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18F-Fluorodeoxyglucose positron emission tomography and infectious diseases: current applications and future perspectives

Bassetti, Matteo; Carnelutti, Alessia; Muser, Daniele; Righi, Elda; Petrosillo, Nicola; Di Gregorio, Fernando; Werner, Thomas J.; Alavi, Abass

Current Opinion in Infectious Diseases: April 2017 - Volume 30 - Issue 2 - p 192–200
doi: 10.1097/QCO.0000000000000354
SKIN AND SOFT TISSUE INFECTIONS: Edited by Matteo Bassetti

Purpose of review: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography is a well-established technique for diagnosis and management of a number of neoplastic conditions. However, in recent years the body of literature regarding its potential role in infectious diseases has progressively increased, with promising results.

Recent findings: So far 18F-fluorodeoxyglucose positron emission tomography/computed tomography has a well-established role and is recommended by guidelines only in a few settings, such as prosthetic valve endocarditis, vascular device infections, and chronic osteomyelitis. However, even the lack of large, prospective randomized trials, an increasing number of small series and case reports suggest a potential role in the diagnosis, disease staging, and monitoring of treatment response of several other infective conditions.

Summary: In this article, we summarize the available evidence and potential future applications of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis and management of infectious diseases.

aInfectious Diseases Division, Santa Maria Misericordia University Hospital

bCardiovascular Medicine Division, Santa Maria Misericordia University Hospital, Udine

cNational Institute for Infectious Diseases Lazzaro Spallanzani-INMI IRCCS, Rome

dNuclear Medicine Division, Santa Maria Misericordia University Hospital, Udine, Italy

eDivision of Nuclear Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence to Dr Matteo Bassetti, MD, PhD, Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy. Tel: +39 0432 559355; fax: +39 0432 559360; e-mail: mattba@tin.it

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INTRODUCTION

In the last few years, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has shown an increasing role in nononcologic fields like infective and inflammatory disorders. Infectious diseases are characterized by a wide spectrum of clinical manifestations ranging from mild, nonspecific symptoms to septic shock [1▪]. Common imaging techniques like echography, computed tomography (CT), and magnetic resonance imaging (MRI) provide structural data that may not be sufficient to differentiate infective lesions from other conditions. Moreover, artifacts related to metallic implants may deeply affect the diagnostic accuracy of such methodologies. Combining functional and anatomic data is of great value to confirm/rule out the disease when infection is suspected and to diagnose multiple organ involvement. In this setting, scintigraphic techniques like radiolabeled white blood cell imaging have been developed. Unfortunately, such techniques are affected by a substantial lack of sensitivity particularly in hematopoietic structures [2,3]. Moreover, the planar imaging may affect precise localization and they are usually expensive and time consuming. Techniques based on evaluation of glucose metabolism (FDG-uptake), like PET/CT and more recently PET/MRI, have overcome those limitations, increasing the use of nuclear imaging in the setting of infectious diseases. Finally, assessment of therapy response by serial PET/CT scans can lead to a patient-tailored approach either for the choice of specific drugs in case of failure of first-line therapies or for the proper timing of drug discontinuation. The optimal indications for PET/CT in case of suspected infections and the appropriate time to repeat the scan remains unclear, with information mostly from small retrospective series and a few meta-analyses. In this review, we summarize the evidence for the use and the potential future applications of FDG-PET in the setting of infectious diseases.

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CENTRAL NERVOUS SYSTEM

Central nervous system (CNS) infections represent a major problem in immunocompromised hosts (i.e., patients with HIV/AIDS and patients affected by hematologic malignancies). In patients with HIV infection, differentiation between malignant and infectious CNS lesions is challenging and in many cases requires a brain biopsy to reach a conclusive diagnosis [4]. The first studies suggesting a potential role of FDG-PET/CT in this setting date to the 1990s and reported a significantly greater FDG-uptake in malignant CNS lesions compared with infective foci [5–7]. In a recent prospective analysis involving 10 HIV-positive patients with MRI evidence of equivocal CNS lesions, FDG-PET/CT was demonstrated to be able to correctly differentiate CNS lymphoma (high metabolic activity) from cerebral toxoplasmosis (reduced intralesional metabolic activity compared with adjacent brain parenchyma) when the diagnosis was subsequently confirmed by brain biopsy. Potential pitfalls were found only in one patient presenting with hemorrhagic brain metastases and in one case of progressive multifocal leukoencephalopathy [8]. All together, these data suggest the ability of FDG-PET/CT to differentiate malignant from nonmalignant CNS lesions, potentially avoiding the need for brain biopsy in selected patients. However, the daily use of FDG-PET/CT in clinical practice still requires further investigations in larger prospective cohorts. Moreover, there is a complete lack of information on the potential role of FDG-PET/CT in other kinds of immunocompromised hosts with well-recognized risk factors for opportunistic CNS infections (i.e., hematopoietic stem-cell transplant and solid-organ transplant recipients) [9,10]. In the setting of nonimmunocompromised patients, a recent small study found FDG-PET effective in discriminating brain abscess from necrotizing high-grade gliomas [11]. Isolate case reports have also suggested a potential role of FDG-PET in the diagnosis of meningomyelitis, ventriculitis, herpes simplex virus encephalitis, neurosyphilis, mucormycosis, and neurocysticercosis [12–16].

