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Biomedicines
Special Issues
Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome
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Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 12755

Special Issue Editors

Prof. Dr. Yasufumi Masaki

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Guest Editor
Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan
Interests: TAFRO syndrome; iMCD; IgG4-related disease; lymphoid malignancy; sjogren syndorme
Prof. Dr. Sadao Aoki

E-Mail Website
Guest Editor
Hematology Division, Faculty of Medical Technology, Niigata University of Pharmacy and Medical and Life Sciences, Niigata, Japan
Interests: CLL; lymphoid malignancy; TAFRO syndrome

Special Issue Information

Dear Colleagues,

This Special Issue, ‘Diagnosis, Pathogenesis and Treatment of TAFRO syndrome’, will mainly focus on the novel severe hyper-inflammatory disorder, called TAFRO syndrome, which was first reported in Japan in 2010. Because lymph node histology is similar in patients with TAFRO syndrome and Castleman disease, TAFRO syndrome is described as a related disorder of Castleman disease; however, the two conditions are markedly different clinically. Cases with hyper-inflammation syndrome, such as TAFRO syndrome, require intensive therapeutic strategy. Further understanding of TAFRO syndrome requires the identification of novel disease-specific biomarkers.
For this Special Issue, we invite authors to submit original research and review articles that focus on the diagnosis, pathogenesis and therapeutic potential of TAFRO syndrome. Potential topics include, but are not limited to, the following:

  • Clinical and Pathological diagnosis;
  • Relationship and differentiation with iMCD, IPL, POEMS syndrome, malignancies, infections and collagen-vascular disorders;
  • Cytokine, chemokine and other factors;
  • Therapeutic trials and experiences.

Prof. Dr. Yasufumi Masaki
Prof. Dr. Sadao Aoki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hyper-inflammation syndrome
  • thrombocytopenia
  • anasarca
  • multicentric Castleman disease
  • renal dysfunction
  • cytokine
  • neoplasm
  • infection
  • collagen-vascular disorder

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Published Papers (8 papers)

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Research

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9 pages, 732 KiB  
Article
Investigation of the Effect of Therapeutic Plasma Exchange for TAFRO Syndrome: A Pilot Study
by Kosuke Sonoda, Masamichi Komatsu, Yoko Ozawa, Hiroshi Yamamoto and Yuji Kamijo
Biomedicines 2024, 12(4), 849; https://doi.org/10.3390/biomedicines12040849 - 11 Apr 2024
Viewed by 1166
Abstract
TAFRO syndrome is a rare systemic inflammatory disorder with a fatal course. Nevertheless, a definitive treatment strategy has not yet been established. Anti-inflammatory therapies, including glucocorticoid treatment and immunosuppressants, have not been satisfactory. Therefore, new treatment options are needed for patients with TAFRO [...] Read more.
TAFRO syndrome is a rare systemic inflammatory disorder with a fatal course. Nevertheless, a definitive treatment strategy has not yet been established. Anti-inflammatory therapies, including glucocorticoid treatment and immunosuppressants, have not been satisfactory. Therefore, new treatment options are needed for patients with TAFRO syndrome. The effectiveness of therapeutic plasma exchange (TPE) has mainly been reported in several case reports. In this case series study, we investigated the effect of TPE on TAFRO syndrome. We reviewed six consecutive cases with TAFRO syndrome treated at Shinshu University Hospital. All of them underwent TPE. A significant improvement in mean blood pressure, albumin, total bilirubin, and C-reactive protein was observed after TPE. Furthermore, early TPE treatment was suggested to have an impact on the prognosis. More intensive studies are needed to emphasize the overall conclusion obtained that TPE can be an effective/acceptable treatment option for TAFRO syndrome. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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Review

