MALARIA IN CHILDREN

H. Hindra Irawan Satari

PENDAHULUAN

Setiap 30 detik 1 anak meninggal disebabkan

malaria
Malaria menewaskan 3.000 anak per hari
sebelum mencapai usia 5 tahun
Afrika:

Usia < 5 tahun: penderita kronik, 6 serangan/tahun

Fatal < 72 jam, yang selamat: gangguan tumbuh kembang

Masa kehamilan: Anemia, kematian ibu hamil

UNICEF

Malaria : 5 besar kematian anak usia < 5 tahun

DEFINITION
Malaria

is an infection disease that

spread by mosquito

Caused

by protozoa parasite
genus Plasmodium that infected
human and insect host alternately

THE PARASITES
P.

falciparum
P.vivax (tertian)
P.ovale (tertian)
P.malariae (quartan)

LIFE CYCLE

PATOGENESIS (1)

Malaria tanpa komplikasi:

Demam: skizon ruptur

1, dll
talamus

monosit

TNF, IL-

Malaria falsiparum dengan komplikasi

Malaria serebral:

Teori lama

Toksin meningkatkan permeabilitas vaskuler

Penyakit kompleks imun
Koagulasi intravaskuler diseminata

Teori baru

Peningkatan tekanan intrakranial

Eritrosit rigid
Formasi rosette

PATOGENESIS (2)
Hipotesis

terkini

Sequestration

mature-stage parasited

erythrocytes
Cascade cytokines

SEKUESTRASI
Sitoadherens sekuestrasi mikrovaskular organ edema otak,
petekie kecil, cincin perdarahan.
Malaria serebral densitas tinggi, pengelompokan erat eritrosit.

ROSETTING
Perlekatan satu EP yang diselubungi oleh 10/lebih eritrosit non parasit
~ bunga.
Obstruksi mikrovaskular iskemia lokal, glikolisis anaerob, asidosis
laktat, dan kerusakan sel.

PERANAN

SITOKIN

TNF-, IFN-, IL-1, IL-6, limfotoksin & IL-3 .

Peran langsung ?.
TNF permeabilitas vaskular , demam, hipoglikemia, marginasi
neutrofil paru, kerusakan hati, laktat darah & ATN.

PERAN NO
Peran NO ?.
sintesis NO predisposisi malaria serebral.
Produksi NO :
[ TNF darah ].
[ IL-10 darah ].
Faktor parasit.

MEKANISME SINDROM
Anemia
SINDROM
SPESIFIK (1)

Hipoglikemi

Destruksi parasitised eritrosit

Destruksi non-parasitised eritrosit
Diseritropoiesis
Puasa
deplesi glikogen hati
Parasit mengkonsumsi glukosa
Iskemia jaringan
glikolisis anaerob
Penurunan glukoneogenesis hati
Disebabkan sitokin

Gagal ginjal

Biasanya disebabkan nekrosis tubuler akut

Didahului syok, hemolisis intravaskuler

MEKANISME SINDROMSINDROM SPESIFIK (2)

Syok (Malaria algid)

Sindrom gawat nafas

Disebabkan sitokin
Kadang-kadang septisemia
Edema dinding alveolus, ditemukan neutrofil pada
kapiler alveolus
Sekuestrasi di paru-paru
Peran sitokin

Sindrom nefrotik P. malariae

Penyebab penting sindrom nefrotik di daerah endemis

malaria

Protein uri non-selektif, prognosis buruk, resisten terhadap

steroid , antimalaria, obat sitotoksik
Kerusakan glomerulus kompleks imun

MEKANISME SINDROMSINDROM SPESIFIK (3)

Hyper-reactive malarial splenomegaly

Splenomegali
IgM ++
Respon terhadap pengobatan anti
malaria
Infiltrasi limfosit pada sinusoid hati

Limfoma Burkit

Malaria merubah respon pejamu pada

virus Epstein Barr

Clinical manifestations
Violent

fever 6-8 hours

Anaemia
Enlargement of the spleen

TYPICAL SYMPTOMS OF MALARIA

The cold stage

The hot stage

Feels very ill, headache, backache

Shivering
1 hour
Body temperature 40-41 0C
1-2 hours

The sweating stage

Profuse sweating
5-8 hours

TYPICAL SYMPTOMS OF MALARIA

PROBLEMS OF DIAGNOSIS OF
SEVERE MALARIA
There no blood film
From history taking: not asking about traveling to
endemic area
Mistake for guessing the degree of the disease
Mistake for examine blood slide under binocular /
microscope
Mistake for diagnose complication
Overlooked hypoglycemia
No funduscopy for preventing retinal bleeding
Mistake to diagnose as malaria

