MALARIA

Carta Gunawan
National Expert Committee on Malaria
Global Warming Increases Malaria, Dengue Fever Threat,
UN Says
By Jason Gale and Bill Varner - November 27, 2007 07:00 EST

Nov. 27 (Bloomberg) -- Global warming will put millions more people at risk of malaria and
dengue fever, according to a United Nations report that calls for an urgent review of the health
dangers posed by climate change.
Increases in rainfall, temperature and humidity will favor the spread of malaria-transmitting mosquitoes
over a wider range and to higher altitudes, according to the 2007-2008 Human Development Report,
released today. That could put 220 million to 400 million additional people at greater risk of the disease
that kills about 1 million a year, mostly in Africa.
``Ill health is one of the most powerful forces holding back the human development potential of poor
households,'' the report said. ``Climate change will intensify the problem.''
The 384-page report commissioned by the UN Development Program was released a week before
delegates to a UN-sponsored conference on Bali, Indonesia, will try to convince the U.S. to join a new
emissions-limiting treaty that will pick up after 2012, when the Kyoto Protocol ends.
Droughts, floods and storms will worsen unless measures are taken to cut emissions in half by 2050
relative to 1990 levels, the report said. About 262 million people were affected by climate disasters
from 2000 to 2004, most of them in developing countries.
Changes in weather patterns may also increase the number of people exposed to dengue fever to 3.5
billion from 1.5 billion by 2080. The potentially lethal viral disease, which is also transmitted by
mosquitoes, is found at higher elevations in previously dengue-free areas of Latin America, the report
said.
``A major public health threat is coming from the vector- borne diseases that depend on
temperature and on humidity,'' said Martin Krause, UNDP's Bangkok-based technical adviser on
climate change for the Asia-Pacific region. ``Occurrences of malaria and dengue fever in
communities'' traditionally unaffected by these diseases would place an additional strain on
public health services, he said.
Malaria endemicity map in Indonesia 2011
NATIONAL MALARIA CONTROL

Objectives :
In 2030, Indonesia achieves malaria free
transmission for healthy life people,
and malaria cases reduction of 2 per
1,000 inhabitants (2010) to less than 1
per 1,000 inhabitants (2030), and
malaria endemic areas declines 50 %
STRATEGY OF PROGRAM
1. Diagnosis
confirmed by microscopy or rapid diagnostic test
(RDT)
STOP CLINICAL MALARIA DIAGNOSIS
2. Treatment
Artemisinin Combination Therapy (ACT)
STOP MONOTHERAPY
3. Prevention
Long-lasting Insecticidal Net (LLIN), Indoor
Residual Spraying (IRS), etc
4. Partnership
WHAT ARE NEW ABOUT MALARIA
IN THE LAST DECADE ?
P. vivax is proved to cause severe malaria
(2000)
P. knowlesi is reported as the fifth
plasmodium species that causes human malaria,
and also causes severe malaria (2004)

Treatment of uncomplicated malaria should

use combination drugs (ACT) (WHO, 2006)

Treatment of complicated (severe) malaria :

parenteral artemisinin derivatives (WHO, 2006)
P. knowlesi (the fifth human plasmodium)
Natural host : Macaca fascicularis/ Macaca
nemestina
First reported in 2004 from Sarawak, Malaysia
Morpholgy similar to P. malariae
Diagnosis by PCR
No hipnozoite
Fever every 24 hours, diarrhea, abdominal pain
Can cause severe malaria (10 % of infected cases;
mortality 1-2 %)
Complications reported : ARDS, liver/ kidney
dysfunction, hypotension
Sensitive to chloroquine
CLINICAL MANIFESTATIONS
and
DIAGNOSIS
Manifestations of plasmodium infection

Benign malaria (uncomplicated malaria)

Severe malaria

(malaria with complications)

2 10 % of malaria cases
mortality rate 10 - 50 %
untreated cases : mortality almost 100 %
P. vivax, P. knowlesi severe malaria

cerebral malaria
severe anemia
severe thrombocytopenia
P. vivax
jaundice
acute renal failure
rupture of spleen
ARDS

