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“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)