INDICATOR OF RISK
DENSITY OF PERIPHERAL PARACITEMIA
Parasite

count < 100,000/ul

Mortality

Parasite

count > 500,000/ul

Mortality

Parasite
=

<1%
> 50%

count > 250,000/ul

> 5% parasitemia
Bad prognosis

Parasite count

Thick smears

Counting the parasite each 200 leucocytes

Example: 1500 parasite / 200 leucocytes and
leucocytes count 8,000/ul

Parasite count: 8000/200 X 1500 parasite = 60,000 parasite/ul

Thin smears

Plasmodium count per 1000 or 10,000 erythrocyte

Example: 50 parasite/1000 erythrocyte = 5% and
erythrocyte count 4,500,000/ul

Parasite count= 4,500,000/1000 X 50 = 225,000 parasite /ul

Manifestations of severe
malaria
Anemia (Hb < 8 g/dl)
Cerebral malaria
Dehydration, electrolyte and acid-base imbalance
Hypoglycemia
Renal failure
Pulmonary edema
Bleeding
Hyper pyrexia
Malaria bilious

THE PROBLEMS IN
SEVERE MALARIA

Hyperparasitaemia

Cerebral malaria

Unconsciousness (delirium, stupor, koma)

Severe anaemia

> 5 % erythrocyte with parasite (> 250,000/mm3)

Hb < 7,1 g/dl

Jaundice

Bilirubin serum > 50 mmol/l

Hypoglycaemia (< 40 mg/dl)

Renal failure

Hyperpyrexia

creatinin serum > 3,0 g/dl and diuresis < 400 ml/24 hours
Temperature > 39 0C

Shock

MALARIA BERAT
Kunci

penilaian awal

Derajat

kesadaran
Denyut nadi dan tekanan darah
Frekuensi dan dalamnya
pernafasan
Suhu tubuh
Adanya anemi
Derajat dehidrasi

SEVERE MANIFESTATIONS OF
PLASMODIUM FALCIPARUM MALARIA
IN ADULTS AND CHILDREN
Prognostic value
Children

Adults

(?)

+++

Clinical manifestations or laboratory

finding

Frequency
Children

Adults

Prostration

+++

+++

++

Impaired consciousness

+++

++

+++

+++

Respiratory distress

+++

++

Multiple convulsions

+++

+++

+++

Circulatory collapse

+++

+++

Pulmonary oedema

+/-

+++

++

Abnormal bleeding

+/-

++

Jaundice

+++

Haemoglobinuria

+/-

Severe anemia

+++

COMA SCALE FOR CHILDREN

(Blantyre coma scale, modified from Glasgow coma scale)
Score
(a)

(b)

(c)

Note:

Best motor response

Localizes painful stimulus

Withdraws limb from pain

Non-specific or absent response

Verbal response
Appropriate cry

Moan or inappropriate cry

None

Eye movements
Directed (e.g., follows mothers face)

Not directed

< 2 indicates ,unrousable coma

Painful stimulus: rub knuckles on patients sternum or
Firm pressure on thumbnail bed with horizontal pencil

DIFFERENCES BETWEEN SEVERE MALARIA

IN ADULTS AND CHILDREN
Adults

Children

Uncommon

Common

Convulsions

Indicates cerebral
involvement or
hypoglycemia

Duration of symptoms before features

of severe disease develop

Commonly several
days

May indicate cerebral

involvement or hypoglycemia,
but may be non-specific
consequence of fever
Usually 1-2 d

Time from start treatment to

resolution of coma in cerebral malaria

Usually 2-4 d

Cough as early symptom

Neurological sequelae after cerebral

malaria
Jaundice

Uncommon

Usually 1-2 d
Occur about 10%

Common

Uncommon

Uncommon

Common

Pulmonary edema

Common

Rare

Renal dysfunction

Common

Rare

Intracranial pressure

Normal

Raised

Uncommon

Common

10%

Rare

Rare

More common

Hypoglycemia

Respiratory distress (asidosis)

