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Malaria Definition Vector-borne disease Caused by parasitic protozoa from genus Plasmodium Transmitted through infected female Anopheles

mosquito Significance Number is climbing due to y Vector resistance to insecticide y Parasite resistant to drug y Human exposure to endemic area y Legal/ illegal migration Association between malaria & HIV y Malaria make HIV worse y HIV make malaria worse World s most significant emerging infectious disease Parasite Morphology (P. falciparum)

Due to y Rise in airport malaria cases jet age (shrinking world) y Climate changes global temperature (vector breeding opportunity) y Natural disasters & wars poor logistics, mass migration Transmission Primary Mode Infected Anopheles bite during meals & transfer parasite into human Malaysia 15 species y Anopheles sundainus y A. maculates y A. balabancensis

Other Mode Blood transfusion y Common in endemic y Donor may remain infective P. falciparum 1-3 years P. vivax 3-4 years P. ovale - >30 years y Blood used < 5 days after donation Congenital malaria y Mother to fetus y Due to heavily infected placenta Accidental transmission y Needle stick injury y Sharing of needle among drug addicts in endemic areas y Blood stages

Epidemiology Most widespread disease worldwide Major health problem of > 100 countries in Sub-Tropical (Tropical, surplus of rain) Altitude <2000 feet In developed countries USA, Europe, Japan (mainly due to airport/ imported malaria) Mix infection between plasmodium species is common (in Malaria endemic areas) Malaysia is endemic for y P. falciparum y P. vivax y P. malariae y P. knowlesi y No P. ovale infection reported locally

Parasite Plosmodium falciparum Plasmodium vivax Most widely spread Common in temperate & tropical climate Benign malaria (recent study severe malaria) Plasmodium ovale Plasmodium malariae Plasmodium knowlesi

Malignant malaria (Most dangerous) 90% of deaths due to malaria Cause complicated/ severe malaria Characterized by y Sequestration y Cytoadherence of knobbed infected RBCs Cerebral malaria Established drug resistance worldwide (tendency for recurrent/ recrudensence) No relapses No hypnozoite Paroxysm after 48h rd Tertian malaria (Fever on 3 day) Infects RBCs from all ages y Severe anaemia y Parasitaemia Gametocytes develop in peripheral blood BFMP seen only (> 1 trophozoites/ RBC) y Young trophozoites (ring forms) y Gametocytes Infected RBCs y Knob formations y No change in size, shape Worldwide distribution Predominant species in y Africa y New Guinea y Haiti Also found in y South America y Part of Asia y Oceania

Benign malaria

Benign malaria

Benign malaria (recent study severe, fatal) Co-exist with P. malariae Malaria parasite of long tail monkey Often misdiagnosed as P. malariae Share similar morphology & symptoms Differentiation only by PCR

Relapses Hypnozoite Paroxysm after 48h rd Tertian malaria (Fever on 3 day) Infects young RBCs (reticulocytes) 1 merozoite/ RBC Infected RBCs Enlarged

Relapses due to hypnozoite Paroxysm after 48h rd Tertian malaria (Fever on 3 day) Infects young RBCs (reticulocytes) Low parasitaemia 1 merozoite/ RBC Infected RBCs y Enlarged y Oval shaped with fimbriated edge Parasite very similar to P. vivax (Differentiation problem)

No hypnozoite Reported up to 53 years post infection Paroxysm after 72h th Quartian malaria (Fever on 4 day) Infects old RBCs Low parasitaemia 1 merozoite/ RBC Infected RBCs y No change in size y Band form trophozoites

Relapse unknown 24h life cycle Paroxysm every 24h Fever every day Can develop severe parasitaemia (fatal) P. knowlesi fatal zoonotic infection y Kelantan y Sabah y Sarawak y Thailand y Singapore y Philippine Zoonotic infection

Most common in y Central America y North Africa y Southern Asia y Western Asia Also found in y South America y Parts of Asia y Oceania

More restricted to certain geographical region Natural distribution in y Sub-Saharan Africa y Island of Western Pacific New Guinea y Timor (Indonesia) y Irian Jaya y West Flores y Timur Timor y Philippines y Vietnam y Thailand y Sub-continent of India Not found in y Sumatra y Jawa y Sulawesi y Solomon Island

More wide spread, Observed in all major malaria-endemic regions of world Commonly found in y Sub-Saharan Africa y Southeast Pacific Also found in endemic area y Asia y Middle East y South Africa y Central America

General Life Cycle

QBC

Suitable for - Malaria infection confirmation Not suitable y Parasite identification y Determine parasite load Experienced lab personnel Screening Laboratory Diagnosis Microscopic Peripheral Blood Film for Malaria Parasite (BFMP) Quantitative Buffy Coat (QBC) Non-microscopic Rapid Test y Parasites antigen detection y Serology antibody detection Polymerase Chain Reaction (PCR) Clinical examination Non-microscopic Absence of trained personnel Useful screening assays Antibody Detection Indirect Fluorescent Antibody (IFA) Enzyme Immunoassays (EIA)

