pidsp 19 th annual convention taming the beasts: top killers of children - malaria dr. fe esperanza...

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


106Per 106

Philippine population and malaria mortality rates (1905-’09), malaria morbidity rates (1945-’09)


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)


(Modified from Gomes, M., et al, 1994, Bull WHOEspino, 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


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


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


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)


'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,


(From Brooker, S. et al. (2007), Am.J.Trop.Med.Hyg., 77(Suppl. 6)


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)


• 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


RECOGNITION AND DIAGNOSIS


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


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)


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)


EVIDENCE-BASED TREATMENT GUIDELINES


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


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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


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)


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)


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


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


• 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


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)


*Days 7, 14, 21 and 28.


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


PREVENTION


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


OTHER ISSUES


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


Cawag village, Subic, Zambales, 2006 and 2009

2009

Malaria cases 1999 to 20102006

Year

No.

cas

es


People at risk for malariaTravelers, overseas contract workers

People living in malaria endemic areas

http://www.pbase.com/tconelly/rural_philippines&page=4




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


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

pidsp 19 th annual convention taming the beasts: top killers of children - malaria dr. fe esperanza...

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