Chronic interstitial lung disease with lung fibrosis in a girl: uncommon sequelae of Epstein-Barr virus infection

A 12-month-old immunocompetent girl presented with tachypnea, inspiratory crackles, mild hypoxemia, and failure to thrive after an acute Epstein-Barr virus (EBV) infection. The course of acute EBV infection was demonstrated by viral load measurement in plasma and peripheral blood mononuclear cells (PBMC) by using real-time polymerase chain reaction (PCR). EBV DNA was further detected by PCR in bronchoalveolar lavage (BAL) fluid and from a lung-tissue specimen obtained by open-lung biopsy, which indicates the pulmonary involvement of active EBV infection. Histology revealed an uncharacteristic interstitial infiltration and fibrosis. Following topic and systemic treatment with corticosteroids, the child became asymptomatic and showed normal weight gain as well as mental and physical development. Pulmonary parenchymal involvement during the course of primary EBV infection may result in interstitial lung disease and fibrosis not only in immunodeficient, but in immunocompetent children as well. Treatment with combined inhaled and oral steroids seems to be a treatment option in these patients.     

Severe respiratory syncytial virus pneumonia associated with primary Epstein-Barr virus infection

This is a case report of a child with severe respiratory syncytial virus (RSV) pneumonia and concurrent infection with Epstein-Barr virus. We hypothesize that immunosuppression due to EBV may have contributed to the severity of his RSV infection. The diagnosis of RSV infection was facilitated by bronchoalveolar lavage.     

Lung adenocarcinoma in lymphocytic interstitial pneumonitis associated with primary Sjögren''s syndrome

We experienced a rare case of lung adenocarcinoma associated with lymphocytic interstitial pneumonitis caused by primary Sjögren’s syndrome. A 78-year-old woman was referred to our hospital because of progressive sicca syndrome and nodular opacities in the right lower lobe on chest radiograph. This patient was diagnosed as primary Sjögren’s syndrome by a labial gland biopsy and classical clinical features including xerophthalmia, xerostomia and immunoserological findings. Pathological findings including immunohistochemical studies in a surgically resected lung revealed adenocarcinoma in lymphocytic interstitial pneumonitis associated with primary Sjögren’s syndrome. There was no evidence of malignant lymphoma in the lymph nodes or resected lung tissue. Pulmonary involvement of Sjögren’s syndrome is now regarded both clinically and histopathologically as a wide spectrum of lymphoproliferative disorders ranging from benign to malignant. However, lung cancer associated with primary Sjögren’s syndrome, as in our case, has apparently not been reported previously.     

Successful umbilical cord blood transplantation for severe chronic active Epstein-Barr virus infection after the double failure of hematopoietic stem cell transplantation

An 11-year-old boy with severe chronic active Epstein-Barr virus infection (CAEBV) underwent successful cord blood transplantation (CBT) after consecutive failure of peripheral blood and bone marrow transplantation from his HLA-mismatched mother. CB cells from an unrelated donor were infused after conditioning with total body irradiation (12 Gy), melphalan (120 mg/m(2)), and etoposide (600 mg/m(2)). Complete remission without circulating EBV-DNA has continued for 15 months after a delayed hematologic recovery. This is the first successful report of CBT for CAEBV. CB may therefore be an alternate source of stem cells for the curative treatment of CAEBV, despite the absence of EBV-specific cytotoxic T lymphocytes.     

Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection

Since the initial report of unusual manifestations possibly associated with chronic active Epstein-Barr virus (EBV) infection (CAEBV), nearly three decades have passed. During this period, reported cases with this entity have dramatically increased in the world. Additionally, recent development of diagnostic procedures, including molecular biological and immunological techniques, have provided us with the ability to define certain diseases, especially malignant disorders. Guidelines, derived mainly from the current literature and recent experiences with CAEBV in Japan, for diagnosing CAEBV are proposed to clarify this enigmatic disease.     

