PIDSP 19th Annual Convention
Taming the beasts: top killers of
children - Malaria
Dr. Fe Esperanza Espino
Research Institute for Tropical Medicine
Outline of presentation
•
•
•
•
•
•
Local epidemiology
Recognition of the disease
Diagnosis
Evidence-based treatment guidelines
Prevention
Summary
Espino, FE, PIDSP Annual Convention February 2012
LOCAL EPIDEMIOLOGY
Espino, FE, PIDSP Annual Convention February 2012
Espino, FE, PIDSP Annual Convention February 2012
Philippine population and malaria mortality rates (1905-’09),
malaria morbidity rates (1945-’09)
Per 106
Espino, FE, PIDSP Annual Convention February 2012
106
Espino, FE, PIDSP Annual Convention February 2012
Espino, FE, PIDSP
PSMIDAnnual
AnnualConvention
ConventionFebruary
November
2012
2011, Manila
Philippine malaria statistics (2009)
Parameter
Population
Population at risk for malaria
Suspected malaria cases
Confirmed malaria cases
Malaria deaths
(Adapted from WHO, 2010)
Espino, FE, PIDSP Annual Convention February 2012
Figures
91, 982,099
6,598,788 (7.2% )
370,802
19,198
(20.9/100,000 pop’n)
24 (0.02/100,000 pop’n)
Espino, FE, PIDSP Annual Convention February 2012
(Modified from Gomes, M., et al, 1994, Bull WHO
Espino, FE, PIDSP Annual Convention February 2012
Espino, FE, PIDSP Annual Convention February 2012
Malaria species by age group, Palawan, Philippines (2006 - ’10)
(Malaria Program, Dept. of Health)
Age group (%)
P. falciparum
P. vivax
(%)
(%)
P. malariae
Mixed Pf/Pv
Total
<2
1,597 (5.2)
(64.6)
835 (7.5)
(33.8)
20
22
2,474
2 to < 5
4,101 (13.3)
(76.9)
1,124 (10.1)
(21.1)
77
32
5,334
5 to 9
6,476 (21.0)
(73.1)
2,229 (20.0)
(25.2)
55
99
8,859
10 to 14
5,213 (16.9)
(73.3)
1,791 (16.1)
(25.2)
68
38
7,110
15 to <30
7,124 (23.1)
(70.8)
2,771 (24.9)
(27.5)
115
49
10,059
> 30
6,319 (20.5)
(71.2)
2,400 (21.5)
(27.0)
112
50
8,881
30,830 (72.2)
11,150 (26.1)
447
290
42,717
Total
(% species)
Espino, FE, PIDSP Annual Convention February 2012
Species reservoir by age group, Palawan (2005-10)*
(Malaria Study Group, RITM)
P. falciparum
P. vivax
(% total)
(% total)
<2
2 (2)
0
0
0
102
2 to < 5
8 (2)
8 (2)
0
0
328
5 to 9
35 (7)
11 (2)
3
0
514
10 to 14
21 (7)
14 (4)
1
1
315
15 to <30
24 (6)
9 (2)
2
0
411
> 30
25 (3)
11 (1)
0
3
755
115 (5)
53
6
4
2,425
Age group
Total
(%
species)
*Community surveys; those with ages available
Espino, FE, PIDSP Annual Convention February 2012
P. malariae P. knowlesi
Total
slides
Severe malaria by species and age group, Philippines (2006-’10)
(Malaria Program, Dept. of Health)
Age groups
(years)
P. falciparum
(%)
P. vivax
Mixed
infections
Total by age
group (%)
0-4
21 (25.9)
3
0
25 (25.5)
5-9
7 (8.6)
2
1
10 (10.2)
10-14
8 (9.9)
0
0
8 (8.16)
>15
45 (55.6)
9
1
56 (57.1)
Total by
species
81 (82.7)
14
3
98
Espino, FE, PIDSP Annual Convention February 2012
1000
Rainfall (mm)
Rainfall
Per 1000 population (in log)
10
Malaria vector (MBR)
800
600
1
400
200
0
0.1
Jan Feb Mar Apr May Jun
Jul
Aug Sep Oct Nov Dec Jan
Figure 4.5. Mean monthly rainfall, and mean monthly malaria incidence (per 1,000
population), 1988 - 1996, and man-biting rates ofAn. flavirostris, January 1992 to
January 1993 (modified from Torres et. al , 1997)
Espino, FE, PIDSP Annual Convention February 2012
Monthly malaria cases and rainfall, Morong, Bataan, 1981 to 1997.
