyline Tetracycline AB inhibits protein synthesis (bacteriostatic) Pyrimethamine with sulfodoxine (Fansidar) Folate antagonist Artemisinin reacts with iron from Hb to produce ROS Malarone combination of Atovaquone + Proguanil Atovaquone blocks parasite mitochondrial electron transport chain Proguanil inhibits parasite DHFR

PREVENTION 1. Vector Control: Insect repellent, protective clothing, insecticide impregnated bed nets (permethrin), elimination of breeding site, avoid dusk/dawn and dark clothing/perfume 2. Prophylactic chemotherapy -Drug used usually: o Atovaquone+Proguanil (Malarone) o Doxycyline o Mefloquine