Unexplained cause of thrombocytopenia, fever, anasarca and hypothyroidism: TAFRO syndrome with thrombotic microangiopathy renal histology

Abstract

TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis or renal dysfunction and organomegaly) syndrome is a systemic inflammatory disease characterised by thrombocytopenia, anasarca, fever or inflammatory syndrome, reticulin myelofibrosis or renal dysfunction and organomegaly. It was first described as a subtype of idiopathic multicentric Castleman disease. Here, we report the case of a 42-year-old woman presenting with thrombocytopenia, anasarca, inflammatory syndrome, renal insufficiency, reticulin myelofibrosis at bone marrow biopsy and cervical and axillary lymph nodes. Kidney biopsy showed double contours of the glomerular basement membrane, mesangiolysis and endothelial swelling compatible with thrombotic microangiopathy (TMA) as well as with TAFRO syndrome. She was successfully treated by corticosteroids, tocilizumab and rituximab. This new case description of TAFRO syndrome underlines three features of this disease rarely described in the literature and never simultaneously in the same patient: the association to severe hypothyroidism, the presence of TMA-like lesions on kidney biopsy and the treatment by the association of steroids, tocilizumab and rituximab.

Background

Castleman’s disease (CD) is a rare lymphoproliferative disorder. It was historically classified as unicentric or multicentric. Multicentric CD (MCD) is subdivided into human herpes virus 8 (HHV-8) associated MCD and HHV-8-negative or idiopathic MCD (iMCD).^{1 2} iMCD is classified into three subtypes: POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell proliferative disorder and skin change) syndrome, TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis or renal dysfunction and organomegaly) syndrome and iMCD-not otherwise specified (iMCD-NOS).³ TAFRO syndrome was first described in Japan by Takai et al.⁴ It is frequently considered as a variant of iMCD.^4–6 It has since been described worldwide.^6–13 If clinical and biological features present in the TAFRO acronym are the most common features, other features include low immunoglobulin levels, high alkaline phosphatase (ALP) without transaminase elevation, anaemia and hypoalbuminaemia.^14–16 Pathophysiology of TAFRO syndrome involves interleukin (IL)-6, IL-2 and vascular endothelial growth factor (VEGF) increases, as well as autoimmunity, that could represent possible therapeutic targets.^{14 17} Given the rarity of the disease and its recent description, the pleomorphic presentation and the fact that pathology (bone biopsy, lymph node biopsy or kidney biopsy) is required as diagnosis criteria, the diagnosis is challenging and the disease is probably underdiagnosed. We present a case of TAFRO syndrome with thrombotic microangiopathy (TMA)-like lesions on kidney biopsy, in a patient affected by Turner’s syndrome, who was referred to intensive care unit (ICU) for management of severe thrombopenia, renal insufficiency and anasarca.

Case presentation

A 42-year-old woman with Turner’s syndrome was referred to the emergency department of a first-line hospital with a history of abdominal pain, pollakiuria and vomiting. Clinical examination found a purpuric rash on the back, ascites with lower limbs oedema and pleural effusion, confirmed by abdominal CT scan. Biological workup revealed low platelet count (PLT) 98×10⁹/L; normal range 155–400), renal insufficiency (serum creatinine 1.96 mg/dL; normal range 0.50–0.90), low albumin levels (18 g/L; normal range 35–55), increased alkaline phosphatase (179 U/L; normal range 35–105) and elevated inflammatory parameters (white cell count 16.9×10⁹/L; normal range 4.0–10.0 and C-reactive protein (CRP) 286.2 mg/L; normal range <10). Besides, severe hypothyroidism was evidenced, in the setting of a previously known Hashimoto’s thyroiditis (40 mU/L; normal range 0.3–4.2, T4 6 pmol/L; normal range 12–22 and antithyroid peroxidase antibodies 170 kU/L; normal range <34 kU/L). There were no biological signs of haemolysis (lactate dehydrogenase within normal levels and elevated levels of haptoglobin). Immunological (including antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibody and platelet-associated IgG) and infectious (with serological testing for cytomegalovirus (CMV), Epstein-barr virus (EBV), toxoplasma, hepatitis B, hepatitis C and HIV) workups were negative. Bone marrow aspiration did not reveal any central cause for thrombocytopenia. Levothyroxine substitution (125 µg) was started. The worsening of thrombocytopenia (PLT 25×10⁹/L) led to the adjunction of intravenous methylprednisolone (mPDN) 1 mg/kg for 7 days, intravenous immunoglobulins (IVIg) at the dose of 2 g/kg over 2 days and platelet transfusion without any improvement (PLT 6×10⁹/L and serum creatinine 2.71 mg/dL). The patient was therefore referred to our university hospital ICU.