400
Malaria cases
Rainfall
Rainfall in mm./mo,
No. of malaria cases
300
200
100
0
'81
'82
'83
'84
'85
'86
Espino, FE, PIDSP Annual Convention February 2012
'87
'88
'89
'90
'91
'92
'93
'94
'95
'96
'97
(From Brooker, S. et al. (2007), Am.J.Trop.Med.Hyg., 77(Suppl. 6)
Espino, FE, PIDSP Annual Convention February 2012
61.5%
4.1%
30.9%
3.9%
Pre-school (n=460)
19.1%
27.8%
17.9%
35.2%
68.5%
21.1%
6.0%
School-age (n=392)
Relationship between plasmodia-hookworm co-infection
mean [Hb], Kenya based on re-analysis of published data
(modified from Brooker, S. et al. (2007), Am.J.Trop.Med.Hyg.,
77(Suppl. 6)
Espino, FE, PIDSP Annual Convention February 2012
Pregnant women (n=251)
4.4%
•
Morphologically similar to P malariae;
may be mistaken to be P falciparum
•
In Rhesus monkey studies
– High parasite densities is possible
– No significant sequestration in
microcirculation
•
In humans
– Reported in children and
relatively older adults
– May present as a mild from of
malaria easily responding to
chloroquine but may also be
severe and fatal
– Fever, headaches, intermittent
chills, abdominal pain, sweating
and malaise
Espino, FE, PIDSP Annual Convention February 2012
RECOGNITION AND DIAGNOSIS
Espino, FE, PIDSP Annual Convention February 2012
Could this be malaria?




Fever and headache
Fever, severe chills and sweats, severe headache
Fever, backache, joint pains
Fever, abdominal pain, jaundice, thrombocytopenia, anemia
Could also be 



Dengue
Typhoid fever
Viral hepatitis
Fever of unknown origin
Ask for
Residence
History of travel
History of blood transfusion
Espino, FE, PIDSP Annual Convention February 2012
Diagnostic options before and now
Clinical algorithm
Fever
Thick and thin malaria blood film
NO
YES
Rural health unit
Non-microscopic rapid diagnostic
tests (RDTs)
YES
Danger signs
Of malaria
NO
NO
Provide chloroquine
(Modified from Gomes, M., et al, 1994, Bull WHO and
ADS-MCP Project Reports, 1997-2002)
Espino, FE, PIDSP Annual Convention February 2012
Make malaria
Blood film
Amplification of specific nucleic
acid sequences (PCR)
Malaria RDTs
Antigens detected by
Malaria RDTs
• HRP-2 – histidine-rich
protein produced by
asexual stages of P.
falciparum
• pLDH – parasite lactatedehydrogenase antigen
produced by asexual and
gametocytes of all human
Plasmodium species
• Aldolase – enzyme in the
glycolysis pathway of
Plasmodium
Espino, FE, PIDSP Annual Convention February 2012
From Malaria Rapid Diagnostic Test Performance – results of WHO product testing
Of malaria RDTs Round 1 (2008)
WHO recommendations for malaria RDTs
• Results should be at least as
accurate as results derived
from microscopy performed by
an average (trained)
microscopist
• Minimum detectable parasite
count by a proficient
microscopist is 10 parasites/ul
blood
• Sensitivity
– 95% compared to microscopy
– Detection of parasitemia of
100 parasites per ul blood* (or
0.002% parasitemia)
Espino, FE, PIDSP Annual Convention February 2012
Espino, FE, PIDSP Annual Convention February 2012
EVIDENCE-BASED TREATMENT
GUIDELINES
Espino, FE, PIDSP Annual Convention February 2012
Currently available antimalarial drugs
•Chloroquine
•Sulfadoxine/
Pyrimethamine
•Quinine
•Mefloquine
ARTEMISININ
COMBINED
THERAPY (ACTs)
•Artemetherlumefantrine (Coartem)
•Artemisinin-piperaquine
•Dihydroartemisinin-piperaquinr
•Artesunate – mefloquine
•Atovaquone –
Chloroguanide
•Artesunate-pyronaridine
•Antibiotics
•Artesunate - amodiaquine
•Artesunate -sulfadoxine/
pyrimethamine
Primaquine
Espino, FE, PIDSP Annual Convention February 2012
Espino, FE, PIDSP Annual Convention February 2012
Coker RJ, et al., 2011; www.thelancet.com; 377:599-609
Monitoring drug resistance
• THERAPEUTIC EFFICACY SURVEILLANCE or TES
– Standardized protocols developed by WHO wherein response is classified using clinical
and parasitological criteria
– Gold standard for treatment guidelines
– Limited by host immunity, prior treatment with antimalarials, and drug
pharmacokinetics/dynamics.
