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Epidemiology and Public Health
Diagnostic parasitologique des accès
palustres: acquis et défis
Valérie D‘Acremont, MD, PhD
Atelier paludisme Madagascar, 22 Mars 2011
How to deal with malaria in patients?
Prompt treatment
Suspected malaria
Early and accurate diagnosis
What is ‘malaria’?
Different definitions depending on the purpose:
1) For epidemiological analysis (malaria infection)
� quantify burden of malaria, modelling...
2) For clinical management (malaria disease)
� to decide who should be treated for an
episode of malaria
Definitions of malaria
What is a true malaria episode (= illness) ?
CoughDiarrhea
ArthralgiaHeadache
General
population
Sick population
Febrile patients
‘Clinical malaria’
What is a true malaria episode (= illness) ?
General
population
Sick population
Febrile patients
Parasites in blood
‘Clinical malaria’
What is a true malaria episode (= illness) ?
‘Clinical malaria’
‘Malaria episode’
General
population
Febrile patients
Sick population
Parasites in blood
What is a true malaria episode (= illness) ?
CoughDiarrhea
ArthralgiaHeadache
Sick population
General
population
Parasites in blood
Sick people withincidental parasitemia
What is a true malaria episode (= illness) ?
‘Clinical malaria’
‘Malaria episode’
General
population
Febrile patients
Sick population
Sick people withincidental parasitemia
OVERDIAGNOSIS
What is a true malaria episode (= illness) ?
‘Malaria episode’
General
population
Febrile patients
Sick population
HEALTH FACILITIES:
Only patients that
should be treated !
Parasites in blood
In the context of elimination ?
General
population
Parasitemia in healthy people
Sick population
Febrile patients
Parasites in blood
POPULATION SURVEYS:
Treatment of the
hidden reservoir
Magnitude of overdiagnosis
Systematic review of 39 studies performed between 1986 and 2007
in 16 African countries including 42,979 patients
Proportion of feversassociated with Pf (%)
0
10
20
30
40
50
60
70
80
90
100
<2000 >2000
44%
22%
D’Acremont, CID 2010
Systematic review
Proportion of malaria among fevers in children < 5 years
81%1986Tanzania (rural)
5%2003Dar es Salaam
57%1995
38%1997
21%2005
4%2004Highlands
urbanruralYearCountry
Rooth, Font, Nsimba, Reyburn, Wang
Systematic review
Studies providing stratified values of PFPf
by age groups, including older children:
<5 years MEDIAN PR = 27% (IQR 20-50%)
5-14 years MEDIAN PR = 40% (IQR 22-48%)
>15 years MEDIAN PR = 24% (IQR 11-27%)
Consequences of over-treatment
Drugs wastage
Left untreatedfor real cause
Reattendances
Costs for patient
Parasite resistanceMistrust
in ACT
Predictors for malaria:
Clinical diagnosis: impossible to rely on it
0
Proportion of malaria
among fevers
Drug wastage (overdiagnosis)
20% 40% 60% 80% 100%
20%
40%
60%
80%
100%
Failure to treat (missed cases)
Reviewed by
Chandramohan et al
in 2002
high temperature of short duration
, absence of abdominal pain, absence of rash
, absence of cough
splenomegaly
How to deal with malaria in patients?
Prompt treatment
Suspected malaria
Early and accurate diagnosisLAB TEST
How to get universal access to
parasitological diagnosis?
Available malaria tests: microscopy
REGIONAL COURSE ON TRAINING OF TRAINERS ON USE OF
MALARIA RAPID DIAGNOSTIC TESTS (RDTS)
Components of good microscopy performance
Competency
Selection
Training
Assessment
Equipment/
reagents
Support networkSlide /results delivery
Work
environment
Performance
Supervisione.g. cross-checking??
