Fluorodeoxyglucose imaging in healthy subjects with HIV infection: impact of disease stage and therapy on pattern of nodal activation
Brust, Douglas; Polis, Michael; Davey, Richard; Hahn, Barbara; Bacharach, Stephen; Whatley, Millie; Fauci, Anthony S; Carrasquillo, Jorge A
From the National Institute of Allergy and Infectious Disease, and the Nuclear Medicine Department, Warren G. Magnuson Clinical Center of the National Institutes of Health, Maryland, USA.
Received 16 March, 2005
Revised 31 October, 2005
Accepted 10 November, 2005
Correspondence to J.A. Carrasquillo, 10 Center Drive MSC 1180, Bethesda, MD, 20892-1180, USA. Tel: +1 301 496 8006; e-mail: email@example.com
Objectives: Nodal uptake in areas of lymphocyte activation can be visualized using fluorodeoxyglucose (FDG). Various patterns of FDG accumulation in HIV-positive subjects have been described previously and hypothesized to potentially represent regions of active HIV replication and or nodal activation. We evaluated the utility of FDG scanning as a tool to study HIV pathogenesis.
Design: We evaluated FDG biodistribution visually and quantitatively in HIV-negative individuals and various groups of HIV-infected subjects to determine the impact on pattern of nodal activation of: HIV infection; stage of HIV infection and degree of viremia; and HAART. In addition, we attempted to image anatomical site(s) of on-going HIV replication in subjects with suppressed HIV viremia on ART, but who subsequently discontinued ART.
Method: We performed FDG imaging on five groups: HIV-negative, HIV-positive with early infection, HIV-positive with advanced disease, HIV-positive with suppressed viral loads, and HIV-positive who stopped ART.
Results: Healthy HIV subjects with suppressed viral loads and HIV-negative individuals had no or little FDG nodal accumulation or any other hypermetabolic areas, whereas viremic subjects with early and advanced HIV had increased FDG in peripheral nodes, indicating that FDG potentially identifies areas of HIV replication. FDG biodistribution was similar between early and advanced-stage. Four of five subjects taken off ART had negative baseline scans but developed nodal uptake and increases in viral load.
Conclusions: Abnormal FDG accumulation occurs in nodes of subjects with detectable viral loads. Interruption of effective ART results in activation of previously quiescent nodal areas.
Understanding the pathogenesis of HIV infection is critical to the rational design of therapies for controlling and preventing the disease. Many studies have evaluated the effects of HIV infection on lymphocytes . A variety of studies have demonstrated that HIV viremia (a marker of actively replicating virus) is associated with accelerated turnover of lymphocytes [2–6], and that this turnover is the result of proliferation and death of both HIV-infected, as well as uninfected, cells [2–5]. Suppression of HIV replication with HAART results in decreased lymphocyte turnover [7–9].
The limited information available about the anatomical sites of viral replication during the natural history of HIV disease was generated by either post-mortem or invasive studies . Subjects with late-stage disease who may have no measurable circulating CD4 T cells, are nevertheless able to maintain extremely high levels of HIV viremia despite destruction of their nodes, causing some investigators to question the role of other non-nodal lymphoid sites and cell types as alternate areas of HIV replication . Actively replicating virus has been isolated from peripheral blood lymphocytes, lymph nodes, and also from tissues such as brain and testis [12,13] that may be sanctuary sites . A method of non-invasively identifying areas of active HIV-replication would prove powerful to study the natural history of HIV infection in vivo.
Because [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) can non-invasively identify tissues with increased glucose metabolism, Scharko et al. have hypothesized that areas of active HIV replication should have increased FDG uptake because of increased tissue activation. Their studies on early SIV-infected rhesus monkeys showed a pattern of FDG imaging consistent with lymphoid activation in nodes with productive SIV infection . In addition, in advanced disease peripheral nodes were not active, but FDG uptake was increased in deep abdominal nodes. Clinical studies by this group concluded that ‘HIV progression was evident by distinct anatomical imaging correlates, suggesting that lymphoid tissues are engaged in a predictable sequence’ . Iyengar et al. evaluated the impact of HIV infection on FDG images and found that “in early and chronic HIV-1 disease, node activation was greater in cervical and axillary than in inguinal and iliac chains” . This group demonstrated a correlation between the level of HIV viremia and FDG uptake in lymph nodes, and stated that “the anatomical sites of greatest HIV-1 induced lymphocyte activation are also the foci of most HIV-1 replication”.
