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Transcript of Introduction to Malaria Prof. Remigius Okea, MD MPH Research Director: American Academy of Primary...
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Introduction to Malaria
Prof. Remigius Okea, MD MPHResearch Director: American Academy of Primary Care Research (AAPCR)Chairman Scientific Advisory Board: Tropical PharmMedics Research Institute
First presented in 2003
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Malaria a word coined from Mal Ar (“Bad Air”)
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Review Objectives 1. Distribution2. Understand malaria cycle3. Transmission4. Understand the treatment 5. Plasmodium life cycle (a basis for understanding the disease)6. Pathophysiology7. Brief description of health significance of Malaria8. Symptoms and signs9. Diagnosis10. Differential diagnosis11. Treatment
(a) Modality(b) Drug classes and uses(c) Drug side effects
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Significance About 40% of the world’s population at
riskWorldwide clinical cases range from
300-500 million per year.Worldwide 1.5-2.7 million deaths per
year
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Areas affected Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, Indian subcontinent, Southeast Asia, Middle East, Oceania Over 100 countries included
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Map distribution of MalariaAdapted from wikipedia
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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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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)
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Anopheles mosquito life cycle (Egg, Larva, Pupa and Adult)Adapted from CDC
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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
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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).
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Plasmodium life cycle Plasmodium type Incubation period Duration 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
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Frequency of symptoms Plasmodium Type Pattern of symptoms
P. Falciparum May be daily, continuous, or tertian
P. Vivax, P. Ovale Tertian
P. Malariae Quartan
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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
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Signs of uncomplicated Malaria Anemia, Hyperpyrexia, Splenomegally (after 4 days) Hepathomegally (infrequent) Hematuria Abdominal tenderness Hemodynamic instability Mental status changes Tarchypnoea
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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
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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)
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Factors that may affect prognosis
Multiple complications 20% of RBC contain mature
parasites 5% of neutrophils contain pigment Concomitant Gram-negative
bacteria infection Cerebral symptoms
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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.
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Diagnosis----- CBC findings:
AnemiaReticulocytosisTransient leukocytosis (during paroxysms)Subsequent leukopenia, with relative elevated large mononuclear cells
LFT may be abnormal
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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
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Differential Diagnosis----- > Sepsis Pneumonia Pharyngitis Gastroenteritis
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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
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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
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Quick Drug Review Drug Class Examples Target site4-Aminoquinoline
Chloroquine, Hydroxy-chloroquine Amodiaquine
Blood Schizonticide (suppressive agent) Gametocide (P. Vivax, P. Ovale)
8-Aminoquinoline
Primaquine Tissue SchizonticideGametocide (P. Falciparum)
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Diaminopyrimidines:
Trimethoprim, Pyrimethamine
Blood schizonticidePyrimethamine also sporonticide
Biguanides: Proguanil, Chlorguanide, Chlorproguanil
Blood schizonticideProguanil also sporonticide
Sulfonamides Sulfadoxine, Sulfadiazine, Sulfamethoxazole
Blood schizonticide
Sulfones Dapsone Blood schizonticide
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Cinchona Alkaloids
Quinine, Quinidine Blood schizonticide
4-quinoline-carbinolamines
Mefloquine Blood schizonticide
Antibiotics Tetracycline Vibramycine Clindamycin
Blood schizonticides
Others Halofantrin Artemisinin (quinghaosu) Atovaquone
Blood schizonticides
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Combination Fansidar (Pyrimethamine + Sulfadoxine) Maloprim (Pyrimethamine + Dapsone) Malarone (Atovaquone + Proguanil)
Blood schizonticides and sporonticidesAtovaquone (also tissue schizonticide for P. falcip)
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Selected DrugsChloroquine: 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
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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
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Mefloquine hydrochloride Indications-Chloroquine resistant malaria (Treatment) Dosage: Oral-20-25mg/kg base single dose or in
divide dosesTypical 750mg start, then 500mg after 6-12 hours
Side effects:Cardiac conduction problems (prolongation of
QT interval), liver effect, ophthalmopathy, neuropsychiatric symptoms (rare)
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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
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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)
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Fansidar Indication-susceptible P. Falciparum, low efficacy
against P. vivax, P ovale and P malariae Dosage:
Each tablet contains 25mg pyrimethamine and 500mg sulfadoxineTypical oral 3 tablets one time
Side effects: Erytheme multiforme and other sulfonamide reactions, Kernicterus in the new born, haemolysis in G6PD deficiency
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Fansidar---- Caution:
Liver and renal impairment, G6PD def, children
Pregnancy: contraindicated Children: with caution
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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
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Quinine Indication-
Life threatening malaria (including cerebral malaria), multidrug resistant malaria
Dosage: IV loading 20mg/kg over 4 hoursThen 10mg/kg over 4 hours at 8-12 hourly interval until patient can swallow tabletsOral-600mg tid x 7 daysFollowed by fansidar 3 tablets one dose or doxycycline
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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.
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Quinine----- Contraindications:
Cardiac conduction problems especially prolonged QT interval or polymorphic ventricular tarchycardia.
Pregnancy: not contraindicated Children: not contraindicated
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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
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Artemisinin and its derivatives- Side effects:
GIT symptoms, fever, headache and pruritus. Study suggest embryotoxicity and
neurotoxicity (not recorded in humans) Pregnancy: contraindicated
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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)
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Prophylaxis For prophylaxis, malaria endemic areas are grouped
intoa. Regions with chloroquine sensitive P falciparum and
b. Regions with chloroquine resistance P falciparum
Regions with chloroquine sensitive P falciparumCentral America west of panama canal, the Caribbean, North Africa, and parts of the middle East
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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
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Prophylaxis----Doxycycline 100mg daily (2 days b/4 entering the area
and 4 weeks after leaving the area)
OrMalarone (atovaquone 250mg + Proguanil 100mg) 1 tablet daily (1 day b/4 entering the area and 1 week after leaving
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Malaria Control and Eradication Strategy will follow soon