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RESPIRATORY TRACT

Among all the infective conditions affecting the respiratory tract, pulmonary tuberculosis (TB) represents the field wherein FDG-PET/CT has been more extensively studied. Active tuberculous lesions are generally characterized by a large amount of activated inflammatory cells, resulting in an intense FDG-uptake [17▪]. Unfortunately, as pointed out by a recent meta-analysis, the high sensitivity of FDG-PET is countered by a substantial lack of specificity in distinguishing tuberculous pulmonary lesions from other conditions showing high-glucose metabolism like lung cancer, particularly in endemic areas [18,19]. This scenario is further complicated by the fact that tuberculous nodules may present variable degrees of inflammatory activity, resulting in a wide variability of FDG-uptake and different radiological patterns [20,21]. However, when the diagnosis of TB is well established, FDG-PET/CT has been shown to be highly effective in assessing early treatment response [22]. In particular, a significant decrease in FDG-uptake has been found after 1 month of effective antimicrobial therapy, either in pulmonary and extrapulmonary disease, including lymph nodal and skeletal tuberculosis [22–26]. The opportunity to evaluate early treatment response seems particularly attractive considering the possibility to promptly modify the antimicrobial regimen in patients with multidrug-resistant isolates or the possibility to consider alternative diagnosis in cases without microbiological documentation available [27,28].

A potential role of FDG-PET beyond TB has been recently pointed out in the setting of invasive fungal infections [29]. Pulmonary lesions related to Aspergillus spp. can be responsible for a wide range of clinical manifestations and radiologic patterns potentially mutating one into the other depending on the immune status of the host (Fig. 1). In this misleading scenario, several case reports have described high FDG-uptake in patients with pulmonary aspergillosis [30–35]. Kim et al. retrospectively reviewed 24 consecutive patients with diagnosis of pulmonary aspergillosis presenting with a lung mass or fever of unknown origin who underwent PET/CT evaluation, finding a significant different FDG-PET/CT pattern in invasive and noninvasive forms of aspergillosis. Specifically, invasive forms were characterized by a hypermetabolic nodular pattern, whereas noninvasive forms showed an isometabolic halo or nodular pattern [36]. However, as mentioned above for TB, a nonnegligible overlap of FDG-PET/CT findings exists between pulmonary aspergillosis and lung cancer, making standalone FDG-PET/CT not sufficient for a conclusive diagnosis [37]. Conversely, an attractive role for FDG-PET in pulmonary aspergillosis might be represented by evaluation of treatment response as demonstrated by complete reversion to normality of FDG-PET/CT findings after appropriate antimicrobial therapy for invasive aspergillosis [38,39]. In current clinical practice, radiologic follow-up of aspergillosis is mostly done by serial CT scans and represents a challenge, because patients are frequently affected by underlying pulmonary diseases (i.e., chronic obstructive pulmonary disease, previous TB, cancer) with baseline CT pathologic findings of difficult interpretation [40,41]. In this setting, FDG-PET/CT may represent a very attractive tool, but further investigations with large prospective studies are needed before safely recommending its routinely use.

A possible application of FDG-PET in diagnosis and monitoring of treatment response has been recently described in other pulmonary fungal infections like Pneumocystis jirovecii pneumonia, cryptococcosis, actinomycosis, and coccidiomycosis as well as for the diagnosis and management of atypical mycobacteriosis [42–48].

