Download Defining the biomedical, environmental and social

“Defining the biomedical, environmental and
social risk factors for human infection with
Plasmodium knowlesi; opportunities for prevention
and control of an emerging zoonotic infection”
Environment & Social Ecology of Human
Infectious Diseases (ESEI)
Phase I
Catalyst grant
Living with environmental change
Background – Phase I
ESEI Catalyst Grant awarded to LSHTM & Uni of Glasgow, UK and Research
Institute for Tropical Medicine & Uni Philippines Los Baños, for the project:
“Defining the biomedical, environmental and social risk factors for
human infection with Plasmodium knowlesi; opportunities for
prevention and control of an emerging zoonotic infection”
Objectives of the Catalyst Grant project:
• To build an interdisciplinary network of researchers on P. knowlesi.
• To hold a workshop.
• To identify and communicate with primary users and stakeholders.
• To collect and analyse preliminary data from fieldwork in the Philippines with
which to inform a broader research strategy and development of a full
consortium proposal.
Phase II - ESEI Research Consortia:
Generate new research paradigm(s)/innovation by interdisciplinary
research into current or future important Public Health problem
(emphasis on zoonosis).
•~ 20 groups to apply for phase II funding
•3 to 4 grants of ~3million GBP will be awarded – 5 year projects
Applications will be scored on both the science and strategic fit to
the call and to the remits of the funders (4 UK Research Councils)
P. knowlesi - Background
1930s, Knowles and Das Gupta working in
India isolated and described P. knowlesi in
long-tailed macaque from Singapore.
Documented extreme virulence of P.
knowlesi in rhesus macaques and relatively
benign course in natural host species, long
and pigtailed macaques.
Successfully infected humans with P.
knowlesi; led to use as therapeutic agent
against neurosyphilis.
Work on P. cynomolgi and P. knowlesi
established transmission potential:
human
anopheline mosquitoes
anopheline mosquitoes
human
primate
P. knowlesi – Background
Could primate malarias cause zoonoses of public health importance?
U.S. National Institutes of Health & Malaysian Institute of Medical Research surveyed human
populations living in proximity to monkeys for evidence of infection.
Blood from 1117 people was inoculated into rhesus monkeys - no malaria infections.
1965 Chin et al described first case of naturally acquired P. knowlesi infection in US
intelligence personnel working in a forested area of peninsular Malaysia.
Not described again until Balbir Singh’s report in 2004:
Singh et al 2004
Late 1990s - Kapit division, Sarawak, Malaysian Borneo
Noted differences in Plasmodium spp frequencies and clinically atypical P. malariae reports
P. malariae variant?? Newly emergent Plasmodium??
2000-2, collected blood from 208 malaria cases
Molecular analysis of ssrRNA and csp genes
Morphological Characteristics
P. knowlesi
Trophozoites
P. falciparum
Schizonts
Gametocytes
P. malariae
On microscopy, P. knowlesi closely resembles P. falciparum at early ring stage, and
P. malariae at later stages; misdiagnosis is likely. (Cox-Singh and Singh (2008) Trends in Parasitology 24: 406-10)
Singh et al 2004
Workshop update:
In Sarawak, 801 cases of P. knowlesi in
humans were confirmed by PCR between
2000 and 2009.
P. knowlesi is now the 2nd most common
malaria, after P. vivax
In 2008, microscopy reporting in Sarawak
changed such that all cases resembling P.
malariae are now reported as P. knowlesi
The number and distribution of reported human infections with P. knowlesi (by 2008)
Cox-Singh and Singh (2008) Trends in Parasitology 24: 406-10
P. knowlesi vectors
J. K. Baird ‘Malaria zoonoses’
Travel Medicine and Infectious Disease (2009) 7, 269e277
Plasmodium knowlesi Workshop
Puerto Princesa, Palawan, The Philippines
18-21 October 2010
Environment & Social Ecology of Human
Infectious Diseases (ESEI)
Phase II
Research Consortium grant
ESEI Phase I Workshop – Palawan, October 2010
Is P. knowlesi a clinical problem?
Drs Timothy William & Nick Anstey, Sabah, Malaysia
Severe Plasmodium knowlesi at Queen Elizabeth Hospital,
Kota Kinabalu, Sabah, Malaysia
In 2008 and 2009, noted increasing
incidence of P. malariae with severe
complications.
