Malaria Updates

Fe Esperanza Espino
Department of Parasitology
Research Institute for Tropical
Medicine
 Outline

General epidemiology of malaria in the
Philippines

P falciparum

Updates in treatment

Recognizing treatment failure

P vivax

Treatment

Chloroquine treatment failure

Severe vivax malaria

P knowlesi

Emergence

Diagnosis

Research
Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008
 Malaria Life Cycle
Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008
 Malaria Triad
•Human host

Mosquito – Anopheles sp. Parasite – Plasmodium sp.

An. flavirostris P. falciparum (60-70%)
An litoralis P. vivax (30-40%)
An. maculatus P. malariae (?)
An. mangyanus P. ovale (?)
An. balabacensis P. knowlesi (?)

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Distribution of anopheline vectors Distribution of malaria cases

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

Plasmodium falciparum
 CQ+SP regimen for uncomplicated falciparum
malaria (2002-07)
Dose(no. of tablets)
Drug
Adult Children
0-4 mos ¼
Sulfadoxine/ pyrimethamine 5-11 mos ½
(500mg/25mg tablet); 1-6 years 1
Sulfadoxine 25 mg/kg
Three
7-11 years 1½
Pyrimethamine 1.2 mk/kg 12-15 years 2
Day 0 > 16 years 3
0-11 mos ½
1-3 years 1
Chloroquine (150 mg base tablet); 10 4-6 years 1½
Four
mg/kg 7-11 years 2
12-15 years 3
>16 years 4
Day 1 Chloroquine (as in D0) Four As in Day 0
< 3 years ½
4-11 years 1
Day 2 Chloroquine; 5 mg/kg Two 12-15 years 1½
>16 years 2
Below 1 year Contraindicated
1-3 years ½
Day 3 Primaquine (15 mg base tablet) Three 4-6 years 1
7-11 years 2
> 12 years 3
Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008
 Coartem (artemether 20mg/ lumefantrine 120mg)
regimen for uncomplicated falciparum malaria
Children 12 years old and below
Adults and
children 13 years <3 years and
and above >8 to 12 years > 3 to 8 years infants above 5
kg body weight
Day 0 4 tabs; repeat 3 tabs; repeat 2 tabs; repeat 1 tab; repeat
after 8 hrs after 8 hrs after 8 hrs after 8 hrs

Day 1 4 tabs BID 3 tabs BID 2 tabs BID 1 tab BID

Day 2 4 tabs BID 3 tabs BID 2 tabs BID 1 tab BID

Day 3 Give primaquine as in uncomplicated falciparum malaria

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Categories of response to treatment of P. falciparum

Therapeutic response Criteria

Early treatment failure (or • Severe malaria and parasitemia
ETF; days 1 - 3) • Day 2 – Parasitemia higher than Day 0
• Day 3 – Parasitemia and fever or parasitemia >
25% of Day 0
Late clinical and Parasitemia and symptoms (severe malaria or fever)
parasitological failure (or
LCPF; days 4 - 28)

Late parasitological failure Parasitemia but no symptoms

(or LPF; days 4 - 28)
Adequate clinico- No parasitemia and fever until Day 28
parasitological response

Modified from WHO, 2003

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Quinine-plus regimen for falciparum malaria
treatment failure

Quinine Plus either

Age group/ sulfate (300
Primaquine
condition or 600 Doxycycline Tetracycline
mg/tablet
Adults 10 mg/kg/ 100 mg BID for 250 mg QID for As in
dose every seven days seven days uncomplicated
eight hours falciparum
for seven malaria
days
Pregnant As above Contraindicated Contraindicated At termination
women of pregnancy
Children > As above 2 mg/kg/day for 4 mg/kg QID for As in
8 years old seven days seven days uncomplicated
falciparum
Children 8 As above Contraindicated Contraindicated malaria
< old and
below

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

Regimen for severe malaria
Quinine dihydrochloride dose
Age group Tetracycline Clindamycin
Loading Maintenance

Adult 20 mg salt/kg in 10 mg salt/kg in 500 mg QID for 10 mg/kg BID

D5W x 4 hours D5W IV drip x 4 seven days for three days
IV drip; do not hours every 8
exceed 1,800 hours; do not
mg; do not exceed 5 mg
exceed 5 mg salt/kg/hr
salt/kg/hr
> 8 years to 16 15 mg salt/kg IV 10 mg salt/kg IV 4 mg/kg QID; As above
years drip x 4 hours drip x 4 hours not to exceed
every 8 hours 250 mg/dose

8 years and 10 mg salt/kg in 10 mg salt/kg IV Contraindicated As above

below IV drip x 4 drip every 12
hours hours

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

Plasmodium vivax
 CQ and primaquine (PQ) regimen for vivax malaria

Dose (no. of tablets)

Drug
Adult Children
Days 0 to 2 Chloroquine as in P. falciparum

Below 1 year Contraindicated

1-3 years 1/3
Primaquine (15 mg base
Days 0 to 13 One 4-6 years ½
tablet); 0.5 mg/kg
7-11 years ¾
> 12 years 1

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Recognizing P vivax chloroquine
treatment failure

Parasitemia and clinical deterioration

Parasitemia and recurrence or persistence of
fever (>37.5C) from Day 3 to Day 28 after start of
treatment

Parasitaemia from Day 7 to 28 after start of
treatment regardless of clinical condition

