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MALARIA Yuankai Wu The Third Affiliated Hospital of Sun Yat-Sen Universicty Department of infectious diseases Malaria • a vector-borne disease caused by single celled parasites, the Plasmodium protozoa, and transmitted by female Anopheles mosquitoes. • Characterized by malarial paroxysm of chills, fever and sweats. Still an enormous pubic health problem and one of the most common infectious diseases. History of malaria • Malaria has infected humans for over 50,000 years. • first recorded in 2700 BC in China. • originates from Medieval Italian: • mala aria — "bad air"; • was formerly called ague or marsh fever due to its association with swamps and marshland History of malaria • 1880, a French army doctor first observed parasites in patient’s RBC. the 1907 Nobel Prize for Physiology or Medicine. • 1898, Britain's Sir Ronald Ross finally proved that malaria is transmitted by mosquito.(received the 1902 Nobel Prize) Charles Louis Alphonse Laveran Malaria • • • • • • • • • 1. Etiology (life cycle) 2. Epidemiology 3. Pathogenesis and pathology 4. Clinical manifestation 5. Diagnosis 6. Differential diagnosis 7. Therapy 8. Prevention 9. Summary Etiology • Plasmodium protozoa – – – – P. falciparum (the deadliest); P. malariae ; P. ovale ; P. vivax (the most common); • Within each species there are variant strains. Life cycle • Sexual cycle in mosquito – Gametocyte, gamete, zygote, ookinete, oocyst, sporoblast, sporozoite • Asexual cycle in Human – Exoerythrocytic stage: sporozoite, tachysporozoite (12-20d), bradysporozoite (hypnozoite) (6-11m), merozoite, schizont, – Erythrocytic stage: ring form, trophozoite, schizont, gametocyte Ring form Trophozoite Schizonte Gametocyte Sporozoite Tachysporozoite Bradysporozoite Merozoite Release merozoites Release merozoites Fertilization 3-6 generations in RBCs Epidemiology • Source of infection – Patients – Asymptomatic carriers Epidemiology • Route of transmission – Bite by female anopheles mosquitoes. – Vertical transmission (placenta) – Blood transfusion Epidemiology • Susceptibility – All susceptible – Travelers and foreigner – Children, pregnant women – Short immunity, without cross immunity. Epidemiology • Epidemiological feature – Seasons: Summer and Autumn (temperature) – In china, P. vivax is predominant, P. falciparum second, P. malariae and P. ovale seldem. – Endemic areas: tropic or sub-tropic area. Endemic countries of malaria (2003) NOTE: In most of these countries malaria was limited to certain areas Death (/10,000) Year The mortality of malaria in china in 1952-1998 Pathogenesis Toxic mediators Inflammatory responses Chill, fever, sweat metabolic disturbances hypoglycaemia Anemia Hemolysis Phagocytosis Adhere to blood vessels Splenomegaly hepatomegaly renal failure Black water fever Cerebral malaria Tissue hypoxia Obstruct blood flow Pulmonary edema Impaired microcirculation DIC The severtity of clinical manifestations • Parasitemia – P. falciparum: 1,000,000/ mm3 – P. vivax and P. ovale: ≤25,000/mm3 – P. malariae: ≤10,000/mm3 • Infected RBC – P. falciparum: RBCs of any age. – P. vivax and P. ovale: younger RBCs. – P. malariae: older RBCs. • Multiply speed – P. falciparum: 36-48h – P. vivax and P. ovale: 48h – P. malariae: 72h Clinical manifestation • • • • • • • • • • • Incubation period: 7~30d (7~12, 13~15, 24~30) Malaria paroxysm: chills, fever and sweating. Periodicity: every 48h (P. vivax, P. ovale) every 72h (P. malariae) every 36-48h (P. falciparum) Between attacks: feel fine (P. vivax, ovale or malariae) or miserable (P. falciparum) Clinical manifestation —typical attack • Chilling stage: 20min~1h, feel cold and true shaking chills, accompanied with malaise, headache, vomiting or diarrhea. • Hot stage: 2~6h, T usually as high as 41℃, tachycardia, hypotension, cough, headache, backache, but normal consciousness. • Sweating stage: 30min~1h, T falls with diaphoresis, fatigue and weak. • Common signs: anemia, splenomegaly. Intermittent fever of P. vivax synchronization ℃ 40 39 38 37 1 2 3 4 5 6 7 8 9 10 11 12 13 Days Clinical manifestation severe attack • Cerebral malaria: – P. falciparum infection, T, antimalarial drugs. – Obstruction of vessels and hypoglycemia. – Severe headache, high fever. – Impairment of consciousness: