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Imaging the Infected Heart Cannot Di Erentiate Between In Ammation Caused by Microorganisms Or by Noninfec- Tious Diseases

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Imaging the Infected Heart Cannot Di Erentiate Between In Ammation Caused by Microorganisms Or by Noninfec- Tious Diseases FOCUS BACTERIAL ENDOCARDITIS or di use infection. In other words, simply visualizing the presence of immune cells Imaging the Infected Heart cannot di erentiate between in ammation caused by microorganisms or by noninfec- tious diseases. Abass Alavi,1* Babak Saboury,1 Sandip Basu2 E orts to radiolabel bacteria at the sites This Focus discusses the merits of modern imaging techniques for the management of of infection have yielded minimal success, patients with suspected or proven infection and also addresses the challenges of detecting and most have not been translated into the infective endocarditis early. clinic. is approach was adopted using single gamma-emitting radionuclides at- tached to bacteria-targeting compounds, THE EVOLUTION OF IMAGING ated with altered glycolysis, such as central including antibiotics (5). In recent years, e current generation of structural imag- nervous system disorders, cancer, and in- e orts have been made to use positron- ing techniques, including magnetic reso- a m m a t i o n . emitting radiotracers instead because of nance imaging (MRI) and computed to- We discuss in detail in this Focus recent favorable physicochemical characteristics. mography (CT), provides anatomical scans e orts to image infection and in amma- With the radiolabled tracers, it is clear that with exquisite detail and high spatial reso- tion, including recent papers on detecting positive results, which were reported by lution. However, many diseases start at the acute infective endocarditis with advanced this approach, mostly re ected nonspeci c molecular and cellular levels, which may imaging methods, such as PET. leakage of the labeled agents at the sites of never translate to gross structural abnor- infection owing to the presence of a large malities. ese technologies have proven VISUALIZING INFECTION AND number of leaky vessels. In other words, to be insensitive for early detection of sev- INFLAMMATION similar and positive results would be ex- eral diseases, including cancer, when thera- In the 1930s, Warburg discovered increased pected to be noted from inert preparations peutic intervention would be desirable. In glycolysis in cancer cells in vitro. It was not- with no known attraction to the site, such addition, because of the low sensitivity of ed therea er that in ammatory cells also as radiolabeled albumin. erefore, there is structural imaging methods, the e ects of have high glycolytic activity that is similar some consensus that compounds that tar- on September 9, 2011 systemic therapy cannot be adequately as- to that of malignant cells (2–4). In recent get bacteria and other microorganisms may sessed, which is pivotal to clinical decision- years, the range of disorders with aberrant not be promising enough to be pursued fur- making. In medicine, it is not uncommon glycolysis that can be assessed by means ther at this time. to encounter suboptimal or no response of FDG-PET has increased and comprises ere are two possible options for visu- to treatment, particularly for infectious common infections (such as an infected alizing in ammatory cells at the infected diseases. As such, undue delays in using prosthesis, osteomyelitis, or a diabetic foot) sites. One method is to label a patient’s alternate therapies may result in further and noninfectious in ammatory disorders, white cells ex vivo, reinfuse them intra- progression of the disease as well as un- such as rheumatoid arthritis, regional il- venously, and monitor cell migration to stm.sciencemag.org desirable side e ects from the initial treat- eitis, sarcoidosis, and atherosclerosis (4). the infected lesions by using conventional ment. ere is thus a dire need for imaging FDG as a unique tracer has been used ex- scintillation cameras. Unfortunately, there approaches that detect disease at the mo- tensively for identi cation of infected sites are serious shortcomings to this approach. lecular and cellular levels during the early in the human body and for monitoring re- e procedure is very time-consuming (3 stages of pathogenesis. sponse to treatment (3, 4). to 5 hours for labeling, 24 hours for imag- In the 1970s, investigators noticed that Two types of biological structures at the ing), which results in many nonfunctional the agent 18F- uorodeoxyglucose (FDG) site of infection can be targeted with exter- cells. In addition, the image quality is very was able to measure glucose metabolism nal imaging. One is microorganisms, such poor (nontomographic), and the radiation Downloaded from in vivo quantitatively and in a dynamic as bacteria; the other is in ammatory cells dose to the sensitive organs is unacceptably manner, thus opening a new era in medical that home to the infected site. Although high. e other option is to label white cells imaging at the molecular level (1). By that either of these could potentially serve as a with