Retrospective survey of all
microscopy diagnosed P. malariae
cases in QEH Dec 2007-Nov 2009
Timothy William, Nick Anstey, Yeo Tsin
(Emerging Infectious Diseases 2011 in press)
74 Microscopy
Diagnosed Plasmodium
malariae mono or mixed
infections
4 Microscopy Diagnosed
as P. falciparum/vivax and
with PCR P. knowlesi
mono or mixed infections
7 clinical records
unavailable
Excluded 2
1 P. falciparum/P.
knowlesi
Excluded 13
PCR
1 P. vivax/P.knowlesi
2 P.vivax/P.knowlesi
1 P. malariae/P.
knowlesi
1 P. vivax
1 P. malariae
2 not detected
PCR confirmed P.
knowlesi monoinfection n=56
6 not available
Uncomplicated
Severe
N=34 (61%)
N=22 (39%)
P. knowlesi severe disease – pathogenesis:
14/22
13/22
12/22
10/22
7/22
(63.6%)
(59.1%)
(54.5%)
(45.5%)
(31.8%)
Respiratory Distress
Acute Renal Failure
Shock
Hyperbilirubinaemia
Acidosis based on arterial blood gas
No Coma (unlike P. falciparum)
•Non-severe treated with chloroquine or artemisinin combination therapy (ACT).
•Severe treated with intravenous quinine or artesunate.
•Parasite clearance time was faster with ACT or artesunate treatment .
•Slow parasite clearance was associated with death in the severe group.
Outcomes
Death
of all PCR-confirmed P. knowlesi mono-infection.
with severe P. knowlesi mono-infection.
This is similar to the death rate from P. falciparum in Africa
In those that died all had >=3 severity criteria:
6/6
(100%) Acute Respiratory Distress
5/6
(83%) Acute Renal Failure
4/6
(67%) Shock
Retrospective study of clinical and laboratory
features of Plasmodium knowlesi in Kudat
Kudat
Study site:
Kudat hospital - serves 5 sub-districts
Population 81,000
Predominantly subsistence farming
No primary rainforest
Bridget Barber, Tim William, Yeo Tsin, Nick Anstey
Unpublished
Retrospective search of laboratory microscopy and PCR records
for all malaria cases 1/1/09 – 30/11/09
87% Pk
What are the vectors of P.knowlesi?
Jenny Luchavez & Fred Aure, Palawan, the Philippines
Malaria vectors in the Philippines
Pk vector?
Malaria vectors in the Philippines:
Ecological distribution
ESEI Phase I
Pilot study to assess the efficacy of different trapping methods for
the collection of Anopheline mosquitoes in Palawan, the Philippines.
CBT = carabao-baited trap
What affects vector / primate host /
human host contact in P.knowlesi?
Jimmy Loh, Singapore
Dr Supargiyono, Kalimantan
• Classic example is temporary
housing in cleared forests close
to monkey roosts
• However other interactions may occur:
– Military personnel training in forests
– Monkeys as workers or pets
– Human proximity to conservation areas
Singapore
•Since 2003, <20 cases of human infections with P. knowlesi, mainly in military personnel.
•Only Macaca fascicularis (long-tailed macaque) is indigenous.
•37 wild macaques from a military training area and 10 peri-domestic macaques sampled.
•No malaria found in peri-domestic monkeys.
•89% of wild macaques tested had
simian malaria parasites, of which 57%
were P.knowlesi.
•P. fieldi and P. cynomolgi also detected.
Relationship between Macaca and Human
Coconut pickers
Macaques used in
the tourism industry,
Indonesia
The Ubud Monkey Forest
Nature reserve and temple complex in Ubud, Bali.
Houses over 200 long-tailed Macaques
“Defining the biomedical, environmental and
social risk factors for human infection with
Plasmodium knowlesi; opportunities for prevention
and control of an emerging zoonotic infection”
Developing a full grant proposal...........
Aims are to determine:
• What is the extent of the problem?
(Burden of Pk-associated disease in humans in study areas?)
• What are the risk factors for exposure to Pk ?
(Same as Pf & Pv? Is there human to human transmission?)
• How can we best diagnose & treat Pk?
(Early diagnosis important due to 24 hour replication.)
Aims are to determine:
• What are the disease dynamics and infection
prevalence in vectors and primate hosts?
(Optimal sampling strategies?)
• How will a risk map be utilised to implement Pk
control?
(Integration into current vector control, or new strategy needed?
How does Pk impact on malaria elimination in WPRO countries?)
