Case Presentation: A 45-year-old Japanese woman with no significant medical history presented to a primary care physician with a four-week history of fever and coughing. She had also developed fatigue and peripheral edema and was therefore admitted to another hospital. On presentation, her body temperature was 37.5℃, pulse was 98 beats per minute, blood pressure was 126/62 mmHg, and respiratory rate was 12 breaths per minute. The physical examination was significant for right cervical and bilateral inguinal lymphadenopathy, bibasilar crackles, abdominal distension, and pitting edema of the bilateral lower extremities. Laboratory data showed the following levels: white blood cells: 6.8×10³/μL, hemoglobin: 9.6 g/dL, platelets: 5.9×10⁴/μL, albumin: 1.9 g/dL, alkaline phosphatase: 548 U/L, creatinine: 1.02 mg/dL, C-related protein: 20.6 mg/dL, ferritin: 466 ng/mL, IL-6: 42.4 ng/mL, and VEGF: 348 pg/mL. A bone marrow aspiration and biopsy revealed reticulin myelofibrosis. An inguinal lymph node biopsy showed atrophic germinal centers, follicular architecture, and the proliferation of highly dense endothelial venules with endothelial cell swelling. The immunostaining results of the lymph node were negative for HHV-8 and EBER. The ascitic fluid was bloody and exudative, but its cytology was negative. She gradually developed thrombocytopenia, acute kidney injury, and hypoxia due to progressive pleural effusion. TAFRO (Thrombocytopenia, Anasarca, reticulin Fibrosis, Renal dysfunction, and Organomegaly) syndrome was suspected, and she was transferred to our hospital for further treatment. On the second day, she developed anuria and severe hyperkalemia, for which emergent hemodialysis was initiated. Glucocorticoid pulse therapy followed by 1mg/kg of prednisolone and weekly tocilizumab was also started. Her respiratory status and abdominal distension as well as auric renal failure subsequently started improving, and hemodialysis was successfully discontinued on the 19th day. However, severe thrombocytopenia persisted, which resulted in daily Rh-negative platelet transfusion and eltrombopag initiation on the 27th day. Despite continued treatment as above, thrombocytopenia did not improve, and she relapsed in terms of fever, pleural effusion, and laboratory abnormalities. After the possibility of infection was ruled out, the patient was considered a refractory case of TAFRO syndrome, and four doses of weekly rituximab were added on the 38th day with the permission of the institutional review board. Her symptoms resolved, and all the laboratory abnormalities had improved to normal by the 71st day.
Discussion: TAFRO syndrome is a distinct variant of HHV8-negative Castleman disease that has recently been identified in Japan. The number of patients in Japan is estimated at around 200. Compared with Castleman disease, severe thrombocytopenia and anasarca are characteristics of TAFRO syndrome. Several reports suggest that the mortality rate is above 10%, but a standard treatment strategy has not been established. On the other hand, HHV8-positive Castleman disease can be treated with tocilizumab and rituximab. In our case, the addition of rituximab to tocilizumab was effective, which suggests that rituximab is a reasonable option for refractory TAFRO cases. While the prognosis of TAFRO syndrome is poor, new therapeutic approaches and future research offer potential for improvement.
Conclusions: The addition of rituximab to tocilizumab could be a treatment option for refractory TAFRO syndrome.