Because we were interested in developing a non-invasive method to answer basic HIV pathogenesis questions (e.g., the source of plasma viremia in late-stage HIV disease or the site of on-going viral replication in patients with suppressed viremia), we evaluated the ability of FDG as a research tool to identify sites of increased FDG uptake and presumptive HIV replication. Initially, we evaluated the biodistribution of FDG in healthy HIV-negative individuals and various groups of healthy HIV-infected subjects to determine the impact of disease status and viremia on pattern of nodal activation. Next, we attempted to identify anatomical areas of on-going HIV replication in subjects who had ART-induced suppression of HIV viremia, but who subsequently discontinued therapy.
Material and methods
This was a prospective study approved by the internal review board of the National Institute of Allergy and Infectious Disease of the National Institutes of Health. All subjects gave written informed consent. The diagnosis of HIV-1 infection was confirmed by two methods. HIV-infected subjects were otherwise healthy, asymptomatic and had no palpable adenopathy (> 1.5 cm) on physical exam. Subjects were excluded if they had a history or evidence of acute or chronic illness, or prior interleukin-2 treatment within 6 months. Viral burden was determined using USbDNA, with a sensitivity of > 50 copies/ml (Bayer Diagnostics, Tarrytown, New York, USA). CD4 T-cell levels were determined by flow cytometry.
Subjects were initially accrued into four groups (Table 1 and Table 2): HIV-negative ‘controls’, ‘early’ stage HIV (CD4 cell count > 200 cells/μl), ‘advanced’ stage HIV (CD4 < 100 cells/μl), and HIV-positive subjects with ‘suppressed’ viral loads (< 50 copies/ml) secondary to ART or because they were long term non-progressors (LTNP). Early and advanced stage subjects had viral loads > 50 000 copies/ml and were either not receiving ART or had incomplete suppression on ART. LTNP patients had viral suppression and normal CD4 T-cell counts without the use of ART . For part two of the study, a ‘stop group’ was recruited consisting of subjects with suppressed viral loads on ART who were interrupting therapy. ‘Stop’ subjects underwent baseline FDG scans before interruption, with two follow-up scans at a mean of 12 and 19 days after stopping ART (Table 2). The ART treatment used was determined by the subject's primary physician and/or protocol. For the purpose of analysis, baseline scans in the ‘stop group’ were analysed together with the ‘suppressed group’.
Subjects received 15.1 ± 2.3 mCi of FDG intravenously after fasting for at least 6 h. Fasting glucose values on the day of scanning were 910 ± 104 mg/L. FDG scans were acquired from the base of the skull to the inguinal region starting 61 ± 5 min after injection using an Advance scanner (General Electric, Milwaukee, Wisconsin, USA). Scans were acquired in two-dimensional mode at 8–10 min/section and attenuation corrected with a 3-min transmission scan. The brain was scanned separately using 10-min emission and 4-min transmission scans. Images were reconstructed using an iterative reconstruction algorithm.
Images were analyzed visually on a computer blinded to the subject cohort and other clinical information. Sites with increased activity beyond that seen physiologically were considered abnormal. In the stop group, baseline scans were interpreted first. Subsequent scans were compared to the baseline scan and each other.
Quantitative analysis was performed by determining the standardized uptake value (SUV) corrected for lean body mass [SUV = (nCi/g in region/nCi injected) × lean body mass] . Regions of interest (ROI) were drawn over the liver, spleen, lung, and gluteal muscle for determination of SUVmean. ROI were drawn over visualized lymph nodes, parotids, tonsils, L5 marrow, and testicles using an automated algorithm to determine the SUVmax and the SUVmean using a threshold of 80% of the maximum counts. When lymph nodes were not visualized, a ROI was drawn over the area where lymph nodes would normally reside. ROI were drawn over the entire brain and the SUVtotal of the brain was obtained. SUVtotal were obtained as described previously . Whole body retention of FDG (SUVtotal_wb) was determined by manually excluding regions of known high physiologic uptake of FDG (kidney, brain, and bladder) and then adding the SUV of all the other pixels greater than 2.5. A minimum SUV value of 2.5 was arbitrarily selected because some normal structures have values in this range and because this value is sometimes used to differentiate between benign and malignant disease. In addition, regions were drawn manually only over all lymph nodes identified visually and the total SUV was obtained (SUVtotal_lymph nodes).