confusion, obtundation, seizures and coma. – Neurologic sign: hyper-reflexion and bilateral Babinski’s sign. Focal neurologic finding occurs rarely. Recrudescence and Relapse • Recrudescence: – residual plasmodium in the bloodstream. – could be found in all the four species infection. – 1~4wk after relieved, or repeatedly. • Relapse: – hypnozoites in the hepatocytes. – only found in P. vivax and P. ovale. – usually 3~6mon after “cured”. Clinical manifestation special type • malaria in pregnancy: – main adult risk group. – 80% death of malaria in Africa. – more aggravated: anemia, fever, hypoglycemia, cerebral malaria, pulmonary edema, puerperal(afte labor) sepsis. – Low birth weight, prematurity. – Vertical transmission. Clinical manifestation special type • Malaria infected by blood transfusion: – Symptoms: the same as malaria transmited by mosquitoes. – Shorter Incubation stage: 7-10d. no exoerythrocytic stage – No hypnozoite, no relapse. • Malaria infected by vertical transmission: – Symptoms: the same – Incubation stage: about 1wk after birth. – No hypnozoite, no relapse. Complications • Hemolytic urinemic syndrome (black water fever) • Pulmonary edema. • Hyperreactive malarial splenomegaly. • Shock, hypotension. • Diarrhoea, jaundice, splenic rupture. • Anemia, hemorrhage, DIC. • Hypoglycaemia, metabolic acidosis. Complications • Hemolytic urinemic syndrome – More common in adults, rare in children. – More frequent in patients without immunity and with high parasitemia and G6PD deficiency after quinine or primaquine. – Intravascular hemolysis, hemoglobinuria. – Lumbago, dark urine(black water), jaundice, oliguria, renal failure. Complications • Hemolytic urinemia syndrome(black water fever). • Pulmonary edema. • Hyperreactive malarial splenomegaly. • Shock, hypotension. • Diarrhoea, jaundice, splenic rupture. • Anemia, hemorrhage, DIC. • Hypoglycaemia, metabolic acidosis. Complications • Pulmonary edema – Uncommon, even in severe infection. – Patients with hyperparasitemia. – Results from capillary leak rather than heart failure. – A fatal complication. – Treated with positive-pressure artificial ventilation. Complications • Hemolytic urinemia syndrome(black water fever). • Pulmonary edema. • Hyperreactive malarial splenomegaly. • Shock, hypotension. • Diarrhoea, jaundice, splenic rupture. • Anemia, hemorrhage, DIC. • Hypoglycaemia, metabolic acidosis. Complications • Hyperreactive malarial splenomegaly – Tropical splenomegaly syndrome (TSS). – Seen in older children and adults. – Associated with repeated infection In hyperendemic area. – Anemia, massive splenomegaly, elevated IgM levels and malarial antibody. – Usually responds to prolonged treatment with prophylactic antimalarial drugs. Complications • Hemolytic urinemia syndrome(black water fever). • Pulmonary edema. • Hyperreactive malarial splenomegaly. • Shock, hypotension. • Diarrhoea, splenic rupture. • Hemorrhage, DIC. • Hypoglycaemia, metabolic acidosis. Diagnosis • Epidemiological history – Traveled in endemic areas (bitten by a mosquito) – Blood transfusion or organ transplantion • Clinical manifestation – Typical malaria paroxysm – Intermittent fever, Several small fever spikes • Pathogenic detection – Thick and thin film • Diagnositic therapy in atypical cases Diagnosis • Pathogenic Investigations – Microscopic diagnosis – Quantitative buffy coat(QBC) – Antigen detection: RDTs – Serology test: ELISA, IFA – Molecular diagnosis: PCR • Other: complete blood count, blood chemical tests of liver function and renal function. Diagnosis Microscopic diagnosis • Blood smear (Gold standard) – The most preferred, economic, and reliable – Thick film: sensitive, diagnosis of infection – Thin film: identification of species – Giemsa's staining positive Ring form and Gametocyte of P. falciparum Diagnosis • Pathogenic Investigations – Microscopic diagnosis – Quantitative buffy coat(QBC) – Antigen detection: RDTs – Serology test: ELISA, IFA – Molecular diagnosis: PCR – others Differential diagnosis • Infectious diseases • – Influenza – Sepsis – Typoid, paratypoid fever – Leptosirosis – Dengue fever – Japanese B encephalitis – toxic dysentery – Hemorrhagic fever with renal failure – Acute intravascular hemolysis Non-infectious diseases – Lymphoma, leukaemia – Malignant histocytosis – Connective