positron-emitting compounds, such as time, positron emission tomography (PET) reliable source for targeted imaging, there FDG, and to image with PET. is method had also emerged as a promising modality are major di erences between the two with has also experienced minimal success. Be- for imaging the biodistribution of labeled regard to modern imaging techniques. For cause of these limitations to ex vivo labeling compounds in the clinic. Ever since, FDG– example, the volume of microorganisms and positron-emitting labels, others have PET has been the workhorse for imaging that reside at these sites is extremely small explored radiolabeled nanoparticles and glucose metabolism and has played a major and provides limited options for detecting FDG for visualizing immune response and role in examining disorders that are associ- the infected areas (because few binding sites in ammation. Further research is needed to are available). Conversely, imaging in am- determine the viability of this nanoparticle- 1Radiology Department, Division of Nuclear Medicine, matory cells has proven to be relatively ef- based technique for routine use in humans. University of Pennsylvania School of Medicine, Phila- fective, as shown by a variety of approaches, delphia, PA 19104, USA. 2Radiation Medicine Centre in particular functional imaging techniques FOCUSING IN ON ENDOCARDITIS (BARC), Tata Memorial Hospital Annexe, Parel, Mumbai, 400012, India. that use radiotracers. Nevertheless, detect- In spite of the successes made by modern *Corresponding author. E-mail: Abass.Alavi@uphs. ing in ammatory cells is nonspeci c and imaging techniques in detecting infections upenn.edu provides indirect evidence at best for local in many organs, their role in visualizing www.ScienceTranslationalMedicine.org 7 September 2011 Vol 3 Issue 99 99fs3 1 FOCUS endocarditis has been limited. A e observations made in Acute endocarditis is classi- mice with experimental endo- cally de ned as in ammation carditis using both FMT-CT and of the endocardium (inner lay- PET-CT imaging are intrigu- er of the heart) and is a major ing and innovative and may clinical problem that progresses provide a powerful means for rapidly. Vegetations, the hall- assessing this potentially life- mark lesions of endocarditis, threatening infectious disease are composed of platelets, - B in humans. It is important mov- brin, microorganisms, and ing forward that this approach inammatory cells. Endocardi- be tested in larger animals in tis occurs as a result of implan- order to determine the merit of tation of circulating bacteria on optical imaging in detecting le- the cardiac or aortic valves that sions that are distant from the have entered the bloodstream imaging devices. Translation of from the mouth cavity or the this approach would also entail gastrointestinal tracts. More- further clarifying the speci city over, preexisting damage to the of this tracer for S. aureus and valve is considered a predispos- no other bacteria. Panizzi et al. ing factor for infection. Of all of tested their agent in coagulase- the modern structural imaging negative S. epidermidis–infected techniques, echocardiography mice, which argues for the spec- (particularly the transesopha- i city of the agent. However, the geal approach) has been the Fig. 1. The role of PET-CT in imaging infection. (A) Transaxial and (B) fact that the S. epidermidis veg- most successful in identifying coronal FDG-PET-CT in a 47-year-old woman with infective endocardi- etations accumulated a small vegetative lesions present in the tis. PET images are on the left; the fused PET-CT images are on the right. amount of tracer (albeit much on September 9, 2011 valves of the heart and the aorta Focal FDG uptake in the heart is noted by arrows in the region of the less than S. aureus) would be in patients with endocarditis. aortic valve. Reproduced with permission from (7). one reason to examine this in Unfortunately, because of the larger vegetation to ensure that small size of the lesions (several the partial-volume e ect com- millimeters), a large number of lesions go aged endothelium) and uoresced brightly mon to imaging is not playing a role in the undetected. In addition, structural imag- in ex vivo sections of the mouse aortas (6). minimal visualization of vegetation. ing is nonspeci c, cannot di erentiate be- A faint response was also noticeable in mice tween active and inactive infection, and is infected with coagulase-negative Staphylo- TRANSLATIONAL CHALLENGES AND stm.sciencemag.org unable to assess response to systemic ther- coccus epidermidis, but none at all was seen PROSPECTS apy. erefore, there is an unmet need for in uninfected control mice. FDG in combination with PET-CT has also methodologies that allow timely detection e goal is to use this noninvasive imag- been used to identify vegetative lesions in the of endocarditis and its complications, such ing method for diagnosis of endocarditis in human heart, as well as at distant sites, owing as embolic lesions at distant locations, and humans. To this end, the authors used their to embolization of detached lesions (7–10). also monitor response to treatment.
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