The small number of evaluable subjects in the advanced group precluded statistical comparisons with these. Comparisons between the remaining groups were made using one-way analysis of variance with post-test comparisons using the Student–Newman–Keuls method. Comparisons between two variables were performed using the two-tailed t test. Correlation of viral load with SUVtotal_wb measurements and SUVtotal_lymph nodes (in HIV patients in whom lymph nodes were visualized) were performed using Pearson's Correlation coefficient; all HIV infected patients were included except for two advanced patients (patients 29 and 30), that were excluded for reasons outlined below. Statistical analyses were performed using SigmaStat (Jandel, San Rafael, California, USA).
We enrolled 30 subjects who each underwent an FDG scan; six of these underwent additional scanning after stopping ART (Table 2). Twenty-eight males and two females (mean age 38.9 ± 9.9 years) were enrolled (18 Caucasian, seven Hispanic, five Black). Seven subjects were excluded from further statistical analysis after their FDG scans were performed, although their data is included in Table 2. Two advanced group subjects were excluded because one (patient 29), on re-interviewing, gave a history of being on granulocyte colony stimulating factor  and another because of viral load ≤ 50 000 copies/ml (patient 30). Two control subjects were excluded because of a history of immune thyroiditis (patient 6) and for untreated, latent tuberculosis (patient 5). Both of these subjects had abnormal FDG scans. Two suppressed subjects (patients 17 and 19) who at screening had viral loads < 50 copies/ml actually had 60 and 99 copies/ml on the day of their scans. One of the stop ART subjects (patient 26) was excluded because of viral load of ≥ 50 copies/ml at baseline scanning (72 copies/ml). The mean CD4 T-cell counts and median viral loads for the early (n = 5), advanced (n = 2), and suppressed (n = 12) groups were 332 cell/μl and 86 262 copies/ml, 42 cells/μl and 104 442 copies/ml, and 575 cells/μl and < 50 copies/ml, respectively.
Visual analysis showed differences in FDG accumulation between certain groups (Table 2, and Fig. 1 upper panel). Control and suppressed subjects did not have abnormal FDG accumulation in nodes, with the exception of faint axillary uptake in one subject in each group. In contrast, the early group had uptake in nodes-typically in more than one region. Splenic uptake was greater than liver in the early group as compared to the control or suppressed group (P ≤ 0.05). The two evaluable subjects in the advanced group had uptake in multiple nodal regions similar to the early group. The advanced patients excluded also had nodal uptake (Table 2). Uptake in small bowel, large bowel, and cecum did not differ among the five groups and was similar to that often seen in patients with a variety of malignant and benign disorders. Mesenteric nodes were not visualized in any subject. The images of brain were grossly normal in all groups, except for subject 27 who showed focal changes consistent with prior head trauma. Of the seven evaluable subjects with early or advanced HIV disease, six had FDG uptake in upper nodes (cervical/axillary) and lower nodes (inguinal/iliac) and one had inguinal nodes only.
The mean and standard deviation of the SUVmax in hypermetametabolic nodes, irrespective of which group the patients were in, was 4.9 ± 1.6 and the maximum SUVmax was 7.3. FDG uptake in normal organs was compared quantitatively among groups using the SUVmean (Table 3) or SUVmax (data not shown). The SUVmean for lung, muscle, marrow, liver, spleen, and brain were similar between control, early, and suppressed subjects. Testicular uptake was higher in the controls than either the suppressed or early group. Uptake in tonsils and parotids was higher in the early group than in the control or suppressed groups (P < 0.05). The uptake in the submandibular salivary glands also appeared visually higher in the early group than in the control or suppressed groups, but was not quantitated because of overall low uptake and inadequate visualization in the latter two groups.
Although no statistical differences in the SUV of liver or spleen were observed, quantitative analysis confirmed the visual findings of higher uptake ratios in the spleen than in the liver in the early group. The spleen:liver SUV ratio was statistically different between the control (1.06 ± 0.1) or suppressed (0.931 ± 0.2) groups versus the early group 1.38 ± 0.4 (P < 0.05), but not different between the control and suppressed groups (P = 0.34).
Total whole body retention (SUVtotal_wb) of FDG using a threshold SUV of 2.5 was not different between controls and suppressed subjects (Table 3). In contrast, significantly higher SUVtotal_wb FDG levels were observed in early subjects compared to the suppressed subjects (P < 0.05). In addition, the early subjects had higher SUVtotal_wb of FDG than the control subjects, although this was not statistically significant. Total whole body FDG retention in the initial studies of all HIV subjects with high viral loads was significantly higher than those with suppresed viral loads: median SUVtotal_wb of 23644 versus 10580 (P = 0.034), respectively. When viral load was correlated with SUVtotal_wb, a significant correlation was observed (r = 0.814, P < 0.0001), but no significant correlations was seen with SUVtotal_lymph nodes (total FDG activity in visualized nodes (Fig. 2).
