Epstein-Barr virus (EBV) has a tropism for B cells but can also infect T cells, epithelial cells, and neural cells (1–4). EBV infection may be associated with a heterogeneous group of diseases, including nonneoplastic and neoplastic diseases, such as infectious mononucleosis (IM), lymphoma, and nasopharyngeal carcinoma (5–7).
EBV infects more than 90% of healthy population. After primary infection, EBV establishes latent infection in B cells and is controlled by the immune system (6, 8). Primary EBV infection or reactivation usually induces asymptomatic infection or IM in immunocompetent people. If the balance between EBV-infected cells and immune system is disrupted, EBV may result in a spectrum of diseases, going from fever to lymphoproliferative diseases in immunocompromised people (9–15). In recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the spectrum of diseases includes fever, posttransplantation lymphoproliferative diseases (PTLD), and end-organ diseases (pneumonia, encephalitis/myelitis, and hepatitis) (16–20). Currently, PTLD has been widely studied. The incidence of PTLD varies from 0.5% to 22% in allo-HSCT recipients depending on the number of risk factors (21, 22). However, there are only scattered reports about EBV-associated diseases other than PTLD (16–20). The aim of this study is to investigate the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases.
Spectrum of EBV-Associated Diseases
With a median (range) follow-up of 374 (27–1554) days after transplantation, 77 patients developed EBV viremia and 36 EBV-associated diseases, including 21 PTLD, 2 PTLD accompanied by EBV pneumonia, 7 EBV fever, and 6 end-organ diseases (1 pneumonia, 1 encephalitis, 1 myelitis, 1 hepatitis, 1 encephalitis accompanied by pneumonia, and 1 encephalitis accompanied by pneumonia and hepatitis). The 3-year cumulative incidence of total EBV-associated diseases, PTLD, fever, and end-organ diseases were 15.6%±2.5%, 9.9%±2.0%, 3.3%±1.3%, and 3.3%±1.2%. In end-organ diseases, the incidence of pneumonia, encephalitis/myelitis, and hepatitis were 2.2%±1.0%, 1.6%±0.8%, and 0.9%±0.6% (Fig. 1). The risk factors for PTLD, fever, and end-organ diseases are shown in Table 1.
Involved Area of EBV-Associated Diseases
Seven patients only had fever without tissue involvement, and 29 had tissue involvement including 19 with extranodal involvement. The involved area included lymph nodes (n=18), central nervous system (CNS; n=14), lung (n=9), tonsil (n=6), liver (n=4), spleen (n=3), and nasal cavity (n=1). Eighteen patients had single organ involvement (lymph nodes in 10, CNS in 6, lung in 1, and liver in 1), and 11 had two or more organ involvement.
Clinical Characteristics of EBV-Associated Diseases
The EBV-DNA loads of blood exceeded the threshold for 0 to 26 (median, 10) days before the clinical manifestations. The median (range) time to disease onset was 63 (22–337) days after transplantation. The median (range) time to onset of PTLD and end-organ diseases was 61 (22–337) and 60 (43–95) days after transplantation (P=0.209). Thirty patients presented with fever, 4 with lymphadenectasis, and 2 with CNS symptoms as initial manifestations. Twelve patients had CNS manifestations (hyperspasmia in 3, limb tremors in 2, visual and auditory hallucinations in 2, headache in 2, apathy in 1, memory impairment in 1, and light coma in 1), and 8 had respiratory system symptoms (shortness of breath in 3, cough in 2, dyspnea in 2, and chest pain in 1) at disease onset.
