Introduction
Invasive fungal infections (IFIs) often occur in immunosuppressed patients and can be life-threatening. Timely monitoring of the efficacy of antifungal drugs in patients with IFIs is crucial. There are only a few classes of antifungals available, and it is crucial to preserve the effectiveness of these agents [
1]. Antifungal drugs are costly and frequently accompanied by severe and sometimes intolerable side-effects. Patients with IFIs are usually treated for extensive periods (months to sometimes even years), and the duration of treatment is not standardized. Inappropriate treatment with antifungal agents may potentially result in potential fungal disease and can induce resistant fungi, which increase morbidity or mortality [
1‐
3]. Morbidity and mortality for IFIs vary considerably depending on the type of IFI and underlying disease predisposing to IFI [
4,
5]. The mortality rates for the most common organisms causing IFIs are usually about 30% [
5]. Inadequate treatment of IFIs may result in dissemination of the infection during immunosuppressive procedures such as intensive chemotherapy or stem-cell transplantation that are often used to treat underlying conditions associated with IFIs. It is therefore critical to determine in a timely manner whether the antifungal treatment regimen is adequate or whether modification of therapy is required. Imaging techniques provide a non-invasive method to determine treatment response and therefore can be used as treatment follow-up of IFIs. Anatomical imaging, particularly with (chest and abdominal) computed tomography (CT) but also with brain magnetic resonance imaging (MRI), is usually used for the management of IFIs [
4,
6]. However, the anatomical changes associated with IFIs may persist for long periods, even after adequate treatment, thereby potentially delaying any further therapy that may be required for the underlying disease [
2]. Functional imaging with 2-fluorodeoxyglucose positron emission tomography integrated with CT (FDG-PET/CT) has been found useful in the monitoring of IFIs in a relatively small numbers of studies and case reports available on this topic [
2].
FDG-PET/CT has been used to monitor treatment in mainly oncological diseases but more recently also in infectious diseases [
7]. In monitoring disease, FDG-PET/CT has the advantage of using metabolic indices which provide absolute quantification of the disease [
8]. The metabolic indices have also been shown to have prognostic value in different diseases [
9,
10]. Most widely used is the maximum standardized uptake value (SUVmax). Other indices include the mean standardized uptake value (SUVmean), peak standardized uptake value (SUVpeak), metabolic volume (MV) and total lesion glycolysis (TLG). Each of these parameters has its advantages and limitations, and there is no real agreement which is the best parameter to use. SUVmean, MV, and TLG utilize the uptake from the whole lesion rather than the highest voxel for SUVmax or the highest uptake in a 1-ml volume (SUVpeak), and may be more representative of disease burden in the lesion. TLG and MV have been evaluated in oncology and more recently in inflammatory processes [
9‐
12]. TLG was found to be reproducible and highly correlated with other PET metrics in the assessment of the response of treatment [
8]. To the best of our knowledge, metabolic parameters such as TLG and MV have not been investigated in infections.
In this study, we (1) examine the role of serial FDG-PET/CT in monitoring IFIs for therapy decision-making, and (2) evaluate the role of the baseline metabolic parameters in predicting the metabolic response to antifungal treatment.
Material and methods
We retrospectively assessed the electronic dossiers of patients with definite or suspected IFIs who had more than one FDG-PET/CT. The requirement for informed consent for this retrospective study was waived by the local institutional review board (UMCG research register number 201600073). Baseline FDG-PET/CT was defined as an FDG-PET/CT performed before or within 2 weeks of the initiation of antifungal therapy. Patients with a definite diagnosis of IFI had fungi cultured at the beginning or during the course of their treatment. Patients who were diagnosed as clinical IFI had a clinical suspicion of IFI with or without positive serological markers for IFIs, and showed improvement on antifungal treatment and clinical follow-up. For treatment evaluation, FDG-PET/CT was only performed when the treating clinician felt the need to evaluate the IFI with imaging. We included patients who had at least two FDG-PET/CT scans (one at baseline, and one or more during treatment). In each patient included in the study, two or more FDG-PET/CT scans at different time points (one at baseline, and one or more during treatment) were performed. The study was conducted at the University Medical Center Groningen, the Netherlands, and the period covered was from October 2009 until March 2018. This time period was chosen since in October 2009 a PET/CT camera system was installed at our center. Patients with no baseline FDG-PET/CT scan, more than 2 weeks interruption of their antifungal therapy between the serial FDG-PET/CT scans, and no lesion on their baseline scans, such as those with only blood-borne IFIs with no tissue localization, were excluded.