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Surveys for chloroquine-resistant P vivax since 2000
COUNTRY YEAR STUDY POP’N % RESISTANT
SIZE
India 2004 287 0
2004 (CQ+PQ) 102 0
2001 480 0
Indonesia 2004 40 65
2000 (CQ+PQ) 60 18
Turkey 2004 91 22
2001 112 15
Thailand 2004 (CQ+PQ) 31 0
2003 161 0
Vietnam 2001 113 16
Colombia 2004 210 0
Peru 2001 177 2
Modified from Baird K., 2007, TRENDS in Parasitology, Vol. 23 No. 11

Philippines 2005 37 0
Espino et al, 2006
Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008
 Plasmodium vivax relapses

Are important sources of reinfection and
transmission

Risk of relapse of tropical strains is higher
than temperate strains

Relapses can occur weeks to years after the
initial infection

Prevention targets the hypnozoites

Primaquine is the only commercially available
anti-relapse drug

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Risk of P vivax relpase according to
primaquine dose (India, Thailand and Brazil)

Odds ratio 95% CI

Primaquine dose (adjusted)
0 1.0
75 0.42 0.34-0.52
210 0.22 0.16-0.30
315 0.01 0.00-0.08
420 0.05 0.01-0.20

(modified from Goller et al., 2007, Amer Jour Trop Med Hyg, Vol 76 No. 2)
Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008
 Reports of severe and complicated P. vivax malaria since 1998
FATAL
COUNTRY YEAR NO. OF CASES PRESENTATION
CASES
Afghanistan 2004 1 adult ARDS 0
Brazil 2000 1 adult Thrombocytopenia 0
Columbia 1998 1 adult ARDS 0
India 1998, 1999, 56 adults; 1 child ARDS (5) 1
2000, 2002, Cerebral (4) 1
2003, 2006 Renal failure (22 adults; 1 5
child)
Liver dysfunction (8)
Jaundice (4)
Thrombocytopenia (5)
Pancytopenia (1)
Indonesia 2000 21 children; 17 ARDS (2) 1
adults Cerebral (5) 3
Renal failure (4)
Liver dysfunction (10) 3
Anemia (24)
Hyperparasitemia (1)
Acidosis (3) 1
Kenya 2004 1 adult Splenic rupture 0
Malaysia 2003 2 adults ARDS (1)
DIC/ renal failure (1) 1
New Guinea 2000 1 adult ARDS 0
Pakistan 2000 1 adult Cerebral 0
Singapore 2003 1 adult ARDS 1
Turkey 2005 2 adults; 1 child Cerebral (child) 0
Splenic rupture (2 adults)
Venezuela 2005 1 adult ARDS 0
Modified from Baird K., 2007, TRENDS in Parasitology, Vol. 23 No. 11
Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008
Plasmodium knowlesi
 P. knowlesi – a new, emerging human
parasite

Malaria parasite of old world monkeys; isolated from
Philippine macaques (Macaca fascicularis) in 1961

Incriminated vector is An balabacensis

First naturally acquired human infections was
reported in 1965 in Malaysia

Foci of cases reported

Sarawak, Malaysia – 2004, 2008

China - 2006

Thailand – 2004

Philippines – 2008 (in press)

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 P. knowlesi (cont.)

Morphologically similar to P malariae; may be
mistaken to be P falciparum because of
abundant ring stages

Rhesus monkey studies

High parasite densities is possible

No significant sequestration in microcirculation

Reported in relatively older adults

May present as a mild from of malaria easily
responding to chloroquine

Fever, headaches, intermittent chills, abdominal
pain, sweating and malaise

May also be severe and fatal

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Comparison of results for detection of Plasmodium
species by PCR and microscopy

Microscopy Pf Pv Pm Po Mixed # PCR

PCR identified

P falciparum 167 18 33 1 0 219

P vivax 23 372 43 1 1 440

P malariae 0 0 1 0 0 1

P ovale 0 2 2 0 0 4

P knowlesi 11 16 216 0 0 243

Mixed infections 15 20 17 0 1 53

TOTAL 216 428 312 2 2 960

Modified from Cox-Singh et al., 2008, Clinical Infectious Diseases, 46, 165-71

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 Details at hospital admission of 4 fatal cases of P knowlesi
Case 1 (66/f) Case 2 (69/m) Case 3 (39/m) Case 4 (40/m)
Parasites 764,720 75,000 112,000 ++++
BP 120/90 124/66 81/51 132/57
T (axilla) 36.8 38 37 36
Hb 10.6 15.2 15.4 11.9
WBC 16,700 6,600 13,400 11,400
APC 22,000 25,000 24,000 24,000
Creatinine 500 NA NA 557
(umol/L)

TB (umol/L) 79 300 NA 490

Conj. bilirubin 59 187 NA 350
AST (U/L) 122 163 NA 87
ALT (U/L) 104 77 NA 82
AlkPO4ase 160 77 NA 151
(U/L)
Modified from Cox-Singh et al., 2008, Clinical Infectious Diseases, 46, 165-71

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008

 P. knowlesi – research questions

For how long has this parasite been infecting
humans in the Philippines?

How is the parasite transmitted –

Primate to human?

Human to human?

Clinical characteristics of knowlesi malaria

What is the phylogenetic origin of the
parasite? Molecular epidemiology?

How are Philippine strains related to those in
other countries that report this infection in
humans?
Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008
 Summary/ conclusion

Epidemiology of malaria in the Philippines is
changing

Response to treatment

Control of relapse

New species in humans

Responsibilities

Suspected malaria cases must be confirmed
(especially species)

Malaria cases treatment must be monitored during
and after treatment

Fe Espino PIDSP 15th Annual Convention, 6-7 February 2008