tissue diseases Prognosis • Curable if treated in early stage. • Chronic malaria in hyperendemic areas. • Kill up to 15%~20% children<5y in Africa. Treatment • Symptomatic and supportive measures – Relief of high fever – Intravenous injection to sustain fluid balance – Treatment hypoglycemia – Dehydration in cerebral malaria – Blood transfusion for severe anemia – Hemodialysis when renal failure – …… • Antimalarial treatments. Antimalarial Treatment • Tissue schizonticides (causal prophylaxis) • Pyrimethamine and Primaquine • Blood schizonticides (terminate attacks) • Chloroquine , Artemisinine, Quinine, Mefloquine, Halofantrine, Pyrimethamine, Sulfadoxine, Sulfones, Tetracyclines, Doxycycline • Tissue schizonticides (prevent relapse) • Primaquine, tafenoquine and Pyrimethamine • Gametocytocides (block transmission) • Primaquine, tafenoquine, Chloroquine, Quinine, Artemisinine • Sporontocides (ablate transmission of mosquito) • Primaquine and proguanil Antimalarial strategy Chloroquine Blood schizonticides ＋ Artimesinine, Artesunate ＋ Gametocytocides / Primaquine Tissue schizonticides Tafenoquine Available drugs • Quinine – 0.65g tid×7d – Seldom used now • The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. Available drugs • Chloroquine (phosphate) – Most common used • 1.0 po., 0.5 po.6~8h later on the first day • 0.5 po. Qd on the second and third day – Drug resistance (P. falciparum) • Quinine + Doxycycline/Tetracycline/clindamycin • Artemisinine or Artesunate Available drugs • Artemisinine and Artesunate – Powerful and less resistant – Artemisinine • 1.0 po., 0.5 po.6~8h later on the first day • 0.5 po. Qd on the second and third day – Artesunate • 100mg bid×1d，50mg bid×4d – Cerebral malaria and pregnant patients Available drugs • Primaquine (phosphate) – Most commonly used Gametocide – Prevent relapse and block transmission • 7.5mg tid × 8d – Acute intravascular hemolysis (black water fever) • Routine G6PD test!! Cerebral malaria • Artesunate – 60mg iv. drip, at 0, 4, 24, 48hr – 50mg bid ×2~3d • Chloroquine – 16mg/kg→8mg/kg → conscious →po. • Quinine – 500mg q12h →conscious →po. Caution • Repeat the thick and thin blood smear • Do not use Doxycycline, Primaquine, Mefloquine, Atovaquone-proguanil in Pregnant women. • Routine G6PD test? Prevention • Control the source of transmission • Cut off the route of transmission • Protection of susceptible population Prevention Source of transmission • Cases management – Cure the patients and carriers – use gametocides and blood schizonticides simultaneously. – Chloroquine / artemisinine / artesunate and primaquine / tafenoquine Prevention Route of transmission • Vector control – Kill anopheles mosquitoes: insecticide spraying – Avoid multiply of mosquitoes: • Personal protection – Mosquito nets – Repellents – Long clothes Prevention Protection of susceptible population • Active prophylaxis – Vaccine • Under development • Passive prophylaxis – Chemoprophylxis • Chloroquine (sensitive, pregnant women or children) • Mefloquine, Doxycycline, Pyrimethamine. summary • Malaria is a vector-borne parasitic disease caused by plasmodium protozoa • All the four species plasmodium need anopheles mosquitoes and human to complete it’s life cycle. • Transmitted by a bite of anopheles mosquito. • Characterized by the malaria paroxysm (chill, high fever,and sweats) • The thick film and thin film can diagnose a malaria. • Use the blood schizonticides and gametocides simultaneously to kill the parasite. • Prevention refers to the cases management, vector control, personal protection, vaccine and chemoprophylaxis. • Malaria is still a enomous public health problem world wide. THANK YOU! Useful Links • Centers for Disease Control and Prevention：http://www.cdc.gov/ Global Fund to Fight AIDS, TB and Malaria：http://www.who.int/malaria/ Global Health Advocates Innovative Vector Control Consortium Lubombo Spatial Development Initiative Malaria Foundation International Malaria Journal Malaria Vaccine Initiative Medical Research Council Medicines for Malaria Venture Multilateral Initiative on Malaria Nature Medicine (Malaria) President's Malaria Initiative Roll Back Malaria Partnership South Africa Department of Health (Malaria) East and Southern African Malaria Control UNICEF World Health Organisation World Bank