Performance of Microscopy for malaria in DSM
Sensitivity = how sensitive is the test to detect the true positive cases
Specificity = how specific is the test to detect the true negative cases
Total
Total
Negative
Positive
Routine microscopy
NegativePositive
Expert microscopy
Sensitivity
= 70%
Specificity
= 45%
328322
148
173
2
5
7
178
150
0
20
40
60
80
100
120
140
0 -<
1010
-<10
010
0 -<
1000
1'00
0 -<
10'0
00
10'0
00 -<
100'
000
>100'
000
Reported parasitemia: routine versus expert
Real positives…
Routine microscopy
Expert microscopy
Parasitemia (parasites/µl)
Number of slides
hospitals 41%
health cent. 49%
dispensaries 65%
(range 13-90%)
Performance of Microscopy for malaria in
other places
In some places, problem of sensitivity
� cases missed:
71% in Moshi Reyburn et al, 2007
But more often, bad specificity
� overdiagnosis:
62% in Kenya Zurovac et al, 2006
Consequences of suboptimal
microscopy for malaria
1) Clinicians do not trust microscopy � overtreatment
Kenya, 2002:
- blood slide performed in 79% of febrile patients
and in 51% of afebrile patients
- 43% (routine) versus 13% (expert) positive slides
- 96% of positive and 79% of negative malaria patients
received treatmentZurovac et al, 2006
High mortality among patients admitted to hospital and incorrectly treated for
malaria, 10 hospitals, NE Tanzania
Admissions for malaria n=17,313Admissions for malaria n=17,313
Severe disease n=4670 (27%)Severe disease n=4670 (27%)
Readable slide results n=4474 (95%)Readable slide results n=4474 (95%)
No criteria forsevere disease n=12,643 (73%)120 deaths (1%)
No criteria forsevere disease n=12,643 (73%)120 deaths (1%)
Expert microscopy negativen=2412 (54%)
Expert microscopy negativen=2412 (54%)
Deadn=142 (7%)
Deadn=142 (7%)
Aliven=1920 (93%)
Aliven=1920 (93%)
Deadn=292 (12%)
Deadn=292 (12%)
Aliven=2120 (88%)
Aliven=2120 (88%)
Expert microscopy positiven=2062 (46%)
Expert microscopy positiven=2062 (46%)
Reyburn H et al. BMJ 2006
2) Clinicians tend to ignore non-malarial fevers
High mortality among patients admitted to hospital and incorrectly treated for
malaria, 10 hospitals, NE Tanzania
Admissions for malaria n=17,313Admissions for malaria n=17,313
Severe disease n=4670 (27%)Severe disease n=4670 (27%)
Readable slide results n=4474 (95%)Readable slide results n=4474 (95%)
No criteria forsevere disease n=12,643 (73%)120 deaths (1%)
No criteria forsevere disease n=12,643 (73%)120 deaths (1%)
Expert microscopy negativen=2412 (54%)
Expert microscopy negativen=2412 (54%)
Deadn=142 (7%)
Deadn=142 (7%)
Aliven=1920 (93%)
Aliven=1920 (93%)
Deadn=292 (12%)
Deadn=292 (12%)
Aliven=2120 (88%)
Aliven=2120 (88%)
Expert microscopy positiven=2062 (46%)
Expert microscopy positiven=2062 (46%)
Reyburn H et al. BMJ 2006
2) Clinicians tend to ignore non-malarial fevers
Dar es Salaam (Muhimbili hospital)
‘cerebral malaria’
22% in slide negative patients13% in slide positive patients
Makani et al 2003
A reliable test available at time and place of need,
used for more than 15 years in Europe
and 7 years in South Africa...