Characteristics of Histopathology
Eighteen patients with lymphadenectasis performed lymph node biopsy. The results showed IM-like lesions (n=3), polymorphic (n=4), CD20+ diffuse large B-cell lymphoma (n=9), anaplastic large B-cell lymphoma (n=1), and natural killer/T-cell lymphoma (n=1). EBV-encoded small nuclear RNA (EBER1) was all positive in biopsy specimens of the 18 patients. Lung biopsy was examined in 5 of the 9 patients with lung involvement, and results revealed EBV pneumonia (n=2) and PTLD (n=3). Histopathology characteristics of EBV pneumonia were interstitial and intra-alveolar infiltrates of inflammatory cells in multiple cell phenotype (mainly CD3+ T cells and CD68+ macrophages); PTLD was interstitial and intra-alveolar infiltrates of single CD19+CD20+ B cells.
Immunophenotypic analysis of cerebrospinal fluid (CSF) cells was performed on all patients with CNS involvement. CSF cell counts of three patients were very low, resulting in inability for analysis. Of the 11 analyzable patients, the results revealed single CD19+CD20+ B-cell phenotype (n=6) and multiple cell phenotype of CD3+ T cells, CD19+ B cells, and CD14+ monocytes (n=5). Cell immunophenotypic analysis was also performed on seven patients with lung and two patients with liver involvement. The results showed that cells in bronchoalveolar lavage (BAL) fluid, hydrothorax, and ascites consisted of mainly CD3+ T cells and CD14+ monocytes in patients with EBV pneumonia and hepatitis and single CD19+CD20+ B cell phenotype in those with PTLD. Three patients performed both lung biopsy and cell immunophenotypic analysis of secretions (Table 2). Cell immunophenotypic analysis of secretions was consistent with histopathology of lung tissue.
EBV-DNA Loads of Blood and Secretions
Thirty-six patients with EBV-associated diseases were all EBV-DNA positive in blood, except one with isolated CNS-PTLD, who was EBV-DNA positive in CSF and EBV-DNA negative in blood. The EBV-DNA loads of secretions (CSF, BAL fluid, hydrothorax, and ascites) from affected tissues were significantly higher than that of blood (39,620±8875 vs. 17,619±5275 copies/mL; P=0.030). There were significant differences in initial and maximal blood EBV-DNA loads in patients with simple EBV viremia, PTLD, end-organ disease, and fever (P=0.009 and 0.020) (Fig. 2).
Chest and abdominal computed tomography (CT) were normal in 24 cases and abnormal in 12 cases, including diffuse lung infiltration (n=4), diffuse lung infiltration accompanied by hepatosplenomegaly (n=3), diffuse lung infiltration and nodules accompanied by mediastinal lymph node enlargement (n=2), lung nodules accompanied by mediastinal lymph node enlargement (n=1), hepatomegaly (n=1), and pelvic lymph node enlargement (n=1). Of the 14 patients with CNS involvement, magnetic resonance imaging (MRI) were normal in 5 cases and abnormal in 11 cases, including 6 with disseminated or localized inflammatory changes and 5 with single or multiple hyperintense on T2-FLAIR images. With development of diseases, two patients who initially presented as disseminated inflammatory changes and normal MRI had space-occupying lesions in CNS.
Treatment and Outcome of EBV-Associated Diseases
Thirty patients received rituximab-based treatments, 1 only received antiviral agents plus reduction of immunosuppressants (RI), and 5 abandoned treatments because of financial constraints. Of the 30 patients receiving rituximab-based treatments, 22 obtained complete responses (CR), 4 partial responses, 1 no response (NR), and 3 died of disease progression within 2 cycles. The 4 patients with partial responses obtained CR after rituximab-based treatments combined with donor lymphocyte infusion (DLI)/EBV-cytotoxic T lymphocytes (EBV-CTL). The one with NR died of disease progression despite receiving DLI (Table 3). The patient without use of rituximab and five patients without treatment all died of disease progression. PTLD had better response to rituximab-based treatment compared with end-organ diseases (including PTLD accompanied by end-organ diseases) (P=0.014).
