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PIDSP 19th Annual Convention
Taming the beasts: top killers of children - Malaria
Dr. Fe Esperanza EspinoResearch 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
106Per 106
Philippine population and malaria mortality rates (1905-’09), malaria morbidity rates (1945-’09)
Espino, FE, PIDSP Annual Convention February 2012
Espino, FE, PIDSP Annual Convention February 2012
Espino, FE, PSMID Annual Convention November 2011, ManilaEspino, FE, PIDSP Annual Convention February 2012
Philippine malaria statistics (2009)Parameter Figures
Population 91, 982,099
Population at risk for malaria 6,598,788 (7.2% )
Suspected malaria cases 370,802
Confirmed malaria cases 19,198 (20.9/100,000 pop’n)
Malaria deaths 24 (0.02/100,000 pop’n)(Adapted from WHO, 2010)
Espino, FE, PIDSP Annual Convention February 2012
(Modified from Gomes, M., et al, 1994, Bull WHOEspino, FE, PIDSP Annual Convention February 2012
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
Total
(% species)30,830 (72.2) 11,150 (26.1) 447 290 42,717
Espino, FE, PIDSP Annual Convention February 2012
Species reservoir by age group, Palawan (2005-10)*(Malaria Study Group, RITM)
Age group P. falciparum
(% total)
P. vivax
(% total)P. malariae P. knowlesi
Total slides
<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
Total (% species)
115 (5) 53 6 4 2,425
*Community surveys; those with ages available
Espino, FE, PIDSP Annual Convention February 2012
Severe malaria by species and age group, Philippines (2006-’10)(Malaria Program, Dept. of Health)
Age groups (years)
P. falciparum (%)
P. vivaxMixed
infectionsTotal 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
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan0
200
400
600
800
1000Rainfall (mm)
0.1
1
10Per 1000 population (in log)
Rainfall Malaria vector (MBR)
Figure 4.5. Mean monthly rainfall, and mean monthly malaria incidence (per 1,000 population), 1988 - 1996, and man-biting rates of An. flavirostris, January 1992 to January 1993 (modified from Torres et al. , 1997)
Espino, FE, PIDSP Annual Convention February 2012
'81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '970
100
200
300
400
No.
of
mal
aria
cas
es
Malaria cases Rainfall
Monthly malaria cases and rainfall, Morong, Bataan, 1981 to 1997.
Rainfall in mm
./mo,
Espino, FE, PIDSP Annual Convention February 2012
(From Brooker, S. et al. (2007), Am.J.Trop.Med.Hyg., 77(Suppl. 6)
Espino, FE, PIDSP Annual Convention February 2012
Pre-school (n=460)
30.9%4.1%
3.9%
61.5%
School-age (n=392)
27.8% 17.9%35.2%
19.1%
Pregnant women (n=251)
68.5%
21.1% 6.0% 4.4%
Relationship between plasmodia-hookworm co-infectionmean [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
• 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
Dengue Typhoid fever Viral hepatitis Fever of unknown origin
ResidenceHistory of travelHistory of blood transfusion
Could also be -
Ask for
Espino, FE, PIDSP Annual Convention February 2012
Diagnostic options before and now
Thick and thin malaria blood film
Non-microscopic rapid diagnostic tests (RDTs)
Amplification of specific nucleic acid sequences (PCR)
Fever
Danger signs Of malaria
Provide chloroquineMake malaria Blood film
Rural health unit
NO
NO
NO
YES
YES
Clinical algorithm
(Modified from Gomes, M., et al, 1994, Bull WHO andADS-MCP Project Reports, 1997-2002)
Espino, FE, PIDSP Annual Convention February 2012
Malaria RDTs
• HRP-2 – histidine-rich protein produced by asexual stages of P. falciparum
• pLDH – parasite lactate-dehydrogenase antigen produced by asexual and gametocytes of all human Plasmodium species
• Aldolase – enzyme in the glycolysis pathway of Plasmodium
Antigens detected byMalaria RDTs
From Malaria Rapid Diagnostic Test Performance – results of WHO product testingOf malaria RDTs Round 1 (2008)Espino, FE, PIDSP Annual Convention February 2012
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
ARTEMISININ COMBINED THERAPY (ACTs)•Artemether- lumefantrine (Coartem)
•Artemisinin-piperaquine
•Dihydroartemisinin-piperaquinr
•Artesunate – mefloquine
•Artesunate-pyronaridine
•Artesunate -sulfadoxine/ pyrimethamine
•Artesunate - amodiaquine
•Chloroquine
•Sulfadoxine/ Pyrimethamine
•Quinine
•Mefloquine
•Atovaquone – Chloroguanide
•Antibiotics Primaquine
Espino, FE, PIDSP Annual Convention February 2012
Coke
r R
