Conférence de la 8ème édition du Cours international « Atelier Paludisme »

1. Epidemiology and Public Health
Diagnostic parasitologique des accès
palustres: acquis et défis
Valérie D‘Acremont, MD, PhD
Atelier paludisme Madagascar, 22 Mars 2011

2. How to deal with malaria in patients?
Suspected
malaria
Early and accurate
diagnosis
Prompt
treatment

3. Definitions of malaria
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

4. What is a true malaria episode (= illness) ?
General ‘Clinical malaria’
population
Sick population Cough
Diarrhea
Headache
Febrile patients
Arthralgia

5. What is a true malaria episode (= illness) ?
General ‘Clinical malaria’
population
Sick population
Febrile patients
Parasites in
blood

6. What is a true malaria episode (= illness) ?
General ‘Clinical malaria’
population
Sick population ‘Malaria episode’
Febrile patients
Parasites in
blood

7. What is a true malaria episode (= illness) ?
Sick people with
incidental parasitemia
General
population
Sick population Cough
Diarrhea
Headache
Arthralgia
Parasites in
blood

8. What is a true malaria episode (= illness) ?
O
V
Sick people with E
incidental parasitemia R
D
I
‘Clinical malaria’ A
General G
population N
O
Sick population ‘Malaria episode’ S
I
S
Febrile patients

9. What is a true malaria episode (= illness) ?
HEALTH FACILITIES:
Only patients that
should be treated !
General
population
Sick population ‘Malaria episode’
Febrile patients
Parasites in
blood

10. In the context of elimination ?
POPULATION SURVEYS:
Parasitemia in
healthy people Treatment of the
hidden reservoir
General
population
Sick population
Febrile patients
Parasites in
blood

11. Magnitude of overdiagnosis
Systematic review of 39 studies performed between 1986 and 2007
in 16 African countries including 42,979 patients
100
Proportion of fevers 90
associated with Pf (%) 80
70
60
50
44%
40
30
20 22%
10
0
<2000 >2000
D’Acremont, CID 2010

12. Systematic review
Proportion of malaria among fevers in children < 5 years
Country Year rural urban
Tanzania (rural) 1986 81%
1995 57%
1997 38%
2005 21%
Dar es Salaam 2003 5%
Highlands 2004 4%
Rooth, Font, Nsimba, Reyburn, Wang

13. 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%)

14. Consequences of over-treatment
Reattendances
Costs for
patient
Left untreated
for real cause
Parasite resistance Drugs wastage
Mistrust
in ACT

15. Clinical diagnosis: impossible to rely on it
Predictors for malaria:
high temperature of short duration , absence of cough
splenomegaly , absence of rash , absence of abdominal pain
100% Drug wastage (overdiagnosis)
Failure to treat (missed cases)
80%
60%
Reviewed by
Chandramohan et al
40% in 2002
20%
Proportion of malaria
0 among fevers
20% 40% 60% 80% 100%

16. How to deal with malaria in patients?
Suspected
malaria
Early and accurate
LAB TEST
diagnosis
Prompt
treatment

17. How to get universal access to
parasitological diagnosis?

18. Available malaria tests: microscopy

19. Components of good microscopy performance
Selection
Training Competency
Assessment
Supervision
e.g. cross-checking??
Performance
Equipment/
reagents
Support network
Slide /results delivery
Work
environment
REGIONAL COURSE ON TRAINING OF TRAINERS ON USE OF
MALARIA RAPID DIAGNOSTIC TESTS (RDTS)

20. 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
Expert microscopy
Positive Negative Total
Positive 5 173 178
Routine Negative 2 148 150
microscopy
Total 7 322 328
Sensitivity Specificity
= 70% = 45%

21. Reported parasitemia: routine versus expert
140
Number of slides
120
Routine
100 microscopy
Expert
80 hospitals 41%
microscopy
health cent. 49%
60
dispensaries 65%
40
(range 13-90%)
Real positives…
20
0
Parasitemia (parasites/ l)
10 0 -< 00
0
10
>1 00
10 0
00
10 < 10
0
10
0
-<
00 10'0
'0
0'
00
-<
-
0
10
0
-<
00
1'
'0

22. 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

23. 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 treatment
Zurovac et al, 2006