Add another malaria diagnostic test
Meta-analysis published in 2006:
HRP2 RDT at least as sensitiveas expert microscopy
REF: Ochola Lancet Infect Dis 2006
100%
90
80
70
60
50
40
30
20
10
0
Microscopy
HRP2 RDT
pLDH RDT
QBCAO
Sensitivity in the absence of a gold standard
Relative performance of each method
Technologies evolve quickly :
REF: Bell AJTMH 2005 Dal-Bianco AJTMH 2007 Stauffer CID 2009
Stauffer 2009
Dal-Bianco2007
Bell 2005
Author, year
SensitivityProportion
RDT(+) / BS(-)
positives by PCR
88%100%60%Travelers USA
22%46%80%Gabon
70%?91%92%Philippines
MicroscopyRDT
Origin of the samples
Conclusion: between 60 and 90% of so-called false-positive RDT
are real positives, reflecting the high sensitivity of HRP2 RDT
Relative performance of each method
Putative explanation for greater sensitivity of a RDT
relying on detection of a persistent antigen
REF: Bell AJTMH 2005
Relative performance of each method
Objective
To evaluate in an uncontrolled setting the
safety (clinical outcome) of withholding antimalarials
in febrile children with a negative RDT
in a moderately endemic area (urban setting)
in a highly endemic area (rural setting)
Safety study of RDT in Tanzania
1000
febrile children
603 (60%) RDTm -ve
396
followed up
591 followed up
387 (98%)
cured573 (97%)
cured
18 (3%)
still sick
15 RDTm -ve
2 RDTm still +ve
1 still no RDTm
1 LOF 12 LOF
2 LOF
2 RDT -ve
9 (2%)
still sick
BS negative
8 cured
1 LOF
1 admitted
2 deceased2 RDTm&BS -ve
14
cured
1 admitted1 RDTm&BS -ve
Day
0 D
ay
7 >
Da
y14
397 (40%) RDTm +ve
Translation of research findings into policy
Translation of research findings into policy
Improve laboratory diagnosis for malaria
in routine management of fever cases at
OPD
Implementation of RDT in Dar es Salaam
Intervention:
Pilot implementation
of RDT in Dar es Salaam
in the 3 district hospitals,
3 health centres
and 3 dispensaries
Methodology
Consultation process:
Baseline survey9 Intervention HF
Consultation process:
Post-intervention survey9 Intervention HF
INTERVENTIONTraining, RDTm implementation, quaterly supervision
3. Routine statistics of Health Facilities
Consultation process:3 Control HF
Consultation process:
3 Control HF
2. Cluster randomizedstudy
1. Before and afterstudy
2007 20082006
1. Before-after cluster randomized study
Patients with history of fever
Proportions of patients treated with antimalarials
9 intervention HF
BEFORE AFTER
3 control HF
81%
24%
65%
0%
20%
40%
60%
80%
100%
Ja
n
Fe
b
Ma
r
Ap
r
Ma
y
Ju
n
Ju
l
Au
g
Se
p
Oc
t
No
v
De
c
Ja
n
Fe
b
Ma
r
Ap
r
Ma
y
Ju
n
Ju
l
Au
g
Se
p
Oc
t
No
v
De
c
Ja
n
Fe
b
Ma
r
Ap
r
Ma
y
Ju
n
Ju
l
Au
g
Se
p
Po
sit
ivit
y r
ate
1) Performance of routine mRDT much better than
routine microscopy
� better specificity � less overdiagnosis
mRDT implementation
2006 2007 2008
Routine microscopy48%
Routine RDT8%
Results 1: why did it work?
2) Negative RDT patients are not treated for malaria
more trust in mRDT � better adherence to the guidelines
Negative patients treated
With microscopy With mRDT
53%
7%
Results 1: why did it work?
0
5000
10000
15000
20000
25000Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
dispensary 3
dispensary 2
dispensary 1
health centre 3
health centre 2
health centre 1
hospital 3
hospital 2
hospital 1
mRDT
2007 2008
Results 2: longitudinal study
Artemether/lumefantrine (ALu)
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
Jan
Mar
May
Jul
Sep
Nov
Jan
Mar
May
Jul
Sep
Nov
Jan
Mar
May
Jul
Sep
dispensary 3
dispensary 2
dispensary 1
health centre 3
health centre 2
health centre 1
hospital 3
hospital 2
hospital 1
mRDT
2007 20082006
Quinine vials
Results 2: longitudinal study
Severe malaria
Give i.v quinine
Severe illness (NOT malaria)
• STOP antimalarials
• Continue with appropriate antibiotic
• Investigate for other causes of fever
• Repeat RDT and BS after 12-24hrs
Admission
Give immediately antimalarial and antibiotic
DANGER SIGNS
Perform RDT or BS
Uncomplicated malaria
Give antimalarial
Febrile illness(NOT malaria)
• Do NOT give
antimalarial
• Invest. for other
causes of fever
Do NOT
perform a
malaria test
NO
YES
NO
YES
Perform BS
+/- RDT
BS and RDT both
negatives
RDT and/or
BS positive
positive negative
Follow-up
PRIMARY AND SECONDARY LEVELPRIMARY LEVEL SECONDARY LEVEL
Refer the
patient
immediately
High malaria risk area
FEVER ANEMIA
Low malaria risk area
FEVER without an
obvious cause of fever ?
