A Case of TAFRO Syndrome Developed after COVID-19 Vaccination

TAFRO syndrome is a systemic inflammatory disorder, which is characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. It often presents with progressive clinical symptoms and can be fatal. COVID-19 vaccination is important to reduce the number of COVID-19-infected populations and lower the risk of becoming severe. However, serious adverse events have been reported. TAFRO syndrome that progresses after the COVID-19 mRNA vaccination has not yet been reported. A 45-year-old man developed fever, gross hematuria, renal dysfunction, pleural effusions, and ascites immediately after vaccination. This case fulfilled three major categories (thrombocytopenia, anasarca, and systemic inflammation) and two minor categories (renal insufficiency and myelofibrosis) and was diagnosed with TAFRO syndrome. High-dose steroid treatment was initiated, followed by prednisolone administration. After treatment, renal dysfunction and fluid retention were resolved. Universal vaccination against COVID-19 is important for lowering the risk of spreading COVID-19 infection. Several complications, such as renal, hematological, and heart diseases, have been reported; however, its pathogenesis is unclear. The possibility of various complications after the COVID-19 vaccination, including TAFRO syndrome, should be considered.


Introduction
Te TAFRO syndrome, a rare systemic disease characterized by thrombocytopenia, anasarca, fever, reticulin myelofbrosis, renal dysfunction, and organomegaly, was frst reported in Japan in 2010.Te diagnostic criteria for TAFRO syndrome were determined by the All Japan TAFRO Syndrome Research Group in the Research Program for Intractable Disease by the Ministry of Health, Labor, and Welfare Japan in 2015 and updated in 2019 [1,2].
Castleman's disease (CD) is classifed into unicentric CD (UCD) and multicentric CD (MCD), and MCD has three subtypes: POEMS syndrome, HHV-8-associated MCD, and idiopathic MCD (iMCD) [3].Several clinical and pathological characteristics of TAFRO syndrome resemble those of iMCD.TAFRO syndrome is distinct from POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell proliferation, and skin change) syndrome or iMCD-not otherwise specifed (iMCD-NOS), as it does not accompany overproduction of immunoglobulin or polyneuropathy.Fujimoto S. et al. reported that iMCD can be classifed into two distinct subtypes: TAFRO-iMCD and iMCD-NOS [4].Although the concepts of iMCD and TAFRO syndrome may overlap, TAFRO syndrome often presents with progressive clinical symptoms and can be fatal.
COVID-19 vaccination is recommended to reduce the number of COVID-19-infected population and lower the risk of becoming severe.However, some serious adverse events have been reported after the COVID-19 vaccination, such as anaphylaxis, thrombosis, Guillain-Barre syndrome, myocarditis, and pericarditis [5,6].Although these complications are not frequent, these incidents may lead people to avoid vaccination and make the pandemic to the worse.
Here, we report a case of TAFRO syndrome that developed after the frst injection of a COVID-19 mRNA vaccine.