P. knowlesi
 SEVERE MALARIA -2010
DEFINITION : patient with plasmodium asexual parasitemia, with
one or more CLINICAL or LABORATORY FEATURES :
PROSTRATION
FAILURE TO FEED
IMPAIRED CONSCIOUSNESS SEVERE ANEMIA (< 5 gr%/15 %)
RESPIRATORY DISTRESS HYPOGLYCEMIA (<40 mg%)
MULTIPLE CONVULSIONS, >2x/ 24 hrs ACIDOSIS (< 15 mmol/L)
CIRCULATORY COLLAPSE RENAL IMPAIRMENT (> 3 mg%)
(systolic < 70, chlidren < 50 ) HYPERLACTATEMIA (> 5mmol/L)
PULMONARY EDEMA ( radiology ) HYPERPARASITEMIA (>2%/ 5%)
ABNORMAL BLEEDING ( spontaneous )
JAUNDICE + other vital organ
dysfunction
HEMOGLOBINURIA
WHO: Guidelines for the Treatment of Malaria 2010- second edition
Severe manifestations of P. falciparum

White NJ. Mansons Tropical Diseases. 22nd edition. 2010

Plasmodium infection in pregnancy

mother fetus
immune system parasite
sequestration
tends to present as in placenta
severe malaria IUGR, IUFD,
low birth weight,
fetal distress,
mortality risk 3 times premature
higher labor
than non-pregnant women(congenital malaria)
DIAGNOSIS

History of traveling to endemic malaria

area
Clinical signs and symptoms
Laboratory examinations and other
examinations
 Patients with fever or fever in the last 3
days (with headache, nausea, vomiting,
diarrhea, muscle pain)

Malaria blood smear (microscopic

examination) or RDT

Positive Negative

Repeat malaria Search for

Malaria
blood smear other causes
every 24 hour of fever
until 48 hour

Positive
Treat
based on
Malaria etiology

Pedoman Tatalaksana Malaria 201

 Laboratory examinations
- Blood smear (thick and thin blood
film)
- Rapid Diagnostic Test
(immunochromatography)
- QBC (quantitative buffy coat)
- PCR (polymerase chain reaction)
MICROSCOPIC EXAMINATION
Giemsa stain (3%); detection threshold 50-
100 parasites/L blood
Thin blood film (better for evaluation parasites
morphology) and thick blood film (higher
sensitivity)
Thick blood film

semiquantitative : +, ++, +++. ++++

quantitative : parasite/ 200 leucocyte x WBC
. parasites/ L blood
Thin blood film : parasite in 25 view fields x 100 %
RBC in 25 view fields
Malaria Rapid Diagnostic Test

Immunochromatographic assay
Monoclonal antibodies directed against the
target parasite antigen
Need small amount of blood, 5-15 L
Results obtained in 5-20 minutes
Room temperature 4-300C
For useful diagnostic, RDT must achieve >
95 % sensitivity
Detection threshold > 100 parasites/L
blood
Wurtz et al. Malaria Journal 2013, 12
RAPID DIAGNOSTIC TEST
MALARIA TREATMENT
 Anti-malarial drug resistance

fforts towards control and elimina

 ARTEMISININ DERIVATIVES :
from ancient herbal medicine
to WHO essential drug
 LONG HISTORY OF ANTIMALARIAL DRUGS

Quinine (1632, Peru)

Artemisinin (1972, China)

Dynamics of parasite-killing activity of artemisinin
and other antimalarial drugs

Dondorp et al. N Engl J Med 2011; 365: 1073-5

ARTEMISININ DERIVATIVES

Artemether (oral, intramuscular injection)

Artesunate (oral, suppository, intravenous
injection/ intramuscular injection)
Artemisinin (oral, suppositoria)
Dihydroartemisinin (oral, suppository)
Artemotile/ arteether ( intramuscular injection)
Artelinic acid ( intravenous injection)
 ARTEMISININ DERIVATIVES
FOR TREATMENT OF MALARIA
Severe Malaria
artesunate (i.v. or i.m)
artemether (i.m.)
artemotile (i.m)

Uncomplicated Malaria
artesunate
artemether
artemisinin
dihydroartemisinin
 TREATMENT
OF UNCOMPLICATED MALARIA
TREATMENT OF UNCOMPLICATED MALARIA

PRIMARY
to cure the infection rapidly and reliably
to prevent both progressions to severe disease
and the additional morbidity associated with
treatment failure

SECONDARY
to prevent the infection from being
transmitted
to prevent resistance to antimalarial drugs
 MALARIA TREATMENT :
CURRENT APPROACH
Based on microscopic diagnosis
Combination therapy
Must be radical treatment
Outcome focused on clinical cure, parasitological
clearance, and blocking transmission
Monitoring therapeutic efficacy of antimalarial
drugs based on clinical and parasitological
responses (in-vivo 28-42 days with or without
ancillary measurements: drug blood level,
genotyping, and strain analysis using molecular
markers)
TREATMENT OF UNCOMPLICATED MALARIA