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17 pages, 2376 KiB  
Review
Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO
by Gordan Srkalovic, Sally Nijim, Maya Blanka Srkalovic and David Fajgenbaum
Biomedicines 2024, 12(6), 1328; https://doi.org/10.3390/biomedicines12061328 - 14 Jun 2024
Cited by 3 | Viewed by 1130
Abstract
TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be [...] Read more.
TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be seen in pathological contexts outside of iMCD, but it is unclear if those cases should be considered representative of a different disease entity or simply a severe presentation of other infectious, malignant, and rheumatological diseases. While interleukin-6 (IL-6) is an established driver of iMCD-TAFRO pathogenesis in a subset of patients, the etiology is unknown. Recent case reports and literature reviews on TAFRO patients suggest that vascular endothelial growth factor (VEGF), and the interplay of VEGF and IL-6 in concert, rather than IL-6 as a single cytokine, may be drivers for iMCD-TAFRO pathophysiology, especially renal injury. In this review, we discuss the possible role of VEGF in the pathophysiology and clinical manifestations of iMCD-TAFRO. In particular, VEGF may be involved in iMCD-TAFRO pathology through its ability to activate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Further elucidating a role for the VEGF-IL-6 axis and additional disease drivers may shed light on therapeutic options for the treatment of TAFRO patients who do not respond to, or otherwise relapse following, treatment with IL-6 targeting drugs. This review investigates the potential role of VEGF in the pathophysiology of iMCD-TAFRO and the potential for targeting related signaling pathways in the future. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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13 pages, 266 KiB  
Review
TAFRO Syndrome and COVID-19
by Misato Tane, Hideki Kosako, Takashi Sonoki and Hiroki Hosoi
Biomedicines 2024, 12(6), 1287; https://doi.org/10.3390/biomedicines12061287 - 11 Jun 2024
Cited by 1 | Viewed by 1339
Abstract
TAFRO syndrome is a systemic inflammatory disease characterized by thrombocytopenia and anasarca. It results from hyperinflammation and produces severe cytokine storms. Severe acute respiratory syndrome coronavirus 2, which led to the coronavirus disease 2019 (COVID-19) pandemic, also causes cytokine storms. COVID-19 was reported [...] Read more.
TAFRO syndrome is a systemic inflammatory disease characterized by thrombocytopenia and anasarca. It results from hyperinflammation and produces severe cytokine storms. Severe acute respiratory syndrome coronavirus 2, which led to the coronavirus disease 2019 (COVID-19) pandemic, also causes cytokine storms. COVID-19 was reported to be associated with various immune-related manifestations, including multisystem inflammatory syndrome, hemophagocytic syndrome, vasculitis, and immune thrombocytopenia. Although the pathogenesis and complications of COVID-19 have not been fully elucidated, the pathogeneses of excessive immunoreaction after COVID-19 and TAFRO syndrome both involve cytokine storms. Since the COVID-19 pandemic, there have been a few case reports about the onset of TAFRO syndrome after COVID-19 or COVID-19 vaccination. Castleman disease also presents with excessive cytokine production. We reviewed the literature about the association between TAFRO syndrome or Castleman disease and COVID-19 or vaccination against it. While the similarities and differences between the pathogeneses of TAFRO syndrome and COVID-19 have not been investigated previously, the cytokines and genetic factors associated with TAFRO syndrome and COVID-19 were reviewed by examining case reports. Investigation of TAFRO-like manifestations after COVID-19 or vaccination against COVID-19 may contribute to understanding the pathogenesis of TAFRO syndrome. