PIDSP 19th Annual Convention Taming the beasts: top killers of children - Malaria

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PIDSP 19th Annual ConventionTaming the beasts
top killers of children - Malaria

• Dr. Fe Esperanza Espino
• Research Institute for Tropical Medicine

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Outline of presentation

• Local epidemiology
• Recognition of the disease
• Diagnosis
• Evidence-based treatment guidelines
• Prevention
• Summary

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Local Epidemiology
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Philippine population and malaria mortality rates
(1905-09), malaria morbidity rates (1945-09)
106
Per 106
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Espino, FE, PSMID Annual Convention November
2011, Manila
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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 popn)
Malaria deaths 24 (0.02/100,000 popn)
(Adapted from WHO, 2010)
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(Modified from Gomes, M., et al, 1994, Bull WHO
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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
lt2 1,597 (5.2) (64.6) 835 (7.5) (33.8) 20 22 2,474
2 to lt 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 lt30 7,124 (23.1) (70.8) 2,771 (24.9) (27.5) 115 49 10,059
gt 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
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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
lt2 2 (2) 0 0 0 102
2 to lt 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 lt30 24 (6) 9 (2) 2 0 411
gt 30 25 (3) 11 (1) 0 3 755
Total ( species) 115 (5) 53 6 4 2,425
Community surveys those with ages available
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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)
gt15 45 (55.6) 9 1 56 (57.1)
Total by species 81 (82.7) 14 3 98
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Rainfall (mm)
Per 1000 population (in log)
1000
10
Rainfall
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
of
An. flavirostris,
January 1992 to
January 1993 (modified from Torres
et al
. , 1997)
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Monthly malaria cases and rainfall, Morong,
Bataan, 1981 to 1997.

400
Malaria cases
Rainfall
300
200
Rainfall in mm./mo,
No. of malaria cases
100
0
'81
'82
'83
'84
'85
'86
'87
'88
'89
'90
'91
'92
'93
'94
'95
'96
'97
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(From Brooker, S. et al. (2007),
Am.J.Trop.Med.Hyg., 77(Suppl. 6)
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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)
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• 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

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Recognition and Diagnosis
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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

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Diagnostic options before and now

• Thick and thin malaria blood film
• Non-microscopic rapid diagnostic tests (RDTs)
• Amplification of specific nucleic acid sequences
  (PCR)

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Malaria RDTs
Antigens detected by 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

From Malaria Rapid Diagnostic Test Performance
results of WHO product testing Of malaria RDTs
Round 1 (2008)
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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)

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Evidence-based treatment guidelines
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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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Coker RJ, et al., 2011 www.thelancet.com
377599-609
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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

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Falciparum malaria
TES categories of response to treatment (blood
schizonticides)
Vivax malaria

• 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

• Adequate clinico-parasitological response (ACPR)
• Early treatment failure (ETF)
• Days 0 - 3
• Late treatment failure (LTF)
• Days 4 28
• Clinico-parasitological failure
• Parasitological failure

