British Journal of Haematology, 2001, 112, 377±380
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Fatal atypical T-cell proliferation associated with Epstein±Barr virus infection Steffen Hauptmann, 1 Nadine Meru, 2 Christiane Schewe, 1 Andreas Jung, 2 Falk Hiepe, 3 Gerd RuÈ diger Burmester, 3 Gerald Niedobitek 2 and Frank Buttgereit 3 1 Institute of Pathology and 3 Department of Rheumatology, Charite Hospital Berlin, and 2 Institute of Pathology, University Erlangen, Erlangen, Germany Received 19 August 2000; accepted for publication 21 August 2000
Summary. We report the case of a young Caucasian man who presented with polyneuropathy and severe, ultimately fatal, congestive heart failure in the context of a chronic active Epstein±Barr virus (EBV) infection. Post-mortem examination revealed both monoclonal and polyclonal proliferation of EBV-positive atypical T lymphocytes within different organs. Predominant infiltration of the nervous system and heart with extensive myocardial scarring
accounted for the clinical symptoms. The remarkable features of this case are (i) the occurrence in a Caucasian patient, (ii) the absence of detectable immunodeficiency, and (iii) the myocardial destruction by EBV-infected monoclonal T cells.
Epstein±Barr virus (EBV) infection is associated with several human malignancies such as Burkitt's lymphoma, Hodgkin's disease and B-cell lymphoproliferative disorders (LPDs) in immunocompromised patients (IARC, 1997). In addition, EBV has been detected in a proportion of T-cell nonHodgkin's lymphomas. Among these, some cases appear to develop as a complication of severe chronic active EBV infection (SCAEBV). Moreover, there are sporadical reports on fulminant T-cell LPDs usually occurring in Asian children that develop shortly after primary, acute EBV infection (IARC, 1997). All these patients suffered from hepatosplenomegaly, jaundice and slight lymphadenopathy, and all had a monoclonal CD41 T-cell proliferation. We describe a Caucasian patient with an EBV-associated fulminant T-cell LPD in the setting of SCAEBV, clinically presenting as polyneuropathy and congestive heart failure.
perimyocarditis and a severe hypaesthesia, paraesthesia and paresis of the lower legs, hands and forearms with beginning muscular atrophy. No improvement was achieved with corticosteroids and azathioprine. A nerve±muscle biopsy revealed perivascular/epineural lymphocytic infiltration, a severe atrophy of muscle fibres and a nerval demyelinization. The patient was transferred to our hospital with persistent severe congestive heart failure [left ventricular ejection fraction (LVEF): 15%]. Serology showed a reduction of IgM, IgG, IgG2 and b2-microglobulin. Screening for autoantibodies and infectious agents was negative. However, IgG and IgM antibodies against the EBV capsid antigen (2300 AU/ml and 1800 AU/ml respectively) were detected. Using the polymerase chain reaction (PCR) technique, EBV DNA was detected in serum samples, albeit inconsistently. In the peripheral blood, a decrease in the number of T lymphocytes, a shift to the left and an increase in transferrin receptor-positive monocytes were found. Taken together, the findings led to a tentative diagnosis of EBV-associated LPD and treatment with polyglobulin N, acyclovir, methylprednisolone and cyclophosphamide was initiated. The patient recovered, with an improvement of neurological symptoms and an increase of LVEF to 35%, but then died unexpectedly. Necropsy revealed a massive dilatation of the heart (weight 500 g) with scarring of the myocardium of both the left and right ventricle and signs of an acute global heart failure. All other organs were macroscopically normal. Histologically, a lymphocytic infiltration was found throughout the myocardium. The pericardium showed chronic pericarditis. In the
CASE REPORT A 28-year-old Caucasian male patient presented with an upper respiratory tract infection and transient facial nerve palsy that responded to treatment with corticosteroids and indomethacin. During the following 2 years, he suffered from repeated episodes of uveitis/iridocyclitis. The patient then developed a severe dilative cardiomyopathy with Correspondence: Steffen Hauptmann, Institute of Pathology, Charite Hospital Berlin, Schumannstr. 20±21, D-10117, Berlin, Germany. E-mail:
[email protected] q 2001 Blackwell Science Ltd
Keywords: EBV infection, atypical T-cell proliferation, myocardial damage.
