1. Introduction to Malaria Prof. Remigius Okea, MD MPH Research Director: American Academy of Primary Care Research (AAPCR) Chairman Scientific Advisory Board: Tropical PharmMedics Research Institute First presented in 2003

2. Malaria a word coined from Mal Ar (“Bad Air”)

3. Review Objectives 1.Distribution 2. Understand malaria cycle 3. Transmission 4. Understand the treatment 5. Plasmodium life cycle (a basis for understanding the disease) 6. Pathophysiology 7. Brief description of health significance of Malaria 8. Symptoms and signs 9. Diagnosis 10. Differential diagnosis 11. Treatment (a) Modality (b) Drug classes and uses (c) Drug side effects

4. Significance  About 40% of the world’s population at risk  Worldwide clinical cases range from 300-500 million per year.  Worldwide 1.5-2.7 million deaths per year

5. Areas affected  Central and South America,  Hispaniola (Haiti and the Dominican Republic),  Africa,  Indian subcontinent,  Southeast Asia,  Middle East,  Oceania  Over 100 countries included

6. Map distribution of Malaria Adapted from wikipedia

7. Plasmodium life cycle (see next slide for diagram)  Cycle A : Pre - Erythrocytic cycle  Cycle B : Erythrocytic cycle  Cycle C : Sporogonic cycle. This cycle occurs in the mosquito  The gamatocytic cycle is a development from the erythrocytic cycle. It is necessary to perpetuate the sporogonic cycle in the mosquito.

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9. Transmission  Causative agent: Plasmodium (falciparum, vivax, ovale and malariae)  Vehicle: Infected female Anopheles mosquitoes that bite between dusk to dawn during its primary feeding time.  Human to human transmission  Except for mosquitoes, no animal reservoirs for human malaria exists  Other modes of transmission: Congenital Blood transfusion (Induced Malaria)

10. Anopheles mosquito life cycle (Egg, Larva, Pupa and Adult) Adapted from CDC

11. Essential point to note for transmission to occur  Egg to adult stage takes 10 – 14 days (may be as short as 5 days)  Adult males live for 1 week  Adult females may live for 2 – 4 weeks  Females need blood meal to produce eggs. May take 2 – 3 days after that meal to complete egg production  Both males and females feed on sugar rich nectar  Once mosquito ingests plasmodium gametes, it takes 10 – 21 days (extrinsic incubation time) for the mosquito to be infective  Thus, mosquito must survive longer than the intrinsic incubation period for transmission to occur

12. Pathophysiology  Malaria parasite infect the RBC and utilize its energy source to multiply by binary fission  Lysis of RBC occur causing haemoglobinemia, anaemia and activation of the haematopoietic system leading to reticulocytosis.  Schizogony leads to release of pyrogen (necrotic factors and other cytokins) that resets the hypothalamic thermoregulatory center causing fever.  In the liver, malaria (especially severe P. falciparum) can cause acute hepatopathy with centrilobular necrosis, jaundice but no liver failure.  P Falciparum (occasionally others) may cause sequestration and cytoadherence of infected RBC to capillaries and post- capillary venules leading to cerebral edema or non-cardiac pulmonary edema (and other related symptoms).

13. Plasmodium life cycle Plasmodium typeIncubation periodDuration of infection if untreated P. Falciparum 12 days (9-60)1.5 years P. Vivax and P. Ovale 14 days (8-27, some temperate strains 8mths) 5 years P. Malariae 30 days(16-60)50 years

14. Frequency of symptoms Plasmodium TypePattern of symptoms P. FalciparumMay be daily, continuous, or tertian P. Vivax, P. OvaleTertian P. MalariaeQuartan

15. Symptoms of uncomplicated malaria  Fever (to 41 C or higher),  Shaking chills,  Marked diaphoresis  Headache,  Dizziness,  Gastrointestinal symptoms,  Arthralgia, myalgia, back ache,  Dry cough  Fatigue  Loss of appetite

16. Signs of uncomplicated Malaria  Anemia,  Hyperpyrexia,  Splenomegally (after 4 days)  Hepathomegally (infrequent)  Hematuria  Abdominal tenderness  Hemodynamic instability  Mental status changes  Tarchypnoea

17. Complications  Haemolytic anaemia  Hyperthermia  Acute tubular necrosis and renal failure (may be associated with black water fever)  Cerebral oedema  Non-Cardiogenic pulmonary oedema  Acute hepatopathy (marked jaundice)  Hypoglycemia  Adrenal insufficiency-like syndrome  Cardiac dysrhythmia