Four of the five evaluable stop subjects developed new FDG uptake in nodal sites on their second or third scans (Table 2, Fig. 1 lower panel). Subject 24 had a negative baseline scan and showed cervical node uptake at 13 days off ART that persisted on day 20, despite having no increase in viral load above 50 copies/ml. In this subject, viral load subsequently increased to 1269 copies/ml by 28 days and continued to increase thereafter. Subject 23 had persistently low viral loads < 50 copies/ml and negative scans, with SUVs in organs and the whole body on the baseline scan that did not statistically differ from those on his follow-up scans off ART (data not shown).
Lymphoid organs function as a major site of HIV replication and HIV infection results in nodal lymphocyte activation . It is not surprising that FDG, a surrogate marker of glucose metabolism, accumulates in activated lymph nodes since activated lymphocytes exhibit increased glucose utilization [23,24]. FDG accumulation has been noted in disorders associated with increased lymphocyte activation or inflammation [17,25–27]. FDG accumulation in lymph nodes of subjects with HIV infection has been reported . Normal individuals usually have no visible FDG accumulation in nodal tissue, as was typically seen in our controls and other studies.
Our study differs from prior reports of Scharko et al. and Iyengar et al. in several ways [16,17]. Subjects were stratified by CD4 T-cell counts, a well-established marker of disease stage, and for level of viremia. We include a group of patients who were taken off ART and studied serially with FDG. We quantitatively evaluated several extra-nodal tissues to assess how they differed between the various HIV groups. In addition, all HIV subjects were screened to be relatively healthy which was similar to Iyengar et al.'s study, but contrasted with Scharko et al., thus eliminating other confounding processes that could result in abnormal FDG imaging. For example, diarrhea is common in late-stage HIV disease and it is possible that prior reports of late-stage subjects having increased uptake in mesenteric nodes (a finding not seen in our study) may simply have represented the failure to screen out other causes of FDG uptake and not signify a true source of virus replication .
As a group, viremic subjects (advanced and early-stage) showed significant differences in FDG uptake when compared to control or suppressed subjects, supporting the hypothesis that increased FDG uptake was the result of active HIV replication. Our studies, similar to those of Iyengar et al., reported quantitatively on the uptake of FDG, whereas in the study of Scharko et al. there was no quantitative evaluation since attenuation correction was not performed. Compared to Iyengar et al. we did not find a good correlation between SUVtotal_lymph nodes and viral load (Fig. 2) . Nonetheless, there was a good correlation between viral load and elevated whole body FDG retention. The reason for the lack of correlation between lymph node uptake and viral load in our study compared to Iyengar et al. are not completely known but may have been in part related to differences in subject population who had different levels of viral load. In contrast to prior FDG studies in HIV patients, we describe several sites of increased extranodal uptake of FDG not previously reported. T-cell activation in tonsils that normalizes with ART has been reported previously and is likely the explanation for the elevated FDG findings in the early group . Evidence of splenic hypermetabolism was suggested by the 1.4-fold higher uptake in spleen compared to liver in early disease subjects versus the 0.9 to 1.1 ratio in the suppressed or control groups, similar to the findings of Iyengar et al. . The increased uptake in the parotids of the early group may be due to infectious processes, diffuse infiltrative lymphocytosis that sometimes involves the salivary glands in HIV-infected subjects, or increased nodal uptake in nodes within the parotids due to activation because of HIV replication [30,31].
Stage of disease, stratified by CD4 T-cell count, did not appear to affect the pattern of FDG biodistribution. Nodal chain FDG uptake in advanced subjects (mean CD4 cell count, 57/μl) was comparable to viremic early stage individuals (mean CD4 cell count, 465/μl). Furthermore, in evaluable subjects with advanced disease, colonic activity was similar to that often seen in healthy controls as well as patients with various malignancies. We did not see mesenteric or prominent bowel FDG uptake, a finding reported in late-stage disease by others . This discrepancy could reflect differences in cohort selection, as mentioned above.