With a median (range) follow-up of 262 (4–1197) days after disease onset, 17 survived and 19 died (Table 3). Causes of death included PTLD progression (n=7), PTLD relapse (n=1), end-organ diseases (n=3), acute graft-versus-host disease (aGVHD; n=3), cytomegalovirus (CMV) pneumonia (n=3), viral myocarditis (n=1), and leukemia relapse (n=1). The 3-year overall survival in patients with EBV-associated diseases was 36.2%±11.1% compared with 57.5%±4.0% in those without EBV-associated diseases (P=0.041). The 3-year overall survival was 37.3%±13.7%, 100.0%, and 0.0%±0.0% in patients with PTLD, fever, and end-organ diseases (including PTLD accompanied by end-organ diseases) (P=0.001).
A growing body of data suggest that PTLD is only the tip of the iceberg of posttransplantation EBV-associated diseases (11, 19, 20). However, there is absence of large sample data about the incidence of EBV-associated diseases other than PTLD in transplant recipients. In this study, our data showed that the 3-year cumulative incidence of PTLD, fever, and end-organ diseases were 9.9%±2.0%, 3.3%±1.3%, and 3.3%±1.2% in allo-HSCT recipients. EBV fever was the most common form in EBV-associated diseases other than PTLD. Whether EBV fever was an independent disease or early clinical manifestation of end-organ diseases or PTLD needs further study. We observed one patient, initially diagnosed as fever, did not respond to rituximab, subsequently had nasal septum and lung involvement, and was diagnosed with PTLD via biopsy finally.
Recognized major risk factors for PTLD are T-cell depletion, antithymocyte globulin (ATG), human leukocyte antigen (HLA) mismatch, and unrelated donor (21, 22). Our result was consistent with previous studies and showed that intensified conditioning was also the risk of PTLD, which might be associated with the effects of intensified conditioning on immune reconstitution. Risk factors for end-organ diseases and fever are rarely reported. In this study, our result showed that only ATG was the risk factor for end-organ diseases and fever, which was different from the risk of PTLD. However, further study is needed because of limited cases allotted.
Fever and lymphadenectasis are the most common symptoms and signs and are usually associated with rapidly progressive multiorgan failure and death if not treated in PTLD (12, 14). We observed that fever was also the most common symptom of end-organ diseases. Despite early intervention with rituximab, two patients with end-organ diseases progressed rapidly and died. The onset time of end-organ disease was similar to PTLD, which mostly occurred in the first 3 months after transplantation. PTLD might co-occur with end-organ diseases (2, 19). Here, we observed two patients with PTLD accompanied by EBV pneumonia. Due to the similar clinical manifestations and onset time, it is difficult to distinguish end-organ disease from PTLD. End-organ diseases usually do not have lymphadenectasis, which might be helpful for differential diagnosis. EBV infection can involve nearly all tissues and organs, and clinical manifestations of the diseases are diverse, thus making it also difficult to distinguish from other diseases, such as aGVHD or other infections (12, 14, 23). Furthermore, the clinical course of EBV-associated diseases often superimpose with aGVHD or infection. Ultimately, it requires histopathologic biopsy to make a definitive diagnosis. However, due to serious disease status and very low platelet counts, some patients are often unsuitable for biopsy. In this study, we used EBV detection and cell immunophenotypic analysis in the secretions of affected tissues combined with corresponding symptoms and/or signs to diagnose five patients unsuitable for biopsy (four with end-organ diseases and one with isolated CNS-PTLD). The result showed that EBV-DNA loads of secretions were significantly higher than that of blood. Cell immunophenotype of secretions was consistent with histopathology of affected tissue. Three of the five patients achieved CR after rituximab-based treatment. Based on these, we considered that EBV detection and cell immunophenotypic analysis in secretions could be proposed as an alternative diagnostic method for patients unsuitable for biopsy.
