Malaria. Anders Björkman

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1 Malaria Anders Björkman 1

2 Malaria major public health problem in the developing world 2

3 History Mal aria = bad air Romans Ancient Chinese and Indian medical texts Hippokrates 500 B.C Linnaeus 1735 Laveran 1880 Discovered the parasite in human blood (Nobel prize 1907) Ross 1898 Described the complete life cycle in birds (Nobel prize 1902) 3

4 What is Malaria? Parasitic disease caused by members of genus Plasmodium >100 species described in mammals, reptiles and birds Five species infect humans P. falciparum P. vivax P. ovale P. malariae P. knowlesi!! 4

5 The species differ in: 1. morphology 5

6 2. Differ in details of their lifecycles... 6

3. Differ in clinical manifestations Plasmodium falciparum Causes the most deadly and severe infections. Infects all ages of erythrocytes leading to a high parasitemia.

7 3. Differ in clinical manifestations Plasmodium falciparum Causes the most deadly and severe infections. Infects all ages of erythrocytes leading to a high parasitemia. Mature stages sequester in the capillaries leading to symptoms. Widespread drug resistance. Incubation time 7 days Found in Tropics/Sub-Tropics Temperature o C 7

8 Plasmodium vivax P. vivax usually does not cause life-threatening infections. P. vivax only infects reticulocytes, gives low parasitemia P. vivax produces hypnozoites which are latent in the liver. Relapses can occur up to 5 years after infection P. vivax uses the Duffy blood receptor to enter erythrocytes P. vivax not found in West Africa. Found Temperate/Tropics/Sub-Tropics 1

9 Plasmodium ovale P. ovale resembles P. vivax in life cycle, appearance, clinical presentation and treatment. However, can infect Duffy negative individuals. Found in Africa 2

Plasmodium malariae P. malariae usually does not cause life-threatening infections. P. malariae causes low grade parasitemia Description of parasite persistence > 40 years exists.

10 Plasmodium malariae P. malariae usually does not cause life-threatening infections. P. malariae causes low grade parasitemia Description of parasite persistence > 40 years exists. Found in Tropics/Subtropics Plasmodium knowlesi Macaca monkeys natural host Proposed as 5th human malaria parasite Resembles P. malariae in microscopy Can cause severe disease and death Found in South East Asia 3

11 To complete the lifecycle 3 players are needed Man = Host Plasmodia = Agent Female Anopheles mosquito = Vector 4

12 Transmission By female Anopheles mosquito Endemic areas Local spread airports Without mosquito Congenital Transfusion accidental Controlled infection to treat other diseases, e.g. Neuro-syphilis 5

Anopheles gambiae complex Most common vector of malaria in Africa General feeding habits: From dusk to dawn Other feeding preferences early evening - late at

13 Anopheles gambiae complex Most common vector of malaria in Africa General feeding habits: From dusk to dawn Other feeding preferences early evening - late at night. antropophilic (humans) - zoophilic (cattle) indoor (endophagic) - outdoor (exophagic) Resting place after blood meal Indoor (endophilic) or outdoor (exophilic) 6

14 Malaria globally 2.5 billion people in >100 countries a risk (40% world population) -300 million people experience clinical disease each year -800 deaths each year 1 death every 45 seconds Majority of deaths are children >5 years and pregnant women in sub-saharan Africa 7

15 Economic analyses indicate that burden of malaria is enormous Highly malarious countries are among the poorest in the world Malaria obstructs economic development/growth Estimated annual loss of economic growth due to malaria 1.3% 8

16 Malaria in Sweden In whole of Europe below 2000 m altitude Last case in Sweden 1933 Known as intermittent summer fever summer agues P. vivax hypnozoites needed to survive the winter 5% of mosquito population Anopheles Malaria disappeared due to improved socio-economic standard Today imported malaria circa 100 patients/year 1

17 Malaria epidemiology Endemic: hypo (<10%), meso (11-50%), hyper (50-75%), holo (>75%) Epidemic Stable transmission Continuous exposure >10 infective mosquito bites per year (Entomological innoculation rate= EIR) Aquired immunity small children + pregnant women affected Unstable transmission Low EIR NO aquired immunity all age groups affected Epidemic prone 2

18 Clinical presentation: fever most common symptom 3

19 Uncomplicated vs. severe malaria syndrome Criteria for severe malaria: Prostration Impaired consciousness Multiple convulsions Severe anaemia (Haemoglobin (Hb) <50 g/l) Hyperparasitaemia (> /μL or >5% of red blood cells) Hypoglycaemia Respiratory distress (acidotic breathing) Pulmonary oedema (radiological) Circulatory collapse Abnormal bleeding Jaundice Haemoglobinuria Hyperlactataemia Acidosis 4