Case Presentation
A 45-year-old man was transferred to our hospital for the evaluation of renal dysfunction and anasarca.After the frst dose of the COVID-19 mRNA vaccine (Moderna mRNA-1273), he developed fever and macrohematuria for 3 to 4 days and developed edema and abdominal distension from the day after the frst COVID-19 mRNA vaccination.Six days after vaccination, his symptom was persisted and he was detected renal dysfunction (eGFR 39.2 mL/min/1.73m 2 , serum creatinine 1.59 mg/dL), elevated C-reactive protein (22.4 mg/dL), and proteinuria.Te patient has a history of atopic dermatitis.It was the frst time COVID-19 vaccination for him, and there were no adverse reactions or allergies caused by the other vaccines.
On admission to our hospital, the patient was 171.0 cm tall and weighed 80.0 kg (weight gain of 7 kg in 1 week), with a blood pressure of 142/73 mmHg, a pulse rate of 60/min, and a body temperature of 37.3 degrees.He complained of epigastric pain, dyspnea, and bilateral pitting edema of the lower extremities.Oxygen saturation was 92% in room air.Electrocardiography was normal, and an echocardiogram revealed normal left ventricular systolic function.Laboratory data revealed elevated levels of C-reactive protein (22.6 mg/dL) and renal dysfunction (eGFR 49 ml/min/1.73m 2 ).Te platelet count was 9.1 × 10 3 /μL.Examination of antinuclear antibody, antidouble-stranded DNA IgG antibody, antineutrophil cytoplasmic antibody, and antiglomerular basement membrane antibody was all negative.Te patient has a history of atopic dermatitis and indicates high level of serum IgE (Table 1).Te PCR test results for COVID-19 were negative.Procalcitonin was slightly high at 2.66 ng/mL; however, antibiotics did not efective to reduce CRP during the clinical course.Physical fndings showed no signs of infection.
Bilateral pleural efusions and a slight accumulation of ascites were detected on computed tomography (CT) (Figure 1).Small lymph nodes in the axilla were detected on CT; however, they were too small to perform biopsy.Tere was no abnormal uptake on gallium scintigraphy.
Bone marrow biopsy showed hyperplastic and increased megakaryocytes, and reticular fber hyperplasia was partially observed by silver staining.Te extent of myelofbrosis was equivalent to MF1-2.
We performed a renal biopsy for the defnitive diagnosis of renal injuries.Light microscopy showed difuse hypercellularity with thrombotic microangiopathy (TMA) lesions of the glomeruli.Tere was difuse and global endothelial cell enlargement due to cytoplasmic swelling, with a large number of infammatory cells (Figure 2(a)).Te partial dissolution of the mesangial matrix (mesangiolysis) is also shown (Figure 2(b)).Endothelial cell swelling occluding the capillary lumen with loss of fenestration and expansion of the subendothelial space was observed by electron microscopy (Figures 2(d) and 2(e)).Immunoperoxidase staining for CD34 and CD68 were positive (Figures 2(f) and 2(g)).Immunofuorescence analysis revealed negative staining for IgG, IgA, IgM, C3, and C1q.
Overall, this patient fulflled three major categories (thrombocytopenia, anasarca, and systemic infammation) and two minor categories (renal insufciency and myelofbrosis).Tus, the patient was diagnosed with TAFRO syndrome by diagnostic criteria for TAFRO syndrome [1,2].After a second high-dose steroid pulse therapy with 500 mg methylprednisolone for 3 days, followed by prednisolone (PSL) 40 mg/day, anasarca, systemic infammation, and renal injuries were improved (C-reactive protein <0.1 mg/dL, eGFR 67 ml/min/1.73m 2 ).Te platelet count increased to the normal range on the 31st day of admission.Eleven months after discharge, the patient had never relapsed under PSL treatment (5 mg/day).
Mizuno et al. reported the renal histology of TAFRO syndrome as a glomerular endotheliopathy that is representative of endothelial cell swelling, mesangiolysis, mesangial loosening (loss of mesangial matrix staining), and GBM double contour and thickening.Electron microscopy shows loss of mesangial architecture and endothelial space, as well as loss of endothelial cell fenestration [15].In the present case, these fndings, except for endothelial cell fenestrations, were detected, confrming the diagnosis of TAFRO syndrome.
Previous reports have suggested that vaccination may trigger an autoimmune response due to antigenic mimicry as well as the activation of quiescent autoreactive T and B cells [16].Tese reports suggest that the COVID-19 mRNA vaccine stimulates the immune system and causes autoimmune reactions.
Although the etiology of TAFRO syndrome has not been revealed, it has been demonstrated that hypercytokinemia related to IL-6 and stimulation of VEGF contributes to the pathophysiological mechanisms [17,18].It is suggested that the abnormal autoimmune response induced by COVID-19 mRNA vaccination caused the overproduction of cytokines, 2 Case Reports in Nephrology Case Reports in Nephrology

Conclusion
Universal vaccination against COVID-19 is important for lowering the risk of spreading COVID-19 infection.Several complications, such as renal, hematological, and heart diseases, have been reported; however, its pathogenesis is unclear.Te possibility of various complications after the COVID-19 vaccination, including TAFRO syndrome, should be considered.contributed to data collection and interpretation.ST provided the pathology results of the renal biopsy.H. S. and Y. S. conceived the idea for this case report, analyzed the patient's clinical course, outcomes, and interpretation of fndings, and provided critical review comments for the manuscript.All authors have read and approved the fnal manuscript.

Table 1 :
Laboratory data on admission.

Table 2 :
Analysis of pleural efusion and ascites.