Haemostatic/coagulation abnormalities
Disturbance brain stem function

Clasification of antimalarial
therapy (WHO)

According to chemical formation:

Alakaloid cinchona: quinine, quinidine

4-aminokuinolin: chloroquine, amodiaquine
8-aminokuinolin: primaquine
Diaminopiridin: pyrimethamine
Sulfonamid: sulfadoxine, sulfadiazine, sulfalene
Sulfon: dapsone
9-aminoakridin: mepakrin
Biguanida: proguanil
4-kuinolin metanol: mefloquine
Antibiotik: tetracycline, minocycline, doxycycline,
clindamisine

Clasification of antimalarial (WHO)

Drugs

under researched

Artemisinin
Halofrantin

(9-fenatren metanol)
Pitonaridin (derivat hidroksi amino benzo
naftridin)

Clacification of antimalarial (WHO)

According to stadium of the disease

Primary skizontiside

Secondary skizontiside

killed Erytrosite: relation with acute case

Gametoside

killed Eksoerytrosite P.vivax dan P. ovale: radikal and anti

relaps

Blood Skizontiside

killed Pre-erytrosite stadium : causal prophylactic

destroyed all sexually, including gametoside P. falsiparum

Sporontoside

Preventing or chasing gametocyte become oocyste and

sporozoit in mosquito

EXISTING ANTI MALARIA DRUG

TREATMENT DEP.KES.RI
Cq
Uncompl. P.f

SP

Qn

(+)

Dx

(+)
(+)

(+)
(+)

Compl. P.f.

Pq

(+)

(+)IM
(+)IV

P.v.

(+)

(+)
(+)

Prophylaxis

(+)

(+)
(+)

ANTI MALARIAL TREATMENT

Out patient clinic (per oral)

Chloroquine base (tab: 500mg equivalen300mgbase)

Total dose 25 mg base/body weight for 3 days

Day I: 10 mg/bw (max.600 mg base)

6 hour after 10 mg/bw
5mg/bw for 24 hour (max.300 mg base)

Primaquine (1 day for P. falciparum, 14 days for P.vivax)

If there is fever in 4th day or there is parasite in 8th day

Quinine sulfate 30 mg/bw/day divided in 3 dose, for 7 day or

Fansidar/suldox, pyrimethamine 1.5 mg/bw atau sulfadoxine
20-30 mg/bw (Single dose !)

If there is fever in 4th day or there is parasite in 8th day

Tetracycline + fansidar + Suldox (if never been giving)

Tetracycline + Quinine (if never been giving)

 If

available:

Mefloquine 15mg/bw (max. 1000 mg) divided

2 dose.

Mefloquine may not giving after 12 hour

parenteral quinine done.

Halofrantin : 8 mg basa/kgBB setiap 6 jam

untuk 3 dosis

DOSAGE
ANTI MALARIAL DRUGS

Primaquine phosphate
0,3 mg base (0,5 mg salt) per body weight
max 26,3 mg base /day for 14 days for P. vivax
dan P. ovale, and maybe for P. Malariae
( radical therapy / prevent relapse)
Single dose
Tab:
500
mg
sulfadoxine

25
mg
pyrimethamine

Ministry of health RI
1 day (to brake spread chain)
AAP (American Academy of Pediatrics)
No need for P. falsiparum

DOSAGE ANTI MALARIAL DRUGS

Mefloquine : 15 mg base/bw single dose.
Halofrantin
: 8 mg/bw repeated every 6-12 hour.
Repeat 1 regimen.
Artesunate
: Combination with Meflokuin single
dose total 25 mg / bw, with dose 10-12 mg/bw diveded
in 3-5 hari (example: 4 mg/bw per day for 3 day or 4
mg/bw followed with 1,5 mg/bw/day for 4 day). If it
taking alone with the same dose for 7 day (usually 4
mg/bw for the first, followed with 2 mg/bw for 2-3
dayi and 1 mg/bw in 4-7 day). Note: 1 tablet = 50 mg.
Artemeter
:same with artesunate. One capsule = 40
mg.