20 Malaria Anaemia Hemolysis (both infected and non-infected RBCs) Removal by the spleen Bone marrow suppression 5

21 Cerebral malaria ARDS Severe malaria 6

22 Malaria immunity Innate immunity Sickle cell trait, Thalassemia trait, G6PD Acquired immunity strain specific 7

23 P. falciparum in the African context - the classical concept.. Fever in an African child = presumed to be malaria Problems Clinical diagnosis difficult Fever a cardinal symptom but not disease specific for malaria Fever overlaps with several other childhood illnesses, e.g. respiratory tract infections, flu, meningitis, septicemia 8

24 Malaria fever Musuja (in Lugando) = fever = malaria Now also musuja from mosquito Heev Taap (in Maharas Iran/Bombay): Shivering with cold - fever 9

25 How to confirm a diagnosis of malaria? Microscopy Needs skilled technician, microscope, slides, staining material etc Time consuming but relatively cheep Detection limit under field conditions parasites/ microlitre Rapid Diagnostic Tests (RDT) Relatively expensive Minimum training needed Can not quantify parasites Remains positiv after treatment not monitor treatment outcome Sensitivity should be 95% for 100 parasites/mikrolitre blood Polymerase chain reaction (PCR) 10

26 Microscopy 11

27 RDT 12

28 However, reality is often: No or limited access to health care available... A majority of fever sick children never reach formal health care Presumptive treatment given at home over/under diagnosis and treatment Treatment often not in correct dose/incomplete treatment course Drug resistance and increased morbidity & mortality 13

29 The ears of the Hippopotamus. Breman

30 Causes of death in malaria Death within hours after onset of disease common! Anemia (<2 years) Cerebral malaria (3-5 years) If surviving 5th birthday in high endemic area decreased risk of malaria associated death Protection against severe disease and death age dependent 15

31 Malaria and co-morbidities Co-infections a reality in rural Africa Worm infestations, respiratory tract infections, septicaemia, HIV/AIDS Measles, influensa decreased risk? Malnutrition 1

32 Driving forces behind drug development Malaria: Major obstacle for expansion of colonial empires More lethal than bullets for soldiers in war 2

33 Quinine - Jesuit s Powder The drug that changed history! 1628 Countess of Cinchon, fever tree bark, Peruvian Indians 1643 Cardinal Juan de Lugo promoted use in Europé Jesuit s bark 1747 Linnaeus named the tree Cinchona officinalis 1820 Quinine isolated by Pelletier and Caventou Jesuit s 1854 large scale cultivation in Indonesia and India Events during First World War indicated shortage of quinine... 3

34 New drugs needed for new wars 1934 German scientists developed chloroquine Second World War 4

35 Development and spread of chloroquine resistance 5

36 US army starts to act New syntetic drugs under development 1975 Mefloquine (Lariam ) introduced for treatment 6

37 China strikes back... Artemisia annua Sweet Wormwood Used for fever treatment in China since ancient days 340AD Ge Hong Modern use from

38 Driving force for drug development Not driven by the need of the poor in endemic areas 8

39 Present drug policies Two outstanding antimalarial drugs are based on herbal medicines Quinine Artemisinin-derivatives WHO advocates combination therapy to Improve efficiacy Delay development of resistance Artemisinin-based combination therapy (ACT) 9

40 Artemisinin-based combination therapy Treatment of choice for uncomplicated malaria, but.. Much more expensive increased need for rational use and improved diagnostics No syntetic artemisinin-derivative available on the market

41 Artemisin based Combination Therapy ACT artemether + lumefantrine (Coartem/Riamet R ) artesunate + amodiaquine (Coarsucam R ) artesunate + mefloquine dihydroartemisinin + piperaquine (Artekin) artesunate + sulfadoxine/pyrimethamine artesunate + pyronaridine (Pyramax) 11

42 Treatment severe malaria Artemisinin derivatives Artesunate (iv) for a total of 7 days, 2.4 mg/kg BW at 0h, 12h and then once daily Artemether i.m. (Pre-referral administration of Rectocaps) Quinine Loading dose 20 mg/kg in 5% dextrose over 4 hours followed by 10 mg/kg x 3 Treatment for 7 days 12

43 Drug Introduction First year Difference resistance (years) reported Quinine Chloroquine Proguanil Sulfadoxine- Pyrimethamine <1 Mefloquine Atovaquone <1 Artemisinins

