The effect of volume of interest definition on quantification of lymph node immune response to a monkeypox virus infection assessed by 18F-FDG-PET
© Chefer et al.; licensee Springer. 2014
Received: 22 May 2014
Accepted: 4 September 2014
Published: 16 September 2014
2-deoxy-2-[18F]fluoro-D-glucose-positron emission tomography (18F-FDG-PET) is applied in the clinic for infection assessment and is under consideration for investigating the inflammatory/immune response in lymphoid tissue in animal models of viral infection. Assessing changes in 18F-FDG uptake of lymph nodes (LNs), primary lymphoid tissues targeted during viral infection, requires suitable methods for image analysis. Similar to tumor evaluation, reliable quantitation of the LN function via multiple 18F-FDG-PET sessions will depend how the volume of interest is defined. Volume of interest definition has a direct effect on statistical outcome. The current study objective is to compare for the first time agreement between conventional and modified VOI metrics to determine which method(s) provide(s) reproducible standardized uptake values (SUVs) for 18F-FDG uptake in the LN of rhesus macaques.
Multiple 18F-FDG-PET images of LNs in macaques were acquired prior to and after monkeypox virus intravenous inoculation. We compared five image analysis approaches, SUVmax, SUVmean, SUVthreshold, modified SUVthreshold, and SUVfixed volume, to investigate the impact of these approaches on quantification of the changes in LN metabolic activity denoting the immune response during viral infection progression.
The lowest data repeatability was observed with SUVmax. The best correspondence was between SUVfixed volume and conventional and modified SUVthreshold. A statistically significant difference in the LN 18F-FDG uptake between surviving and moribund animals was shown using modified SUVthreshold and SUVfixed volume (adjusted p = 0.0037 and p = 0.0001, respectively).
Quantification of the LN 18F-FDG uptake is highly sensitive to the method applied for PET image analysis. SUVfixed volume and modified SUVthreshold demonstrate better reproducibility for SUV estimates than SUVmax, SUVmean, and SUVthreshold. SUVfixed volume and modified SUVthreshold are capable of distinguishing between groups with different disease outcomes. Therefore, these methods are the preferred approaches for evaluating the LN function during viral infection by 18F-FDG-PET. Validation of multiple approaches is necessary to choose a suitable method to monitor changes in LN metabolic activity during progression of viral infection.
Assessment of cell glucose metabolism by 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) and positron emission tomography (PET) is a powerful supplement to conventional studies of viral infection in animal models to characterize disease progression and evaluate the efficacy of potential treatments ,. Lymphadenopathy is one of the predominant clinical signs of monkeypox virus infection in nonhuman primates (NHPs) and humans. Therefore, a reasonable method to monitor the evolving lymph node (LN) immune response is assessment of LN metabolic activity using standardized uptake value (SUV) as a simple semiquantitative measure of 18F-FDG uptake ,. Similar to the methodological issues associated with the analysis of 18F-FDG-PET images in oncology , computing the SUVs and reliably evaluating the LN immune response to viral infection will depend on an exact and reproducible definition of the volume of interest (VOI). VOI definition for PET image quantitation is still an open research area, and users are applying the most reliable and reproducible techniques suitable for analysis of different types of disease (e.g., tumors, inflammatory conditions). Although the VOI definition is not the only factor that can affect the reproducibility of SUV estimates in the LN -, the type and size of a VOI may greatly contribute to the variability of such measurements. Such variation has been previously demonstrated with tumor quantitation using 18F-FDG-PET imaging ,.
A variety of methods have been proposed to define tumor VOI, but no reference standard has been accepted. Commonly used approaches for quantitative analysis of 18F-FDG-PET images include the following: 1) measuring the value of the voxel with the highest activity within the tumor (SUVmax) ,, 2) averaging the SUVs from the voxels inside the whole tumor defined by freehand outline of tumor boundaries (SUVmean) -, 3) averaging the voxels with the SUVs greater than a certain percentage of SUVmax using thresholding techniques (SUVthreshold) ,,, or 4) using fixed volume (SUVfixed volume) defined as the average SUV within a fixed-size VOI centered over a region with high metabolic activity without conforming to the precise tumor outline. A similar concept of SUVfixed volume has been used by Boellaard et al. and was called SUVpeak.