Rituximab has been applied as first-line treatment for PTLD in allo-HSCT recipients, with initial response rates between 55% and 100% (12, 14, 24). Our result was consistent with current studies (12, 14, 24). There are only case reports about therapy for EBV-associated other diseases (11, 19, 20). Kinch et al. reported that three of four patients with EBV-associated other diseases obtained CR after rituximab treatment (20). Our study showed patients with end-organ diseases had poorer response to rituximab compared with PTLD. Of the six patients with end-organ diseases (including one with PTLD accompanied by pneumonia), three achieved CR after rituximab-based therapy. The CD20 expression on B-cell surface is suggested as the reason for rituximab use in treating PTLD (25, 26). However, the mechanism of rituximab therapy for end-organ diseases remains unclear. Based on the pathogenesis of EBV-associated diseases (3, 11, 27, 28), we deduced the mechanisms that rituximab was effective to end-organ diseases might be associated with rituximab effective depletion of latent EBV-infected B cells and EBV gene products, and ineffectiveness might be associated with no CD20 expression in EBV affected non-B cells. Further studies are needed to clarify the mechanism of rituximab in treating end-organ diseases.
Recently, DLI and CTL for therapy of PTLD also reveal promising efficacy, with response rates between 41.0% and 88.2% (14). However, the time (2–3 months) and facilities required for CTL production and severe GVHD induced by DLI have limited their use as frontline approach (12, 14). In this study, DLI/CTL combined with rituximab-based treatments was conducted in patients without CR within two cycles of rituximab-based treatment. Of the five patients without CR within two cycles, two achieved CR after DLI and two after EBV-CTL combined with rituximab-based treatment. The advantages of strategy were that it could decrease the risk of severe GVHD and reserve time for EBV-CTL production.
In conclusion, EBV-associated diseases other than PTLD are not rare in allo-HSCT recipients. The clinical manifestations and onset time of end-organ diseases and PTLD are similar. EBV detection and cell immunophenotypic analysis in the secretions of affected tissues could be proposed as an alternative diagnostic method for patients unsuitable for biopsy. Compared with PTLD, end-organ diseases had poorer response to rituximab-based therapy.
MATERIALS AND METHODS
From July 2008 to June 2012, 263 patients undergoing allo-HSCT at Nanfang Hospital were enrolled in this prospective study. The median (range) age was 29 (11–63) years; 101 patients were female and 162 were male. Primary diseases included acute leukemia (n=197), chronic myeloid leukemia (n=44), lymphoma (n=10), severe aplastic anemia (n=7), and other diseases (n=5). All recipients were EBV-DNA negative in blood before transplantation. Three donors were EBV-DNA positive and became EBV-DNA negative with antiviral agents before collection of stem cells. The study was performed in accordance with modified Helsinki Declaration, and the protocol was approved by our ethical review boards before study initiation. All recipients, donors, and/or guardians provided written informed consent.
Two patients received bone marrow grafts, 206 received peripheral blood stem cell grafts, and 55 received peripheral blood stem cell and bone marrow mixed grafts. None of these patients received a T-cell–depleted transplant. One hundred ninety-four patients received related donor transplants (169 sibling and 25 family donors) and 69 received unrelated donor transplants; 188 were HLA locus matched and 75 were mismatched. As described previously (29), six conditioning regimens were adopted, including (a) total body irradiation (TBI)+cyclophosphamide (CY) in 40, (b) busulfan (Bu)+CY in 66, (c) Bu+fludarabine (Flu) in 28, (d) TBI+CY+etoposide (VP-16) in 48, (e) Flu+cytarabine (Ara-C)+TBI+CY in 74, and (f) CY+ATG in 7. According to the intensity of conditioning, conditioning was divided into standard conditioning (TBI+CY, Bu+CY, Bu+Flu, and CY+ATG) and intensified conditioning (TBI+CY+VP-16 and Flu+Ara-C+TBI+CY). GVHD prophylaxis was according to our previous description (29).
Oral sulfamethoxazole and norfloxacin were given to all patients. Acyclovir was given daily from the beginning of conditioning therapy to engraftment and was then administered daily for 7 days every 2 weeks until 1 year after transplantation. Ganciclovir was given for 2 weeks before transplantation for prophylaxis of CMV infection and was administered once again when CMV viremia occurred. Antifungal agents were administered 5 days before transplantation and continued for +30 to +90 days after transplantation.
