Transcript to View - American Tropical Disease Conference

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
Malaria a word coined from
Mal Ar (“Bad Air”)
Review Objectives
1.
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11.
Distribution
Understand malaria cycle
Transmission
Understand the treatment
Plasmodium life cycle (a basis for understanding the disease)
Pathophysiology
Brief description of health significance of Malaria
Symptoms and signs
Diagnosis
Differential diagnosis
Treatment
(a) Modality
(b) Drug classes and uses
(c) Drug side effects
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
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 Malaria
Adapted 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
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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
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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
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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 postcapillary venules leading to cerebral edema or non-cardiac
pulmonary edema (and other related symptoms).
Plasmodium life cycle
Plasmodium type
Incubation period
P. Falciparum
12 days (9-60) 1.5 years
P. Vivax and P. Ovale
14 days (8-27, 5 years
some
temperate
strains 8mths)
30 days(16-60) 50 years
P. Malariae
Duration of infection
if untreated
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
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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..
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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
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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:
Anemia
Reticulocytosis
Transient leukocytosis (during paroxysms)
Subsequent leukopenia, with relative elevated
large mononuclear cells
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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
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Hepatitis
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Leptospirosis
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Relapsing fever
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Pneumonia, etc
Differential Diagnosis----
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>


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
4Aminoquinolin
e
Examples
Chloroquine,
Hydroxy-chloroquine
Amodiaquine
8Primaquine
Aminoquinolin
e
Target site
Blood
Schizonticide
(suppressive
agent)
Gametocide (P.
Vivax, P. Ovale)
Tissue
Schizonticide
Gametocide (P.
Falciparum)
Diaminopyrimi Trimethoprim,
dines:
Pyrimethamine
Blood
schizonticide
Pyrimethamine
also
sporonticide
Blood
schizonticide
Proguanil also
sporonticide
Biguanides:
Proguanil,
Chlorguanide,
Chlorproguanil
Sulfonamides
Sulfadoxine,
Sulfadiazine,
Sulfamethoxazole
Blood
schizonticide
Sulfones
Dapsone
Blood
schizonticide
Cinchona
Alkaloids
Quinine, Quinidine
Blood
schizonticide
4-quinolinecarbinolamine
s
Antibiotics
Mefloquine
Blood
schizonticide
Tetracycline
Vibramycine
Clindamycin
Halofantrin
Artemisinin
(quinghaosu)
Atovaquone
Blood
schizonticides
Others
Blood
schizonticides
Combination
Fansidar
(Pyrimethamine +
Sulfadoxine) Maloprim
(Pyrimethamine +
Dapsone) Malarone
(Atovaquone +
Proguanil)
Blood
schizonticides
and
sporonticides
Atovaquone
(also tissue
schizonticide for
P. falcip)
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
Chloroquine---
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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
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Indications-Chloroquine resistant malaria (Treatment)
Dosage: Oral-20-25mg/kg base single dose or in
divide doses
Typical 750mg start, then 500mg after 612 hours
Side effects:
Cardiac conduction problems (prolongation of QT
interval), liver effect, ophthalmopathy,
neuropsychiatric symptoms (rare)
Mefloquine----
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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
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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
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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
Fansidar---
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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
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IndicationLife 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
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----
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Contraindications:
Cardiac conduction problems especially prolonged
QT interval or polymorphic ventricular
tarchycardia.
Pregnancy: not contraindicated
Children: not contraindicated
Artemisinin and its derivatives

IndicationsAll 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
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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

a.
For prophylaxis, malaria endemic areas are grouped
into
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
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)
Or
Malarone (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