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
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DB. FIND 11 2009
Amexo M, Tolhurst R, Barnish G, Bates I. Malaria Misdiagnosis: effects on the poor and vulnerable. Lancet 2004; 364:1896-98
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DB. WHO/GMP
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
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DB. WHO/GMP
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
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DB. WHO/GMP
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.
Symptom
-based
Microscopy
RDT
Symptombased
Microscopy
RDT
Referral Hospitals
District Hospitals
Health Centers
Private Clinics
Aid Posts/Volunteers
Private Pharmacies
Households
?
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DB. WHO/GMP
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
Introduction of RDTs
12000
10000
ACT
8000
6000
4000
IRS
Bednet introduction
2000
0
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DB. WHO/GMP
Accurate malaria diagnosis can
now be accessible to all.
Courtesy: Malaria Consortium
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DB. WHO/GMP
Field alternatives for parasite-based diagnosis
About 75 million RDTs
procured in 2009 (RBM, MMV)
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DB. WHO/GMP
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
DB. WHO/GMP
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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
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DB. WHO/GMP
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??
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DB. WHO/GMP
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
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DB. WHO/GMP
Lot Testing
Collection and testing site
Specimen characterization
Regional lot-testing site
HTD
CDC
DMR
UCAD
UL
CIDEIM
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)
DB. WHO/GMP
2010: +++
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Future in-country monitoring of RDT quality
Now: Compare routinely with microscopy (often difficult)
Future: Positive Control Wells
Water added
Dried
antigen
Contents
placed on
RDT
Future lot-testing panels
1
2
3
Antigen types
4 5 6 7
8
9 10
Antigen
concentration
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DB. WHO/GMP
Addressing heath-worker performance - Zambia
Suite of products:
Job-aid
Training manual
100%
96%
90%
90%
86%
81%
80%
72%
Photographic result guide
Proficiency tests
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’
DB. WHO/GMP
Zambia MoH, URC, WHO, TDR, FIND, Malaria Consortium
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www.wpro.who.int/sites/rdt,
Managing fever, not malaria
Febrile patient
Anti-malarial medicine
RDT / microscopy
~20%
Malaria
Anti-malarial medicine
~80%
Non-malaria
Severe symptoms
Refer
Not severe
Manage in community
? review
? Antibiotics
? Other
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DB. WHO/GMP
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
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DB. WHO/GMP
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
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DB. WHO/GMP
Where do we go after we are successful?
Reported malaria cases, Zambia Livingstone
District, 2004 - 2008
14000
Introduction of RDTs
Successful intervention
10 cases per month.
12000
10000
8000
6000
4000
IRS
Bednet introduction
Malaria now down from 1st to 16th district
health priority….other disease priorities
are more urgent
2000
20
04
20 Q 1
04
20 Q 2
04
20 Q 3
04
20 Q
05 4
20 Q 1
05
20 Q 2
05
20 Q 3
05
20 Q
06 4
20 Q 1
06
20 Q 2
06
20 Q 3
06
20 Q
07 4
20 Q 1
07
20 Q 2
07
20 Q 3
07
20 Q 4
08
20 Q 1
08
20 Q 2
08
20 Q 3
08
Q
4
0
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
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DB. WHO/GMP
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.
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DB. WHO/GMP
Towards elimination:
Screening populations for ‘reservoirs’ of transmission
Parasite density (and pLDH concentration)
Antigen concentration
Thresholds of good RDT
/microscopy
PCR/LAMP
symptoms
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
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DB. WHO/GMP
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
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DB. WHO/GMP
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
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DB. WHO/GMP
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’
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DB. WHO/GMP
Current maps of malaria incidence
WHO 2009
www.map.ox.ac.uk
2009
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DB. WHO/GMP
Possible future for malaria??
Polio case numbers
1988: 350,000
1999: 7,141
2000: 2,979
2001: 483
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DB. WHO/GMP
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
DB. WHO/GMP
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(see also Henk Schallig’s paper)
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
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DB. WHO/GMP