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
13 pages, 2550 KiB  
Review
TAFRO Syndrome: Guidance for Managing Patients Presenting Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly
by Katsuhiro Miura, Haruna Nishimaki-Watanabe, Hiromichi Takahashi, Masaru Nakagawa, Shimon Otake, Takashi Hamada, Takashi Koike, Kazuhide Iizuka, Yuuichi Takeuchi, Kazuya Kurihara, Toshihide Endo, Shun Ito, Hironao Nukariya, Takahiro Namiki, Yoshiyuki Hayashi and Hideki Nakamura
Biomedicines 2024, 12(6), 1277; https://doi.org/10.3390/biomedicines12061277 - 8 Jun 2024
Cited by 1 | Viewed by 1708
Abstract
TAFRO syndrome is an inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly. Despite great advancements in research on the TAFRO syndrome in the last decade, its diagnosis and treatment are still challenging for most clinicians [...] Read more.
TAFRO syndrome is an inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly. Despite great advancements in research on the TAFRO syndrome in the last decade, its diagnosis and treatment are still challenging for most clinicians because of its rarity and severity. Since the initial proposal of the TAFRO syndrome as a distinct disease entity in 2010, two independent diagnostic criteria have been developed. Although these are different in the concept of whether TAFRO syndrome is a subtype of idiopathic multicentric Castleman disease or not, they are similar except for the magnitude of lymph node histopathology. Because there have been no specific biomarkers, numerous diseases must be ruled out before the diagnosis of TAFRO syndrome is made. The standard of care has not been fully established, but interleukin-6 blockade therapy with siltuximab or tocilizumab and anti-inflammatory therapy with high-dose corticosteroids are the most commonly applied for the treatment of TAFRO syndrome. The other immune suppressive agents or combination cytotoxic chemotherapies are considered for patients who do not respond to the initial treatment. Whereas glowing awareness of this disease improves the clinical outcomes of patients with TAFRO syndrome, further worldwide collaborations are warranted. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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14 pages, 6427 KiB  
Review
Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives
by Juan Carlos Caballero, Nazaret Conejero, Laura Solan, Francisco Javier Diaz de la Pinta, Raul Cordoba and Alberto Lopez-Garcia
Biomedicines 2024, 12(5), 1076; https://doi.org/10.3390/biomedicines12051076 - 13 May 2024
Cited by 2 | Viewed by 2005
Abstract
TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman’s disease. However, distinct clinical and histological features warrant [...] Read more.
TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman’s disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman’s disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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Other