Detection of EBV in Blood and Secretions of Affected Tissues
Quantitative real-time polymerase chain reaction assay for detection of EBV-DNA in blood and secretions and in situ hybridization for detection of EBER1 in tissue have been described previously (19, 29). According to the manufacturer (ZJ Bio-Tech, Shanghai, China), it was defined as positive if EBV-DNA were higher or equal to 500 copies/mL.
EBV-DNA loads of blood were monitored weekly for the first 3 months, every 2 weeks from 4 to 9 months, monthly from 10 to 24 months, and every 3 months from 25 to 36 months after transplantation. If EBV-DNA was positive, it was monitored twice a week. For patients considered with EBV-associated diseases, paired blood and corresponding secretions were detected for EBV-DNA during disease and follow-up. Other pathogens including bacterial, fungus, CMV, herpes simplex virus types 1 and 2, adenovirus, varicella zoster virus, human herpesvirus types 6 and 8, parvovirus B19, and BK virus were excluded in blood and secretions of affected tissue (29).
Other Parameters of Monitoring
When EBV-associated disease was considered, other parameters including cell immunophenotypic analysis, CT, and MRI were performed. Flow cytometry was used to analyze immunophenotype of cells in affected tissue and/or secretions. CT and MRI were performed within 7 days after disease onset and during follow-up.
Intervention for EBV Viremia
When blood EBV-DNA was positive twice consecutively, intervention was taken, including antiviral agents (ganciclovir [10 mg/kg/day]/foscarnet [100 mg/kg/day]) and RI if the condition of the patient was acceptable. If blood EBV-DNA was continuously positive four times with a rising trend, rituximab (375 mg/m2) was administered weekly until EBV-DNA was negative or for a total of 4 weeks (30).
Definition and Diagnosis of EBV-Associated Diseases
Definition and diagnosis of EBV-associated diseases was based on the criteria of European Conference on Infections in Leukemia and literatures, including EBV-associated PTLD and EBV-associated other diseases (20, 31–37). EBV-PTLD was diagnosed according to the criteria of World Health Organization (14, 32). EBV-associated other diseases included EBV fever and EBV-associated diseases with tissue other than lymphatic tissue involvement (end-organ diseases) (14, 19, 20, 31). EBV fever was defined and diagnosed as follows: (a) EBV viremia, (b) fever of unknown origin, (c) ineffective after 5 days’ anti-infective treatment but effective with rituximab treatment, (d) absence of other etiologic evidence or established diseases (20, 31). The diagnostic criteria for end-organ diseases included (a) clinical manifestations from the affected organ, (b) evidence of EBV in the affected tissue and/or secretions, (c) histopathologic evidence or cell immunophenotypic analysis revealing multiple cell phenotype in the affected tissue and/or secretions, and (d) absence of other etiologic evidence or established diseases (20, 31, 34–37). The diagnosis of EBV encephalitis/myelitis included the criteria above and (e) diffuse lesions or normal images with neuroimaging (36, 38). If patients had space-occupying lesions in CNS images, PTLD was diagnosed (36, 38).
Treatment of EBV-Associated Diseases
When EBV-associated diseases were diagnosed, rituximab-based treatments were taken promptly, including antiviral agents, RI, rituximab, and chemotherapy. If patients did not obtain CR after two cycles of rituximab-based treatments, DLI or EBV-CTL would be conducted combined with rituximab-based treatments.
Evaluation Points and Statistics
Our data were analyzed on October 31, 2012. Main evaluation points were the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases. Comparisons of categorical variables were made by means of chi-square tests. Differences between numerical variables were calculated by means of Mann–Whitney U test. Incidence of time-dependent variables was estimated by Kaplan–Meier test. Univariate and multivariate Cox regression models were used to analyze risk factors for EBV infections after transplantation.
The authors thank Beijing Daopei Hospital for its help in EBV-CTL.
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