Despite the ability of ART to suppress HIV viremia below the sensitivity levels of commercially available assays, there is strong evidence that HIV is not eradicated but, rather, continues to replicate at low levels. Likely explanations for this are either that therapy is not potent enough to completely shut down replication, or that areas of on-going replication are at pharmacologically privileged sites where required levels of drug cannot reliably be delivered [32,33]. Because the vast majority of subjects are not able to control HIV replication immunologically, HIV viremia invariable rebounds when ART therapy is withdrawn . In an attempt to locate areas of low-level, on-going replication during effective ART, we performed a series of scans in subjects with suppressed viremia who were withdrawing from ART. We hypothesized that new FDG uptake detected prior to developing viremia in the blood may represent sites of early HIV rebound and presumably the source of subsequent viral dissemination and peripheral viremia. In four of the five evaluable subjects in this stop group, new increased FDG uptake developed in lymph nodes after therapy interruption. However, only one of the subjects (24) had new FDG lymph node uptake prior to the development of viremia. FDG in other tissues remained similar to baseline (data not shown). Interestingly, the subject (23) whose serial scans remained persistently negative after ART withdrawal also failed to demonstrate a rebound in viral load. These findings suggest that FDG nodal uptake is closely linked to, and may actually precede, viral proliferation, and that after ART withdrawal, these nodes are sites of early proliferating virus that activate lymphocytes, thus causing increased FDG uptake. These in vivo results are consistent with the ex vivo finding that nodal lymphocyte activation and viral expression occurs rapidly after ART interruption in previously suppressed subjects .
In contrast to the significant difference in whole body FDG retention in subjects with early disease versus control or suppressed subjects, we did not see any significant differences between the baseline and follow-up studies of stop group subjects, although as noted above there were qualitative differences in lymph node chains. This lack of difference may be due to the subtle changes in lymph node uptake that occurred early and/or to the relatively low degree of viremia seen in the stop group compared to the early group (median 11851 copies/ml versus 86262 copies/ml, respectively).
In the suppressed group, the two evaluable LTNP did not have nodal FDG uptake, similar to the controls, and subjects with suppressed viremia on ART. In contrast, the one excluded LTNP subject (baseline viral load ≥ 50 copies/ml) had peripheral node uptake. It is unclear if this pattern was related to low detectable viremia (60 copies/ml) or perhaps to a nodal activation process associated with relative immunological control of viral replication, such as CD8 T-cell proliferation . The lack of increased signal from FDG in the tissue of suppressed or LTNP compared to control subjects (Table 3) show that the method is insensitive to detect low levels of viral replication.
This and previous reports have not addressed fundamental questions of the specificity and sensitivity of FDG to detect specific anatomical sites of HIV replication. These parameters must be defined prior to our being able to recommend FDG scanning for the non-invasive in vitro study of HIV infection. By carefully screening for healthy HIV-infected subjects, we feel that the increased nodal FDG uptake seen in viremic HIV-infected subjects, but not in HIV-negative controls or suppressed subjects, is directly a result of HIV replication. However, although areas of FDG uptake in viremic subjects clearly represent areas of lymphocyte activation, it is unclear if this activation is due to local HIV replication or, alternatively, to systemic factors that induce lymphocyte activation but are not necessarily produced in that given node. Similarly, in a given viremic subject, the biological reason that some nodal chains have FDG uptake and other do not is unclear. In subjects with significant viremia such as those in this study, presumably all nodes contain infected lymphocytes. Differential uptake of FDG may simply be a matter of sensitivity even if not pathologically enlarged, anatomically distinct nodal chains vary in size, and, as seen in nodal evaluation for lung cancer, the detection rate may be size-dependent . Moreover, because the FDG signal intensity is less in HIV infection than in most neoplastic processes, node size probably plays a more important role in sensitivity determination in these patients. Future studies will have to pathologically compare the degree of HIV replication between FDG positive and FDG negative nodes in order to better delineate the utility of this potentially powerful non-invasive method.
In summary, our findings suggest that HIV viremia is associated with increased nodal activation that is detectable by FDG. In subjects with suppressed viral loads there is limited lymphocyte activation and a corresponding lack of FDG accumulation in nodes. The FDG pattern seen in suppressed patients resembles that of HIV-negative controls. Further studies in subjects with advanced disease may be useful to clarify the role of gut or mesenteric nodes as a reservoir of HIV in late-stage infection. In addition, serial evaluation of subjects with HIV before and after starting ART may be useful to determine the speed at which nodal uptake resolves.
We thank Dr. Clara C. Chen for her review of the manuscript and her constructive comments and critique.
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