Single nucleotide polymorphisms of matrix metalloproteinase 9 (MMP9) and tumor protein 73 (TP73) interact with Epstein-Barr virus in chronic lymphocytic leukemia: results from the European case-control study EpiLymph

Using EpiLymph case-control data, we found that chronic lymphocytic leukemia patients were more likely to have abnormal reactive serological patterns to Epstein Barr virus than controls. Here, we aimed to assess whether this association is modified by genetic variants. We examined 1,305 Single Nucleotide Polymorphisms from 300 selected genes related to various pathways in 240 cases and 513 controls from five European centers. In a recessive model, patients positive to aberrant antibody pattern and homozygous for rare genotypes in rs8113877T>G or rs17576A>G of the MMP9 gene were at highest risk of chronic lymphocytic leukemia. In a dominant model, TP73 showed the highest risk in patients positive to aberrant antibody pattern and homozygous for the wild-type genotype in rs1885859G>C or rs3765701A>T. All interactions were additive and no main effect was observed. The strong interactions observed may be indicative of a specific pathway in cancer genesis. Confirmation of these results is warranted.     

肠道T细胞淋巴瘤中EB病毒感染的研究

目的 了解我国肠道T细胞淋巴瘤（ITCL）中EB病毒（EBV）潜伏感染的状态，其亚型的感染情况，基因产物表达与EBV阳性细胞的性质。方法采用PCR检测42例ITCL中的不同EBV亚型的核抗原基因（EBNA－3C），并对其扩增产的行DNA序列分析。运用EBER1／2－RNA原位杂交证实EBV潜伏感染，IHC／ISH双重染色技术判断EBV阳性细胞性质。免疫组化检测EBV基因产物（LMP－1，EBNA－2）的表达。结果 42例ITCL中EBV的阳性率为97．6％，以A型EBV感染居多（32／38例，84．2％），B型为2／38例（5．3％），混合型为4／38例（10．5％）。EBNA－3C基因的PCR产物DNA序列中存在个别碱基的缺失和插入.EBER1/2的检出率为85．7％。EBER1／2阳性细胞同时表达CD45RO和TIA－1，且表达CD4，CD8及CD56的肿瘤细胞呈EBER1／2阳性。16／42例ITCL（38．1％）表达LMP－1。ITCL中EBV的潜伏感染模式多为I型（24／42，66．7％），Ⅱ型次之（12／42，33．4％）。结论 在我国，ITCL中存在高水平的EBV潜伏感染，且多为A型EBV感染，感染模式为Ⅰ型和Ⅱ型。部分ITCL可能与鼻NK／T细胞淋巴瘤属于同一疾病谱系。     

Familial interstitial lung disease in children: Response to chloroquine treatment in one sibling with desquamative interstitial pneumonitis

We describe a male infant with biopsy-confirmed interstitial lung disease (ILD) who responded to chloroquine, after he failed to improve on oral corticosteroids or cyclophosphamide. The infant presented at 8 days of age with respiratory distress and cyanosis. Lung biopsy at 8 weeks of age was consistent with desquamative interstitial pneumonitis (DIP). He was treated with corticosteroids at 2 weeks of age because of a family history of two siblings who died during infancy and who had DIP on postmortem examination. At 8.5 months, our patient was treated with cyclophosphamide because of lack of response to corticosteroids therapy. At 14 months of age, he began treatment with chloroquine in addition to corticosteroids and had a dramatic response within 3 weeks. The patient has been maintained successfully on continuous treatment with chloroquine alone for more than 9 years since this treatment was started. Pediatr. Pulmonol. 1997; 23:55–61. © 1997 Wiley-Liss, Inc.     

Granulomatous‐lymphocytic interstitial lung disease as the first manifestation of common variable immunodeficiency

Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies, which is characterized by reduced serum immunoglobulin levels and B‐lymphocyte dysfunction. There are many clinical manifestations of this disease, the most common of which are recurrent respiratory tract infections. Among the most recently recognized autoimmune manifestation of CVID is a disease described as granulomatous‐lymphocytic interstitial lung disease (GLILD), where CVID coexists with a small airway lymphoproliferative disorder, mimicking follicular bronchiolitis, or lymphocytic interstitial pneumonitis (LIP) on histology specimens. We herein describe the clinical and radiological features of GLILD in a 55‐year‐old woman where the diagnosis of CVID was actively pursued and eventually confirmed after her lung biopsy showed characteristic features of GLILD. The patient had dramatic response to treatment with IVIG and corticosteroids for 3 months followed by Mycophenolate mofetil for maintenance therapy.     

