Increased Metabolic Activity on 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in Human Immunodeficiency Virus-Associated Immune Reconstitution Inflammatory Syndrome

Abstract

Background: Immune reconstitution inflammatory syndrome (IRIS) represents an unexpected inflammatory response shortly after initiation of antiretroviral therapy (ART) in some human immunodeficiency virus (HIV)-infected patients with underlying neoplasia or opportunistic infections, including tuberculosis. We hypothesized that IRIS is associated with increased glycolysis and that 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) could help identify high-risk subjects.

Methods: In this prospective cohort study, 30 HIV-infected patients (CD4+ count <100 cells/µL) underwent FDG-PET/CT scans at baseline and 4-8 weeks after ART initiation. Ten patients developed IRIS (6 mycobacterial).

Results: At baseline, total glycolytic activity, total lesion volume, and maximum standardized uptake values (SUVs) of pathologic FDG uptake (reflective of opportunistic disease burden) were significantly higher in IRIS vs non-IRIS (P = .010, .017, and .029, respectively) and significantly correlated with soluble inflammatory biomarkers (interferon-γ, myeloperoxidase, tumor necrosis factor, interleukin 6, soluble CD14). Baseline bone marrow (BM) and spleen FDG uptake was higher in mycobacterial IRIS specifically. After ART initiation, BM and spleen mean SUV decreased in non-IRIS (P = .004, .013) but not IRIS subjects. Our results were supported by significantly higher glucose transporter 1 (Glut-1) expression of CD4+ cells and monocytes after ART initiation in IRIS/mycobacterial IRIS compared with non-IRIS patients.

Conclusions: We conclude that increased pathologic metabolic activity on FDG-PET/CT prior to ART initiation is associated with IRIS development and correlates with inflammatory biomarkers. Abnormally elevated BM and spleen metabolism is associated with mycobacterial IRIS, HIV viremia, and Glut-1 expression on CD4+ cells and monocytes.

Clinical trials registration: NCT02147405.

Figures

Figure 1.

Delineation method for estimating whole-body pathologic uptake values (lesion load). All regions with standardized uptake value (SUV) >4 are first automatically delineated throughout the regions of interest. This is followed by manual exclusion of regions of physiologic uptake, such as the myocardium, kidneys, and bladder. The final contour represents the whole-body pathologic 18F-fluorodeoxyglucose uptake for the patient. Mean SUV, maximum SUV, total glycolytic activity, and total lesion volume are then calculated. Note that in this patient, myocardial SUV values were below the threshold of 4 and thus the heart was not included in the comprehensive volume of interest and did not need to be excluded afterward. Abbreviations: FDG, 18F-fluorodeoxyglucose; SUV, standardized uptake value.

Figure 2.

Changes in whole-body pathologic 18F-fluorodeoxyglucose uptake (total glycolytic activity [TGA] and total lesion volume [TLV]) in representative non–immune reconstitution inflammatory syndrome (IRIS) and IRIS patients. A, A 26-year-old male non-IRIS subject (non-IRIS-05) who presented with diffuse mycobacterium avium complex lymphadenopathy in the neck, chest, abdomen, and pelvis with involvement of the axillary and inguinal lymph nodes (LNs; pink outline). Following antiretroviral therapy (ART) initiation, there was a marked improvement in his lesion load (blue outline) as is reflected in the decrease of both TGA and TLV. B, A 34-year-old male subject diagnosed with varicella zoster virus IRIS, involving >1 dermatome with lesions crossing the midline (IRIS-05). Mediastinal and hilar lymphadenopathy (pink outline) worsened after starting ART, with further involvement of upper abdominal LNs (blue outline). TGA and TLV increased after ART initiation by 153% and 131%, respectively. Abbreviations: ART, antiretroviral therapy; IRIS, immune reconstitution inflammatory syndrome.

Figure 3.

Mean standardized uptake values in individually assessed organs at baseline. Mycobacterial immune reconstitution inflammatory syndrome (IRIS) patient values are presented in red circles. P values between IRIS and non-IRIS (in black triangles) and between mycobacterial IRIS and non-IRIS (in red) are included. *Denotes statistical significance, P < .05. Abbreviations: IRIS, immune reconstitution inflammatory syndrome; LN, lymph node.

Figure 4.

Changes in spleen 18F-fluorodeoxyglucose (FDG) uptake in representative non–immune reconstitution inflammatory syndrome (IRIS) and IRIS patients. A, A 26-year-old male non-IRIS subject (non-IRIS-05) showing decreased spleen FDG uptake (black arrows) after antiretroviral therapy (ART) on coronal reconstruction positron emission tomography images of the upper abdomen. This is reflected as 45% decrease in mean standardized uptake (SUVmean) and 36% decrease in maximum standardized uptake (SUVmax) values with respect to baseline. B, A 37-year-old male IRIS subject (IRIS-01) with paradoxical mycobacterial IRIS showing slightly increased spleen FDG uptake (black arrows) after ART initiation with 22% increase in SUVmean and 19% increase in SUVmax values with respect to baseline. Abbreviations: ART, antiretroviral therapy; IRIS, immune reconstitution inflammatory syndrome; SUVmax, maximum standardized uptake value; SUVmean, mean standardized uptake value.

Figure 5.

Correlation of whole-body pathologic 18F-fluorodeoxyglucose uptake with inflammatory cellular and soluble biomarkers measured in all patients at baseline. Correlations for maximum standardized uptake, mean standardized uptake, total glycolytic activity, and total lesion values are shown. Abbreviations: CRP, C-reactive protein; GM-CSF, granulocyte macrophage–colony-stimulating factor; FDG, 18F-fluorodeoxyglucose; IFN, interferon; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; MPO, myeloperoxidase; sCD14, soluble CD14; sPD-1, soluble programmed death receptor-1; SUVmax, maximum standardized uptake; SUVmean, mean standardized uptake; TGA, total glycolytic activity; TLV, total lesion value; TNF, tumor necrosis factor.

Figure 6.

Immunophenotyping examples from mycobacterial immune reconstitution inflammatory syndrome (IRIS) and non-IRIS subjects. A, Glucose transporter 1 (Glut-1+) cells within the CD4+ cell population. B, Glut-1+ cells within the CD14+ cell population (monocytes). C and D, Distribution of Glut-1 percentage positive staining in CD4 and CD14 cells, respectively, at baseline and post–antiretroviral therapy initiation. Median values and interquartile ranges are shown. *xxx; **xxx. Abbreviations: ART, antiretroviral therapy; Glut-1, glucose transporter 1; HC, healthy control; IRIS, immune reconstitution inflammatory syndrome; myco-IRIS, mycobacterial immune reconstitution inflammatory syndrome.