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Summary of TES late 1990s to 2011
Drug/ drug combination Provinces Years
Falciparum malaria Chloroquine (Cq) Apayao, Agusan del Sur, Compostela Valley Late 1990s 2002
Falciparum malaria Sulfadoxine/ pyrimethamine (SP) Agusan del Sur, Apayao, Kalinga 2001-02
Falciparum malaria CqSP Agusan del Sur, Compostela Valley 2001-02
Falciparum malaria CqSP Agusan del Sur, Compostela Valley 2002-07
Falciparum malaria CqSP Davao del Sur, Sultan Kudarat 2003-07
Falciparum malaria CqSP CARAGA 2005-06
Falciparum malaria Coartem (artemether/ lumefantrine) Compostela valley 2001-02
Falciparum malaria Coartem (artemether/ lumefantrine) Isabela 2002-03
Falciparum malaria Coartem (artemether/ lumefantrine) Kalinga 2002-03
Falciparum malaria Coartem (artemether/ lumefantrine) Palawan 2005-06
Falciparum malaria Coartem (artemether/ lumefantrine) Davao del Sur 2006-07
Falciparum malaria Coartem (artemether/ lumefantrine) Sultan Kudarat 2006-07
Falciparum malaria Coartem (artemether/ lumefantrine) Zamboanga city 2006-07
Falciparum malaria Coartem (artemether/ lumefantrine) Palawan/Tawi-Tawi 2011-12?
Vivax Malaria Chloroquine CARAGA 2005-06
Vivax Malaria Chloroquine Tawi-Tawi 2012?
Vivax Malaria Chloroquine Palawan 2009 2011 2012?
Vivax Malaria Primaquine (Pq) Palawan 2009 2011 2012?
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Changing treatment guidelines for uncomplicated
falciparum malaria based on TES
Year Malaria treatment level lt 2002 2002-08 2009-?
Firstline Chloroquine (CQ) CQSP 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
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Treatment regimen for uncomplicated falciparum
malaria
Day 0 2 Artemether (20mg)/ lumefantrine (120 mg) Day 0 2 Artemether (20mg)/ lumefantrine (120 mg) 34 kg 34 kg 25 to 34 kg 25 to 34 kg 25 to 34 kg 15 to 24 kg 15 to 24 kg 5 to 14 kg 5 to 14 kg
Day 0   8 hrs later   Day 1   Day 2 Day 0   8 hrs later   Day 1   Day 2 4 tabs   4 tabs   4 tabs BID   4 tabs BID 4 tabs   4 tabs   4 tabs BID   4 tabs BID 3 tabs   3 tabs   3 tabs BID   3 tabs BID 3 tabs   3 tabs   3 tabs BID   3 tabs BID 3 tabs   3 tabs   3 tabs BID   3 tabs BID 2 tabs   2 tabs   2 tabs BID   2 tabs BID 2 tabs   2 tabs   2 tabs BID   2 tabs BID 1 tab   1 tab   1 tab BID   1 tab 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 Adults Above 12 years Above 12 years 7 to 11 years old 4 to 6 years old 4 to 6 years old 1 to 3 years old 1 to 3 years old Below 1 year
Day 3 Primaquine (26.3 mg or 15 mg base tablet 0.75mg/ kg single dose) 3 tabs 3 tabs 3 tabs 3 tabs 2 tabs 1 tab 1 tab ½ tab ½ tab Contra-indicated
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Treatment regimen for uncomplicated vivax malaria
Day of treatment Drug Dose (no. of tablets) Dose (no. of tablets) Dose (no. of tablets)
Day of treatment Drug Adult Children Children
0 and 1 Chloroquine 150 mg base tablet 10 mg/kg/day Four tablets once a day for Days 0 and 1  0-11 mos 1-3 years 4-6 years 7-11 years 12-15 years gt16 years  ½ 1 1 ½ 2 3 4
2 Chloroquine 150 mg base tablet 5 mg/kg Two tablets Half the above dose per age group Half the above dose per age group

3 to 17 Primaquine 15 mg base tablet 0.5 mg/kg/day One tablet each day Below 1 year 1-3 years 4-6 years 7-11 years gt 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.

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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

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Drug (2009 ongoing) Duration of ff-up Recurence of parasitemia ()
Chloroquine 4 wks 1/119 (0.8)
Primaquine 6 mos 17/95 (17.9)
Days 7, 14, 21 and 28.
Drug (2005) Duration of ff-up Recurence of parasitemia ()
Chloroquine 4 wks 0/37
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Implications?

• Primaquine dose increased to 30 mg
• 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

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prevention
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Malaria vaccines
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
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 Africa AMA 1 based vaccine Phase I and
II RTS,S - Phase III
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Other issues
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• Provinces declared malaria-free

• Urban and semi-urban areas where malaria reported

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

• Antipolo
• Fairview
• Taytay, Rizal

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Cawag village, Subic, Zambales, 2006 and 2009
2006
Malaria cases 1999 to 2010
No. cases
2009
Year
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People at risk for malaria

• Travelers, overseas contract workers

• People living in malaria endemic areas

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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

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Acknowledgement

• Institutional Partners

Malaria Study Group, RITM

• Malaria Program, Dept. Health, Manila
• CHD Offices, ARMM
• UP Manila and UP NIH
• Pilipinas Shell Foundation, Inc.
• University of Queensland
• Others

• 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

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