• IN VITRO TESTS
– Parasites are allowed to mature in microplates pre-dosed with differing dilutions of
antimalarial drug
– These tests provide baseline data and trends; forecast; precede in vivo resistance
– HRP2 or pLDH, enzymes produced by the parasite can also be measured
• MOLECULAR MARKERS of drug resistance
– P. falciparum – Chloroquine (pfcrt76), sulfadoxine (dhfr51, dhfr59, dhfr108), and pyrimethamine
(dhps436, dhps437, and dhps540),
– Provide baseline data and trends
– Correlation between mutations and in vivo/in vitro data
Espino, FE, PIDSP Annual Convention February 2012
TES categories of response to treatment (blood schizonticides)
Falciparum malaria
•
•
•
Vivax malaria
Adequate clinico-parasitological response
(ACPR)
Early treatment failure (ETF)
– Days 0 - 3
Late treatment failure (LTF)
– Days 4 – 28
– Clinico-parasitological failure
– Parasitological failure
• Adequate response
• Treatment failure
• Parasitemia and fever from Day 3 to
Day 28 after start of treatment
• Parasitaemia from Day 7 to 28 after
start of treatment regardless of clinical
condition
30000
25000
20000
Parasite count
Parasite count
25000
20000
15000
10000
15000
10000
5000
5000
0
0
0
1
2
3
4
7
14
21
28
Day after start of treatment
Adequate
Early tx failure
Espino, FE, PIDSP Annual Convention February 2012
0
1
2
3
4
7
14
21
Day after start of treatment
Late tx failure
Adequate
Treatment failure
28
Summary of TES late 1990s to 2011
Drug/ drug
combination
Provinces
Years
Chloroquine (Cq)
Apayao, Agusan del Sur, Compostela
Valley
Late 1990s – 2002
Sulfadoxine/
pyrimethamine (SP)
Agusan del Sur, Apayao, Kalinga
Agusan del Sur, Compostela Valley
Cq+SP
Falciparum
malaria
2002-07
Davao del Sur, Sultan Kudarat
2003-07
CARAGA
2005-06
Compostela valley
2001-02
Isabela
Kalinga
Coartem
(artemether/
lumefantrine)
2001-02
Palawan
2002-03
2005-06
Davao del Sur
Sultan Kudarat
2006-07
Zamboanga city
Vivax
Malaria
Chloroquine
Primaquine (Pq)
Espino, FE, PIDSP Annual Convention February 2012
Palawan/Tawi-Tawi
2011-12?
CARAGA
2005-06
Tawi-Tawi
2012?
Palawan
2009 – 2011; 2012?
Changing treatment guidelines for uncomplicated
falciparum malaria based on TES
Year
< 2002
Malaria
treatment level
2002-08
2009-?
Firstline
Chloroquine (CQ)
CQ+SP
Coartem
Secondline
Sulfadoxine/
pyrimethamine
(SP)
Coartem
QN plus, oral
Thirdline
Quinine (QN) oral
Severe
Quinine parenteral QN plus
(clindamycin or
tetracycline or
doxycycline)
Espino, FE, PIDSP Annual Convention February 2012
QN plus
Treatment regimen for uncomplicated falciparum malaria
Day 0 – 2
Artemether (20mg)/
lumefantrine (120 mg)
34 kg
25 to 34 kg
15 to 24 kg
5 to 14 kg
Day 0
4 tabs
3 tabs
2 tabs
1 tab
8 hrs later
4 tabs
3 tabs
2 tabs
1 tab
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 –
Adults
Above 12
years
7 to 11
years old
4 to 6
years old
1 to 3
years old
Below 1
year
3 tabs
3 tabs
2 tabs
1 tab
½ tab
Contraindicated
Primaquine
(26.3 mg or 15 mg
base tablet; 0.75mg/
kg single dose)
Espino, FE, PIDSP Annual Convention February 2012
Treatment regimen for uncomplicated vivax malaria
Day of
treatment
•
Drug
0 and 1
Chloroquine
150 mg base tablet;
10 mg/kg/day
2
Chloroquine
150 mg base tablet;
5 mg/kg
3 to 17
•
Dose (no. of tablets)
Primaquine
15 mg base tablet;
0.5 mg/kg/day
Adult
Four tablets once a day for
Days 0 and 1
Two tablets
One tablet each day
Children
0-11 mos
1-3 years
4-6 years
7-11 years
12-15 years
>16 years
½
1
1½
2
3
4
Half the above dose per age group
Below 1 year
1-3 years
4-6 years
7-11 years
> 12 years
Contra- indicated
1/3
½
¾
1
In mild-to-moderate G6PD deficiency, primaquine 0.75 mg base/kg body weight given once a
week for 8 weeks.
In severe G6PD deficiency, primaquine is contraindicated and should not be used.