X-linked lymphoproliferative syndrome presenting with systemic lymphocytic vasculitis

X-linked lymphoproliferative syndrome (XLP) is a rare, often fatal, primary immunodeficiency disease characterized by an abnormal response to Epstein-Barr virus (EBV) infection. The gene responsible for XLP has been identified as SH2D1A/DSHP/SLAM-associated protein (SAP). The major clinical manifestations include fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia. Affected males uncommonly present with lymphocytic vasculitis in addition to aplastic anemia. In this study, we describe a Japanese XLP patient who presented with hypogammaglobulinemia following acute EBV-induced infectious mononucleosis in the infancy and later had systemic lymphocytic vasculitis and hemophagocytic lymphohistiocytosis in the adulthood, which resolved by steroid pulse therapy. The patient's SAP gene was found to harbor a missense mutation (His8Asp), presumably resulting in defective expression of SAP in T cells. Biopsy specimens of lung and skin disclosed that CD8+ T cells predominantly infiltrated vascular vessels. However, immunohistochemical examination showed that EBV-infected cells were not identifiable in the vessels. We propose that T-cell-mediated immune dysregulation in XLP can cause vasculitis by EBV infection-unrelated mechanism.     

Epstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia

Epstein-Barr virus (EBV) infection and reactivation is an increasing complication in immune deficient patients, particularly after allogeneic hematopoietic stem cell transplantation (HSCT). Therapy with anti-thymocyte globulin (ATG) is associated with higher incidence of EBV-related disease in HSCT patients, but this risk is not documented in patients receiving ATG for severe aplastic anemia (SAA). We describe the case of a patient who developed an EBV infection, with the clinical features of an infectious mononucleosis, after immune suppression with cyclosporine and two courses of ATG for SAA.     

Epstein-Barr virus-associated bronchial leiomyoma in a boy with cellular immunodeficiency

Bronchial leiomyoma is a rare disease in children. Recently, the association of leiomyoma and HIV infection was reported. We describe a boy with a cellular immunodeficiency, who had endobronchial leiomyoma. The tumor cells were positive for Epstein-Barr virus-encoded RNA-1 (EBER-1) and Epstein-Barr virus-determined nuclear antigen-2, suggesting a role of Epstein-Barr virus in the pathogenesis of leiomyoma.     

Cyclosporine treatment of advanced interstitial pneumonitis associated with systemic sclerosis

Abstract

A patient who had systemic sclerosis (SSc) with interstitial pneumonitis (IP) was being treated with prednisolone,d-penicillamine (D-P) and colchicine but developed progressive respiratory insufficiency. His ventilatory function showed the progression of restrictive disturbance without an obstructive one. We thought that this worsening was due to the developing IP but not bronchiolitis obliterans induced by D-P and started cyclosporine (CSA) therapy at 3 mg/kg/day. His symptoms improved after 3 months, and pulmonary function tests and blood gas analysis showed the best results after 1 year. There were no life-threatening side effects. CSA is an acceptable agent for advanced interstitial pneumonitis associated with SSc.     

Cyclosporine treatment of advanced interstitial pneumonitis associated with systemic sclerosis

A patient who had systemic sclerosis (SSc) with interstitial pneumonitis (IP) was being treated with prednisolone,d-penicillamine (D-P) and colchicine but developed progressive respiratory insufficiency. His ventilatory function showed the progression of restrictive disturbance without an obstructive one. We thought that this worsening was due to the developing IP but not bronchiolitis obliterans induced by D-P and started cyclosporine (CSA) therapy at 3 mg/kg/day. His symptoms improved after 3 months, and pulmonary function tests and blood gas analysis showed the best results after 1 year. There were no life-threatening side effects. CSA is an acceptable agent for advanced interstitial pneumonitis associated with SSc.     