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CARDIOVASCULAR SYSTEM

Molecular nuclear imaging has a well-established role in the setting of infective endocarditis and has recently been introduced as a major criterion for the diagnosis of prosthetic valve infections in international guidelines (Fig. 2) [49,50]. The diagnosis of infective endocarditis is multiparametric and includes clinical, microbiological, and imaging findings classically summarized in the Duke's criteria [51]. Original Duke's criteria considered echocardiography as the only imaging tool for diagnosis of infective endocarditis. In particular, findings like oscillating intracardiac masses on valves or on implanted material as well as abscess and new dehiscence of prosthetic valves were considered highly suspicious and led to the diagnosis of infective endocarditis if combined with other microbiological (positive blood cultures for typical infective endocarditis organisms) or clinical (i.e., predisposing heart conditions, vascular phenomena) elements. Overall sensitivity of Duke's criteria reaches 80% but significantly decreases to less than 30% when they are applied to prosthetic valve endocarditis (PVE) and pace-maker or implantable cardioverter-defibrillator leads infective endocarditis [52]. This lack of sensitivity is mostly driven by inconclusive or normal echocardiography [53,54].

The addition of FDG-PET to standard echocardiography was shown to significantly improve diagnostic sensitivity and specificity, reducing the rate of misdiagnosed infective endocarditis particularly in the setting of PVE [55,56▪]. Moreover, FDG-PET has shown to be extremely helpful in local and systemic disease staging. Perivalvular extensions can be extremely harmful leading to conditions like complete heart block that requires urgent medical care and are frequently missed by standard echocardiography because of its limited resolution power in case of small abscesses or artifacts preventing a clear evaluation in case of valvular annular calcifications or metallic structures [57]. Whole-body PET scan can also allow for early identification of septic embolisms, coexistence of vertebral osteomyelitis or infective endocarditis associated with occult cancer that may deeply modify the therapeutic approach (i.e., large splenic abscesses or splenic rupture may require splenectomy) [58–60].

Abnormal FDG-uptake should be considered with extreme caution in patients who recently underwent cardiac surgery, because of the postoperatory inflammatory tissue reaction leading to nonspecific increase in glycolytic activity. In this regard, abnormal FDG-uptake around the site of a prosthetic valve implanted less than 3 months before should be considered aspecific [49].

Cardiovascular electronic implanted device infections represent a real challenge for the difficulty in accurate diagnosis and their relevant clinical consequences (need for prolonged antibiotic therapy associated with complete device removal in patients frequently dependent from the device). Infections of the subcutaneous pocket of the device can be easily suspected by clinical examination (presence of local signs of inflammation) whereas infection limited or extending to the electrode leads is extremely difficult to diagnose [61]. Documented vegetations on device leads and positive blood cultures represent the cornerstones of the diagnosis. Presence of aseptic thrombi along the lead course is a common finding but their differentiation from septic vegetations in patients with unexplained fever can be extremely challenging. In this difficult setting, FDG-PET was shown to be able to confirm the spread of infection along the cardiovascular electronic implanted device. As mentioned above for PVE, even in this setting, abnormal FDG-uptake between 4 and 8 weeks after device implantation should be considered with extreme caution [62].

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BONE-RELATED INFECTIONS

Although acute osteomyelitis usually does not represent a diagnostic challenge by putting together local signs of inflammation (i.e., reduced motion, pain, and tenderness of the involved bone) with conventional imaging findings, accurate diagnosis of chronic osteomyelitis is often difficult [63]. Chronic osteomyelitis is a severe orthopedic complication which may be extremely difficult to diagnose and treat, particularly in presence of pre-existing alterations because of previous trauma or surgery. Compared with conventional imaging or other nuclear medicine modalities, FDG-PET has shown a robust sensitivity and specificity reaching 96 and 91%, respectively, in a published meta-analysis [64]. More recently, another large meta-analysis by Wang et al.[65] confirmed this result, finding a pooled sensitivity and specificity of approximately 92% for the diagnosis of chronic osteomyelitis compared with other radionuclide imaging modalities like labeled leukocyte scintigraphy, thus supporting the routine use of FDG-PET/CT in clinical practice.

In the subset of spondylodiscitis FDG-PET/CT should probably be considered the imaging modality of choice having demonstrated an overall sensitivity of 97% and specificity of 88% even in patients treated with antibiotics prior to imaging [66▪▪,67,68] or in cases of uncommon pathogens like Mycobacterium tuberculosis or Brucella[69–71]. Interestingly, FDG-PET was demonstrated to be capable to distinguish degenerative disc changes from infection, and is unaffected by the presence of metallic implants, which may limit the diagnostic accuracy of other imaging modalities (Fig. 2) [66▪▪]. Moreover, FDG-PET/CT has recently shown a higher performance compared with MRI in early diagnosis of spondylodiscitis within 2 weeks after symptoms onset [72]. The potential role of FDG-PET/CT in evaluation of treatment response has been proposed and looks extremely attractive in a condition that often requires several months of antibiotic treatment, but larger, prospective studies are required [73–75].