Review of medical records
The following data were retrieved from the electronical patient files: (1) the microbiology (serology, microscopy, and culture) and pathology (biopsy or surgical excised lesion) that resulted in the identification of IFI, (2) any other imaging that was performed within 2 weeks of each FDG-PET/CT, (3) any procedure that was performed as a result of the FDG-PET/CT scan, (4) start date and duration of antifungal therapy, (5) changes in treatment, (6) whether the patient was dead or alive at the time of data collection, and (7) date and cause of death were documented. We also reviewed the computer-based patient dossiers to determine what decision had been made based on the FDG-PET/CT scan results.
FDG-PET/CT acquisition for IFIs
All scans were performed according to the EANM procedure guideline for FDG-PET/CT studies [
13]. Patients fasted for at least 6 h before the study. The blood glucose was checked to be less than 11 mmol/l before the injection of 3 MBq/kg
18F-FDG. PET images were acquired on a research 4 Life (EARL)-accredited integrated PET/CT camera system (Biograph mCT 64 slice PET/CT, Siemens, Knoxville, TN, USA) approximately 1 h after injection of the FDG. Patients were imaged from mid-thigh to vertex of the skull with 3 min per bed position. Low-dose CT was performed for attenuation correction and anatomical localization with the following settings: tube voltage reference 100 kV (adjusted to 80–140Kv as per departmental protocol) with Siemens CarekV switched on, gantry rotation time of 0.5 s, pitch factor of 1, automated exposure control switched on during all acquisitions (Siemens CARE Dose4D), with a quality reference tube-current product of 30mAs (adjusted to 20–50mAs as per departmental protocol). CT images were not enhanced with contrast.
Analysis of FDG-PET/CT scans
Images were interpreted by experienced nuclear medicine physicians as part of routine clinical care, using Syngo.Via software (Siemens Healthcare, Erlangen Germany). Each scan was re-evaluated by a nuclear physician (AA) who was blinded to the original FDG-PET/CT interpretations. The parameters TLG, MV, SUVmax, and SUVpeak were pre-defined in the Syngo.Via software. For each FDG-PET/CT study, lesions due to IFI were identified, the number of lesions were counted, and volume of interests (VOIs) were drawn around the lesions. IFI lesions were defined as abnormal focal lesions with or without hypometabolic center not related to any procedure or other existing pathology. TLG, MV, SUVmax, and SUVpeak was recorded for every lesion due to IFI for each FDG-PET/CT study. The findings of this second reading by the blinded nuclear physician (AA) were compared to the original FDG-PET/CT reports and any discrepancies were resolved by an independent nuclear physician (AWJMG).
The TLG of the individual IFI lesions were summed for each scan to calculate the global TLG for every FDG-PET/CT study. The global MV of the IFI on each scan was also determined by the summation of the MV of the individual lesions. The overall SUVmean of the lFI lesions was calculated by dividing the global TLG by the global MV. The highest SUVmax and SUVpeak for each study were also recorded. SUVmax, SUVpeak, and TLG were corrected for glucose by the formula (parameter × 5/blood glucose in mmol/l) according to the EANM standards.
The responses of IFIs to treatment were classified into three groups based on FDG-PET/CT findings on the final study: (1) patients with a complete metabolic response (CMR), (2) with a partial response, and (3) patients with progression of the infection. CMR was defined as a complete resolution of the FDG uptake due to IFI compared to the background at the site of IFI. A partial response was defined as any reduction in FDG uptake not reaching complete normalisation. Progression of the infection was defined as the appearance of new lesions or an increase in the size or intensity of existing lesions due to IFIs. When FDG-PET/CT led to a cessation or change in antifungal drugs or resulted in surgery, it was defined as alteration of the therapy and having added value. If FDG-PET/CT led to a prolongation of therapy (because of partial response) it was considered as having added value.
Statistical analysis
Descriptive statistics (mean and standard deviation or mode and range) was used to describe patient and scan data. Data was tested statistically using SPSS Version 23 (IBM Inc., Armonk, NY). Receiver operator characteristic (ROC) analysis was performed to determine whether the metabolic parameters would be able to discriminate patients who had a complete metabolic response (CMR) on their final scan from those who did not have a CMR. Independent t-test was used to determine differences in means, and Fisher’s Exact test was used for the difference of categorical values. P-values of less than 0.05 were considered significant.
Discussion
IFI is a life-threatening condition, and only scarce data are available with regard to imaging. Our study provides important data on the role of FDG-PET/CT in monitoring IFIs. Of particular importance is the ability of TLG to provide quantification of the burden of disease due to IFI, the ability of the baseline TLG to predict patients who will achieve a CMR when patients are treated with antifungal drugs, and the fact that FDG-PET/CT has added value in therapy decision-making in a large proportion of the patients.
