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MALARIA:

Update of Management

HENDRATA
Dvision of Infectious and Tropical Disease
Departement of Internal Medicine
UDAYANA School Medicine
Sanglah General Hospital
Denpasar BALI
Malaria Infection
• Agent
– P. Vivak
– P. Ovale
– P. malariae
– P. falciparum
– P. knowlesi
• Vector
– Anopheles sp
Malaria Endemicity in Indonesia
2008

Profil P2PL 2008, Depkes RI


Morbidity rate of Malaria

Profil P2PL 2008, Depkes RI


Malaria Life Cycle
Sporogony
m
O Oocyst
S Sporozoites
Q
U Mosquito Salivary
Zygote
I Gland
T
O

Hypnozoites
Exo- (for P. vivax and
erythrocytic P. ovale)
H Gametocytes
(hepatic) cycle

U
M
A Erythrocytic
Cycle

N
Schizogony
Patogenesis
• Invasion of red cell
• Cytoadherence
– Process whereby mature infected cells specifically
bind to endothelial cells in postcapillary venule
• Rosetting
– Red cell containing the more mature stages of
parasite bind uninfected red cells to their surface
• Parasite toxin and cytokines
– TNF α, IF gamma, IL-1,IL-6
– GPI
Types of Infections
• Recrudescence
– exacerbation of persistent undetectable parasitemia,
due to survival of erythrocytic forms, no exo-
erythrocytic cycle (P.f., P.m.)
• Relapse
– reactivation of hypnozoites forms of parasite in liver,
separate from previous infection with same species
(P.v. and P.o.)
• Recurrence or reinfection
– exo-erythrocytic forms infect erythrocytes, separate
from previous infection (all species)
• Can not always differentiate recrudescence from
reinfection
Clinical presentation
Varies in severity and course:
• Parasite factors
– Species and strain of parasite
– Geographic origin of parasite
– Size of inoculum of parasite
• Host factors
– Age
– Immune status
– General health condition and nutritional status
– Chemoprophylaxis or chemotherapy use
• Mode of transmission
– Mosquito
– Blood borne, no hepatic phase (transplacental,
needle stick, transfusion, organ donation/transplant)
Clinical presentation
Symptoms and sign are non specific

• Early symptoms
– Headache
– Malaise
– Fatigue
– Nausea
– Muscular pains
– Slight diarrhea
– Slight fever, usually not intermittent
• Could mistake for influenza or gastrointestinal
infection
Clinical presentation
• Signs
– Anemia
– Thrombocytopenia
– Jaundice
– Hepatosplenomegaly
– respiratory distress syndrome
– renal dysfunction
– Hypoglycemia
– Mental status changes
– Tropical splenomegaly syndrome
Malarial Paroxysm
• Paroxysm
– Cold stage – rigors (15 minute – 1 hours)
– Hot stage – Max temp can reach 40-41o C,
splenomegaly easily palpable (≥ 2 hours)
– Sweating stage
– Lasts 8-12 hours, start between midnight and
midday
• Periodicity
– Days 1 and 3 for P.v., P.o., (and P.f.) - tertian
– Usually persistent fever or daily paroxyms for P.f.
– Days 1 and 4 for P.m. - quartian
Severe malaria (1)
• Cerebral malaria
– Coma with peripheral parasitemia and the other
cause of encephalopathy excluded
• Generalized convulsions
• Severe normocytic anemia
– Normocytic anemia with Hb < 5 g/dl, < 15 %
hematocrit, in presence of parasitemia > 10.000 /uL
• Hypoglycemia
– Whole blood glucose < 40 mg/dl (2.2 mmol/l)
• Metabolic acidosis with respiratory distress
– Acidosis (BE ≤ 12) or acidemia (pH < 7.3)
• Fluid and electrolyte disturbance
– Hypovolaemia  dehydration
WHO,2006
Severe malaria (2)
• Acute renal failure
– Urine output less than 400 ml/24 h and a serum creatinine > 3.0
mg/dl
• Acute Respiratory Distress Syndrome
• Circulatory collapse, shock, septicaemia (“algid malaria”)
– Systolic blood pressure less than 70 mmHg or core skin
temperature difference > 10C
• Jaundice
– Icteric (serum bilirubin > 3 mg%)
• Haemoglobinuria (black water fever)
• High fever
– Rectal temperature > 400C
• Hyperparasitaemia
– High parasite densities (>5%) in non-immune subjects

WHO,2006
Severe Vivax malaria
• Although benign malaria, reported also
causing severe and debilitating illness.
• Severe vivax manifestation : cerebral
malaria, severe anaemia, severe
thrombocytopenia, pancytopenia,
jaundice, spleen rupture, acute renal
failure and acute respiratory distress
syndrome
Diagnosis
• Clinical presentations
• Microscopic examination
– Thick blood film
– Thin blood film
• MRDT (Rapid diagnostic test for Malaria)
– Serologic
• Antibody detected:
– indirect immunofluorescence test, haemaggutination/latex
agglutination test, enzyme linked immunoassay (ELISA)
• Antigen detected:
– radioimmunoassay, ELIZA
• PCR
Management
• Falciparum or
non Falciparum
• Uncomplicated or
Complicated/Severe

