TY - JOUR
T1 - Unsupervised Clustering Reveals Sarcoidosis Phenotypes Marked by a Reduction in Lymphocytes Relate to Increased Inflammatory Activity on 18FDG-PET/CT
AU - Vagts, Christen
AU - Ascoli, Christian
AU - Fraidenburg, Dustin R.
AU - Baughman, Robert P.
AU - Huang, Yue
AU - Edafetanure-Ibeh, Russell
AU - Ahmed, Samreen
AU - Levin, Benjamin
AU - Lu, Yang
AU - Perkins, David L.
AU - Finn, Patricia W.
AU - Sweiss, Nadera J.
N1 - Funding Information:
The authors would like to thank Martha Menchaca, MD Ph.D. for acquiring 18FDG-PET-CT images and transferring to DICOM format. Funding. Support for this study was provided by NIH grant numbers: R01 HL138628-01A1S1 and T32 HL144909; the Bernie Mac Foundation; and a donation by the University of Illinois at Chicago Vice-Chancellor of Health Affairs, Robert Barish, MD MBA.
Publisher Copyright:
© Copyright © 2021 Vagts, Ascoli, Fraidenburg, Baughman, Huang, Edafetanure-Ibeh, Ahmed, Levin, Lu, Perkins, Finn and Sweiss.
PY - 2021/2/24
Y1 - 2021/2/24
N2 - Introduction: Sarcoidosis is a T-helper cell mediated disease characterized by granulomatous inflammation. We posited that unsupervised clustering of various features in sarcoidosis would establish phenotypes associated with inflammatory activity measured by 18FDG-PET/CT. Our goal was to identify unique features capable of distinguishing clusters and subsequently examine the relationship with FDG avidity to substantiate their potential use as markers for sarcoidosis inflammation. Methods: We performed a retrospective study of a diverse, but primarily African American, cohort of 58 subjects with biopsy proven sarcoidosis followed at the University of Illinois Bernie Mac Sarcoidosis Center and Center for Lung Health who underwent 18FDG-PET/CT scan. Demographic, therapeutic, radiographic, and laboratory data were utilized in unsupervised cluster analysis to identify sarcoidosis phenotypes. The association between clusters, their defining features, and quantitative measurements on 18FDG-PET/CT was determined. The relevance of these features as markers of 18FDG-PET/CT inflammatory activity was also investigated. Results: Clustering determined three distinct phenotypes: (1) a predominantly African American cluster with chronic, quiescent disease, (2) a predominantly African American cluster with elevated conventional inflammatory markers, advanced pulmonary disease and extrathoracic involvement, and (3) a predominantly Caucasian cluster characterized by reduced lymphocyte counts and acute disease. In contrast to the chronic quiescent cluster, Clusters 2 and 3 were defined by significantly greater FDG avidity on 18FDG-PET/CT. Despite similarly increased inflammatory activity on 18FDG-PET/CT, Clusters 2, and 3 differed with regards to extrathoracic FDG avidity and circulating lymphocyte profiles, specifically CD4+ T-cells. Notably, absolute lymphocyte counts and CD4+ T-cell counts were found to predict 18FDG-PET/CT inflammatory activity by receiver operating curve analysis with a 69.2 and 73.42% area under the curve, respectively. Conclusions: Utilizing cluster analysis, three distinct phenotypes of sarcoidosis were identified with significant variation in race, disease chronicity, and serologic markers of inflammation. These phenotypes displayed varying levels of circulating inflammatory cells. Additionally, reduction in lymphocytes, specifically CD4+ T-cells, was significantly related to activity on 18FDG-PET/CT. Though future studies are warranted, these findings suggest that peripheral lymphocyte counts may be considered a determinant of sarcoidosis phenotypes and an indicator of active inflammation on 18FDG-PET/CT.
AB - Introduction: Sarcoidosis is a T-helper cell mediated disease characterized by granulomatous inflammation. We posited that unsupervised clustering of various features in sarcoidosis would establish phenotypes associated with inflammatory activity measured by 18FDG-PET/CT. Our goal was to identify unique features capable of distinguishing clusters and subsequently examine the relationship with FDG avidity to substantiate their potential use as markers for sarcoidosis inflammation. Methods: We performed a retrospective study of a diverse, but primarily African American, cohort of 58 subjects with biopsy proven sarcoidosis followed at the University of Illinois Bernie Mac Sarcoidosis Center and Center for Lung Health who underwent 18FDG-PET/CT scan. Demographic, therapeutic, radiographic, and laboratory data were utilized in unsupervised cluster analysis to identify sarcoidosis phenotypes. The association between clusters, their defining features, and quantitative measurements on 18FDG-PET/CT was determined. The relevance of these features as markers of 18FDG-PET/CT inflammatory activity was also investigated. Results: Clustering determined three distinct phenotypes: (1) a predominantly African American cluster with chronic, quiescent disease, (2) a predominantly African American cluster with elevated conventional inflammatory markers, advanced pulmonary disease and extrathoracic involvement, and (3) a predominantly Caucasian cluster characterized by reduced lymphocyte counts and acute disease. In contrast to the chronic quiescent cluster, Clusters 2 and 3 were defined by significantly greater FDG avidity on 18FDG-PET/CT. Despite similarly increased inflammatory activity on 18FDG-PET/CT, Clusters 2, and 3 differed with regards to extrathoracic FDG avidity and circulating lymphocyte profiles, specifically CD4+ T-cells. Notably, absolute lymphocyte counts and CD4+ T-cell counts were found to predict 18FDG-PET/CT inflammatory activity by receiver operating curve analysis with a 69.2 and 73.42% area under the curve, respectively. Conclusions: Utilizing cluster analysis, three distinct phenotypes of sarcoidosis were identified with significant variation in race, disease chronicity, and serologic markers of inflammation. These phenotypes displayed varying levels of circulating inflammatory cells. Additionally, reduction in lymphocytes, specifically CD4+ T-cells, was significantly related to activity on 18FDG-PET/CT. Though future studies are warranted, these findings suggest that peripheral lymphocyte counts may be considered a determinant of sarcoidosis phenotypes and an indicator of active inflammation on 18FDG-PET/CT.
KW - 18FDG-PET/CT
KW - cluster analysis
KW - immunopathogenesis
KW - lymphopenia
KW - phenotype
KW - sarcoidosis
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U2 - 10.3389/fmed.2021.595077
DO - 10.3389/fmed.2021.595077
M3 - Article
C2 - 33718397
AN - SCOPUS:85102385689
SN - 2296-858X
VL - 8
JO - Frontiers in Medicine
JF - Frontiers in Medicine
M1 - 595077
ER -