24. 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=17,313
Admissions for malaria n=17,313 No criteria for
No criteria for
severe disease
severe disease
n=12,643 (73%)
n=12,643 (73%)
Severe disease n=4670 (27%)
Severe disease n=4670 (27%) 120 deaths (1%)
120 deaths (1%)
Readable slide results n=4474 (95%)
Readable slide results n=4474 (95%)
Expert microscopy positive
Expert microscopy positive Expert microscopy negative
Expert microscopy negative
n=2062 (46%)
n=2062 (46%) n=2412 (54%)
n=2412 (54%)
Dead
Dead Alive
Alive Dead
Dead Alive
Alive
n=142 (7%)
n=142 (7%) n=1920 (93%)
n=1920 (93%) n=292 (12%)
n=292 (12%) n=2120 (88%)
n=2120 (88%)
Reyburn H et al. BMJ 2006

25. 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=17,313
Admissions for malaria n=17,313 No criteria for
No criteria for
severe disease
Dar es Salaam (Muhimbili hospital) severe disease
n=12,643 (73%)
n=12,643 (73%)
Severe disease n=4670 (27%)
Severe disease n=4670 (27%) 120 deaths (1%)
120 deaths (1%)
‘cerebral malaria’
Readable slide results n=4474 (95%)
Readable slide results n=4474 (95%)
Expert microscopy positive
Expert microscopy positive Expert microscopy negative
Expert microscopy negative
n=2062 (46%)
n=2062 (46%) n=2412 (54%)
n=2412 (54%)
Dead Alive Dead Alive
13%Dead
in slide
n=142 (7%)
n=142 (7%)
Alive
positive patients
n=1920 (93%)
n=1920 (93%)
22%Deadslide
n=292in
n=292(12%)
(12%)
Alive
negative patients
n=2120 (88%)
n=2120 (88%)
Reyburn H et al. 20032006
Makani et al BMJ

26. Add another malaria diagnostic test
A reliable test available at time and place of need,
used for more than 15 years in Europe
and 7 years in South Africa...

27. Relative performance of each method
Sensitivity in the absence of a gold standard
100%
90
HRP2 RDT
80 AO
QBC
70
60 pLDH RDT Microscopy
50
40
Meta-analysis published in 2006:
30
HRP2 RDT at least as sensitive
20 as expert microscopy
10
0
REF: Ochola Lancet Infect Dis 2006

28. Relative performance of each method
Technologies evolve quickly :
Proportion Sensitivity
Author, Origin of the
RDT(+) / BS(-)
year samples RDT Microscopy
positives by PCR
Bell 2005 Philippines 92% 91% 70%?
Dal-Bianco Gabon 80% 46% 22%
2007
Stauffer Travelers USA 60% 100% 88%
2009
Conclusion: between 60 and 90% of so-called false-positive RDT
are real positives, reflecting the high sensitivity of HRP2 RDT
REF: Bell AJTMH 2005 Dal-Bianco AJTMH 2007 Stauffer CID 2009

29. Relative performance of each method
Putative explanation for greater sensitivity of a RDT
relying on detection of a persistent antigen
REF: Bell AJTMH 2005

30. Safety study of RDT in Tanzania
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)

31. 1000
febrile children
Day 0
397 (40%) RDTm +ve 603 (60%) RDTm -ve
1 LOF 12 LOF
396 591 followed up
followed up
1 admitted
1 RDTm&BS -ve
1 admitted
18 (3%)
Day 7
387 (98%) 9 (2%) 573 (97%) still sick
cured still sick cured
15 RDTm -ve
BS negative 2 RDTm still +ve
1 still no RDTm
2 LOF
1 LOF 2 RDT -ve
> Day 14
14 2 deceased
8 cured cured 2 RDTm&BS -ve

32. Translation of research findings into policy
Translation of research findings into policy

33. Implementation of RDT in Dar es Salaam
Improve laboratory diagnosis for malaria
in routine management of fever cases at
OPD
Intervention:
Pilot implementation
of RDT in Dar es Salaam
in the 3 district hospitals,
3 health centres
and 3 dispensaries

34. Methodology
INTERVENTION
Training, RDTm implementation, quaterly supervision
Consultation process: Consultation process:
Baseline survey Post-intervention survey
9 Intervention HF 9 Intervention HF
1. Before and after
study 2. Cluster randomized
study
Consultation process: Consultation process:
3 Control HF 3 Control HF
3. Routine statistics of Health Facilities
2006 2007 2008

35. 1. Before-after cluster randomized study
Proportions of patients treated with antimalarials
9 intervention HF
BEFORE AFTER
24%
3 control HF
81%
65%
Patients with history of fever

36. Results 1: why did it work?
1) Performance of routine mRDT much better than
routine microscopy
better specificity less overdiagnosis
mRDT implementation
100%
80%
Routine microscopy Routine RDT
P o sitivity rate
48% 8%
60%
40%
20%
0%
Nov
Nov
J ul
J ul
J ul
J an
J un
J an
J un
J an
J un
M ar
A pr
M ar
A pr
M ar
A pr
Feb
A ug
S ep
Feb
A ug
S ep
Feb
A ug
S ep
Oct
Oct
M ay
Dec
M ay
Dec
M ay
2006 2007 2008