Suspected malaria case
NO
Antibiotic prescriptions in Dar es Salaam
Antibiotics
Antimalarials
� Proportion of febrile patients receiving:
D’Acremont et al, 2010, submitted
Before RDT implementation
After RDT implementation
49% 73%
81% 24%
But what are the causes of all these fevers
that are not malaria ?
?
8%
Study on etiologies of fever in children
To determine the etiology of fever
episodes in small children living in urban
and rural Tanzania
children 2 months - 10 yrs
temperature > 38°C
Methodology of the fever study
1005 patients
(507 in Dar es Salaam
and 498 in Ifakara)
Methodology
• Prospective study including children attending two outpatient
clinics (one urban and one rural) in Tanzania
• Inclusion criteria:
- aged 2 months - 10 yrs
- temperature > 38°C
• Full clinical assessment and investigations
based on pre-defined algorithms
• Computer-based diagnosis with levels of probability
• Real-time (RT-)PCR of naso-pharyngeal swabs for 13 viruses
• PCR and serologies on blood ongoing
All ARI50%
4%
12%
1%
5%
3%
20%
1%
3%
10%
31%
All gastroenteritis9%
Acute Resp. Infect.
URTI
Bronchiolitis
Non-doc. pneumonia
Doc. pneumonia
Gastroenteritis
amoeba
Rota/Adenovirus
Salmonella/Shigella
unknown etiology
Urine infection
Skin infection
Other
Sepsis due tobacteriemia
TyphoidMalaria
Unknown
Results 1: etiologies in all patients
All ARI38%
All gastroenteritis8%
Acute Resp. Infect.
URTI
Bronchiolitis
Non-doc. pneumonia
Doc. pneumonia
Gastroenteritis
amoeba
Rota/Adenovirus
Salmonella/Shigella
unknown etiology
Urine infection
Skin infection
Other
Sepsis due tobacteriemia
TyphoidMalaria
Unknown
5%
20%
2% 4%
6%
10%
36%
2%
7%
Results 2: etiologies in severe patients
Results 3: proportion of children infected with viruses
0%
20%
40%
60%
80%
100%
severe
pneumoniapneumonia URTI
unknown
fever
other
disease
any virus
any virus except PIC
Kenyan study (same
viruses)
Ref: Berkley JAMA 2010
86% 87%
82% 80%
64%
WHO definition
‘control
group’
Results 6: seasonality of influenza
0%
10%
20%
30%
40%
50%
Apr May Jun Jul Aug
FLUAV
FLUBV
0%
10%
20%
30%
40%
50%
Jul Aug Sep Oct Nov
Dar es Salaam
Ifakara
Development of improved practice guidelines for clinicians
Modified IMCI including
1. laboratory tools : malaria test, urine dipstick
2. additional clinical criteria: predictors for bacterial infections
(Acute Resp. Infect., typhoid)
Emphasis on rationale use of drugs (antimalarials and antibiotics)
Fever study: beyond the findings
Development of improved practice guidelines for clinicians
Modified IMCI including
1. laboratory tools : malaria test, urine dipstick
2. additional clinical criteria: predictors for bacterial infections
(Acute Resp. Infect., typhoid)
Emphasis on rationale use of drugs (antimalarials and antibiotics)
Fever study: beyond the findings
The e-IMCI interface
Remerciements
DSM City Medical Office of Health, Tanzania
Judith Kahama (co-researcher)
Ndeniria Swai (research assistant)
Gerumana Mpawa (logistics and data entry)
Ministry of health and Welfare, Tanzania
Deo Mtasiwa (Chief Medical Officer)
Ifakara Health Institute, Tanzania
Hassan Mshinda (ex-director)
Amana and St Francis hospital, Tanzania
Willy Sangu and P. Kibatala (directors)
Swiss Tropical and Public Health Institute
Christian Lengeler & Blaise Genton
Hôpitaux Universitaires de Genève
Laurent Kaiser & Pascal Cherpillod
Support financier de la part du Fonds National de la Recherche Suisse
TDR fournis en grande partie par USAID/Tanzania sous President Malaria Initiative