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

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

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

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

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

Map distribution of MalariaAdapted from wikipedia

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.

.

.

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)

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

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

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).

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

Frequency of symptoms Plasmodium Type Pattern of symptoms

P. Falciparum May be daily, continuous, or tertian

P. Vivax, P. Ovale Tertian

P. Malariae Quartan

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

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

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

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)

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

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.

Diagnosis----- CBC findings:

AnemiaReticulocytosisTransient leukocytosis (during paroxysms)Subsequent leukopenia, with relative elevated large mononuclear cells

LFT may be abnormal

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

Differential Diagnosis-----  > Sepsis Pneumonia Pharyngitis Gastroenteritis

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

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

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)

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

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

Combination Fansidar (Pyrimethamine + Sulfadoxine) Maloprim (Pyrimethamine + Dapsone) Malarone (Atovaquone + Proguanil)

Blood schizonticides and sporonticidesAtovaquone (also tissue schizonticide for P. falcip)

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

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

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)

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

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)

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

Fansidar---- Caution:

Liver and renal impairment, G6PD def, children

Pregnancy: contraindicated Children: with caution

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

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 

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.

Quinine----- Contraindications:

Cardiac conduction problems especially prolonged QT interval or polymorphic ventricular tarchycardia.

Pregnancy: not contraindicated Children: not contraindicated

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

Artemisinin and its derivatives- Side effects:

GIT symptoms, fever, headache and pruritus. Study suggest embryotoxicity and

neurotoxicity (not recorded in humans) Pregnancy: contraindicated

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)

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

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

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

Malaria Control and Eradication Strategy will follow soon