What is TAFRO (Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis, and Organomegaly) syndrome?

TAFRO Syndrome: A Rare and Aggressive Inflammatory Disorder

Definition and Core Features

TAFRO syndrome is a rare, rapidly progressive, and potentially fatal systemic inflammatory disorder characterized by five cardinal features: Thrombocytopenia, Anasarca (edema, pleural effusion, and ascites), Fever, Reticulin fibrosis (or renal insufficiency), and Organomegaly with Castleman disease-like histological features in lymph nodes. 1, 2

The syndrome was first described in Japan in 2010 and represents a distinct clinical entity, though its relationship to idiopathic multicentric Castleman disease (iMCD) remains controversial 2, 3, 4. The etiology remains unknown, but complex molecular signaling pathways including JAK-STAT, NF-kB, and signal amplifiers such as IL-6 and VEGF are involved 3.

Clinical Presentation

Cardinal Features

• Thrombocytopenia: Severe platelet count reduction, distinguishing TAFRO from typical multicentric Castleman disease 4
• Anasarca: Generalized edema with pleural effusion and ascites that can be treatment-resistant 1, 5
• Fever: Persistent fever or inflammatory syndrome with elevated C-reactive protein 1, 5, 4
• Reticulin fibrosis or renal dysfunction: Bone marrow biopsy shows reticulin myelofibrosis; renal insufficiency with progressive creatinine elevation 5, 4
• Organomegaly: Hepatomegaly, splenomegaly, and lymphadenopathy (typically mild to moderate) 2, 4

Additional Clinical Features

• Anemia and leukopenia may be present 4
• Elevated alkaline phosphatase and hepatic transaminases 4
• Hypoalbuminemia from capillary leak 2
• Rare complications include adrenal necrosis (without hemorrhage), thrombotic microangiopathy on renal biopsy, and severe hypothyroidism 5, 4

Diagnostic Approach

Essential Diagnostic Criteria

Two independent diagnostic criteria exist, differing primarily in whether TAFRO syndrome is considered a subtype of iMCD or a distinct entity, but both require similar clinical and laboratory features except for the magnitude of lymph node histopathology 2.

Critical diagnostic steps include:

• Complete blood count: Documenting severe thrombocytopenia, anemia, and potential leukopenia 4
• Peripheral blood smear: Excluding pseudothrombocytopenia from EDTA-dependent platelet agglutination 6
• Inflammatory markers: Elevated C-reactive protein and IL-6 levels 1, 5
• Bone marrow biopsy: Demonstrating reticulin myelofibrosis 5, 4
• Lymph node biopsy: Showing Castleman disease-like histological features 2
• Renal biopsy: May reveal thrombotic microangiopathy with double contours of glomerular basement membrane, mesangiolysis, and endothelial swelling 5
• Imaging: CT scan to document ascites, organomegaly, and lymphadenopathy 4

Differential Diagnosis and Exclusions

Because no specific biomarkers exist, numerous diseases must be ruled out before diagnosing TAFRO syndrome 2:

• Hemophagocytic syndrome: Fever, hepatosplenomegaly, and cytopenias, but typically associated with viral infections (CMV, EBV) or malignancy 7
• Thrombotic thrombocytopenic purpura (TTP): Neurologic manifestations, renal failure, and thrombocytopenia, but distinguished by schistocytes on peripheral smear 7, 6
• Adult-onset Still's disease: Quotidian fever, evanescent rash, arthritis, and elevated ferritin, but lacks the anasarca and lymph node pathology of TAFRO 7
• Systemic lupus erythematosus: Constitutional symptoms, hepatomegaly, lymphadenopathy with secondary immune thrombocytopenia 8
• HIV and hepatitis C: Can cause thrombocytopenia and systemic inflammation; mandatory testing in all adults with unexplained thrombocytopenia 6, 8
• Idiopathic multicentric Castleman disease: Shares histological features but typically lacks severe thrombocytopenia 2, 3

Treatment Strategy

First-Line Therapy

High-dose corticosteroids combined with IL-6 blockade (tocilizumab or siltuximab) represent the most commonly applied initial treatment for TAFRO syndrome. 2, 3

• Corticosteroids: Methylprednisolone or equivalent high-dose glucocorticoids as anti-inflammatory therapy 1, 5, 4
• IL-6 blockade: Tocilizumab (anti-IL-6 receptor antibody) or siltuximab (anti-IL-6 antibody) targeting the IL-6 signaling pathway 5, 2, 3

Stepwise Immunotherapy for Refractory Cases

For steroid-refractory TAFRO syndrome, rituximab induction therapy followed by cyclosporine maintenance therapy is effective if initiated at an early stage. 1

The treatment algorithm for refractory disease:

1. Rituximab induction: Normalizes C-reactive protein and IL-6 levels, though ascites may persist with increasing resistance 1
2. Cyclosporine maintenance: Administered when rituximab resistance develops; leads to resolution of ascites and sustained remission 1
3. Alternative agents: Other immunosuppressive agents or combination cytotoxic chemotherapies for patients who do not respond to initial treatment 2

Combination Therapy

The triple combination of corticosteroids, tocilizumab, and rituximab has been successfully used in severe cases with thrombotic microangiopathy and hypothyroidism 5.

Prognosis and Critical Considerations

Mortality Risk

TAFRO syndrome is a rapidly progressive and potentially fatal disease 1, 2. Delay in diagnosis and treatment initiation significantly increases mortality risk, similar to Rocky Mountain spotted fever where treatment after the fifth day of illness increases death rates 7.

Timing of Intervention

Early intervention with appropriate targeted treatment is critical for survival. 2 The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of:

• Maintaining high clinical suspicion in cases of unexplained thrombocytopenia with systemic inflammation 2
• Rapid initiation of immunosuppressive therapy once diagnosis is established 1, 4
• Avoiding delays from extensive differential diagnosis workup when clinical features are highly suggestive 2

Treatment-Related Complications

Immunosuppressive therapy carries significant risks:

• Opportunistic infections: Herpes zoster encephalitis leading to death has been reported in patients receiving multiple immunosuppressive agents 1
• Treatment resistance: Some patients show persistent symptoms despite methylprednisolone, rituximab, tocilizumab, and cyclosporine 1

Common Pitfalls to Avoid

• Misdiagnosing as primary immune thrombocytopenia (ITP): TAFRO syndrome presents with systemic features (fever, organomegaly, anasarca) that distinguish it from ITP, which typically shows isolated thrombocytopenia with normal physical examination except bleeding manifestations 6
• Delaying bone marrow biopsy: Reticulin myelofibrosis is a diagnostic criterion and cannot be assumed without histological confirmation 5, 4
• Overlooking renal biopsy: Thrombotic microangiopathy on renal biopsy provides important diagnostic and prognostic information 5
• Treating as typical multicentric Castleman disease: TAFRO syndrome may not respond to standard iMCD therapies and requires more aggressive immunosuppression 2, 3
• Failing to exclude infectious causes: HIV, hepatitis C, CMV, and EBV must be ruled out as they can mimic TAFRO syndrome and require different treatment approaches 7, 6, 8