Double hit: Evans syndrome after malignant thymoma treatment and parvovirus B19 infection

Abstract

Malignancies are often associated with autoimmune diseases, which are addressed by treating the underlying cancer. However, there are rare malignancies that can cause autoimmune diseases even after appropriate treatment. Our patient is a 39-year-old Hispanic man with a malignant thymoma recently treated with chemotherapy and radiation who presented with syncope and dyspnoea. He was found to be both anaemic and thrombocytopenic. His labs were consistent with autoimmune haemolytic anaemia (AIHA), except his reticulocyte count was unexpectedly low. Bone marrow biopsy supported a diagnosis of Evans syndrome, a rare autoimmune condition characterised by (AIHA) combined with immune thrombocytopenia. He was also found to have an acute parvovirus B19 infection. He was treated with steroids and RBC transfusion. His blood counts gradually returned to baseline, with improvement in symptoms. This patient’s thymoma treatment and active parvovirus B19 infection likely both played a role in the development of Evans syndrome.

Background

Autoimmune diseases can be caused by a variety of aetiologies, which can include malignancies. Therefore, a careful review of the patient’s medical history remains important. This report describes an autoimmune disease with atypical findings. In the setting of autoimmune haemolytic anaemia (AIHA) with a low reticulocyte count, several changes to the traditional workup and management need to be considered.

Malignancies are often associated with paraneoplastic disorders and autoimmune diseases, which are addressed by treating the underlying cancer. However, there are rare malignancies, such as thymomas, that can still cause autoimmune diseases even after appropriate treatment. One such condition is Evans syndrome, characterised by AIHA combined with immune thrombocytopenia (ITP).

We report a case of Evans syndrome in a patient likely triggered by his recently treated thymoma and active parvovirus B19 infection. Evans syndrome has been previously linked to both thymoma¹ and parvovirus B19 infection.^{2 3} However, this is the first known case to involve both simultaneously in the development of Evans syndrome.

Case presentation

A 39-year-old Hispanic man with a history of thymoma presented with syncope, fatigue and exertional dyspnoea for 3 days. He had an episode of syncope while walking out of the bathroom and had to be helped by family members before he collapsed. He previously presented with exertional dyspnoea 8 months previously, and CT scan of the chest revealed a large, anterior mediastinal mass with invasion of the major vessels and right pleural effusion. Interventional Radiology-guided biopsy of the pleural effusion was confirmed to be type B2 thymoma. He was deemed not to be a surgical candidate due to neurovascular invasion and pleural involvement. Radiation therapy was also delayed until after chemotherapy completion due to involvement of the cardiac vessels. He underwent eight cycles of chemotherapy with cisplatin, doxorubicin and cyclophosphamide. Restaging after cycle six showed an interval decrease in the size of the mediastinal mass, while restaging after cycle 8 showed stable disease. After completion of chemotherapy, he received definitive radiation therapy, which he completed a month prior to presentation. He then reported an improvement in symptoms, until this latest episode.

His examination was notable for blood pressure of 97/41 and pulse of 138. His eye examination revealed scleral icterus and pale conjunctiva.

Investigations

On this present admission with syncope and exertional dyspnoea, laboratory findings were significant for a haemoglobin of 2.9 mg/dL and initial platelet count of 166 000/μL, which later dropped to 89 000/μL. Other relevant lab findings included low reticulocyte count percentage (0.1%), low reticulocyte production index (0.02), elevated lactate dehydrogenase (497 units/L) and low haptoglobin (<30 mg/dL). He also had a positive direct antiglobulin test (DAT) for IgG. Finally, he had a strongly positive parvovirus B19 IgM level in serum, with negative HIV and hepatitis panel. The patient then underwent a bone marrow biopsy, which showed erythroid hyperplasia (figures 1–3), and had a negative stain for parvovirus B19 (figure 4).

Figure 1.

Increased erythroid precursors in all stages of maturation and admixed maturing granulocytes on bone marrow aspirate smear (Wright stain).

Figure 2.

Trilineage haematopoiesis, mildly left-shifted erythroid hyperplasia, few admixed granulocytic precursors and scattered megakaryocytes on bone marrow clot preparation (H&E, intermediate magnification).

Figure 3.

Immunohistochemical stain for E-cadherin highlights prominent colonies of left-shifted erythroid cells on bone marrow clot preparation (immunohistochemical stain for E-cadherin, intermediate magnification).

Figure 4.

Erythroid precursors are negative for parvovirus on bone marrow clot preparation (immunohistochemical stain for parvovirus, intermediate magnification).

Differential diagnosis

Our initial work-up in this patient with syncope and dyspnoea begins with a complete blood count, and we first noted his severe anaemia. We then obtained a reticulocyte count, which was also low. This generally indicates a non-regenerative anaemia caused by ineffective erythropoiesis (due to bone marrow suppression and myelodysplasia). However, his other lab work indicated an element of haemolysis, including elevated LDH and decreased haptoglobin. The peripheral blood smear revealed spherocytes, which suggests intravascular haemolysis. Finally, the DAT was positive for IgG. All of these findings indicate a warm agglutinin AIHA. However, haemolytic anaemia is generally associated with reticulocytosis due to increased bone marrow activity. This discrepancy raised our concern for a separate process in the bone marrow causing the decreased reticulocytes, most notably pure red cell aplasia (PRCA), which has a well-known association with thymomas. This prompted further investigation with a bone marrow biopsy, which showed erythroid hyperplasia, consistent with AIHA (whereas erythroid hypoplasia would point towards bone marrow suppression and PRCA). Low reticulocyte counts can occur in severe, acute haemolytic stress when the bone marrow does not have time to respond appropriately,⁴ which is most likely what happened in this case.