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10 pages, 2034 KiB  
Case Report
Tacrolimus Treatment for TAFRO Syndrome
by Taiichiro Shirai, Shinya Ichikawa and Jun Saegusa
Biomedicines 2024, 12(5), 1070; https://doi.org/10.3390/biomedicines12051070 - 12 May 2024
Viewed by 1105
Abstract
TAFRO syndrome is an acute systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. While its lymph node pathology is similar to that of idiopathic multicentric Castleman disease (iMCD), the clinical features of TAFRO syndrome differ from those [...] Read more.
TAFRO syndrome is an acute systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. While its lymph node pathology is similar to that of idiopathic multicentric Castleman disease (iMCD), the clinical features of TAFRO syndrome differ from those of typical iMCD, as they include a more aggressive clinical course and high mortality. However, an optimal treatment strategy for TAFRO syndrome has not yet been established, owing to a poor understanding of its pathogenesis. The limited cases we encountered suggest that tacrolimus treatment in combination with glucocorticoids may potentially be effective and well tolerated as an initial treatment, and hold promise as a glucocorticoid-sparing agent. Herein, we report an additional case and review the sparse literature available regarding TAFRO syndrome treated via tacrolimus. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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12 pages, 1711 KiB  
Systematic Review
Radiological Imaging Findings of Adrenal Abnormalities in TAFRO Syndrome: A Systematic Review
by Ryo Kurokawa, Akira Baba, Rui Kano, Yo Kaneko, Mariko Kurokawa, Wataru Gonoi and Osamu Abe
Biomedicines 2024, 12(4), 837; https://doi.org/10.3390/biomedicines12040837 - 10 Apr 2024
Cited by 4 | Viewed by 1476
Abstract
This systematic review article aims to investigate the clinical and radiological imaging characteristics of adrenal abnormalities in patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome. We searched the literature in PubMed, the Cochrane Library, and the Web of [...] Read more.
This systematic review article aims to investigate the clinical and radiological imaging characteristics of adrenal abnormalities in patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome. We searched the literature in PubMed, the Cochrane Library, and the Web of Science Core Collection. Ultimately, we analyzed 11 studies with 22 patients plus our 1 patient, totaling 23 patients. The mean age was 47.0 ± 12.6 years. There were 20 male and 3 female patients, respectively. The histopathological analysis of lymph nodes was conducted in 15 patients (65.2%), and the diagnosis was consistent with TAFRO syndrome in all 15 patients. Among the 23 patients, 11 patients (18 adrenal glands) showed adrenal ischemia/infarction, 9 patients (13 adrenal glands) showed adrenal hemorrhage, and 4 patients (7 adrenal glands) showed adrenomegaly without evidence of concurrent ischemia/infarction or hemorrhage. One patient demonstrated unilateral adrenal hemorrhage and contralateral adrenomegaly. In patients with adrenal ischemia/infarction, the adrenal glands displayed poor enhancement through contrast-enhanced computed tomography (CT). In patients with adrenal hemorrhage, the adrenal glands revealed high attenuation through non-enhanced CT and hematoma through magnetic resonance imaging. Adrenomegaly, with or without adrenal ischemia/infarction or hemorrhage, was observed in all patients (23/23, 100%). The subsequent calcification of the affected adrenal glands was frequently observed (9/14, 64.3%) when a follow-up CT was performed. Abdominal pain was frequent (15/23, 65.2%), all of which occurred after the disease’s onset, suggesting the importance of considering TAFRO syndrome as a cause of acute abdomen. Given the absence of evidence of adrenal abnormalities in non-TAFRO-idiopathic multicentric Castleman disease (iMCD), they may serve as diagnostic clues for differentiating TAFRO syndrome from non-TAFRO-iMCD. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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7 pages, 178 KiB  
Viewpoint
TAFRO Syndrome: A Syndrome or a Subtype of Multicentric Castleman Disease?
by Kazue Takai
Biomedicines 2024, 12(3), 652; https://doi.org/10.3390/biomedicines12030652 - 14 Mar 2024
Cited by 1 | Viewed by 1655
Abstract
TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow/renal dysfunction, organomegaly) syndrome is a systemic inflammatory disorder of unknown etiology. It has been recognized as a subtype of idiopathic multicentric Castleman disease (iMCD), and the international diagnostic criteria for iMCD-TAFRO require a lymph [...] Read more.
TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow/renal dysfunction, organomegaly) syndrome is a systemic inflammatory disorder of unknown etiology. It has been recognized as a subtype of idiopathic multicentric Castleman disease (iMCD), and the international diagnostic criteria for iMCD-TAFRO require a lymph node histopathology consistent with iMCD. Furthermore, TAFRO syndrome is defined as a heterogeneous clinical entity caused by underlying diseases such as malignancy, autoimmune diseases, or infections. However, the cases that led to the proposal of TAFRO syndrome lacked recognizable lymphadenopathy and were inconsistent with any other diseases, despite vigorous efforts in differential diagnosis. Irrespective of the presence or absence of Castleman disease (CD)-like histology, TAFRO syndrome exhibits homogeneous clinical, laboratory, and prognostic features, setting it apart from iMCD without TAFRO syndrome. Defining iMCD-TAFRO apart from TAFRO syndrome is deemed meaningless and confusing. MCD is a heterogeneous lymphoproliferative disorder consisting of several subtypes with different pathogenesis, clinical manifestations, and histological features. Typical MCD in Japan, characterized by the histology of plasma cell type and marked polyclonal hypergammaglobulinemia, is identical to idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). Although IPL is classified into iMCD-NOS (not otherwise specified), it should be recognized as a distinct clinicopathological entity. Furthermore, we propose to separate TAFRO syndrome from the MCD category as a defined disorder. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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