Artemisinin Combination Therapy

(ACT)
 Study in Lampung 2002 :
chloroquine resistance to Pf 68 %, to
Pv 43 % (Sutanto, et al)
Study in Kabupaten Pesisir Selatan
ACT

(West Sumatera ) 2004 : treatment

failure of chloroquine 78.4 % & SP
80.77 % for uncomplicated
Artesunate + amodiaquine
(Artesdiaquine)
falsiparum malaria (Irawati, et al)
efficacy > 95 % against
P. falciparum and
P. vivax
Artemether lumefantrine

x
(Coartem)
(Papua & East Sumba )
CQ, SP efficacy > 95 % (PCR
corrected)
against P. falciparum
Dihydroartemisinin + piperaquine
(Artekin)
(Papua & South Lampung )
efficacy > 95 % against Pf
and Pv
ARTEMISININ COMBINATION THERAPY
(ACT)
Combination of artemisinin derivatives with other
anti-malarial agent(s) which are blood
schizontocides, with different mechanisms of
action and different biochemical targets against
parasite
Increase therapeutic efficacy and prevent/ slower
the emergence of resistance to single drug
Fixed dose combination or non fixed dose
combination
First line treatment for uncomplicated malaria
(WHO, 2006)
Accepted in 90 countries in 2009
Guideline for the treatment of malaria
WHO 2010
ACT
Artemether + lumefantrine (20/120) 2 x 4, 3 days
Artesunate (50) + amodiaquine (200), 3 days
Artesunate (50) + mefloquine (250)
artesunate 200 mg/ day for 3 days
mefloquine 1000 mg day II, 500 mg day III
Artesunate (50) + SP (500/25)
artesunate 200 mg/ d 3 days, SP 3 tablets single dose day I
Dihydroartemisinin (40) + piperaquine (320), 3 days
ACT USED IN INDONESIA

Artemether-lumefantrine (private sector)

Artesunate+amodiaquine

(MOH program)
Dihydroartemisinin-piperaquine

(MOH program)
Artemisinin-naphtoquine (armed-forces)
 TREATMENT OF
UNCOMPLICATED MALARIA
2012

National Expert Committee on Malaria

Guidelines
 First line ACT
Dihydroartemisinin-piperaquine (DH-P)

Day Drugs Dosage (tablets) based on age-groups and

body weight (single dose)

0-1 2 11 1 4 59 10 14 > 15 15
mos mos yrs yrs yrs yrs Yrs
5 6-10 11-17 18-30 31-40 41-59 60
1--3 DHP 1 1,5 2 3 4
F, D1 Primaquin -- -- 1 2 2 3
e
V,D1 Primaquin - - 1 1
14 e

Dihydroartemisinin(DH) : 2-4 mg ( 2.2mg)/kgBW (1tablet = 40 mg)

Piperaquine phosphate(P): 16-32mg (18mg/kgBW (1tablet = 320 mg)
Primaquine : 0.25 mg 0.75 mg/kg BW
 Artesunate+amodiaquine

Drugs Number of tablets based on age-groups

Da Single 0 2 11 1 - 4 5 - 9 10 - > 15
y dose 1 mos yrs yrs 14 yrs
mos yrs
1 Artesunate 1 2 3 4
Amodiaquin 1 2 3 4
e
Primaquin -- -- 1 2 2-3
e
2 Artesunate 1 2 3 4
Amodiaquin 1 2 3 4
e
3 Artesunate 1 2 3 4
Amodiaquin 1 2 3 4
e

P. vivax : primaquine 15 mg OD for 14 days

 Artemether-lumefantrine (A-L)

Drugs <3 >3-8 >9 > 14

Age yrs yrs 14 yrs yrs
Da BW (kg) Time 5 14 15 24 25 34 > 34 kg
y kg kg kg
1 A-L 0 hr 1 2 3 4
A-L 8 hrs 1 2 3 4
Primaquin 12 1 2 2-3
e hrs
2 A-L 24 1 2 3 4
hrs
A-L 36 1 2 3 4
hrs
3 A-L 48 1 2 3 4
hrs
A - L P. vivax60 1 15 mg OD
: primaquine 2 for 14 days3 4
hrs
Artemisinin-napthoquine
FDC of artemisinin 250 mg and
naphtoquine 100 mg
Single dose