Prosthetic joint infections represent a relevant clinical problem and a diagnostic challenge. The risk of infective complications after initial arthroplasty is estimated within 1–4% and approximately 25% after revision arthroplasty. Moreover, even if approximately 10% of patients suffer from chronic pain after surgery, only 1% is finally diagnosed having a periprosthetic infection [76]. Aseptic loosening is a common long-term complication of hip arthroplasty related with significant chronic pain and it can be extremely difficult to differentiate from superimposed infection. Standard FDG-PET imaging (not PET/CT) is highly sensitive and is not affected by artifacts caused by metal implants. Unfortunately, noninfectious reactions around the neck of the prosthesis are common findings even years after surgery [77]. Consequently, increased FDG-uptake in this location should not be considered suggestive of infection whereas infections usually show increased FDG-uptake at the interface between prosthesis and bone. According to this finding, patterns of FDG-uptake seem to be more important than intensity of uptake in differentiating septic and aseptic loosening [78]. Imaging with FDG-PET/CT has been reported also for the diagnosis of implant-related infections, as suggested by studies conducted both in murine models and humans [79,80]. The major limitation is represented by early diagnosis of postsurgical and posttraumatic osteomyelitis due to a substantial lack of specificity for differentiating acute infection from sterile inflammatory reaction related to normal healing, particularly during the first 2 weeks after surgery/trauma [81,82].

In complicated diabetic foot, FDG-PET/CT has been demonstrated not only to be highly sensitive in excluding osteomyelitis but also highly specific in differentiation from Charcot neuropathy compared with MRI that often shows misleading findings caused by soft tissue edema [83–85].

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FUTURE PERSPECTIVES

Monitoring of treatment response currently represents the most promising application of FDG-PET/CT in the setting of infectious diseases [86]. Establishing optimal treatment duration is of great value considering potential drug toxicity, resistance selection, and healthcare costs related to prolonged antibiotic therapies. While evaluating infective lesions, FDG-PET analysis is often based on visual-normalized interpretation with only a few reports analyzing a quantitative approach and a substantial lack of standardized methods [87]. Quantitative FDG-PET analysis has been proven to be more sensitive and specific than visual-normalized interpretation and to be superior in the evaluation of response to therapy in noninfective disorders like sarcoidosis and hematologic malignancies [88]. Visual reduction of FDG-uptake has already been associated with treatment response in various conditions like pulmonary tuberculosis, aspergillosis, and spondylodiscitis. However, it remains to be determined how quantitative changes in FDG-uptake are associated with improved clinical outcomes as well as the clinical relevance of persistent residual FDG-uptake after effective treatment. Moreover, even if available data on tuberculosis and spondylodiscitis suggest the possibility of observing a significant reduction of FDG-uptake after only 1 month of effective therapy, the optimal timing for serial FDG-PET/CT scans has not been established yet. In the future, quantitative parameters taking into account the extension of inflammation in terms of FDG-avid lesion volume (metabolic volume) and/or product of standardized uptake value and lesion volume (glycolytic activity) may help to accurately assess the severity of the disease and objectify treatment response guiding escalation/de-escalation therapy and treatment duration. The potential advantages and limitations of FDG-PET/TC in different settings in infectious diseases are reported in Table 1. Table 2 describes some possible fields of application of FDG-PET/TC for the management of infectious diseases into the everyday clinical practice.

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CONCLUSION

The data presented in this review clearly demonstrate how FDG-PET/CT will increasingly play a major role in the assessment of patients affected by a wide range of infectious diseases like osteomyelitis, infected prostheses, endocarditis, and even lung and CNS infections. FDG-PET has proven to be an excellent imaging modality not only for the diagnosis, but also for the staging and evaluation of treatment response overcoming many limitations associated with structural imaging techniques or conventional scintigraphic methodologies. The ability of FDG-PET to quantify disease activity seems particularly attractive, providing the possibility to avoid invasive diagnostic tests, to identify multifocal infection and to monitor early response to antibiotic treatment. At this juncture, FDG-PET should be used to improve the clinical management of infectious disorders although further validation with prospective randomized/controlled studies is strongly encouraged.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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Keywords:

18F-fluorodeoxyglucose positron emission tomography; infection; treatment monitoring

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