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Comparison of 18F-FDG PET/CT and 67Ga-SPECT for the diagnosis of fever of unknown origin: a multicenter prospective study in Japan

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Abstract

Objective

The aim of this multicenter prospective study was to compare the sensitivity of 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) with that of 67Ga single photon emission computed tomography (SPECT) for the identification of the site of greatest importance for the final diagnosis of the cause of fever of unknown origin (FUO).

Methods

The study participants consisted of patients with an axillary temperature ≥ 38.0 °C on ≥ 2 occasions within 1 week, with repeated episodes for ≥ 2 weeks prior to providing consent, and whose final diagnosis after undergoing specific examinations, including a chest-to-abdomen CT scan, was uncertain. All the patients underwent FDG-PET/CT imaging first, followed by 67Ga-SPECT imaging within 3 days. The results of the FDG-PET/CT and 67Ga-SPECT examinations were reviewed by the central image interpretation committee (CIIC), which was blinded to all other clinical information. The sensitivities of FDG-PET/CT and 67Ga-SPECT were then evaluated with regard to identifying the site of greatest importance for a final diagnosis of the cause of the fever as decided by the patient’s attending physician. The clinical impacts (four grades) of FDG-PET/CT and 67Ga-SPECT on the final diagnosis were evaluated.

Results

A total of 149 subjects were enrolled in this study between October 2014 and September 2017. No adverse events were identified among the enrolled subjects. Twenty-one subjects were excluded from the study because of deviations from the study protocol. Among the 128 remaining subjects, a final diagnosis of the disease leading to the appearance of FUO was made for 92 (71.9%) subjects. The final diagnoses in these 92 cases were classified into four groups: noninfectious inflammatory disease (52 cases); infectious disease (31 cases), malignancy (six cases); and other (three cases). These 92 subjects were eligible for inclusion in the study’s analysis, but one case did not meet the PET/CT image acquisition criteria; thus, PET/CT results were analyzed for 91 cases. According to the patient-based assessments, the sensitivity of FDG-PET/CT (45%, 95% CI 33.1–58.2%) was significantly higher than that for 67Ga-SPECT (25%, 95% CI 15.5–37.5%) (P = 0.0029). The clinical impact of FDG-PET/CT (91%) was also significantly higher than that for 67Ga-SPECT (57%, P < 0.001).

Conclusions

FDG-PET/CT showed a superior sensitivity to 67Ga-SPECT for the identification of the site of greatest importance for the final diagnosis of the cause of FUO.

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Acknowledgements

No potential conflicts of interest were disclosed. We thank all the research collaborators, research coordinators, radiochemistry staff, nuclear medicine technologists, third-party monitors at each facility, third-party auditors, the Japan Clinical Research Assist Center, Tokyo, Japan, and all the patients who agreed to participate in the study. The members of this study are listed below.

Contributors to the research group of the Japanese multi-center FDG-PET/CT study for FUO (JPET-FUO)*

Primary Investigator: Ryogo Minamimoto (from April 2016). Former primary investigator: Kazuo Kubota (from 2012 to March 2016). Central office: National Center for Global Health and Medicine, Tokyo 162–8655 Japan. Protocol committee: Masao Kobayakawa (C.), Noriko Tanaka, Yasuhiro Tanaka, Shizue Izumi, Kazuo Kubota. Statistician: Noriko Tanaka (C.), Joe Matsuoka, Yosuke Inaba. Data management: Yasuhiro Tanaka, Hiroshi Ohtsu, Akemi Yasuhara and JCRAC Data Center National Center for Global Health and Medicine. Image Quality Control: Kei Sato, Hironori Kajiwara. Secretariat: Yoko Miyata (C.), Yukie Ando, Aiko Tomita, Kaoru Sugawara, Kahori Miyake. Clinical research coordinator: Hiromi Wada, Otoe Hirai, Mari Terada. Monitoring: Yuichi Nozaki, Kiyoshi Takase, Haruhiko Sakamoto, Naoko Goto, Yasuo Naito. Audit: Yumi Matsushita, Akira Kitagawa, Haruhisa Kubota. Central image interpretation committee: Hiroaki Kurihara, Masamichi Koyama, Shinichi Taura. Observer: Kiyoyuki Kodama, Fumio Sunaoka. The final assessment committee: Kenji Itoh, Hiroyuki Nagase, Keiichi Ishihara, Koichiro Abe. Observer: Aiko Tomita.