6 10 kg : tablet

11 15 kg : 1 tablets

16 25 kg : 2 tablets

26 35 kg : 3 tablets
> 35 kg : 4 tablets
TREATMENT of MIXED INFECTION
P. vivax and P. falciparum
First line treatment :
ACT (DHP/ A-L/ AS+AQ)
+ Primaquine day 1 : 0.75 mg/kg BW/ single
dose , day 2 14 : 0.25 mg/kg BW
Treatment of Relapse Vivax Malaria

ACT 3 days
double-dose of primaquine 14 days
TREATMENT OF UNCOMPLICATED
MALARIA IN PREGNANCY
First trimester : quinine 10 mg/ kg BW / 8
hours + clindamycin 10 mg/ kg BW/ 12 hours
for 7 days
Second & third trimester :

first line : ACT

second line : quinine + clindamycin
Monitoring of treatment response (WHO 2001)
1. Early Treatment Failure/ETF
if found one of the followings :
- D1-D3 worsening clinical conditions/ become severe malaria
- D2 parasite count > D0
- D3 parasite count > 25 % D0
- D3 parasites in asexual form remain positive & t > 37.50 C
2. Late Treatment Failure/ LTF
LCPF (Late Clinical & Parasitological Failure)
- D4 D28 occurrence of severe malaria
- parasites in asexual form remain positive & t > 37.50 C
LPF (Late Parasitological Failure)
parasites in asexual form remain positive on D7,D14,
D21, D28 although without fever
Monitoring of treatment response (WHO
2001)

ACPR (Adequate Clinical & Parasitological

Response)

No parasitemia until day -28 and

not applicable to the criteria of ETF/ LTF
 Management of Treatment Failure
Treatment failure within 14 days very
unusual :
32 trials (4917 patients), no failure on D14
7 trials failure at D14 ( 1 7 %)
Failure after 14 days : recrudescence or re-
infection
Rescue treatment :
Alternative ACT known effective in this region
Artesunate + tetracycline/ doxycycline/ clindamycin
Quinine + tetracycline/ doxycycline/ clindamycin
Dihydroartemisinin-piperaquine (40/320)
Dihydroartemisinin
The main active metabolite of the artemisinin derivatives
Relatively insoluble in water
Oral and rectal preparation
Peak plasma level 2.5 hours after oral administration;
elimination half-life 45 minutes
Piperaquine
4-aminoquinoline, blood-schizontocide for P. falciparum
Synthesized in 1960, widely used in China since 1990s
for treatment and prophylaxis of malaria
Repeated dosage : multiple concentration peak
Very long terminal half life : 2 4 weeks
Adverse effect : nausea, vomiting
Available in fixed-dose combination with
dihydroartemisinin
Malaria Journal 2012, 11 ; 153
Time and study location
The trial was carried out in 20072008 at four hospitals, three Armed Forces hospitals in Jayapura
(Marthen Indeys/Army, Soedibjo Sardadi/Navy and Bhayangkara/Police Hospitals), and one public
hospital in Maumere (St Gabriel Hospital).
 TREATMENT
OF SEVERE MALARIA
AIMS OF TREATMENT OF COMPLICATED
AND SEVERE MALARIA

PRIMARY
To prevent the patient from dying

SECONDARY
To prevent disabilities, recrudescence,
transmission, emergence of resistance
General Principles :
1. Anti malarial agents
- parenteral anti malarial agents
2. Supportive & symptomatic treatments
- fluid, nutrition, electrolytes
3. Treatment of organ complications
- hemodialysis, ventilator
 Treatment Severe Malaria -2010
Severe malaria is a medical emergency
Adult : artesunate iv / im
Children : artesunate iv/im, quinine iv/ im,
artemeter im
Give parenteral at least 24 hours
Switch to oral : ACT, artesunate + clindamycin/
doxycycline, quinine + clindamycin/ doxycycline
If not possible, give pre-referal Rx, then refer
immediately
 FURTHER TREATMENT

When conscious/ getting better, initial parenteral

treatment can be changed with oral medication as
follows :
ACT full dose (3 days): DHP, A-L , AS + AQ
Artesunate/ artemether tab. (total 7 days) +
doxycycline 7 days
Quinine tab.(total 7 days) + doxycycline 7 days
Pregnant women/ children : avoid doxycycline, use
clindamycin 10 mg/Kg BW twice a day
Anti malarial in severe malaria