44 Malaria in pregnancy More sensitive to malaria compared to non-pregnant women Women in first pregnancy in highly endemic areas have higher risk for malaria parasitaemia compared to later pregnancies Parasitized erythrocytes adhere to chondroitinsulfate A (CSA) in placenta accumulation of infected erythrocytes chronic inflammation 14

Effects/risk of malaria in pregnancy Maternal anemia and death (responsible for 10 000 maternal deaths in Africa annually) Preterm

45 Effects/risk of malaria in pregnancy Maternal anemia and death (responsible for maternal deaths in Africa annually) Preterm labour and fetal growth restriction resulting in low birth weight (<2500 g) (Responsible for LBW yearly) Stillbirth, abortion 15

46 Interventions in pregnancy Insecticide treated nets (ITN) Intermittent preventive treatment (IPTp) Early access to prompt and effective treatment 1

47 Intermittent preventive treatment (IPTp) At least two separate doses of sulfadoxine-pyrimethamine (SP) in second and third trimester given as a single dose under observation of a health worker. First dose when fetal movements are felt (18-20 weeks gestation) and the second a month later. HIV-positive women should receive three doses or all women if HIV prevalence exceeds 10% and HIV testing is not available 2

48 Effects of IPTp Clears infection, prevents clinical malaria and provides posttreatment prophylaxis Improves birthweight, reduces significantly the risk of low birthweight, especially in primigravidae 3

49 ITNs 4

50 History of mosquito nets Bed nets made of silk were used by the Chinese 1000 years ago A long tradition of mosquito net use is found in West-Africa, e.g. Ghana DDT treated bed nets were first used during World War II Late 1970s synthetic Pyrethroids were developed to mimic natural insecticidal compounds found in Chrysanthemums 5

51 WHO starts to show interest in ITNs... In the mid 1980s studies confirmed the safety of using pyrethroid insecticides to treat nets and demonstrated substantial effects on entomological measures such as EIR 6

52 Untreated Nets Untreated vs Insecticide Treated Nets Protective barrier around persons using them Mosquitoes can feed on people through the nets or holes Efficacy data scarce, but probably effective ITNs enhanced efficacy Knock-down/lethal effect on insects Repellent + effect on other night biting insects 7

53 Impact of ITNs on morbidity and mortality The initial reports led to Phase II and III clinical field trials, which provided evidence that ITNs are successful in reducing both malaria morbidity (50%) all-cause child mortality (20%) ITNs are important component of global and national malaria control policies since the mid-1990s. Recently Long lasting insecticidal nets (LLINs) with an effect up to 5 years are available and recommended 8

54 Global strategies to fight malaria Eradication Vertical program Lack of commitment and community participation Miss use of chloroquine added in Salt etc Chloroquine and DDT resistance Failed malaria stroke back!! 9

55 Modern malaria control strategies Early diagnosis and effective treatment with ACT Insecticide treated nets (ITN) or rather LLIN Indoor residual spraying (IRS) Intermittent preventive treatment (IPT - pregnancy/infants) Seasonal malaria chemoprevention (SMC children) Improved diagnostics (Rapid Diagnostic Tests) 10

56 Roll Back Malaria (Abudja, Nigeria, April 25, 2000) Halve the malaria mortality for Africa's people by 2010, through implementing the strategies and actions for Roll Back Malaria >60% of malaria patients should access correct, affordable and appropriate treatment within 24 hours >60% at risk, children <5 and pregnant women, to sleep under Insecticide treated nets (ITP) >60% of pregnant women should have access to Intermittent Preventive Treatment (ITPp) The above targets have later been revised to 80% 1

57 Millenium Development Goals 1. Eradicate Extreme Poverty and Hunger 2. Achieve Universal Primary Education 3. Promote Gender Equality and Empower Women 4. Reduce Child Mortality Reduce by two-thirds, between 1990 and 2015, the under-five mortality rate 5. Improve Maternal Health 6. Combat HIV/AIDS, Malaria and other Diseases Halt and begin to reverse the incidence of malaria and other major diseases 7. Ensure Environmental Sustainability 8. Develop a Global Partnership for Development 2

58 Is there hope for Africa in the battle against Malaria?? Malaria is on the agenda! Commitment higher from leaders International initiatives/collaborations Global Fund New donors - Bill and Melinda Gates Combined interventions giving positive results e.g. Zanzibar Sustainability? Elimination? 3

59 an emerging threat against global malaria control.. 4

60 5

61 Remember the history of development and spread of chloroquine resistance 6

Invest in the future, defeat malaria

Invest in the future, defeat malaria Malaria is caused by parasites from the genus Plasmodium, which are spread to people by infected mosquitoes. There are five species of Plasmodium that can infect humans.