At admission, clinical examination revealed an anasarca with oligoanuria. The patient underwent continuous venovenous haemofiltration followed by haemodialysis for acute kidney injury with the persistence of oligoanuria. Repeated biological investigations showed low albumin levels, increased alkaline phosphatase, renal insufficiency and inflammatory syndrome. Serological tests were negative. Bone marrow biopsy and axillary lymph node biopsies were performed but were not helpful for the diagnosis.

At day 6 after admission, the patient presented a cardiac arrest during dialysis in a context of low output. Immediate resuscitation was successful. Haemodynamic and neurological improvements were seen within a week. Evolution was marked by a delayed improvement—without any specific treatment—of thrombocytopenia, inflammatory syndrome and renal insufficiency (with complete recovery of renal function and the possibility of transient weaning from dialysis) despite persistent anasarca (without signs of liver disease). Reoccurrence of the inflammatory syndrome and renal insufficiency with hypercapnic respiratory failure and worsening cholestasis prompted a transfer to ICU on day 42 of admission. Pleural effusion drainage and non-invasive ventilation were initiated. Bone marrow (dysplasia signs at the levels of the three haematopoietic lineages) and liver (intrahepatocytic cholestasis without steatosis nor fibrosis) biopsies were performed but were non-contributive. The analysis of the ascitic tap fluid did not find any neoplastic cell or g infectious micro-organism, with normal values of protein (24 g/L, normal <30) and lipase (<5 U/L, normal <10). Finally, a kidney biopsy was performed and showed TMA-like lesions: double contours of the glomerular basement membrane, mesangial expansion, mesangiolysis and endothelial swelling, as seen in TAFRO syndrome. There was positivity for IgM, C3, kappa and lambda and negative for IgG and C1q (figure 1) on immunofluorescence. Of note, persistently elevated levels of haptoglobin allowed us to rule out a genuine TMA.

Figure 1.

Histopathology and immunofluorescence of kidney biopsy. Histological findings. (High power view, ×400) Light microscopy (A: H&E, B: periodic acid–silver methenamine stain, C, D: periodic acid–Schiff stain. (A) and (B) lobulations of glomeruli with swelling of endothelial cells and double contours of the glomerular basement membrane, (C) mesangiolysis, (D) arteries with swelling of endothelial cells. Immunoflorescence: (E) anti-IgM: granular positivity in the glomerular capillaries, (F) anti-lambda: linear positivity in the glomerular capillaries, (G) anti-kappa: linear positivity in the glomerular capillaries, (H) anti-C3: granular positivity in the glomerular capillaries. Arrows indicate the anomalies on the pictures.

Investigations

At the admission, severe thrombocytopenia, low albumin levels, increased alkaline phosphatase, renal insufficiency and elevated inflammatory parameters were confirmed. The urinalysis showed isomorphic haematuria (1–4 red blood cells/high-power field) and a protein level of 0.30 g/day when the daily urine volume was 200 mL/day. Infectious workup, including hepatitis B and C, Bartonella, Borrelia, EBV, CMV and HHV-8 serologies were negative. Hantavirus PCR was negative.

Immunological testing was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, platelet-associated IgG and glomerular basal membrane antibody. IgG4, complement and immunoglobulins levels were normal.