37. Results 1: why did it work?
2) Negative RDT patients are not treated for malaria
more trust in mRDT better adherence to the guidelines
With microscopy With mRDT
Negative patients
treated 7%
53%

38. Results 2: longitudinal study
25000 mRDT
Artemether/lumefantrine (ALu)
20000
dispensary 3
dispensary 2
dispensary 1
15000
health centre 3
health centre 2
health centre 1
10000
hospital 3
hospital 2
hospital 1
5000
0
Nov
Jan
Jun
Jan
Jun
Jul
Jul
Mar
Apr
Mar
Apr
Feb
Aug
Sep
Feb
Aug
Sep
Oct
May
Dec
May
2007 2008

39. Results 2: longitudinal study
18000
Quinine vials
mRDT
16000
14000
dispensary 3
12000 dispensary 2
dispensary 1
10000 health centre 3
health centre 2
8000 health centre 1
hospital 3
6000 hospital 2
hospital 1
4000
2000
0
May
May
May
Mar
Mar
Mar
Nov
Nov
Jan
Jan
Jan
Jul
Jul
Jul
Sep
Sep
Sep
2006 2007 2008

40. Suspected malaria case
High malaria risk area Low malariaNO area
risk Do NOT
NO
perform a
FEVER without an
FEVER ANEMIA malaria test
obvious cause of fever ?
YES
YES DANGER SIGNS NO
Give immediately antimalarial and antibiotic
PRIMARY LEVEL SECONDARY LEVEL PRIMARY AND SECONDARY LEVEL
Refer the Perform RDT or BS
patient positive negative
Admission
immediately
Uncomplicated Febrile illness
Perform BS BS and malaria (NOT malaria)
RDT and/or RDT both
+/- RDT Give antimalarial • Do NOT give
BS positive negatives antimalarial
• Invest. for other
Severe malaria Severe illness (NOT malaria) causes of fever
Give i.v quinine • STOP antimalarials
• Continue with appropriate antibiotic Follow-up
• Investigate for other causes of fever
• Repeat RDT and BS after 12-24hrs

41. Antibiotic prescriptions in Dar es Salaam
Proportion of Before RDT After RDT
febrile patients implementation implementation
receiving:
81% 24%
Antimalarials
49% 73%
Antibiotics
D’Acremont et al, 2010, submitted

42. Study on etiologies of fever in children
But what are the causes of all these fevers
that are not malaria ?
8%
?

43. Methodology of the fever study
To determine the etiology of fever
episodes in small children living in urban
and rural Tanzania
children 2 months - 10 yrs
temperature > 38°C
1005 patients
(507 in Dar es Salaam
and 498 in Ifakara)

44. 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

45. Results 1: etiologies in all patients
Malaria
Acute Resp. Infect.
Typhoid
URTI
Sepsis due to 1% 10% Bronchiolitis
bacteriemia 3% Non-doc. pneumonia
31% Doc. pneumonia
Unknown 20% All ARI
50%
4%
Other
1% 5% 12%
Skin infection Gastroenteritis
amoeba
Urine infection 3%
Rota/Adenovirus
All gastroenteritis Salmonella/Shigella
9% unknown etiology

46. Results 2: etiologies in severe patients
Malaria
Acute Resp. Infect.
Typhoid
URTI
Sepsis due to 7% 5% Bronchiolitis
bacteriemia Non-doc. pneumonia
36% Doc. pneumonia
20%
Unknown
All ARI
38%
Other 6%
2% 10% Gastroenteritis
Skin infection 4%
2%
amoeba
Urine infection
Rota/Adenovirus
All gastroenteritis Salmonella/Shigella
8% unknown etiology

47. Results 3: proportion of children infected with viruses
any virus
86% 87%
100%
82% 80% any virus except PIC
Kenyan study (same
80% viruses)
64%
60%
40%
20%
0%
severe unknown other ‘control
pneumonia URTI
pneumonia fever disease group’
WHO definition Ref: Berkley JAMA 2010

48. Results 6: seasonality of influenza
50%
Dar es Salaam
40%
FLUAV
30%
20% FLUBV
10%
0%
Apr May Jun Jul Aug
50%
Ifakara
40%
30%
20%
10%
0%
Jul Aug Sep Oct Nov

49. 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)

50. 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)
The e-IMCI interface

51. 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