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Loop-mediated isothermal amplification for Rickettsia typhi (the causal agent of murine typhus): problems with diagnosis at the limit of detection.
[scrub typhus]
Murine
typhus
is
a
flea-borne
disease
of
worldwide
distribution
caused
by
Rickettsia
typhi
.
Although
treatment
with
tetracycline
antibiotics
is
effective
,
treatment
is
often
misguided
or
delayed
due
to
diagnostic
difficulties
.
As
the
gold
standard
immunofluorescence
assay
is
imperfect
,
we
aimed
to
develop
and
evaluate
a
loop-mediated
isothermal
amplification
(
LAMP
)
assay
.
LAMP
assays
have
the
potential
to
fulfill
the
WHO
ASSURED
criteria
(
affordable
,
sensitive
,
specific
,
user
friendly
,
robust
and
rapid
,
equipment
free
,
deliverable
to
those
who
need
them
)
for
diagnostic
methodologies
,
as
they
can
detect
pathogen-derived
nucleic
acid
with
low
technical
expenditure
.
The
LAMP
assay
was
developed
using
samples
of
bacterial
isolates
(
n
=
41
)
,
buffy
coat
specimens
from
R
.
typhi
PCR-
positive
Lao
patients
(
n
=
42
)
,
and
diverse
negative
controls
(
n
=
47
)
.
The
method
was
then
evaluated
prospectively
using
consecutive
patients
with
suspected
scrub
typhus
or
murine
typhus
(
n
=
266
)
.
The
limit
of
detection
was
∼
40
DNA
copies
/
LAMP
reaction
,
with
an
analytical
sensitivity
of
<
10
DNA
copies
/
reaction
based
on
isolate
dilutions
.
Despite
these
low
cutoffs
,
the
clinical
sensitivity
was
disappointing
,
with
48
%
(
95
%
confidence
interval
[
95
%
CI
]
,
32
.
5
to
62
.
7
%
)
(
specificity
,
100
%
[
95
%
CI
,
100
to
100
%
]
)
in
the
developmental
phase
and
33
%
(
95
%
CI
,
9
.
2
to
56
.
8
%
)
(
specificity
,
98
.
5
%
[
95
%
CI
,
97
.
0
%
to
100
%
]
)
in
the
prospective
study
.
This
low
diagnostic
accuracy
was
attributed
to
low
patient
R
.
typhi
bacterial
loads
(
median
,
210
DNA
copies
/
ml
blood
;
interquartile
range
,
130
to
500
)
.
PCR-
positive
but
LAMP-negative
samples
demonstrated
significantly
lower
bacterial
loads
than
LAMP-
positive
samples
.
Our
findings
highlight
the
diagnostic
challenges
for
diseases
with
low
pathogen
burdens
and
emphasize
the
need
to
integrate
pathogen
biology
with
improved
template
production
for
assay
development
strategies
.
Diseases
Validation
Diseases presenting
"developmental phase"
symptom
scrub typhus
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