Due to the anaemia with low reticulocyte count, we also checked for parvovirus B19 IgM titre in the serum, which came back strongly positive. This infection may have also contributed in part to this patient’s low reticulocyte count but did not cause a PRCA picture based on bone marrow biopsy findings. Finally, the negative stain for parvovirus B19 in the bone marrow further supports the notion that destruction of erythrocyte precursors in the bone marrow was not the primary pathology involved in this case.

In regard to thrombocytopenia work-up, there was no evidence of platelet abnormalities on peripheral smear. Although it is a diagnosis of exclusion, ITP, which describes autoantibodies against platelet antigens, makes sense in this clinical scenario. It is also supported by bone marrow biopsy results, which showed an adequate number of megakaryocytes (figure 2), indicating production of platelets was not an issue. The combination of AIHA and ITP in this patient therefore led us to the diagnosis of Evans syndrome. The subsequent improvement in both anaemia and thrombocytopenia after treatment further solidified this diagnosis (see further).

Treatment

AIHA is typically not treated with RBC transfusion, as the autoantibodies can react with the transfused RBCs as well. However, RBC transfusion is warranted in AIHA with severe anaemia and a low reticulocyte count, which can be life-threatening due to insufficient bone marrow response.⁵ In this case, he was treated with 4 units of packed RBCs and intravenous solumedrol 250 mg daily for 4 days. He was then transitioned to oral prednisone 50 mg daily and discharged on a prednisone taper with close follow-up with the haematology–oncology clinic.

Outcome and follow-up

His haemoglobin rose from 2.9 to 6.0 mg/dL after the 4 units of packed RBCs, and remained stable at 7.7 mg/dL at discharge (5 days after admission). His platelets nadired at 89 000/μL during hospitalisation. After discharge, his haemoglobin and platelets started to rise, such that haemoglobin was 11.2 mg/dL and platelets were 211 000/μL 1 month later in the haematology–oncology clinic. His haemolysis labs (LDH, haptoglobin) also improved. His dyspnoea on exertion and syncopal episodes resolved, and he continues to do well 3 months later.

Discussion

The thymus has a protective role against autoimmunity through the positive and negative selection of T-lymphocytes. Thymomas, a malignancy of the epithelial lining of the thymus, can disrupt this function. Therefore, it is not surprising that thymomas have been associated with various autoimmune diseases, including myasthenia gravis, Hashimoto’s thyroiditis and PRCA.⁶ PRCA was initially high on our differential, given the patient’s anaemia with low reticulocyte count and history of thymoma. However, the erythroid hyperplasia on bone marrow biopsy is not seen in PRCA and points more towards peripheral destruction of RBCs. PRCA would also not account for this patient’s concurrent thrombocytopenia. Evans syndrome is a rare phenomenon that has been reported with thymomas.¹ Interestingly, the treatment of the thymoma itself can also be a risk factor. The thymus contains regulatory T cell (Treg), which plays a pivotal role in maintaining immunological self-tolerance. One of the functions of Treg is to regulate innate immune cells (dendritic cells, macrophages and neutrophils). When Treg function is defective, there is an exaggerated response by these innate immune cells, which increases the propensity for autoimmune diseases. After thymoma treatment with either surgery or chemoradiation, it is believed that the Treg pool is reduced.⁷ The production and maintenance of these Treg cells may also be altered, possibly resulting in increased autoimmune phenomenon. There are reported cases of AIHA after thymectomy,⁷ Evans syndrome after thymectomy⁸ and systemic lupus erythematosus after chemotherapy and radiotherapy for malignant thymoma.⁹ Thus, our patient remained at risk of developing an autoimmune condition, even after his thymoma treatment. This risk was likely compounded by the presence of another trigger, in the form of an active parvovirus B19 infection.

Parvovirus B19 is a common virus that has a propensity for triggering autoimmune diseases, particularly PRCA, characterised by destruction of erythrocyte precursors in the bone marrow. Although the mechanism is not entirely understood, recent research indicates that parvovirus B19 causes apoptosis through the NS1 protein, which binds to dsDNA. This causes host cellular DNA bound to viral protein to be released, and recognised by the immune system as foreign. A recent study on mice showed that infection with parvovirus B19 initiated the production of autoantibodies against cellular DNA, which resulted in tissue damage to vital organs.¹⁰ Through this mechanism, parvovirus B19 has the potential to trigger a variety of autoimmune diseases. There have been case reports of parvovirus B19 causing either AIHA or ITP,^11–13 while Evans syndrome has also been reported.^{2 3 14}

Autoimmune diseases can be caused by a variety of aetiologies, including malignancy and infection. This is the first case of Evans syndrome believed to be caused by the combination of recent thymoma treatment and parvovirus B19 infection.

Learning points.

• In an anaemic patient with low reticulocyte count, check a parvovirus B19 IgM level in the serum to investigate pure red cell aplasia. A bone marrow biopsy might be needed to determine the cause if labwork does not point to a single diagnosis.

• Red blood cell transfusion is generally not indicated in autoimmune haemolytic anaemia (AIHA) but can be given in severe anaemia with a low reticulocyte count.

• Evans syndrome is a rare autoimmune disease that should be considered in the setting of AIHA with concurrent thrombocytopenia.

• Thymomas are one of few malignancies that can still cause autoimmune diseases even after appropriate treatment.

• Parvovirus B19 infection is classically associated with pure red cell aplasia but can lead to other autoimmune diseases by causing host cell apoptosis.