J, e
t al., 2
01
1;
ww
w.t
hela
nce
t.co
m;
37
7:5
99
-60
9
Espino, FE, PIDSP Annual Convention February 2012
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
Falciparum 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
0
5000
10000
15000
20000
25000
30000
0 1 2 3 4 7 14 21 28
Day after start of treatment
Para
site
cou
nt
Adequate Early tx failure Late tx failure
0
5000
10000
15000
20000
25000
0 1 2 3 4 7 14 21 28
Day after start of treatment
Para
site
cou
nt
Adequate Treatment failure
Vivax malaria
TES categories of response to treatment (blood schizonticides)
Espino, FE, PIDSP Annual Convention February 2012
Summary of TES late 1990s to 2011Drug/ drug
combinationProvinces Years
Falciparum malaria
Chloroquine (Cq) Apayao, Agusan del Sur, Compostela Valley Late 1990s – 2002
Sulfadoxine/ pyrimethamine (SP) Agusan del Sur, Apayao, Kalinga
2001-02
Cq+SP
Agusan del Sur, Compostela Valley2002-07
Davao del Sur, Sultan Kudarat 2003-07
CARAGA 2005-06
Coartem (artemether/ lumefantrine)
Compostela valley 2001-02
Isabela2002-03
Kalinga
Palawan 2005-06
Davao del Sur
2006-07Sultan Kudarat
Zamboanga city
Palawan/Tawi-Tawi 2011-12?
VivaxMalaria
Chloroquine
CARAGA 2005-06
Tawi-Tawi 2012?
Palawan 2009 – 2011; 2012?Primaquine (Pq)
Espino, FE, PIDSP Annual Convention February 2012
Changing treatment guidelines for uncomplicated falciparum malaria based on TES
YearMalaria treatment level
< 2002 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)
QN plus
Espino, FE, PIDSP Annual Convention February 2012
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
8 hrs later
Day 1
Day 2
4 tabs
4 tabs
4 tabs BID
4 tabs BID
3 tabs
3 tabs
3 tabs BID
3 tabs BID
2 tabs
2 tabs
2 tabs BID
2 tabs BID
1 tab
1 tab
1 tab BID
1 tab BID
Day 3 – Primaquine
(26.3 mg or 15 mg base tablet; 0.75mg/ kg single dose)
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 Contra-indicated
Espino, FE, PIDSP Annual Convention February 2012
• 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.
Day of treatment
DrugDose (no. of tablets)
Adult Children
0 and 1Chloroquine
150 mg base tablet; 10 mg/kg/day
Four tablets once a day for Days 0 and 1
0-11 mos1-3 years4-6 years7-11 years12-15 years>16 years
½11 ½234
2Chloroquine
150 mg base tablet; 5 mg/kg
Two tablets Half the above dose per age group
3 to 17Primaquine
15 mg base tablet;0.5 mg/kg/day
One tablet each day
Below 1 year1-3 years4-6 years
7-11 years> 12 years
Contra- indicated1/3½¾1
Treatment regimen for uncomplicated vivax malaria
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 anti-relapse drug
Risk of P. vivax relapse by primaquine dose (in India, Thailand and Brazil)
(modified from Goller et al., 2007, Amer Jour Trop Med Hyg, Vol 76 No. 2)
Espino, FE, PIDSP Annual Convention February 2012
*Days 7, 14, 21 and 28.
Espino, FE, PIDSP Annual Convention February 2012
Implications?1. Primaquine dose increased to 30 mg2. 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 vaccinesGoal 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
GoalTarget
population
Reduce disease severity and death
Children and pregnant women in high transmission areas
Goal Target population
Prevent transmission
Endemic communities
Together with blood-stage vaccines, limit spread of vaccine resistance
Any population and situation
In AfricaAMA 1 –based vaccine – Phase I and IIRTS,S - Phase III
Espino, FE, PIDSP Annual Convention February 2012
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
Urban and semi-urban areas where malaria reported
• Antipolo• Fairview• Taytay, Rizal
Espino, FE, PIDSP Annual Convention February 2012
Cawag village, Subic, Zambales, 2006 and 2009
2009
Malaria cases 1999 to 20102006
Year
No.
cas
es
Espino, FE, PIDSP Annual Convention February 2012
People at risk for malariaTravelers, overseas contract workers
People living in malaria endemic areas
http://www.pbase.com/tconelly/rural_philippines&page=4
Espino, FE, PIDSP Annual Convention February 2012
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
Sponsors
Institutional Partners
• 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
• Malaria Program, Dept. Health, Manila• CHD Offices, ARMM• UP Manila and UP NIH• Pilipinas Shell Foundation, Inc.• University of Queensland• Others
Community PartnersAgusan 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
Malaria Study Group, RITM