These VOI metrics are rather general and, as such, are not optimized to detect reproducible changes in 18F-FDG uptake (as measured by SUVs) during viral infection progression in a small target organ (LN). In particular, 18F-FDG uptake during early viral infection is difficult to measure as normal or near normal LNs have low glycolytic activity comparable to background. The lack of data on the agreement between varied methods to provide reproducible SUV estimates of the metabolic activity of LN has prompted us to develop new methods for VOI metrics. We evaluated new methods, SUVfixed volume and modified SUVthreshold (mSUVthreshold), against conventional (SUVmax, SUVmean, SUVthreshold) metrics. Here, we report the statistical reliability of each of these methods on quantitative assessment of 18F-FDG uptake changes in axillary LNs of rhesus macaques (Macaca mulatta) following a monkeypox virus intravenous challenge. To test interscan reproducibility, data from three baseline computed tomography (CT) and PET scans prior to monkeypox virus inoculation were used to measure LN volumes and SUVmax, SUVmean, SUVthreshold, SUVfixed volume, and mSUVthreshold in these animals.
Animals were housed in a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. All experimental procedures were approved by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research, Animal Care and Use Committee and were in compliance with the Animal Welfare Act regulations, Public Health Service policy, and the Guide for the Care and Use of Laboratory Animals recommendations.
Six male rhesus macaques housed in biosafety level 3 containment, weighing 3 to 4 kg, were infected intravenously with 5 × 107 plaque forming units of monkeypox virus (MPXV Zaire 79 strain [V-79-I-005]) (for virus preparation and inoculation procedures, see Additional file 1). Three animals were treated intravenously with cidofovir (5 mg/ml/kg in Dulbecco's modified Eagle's medium; Gilead Sciences, Foster City, CA, USA) that has been shown to protect against monkeypox virus infection. The antiviral agent, cidofovir, was administered on day -1 prior to monkeypox virus challenge and on days +1, +3, +5, +7, +10, and +13 after challenge. NHPs received 25 mg/kg of probenecid by gavage 1 h before cidofovir injection to prevent cidofovir nephrotoxicity. Three animals comprised the untreated control group.
Up to nine imaging sessions were conducted in each of the six animals following the procedures described previously . Briefly, imaging data were acquired in animals anesthetized with isoflurane (2% to 2.5%) (Piramal Critical Care, Orchard Park, NY, USA) using a microPET scanner Focus-220 (Siemens AG, Malvern, PA, USA). This scanner has a bore size of 22 cm with an axial field-of-view of 7.6 cm and a transverse field-of-view of 19 cm . Multiple static PET scans were initiated 1 h after the intravenous 18F-FDG injection (9.25 MBq/kg) and continued for 10 min for each of two bed positions on different days over 1.5 months. Three scans were performed prior to monkeypox virus inoculation (days -20, -15, and -5) and up to six scans were conducted postinoculation (days +1 or +2, +3 or +4, +7 or +8, +10, +16, and +21). The scans were conducted in the morning; the animals were fasted overnight for 12 h prior to the scanning session. The blood glucose concentrations were measured prior to the 18F-FDG injection before each scanning sessions. PET images were acquired in three-dimensional (3D) mode and reconstructed iteratively using 3D-ordered subsets expectation maximization algorithm with two iterations and nine subsets followed by 18 iterations of maximum a posteriori reconstruction . Maximum a posteriori parameters were adjusted to provide a uniform spatial resolution of 1.8 mm (FWHM = 1.8 mm) in all three directions. Methods for scatter, decay, random, and attenuation correction were applied during the process of PET image reconstruction.
CT images were acquired with a CereTom® (NeuroLogica Corp., Danvers, MA, USA) 8-slice mobile head-and-neck CT scanner that was installed in close proximity to the microPET scanner. The CereTom® CT scanner provided 190 slices with 0.49 × 0.49 mm in-plane resolution and 1.25-mm slice thickness that were acquired at 120 kVp and 5 mA. CT scans were taken either immediately before or after PET imaging to ensure consistent animal position and fusion of the PET and CT scans for data analysis. Incorporating the use of the same table for both scanners eliminated the need for animal repositioning. To restrict animal motion, the animal was secured by anchoring the limbs and by controlling the level of anesthesia. CT scans were used for attenuation correction and coregistration with PET images to define anatomical localization of the LNs of interest. In addition, CT images were used to obtain the LN volume applied for SUVmean computation to determine interscan data reproducibility prior to viral challenge.
