Molecular Imaging of Infections: Advancing the Search for the Hidden Enemy

Abstract

Even before the coronavirus disease 2019 pandemic, infections were a major threat to human health, as the third leading cause of death and the leading cause of morbidity among all human diseases. Although conventional imaging studies are routinely used for patients with infections, they provide structural or anatomic information only. Molecular imaging technologies enable noninvasive visualization of molecular processes at the cellular level within intact living subjects, including patients, and hold great potential for infections. We hope that this supplement will spur interest in the field and establish new collaborations to develop and translate novel molecular imaging approaches to the clinic.

Infections remain a major threat to human health and they are a leading cause of death and disability [1]. Even before the coronavirus disease 2019 pandemic, more than 8 million people died and almost 400 000 years of life were lost every year across the globe due to infections. Infectious diseases are the third leading cause of mortality and the main cause of morbidity among all human diseases [2]. Structural (conventional) imaging studies such as chest x-rays, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are routinely used for the management of patients with infections, because they provide a noninvasive and rapid readout and allow longitudinal monitoring. These imaging techniques, although of enormous value in providing “pictures”, represent only one component of the type of information that can be obtained through “imaging”. Molecular imaging technologies allow noninvasive visualization, characterization, and quantification of cellular and subcellular molecular processes in living subjects, including animal models and patients. Those technologies can thus powerfully augment the pictures of conventional imaging. Those imaging modalities have already been proven to be of enormous value in cardiovascular disease, neurology, and oncology and are now just being applied to the study of infectious diseases. Characteristics of common imaging approaches are outlined in Table 1.

Table 1.

Available Imaging Approaches

Imaging technique	Molecular (M) or Structural (S) Imaging	Signal source	Sensitivity (mol/L)	Cost	Comments
Radiography	S	X-rays	N/A	Low	Radiation; Inter and intra-reader variability; digital computer-assisted tools available
Computed Tomography (CT)	S	X-rays	N/A	Moderate	Radiation; High spatial resolution, low tissue contrast; digital computer-assisted tools emerging
Ultrasonography	S, M	Sound waves	Variable (improved with microbubbles)	Low-medium	No radiation; Operator dependent; portable
Magnetic Resonance Imaging (MRI)	S, M	Radio waves (Hydrogen-1, Fluorine-19, hyperpolarized Carbon-13)	Micro- to millimolar	High	No Radiation; Excellent tissue contrast and spatial resolution
Single-Photon Emission Computed Tomography (SPECT)	M	Gamma rays (Technetium-99m, Indium-111, Gallium-67, Iodine-123)	Nano- to picomolar	Moderate	Radiation; low spatial resolution
Positron Emission Tomography (PET)	M	511 KeV Photons (Fluorine-18, Gallium-68, Carbon-11, Zirconium-89 Iodine-124)	Nano- to picomolar	High	Radiation; low spatial resolution
Optical Imaging	M	Fluorescence, bioluminescence	Pico- to femtomolar	Low	Limited depth penetration, mainly applicable to imaging of small animals or superficial sites only; generally 2D

Among the various molecular imaging technologies, nuclear medicine techniques (single-photon emission computed tomography [SPECT] and positron emission tomography [PET]) are the most commonly used and most likely to get translated to the study of infectious diseases. Radiopharmaceutical molecular imaging is based on “tracers” that chemically interact with specific biological systems and are spatially localized by accurately measuring the energy source from the radiolabel bound to the imaging tracer. The SPECT and PET scanners provide 2- or 3-dimensional quantitative readouts which reflect the molecular changes occurring within the area(s) of interest. Similar approaches utilizing magnetic resonance spectroscopy and related technologies can be performed without radiation exposure, albeit at a much lower sensitivity. All of these molecular imaging approaches open exciting new avenues for precision medicine, including early detection, diagnosis, and monitoring of diseases. They also provide tools to enhance our understanding of basic biology and pathogenesis. A very important advantage of molecular imaging is the 3-dimensional visualization of the subject, which better reflects the entire disease process and thus significantly decreases the likelihood of sampling errors associated with local targeting of affected organs (Figure 1).

