Download Challenges in Infectious Disease: Need for Imaging

Sanjay K Jain, MD
Director, Ci3R
Associate Professor of Pediatrics & International Health
Department of Pediatrics & Center for TB Research
Johns Hopkins University
Baltimore, Maryland, USA
• Most experts agree that Infections will not be
eradicated for decades, or maybe never . . .
• Are we planning for the future, and utilizing the
advances in technology that may be applicable to
Infectious Diseases?
• Does diagnosis and monitoring of infections in
special situations (hard to get locations, difficult to
grow bugs, e.g. M.tb.) merit the development and / or
use of technologies, that may be different from those
being developed currently?
The future is not what it used to be
MGIT
Fundamental
diagnostic: 1882
Need to isolate the bug
Fundamental
diagnostic: 2013
GeneXpert
Need to isolate the bug
• Bugs: “need to bring them out, or go in and get them”
• Often impractical or dangerous
• Whole organ / body view of disease not available
Inject radiotracer
Uptake by
target cells
or bugs
ENERGY
Take
pictures
X-ray
CT
PET
http://www.musc.edu/fnrd/primary.psych.images/page%2053.GIF
Goo JM et al. Radiology 2000
• Rapid, and easily scalable to humans
•
Major investment by
Oncologist to develop this
technology for cancers
•
Now used extensively for
monitoring cancer patients
during clinical trials and also
for patient care
•
Can these technologies be
used in Infectious Diseases?
• Provides spatial information, and holistic 3-D views of
disease, not limited by sampling errors / contamination
• Capable of visualizing processes deep within the body
• Noninvasive (fundamental advantage):
• study unaltered physiology
• longitudinal assessments in the same individual
• Relatively rapid
•
•
•
•
Uniform cross-species platform for animal studies
Easy translation to the clinic
Allow adaptive designs for clinical trial
Enabling personalized medicine
Sensitivity
Modality
Agents
H
R
Primary uses
Examples
Optical
pM
FMT
fluorescent
proteins
X
gene expression, tagging
superficial structures
GFP, RFP, NIRF
probes
BLI
luciferin
X
gene expression,
therapeutic monitoring
fLuc rLuc
X
site-selectivity, protein
labeling
99mTc-annex
site-selectivity, gene
expression, drug
development
11C-RAC, 124I-FIAU,
X
CNS, prostate , heart ,
breast
NAA, Cr, Cho, Glx,
mI, 31P
X
cell trafficking, enzymatic
activation
poly-L-lysine,
dendrimers, MION
X
drug-delivery, gene
transfection
human albumin
(Optison)
Nuclear
SPECT
99mTc, 123/5I,
X
111In
nM
PET
11C, 18F, 124I,
X
X
64/62/60Cu
in V,
123I-A85380
64Cu-ATSM
MRI
µM
spectroscopy
endogenous
metabolites
contrast
agents
Gd, Mn, FeO
X
Ultrasound
(10 µm)
contrast
agents
perfluorinated
microbubbles
H=human, R=rodent
Courtesy Marty Pomper (JHU)
JOHNS HOPKINS
U
N
I
V
E
R
S
I
T
Y
Center for Infection and Inflammation Imaging Research
http://www.hopkinsmedicine.org/ci3r
Working in a TB Lab!
BSL-3 containment and anesthesia protocols
• We use a commercially available portable
anesthesia machine and isoflurane
anesthesia
• All animals are imaged only while inside of
an appropriate BSL-3 container which is
air tight, unbreakable and transparent
• Temperature is monitored using an
infrared thermometer and maintained
using a heat lamp
• More than 1000 M. tuberculosis-infected
mice / rabbits have been anesthetized and
imaged so far (some anesthetized for > 4
hrs)
Lung CFU (log10)
a
AFB
8
c
4
0
0
14
28
42
Days after infection
b
Pan HB et al. Nature 2005.
Davis SL et al. PLoS ONE 2009
Davis SL et al. Antimicrob Agents Chemother. 2009
Davis SL et al. Antimicrob Agents Chemother. 2009
Bug count (log scale)
Old
Method
Bug counts
9
Untreated
6
1 – ineffective
3 – effective
3
Ineffective
treatment
0
-2 0 2 4
8
12
Weeks after starting
treatment
Infection
Effective
treatment
New
method
Functional
Imaging
PET Activity
1.8
Ineffective
treatment
1.4
Effective
treatment
1.0
0
4
8
• 2-weeks after infection, mice
received 2 treatments (1 –
ineffective, 2 – effective)
• Mice killed at different times
after starting treatment for
counting bugs (old method)
• Another group of mice
imaged (new method) at the
same times after starting
treatment
• Activity measured using
imaging correlated with the
effectiveness of the TB
treatments (p < 0.033)
• Imaging was real-time,
compared with 4-weeks
delay with the standard
method
• Relapse could be also be
detected non-invasively
12
Weeks after starting
treatment
Davis SL et al. Antimicrob Agents Chemother. 2009
Serial PET activity in low-dose aerosol TB-infected
lungs (segmented) of a C3HeB/FeJ mouse
Partial segmentation of
infected lungs. Holes appear
in lieu of lesions.
Complete segmentation of
healthy lungs, used as
template shape.
