This document summarizes a presentation on immunological testing for tuberculosis (TB) and HIV co-infection. It discusses the clinical utility of interferon gamma release assays (IGRAs) for detecting latent TB infection (LTBI) in HIV-infected individuals. While IGRAs perform similarly to the tuberculin skin test (TST) in identifying those who could benefit from LTBI treatment, important questions remain about their use in HIV-positive populations with different CD4 counts. The document also examines the diagnostic value of IGRAs for active TB, finding no evidence they are more sensitive than the TST, especially in low- and middle-income countries.

1. Immunologia
TB/HIV
Andrea
Gori
UO
Mala/e
Infe23ve
AO
San
Gerardo,
Monza
Università
Milano-­‐Bicocca
andrea.gori@unimib.it
Milano,
21-­‐22
Marzo
2014
!

2. Interferon
Gamma
Release
Assay
(IGRA)
tes;ng

4. Clinical
u;lity
of
interferon
gamma
release
assays
(IGRAs)

7. Biological
phenomena
of
mother-­‐newborn
immune
interac;on
which
can
theore;cally
affect
newborn
immune
responses
to
microbial
an;gens

9. Sensi;vity
of
IGRAs
in
HIV-­‐infected
individuals
with
confirmed
ac;ve
tuberculosis

10. Propor;on
of
indeterminate
IGRA
results
in
HIV-­‐infected
persons
screened
for
LTBI

11. Impact
of
CD4+
cell
count
on
the
propor;on
of
posi;ve
IGRA
results

12. Impact
of
CD4+
cell
count
on
the
propor;on
of
indeterminate
IGRA
results

13. IGRA
test
for
the
Diagnosis
of
LTBI
in
HIV-­‐
Infected
Individuals
- Current
evidence
suggests
that
IGRA
perform
similarly
to
the
TST
at
iden3fying
HIV+
individuals
who
could
benefit
from
LTBI
treatment
- Important
ques3ons
remain
unanswered
despite
the
substan3al
body
of
literature
on
IGRAs:
- HIV+
individuals
with
a
nega3ve
IGRA
result
may
have
a
low
risk
of
progression
to
ac3ve
TB
- IGRAs
(par3cularly
TSPOT)
may
be
more
sensi3ve
than
TST
in
HIV-­‐
infected
individuals
and
less
affected
by
advanced
immunosuppression
- Clinical
Trials
are
needed
to
more
defini3vely
determine
whether
IGRAs
could
improve
the
iden3fica3on
of
people
living
with
HIV
- Un3l
such
data
are
available,
the
decision
to
use
IGRA
or
TST
(or
both)
will
depend
on
na3onal
guidelines
as
well
as
resource
and
ogis3c
considera3ons.

15. - The
diagnos3c
value
of
interferon-­‐γ
release
assays
(IGRAs)
for
ac3ve
tuberculosis
in
low-­‐
and
middle-­‐income
countries
is
unclear
- There
was
no
consistent
evidence
that
either
IGRA
was
more
sensi3ve
than
the
tuberculin
skin
test
for
ac3ve
tuberculosis
diagnosis
- Conclusions:
neither
the
tuberculin
skin
test
nor
IGRAs
have
value
for
ac3ve
tuberculosis
diagnosis,
especially
in
the
context
of
HIV
coinfec3on
Interferon-­‐γ
Release
Assays
for
Ac;ve
Pulmonary
Tuberculosis
Diagnosis

16. Comparison
of
sensi;vity
of
T-­‐SPOT
VS
QFT-­‐GIT
among
persons
with
suspected
ac;ve
tuberculosis

17. Sensi;vity
of
QFT-­‐GIT
and
T-­‐SPOT
in
HIV-­‐
and
HIV
+
persons
with
confirmed
ac;ve
tuberculosis

18. Sensi;vity
difference
between
IGRA
and
TST
Plots
display
%
differences
(IGRA
sensi3vity–TST
sensi3vity)
for
confirmed
ac3ve
pulmonary
tuberculosis

19. Interferon-­‐γ
Release
Assays
for
Ac;ve
Pulmonary
Tuberculosis
Diagnosis
- As
in
the
case
of
the
TST,
the
data
suggest
no
role
for
using
IGRAs
for
ac3ve
tuberculosis
diagnosis
for
adults
living
in
low-­‐
and
middle-­‐income
countries
- These
data
should
not
help
inform
evidence-­‐based
policies
on
the
role
of
IGRAs
in
ac3ve
tuberculosis
diagnosis
- Indeed,
a
WHO
Expert
Group
considering
this
evidence
recently
recommended
that
IGRAs
should
not
be
used
as
a
replacement
for
conven3onal
microbiological
diagnosis
of
pulmonary
and
extrapulmonary

