Malaria diagnosis WHO Guidelines and their implementation Optimizing control of infectious diseases in resource poor countries: Malaria Diagnosis, Fever home-based-management and New tools European Commission research Workshop Aug 31 Sept 01, 2010 David Bell WHO Global Malaria Programme DB. FIND 11 2009 1
Amexo M, Tolhurst R, Barnish G, Bates I. Malaria Misdiagnosis: effects on the poor and vulnerable. Lancet 2004; 364:1896-98 2
Magnitude of over-diagnosis /over-treatment Systematic review: 24 studies conducted between 1989 and 2005 in 15 different African countries including 15 331 patients Proportion of malaria among fevers highly variable: 2% to 81% MEDIAN PR = 26% Before 2000 MEDIAN PR = 36% From 2000-2005 MEDIAN PR = 19% Courtesy of: V. D Acremont, C. Lengeler, B. Genton, Philadelphia, November 2007 3
Previous WHO guidance on parasite-based diagnosis Excluded under 5s in high transmission areas More recently: More evidence/ confidence in RDT performance product testing, lot-testing, field experience Experience in children e.g. Faucher et al. 2010. Malar. J. (Benin) Fever + neg RDT vs. afebrile + neg RDT: no difference D Acremont et al. 2010. CID. (Tanzania) RDT negatives well on follow-up after anti-malarials are with-held 4
Malaria Diagnosis, WHO, 2009 Prompt parasitological confirmation by microscopy or alternatively by RDTs is recommended in all patients suspected of malaria before treatment is started. Treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible. Referral Hospitals Symptom -based RDT Microscopy Symptombased Microscopy RDT District Hospitals Health Centers Private Clinics Aid Posts/Volunteers Private Pharmacies Households? 5
12 month health worker follow-up Zambia 2007-8 Zambia NMCC, Mal Consortium, WHO, FIND, URC Reported malaria cases, Zambia Livingstone District, 2004-2008 14000 12000 10000 8000 6000 4000 2000 0 IRS Bednet introduction Introduction of RDTs ACT 6
Accurate malaria diagnosis can now be accessible to all. Courtesy: Malaria Consortium 7
Field alternatives for parasite-based diagnosis About 75 million RDTs procured in 2009 (RBM, MMV) 8
Addressing microscopy performance % improvement in expert microscopy performance, pre and post-test, WHO/WPRO accreditation programme, 2006-8. Laboratory microscopy improvement after introduction of a slide validation programme, MSF, South Sudan, 2005-2007 9 Courtesy MSF, Holland
Challenges to ensuring access to accurate RDT-based diagnosis Sensitivity 20% to 99% in published studies Stability Recommended storage temperature often inappropriate for rural health clinic in tropics (e.g. <30 C) User safety Blood safety (gloves, sharps disposal, HIV risk) Programmatic Managing negative results (non-malaria fever patients) Logistics Monitoring Treatment ignoring diagnostic results Private sector 10
RDTs in the field Sometimes poor field results Reyburn et al. 2007 (Tanzania) More than 90% of prescriptions for antimalarial drugs in low-moderate transmission settings were for patients for whom a test requested by a clinician was negative for malaria. Bisoffi et al. 2009 (Burkina Faso) In the dry season, 80.8% and 79.8% of patients with a negative RDT were nevertheless diagnosed and treated for malaria.. but successful elsewhere. Why?? 11
WHO malaria RDT product testing Round 1 & 2 results Rnd 1 (2008) 41 products Rnd 2 (2009) 29 products Rnd 3 (2010) 53 products P. falciparum 12
Lot Testing Collection and testing site Specimen characterization Regional lot-testing site HTD CDC CIDEIM UCAD DMR UL IPB EHNRI IPC RITM KEMRI IMT IHRDC IPM AMI 2006: 41 lots 2007: 81 lots 2008: 167 lots 2009: 196 lots (?15% of public sector procurement) 13 2010: +++
Future in-country monitoring of RDT quality Now: Compare routinely with microscopy (often difficult) Future: Positive Control Wells Dried antigen Water added Contents placed on RDT Future lot-testing panels Antigen types 1 2 3 4 5 6 7 8 9 10 Antigen concentration 14
Suite of products: Job-aid Training manual Photographic result guide Proficiency tests Addressing heath-worker performance - Zambia 100% 96% 90% 90% 86% 81% 80% 72% 70% 61% 60% 50% 40% 30% 20% 10% 0% Test prep RDT reading Package directions Job aid only Job aid + training 12 month follow-up 2008-9: Performance of critical steps Zambia MoH, URC, WHO, TDR, FIND, Malaria Consortium 15 www.wpro.who.int/sites/rdt,
Managing fever, not malaria Febrile patient Anti-malarial medicine RDT / microscopy ~20% ~80% Malaria Non-malaria Anti-malarial medicine Severe symptoms Not severe Refer Manage in community? review? Antibiotics? Other 16
