Transcript Ensuring quality and access for malaria diagnosis: how can

“Ensuring quality and access for malaria
diagnosis: how can it be achieved?”
Nat Rev Microbiol. 2006 Sep;4(9 Suppl):S7-20.
Amy Storfa
3/23/2007
Background
• Symptoms (fever, rigors, headache) overlap with
presentations of other febrile illnesses
• P. falciparum can often lead to coma and death; other
Plasmodium spp. cause acute severe illness but rarely fatal
• Despite microscopy, most diagnoses with subsequent
treatment made based on symptoms
• Estimates of malaria deaths estimated at ~1-2 million/y
– 350-500 million cases of malaria occur annually
• Programs developed for treatment but accurate diagnosis
not emphasized
Background
• Some countries maintain microscopy-based diagnosis
programs (e.g. India)
• BUT, microscopy largely unavailable to providers of most
patients with tropical febrile illness
• Requires organized health system, supplies, reagents, good
microscopes, maintenance, competence, ability to make
blood films
• Antigen-detecting rapid diagnostic tests (RDTs) first
introduced in early 1990s and used sparingly in malaria
endemic areas
Background
• More recently, drug resistance is increasing, necessitating
switch to artemisinin-based combination therapy (ACT),
more $
• Shift has led to upsurge in use of RDTs
• But many areas (particularly sub-Saharan Africa) still rely
on symptom-based diagnosis
Early diagnosis
• Differential diagnosis of febrile tropical illness: respiratory
tract infxn, typhus, viral illness, meningitis
• Early detection/treatment likely to occur if microscopy
services are offered within 15-20 minutes of residence
• ACT ~$1.60 per course
• RDT ~$0.55 to $1.00 each
• Overall funding for research and development
– Diagnosis receives <1%, vs 37% for drug development
Advantages:
-Improved
management of
non-malarial
disease
-Savings in drug
costs
-Improved
adherence to
therapy
Implications on health care
system
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Preparation and interpretation can be poor
Requires adequate level of training, supervision
Appropriate instructions developed
Requires temperature controlled distribution and
storage facilities
• Need to be stable, simple to use, able to detect
clinically significant disease (100 parasites/uL)
• Need quality assurance and control
Bell et al. Nature Reviews Microbiology 4, S7–S20 (September 2006) | doi:10.1038/nrmicro1525
Bell et al. Nature Reviews Microbiology 4, S7–S20 (September 2006) | doi:10.1038/nrmicro1525
1. HRP2
2. pLDH
3. aldolase
P. falciparum HRP-2
pLDH
Further development/study
needed
• Field trials needed to see how tests perform in field
• WHO initiative to test accuracy and stability of RDTs
• Previous studies based on various RDT types in different
clinical and epidemiological settings are difficult to
compare
• Difficult to generate conclusive comparisons of RDT
performance
• Timing of treatment and effectiveness of therapy also
complicates comparative studies
– pLDH is rapidly cleared but HRP2 persists for weeks
Malaria Review
Malaria review
• Plasmodium: four species
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P. falciparum (~45%)
P. vivax (~45%)
P. ovale (rare, <5%, limited to W. Africa)
P. malariae (<5%)
• Acquired via anopheles mosquito
Malaria review: multiple forms
• Trophozoites (=ring forms): most numerous form to see in
peripheral blood, ring like structure (<1/2 diameter of cell),
progressively enlarge and mature to…
• Schizont: multinuclear structure, appear as intraerythrocytic
collection of merozoites (each with its own nucleus)
• Gametocyte: mononuclear structure occupying >1/2 the red
cell, usually amoeboid in shape and nearly fills entire RBC
Life cycle
• Mosquitoes inject
sporozoites, divide in liver
into schizonts (containing
merozoites)
• Merozoites infect RBC
and then become
trophozoites
• Again divide into
merozoites
– Can infect more RBCs
or become gametocytes
(ingested by
mosquitoes)
Malaria review
• Infects RBCs; causes intermittent hemolysis
with paroxysmal fevers
• Fever q48 h (tertian fever): P. falciparum, P.
ovale; P. vivax
• Fever q72 h (quartan fever): P. malariae
• Examine thick (for screening) and thin (for
species identification) films
Malaria review
• Signs/symptoms
– Splenomegaly
– Periodic shaking chills (rupture of RBCs)
followed by spiking fevers (merozoites
penetrating other RBCs)
– Sweats
– Anorexia
– Joint pain
P. falciparum
• Malignant tertian fever because potentially lethal
• Must be identified
• Usually only early ring forms and gametocytes
seen
– Ring forms: may have double chromatin dots, may be
multiply infected; accole or applique forms present; less
than 1/5 size of RBC
– Gametocytes: banana shaped
• Infected red cells NOT enlarged, infects RBCs of
all stages of maturation
P. falciparum
• Acute intravascular hemolysis with
hemoglobinuria (“blackwater fever”)
• Infected RBCs have “sticky knobs” leading
to sludging, infarcts of brain, kidneys
• With no treatment, patients either die or
spontaneously resolve within one year
P. falciparum
P. vivax and P. ovale
• Benign tertian fever
• Morphologically very similar
• P. ovale very rare, confined to Western
Africa
• Both infect young RBCs and appear
enlarged and pale
• All stages seen (early and developing rings,
schizonts, gametocytes)
P. vivax and P. ovale
• Schuffner’s dots may be present
• Gametocytes are amoeboid shaped, not
banana
• Schizonts have 12-14 merozoites
P. malariae
• Associated with nephrotic syndrome
• Infects older erythrocytes, normal to small sized
RBCs
• No Schuffner’s dots
• All stages seen
• Schizonts have 6-12 merozoites, rosette pattern
• Coarse pigment may be present
• Occasional band forms (trophozoite form) seen
• Low grade cryptic infections can occur up to 40 y
P. malariae
Malaria and RBC associations
• Hemoglobin S trait (HbSA) protective
against P. falciparum
• Duffy antigens mediate attachment of P.
vivax (Duffy negative patients protected
from P. vivax)
• Glucose-6-phosphate dehydrogenase
deficiency protects against ALL
Plasmodium spp.
References
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Bell D et al. “Ensuring quality and access for malaria diagnosis: how can it be
achieved?” Nat Rev Microbiol. 2006 Sep;4(9 Suppl):S7-20.
Jones SL. Clinical Laboratory Pearls. Lippincott Williams and Wilkins, 2001.
Mais DD. Quick Compendium of Clinical Pathology. ASCP Press, 2005.