RESISTANCE TO THE THERAPY FOR

MALARIA
Caused

by continuous therapy and

inadequate
Adaptation and mutation of parasite
The parasite taking from resistance
area.

Management of severe
malaria
Malaria cerebral:
Parenteral

quinine dihydrochloride 10
mg/bw/dose diluted with 50-100 ml NaCl
0,9% or 2A or dextrose 5 % for 2-4 hour,
3 times a day. If patient conscious,
continue the same dosage by oral until
7 day.

Fansidar atau suldox can be consider

Management of severe
malaria
Anaemia

(Hb < 5 g/dl)

Ht < 15 %, transfusion 10ml/bw PRC or

20ml/bw WB.

Convulsion

Diazepam 0.5mg/bw, IV.

Management of severe
malaria

Dehydration, acid-base and electrolyte

imbalance

if urine < 1 ml/bw/hour give furosemid inisial 2

mg/bw, followed by 2 X dose max. 8 kg/bw (in 15
minute).
Oxygen, ventilator if necessary.

Hypoglycemia

If hypoglycemia occurred : glucose 40% (0.5-1.0

ml/bow) followed by glucose 10% as
maintenance. Check blood glucose / dextrostick.

Management of severe
malaria

Renal failure

Manage the dehydration, if still olyguria and ureum dan

creatinine increase, do the peritoneal dialysis

Acute pulmonary edema

Up right position
Oxygen high concentration and diuretic intravenous
Apnea ventilator
Pulmonary
edema
stop
IV.,
give
furosemide
1mg/bw/time, repeated if necessary.

Management of severe malaria

Bleeding
FFP
TC
PT

and PTT longer, give Vit. K 10 mg

slowly

Hyper

pyrexia

>390C,

Malaria

paracetamol 15 mg/bw/dose

biliosa

RESISTANCE OF P. FALCIPARUM WITH

SOME ANTIMALARIAL DRUGS
Quinine
Pyrimethamine
Proguanil
Chloroquine
Amodiaquine
Sulfadoxin-pyrimethamine
Mefloquine

DETECTION OF RESISTANCE FOR

ANTIMALARIAL DRUGS
(WHO)

Degree of sensitivity for Plasmodium

falsiparum in vivo are:

S
= sensitive, if the parasite gone after
therapy, and followed in 4 week
R I
= Resistance grade I if there is late
recrudesced ( in 3th week and 4th ) or early in
2nd week
R II
= Resistance grade II if number of
parasite decrease in first week
R III
= Resistance grade III, if number of
parasite still the same or increase in 3th week

DETECTION OF RESISTANCE
ANTIMALARIAL DRUGS
(WHO)

MICROSCOPE RESULTS
WHO
(-)

: no plasmodium per 100 fields

(+)
: 1-10 per 100 fields
(++)
: 11-100 per 100 fields
(+++) : 1-10 per fields
(++++): 11-100 per fields

Note: 500-700 X power under oil-immersion

STRATEGY FOR PLASMODIUM

FALSIPARUM RESISTANCE TO
CHLOROQUINE

Mefloquine: drug of choice for manage

patient with resistance to chloroquine and
fansidar or both

The boundary of this combination are:

Only for P.f. which confirmed microscopically

Do not use in chloroquine resistance area
Do not use as prophylactic or suppression except for
traveler

COMBINATION DRUGS
To prevent

resistance

Arthemether

dan lumefantrine (Riamet)

Artesunate-atovaquone-proguanil
Artesunate-Pyrimethamine-sulfadoxine
(PSD)
Chlorproguanil-dapsone (Lapdap)

FUTURE AMD TREATMENT

(CQ & SP FAILURE AREAS)
Uncpl.
P.f.

Arts

Amo

(+)

(+)

(+)

SP

Mef

DHA

Pip

(+)

(+)

Artm Lum

Qn

Dx

(+)

(+)

(+)(?)

(+)

(+)(?)
(+)

(+)

Compl. IM/IV
P.f.
IM

(+)
IV

FUTURE AMD TREATMENT

(CQ & SP FAILURE AREAS)
P.v.

Arts

Amo

Pq

(+)

(+)

(+)
(+)

Prophl.