• Supportive
– Nutrition
– Fluid and electrolytes
balance
– Antipyretic, etc
• Causal (antimalarial)
– Chloroquine
– Primakuine
– Quinine
– Artemesinin derivat
• Treatment for complication
– Depend of kind of the
complication
Treatment of uncomplicated vivax
• Choice: Chloroquine 25 mg base/KgBW divided over 3
days, combined with Primaquine 0.25 mg base/KgBW,
taken with food once daily for 14 days (O,E)
• Amodiaquine (30 mg base/KgBW divided over 3 days as
10 mg/KgBW single daily doses) combined with
Primaquine should be given for chloroquine-resistant
vivax malaria (O,E)
• Where ACT has been adopted as the first-line treatment
for P.falciparum malaria, it may also be used for P vivax
in combination with primaquine.
AS + SP is the exception as it will not be effective
againts P. vivax (O,E)

Treatment for P Ovale and P Malariae are same


with for P vivak Malaria
Treatment for uncomplicated falciparum
malaria
• Combination of two or more antimalarial with different
mechanism of action (level: S,T,O)
• ACTs are recommended (level: S,T.O):
– Artemether-lumefantrine ( AL )  FDC
– Artesunate + amodiaquine ( AS + AQ )
– Artesunate + mefloquine ( AS + M )
– Artesunate + sulfadoxine-pyrimethamine ( AS + S-P )
• The artemisinin derivative components of the combination
must be given for at least 3 days for an optimum effect (S)
• AL should be used with a 6-dose regimen
• Amodiaquine + SP may be considered as an interim option in
situations where ACTs cannot be made available
Dosing schedule
for artesunate + amodiaquine
Second line antimalarial treatment for
uncomplicated falciparum malaria
Uncomplicated falciparum malaria in
pregnancy
Uncomplicated falciparum in patients
with HIV infection
Severe Malaria
• Required parenteral or suppossitoria treatment
• Decreased parasitemia rapidly
• Less side effect
• Quinine vs Artemisinin
– ARTS Better than Quinine ( SEQUAMAT )
Recommended Doses of Antimalarial drugs for
treatment of severe/cerebral Malaria

DRUGS SIDE EFFECTS


i.v. 2.4 mg/kg at 0 & 12 hr
ARTESUNATE followed at 24, 48,72 hr
( 1 amp = 60 mg)

IM. 1.6 mg/kg at 0 & I2 hr


Artemeter followed at 24,48,72 hr. Neurotoxicity in
(1 amp = 80 mg) animal not human

Suppositories, 10 mg/kg at 0 &


4 hr followed by 7 mg/kg at
Artemisinin 24,36,48 & 60 hrs.
Artemisinin for Severe Malaria

0 hr 12 hr. 24 hr. 48 hr. 72 hr. Max 7 days

2.4 2.4 2.4 2.4 2.4 2.4


Mg/ Mg/ Mg/ Mg/ Mg/ Mg/
KgBw KgBw KgBw KgBw KgBw KgBw

ARTESUNATE I.V/ I.M

ARTEMETER
•only I.M ,
•dose 1,6 mg/kg BW
Adjustment of dosing in organ
disfunction
• The dosage of artemisinin derivates does not
need adjustment in vital organ dysfunction
• The dosage of Quinine should be reduced by
one-third after 48 hours if:
– Acute kidney injury
– Hepatic dysfunction
– No clinical improvement after 48 hours of treatment
The dosage adjustments are not necessary if patients
are receiving either hemodialysis or hemofiltration
Follow on treatment
• After patient can tolerate oral therapy
change to oral antimalarial
• Continue with
– Same medicine orally as given parentrally to
complete a full 7 days of treatment
– Added with doxycycline for 7 days
– If pregnant and children: doxycycline
substituted by clindamycin
Treatment of severe falciparum malaria in
pregnant women
• Use the parentral antimalarial treatment
locally available for severe malaria in full
doses.
• First trimester, until more evidence
become available, both artesunate and
quinine may be considered as option
• Where available, artesunate is the first,
and artemether the second option in the
second and third trimester
Basis of decision:expert opinion (Level E)
Response of treatment
Response
Early Treatment Failure One or more
•Sign and symptoms severe
malaria
•Parasetemia at D2 ≥ D0
•Parasetemia at D3 ≥ 25% D0
Late Treatment Failure One or more condition at H4-
H28
•Sign and symptoms of severe
malaria after D3
•Parasetemia at D7/D14/D21/D28
(type of parasite = D0)
Adequte Clinical •No fullfill criteria for ETF and LTF
Respon
Pre-referral Treatment The risk
of death from severe malaria is greatest in the first 24
hours

• Recommended: Patients are treated with


the first dose of one of the recommend
treatment before referral
• Drugs of choice :
– Artesunate iv or artemether i.m
– Artesunate or artemisinin supositoria
– Kina i.m.
– Kina i.v. (didampingi petugas medis ) ??
Malaria:
Algorithm for initial assement and management in adult
All febrile or ill patients with a history of travel to a malaria area
in the prior 6 months

Urgent Investigation:
Thick & Thin blood film and Malaria rapid antigen test, CBC,LFT, RFT, Blood
glucose
Blood tests show:

Falciparum malaria No evidence of malaria.


Non-Falciparum malaria A single negative film and/or
Falciparum, Mixed infection antigent does not exclude
•Vivax Outpatient therapy Assess severity
malaria
•Ovale usually appropiate WHO Criteria Stop prophylaxis until
depending on malaria excluded
•malaria clinical judgement
Empirical therapy for
malaria should be avoided
unless the patients is
Non falciparum Complicated or if severly ill
Uncomplicated
antimalarial patients is vomiting
Falciparum: Blood films daily for 2 more
•Chloroquine Parentral antimalarial days
Oral falciparum
•ACT antimalarial (ACT) Malaria is unlikely with 3
Admission to high negative blood film.
dependency/ Consider other febrile
•Primaquine intensive care illness