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brain, the spinal medulla and the oesophagus a perivascular and diffuse lymphocytic infiltration was seen. The vast majority of cells were CD45RO/CD3/CD43-positive T cells. CD30 and CD21 (C3d/EBV receptor) were not detected. PCR
analysis of DNA extracted from paraffin sections detected EBV in brain, lymph nodes, heart, lung, liver, eye, kidney, adrenal gland and nerve. The majority of infiltrating lymphoid cells were shown to be EBV-positive using EBER (EBV early RNA-1) in situ hybridization. The largest numbers of EBV-infected cells were found in the heart, oesophagus and Cauda equina, and these tissues were subjected to double-labelling immunohistochemistry and in situ hybridization (Niedobitek et al, 1997). This revealed the presence of the virus in the majority of T cells and in occasional B cells (Fig 1). EBNA2, LMP1 and the BZLF1 trans-activator protein were not detectable. Clonality analysis (Sukpanichnant et al, 1994; Diss et al, 1995) revealed an oligoclonal B-cell pattern in the myocardium and Cauda equina. In contrast, a monoclonal T-cell proliferation was found within the heart, the oesophagus and the lungs. Polyacrylamide gel electrophoresis revealed identical-sized bands, suggesting the presence of the same T-cell clone. A polyclonal T-cell proliferation was observed in the Cauda equina, liver and spleen (Fig 2). DISCUSSION We report the case of a young Caucasian man with T-cell LPD associated with severe chronic active EBV infection (SCAEBV), who presented with polyneuropathy and severe, ultimately fatal, congestive heart failure. The diagnosis of SCAEBV has been suggested by the constellation of anti-EBV antibodies and by the history of uveitis (IARC, 1997). Postmortem examination identified a systemic proliferation of both monoclonal and polyclonal atypical, EBV-infected T cells. The most intensely infiltrated organ was the heart, which is an unusual finding in patients with SCAEBV. Although up to 6% of the patients with infectious mononucleosis (IM) demonstrate electrocardiographic abnormalities (Hoagland, 1964), there are only a few reports on fatal acute myocarditis occurring in the setting of fulminant acute IM (Hebert et al, 1995). However, it is remarkable that, even in these cases, the lymphocytic infiltrate within the heart was predominantly composed of T lymphocytes. Another uncommon localization of the infiltrates is the nervous system, accounting for the neurological symptoms in our case. Although EBV is primarily a B-lymphotropic virus, it is increasingly recognized that EBV can also infect T lymphocytes. This is illustrated by the frequent detection of the virus in T-cell non-Hodgkin's lymphomas (IARC, 1997), as well as by the establishment of EBV-carrying Tcell lines from cultures of peripheral blood lymphocytes from patients with SCAEBV. Notably, the first description of EBVassociated T-cell lymphoma was in the setting of SCAEBV.
Fig 1. In situ hybridization for the detection of the EBERs (black silver grains), in conjunction with immunohistochemistry (red staining), reveals the presence of EBV in numerous CD3-positive (A) and CD45RO-positive (B) T lymphocytes. Only a few EBV-carrying CD20-positive B lymphocytes are detectable (C). Original magnification 100. q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 377±380
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Fig 2. T-cell-receptor gamma (TCRg) rearrangement and immunoglobulin heavy chain (IgH) rearrangement confirming a monoclonal T-cell proliferation within heart, lungs and oesophagus (1C positive control, Jurkat cells; ±C negative control, water). The B-cell proliferation was polyclonal (1C positive control, follicular centre lymphoma; ±C negative control, tonsil).
However, atypical EBV-associated T-cell proliferation similar to this case has been described mainly in the context of an atypical primary EBV infection, sometimes presenting as a haemophagocytic syndrome (Kawaguchi et al, 1993). Interestingly, most cases have been reported from Asian countries, suggesting a particular susceptibility for the development of EBV-associated T-cell proliferations that is possibly based on certain HLA types. The current and most previously reported cases showed a monoclonal expansion of the EBV-infected T cells, as assessed by analysis of T-cell receptor gene rearrangements or the EBV terminal repeat regions (Ishihara et al, 1989). In a recent report on six patients with fulminant T-LPD, arising in the setting of acute EBV infection or following SCAEBV, monoclonal T-cell infiltrates were found in the liver and spleen (QuintanillaMartinez et al, 2000). Two other children with SCAEBV have been described presenting with EBV-infected peripheral blood CD41 T cells, who subsequently developed EBVpositive monoclonal T-cell lymphoma (Kanegane et al, 1998). These findings suggest a similar pathogenetic scenario for EBV-associated T-cell proliferations to that proposed for EBV-associated B-cell proliferations in transplant patients, leading from initially polyclonal proliferations to monoclonal malignant lymphoma (Niedobitek et al, 1997). An alternative explanation is suggested by the observation that EBV-specific T cells in IM frequently represent oligo- or monoclonal expansions (Callan et al, 1996). This raises the possibility that the infection of EBV-specific T cells with the virus during IM may give rise to atypical EBVassociated monoclonal T-cell proliferations. EBV infection of T cells in vitro has been shown to stimulate T-cell growth in conjunction with CD2 antibodies and interleukin-2 (IL-2) (Kelleher et al, 1996). In these T cells, the viral genome is mainly present as a linear, extrachromosomal molecule and lytic cycle antigens are expressed (Kelleher et al, 1996). The significance of this observation for EBV infection in vivo remains uncertain, as the EBV-encoded latent proteins, EBNA2 and LMP1, as well as the early lytic cycle protein, BZLF1, were not detectable in EBV-infected T cells in our case or in previous studies of infectious mononucleosis (Niedobitek et al, 1997). Nevertheless, the evidence from the
in vitro experiments suggests that the interaction of EBV with T cells is fundamentally different from that with B cells. It is conceivable that, unlike B cells, T cells are not adapted to EBV infection and, therefore, accidental infection may lead to severe disease, such as T-cell lymphoma or fatal, atypical T-cell proliferation. As in our case, all previously reported patients described with EBV-associated T-cell LPD were previously healthy, without opportunistic infections or other indicators of congenital immunodeficiency, and had a rapid and fatal course. Therefore, a specific (genetically determined?) vulnerability to EBV has been suggested. The reduced level of immunoglobulins observed in our patients and mentioned in some reports suggests an impaired humoral response to the virus. This could be the result of a failure of EBV infected T cells to differentiate towards functional competent CD41 helper cells, as indicated by the absence of these cells in our patient. Alternatively, in the case of maximal activation of cytotoxic T-cell response, a Th1/Th2 cross-inhibition could explain the downregulation of humoral immunity. A dominant cytotoxic response would also explain the severe myocardial damage because it has been suggested that this is rather the result of an immune reaction to cardiomyocytes (probably also related to a specific HLA constellation) than a direct cytotoxic viral effect (Hebert et al, 1995).
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