Espino, FE, PIDSP Annual Convention February 2012
Plasmodium vivax relapses
• Are important sources of
reinfection and transmission
• Relapses can occur weeks to
years after the initial infection
• Risk of relapse of tropical
strains is higher than
temperate strains
• Primaquine is the only
commercially available antirelapse drug
Risk of P. vivax relapse by primaquine dose
(in India, Thailand and Brazil)
Dose
Odds ratio
(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
95% CI
(modified from Goller et al., 2007, Amer Jour Trop Med Hyg, Vol 76 No. 2)
Espino, FE, PIDSP Annual Convention February 2012
Drug (2009
– ongoing)
Duration of
ff-up
Recurence of
parasitemia (%)
Chloroquine
4 wks*
1/119 (0.8)
Primaquine
6 mos
17/95 (17.9)
Drug (2005)
Duration of
ff-up
Recurence of
parasitemia (%)
Chloroquine
4 wks
0/37
*Days 7, 14, 21 and 28.
Espino, FE, PIDSP Annual Convention February 2012
Implications?
1. Primaquine dose increased to 30 mg
2. G-6-PD deficiency
– Estimations of prevalence
• 5.5% in malaria endemic areas in the Philippines(Salazar NP, et
al., 1987)
• 1.9% Philippine Newborn Screening Program (Silao CLT, et al.,
2009)
• 2011- Palawan – ongoing survey among high school students
– Point-of-care issues
• Screening in malaria endemic areas
• Confirmation in nearest tertiary hospital with proper equipment
and trained staff
Espino, FE, PIDSP Annual Convention February 2012
PREVENTION
Espino, FE, PIDSP Annual Convention February 2012
Malaria vaccines
Goal
Reduce disease
severity and
death
Goal
Target population
Block infection of
liver
Non-immune travelers
in low transmission
areas
Block emergence
from liver or RBC
infection
Children and pregnant
women in high
transmission areas
Goal
Target population
Target population
Children and pregnant
women in high
transmission areas
In Africa
AMA 1 –based vaccine – Phase I and II
RTS,S - Phase III
Espino, FE, PIDSP Annual Convention February 2012
Prevent
transmission
Endemic communities
Together with
blood-stage
vaccines, limit
spread of vaccine
resistance
Any population and
situation
OTHER ISSUES
Espino, FE, PIDSP Annual Convention February 2012
Provinces declared malaria-free
Aklan
Guimaras
Albay
Iloilo
Batangas
Leyte
Benguet
Marinduque
Biliran
Masbate
Bohol
No. Samar
Camiguin
Siquijor
Capiz
Sorsogon
Catanduanes
So. Leyte
Cavite
Surigao del Norte
Cebu
Western Samar
Ea. Samar
Espino, FE, PIDSP Annual Convention February 2012
Urban and semi-urban areas
where malaria reported
• Antipolo
• Fairview
• Taytay, Rizal
Cawag village, Subic, Zambales, 2006 and 2009
2006
Malaria cases 1999 to 2010
450
400
No. cases
350
300
250
200
150
100
2009
50
0
99
00
01
02
03
04
Year
Espino, FE, PIDSP Annual Convention February 2012
05
06
07
08
09
10
People at risk for malaria
People living in malaria endemic areas
http://www.pbase.com/tconelly/rural_
philippines&page=4
Espino, FE, PIDSP Annual Convention February 2012
Travelers, overseas contract workers
Summary
• Malaria is still a parasitic disease of public health importance in the Philippines
• Epidemiology of malaria in the Philippines is changing
– Response to treatment (drug resistance)
– Control of relapse
– New species in humans
• Responsibilities of clinicians and public health physicians:
– Suspected malaria cases must be confirmed (especially species)
– Response to treatment (including anti-relapse treatment) must be
monitored during and after treatment
– Malaria cases (and response to treatment) must be reported
Espino, FE, PIDSP Annual Convention February 2012
Acknowledgement
Malaria Study Group, RITM
Sponsors
•
•
•
•
•
•
•
•
•
Asia Pacific Malaria Elimination
Network (APMEN)
AusAID
Embassy of France
GFTAM
Pilipinas Shell Foundation, Inc.
Roll Back Malaria
USAID
WHO (WPRO and WR Office)
Others
Institutional Partners
•
•
•
•
•
•
Malaria Program, Dept. Health, Manila
CHD Offices, ARMM
UP Manila and UP NIH
Pilipinas Shell Foundation, Inc.
University of Queensland
Others
Community Partners
Agusan del Sur, Agusan del Norte, Apayao, Davao
del Sur, Compostela Valley, Isabela, Kalinga,
Palawan, Sultan Kudarat, Surigao del Sur, Surigao
del Norte, Zamboanga City, Others