Registration of the complete
template shape onto the
incomplete segmentation.
Notice how the template
fills in the holes of the
lesions.
After registration, a one-to-one correspondence between all CT and PET
image sets is achieved making it possible to trace a region of interest (ROI) in
one image and extract activities at corresponding locations across time-point
Vidal C et al. Proceedings of the IEEE International Symposium on Biomedical Images 2009
Normalized mean PET Activity
4.5
Inf C3H
3.5
3.0
1.5
Inf Balb/c
Uninf C3H
0.0
0
5 10 15 20 25 30 35 40 45 50 55 60
Harper et al. J Infect Dis. 2012
Time (minutes)
Absorption
Distribution
Metabolism
Elimination
Biomarkers
Toxicity
Special Populations
Courtesy Ed Weinstein (JHU)
Lung
Brain
Liver
Weinstein EA, Liu L et al. Antimicrob Agents Chemother. 2012
Pros
Readily
Available
Readily
Available
Bacteria
Specific
Cons
CT / MRI / US
Not
specific for
bacteria or
infection
FDG-PET
Not
specific for
bacteria or
infection
FIAU (Phase II)
Difficult to
synthesize
Courtesy Ed Weinstein (JHU)
• Readout
•
•
•
•
better / worse (qualitative, quantative)
infection or not?
(Gen I)
bacteria type?
(Gen II)
drug-susceptibility?
(Gen III)
INFECTION
IDENTIFICATION
EFFICACY
• Purpose
• diagnosis
• monitoring disease
• prognostic – correlates of protection, relapse
• Setting
• pre-clinical (uniform cross-species platform; allow unique insights
into disease pathogenesis; expedite bench-to-bedside translation
of new therapeutics)
• clinical studies (multi-compartment PK; diagnostics; monitoring
disease; disease pathogenesis; adaptive designs)
• use in patients (diagnosis / monitoring; personalized medicine)
• Due to the use of sub-pharmacological doses, the risk to
human subjects is very limited in microdose studies.
• Therefore, the requirements for preclinical safety testing
are significantly simpler.
• The FDA currently accepts the use of extended (14-days)
single-dose toxicity studies in one mammalian species to
support single-dose studies in humans.
FDA. Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies.
• Imaging of Infections Interest Group has been formed
under the aegis of the World Molecular Imaging Society
(WMIS).
• The first meeting was held at the World Molecular Imaging
Congress 2013 (Savannah, GA).
• “The goal of this subgroup is to globally advance the
implementation of imaging technologies as well as the
development of new biomarkers for infections of various
origin”, Neil Jarvis (Pretoria) , 2013
• We plan to centralize Infection Imaging initiatives under
one roof and get endorsements from imaging and national
infectious diseases societies - SNM, IDSA, PIDS, etc.
• It is a good time to participate!
Some “developing worlds” are more
developed than you think
accounts for a majority of TB worldwide
World-at-Night Satellite Image Reveals Economic Activity
Satellite Image of Earth at Night by Craig Mayhew and Robert Simmon,
NASA GSFC http://geology.com/press-release/world-at-night/
Slums
and skyscrapers
Some
“developing
worlds”co-exist
are more
developed than you think
PET scans for just Rs 7,500
Kounteya
Sinha, TNN
2005, 11.43pm
of India
accounts
for Jula 23,
majority
ofIST,
TBTimes
worldwide
World-at-Night Satellite Image Reveals Economic Activity
Satellite Image of Earth at Night by Craig Mayhew and Robert Simmon,
NASA GSFC http://geology.com/press-release/world-at-night/
• Multidisciplinary approach (biologists, chemists, mathematicians, clinicians)
for developing imaging tracers for infection & inflammation
• Goals
• develop “pathogen-specific” imaging tracers
• monitor the pathogen and their host-microenvironment simultaneously
• track “hideouts” of infections in the body
• better understanding of disease pathogenesis
• Innovative
• uniform cross-species platform for animal studies
• allow unique insights into disease pathogenesis
• expedite bench-to-bedside translation of new therapeutics
• Translational
• diagnosis / monitoring disease
• understand pathogenesis
• multi-compartment PK - phase 0 studies
• personalized medicine
Potential to change how the world sees infections
National Institutes of Health (OD, NHLBI, NIAID)
Thanks
Organization
Mariah Klunk
Jin Lee
Pauline Myles
Alvaro Ordonez
NIAID (DAIDS, CIDI, DMID)
Richard Hafner
Dima Hammoud
Peter Kim
Karen Lacourciere
Dan Mollura
Abstract Reviewers
Kevin Francis (PerkinElmer)
Dima Hammoud (NIH)
Sanjay Jain (JHU)
Philana Lin (Univ. of Pitts)
Speakers
Sanjay Jain (JHU)
Clif Barry (NIH)
Dima Hammoud (NIH)
Marie-France Penet (JHU)
Assaf Gilad (JHU)
Catherine Foss (JHU)
Ed Weinstein (JHU)
Kevin Francis (PerkinElmer)
Lloyd Miller (JHU)
Peter Tonge (Stony Brook Univ.)
Ulas Bagci (NIH)
Bruno Jedynak (JHU)
Welcome
Prof. Chris Meier
Vice-Dean for Research
Faculty of Sciences
University of Hamburg