CD4-CD8- T-cell polymyositis in a patient with chronic active Epstein-Barr virus infection

We describe a 17-year-old woman with chronic active Epstein-Barr virus infection (CAEBV), who developed EBV+CD4-CD8- T-cell polymyositis. At 14 years of age, CAEBV was diagnosed with fever, cytopenia, liver dysfunction, and hepatosplenomegaly. Despite the transient remission of interferon-alpha therapy, migratory lesions emerged in back and extremities. MRI indicated polymyositis. Biopsy specimens revealed intramuscular infiltration of CD3+, CD4-, CD8-, CD56-, and EBV-encoded RNA 1+ cells. Circulating CD4-CD8-Vdelta2/Vgamma9 cells increased. gammadeltaT-cells contained 20-200 times higher EBV-DNA (2 x 10(4) copies/microgDNA) than alphabetaT-cells or NK-cells. The ominous polymyositis might denote the musculotropic invasion of EBV+gammadeltaT-cell lymphoproliferative disease as a consequence of CAEBV.     

HIV-related Hodgkin's disease with central nervous system involvement and association with Epstein-Barr virus

Central nervous system (CNS) involvement is a rare occurrence in the course of human immunodeficiency virus (HIV)-related Hodgkin's disease (HD). We report the clinical course of a patient with HIV infection who developed systemic HD, mixed cellularity subtype, later complicated by leptomeningeal involvement. The patient died from his illness, and autopsy was performed. Examining the brain lesion, Epstein-Barr virus (EBV) presence was demonstrated in Reed-Sternberg cells by immunohistochemistry using an EBER probe for EBV RNA. This is the second case report in the English literature of HD involving the CNS in an HIV-positive individual, and the first demonstrating EBV presence. Extranodal presence of Hodgkin's disease in patients with HIV infection is probably related to immunosuppression, and physicians treating this illness should be alert to the potential of unusual sites of involvement.     

The significance of Epstein-Barr virus detected in the cerebrospinal fluid of people with HIV infection

INTRODUCTION: Epstein-Barr virus (EBV) is detected in the cerebrospinal fluid (CSF) in people with HIV infection who develop primary cerebral lymphoma (PCL). However, EBV may also be detected in the CSF of patients without PCL, and here the significance is uncertain. METHODS: Ninety-eight HIV-positive patients had lumbar punctures performed and polymerase chain reaction (PCR) for EBV was undertaken on the CSF. Thirty-eight patients had non-Hodgkin's lymphoma (NHL), including four with PCL. Sixty patients had a CSF examination for other indications. The clinicopathological details, symptoms, diagnosis, CSF and neuroimaging findings and therapy at time of CSF were recorded and correlated with CSF EBV PCR results. RESULTS: EBV was detected in the CSF in three of four patients (75%) with PCL, one of three (33%) with systemic lymphoma and meningeal involvement, and four of 31 (13%) with systemic lymphoma and no meningeal disease. Seven of 60 patients (12%) without lymphoma were CSF EBV-positive. There were no differences in immunological, clinical, biochemical or radiological parameters between patients with and without EBV in the CSF. After a median follow-up time of 30 weeks (maximum 102 weeks), none of the seven CSF EBV-positive patients has developed PCL. CONCLUSION: EBV was detected in up to 12% of patients with neurological symptoms but without lymphoma. A positive result did not correlate with more advanced immunosuppression or a particular neurological diagnosis. Patients with EBV in their CSF did not appear to be at increased risk of developing PCL in the short term.     

Successful treatment of severe aplastic anemia associated with human parvovirus B19 and Epstein-Barr virus in a healthy subject with allo-BMT.

Several reports have noted pancytopenia associated with Human parvovirus B19 (PVB19) or Ebstein-Barr virus (EBV) infections in patients who have no history of immunodeficiency. To our knowledge, we report the first case of severe aplastic anemia associated with both EBV and PVB19 infections in a previously healthy 22-year-old man. He was admitted to our hematology service due to anemia and thrombocytopenia. He had no symptoms or signs of infections of these viruses. His bone marrow biopsy revealed a hypocellular marrow. Specific IgM and IgG antibodies to EBV and PVB19 were elevated. EBV and PVB19 virus genomes were detected by PCR in the bone marrow nucleated cells and the peripheral blood lymphocytes. Two months after treatment with prednisone, acyclovir, and intravenous immune globulin (IVIg), the genomes of both these viruses disappeared. However, his transfusion requirement for platelet suspensions and packed red blood cells persisted. The patient underwent allogeneic bone marrow transplant (allo-BMT) and has had an enduring complete hematological response for 8 months.