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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, TH E 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

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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 in
ammatory 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. prothrombin probe with
uorescence mo- FDG binds to both clots and in
ammatory A recent technical report by Panizzi et lecular tomography combined with x-ray cells and has therefore been used with great al. (6) describes in vivo detection of en- computed tomography (FMT-CT) to im- interest. Early clinical trial observations us- Downloaded from docarditis caused by coagulase-positive age bacterial growths in vivo in living mice. ing FDG-PET show promise for the routine, Staphylococcus aureus, which is the most  ey were able to con rm the presence of noninvasive detection of endocarditis (7–10). dangerous and virulent type that might not such vegetations 24 hours a er injection As shown in Fig. 1, FDG-PET-CT was used respond readily to treatment.  e authors with high speci city and high signal over to detect suspected infective endocarditis in a introduce an interesting method that incor- background when compared with various 47-year-old woman (7). One hour a er injec- porates both noninvasive
uorescence and control animals. Furthermore, Panizzi and tion, there was substantial uptake of FDG in PET imaging to visualize growing bacte- colleagues were able to visualize in vivo the the infected areas of the aortic valve, which rial vegetations. First, a mouse model of S. response to treatment with the antibiotic was con rmed with separate blood cultures aureus endocarditis was developed that re- vancomycin, which resulted in a decrease in to be coagulase-negative Staphylococci. Other capitulates the bacterial lesions seen in the signal over the course of 48 hours. Lastly, a single-case studies have described the appli- human condition. Because S. aureus is able new prothrombin-based probe was gener- cability of FDG-PET for diagnosing infection to induce blood coagulation via staphyloco- ated for PET-CT imaging, which allowed for in the heart (8–10), especially when echocar-

JOU R N A L O F U C LE D I LOG Y agulase, Panizzi et al. created a
uorescent radiological imaging with standard instru- diography presents unclear results, such as in prothrombin-based probe that could be ac- mentation widely available in clinics.  is the case of patients with prosthetic vales or tivated in vivo by the enzyme. When inject- radiolabeled prothrombin probe was simi- indwelling pacemakers (7). : S P R IN GE / ed into mice with endocarditis, the probe larly able to con rm the presence of vegeta-  e method described by Panizzi et al.

C R E D IT deposited at the sites of vegetation (dam- tions in damaged aortas in living mice. allows for concurrent imaging to detect