Additional file 2:Elevated 18 F-FDG uptake in tissue surrounding the LN on day 3 after virus inoculation. Maximum intensity projection (MIP) movie and representative 18F-FDG-PET images fused with CT images of an axillary LN in sagittal view acquired -5 days before and day +3 and 10 after virus inoculation. High 18F-FDG uptake is observed in tissue surrounding the LN on day +3 after virus inoculation. (MP4 4 MB)
Additional file 3:Elevated 18 F-FDG uptake in axillary LN of an animal that eventually became moribund. MIP movie and representative 18F-FDG-PET images fused with CT images of an axillary LN in sagittal view acquired before and on day 3 after monkey virus inoculation showing elevated 18F-FDG uptake in axillary LN of an animal that eventually became moribund. (MP4 5 MB)
We also applied a fixed dimension method, SUVfixed volume, by creating a template of three identical small spheres (0.2 cm diameter, total of 21 full voxels in all three spheres), placed contiguously within the longest axis of the LN. The sphere diameter was chosen based on the smallest LN axis (range 0.25 to 0.39 cm) among all animals determined on baseline CT images. The three spheres were transferred to each new data set by determining the center of the LN (defined by the intersection of axes in 3D view, Figure 1c), placing the middle sphere in the LN center and the other two spheres adjacent to the first one along the long axis of a LN in transaxial view. By using three small spherical VOIs, we adjusted the VOI location to the shape of the LN of each subject. Although the size and shape of the LNs differed, the VOI covered similar locations in the middle of each LN. The SUVfixed volume was computed by averaging the SUVs from 21 voxels covered by three spheres.
The correlation between the volume measurement on pre-inoculation CT scans 1 and 2, 1 and 3, and 2 and 3 was calculated using the Pearson product-moment correlation coefficient (r). Application of the Kolmogorov-Smirnov test  confirmed that the difference between the pairs of scans followed a Gaussian distribution. To investigate the interscan reproducibility of three baseline scans, we compared scans 1 and 2, 1 and 3, and 2 and 3 for LN volumes and SUVmean, SUVmax, SUVthreshold, mSUVthreshold, and SUVfixed volume using Bland-Altman analysis . The mean difference, standard deviation of the mean differences (SD), coefficient of repeatability (CR), and limits of agreement (LoA) were calculated and represented as Bland-Altman plots. The SD was calculated by squaring all the differences, adding them up, dividing them by the number of measurements, and taking the square root. The LoA were calculated by adding (upper limit) or subtracting (lower limit) the CR, defined as CR = 1.96 × SD, from the mean difference. This analysis of data reproducibility was performed with the assumption that the animal health status did not change during the time the scans were obtained 5 to 21 days prior to monkeypox virus inoculation. Unchanged animal health status was confirmed by physical examination.
Bland-Altman analysis was subsequently used to investigate the agreement between five VOI metrics for peak 18F-FDG uptake in the LNs of survivors on day 10 after inoculation. The differences obtained for each animal were plotted against the mean differences of the respective pairs of VOI measures. For acceptable agreement, the 95% LoA (±1.96 SD of the mean difference) should include 95% of the difference between the methods of measurement. Two-way repeated measures analysis of variance (ANOVA) was employed to explore the difference between treated and untreated groups or surviving and moribund groups in LN 18F-FDG uptake using SUVs with five different VOI metrics. We used 18F-FDG uptake value at different time points (days -1, -2, -3 pre- and days +1 or +2 and +3 or +4 postinoculation with monkeypox virus) as within factor and treatment or disease outcome as between factors, respectively. Post hoc comparisons were performed using Bonferroni test. GraphPad Prism 6.01 (GraphPad Software Inc., La Jolla, CA, USA) was used for all statistical analyses.
The range of blood glucose concentrations for all animals (n = 6) measured before each scanning session varied between 60 and 72 mg/dL. No correlation was noted between changes in 18F-FDG uptake over the course of monkeypox virus infection and the variation in glucose concentration measured before each scanning session on different days before and after virus inoculation.