First choice : artesunate iv

Alternative : artemether im or quinine infusion
ARTESUNATE
1 ampoule = 60 mg + 0.6 ml NaHCO 5 %, diluted
3
with 5.4 ml dextrose 5 %
Slow intravenous injection (~ 2 minutes)
Plasma peak level ~ 1 hour after injection,
elimination half-life ~ 45 minutes
Dosage :

2.4 mg/kg BW then 2.4 mg/kg BBW 12th hour and

24th hour, followed by 2.4 mg/ kg BW/ 24 hours until
7th day (17-18 mg/ kg BW for 7 days)
Adverse effects : nausea, diarrhea, rash, drug-fever,
reduced reticulocyte count
Toxicity rare ~ 1 : 3000 treatment
MANAGEMENT OF CEREBRAL MALARIA
Management of airway, breathing, circulation
Treat seizure : benzodiazepine, phenytoin,
phenobarbital
Monitoring of vital signs, urine production
Be aware of hypoglycemia, electrolytes and acid-
base disorders, orthostatic pneumonia, corneal
ulcer
Parenteral anti-malarial
Antibiotics if necessary
Use of steroid, manitol
NOT recommended
3
MANAGEMENT OF MALARIA WITH
JAUNDICE
Parenteral anti-malarial; if use quinine, reduce dose
30 50 % after 48 hours
Treat hypoglycemia with dextrose 40 %
Vitamin K iv
Avoid using hepatotoxic drugs
MANAGEMENT OF ACUTE KIDNEY
INJURY
Parenteral anti malarial; reduce quinine dose 30-
50 % after 48 hours
Monitor urine production
Correction of electrolyte and acid-base disorders
Be aware of lung edema
Dopamine renal dose : controversy
Dialysis as early as possible
TREATMENT OF SEVERE MALARIA IN
PREGNANCY
First line : artesunate iv (especially for
second and third trimester; can also be
given in first trimester)
Second line : quinine infusion
(safe for 1st, 2nd, 3rd trimester)
 KEYS FOR SUCCESSFUL MANAGEMENT
OF SEVERE MALARIA

Accurate diagnosis ( microscopic biochemical )

Anti malarial drugs ( to combat resistance )
Ability to treat organ failure ( ICU & medical
equipment )
Good man power ( nurses --- doctors )
Good referral system
PROGNOSIS
Mortality of severe malaria : 10 50 %
Early diagnosis and prompt & adequate
treatment are very important
Severity of vital organs dysfunction and number
of organs involved are related to mortality
One complication : mortality ~ 10 %
Two complications : mortality ~ 20 %
Three complications : mortality > 50 %
Four complications : mortality > 75 %
Parasitemia > 500,000/L : mortality > 50 %
 NEW REGIMEN OF MALARIA TREATMENT
National Expert Committee, 2012

Pf without complication : Pf with complications :

1. PRQ-DHA+ PQ1 1. Artemether im
2. QN7+DX7 +PQ1 NEW
NEW
PRQ-DHA+PQ1
(PHC)
Vivax malaria :
ACT
ACT
3. PRQ-DHA+PQ14 Artesunate iv
4. QN7+PQ14 PRQ-DHA+PQ1
(Hospital)

2. QN per-infusion
-QN7+Dx7+PQ1

Prophylaxis Pf
Doxycycline
 Drug regimens for prophylaxis against malaria
Drugs Tab size Adult Child Preg Initiate Discontinued
mg dose

areas with chloroquine resistant falciparum

Atovaquone- 250-100 tb/d 1 Yes No 1-2 d 7 days

Proguanil 62.5-25

Mefloquine HCl 250 tb/w 1 Yes Yes 2 wks 4 wks

Doxycycline 100 tb/d 1 No No 1-2 d 4 wks

areas with chloroquine- sensitive falciparum

Chloroquine 500 1tb/w Yes Yes 2 wks 4 wks

areas with P. vivax, P ovale with/ without P. falciparum

Primaquine 15 2 Yes No 1d 7 days

primary tb/d

Primaquine 15 2 Yes No 1d 14 days

anti-relapse tb/d
SUMMARY
Artemisinin derivatives are the first line
treatment for uncomplicated malaria (ACT)
and severe malaria (artesunate iv, artemether
im)
Early diagnosis, rapid and proper
administration of anti malarial drugs are crucial
for good outcome
Resistance to antimalarial drugs is a major
concern in global malaria control and
elimination program
 TRAINING ON ANTI-MALARIAL
TREATMENT FOR DEVELOPING
COUNTRIES

Shanghai, December 2007

 THANK YOU

IGUAZU, September 28, 201