An abdominal CT scan revealed bilateral pleural effusion and an important ascites (figure 2). ¹⁸F-fluorodeoxyglucose-positron emission tomography/CT showed multiples lymph nodes at the lateral side of the neck, axillary, right lung apex with moderate hypermetabolism and a hypermetabolic spleen (figure 3).

Figure 2.

Ascites and pleural effusion on abdominal CT scan.

Figure 3.

¹⁸F-fluorodeoxyglucose-positron emission tomography/CT findings. (A) Moderate hypermetabolic lymph nodes at lateral side of the neck, axillary, right lung apex. (B) Moderate hypermetabolic spleen.

Bone marrow aspiration and biopsy were not in favour of a central cause of thrombocytopenia with rich marrow and no excess of blasts. Furthermore, there were no abnormal cells or parasites but reticulin fibrosis was found. An axillary lymph node biopsy did not show clonal lymphocytes or granuloma or plasma cells proliferation suggestive of CD, although the interpretation was hampered by coagulation artefacts. Given the persistence of severe thrombocytopenia and altered liver tests, new bone marrow and liver biopsies were performed but were non-contributive.

Finally, a kidney biopsy was performed and showed TMA-like lesions: double contours of the glomerular basement membrane, mesangial expansion, mesangiolysis and endothelial swelling, as seen in TAFRO syndrome. Immunofluorescence results were positive for IgM, C3, kappa and lambda and negative for IgG and C1q. Unfortunately, electronic microscopy was not performed (figure 1). Although not mandatory (elevated haptoglobin levels ruling out TMA), the ADAMS13 activity assay was performed and was only slightly abnormal (37%, normal range 69%–144%). There was none of the complement abnormalities associated with atypical haemolytic-uraemic syndrome.

Differential diagnosis

At first, the hypothesis of immune thrombocytopenia (ITP) was considered, leading to treatment by mPDN for 7 days and IVIg 2 g/kg over 2 days. But the presence of unexplained acute kidney injury, anasarca and elevated inflammatory parameters further challenged that hypothesis.

Treatment

The patient was successfully treated by mPDN (1 mg/kg) planned to be gradually tapered, rituximab (375 mg/m², four courses at 1-week interval) and tocilizumab (8 mg/kg, four courses at 2 weeks interval) with normalisation of the serum creatinine, albumin and PLT levels and disappearance of anasarca. Figure 4 shows the evolution of albumin, creatinine and platelet during the course of hospitalisation. Haemodialysis was completely stopped 2 weeks after the last course of tocilizumab and 1 week after the last course of rituximab were given. mPDN has been stopped at day 118.

Figure 4.

Evolution of platelet, albumin and creatinine during the admission. CRP, C-reactive protein; PLT, platelet count.

Outcome and follow-up

Evolution was marked on this treatment by regression of inflammatory syndrome, normalisation of platelets and renal function and regression of ascites. The evolution of CRP, creatinine, platelets during the admission is presented below (figure 4). The patient has now been discharged and is currently in a revalidation centre. She received a maintenance course of 400 mg of tocilizumab 4 weeks after the fourth course.

DISCUSSION

We report a middle-aged woman diagnosed with TAFRO syndrome associated with severe hypothyroidism. Although the lymph node histology was not contributive to diagnosis, kidney biopsy revealed an anatomopathological pattern consistent with TAFRO syndrome. At first, the hypothesis of ITP was considered, leading to treatment by mPDN for 7 days and IVIg 2 g/kg over 2 days. But the presence of unexplained acute kidney injury, anasarca and elevated inflammatory parameters further challenged that hypothesis.