Clinical investigators and Institutions*

National Center for Global Health and Medicine, Tokyo 162–8655 Japan.

Kazuo Kubota, Ryogo Minamimoto, Miyako Morooka, Momoko Okasaki, Masashi Kameyama, Masatoshi Hotta, On Kato, Junwa Kunimatsu, Junko Maeda, Tatsuya Sato, Masaaki Maki, Satosi Fujie, Mikiko Arai, Ayumu Kawakami, Ippei Suzuki, Kenichi Hiraga, Hiroshi Kaneko, Hiroyuki Yamashita, Masanori Kawano, Hiroaki Hatano, Arisa Yashima, Akio Mimori, Norio Ohmagari, Satoshi Kutsuna, Kei Yamamoto, Yuichi Katanami, Yoshihiro Fujiya, Momoko Mawatari, Kayoko Hayakawa, Akiyoshi Hagiwara, Yoshimi Kikuchi, Satoshi Shibata, Yasuaki Yanagawa, Shinichi Oka.

Tohoku University Hospital, Sendai 980–8574 Japan.

Yasuyuki Taki, Hideo Shimomura, Tomonori Ishii.

Yokohama City University Hospital, Yokohama 236–0004 Japan.

Tsuyoshi Kawano, Tomohiro Kaneta, Ryo Fujita, Ryusuke Yoshimi.

Tokyo Medical and Dental University Medical Hospital, Tokyo 113–8519 Japan.

Ukihide Tateishi, Akira Toriihara, Jun Oyama, Waka Yokoyama, Yusuke Matsuo.

Yamagata University Hospital, Yamagata 990–9585 Japan.

Kazukuni Kirii.

Osaka City University Hospital, Osaka 545–8586 Japan.

Joji Kawabe, Shigeaki Higashiyama, Shigeki Kinuhata, Noriyuki Hayashi, Norikazu Toi.

Kagawa University Hospital, Kagawa 761–0793 Japan.

Yoshihiro Nishiyama, Yuka Yamamoto, Hanae Okuda, Shusaku Nakashima, Risa Wakiya, Yohei Takeuchi, Hiroki Ozaki, Hiroaki Dobashi.

Osaka University Hospital, Osaka 565–0871 Japan.

Jun Hatazawa, Hiroki Kato, Sumiyuki Nishida.

Keio University Hospital, Tokyo 160–8582 Japan.

Koji Murakami, Tadaki Nakahara, Yasushi Kondo, Kotaro Matsumoto.

University of Miyazaki Hospital, Miyazaki 889–1692 Japan.

Shigeki Nagamachi, Youichi Mizutani, Kunihiko Umekita.

Public Central Hospital of Matto Ishikawa, Ishikawa 924–8588 Japan.

Kunihiko Yokoyama.

Osaka Saiseikai Nakatsu Hospital, Osaka 530–0012 Japan.

Terue Okamura.

Tokyo Metropolitan Geriatric Hospital, Tokyo 173–0015 Japan.

Masashi Kameyama.

Dokkyo Medical University Hospital, Tochigi 321–0293 Japan.

Setsu Sakamoto, Takanobu Hirosawa, Yuta Takamura, Harutsugu Okada, Taku Harada.

Kyoto University Hospital, Kyoto 606–8507 Japan.

Yuji Nakamoto, Takayoshi Ishimori, Yoshitaka Imura, Ran Sasai, Nobuo Kuramoto.

Nagasaki University Hospital, Nagasaki 852–8501 Japan.

Takashi Kudo, Toshimasa Shimizu, Yushiro Endo, Yoko Obata, Ayuko Takatani, Shota Nakashima.

Kyushu University Hospital, Fukuoka 812–8582 Japan.

Shingo Baba, Masayuki Murata.

*Note: The affiliation of each investigator was for during the study. Titles are not shown because of space limitations. C.: Chief.

Funding

This work was supported in part by a Grant from the National Center for Global Health and Medicine (24–203, 26–116 and 29–1038).