Figure 1.

Comparison of traditional and molecular imaging approaches for infections. Adapted with permission from Ordonez et al Sci Transl Med [3]. Copyright 2019 The American Association for the Advancement of Science.

More importantly, the recently developed specific molecular imaging approaches for cancer have clearly demonstrated the added value of these imaging approaches for the management of patients, and they could be a model for developing similar complementary imaging approaches for infections. For example, estrogen receptor (ER) is an important target for breast cancer, and the gold standard for determining ER status has been pathology. However, obtaining tissue samples requires an invasive procedure and only provides information on individual lesions. ¹⁸F-Fluoroestradiol (¹⁸F-FES) is a newly approved molecular imaging agent that targets ER with high specificity [4]. Therefore, whole-body ¹⁸F-FES PET is being used to not only detect ER⁺ breast cancer and metastasis throughout the body, but also to drive ER-specific treatments for breast cancer as well as significantly contributing to clinical decision making when conventional imaging is equivocal and biopsy is difficult [5]. Similarly, molecular imaging agents that target prostate-specific membrane antigen, regarded as a marker of prostate cancer cells, have significantly improved the management of patients with prostate cancer [6], given that currently approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence. A PET/CT study with a recently approved PET agent, ¹⁸F-DCFPyL, localized disease in the setting of negative standard imaging, providing clinically meaningful and actionable information in men with biochemical recurrence of prostate cancer [7]. In a similar manner to the above-mentioned examples, novel molecular imaging approaches for infection may provide a uniform cross-species platform for animal and human studies, allowing unique insights into understanding the pathogenesis of infections [8, 9]. In addition, these approaches could be applied to patient management for the diagnosis of specific infections [10], therapeutic drug monitoring [11], and following response to treatment [10, 12].

Imaging work with infectious pathogens requires trained personnel and often specialized facilities. Working with pathogens designated as biosafety level-3/4 (BSL-3/4) by the US Centers for Disease Control and Prevention may require highly specialized containment, trained personnel, and regulatory approvals. For the purposes of preclinical molecular imaging, biocontainment has been achieved by placing the scanners inside the BSL-3/4 barrier (eg, National Institute of Allergy and Infectious Diseases, University of Pittsburg) or the use of portable biocontainment cells that can seal infected-animals within, and which can be transported safely to and from the imaging suite (housed in standard environments) [13, 14]. One group has used polycarbonate plastic tubes extending from the biocontainment space to the imaging equipment [15]. Although local guidelines need to be considered, use of biocontainment cells for animals rather than placement of scanners inside the BSL-3/4 barrier allows for easier maintenance of the equipment, which can also be shared with other investigators who do not work within the BSL-3/4 barrier.

This supplement was inspired by a series of workshops and meetings focusing on molecular imaging of infectious diseases and brings together leading investigators from several disciplines to summarize recent advances in the field of imaging infectious diseases. Development and utilization of molecular imaging approaches for infectious diseases holds great potential and may be well informed by what has been done in other fields. We hope that this supplement will spur interest in the field and establish new collaborations to develop and translate novel molecular imaging approaches to the clinic.

Notes

Author contributions. DAH and SKJ wrote the initial draft and all authors edited the manuscript.

Financial support. DAH and HCL are supported through the Intramural Research Program at the National Institutes of Health (NIH). SKJ is supported by the NIH Grants R01-AI145435-A1 and R01-AI153349.

Supplement sponsorship. This article appears as part of the supplement “Seeing Is Believing: The Potential of Molecular Imaging Approaches for Infectious Diseases,” sponsored by the Center for Infectious Disease Imaging, Clinical Center, NIH (Intramural Research Program), and the Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, with individual contributions from Long Island Jewish Medical Center; University of California, San Francisco; and University of Maryland School of Pharmacy.