Qn

Dx

Mef

(+)
(+)
(+)

(+)

PROPHYLACTIC
DOSES
Drug Formula

Dose

Chloroquin
e

Tablet 300 mg

5 mg base bw/week
(max. 300mg/day)
until 4 weks after
arrival

Mefloquin
e

Tablet 228 mg

<15kg: 5 mg/ week

15-19 kg; tb/ week
20-30 kg ; tb/ week
31-45; tb/week
> 45 kg: 1 tb /week

PROPHYLACTIC
DOSES
Drug
Formula
Doxycyclin 100 mg capsul
Proguanil

100 mg salt

Dose
> 8 th: 2 mg/bw; until 100
mg/day
5-8 kg: tb/d
9-16 kg: tb/d
17-24 kg: tb/d
25-35 kf: 1 tb / d
36-50 kg: 1 + tb/d
>50 kg: 2 tb/ d

MALARIA VACCINE
Manuel

Patarroyo (Colombia, 1980)

SPF66:

1999,

efficacy 80%

Oxford

MVA (Non-replicating

1999,

USA

RTSS

(Viral vaccine)

vaccinia virus)

THANK YOU

In vivo test for field standard (WHO)

Field standard test: 7 dayi

Chloroquine base 25 mg/bw for 3 day, observe and check blood

slide everyday in a week counted from the day that drug was
taken,

Long Field standard test : 28 day

Alternatif test or single dose test

Chloroquine base 10 mg/bw

If therapy can not been given for 3 day continouosly

In endemic area
As preface survey

Simplified test

Only for patient resistant chloroquine. Blood sampling on 1st,2nd

and 7th day.

MOLECULAR INTERACTIONS IN
FALCIPARUM MALARIA
Interaction
Invasion of red cells
(merozoite and
uninfected red
cells)

Parasite/parasitized
red cell molecule(s)

Host cell
molecule(s)

EBA-175

Sialic acid on
glycophorin

MSP-1

Possibly glycophorin

Cytoadherence
(mature infected
cell and endothelial
cell)

PfEMP-1

Cd36, ICAM-1, VCAM1, E-selectin,

thrombospondin,
CSA

Rosetting (mature
infected cell and
endothelial cell)

Rosettin

Possibly ABO blood

group molecules

PfEMP-1

CR1

GPI-anchored
molecules parasit
Hemozoin-associated
protein

Red cell membrane

components

Toxin release

 Mechanism

chloroquine

resistency of

MECHANISM OF
CHLOROQUINE

Parasite accumulate chloroquine in acid vakuola

P.f. multiplication

Digesting Hb and feeding vacuole

Erythrocyte breakdown, merozoite do the invasion

One cycle : 48 hour
Hb produce toxic agent: ferriprotoporphyrin IX (FPIX)
Chloroquine performe complex with FPIX
This toxin poisoned the vacuole , delayed food intake,
so parasite would died
Delayed the enzyme to polymerized and detoxified
FPIX

Resistant mechanism of
chloroquine
P-glicoprotein
Dependen ATP pump

Cytocrome P-450

Exporter drug to outer cell

Increased biochemical detoxification of chloroquine by the parasite
(chloroquine was metabolite by the cytochrome P-450 become
diacetichloroquine and didecetilchloroquine)
P.f. contain aminopyrin demetilase dan etoksicoumarine diethylase (P450 inhibitor cimetidine will decrease enzyme activity)

Pfmdr 1 and 2 (mdr-like genes)

Some researcher

Others

Relation of pfmdr 1 and resistant phenotype

No relation

Function pfmdr 2

Not known yet

copy by tigor00

KLASIFIKASI MALARIA BERAT

PADA ANAK

Grup 1

Memerlukan pengobatan parenteral dan suportif

Prostrated childen

Distres pernafasan

Ringan - nafas cuping hidung / retraksi interkostal ringan

Berat - pernafasan Kusmaul

Grup 2

Anak dapat minum obat oral tetapi perlu pengawasan oleh

karena dapat memburuk dan tidak menunjukkan gejala
grup 1

Tetapi sadar penuh

Dengan penurunan kesadaran tetapi tidak koma yang dalam
Koma

Hb < 5 g/dL atau Ht < 15%

Grup 3

Anak memerlukan pengobatan parenteral oleh karena

muntah persisten tanpa gejala klinis atau lab grup 1 atau 2