www.ScienceTranslationalMedicine.org 7 September 2011 Vol 3 Issue 99 99fs3 2 FOCUS vegetative lesions and con rmation of the several millimeters under ideal conditions) 4. S. Basu, T. Chryssikos, S. Moghadam-Kia, H. Zhuang, D. type of bacteria present by use of the pro- in detecting small lesions will prevent the A. Torigian, A. Alavi, Positron emission tomography as a diagnostic tool in infection: Present role and future pos- thrombin dye.
is multifaceted approach is accurate diagnosis of endocarditis. To over- sibilities. Semin. Nucl. Med. 39, 36–51 (2009). promising for early detection and treatment come further deterioration of image qual- 5. K. E. Britton, D. W. Wareham, S. S. Das, K. K. Solanki, H. in humans; however, further validation will ity owing to cardiac motion, gated imaging Amaral, A. Bhatnagar, A. H. Katamihardja, J. Malamitsi, be needed to assess its utility in routine di- based on cardiac cycle by using ECG may H. M. Moustafa, V. E. Soroa, F. X. Sundram, A. K. Padhy, Imaging bacterial infection with (99m)Tc-ciprofl oxacin agnosis.
e major concern is that a very improve image resolution and, in turn, the (Infecton). J. Clin. Pathol. 55, 817–823 (2002). small fraction of the vegetations might be sensitivity of the PET-based approach. As- 6. P. Panizzi, M. Nahrendorf, J. L. Figueiredo, J. Panizzi, B. stained super cially with the compounds sessing global disease activity in the entire Marinelli, Y. Iwamoto, E. Keliher, A. A. Maddur, P. Water- described, which may not be resolved by ex- heart may prove to be a possibility in this man, H. K. Kroh, F. Leuschner, E. Aikawa, F. K. Swirski, M. isting PET imaging instruments.
erefore, setting. J. Pittet, T. M. Hackeng, P. Fuentes-Prior, O. Schneewind, P. E. Bock, R. Weissleder, In vivo detection of Staphy- there is a need for novel imaging e orts that As described in this Focus, there are sev- lococcus aureus endocarditis by targeting pathogen- overcome some of the de ciencies associ- eral emerging and novel approaches to di- specifi c prothrombin activation. Nat. Med. (2011). ated with PET and CT.
e major challenges agnosing and treating infective endocarditis 10.1038/nm.2423 of visualizing relatively small lesions, such early (6–10). Large-scale, prospective multi- 7. S. H. Vind, S. Hess, Possible role of PET/CT in infective en- docarditis. J. Nucl. Cardiol. 17, 516–519 (2010). as vegetations due to endocarditis in the center trials should be carried out to de ne 8. S. Moghadam-Kia, A. Nawaz, B. C. Millar, J. E. Moore, S. heart and aortic valves, are twofold: the size the merits of these novel imaging methodol- E. Wiegers, D. A. Torigian, S. Basu, A. Alavi, Imaging with of the abnormalities to be detected and the ogies in the near future. Until more human (18)F-FDG-PET in infective endocarditis: Promising role constant rhythmic motion of the heart. Al- trials are undertaken, the potential role and in diffi cult diagnosis and treatment monitoring. Hell. J. 12 though modern structural imaging modali- bene t of such approaches in the clinic will Nucl. Med. , 165–167 (2009). 9. R. F. Yen, Y. C. Chen, Y. W. Wu, M. H. Pan, S. C. Chang, Using ties, such as CT and ultrasound, have high remain unclear. 18-fl uoro-2-deoxyglucose positron emission tomogra- spatial resolution and can generate scans phy in detecting infectious endocarditis/endoarteritis: A quickly, they lack high-contrast resolution REFERENCES AND NOTES preliminary report. Acad. Radiol. 11, 316–321 (2004). and therefore su er from low sensitivity in 1. J. B. Alavi, A. Alavi, J. Chawluk, M. Kushner, J. Powe, W. 10. J. Van Riet, E. E. Hill, O. Gheysens, S. Dymarkowski, M. C. detecting these lesions. Hickey, M. Reivich, Positron emission tomography in pa- Herregods, P. Herijgers, W. E. Peetermans, L. Mortelmans, tients with glioma: A predictor of prognosis. Cancer 62, (18)F-FDG PET/CT for early detection of embolism and

PET-CT has the greatest potential for on September 9, 2011 1074–1078 (1988). metastatic infection in patients with infective endocar- 37 overcoming these de ciencies and should 2. H. Zhuang, M. Pourdehnad, E. S. Lambright, A. J. Yama- ditis. Eur. J. Nucl. Med. Mol. Imaging , 1189–1197 (2010). be pursued as a viable option for managing moto, M. Lanuti, P. Li, P. D. Mozley, M. D. Rossman, S. M. patients with this serious heart infection. Albelda, A. Alavi, Dual time point 18F-FDG PET imaging Newly developed PET compounds should for diff erentiating malignant from infl ammatory pro- cesses. J. Nucl. Med. 42, 1412–1417 (2001). 10.1126/scitranslmed.3003044 label the entire lesion and not bind super- 3. S. Basu, A. Alavi, Unparalleled contribution of 18F-FDG cially to the surface. At present, the sub- PET to medicine over 3 decades. J. Nucl. Med. 49, 17N– Citation: A. Alavi, B. Saboury, S. Basu, Imaging the infected optimal spatial resolution of PET (around 21N, 37N (2008). heart, Sci. Transl. Med. 3, 99fs3 (2011). stm.sciencemag.org Downloaded from

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