Repeatability of 18 F-FDG SUV measurements in the LN of normal rhesus macaques using SUVs with different VOI metrics
SUV method scan pair comparison
Mean difference ± SD
95% limits of agreement: lower limit, upper limit
Coefficient of repeatability
Scans 1 and 2
-0.40 ± 1.84
Scans 1 and 3
0.16 ± 1.74
Scans 2 and 3
0.57 ± 1.18
Scans 1 and 2
-0.89 ± 1.42
Scans 1 and 3
-0.41 ± 0.92
Scans 2 and 3
0.22 ± 1.94
Scans 1 and 2
-0.28 ± 0.89
Scans 1 and 3
-0.21 ± 0.50
Scans 2 and 3
0.19 ± 1.26
Scans 1 and 2
0.004 ± 1.08
Scans 1 and 3
0.15 ± 0.72
Scans 2 and 3
0.12 ± 0.78
Scans 1 and 2
-1.61 ± 3.01
Scans 1 and 3
0.004 ± 1.82
Scans 2 and 3
1.65 ± 3.51
Following inoculation of monkeypox virus, the characterization of infection in NHPs and histological evaluation of LN tissue during infection is described in Additional file 1. One animal in the untreated group survived the infection, while the remaining two subjects became moribund on day 7 after inoculation.
Current use in clinical settings
Major drawbacks or advantages
Statistically significant effects in current study
• PVE at the edges of target region
• Time consuming to outline target region
• Inclusion of nontarget tissue
• Susceptible to noise
• Random voxel location
• Independent of observer
• Easy to apply
• Inclusion of nontarget tissue
• Less sensitive to noise
• Easy to apply
• More reproducible than SUVmean
SUVfixed volume (placement adjusted in current study)
• Less sensitive to noise than SUVmax
• Limits PVE at edges of target region
• Relatively similar location of voxels between scans and between animals
• Less sensitive to noise than SUVmax
• Relatively easy to apply
• Limits PVE at edges of target region
Overall, the qualitative pattern of changes in LN 18F-FDG uptake over the course of monkeypox virus infection is similar between SUVs with the five VOI metrics evaluated in this study (Figure 3). However, SUVs vary substantially depending on VOI definition. The SUVs obtained with SUVthreshold, mSUVthreshold, and SUVfixed volume VOI metrics are within similar ranges and always above the range for the SUVmean and below the SUVmax. SUVmax could be the most attractive method to use for monitoring an immune response using multiple sequential PET scans because SUVmax is independent of the observer and simple to apply, Table 2,,. Despite these advantageous properties, the use of SUVmax is greatly influenced by adverse effects of noise . This weakness of SUVmax in combination with a random voxel location limit the ability of SUVmax not only to reproduce the measurement under normal conditions (baseline scans) but also to quantify reliably real changes in the LN metabolic activity during viral infection.
The major drawback of SUVmean is the time consuming process of manual LN delineation on each of the slices in the 3D CT images set. Similar to small tumors, LN PET images are difficult to align perfectly with CT images that often have poor soft tissue contrast. As a result, individual SUVmean during infection could be underestimated by inclusion of voxels with lower metabolic activity from surrounding tissue when manually defining the LN boundaries on CT images (Figure 6e). Partial-volume effect (PVE) at the edges is another factor contributing to underestimation of the values with SUVmean,,. Consequently, SUVmean is characterized by substantial data variability within the VOI as shown by CVs generally greater than 40% (Figure 4). Similarly, the dynamic range of the SUVmean is the widest compared with other methods (see Additional file 4).
The use of threshold-based methodology is attractive since the LN delineation on 18FDG-PET images is easy to perform, and this method provides more reproducible measures than SUVmax and SUVmean,. A disadvantage of the threshold technique is that the threshold is chosen rather arbitrarily, and only metabolically active tissue can be used for its application. Setting a threshold in normal LNs is more difficult compared with active LNs as metabolic activity in normal LNs appears to be similar to that in surrounding tissue (Additional files 2 and 5). At early time points postinoculation, the 18F-FDG uptake in surrounding tissue is often higher than that in the LN leading to an inclusion of the majority of the voxels outside the LN edges in SUVthreshold computation (Figure 1b, Additional file 2). Similarly, this method proved to be unsuitable to monitor tumor response after treatment since nontumor tissue is very often also included in the VOI . To eliminate inclusion of voxels from surrounding tissue with high 18F-FDG uptake, we limited the volume for thresholding by placing a spherical VOI in the middle of a LN. This modification in the procedure improves data variability as shown in Figure 4.