Proposed study sites
Palawan, Philippines
Sabah, Malaysia
ESEI P. knowlesi PROJECT PLAN
Objectives
Project Activity
Year 1
Year 3
Year 4
Year 5
Pre-Oct 2011
2012
2013
2014
2015
2016
2011 Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep
1. Preparatory period
Year 2
Exis ting data collation
Site / s takeholder vis its
Ethical permis s ions
Community s ens itis ation
Full network planning and progres s meetings
2) Case control study for risk factors
Meas ure burden of human Pk morbidity in s tudy areas
Des cribe and as s es s ris k factors for infection
Meet
Case series report Sabah
Meet
Meet
Meet
4) Disease Dynamics
Identify the vector(s ) of Pk and des cribe bionomics
and hos t preference
Meet
Case control study - Sabah and Palawan defined s ites
Dis s emination of res ults
& recommendations
same Pk cases recruited for each
3) Randomised Controlled Trial
Determine guidelines for optimal treatment of Pk
Meet
Randomised controlled trial - Sabah only
Entomology
Mos quito s ampling, human and macaque biting
sample sites determined by Pk cases
Identify perceptions of malaria ris k
Es tablis h relations hip between Pk infection
and s ocio-economic / behavioural factors
Social science
Ques tionnaire, focus group dis cus s ions , photo-voice
examining nature of human/macaque interaction
Meas ure prevalence of Plas modia in macaques
Determine relations hip between dis tribution
of macaques and Pk ris k in humans
Primatology
Survey of wild population of macaques
faecal sampling feasibility
Produce bes t practice SOPs for diagnos is of
Pk and other primate malarias , mos quito bloodmeal
analys is and STR typing of macaques
Parasitology
Development and rolling out of molecular methods
Parasitology
Diagnos e potential as ymptomatic cas es
determining areas of Pk transmission
Des cribe land us e/population changes
with res pect to human/vector/primate habitats
Produce ris k map for human Pk infection
As s es s importance of identified factors that
drive Pk into human populations
Make predictions regarding potential for
human-human trans mis s ion & control meas ures
5) Population-based exposure survey
Meas ure community wide expos ure to Pk
Determine s cale of infection burden
Refine ris k factor as s es s ment
Land use survey/GIS/Remote sensing
Ecological modelling
Identify key parameters
Ecological modelling
Build and tes t models
Interim analys is
and refining
des ign for:
Cross sectional survey
Analysis,
feedback,
dissemination,
recommendations,
further study planning,
new grant proposals,
recruit additional sites
Case control study
• All patients with malaria reporting to selected
health facilities in study area.
• In Sabah confirmed Pk mono-infection
assigned to ACT or Chloroquine.
• Controls for each malaria case age/sex
matched from attendees at same facility.
Socio-behavioural studies
• Human – primate and human – vector interactions
• Initial studies focus on interviews and group discussion in
case/control study:
– Perceptions of causes, symptoms and cures for mild febrile
illness
– Perceptions of relationship between the environment, disease
and illness and ‘vulnerability’ of individuals/households and
communities to those illnesses.
– Perceptions of the health effects of de-forestation and
changes in land-use patterns (Photo-voice)
– Views on the best methods to prevent mosquito nuisance and
malaria (Photo-voice).
– Examination of daily movement patterns (GPS watches).
Entomology
• More than 20 potential vectors
• Will require combination of trapping methods
and approaches
– Monkey baited traps
– Odour baited traps
• Sampling at different times and places in
forest/canopy
Primatology
• Monitoring of monkey troops movements
• Roosting behaviour
• Collection of faecal samples for parasite PCR
giving prevalence estimates & monkey ‘typing’
Environmental factors
• Collection of existing satellite and local data to
classify entomological and primate habitats.
• Preliminary data suggest Sabah is very
different to Palawan.
• Social science to provide information on
where human- primate and human-vector
interactions occur.
Palawan
Predicted primary forest cover in green
Area expanded on next slide
‘Ground-truthing’
Predicted primary forest cover overlaid onto satellite image of......
Actual primary forest cover
Significant discrepancy at fringes
Deforestation is not uniform and is likely to have increased
area for potential human-vector-monkey interaction.
Local information
Palawan
Integration
• Combine primatology, entomology, social
science, clinic monitoring and environmental
classification to generate ecological strata
• Large cross sectional surveys to be conducted
in these defined ecological strata
• Generate estimates of population level
infection and risk factors for infection
Is Pk like yellow fever ?
Rural cycle:
Aedes africanus
Ae. simpsoni
Urban cycle:
Ae. aegypti
Interdisciplinarity
BBSRC
MRC
Diagnostics for exposure and infection
NERC
ESRC
Seasonal population movement
Treatment access
Mosquito distribution
Host vector contact patterns
Parasite response to treatment
Primatology
Conservation & disease
Risk factors for P.knowlesi infection
Stakeholders:
Stakeholders:
LSHTM
WHO
Clinicians and
Community
health workers
Malaria Control
Programs
Coordinating Institution
Ministries of
Health
Environmental
and conservation
groups
Uni Glasgow, UK
Greenwich Uni (NRI), UK
Eco-modelling (lead)
Entomology (lead)
Sabah, Malaysia (MY)
QEH Clinical Research Centre
Case control MY
Disease dynamics MY
Cross-sectional survey MY
Clinical and diagnostics (lead)
The Consortium
Participants
Palawan, Philippines (PH)
Menzies School of
Health Research, Aus
Research Institute for
Tropical Medicine
Uni of Philippines, Los
Banõs
Randomised
Controlled Trial MY
(in conjunction with
CRC)
Case control PH
Disease dynamics PH
Cross-sectional survey PH
Social Science (lead)
Disease dynamics PH
Primatology (lead)