18. Complications..  Water and electrolyte imbalance  Lactic acidosis  Coexisting pneumonia  GIT syndromes (secretory diarrhoea, dysentery) Complications with long term infection:  TSS (immunologic)  Quartan malaria nephropathy (immunologic)

19. Factors that may affect prognosis   M ultiple complications   20% of RBC contain mature parasites   5% of neutrophils contain pigment  Concomitant Gram-negative bacteria infection  Cerebral symptoms

20. Diagnosis  Microscopy: Thick and thin films (variation in level of parasitemia with time, examine 8 hourly x 3 days, during and between fever). Skills and expertise required.  Buffy coat method (more sensitive, requires fluorescent microscopy)  P. Falciparum dipstick antigen capture assay (sen & spe 75% & 95%)  Serology tests (ELISA): antibody available after 8-10 days and remains 10 or more years  PCR: highly specific but requires special labs.

21. Diagnosis-----  CBC findings: Anemia Reticulocytosis Transient leukocytosis (during paroxysms) Subsequent leukopenia, with relative elevated large mononuclear cells  LFT may be abnormal

26. Differential Diagnosis Causes of fever, anemia, splenomegally, hepatomegally, etc should be excluded. Malaria can mimic many diseases depending on the complications and stage of presentation  Influenza   Dengue Fever & Dengue Hemorrhagic Fever   Typhoid   UTI   Hepatitis   Leptospirosis   Relapsing fever  Pneumonia, etc

27. Differential Diagnosis-----  > Sepsis   Pneumonia   Pharyngitis  Gastroenteritis

28. Treatment Modality  Always suspect malaria for fever in an endemic area or after visit to an endemic area  Single negative Laboratory test does not rule out the disease  Think about the type of plasmodium and aim at eradication treatment  Think about drug resistance  Chloroquine is no longer used for treatment in many areas due to resistance  For P. Vivax and P. Ovale always give eradication treatment

29. Treatment Modality-----  Drug side effects and appropriateness to patient group  Talk about prevention at each patient visit to emphasize the role of the individual and the community

30. Quick Drug Review Drug ClassExamplesTarget site 4- Aminoquinolin e Chloroquine, Hydroxy-chloroquine Amodiaquine Blood Schizonticide (suppressive agent) Gametocide (P. Vivax, P. Ovale) 8- Aminoquinolin e PrimaquineTissue Schizonticide Gametocide (P. Falciparum)

31. Diaminopyrimi dines: Trimethoprim, Pyrimethamine Blood schizonticide Pyrimethamine also sporonticide Biguanides:Proguanil, Chlorguanide, Chlorproguanil Blood schizonticide Proguanil also sporonticide SulfonamidesSulfadoxine, Sulfadiazine, Sulfamethoxazole Blood schizonticide SulfonesDapsoneBlood schizonticide

32. Cinchona Alkaloids Quinine, QuinidineBlood schizonticide 4-quinoline- carbinolamine s MefloquineBlood schizonticide AntibioticsTetracycline Vibramycine Clindamycin Blood schizonticides OthersHalofantrin Artemisinin (quinghaosu) Atovaquone Blood schizonticides

33. CombinationFansidar (Pyrimethamine + Sulfadoxine) Maloprim (Pyrimethamine + Dapsone) Malarone (Atovaquone + Proguanil) Blood schizonticides and sporonticides Atovaquone (also tissue schizonticide for P. falcip)

34. Selected Drugs Chloroquine:  Indications- Chloroquine sensitive all forms except resistant P. falciparum and P. Vivax  Dosage: Oral-25mg/kg base in divided doses: typical 600mg start, 300mg after 6-8 hours, 300mg every day for 2 more days IM or slow IV-10mg/kg over 8 hours,  then 5mg/kg q 8 hours x 3 doses  then oral dosing until a total of 25mg/kg is given

35. Chloroquine----  Side effects: Impaired hearing, psychosis, convulsions, blood dyscrasias, skin allergy, hypotension, haemolysis in G6PD. Long term use may cause dose dependent retinopathy, ototoxicity and myopathy.  Pregnancy: not contraindicated  Children: not contraindicated

36. Mefloquine hydrochloride  Indications-Chloroquine resistant malaria (Treatment)  Dosage: Oral-20-25mg/kg base single dose or in divide doses Typical 750mg start, then 500mg after 6- 12 hours  Side effects: Cardiac conduction problems (prolongation of QT interval), liver effect, ophthalmopathy, neuropsychiatric symptoms (rare) 