Antigen Detection Immunochromatographic

Peripheral Blood Film for Malaria Parasite (BFMP) Stained with Giemsa stain Gold standard (laboratory confirmatory of malaria) Films Thick Film Thin Film Concentration technique Concentration technique 10-30X more sensitive than thin film Less sensitive than Thick Film 30 min 3-5 (10) min Useful for Useful for y Parasites identification y Parasite detection y Quantitate y Quantitate (% of parasitaemia) (no. of parasite/uL blood)

Malaria IFA & EIA Antibody against malaria parasites Possible in non-immune individuals with 1 infection Not possible in immune individuals (antibody response reflects multiple infections with multiple species) Malaria Serology Test Antibody test Only P. falciparum cultivated in vitro To exclude malaria (eg. among travellers) Blood donation from travellers For epidemiological reasons Immunochromatographic Dipstick (Malaria Antigen Detection)

Polymerase Chain Reaction (PCR)

Detect 4 Plasmodium species in blood from humans (by 18S rRNA gene) y P. vivax y P. malariae y P. falciparum y P. ovale Species-specific PCR diagnosis of malaria (CDC)

Pathology & Symptoms of Malaria Febrile illness (Fever) Characterized by y Bursting of RBCs y Clogged capillaries of major organs

Stages of Malaria Attack

Life cycle of Malaria Involvements Blood Anaemia, Cytoadherence Bone marrow Megakaryocytes Spleen Spleenic rupture, Tropical splenomegaly Liver Hepatomegaly Lungs Pulmonary edema CVS Cardiac dilation GIT Colitis, Severe diarrhoea Kidney Renal failure CNS Cerebral malaria Knob formation Normal uninfected human RBC

Infected human RBC

Early symptoms (could be mistaken with Influenza or GIT infection) Mild fever (usually no intermittent) Headache Nausea Vomiting General malaise Fatigue Muscular pains (bodyache) Slight diarrhoea Anorexia Febrile paroxysms Acute febrile paroxysms (characteristic of malaria infection) Periodic febrile paroxysms every y 48h tertian (Pf, Pv, Po) y 72h quartian (Pm) y 24h (P.knowlesi) Usually accompanied by y Headache y Vomiting y Delirium y Anxiety y Restlessness But disappear with normalization of body temperature

Smooth surface Sequestration & Cytoadherence Rosetting

Rough surface (knobs formation)

Clumping

Adhesion of infected RBCs to other RBCs Pathology & Symptoms Bursting of RBCs Clogged capillaries of major organs

Adhesion between infected cells

Severe malaria Complex multisystem disorder with similarities to Sepsis Syndrome (Complicated malaria) Major complications Other complications Cerebral malaria (coma) Electrolyte disturbances Severe anemia Jaundice Hypoglycemia Lactic acidosis Acute renal failure (ARF) Thrombocytopenia Pulmonary edema Respiratory distress syndrome (RDS) Mental status change Hepatomegaly Splenomegaly Tropical splenomegaly syndrome Haemoglobinuria

Adherent parasites in brain

Clogging of small blood vessels (by parasites & infected RBCs)

Cerebral malaria

Severe anaemia

Tropical splenomegaly syndrome

Immunity Influenced by y Genetics y Age y Health condition y Pregnancy status y Intensity of transmission in region y Length of exposure y Maintenance of exposure Immunity Acquired y No complete immunity (can be parasitaemic without clinical disease) y Need longer period of exposure for induction y May need continued exposure for maintenance y Immunity can be unstable o Can wane (when spend time outside endemic area) o Can change with movement to area with different endemicity o Decreases during pregnancy (risks improves with increasing gravidity) Acquired Transferred from mother to child y 3-6 months protection y Then children has susceptible Susceptibility in early childhood Hyper & Holoendemic areas By age 5 attacks usually less frequent & severe Can have more parasite densities (with fewer symptoms)

Sickle cell Low oxygen rate Innate RBC cytoskeleton abnormality (ovalocytosis) y Elliptical red cell y Papua New Guinea population Red cell polymorphisms associated with some protection y HbS sickle cell trait/ disease y HbC & HbE y Thalessemia , y G6PD deficiency Red cell membrane changes y Absence of certain Duffy coat antigens (Duffy ve) Improve resistance to P.vivax West Africa

Treatment Most drugs used in treatment are active against parasite forms in blood (the form that cause disease) y Chloroquine y Sulfadoxine-pyrimethamine (Fansidar) y Mefloquine (Lariam) y Atovaquone-proguanil (Malarone) y Quinine y Doxycycline y Artemisin derivatives (not allowed in USA use, but found overseas) Control & Prevention Vector control & sanitation Vaccines Chemotherapy Protective (prophylaxis) Curative Prevention of transmission

Meso- or Hypoendemic areas Less transmission & repeated attacks May acquire partial immunity & be at higher risk for symptomatic disease as adults