Author information

Authors and Affiliations

  1. Division of Nuclear Medicine, National Center for Global Health and Medicine, Tokyo, Japan

    Kazuo Kubota, Yoko Miyata & Ryogo Minamimoto

  2. Department of Radiology, Southern TOHOKU General Hospital, Koriyama City, 7-115 Yatsuyamada, Fukushima, 963-8563, Japan

    Kazuo Kubota

  3. Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan

    Noriko Tanaka & Masao Kobayakawa

  4. Department of Radiology, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan

    Yoko Miyata

  5. Clinical Epidemiology/JCRAC Data Center, Department of Data Science National Center for Global Health and Medicine Center for Clinical Sciences, Tokyo, Japan

    Hiroshi Ohtsu

  6. Department of Radiology, Keio University School of Medicine, Tokyo, Japan

    Tadaki Nakahara & Koji Murakami

  7. PET Center, Dokkyo Medical University Hospital, Tochigi, Japan

    Setsu Sakamoto

  8. Department of Diagnostic Radiology, Hyogo Cancer Center, Hyogo, Japan

    Setsu Sakamoto

  9. Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Takashi Kudo

  10. Department of Radiology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Yoshihiro Nishiyama

  11. Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Ukihide Tateishi

  12. Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Yuji Nakamoto

  13. Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

    Yasuyuki Taki

  14. Department of Radiology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan

    Tomohiro Kaneta & Tsuyoshi Kawano

  15. Department of Nuclear Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan

    Joji Kawabe

  16. Department of Radiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Shigeki Nagamachi & Youichi Mizutani

  17. Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University, Osaka, Japan

    Jun Hatazawa

  18. Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shingo Baba

  19. Department of Diagnostic Radiology, Yamagata University, Faculty of Medicine, Yamagata, Japan

    Kazukuni Kirii

  20. Department of Thyroidology, Public Central Hospital of Matto Ishikawa, Ishikawa, Japan

    Kunihiko Yokoyama

  21. PET Center, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan

    Terue Okamura

  22. Department of Diagnostic Radiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan

    Masashi Kameyama

  23. Department of General Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan

    Junwa Kunimatsu & On Kato

  24. Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo, Japan

    Hiroyuki Yamashita & Hiroshi Kaneko

  25. Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan

    Satoshi Kutsuna & Norio Ohmagari

  26. Department of Emergency Medicine and Critical Care, National Center for Global Health and Medicine, Tokyo, Japan

    Akiyoshi Hagiwara

  27. AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan

    Yoshimi Kikuchi

  28. Medical Research Center, Fukushima Medical University, Fukushima, Japan

    Masao Kobayakawa

Authors
  1. Kazuo Kubota
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  2. Noriko Tanaka
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  3. Yoko Miyata
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  6. Setsu Sakamoto
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  7. Takashi Kudo
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  9. Ukihide Tateishi
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  10. Koji Murakami
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  13. Tomohiro Kaneta
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  20. Kazukuni Kirii
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  22. Terue Okamura
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  23. Masashi Kameyama
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  24. Ryogo Minamimoto
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  25. Junwa Kunimatsu
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  26. On Kato
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  32. Yoshimi Kikuchi
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  33. Masao Kobayakawa
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Corresponding author

Correspondence to Kazuo Kubota.

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Appendix

Appendix

List of PET/CT and SPECT equipment (and their manufacturers) used in this study

(Note: The names of the institutions have been withheld, because the imaging data were handled in a manner such that the evaluators were blinded to both the patient information and the institution).

PET/CT

Discovery 710 (General Electric).

Discovery PET/CT 600 M (General Electric).

Discovery STE (General Electric).

Biograph16 (Siemens).

Biograph mCT-S(64) 4R (Siemens).

Biograph mCT40 4R (Siemens).

Biograph mCT-S(40)3R (Siemens).

Biograph mCT-X3R (Siemens).

Biograph Sensation 16 (Siemens).

True point Biograph40 (Siemens).

Aquiduo (Toshiba).

Celesteion (Toshiba).

SPECT (including SPECT/CT)

Discovery NM/CT670 NT1008 (General Electric).

Infinia Hawkeye4 (General Electric).

Infinia GP3 (General Electric).

Bright View X (Philips).

Symbia E 4C-2 (Siemens).

Symbia E 4G-1 (Siemens).

Symbia Intevo NM07 (Siemens).

Symbia S (Siemens).

Symbia T (Siemens).

Symbia T16 (Siemens).

Symbia T16 1091 (Siemens).

Symbia T16 1092 (Siemens).

Symbia T16 1213 (Siemens).

Symbia T16 1279 (Siemens).

Symbia T6 NM04 (Siemens).

Symbia E (Toshiba).

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Kubota, K., Tanaka, N., Miyata, Y. et al. Comparison of 18F-FDG PET/CT and 67Ga-SPECT for the diagnosis of fever of unknown origin: a multicenter prospective study in Japan. Ann Nucl Med 35, 31–46 (2021). https://doi.org/10.1007/s12149-020-01533-z

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