37. Mefloquine-----  Contraindications: Cardiac conduction problems, Neuropsychiatric problems (including epilepsy, depression, psychosis etc), Liver dysfunction, Concurrent use of quinine, quinidine, or halofantrin (allow 12 hours after these drugs b/4 mefloquine, and allow 13-26 days (the elimination ½ life) after mefloquine before these drugs)  Pregnancy: Not contraindicated  Children: Can be given to children above 12 weeks

38. Primaquine  Indications-P.vivax, P.Ovale, P. Falciparum (gametocyte specific, active against hypnozoids)  Dosage: 15mg daily for 14-21 days  Side effects: Haemolysis in G6PD deficiency, GIT disturbance, headache, dizziness  Contraindications: Autoimmune dx, pregnancy, quinine use, G6PD deficiency (all Africans, E. Asians and Mediterranean should have blood check for G6PD before medication)

39. Fansidar  Indication-susceptible P. Falciparum, low efficacy against P. vivax, P ovale and P malariae  Dosage: Each tablet contains 25mg pyrimethamine and 500mg sulfadoxine Typical oral 3 tablets one time  Side effects: Erytheme multiforme and other sulfonamide reactions, Kernicterus in the new born, haemolysis in G6PD deficiency 

40. Fansidar----  Caution: Liver and renal impairment, G6PD def, children  Pregnancy: contraindicated  Children: with caution

41. Doxycycline  Indications-all plasmodium types  Dosage: Oral 200mg daily for 7 days (note milk reduces absorption)  Side effects: GIT symptoms, Oesophageal irritation (take with food and water), Candidal vaginitis, photosensitivity (use sunscreens), chemical hepatitis.  Contraindication: Pregnancy, children below 8 years, hepatic dysfunction

42. Quinine  Indication- Life threatening malaria (including cerebral malaria), multidrug resistant malaria  Dosage: IV loading 20mg/kg over 4 hours Then 10mg/kg over 4 hours at 8-12 hourly interval until patient can swallow tablets Oral-600mg tid x 7 days Followed by fansidar 3 tablets one dose or doxycycline 

43. Quinine-----  Side effects: Cinchonism (headache, nausea, dizziness, visual disturbances, tinnitus) Severe reaction include: fever, deafness, visual effects (blindness, optic atrophy, diplopia, scotomas, retinal vessel spasticity, etc). Vertigo, confusion, seizures may occur. Cardiac conduction abnormalities(do not give with mefloquine, halofantrin), thrombophlebitis.  Drug interactions: Aluminium containing antacids, digoxin, anticoagulants and cimetidine.

44. Quinine-----  Contraindications: Cardiac conduction problems especially prolonged QT interval or polymorphic ventricular tarchycardia.  Pregnancy: not contraindicated  Children: not contraindicated

45. Artemisinin and its derivatives  Indications- All malaria parasites. Most rapidly acting blood schizonticide. No resistance reported as yet. Used for quinine resistant p falciparum. Can not be used for prophylaxis (short ½ life)  Dosage: oral/IV artesunate 4mg/kg/d for 3 days, followed by mefloquine. IM artemether 3.2mg/kg, then 1.6mg/kg daily, followed by mefloquine

46. Artemisinin and its derivatives-  Side effects: GIT symptoms, fever, headache and pruritus. Study suggest embryotoxicity and neurotoxicity (not recorded in humans)  Pregnancy: contraindicated

47. Preventing vector bite  Repellant: DEET (N, N-diethyl-3-methylbenzamide) used on the exposed parts of the body may be effective for 2-4 hours.  Risk: there is a slight risk of toxic encephalopathy with the use of DEET. (apply sparingly on the exposed parts only and wash off when indoors)

48. Prophylaxis  For prophylaxis, malaria endemic areas are grouped into a. Regions with chloroquine sensitive P falciparum and b. Regions with chloroquine resistance P falciparum  Regions with chloroquine sensitive P falciparum Central America west of panama canal, the Caribbean, North Africa, and parts of the middle East

49. Prophylaxis----- Chloroqiune phosphate 300mg base/week plus or minus proguanil 100mg daily is recommended in these areas  Regions with chloroquine resistance P falciparum All other areas of the endemic areas belong to this region. Mefloquine 250mg weekly (1 week b/4 entering the area and 4 weeks after leaving the area) Or

50. Prophylaxis---- Doxycycline 100mg daily (2 days b/4 entering the area and 4 weeks after leaving the area) Or Malarone (atovaquone 250mg + Proguanil 100mg) 1 tablet daily (1 day b/4 entering the area and 1 week after leaving

51. Malaria Control and Eradication Strategy will follow soon