Our study is the first study to evaluate the role of TLG and MV in infectious diseases. We found TLG was able to provide a quantitative measurement of IFI burden, which correlates well with the reports which were based on visual analysis. TLG and MV were found to be able to predict whether a patient will achieve CMR. This was not the case for the SUVmax, SUVpeak, and SUVmean. This finding indirectly supports the idea that either TLG or MV may be a better parameter to use when comparing scans of patients with systemic diseases such as IFIs compared to SUV parameters. The global TLG at baseline may be used to predict patients who will not completely respond to an antifungal agent and will have persistent FDG uptake or will require surgical resection of IFI lesion. This distinction is essential to avoid unnecessary delay in instituting further therapies such as allogeneic stem cell transplantation (ASCT) based on when FDG-PET/CT is used for monitoring IFIs. While a CMR is achievable in the majority of cases, in some patients this may not always be possible. This may result in unnecessary prolongation of antifungal therapy, with associated side-effects and costs. Furthermore, it may delay further necessary intervention such as ASCT if the monitoring was based on FDG-PET/CT only in these patients. This persistent FDG activity in IFIs has been documented by other authors [
14], and has also been reported in other nonfungal infections after patients have been cured of infection [
15]. The persistent uptake may be related to old lesions such as fibrosis that the body is trying to eradicate by activated immune cells such as macrophages, giant cells, and lymphocytes with FDG uptake not due to active IFI.
Our findings on the added value of FDG-PET/CT in therapy decision-making in patients with IFIs are in support with other studies that demonstrated the value of FDG-PET/CT in monitoring treatment of IFIs. In one study, FDG-PET/CT was compared to conventional CT in detecting and guiding management of IFIs. This study found 94% (30/32) of the FDG-PET/CT scans to be useful in evaluating therapy response [
16]. In another study, FDG-PET/CT was found to lead to altered treatment by stopping or reducing the dose in 15% (8/54) or changing or increasing the dose of antifungal drugs in 31% (17/54) cases [
17]. IFI is a rare disease, and a large multi-centre study will be necessary to validate our findings.
In patients with underlying hematologic malignancies who develop IFI after neutropenia, antifungal therapy is usually necessary for an extensive period of time (months to even years) as the immune system of the host is not effective in clearing the organism. If the treatment of the underlying condition of the IFI involves further depression of the immune system such as ASCT, there is the risk of dissemination of IFI during treatment. Monitoring is crucial to treat IFIs adequately, but also not to subject the patients to unnecessary treatment with toxic effects and to lower the expensive costs of the treatment [
2]. In our study, the mean duration of treatment till the last FDG-PET/CT was 33.5 weeks (range, 5–242). International organizations such as the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), and the European Conference on Infection in Leukaemia recommend a search for disseminated infection in a leukemic patient with an IFI recovering from neutropenia [
18]. The methods they recommended for excluding a disseminated IFI included transoesophageal echocardiography, funduscopic evaluation, and/or abdominal imaging. These methods are region- or organ-specific, and are not able to detect occult IFIs at other sites concurrently. FDG-PET/CT as a whole body tool is able to evaluate several sites in one study.
Organs in the body that have a high metabolic signal may limit the role of FDG-PET/CT as a monitoring tool [
4]. FDG-PET/CT monitoring of IFIs was not optimal in patients with predominantly cerebral and renal lesions in our study. The advantages and disadvantages of the various imaging tools must be appreciated by the clinician, and the most appropriate utilized for the best patient outcome.
The serial FDG-PET/CT scans for IFI monitoring were acquired at different time points during the treatment. This is because the patients with IFIs have different underlying risk factors with different degrees of immune suppression. Furthermore, the genus and species of fungi causing IFIs are also different, making it difficult to perform FDG-PET/CT at a fixed point in time. The timing of the follow-up scan should be dictated by the clinical condition of the patient, allowing personalized therapy decisions of this life-threatening infection.
The mortality in our patients directly due to IFIs was 11%, and the overall mortality was 25%. All the patients who died due to IFIs were patients who did not have a CMR at the last scan. The mortality of 11% of IFI patients who were on treatment underscores the importance of developing new strategies for the management of IFIs. New strategies including vaccine, cytokiness, and cellular immunotherapy have been investigated at a preclinical level [
19]. FDG-PET/CT is well positioned to provide quantitative assessment of the burden of IFI in patients when these therapeutic interventions are translated to humans. Furthermore, the lack of statistical significance between the mortality of the CMR group and non-CMR group, but the significant difference when mortality due to IFI is considered, may suggest a prognostic role of metabolic response on the last study. However, our sample size is too small to fully explore this. Larger multicentre prospective studies are needed to confirm the prognostic value of FDG-PET/CT study in monitoring IFIs.
Our study has some limitations regarding the small sample size, the retrospective nature of our study, and data coming from a single center, which may limit its generalization. Our strict inclusion criteria may have systematically excluded very ill patients who were unable to undergo several FDG-PET/CT scans. In some of our patients the IFIs were not proven by biopsy, but this is in our opinion the clinical practice; it is not always possible to have full proof by biopsies.
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