Minimum requirements for supporting and managing a diagnostic programme? Transport and storage Training, drugs / supplies for non-malarial fever Community education Training and supervision Monitoring accuracy in field Lot-testing and laboratory monitoring Procurement of gloves, sharps disposal containers etc Procurement of RDTs Need to build programmes, not just fund procurement 17
Other current possibilities for case management Non-invasive screening In-vivo haemazoin detection Salivary screening Urine?? Mobile microscopy hand-held digital microscopes /cameras Will need to demonstrate at least equivalent detection to current best-performing RDTs to be useful 18
Where do we go after we are successful? 14000 12000 10000 8000 6000 4000 2000 0 2004 Q 1 2004 Q 2 Reported malaria cases, Zambia Livingstone District, 2004-2008 IRS 2004 Q 3 2004 Q 4 2005 Q 1 2005 Q 2 2005 Q 3 2005 Q 4 2006 Q 1 2006 Q 2 Bednet introduction Introduction of RDTs 2006 Q 3 2006 Q 4 2007 Q 1 2007 Q 2 2007 Q 3 2007 Q 4 2008 Q 1 2008 Q 2 2008 Q 3 2008 Q 4 Successful intervention 10 cases per month. Malaria now down from 1 st to 16 th district health priority.other disease priorities are more urgent But the mosquitoes and the people are still there We have the tools to identify and manage malaria as a common disease We need new tools and strategies to manage malaria as a rare disease 19
Towards elimination: Screening populations for reservoirs of transmission Examples of long-term course of untreated P. falciparum infections Source: Therapeutic malaria in man: Sporozoite and blood-induced infections with Plasmodium falciparum. William E Collins and Geoffrey M Jeffrey. Unpublished. 21
Towards elimination: Screening populations for reservoirs of transmission Parasite density (and pldh concentration) Antigen concentration Thresholds of good RDT /microscopy symptoms PCR/LAMP months Asymptomatic reservoir Must be detected to assess true prevalence of parasitaemia, prevent re-introduction Must detect in field if case finding and treatment (MSAT) is employed 22
Very low prevalence settings in resource-limited countries Unlikely to sustain microscopy competence or infrastructure when slides ~always negative Difficult to maintain financing Hard to maintain MoH priority But Still high probability of focal transmission and re-introduction Need screening, surveillance, and rapid management of outbreaks Need to identify high-priority areas (continuing transmission) Need to detect asymptomatic cases that are acting as reservoirs to maintain transmission 23
Strategy in countries approaching elimination In regions with significant transmission: 1. Continued case management diagnostic tools for symptomatic cases in high-priority areas (RDTs / microscopy) In regions with little or no transmission: 2. A low-cost screening tool that can rapidly survey large areas to identify hot-spots of continued transmission 3. A highly sensitive field diagnostic tool to screen all people in these hots-spots to ensure all cases are detected and treated 24
New diagnostic strategies to achieve and maintain elimination Possibilities for finding and eliminating hidden parasite reservoirs Serology Screen large populations for signs of recent malaria transmission Molecular diagnostics (e.g. Malaria LAMP) Detects 1 parasite/µl Potential for district / clinic level use Find and treat malaria carriers 25
Current maps of malaria incidence WHO 2009 www.map.ox.ac.uk 2009 26
Possible future for malaria?? Polio case numbers 1988: 350,000 1999: 7,141 2000: 2,979 2001: 483 27
Other priorities G6PD screening (P. vivax and/or reducing gametocytes): Better tools and /or methods for using them Markers of drug resistance Non-malarial febrile illness Disease multiplexing? Markers of severity or bacterial illness? Costs and models for extending good public sector diagnostic management to the private sector Models for supporting community health workers adequately as diagnostic practitioners (see also Henk Schallig s paper) 28
Summary Universal parasite-based diagnosis now recommended for case management and adequate tools are available Programmatic issues are impeding effective use of these tools Monitoring of results is often inadequate for planning New needs (non-malarial febrile illness) must be addressed Translating public policy into private sector action is essential if policy is to make an impact Very low transmission areas require innovative tools and methods to detect very low parasite densities 29