20. - Tuberculosis
is
unique
among
the
major
infec3ous
diseases
in
that
it
lacks
accurate
rapid
point-­‐of-­‐care
diagnos3c
tests
- Failure
to
control
the
spread
of
tuberculosis
is
largely
due
to
our
inability
to
detect
and
treat
all
infec3ous
cases
of
pulmonary
tuberculosis
in
a
3mely
fashion,
allowing
con3nued
Mycobacterium
tuberculosis
transmission
within
communi3es

22. Analysis
of
Mtb-­‐specific
T
cell
responses
in
the
valida;on
cohort

23. Quan;ta;ve
and
qualita;ve
analysis
of
Mtb-­‐
specific
T
cell
responses
Latent
infec3on
Ac3ve
disease

24. Func;onal
profile
of
Mtb-­‐specific
CD4+
T
cells
on
the
basis
of
IFN-­‐γ,
IL-­‐2
or
TNF-­‐α
produc;on

25. Percentages
of
CFP-­‐10–
or
ESAT-­‐6–specific
single-­‐posi;ve
TNF-­‐α–producing
CD4+
T
cells

26. Profile
of
Mtb-­‐specific
CD4+
T
cells
during
untreated
TB
disease
and
then
aZer
TB
treatment

27.
M.
tuberculosis–specific
CD4+
T
cell
responses
and
latent
infec;on
or
ac;ve
disease
- Rapid
diagnosis
of
ac3ve
Mycobacterium
tuberculosis
(Mtb)
infec3on
remains
a
clinical
and
laboratory
challenge
- We
have
analyzed
the
cytokine
profile
IFN-­‐γ,
TNF-­‐α
and
IL-­‐2
of
Mtb-­‐specific
T
cells
by
polychroma3c
flow
cytometry
- Substan3al
increase
in
the
propor3on
of
single-­‐posi3ve
TNF-­‐
α
Mtb-­‐specific
CD4+
T
cells
in
subjects
with
ac3ve
disease,
and
this
parameter
was
the
strongest
predictor
of
diagnosis
of
ac3ve
disease
versus
latent
infec3on
- Therefore,
the
propor3on
of
single-­‐posi3ve
TNF-­‐α
Mtb-­‐
specific
CD4+
T
cells
is
a
new
tool
for
the
rapid
diagnosis
of
ac3ve
tuberculosis
disease

28. Division
of
Onco-­‐Haemathology,
“San
Gerardo”
Hospital,
University
Milano-­‐Bicocca
Monza,
Italy
Luisa
Verga
Fausto
Rossini
Pietro
Pioltelli
Enrico
Pogliani
Division
of
Division
of
Pathology,
“San
Gerardo”
Hospital,
University
Milan-­‐Bicocca
Monza,
Italy
Ambrogio
Brenna
Serena
Cu`n
Giorgio
Catore`
Division
of
Microbiology
and
Virology
Laboratories,
“San
Gerardo”
Hospital,
Monza,
Italy
Sergio
Malandrin
Annalisa
Cavallero
Haemathology
and
Transfusion
Center,
“San
Gerardo”
Hospital,
Monza,
Italy
Paolo
Perseghin
Arianna
Incontri
Chair
of
Immunology,
University
of
Milan,
Milan,
Italy
Daria
Trabaaoni
Marina
Saresella
Mara
Biasin
Mario
(Mago)
Clerici
Department
of
Infec;ous
Diseases,
“L.
Sacco”
Hospital,
University
of
Milan
Milan,
Italy,
Fabio
Franze`
Fabio
Zanini
Stefano
Rusconi
Stefania
Piconi
Giuliano
Rizzardini
Clinic
of
Infec;ous
Diseases,
“San
Paolo”
Hospital,
University
of
Milan
Milan,
Italy
Giulia
Marche`
Camilla
Tinca;
Antonella
d’Arminio
Monforte
Divisione
di
Mala`e
Infe`ve
A.O.
“San
Gerardo”
Monza
Giuseppe
Lapadula
Silvia
Costarelli
Alessandra
Bandera
Marianna
Rossi
Nicola
Squillace
Alessandro
Soria
Antonio
Muscatello
Sebas;ano
Leone
Guglielmo
Migliorino

29. BACK
UP
SLIDES

31. Interferon
Gamma
Release
Assay
(IGRA)
tes;ng

32. summary curves from the HSROC model
contain a summary operating point (red square)
representing
summarized sensitivity and specificity point
estimates for individual study estimates (open
circles). The 95% confidence region is
delineated by the area
in the orange dashed line.