TAFRO is a very rare disease, generally considered as a subtype of iMCD. It has been mainly described in reports or short case series.4 8–12 15 18–30 Although described in Japanese patients, it is now clear that it can affect patients all over the world. The ethnic difference were found regarding the mean age of onset (52 years old for Japanese patients vs 37 years old for non-Japanese), and the higher frequency of kidney damage and auto-antibodies (more frequent in Caucasians patients).^{11 12} If thrombocytopenia, anasarca, fever, renal insufficiency, organomegaly, hypoalbuminaemia, anaemia and increased ALP are found in almost all patients, diagnosis confirmation requires the exclusion of others diagnosis (autoimmune or inflammatory diseases, infectious and neoplastic diseases) and histopathological confirmation.3 14 16 31 The 2017 consensus criteria for iMCD recommended to evidence either the presence of a lymph node histology consistent with CD or the presence of reticulin myelofibrosis on bone biopsy. However, Masaki et al have suggested another set of diagnosis criteria without the necessity of lymph node biopsy. Furthermore, Fujimoto et al showed that TAFRO-iMCD and TAFRO syndrome without proven iMCD are the same disease.^{5 32} There is an unmet need for a consensus about the contribution of lymph node biopsy results in TAFRO’s diagnosis criteria.

Endocrine diseases have been described in association with TAFRO syndrome.8 10 18 25 Hypothyroidism is one of the most common endocrinopathy found, generally associated with positive thyroid antiperoxidase antibodies. This hypothyroidism is generally subclinical and correlates with VEGF levels. In three cases, VEGF levels reduced with thyroid hormone therapy.²⁵ Giving the participation of autoimmune phenomenon in TAFRO syndrome, autoimmunity may trigger this situation via autoantibody antigenic stimulation. Interestingly, there is a description of a case of a refractory TAFRO successfully treated using thyroxine supplements, while tocilizumab and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone were not sufficient.³³

Another particularity of this case description was the histology of kidney biopsy. One of the hallmarks of TAFRO syndrome is renal insufficiency, a kidney biopsy is often performed. Some authors reported membranoproliferative glomerulonephritis (MPGN)-like lesions as common in TAFRO syndrome, although others have described TMA-like lesions.20 22 24 27 However, some patients present both lesions on kidney biopsy.^{7 28} This raises the hypothesis of a continuum between TMA and MPGN in TAFRO syndrome. However, in patients with TMA-like lesions, normal lactate dehydrogenase levels and elevated haptoglobin levels contradict the hypopothesis of a TMA.

Given the pathophysiology of this disease, characterised by a cytokinic storm with increased IL-2, IL-6 and VEGF levels and a possible autoimmune phenomenon (partially explaining hypothyroidism and thrombocytopenia),^{14 16} different treatments have been used. In addition, no study shows which treatment is the best. Corticosteroids (CS) is the most commonly used first-line therapy in patients with TAFRO, but is expected to work in around 50% of cases. Others therapeutic choices include immunomodulators (thalidomide, IVIg, bortezomib), cyclosporine A (CyA), sirolimus, cytotoxic chemotherapies mainly based on cyclophosphamide and biotherapies like tocilizumab and rituximab.^{14 16 31} Various associations between high-dose CS, CyA, tocilizumab or rituximab have been used according to the physician experience and the characteristics of the disease. In patients with renal insufficiency, cyclosporine is contraindicated, and tocilizumab and rituximab are therefore preferred.16–18 24 29 32 Another particularity of this case was the atypical use of an association of tocilizumab and rituximab. The concomitant use of those two drugs was reported by Louis et al and José et al and turned out to be safe in the short-term.^{11 34} A recent study revealed an inferior survival of TAFRO’s patients compared with iMCD-NOS.³⁵ Mortality is high, approximatively 12%, due to disease progression or infection. There is no case of secondary malignancy to TAFRO reported.^{31 32} Relapse is frequent, particularly during CS tapering and requires adjunctive treatment.^{14 16 17}

Learning points.

• The diagnosis of TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis or renal dysfunction and organomegaly) syndrome remains challenging due to its rare occurrence, the pleomorphic clinical presentation and the lack of consensual diagnostic criteria.

• This case supports the recommendation of a thorough aetiological workup in an adult with unexplained ascites and thrombopenia.

• Another particularity of this case was the association to severe hypothyroidism, the presence of thrombotic microangiopathy-like lesions on kidney biopsy and the treatment by the association of steroids, tocilizumab and rituximab.

• There is a need for consensual recommendations on the requirement of a histological confirmation to support the diagnosis on the therapeutic strategies according to the severity of the disease.