SUVfixed volume focuses on the metabolic response within a restricted location of the LN taking into account changes in LN shape and size in rhesus macaques over the course of infection. This VOI metric includes selected voxels from a slice in the middle of a LN, where metabolic activity is usually higher compared with the LN edges, and covers relatively similar locations standardized between different animals and scanning sessions. Thus, by avoiding the edges of the LN, we minimize the PVE associated with SUVmean metrics, and, similar to mSUVthreshold, SUVfixed volume excludes voxels from tissues surrounding the LN. SUVfixed volume and mSUVthreshold demonstrate the best agreement among other SUVs between the values for the peak response in survivors (Figure 6). These two methods are associated with similar statistically significant increases in 18F-FDG uptake in moribund group at day +3 or +4 postinoculation of monkeypox virus compared with surviving group.
There are several limitations in our present work. Although the size of the LNs assessed in this study was within the scanner resolution, PVE correction was not applied. The best method to correct for PVE has yet to be determined as such correction by itself can produce a bias in measured uptake. Further studies are needed to explore the relevance of PVE correction in the context of PET imaging of the LN immune response.
The aim of this preliminary study in a limited number of subjects is to compare different methods for determining the SUV and choose the method(s) with the best agreement to be applied in future characterization of a LN response to viral infection. The low number of subjects is not sufficient to demonstrate whether other more subtle effects (e.g., treatment effects), besides differentiating between disease outcomes, can be demonstrated from application of the SUVfixed volume and mSUVthreshold metrics. The current data do not provide any explanation for the lack of difference between treated and untreated survivors in terms of 18FDG uptake by the LN. Perhaps the lack of difference may be related to the sensitivity of the methods or the contribution of other processes not associated with metabolic activity.
Also, we cannot rule out the possibility that differences at day +3 or +4 postvirus inoculation could be explained by a suboptimal study design. To ensure consistency in viral stock properties (e.g., titers, number of passages) and in inoculation procedures, all NHPs were infected on the same day (day 0). However, imaging of treated and untreated groups was staggered over 2 days (e.g., days +3 or +4 postinoculation) to accommodate PET scanner availability and duration of pre- and postscan procedures in sick animals in a biosafety level 3 environment. Despite these limitations, a similar pattern of changes in 18F-FDG uptake in the LNs is observed in treated and untreated surviving NHPs irrespective of timing of scans but is not observed between untreated surviving and moribund animals scanned on the same day. Future studies with larger group of animals and improved study design will be able to clarify this issue. In addition, an intra- and interrater reliability evaluation of LN volume and SUVs should be considered in further studies. Another point for potential criticism for the current study could be the lack of ground truth for LN 18F-FDG uptake.
We confirmed results of previous studies that quantification of changes in 18F-FDG-PET is highly sensitive to the method applied for PET image analysis. Evaluation of multiple approaches is necessary in choosing appropriate method(s) to monitor changes in LN metabolic activity during progression of infection. Results of our study indicate that SUVfixed volume and mSUVthreshold are more reproducible than the other methods and provide the best agreement for SUV calculation. Both methods reduce the impact of noise, minimize the PVE, limit inclusion of background signals, and substantially decrease the SD of the mean SUVs. The improved precision of the SUV estimates with the proposed methods results in statistically significant difference between moribund and surviving groups at an early stage of monkeypox virus infection that is not detected with the other three methods. Therefore, SUVfixed volume and mSUVthreshold are the preferred approaches rather than SUVmax, SUVthreshold, or SUVmean for quantitative analysis of LN immune response over the course of monkeypox virus infection using 18F-FDG-PET. Consequently, these preferred methods may provide better tools for establishing 18F-FDG uptake by the LNs as a marker of functional response at an early stage of monkeypox virus infection.
JD and RFJ were involved in the study design, implementation, data collection, and manuscript preparation. RCR participated in the design of the study, data analysis, and manuscript preparation. JS and CZL were involved in the study implementation and data analysis. JEB and PBJ were involved in study design. SC was involved in development of methods for image quantitation and statistical analysis and wrote the manuscript. All authors read and approved the final manuscript.
We thank Jennifer Hufton from the imaging team, Russell Byrum from the NIAID Comparative Medicine Branch, and Comparative Medicine veterinarians for successful implementation of PET-CT scanning protocols in the biosafety level 3 suite. In addition, we acknowledge Shen Kui for help with statistical analysis. We thank Laura Bollinger and Jiro Wada for outstanding assistance in technical writing and figure preparation of this manuscript on behalf of the Battelle Memorial Institute. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), Integrated Research Facility (NIAID, Division of Clinical Research), and Battelle Memorial Institute's prime contract with NIAID (Contract number HHS N272200700016I).
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