Infectious mononucleosis and Epstein-Barr virus

Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects over 90% of the human population worldwide. It is usually transmitted between individuals in saliva, and establishes replicative infection within the oropharynx as well as life-long latent infection of B cells. Primary EBV infection generally occurs during early childhood and is asymptomatic. If delayed until adolescence or later, it can be associated with the clinical syndrome of infectious mononucleosis (also known as glandular fever or 'mono'), an illness characterised by fevers, pharyngitis, lymphadenopathy and malaise. EBV infection is also associated with the development of EBV-associated lymphoid or epithelial cell malignancies in a small proportion of individuals. This review focuses on primary EBV infection in individuals suffering from infectious mononucleosis. It discusses the mechanism by which EBV establishes infection within its human host and the primary immune response that it elicits. It describes the spectrum of clinical disease that can accompany primary infection and summarises studies that are leading to the development of a vaccine designed to prevent infectious mononucleosis.     

Chronic active Epstein-Barr virus infection

The ubiquitous Epstein-Barr virus (EBV), which establishes latency after primary infection, does not cause any symptomatic diseases as long as cellular immunity is intact. In apparently immunocompetent individuals, a chronic infection can develop, and this has been called as chronic active EBV infection (CAEBV). CAEBV is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and, hepatosplenomegaly. This disease is rare but severe with high morbidity and mortality. Recently, its pathophysiology is not an infection but a clonal expansion of EBV-infected T or natural killer NK cells. In this review, I discuss our current understanding of the pathogenesis of CAEBV and summarize its clinical features, therapies, and prognosis.     

Dermatopathic Lymphadenopathy—A Clinicopathologic Analysis of Lymph Node Biopsy Over a 15-Year Period

Forty cases of dermatopathic lymphadenopathy were found in a series of 906 consecutive lymph node biopsies (4.8 per cent).The histologic development and progression of the disease was correlated with the clinical state of the patient.In 35 of 40 cases the patients had active skin disease at the time of the biopsy; one of the remaining five patients had Hodgkin''s disease, one had multiple myeloma and one had secondary syphilis. In the other two, no organic cause was found.In nine cases (22.5 per cent), the histological pattern typical of dermatopathic lymphadenopathy was associated with malignant lymphoma. Except for two biopsies, which showed coexisting malignant lymphoma and dermatopathic lymphadenopathy, no histologic features were found which distinguished patients with malignant lymphoma from the remainder.While the pathogenesis of the lymph node changes remains obscure, the histologic features suggest that it is at least in part an immune response, although the nature of the responsible antigen is unknown.     

Silicone lymphadenopathy in a patient with a mammary prosthesis. Fine needle aspiration cytology, histology and analytical electron microscopy

Fine needle aspiration biopsy of an enlarged axillary lymph node in a patient with an intact mammary prosthesis yielded a cellular sample in which there were numerous macrophages containing large cytoplasmic vacuoles, a picture suggestive of granulomatous inflammation of the foreign-body type. Subsequent excision of the lymph node confirmed the diagnosis. Analytical electron microscopy identified the foreign material as silicone. While the cytologic features of silicone lymphadenopathy are diagnostic in the appropriate clinical setting, excision of the lymph node may be advisable to exclude a concomitant malignant neoplasm.     

Hashimoto's thyroiditis with immunoblastic lymphadenopathy and unusual "macaroni cells".

Light and electron microscopic study of the thyroid gland and an enlarged cervical lymph node in a 75-year-old woman with Hashimoto''s thyroiditis disclosed immunoblastic proliferation in the lymph node, marked by collections of striking round cells positive to periodic acid-Schiff (PAS) staining, immunoblasts and plasmacytoid elements in a vascular, fibrous framework. The PAS-positive cells ("macaroni cells") were distended with whorls of angulated tubular material resembling endoplasmic reticulum. Parafollicular-cell hyperplasia and an atypical plasmacytoid focus were noted in the thyroid. Hashimoto''s disease is known to be associated with malignant lymphoma, as are autoimmune and malignant diseases with immunoblastic lymphadenopathy. This is the first report of the association of Hashimoto''s disease and immunoblastic lymphadenopathy. The atypical plasma cells have not previously been described.     

A case of Lymphoepithelioma-like carcinoma (LELC) developed in the rectum

Lymphoepithelioma-like carcinoma (LELC) is histologically similar in form to nasopharyngeal carcinoma (NPC) and is an epithelial tumor that is suggested to be involved in infection with Epstein-Barr virus (EBV), but it is rare to occur in the colon. A 35-year-old woman was found to have a rectal wall thickening by follow-up computed tomography (CT) image after sigmoidectomy and left salpingo-oophorectomy. Biopsy under colonoscopy revealed recurrence of ovarian cancer, and she underwent a low anterior resection. Pathological diagnosis was LELC. Although LELC of the stomach has been reported to have a high EBV infection rate as NPC, EBV infection was not detected in our case. Pelvic lymph node dissection was also performed, and metastasis was recognized around the iliac artery. There have been few reports of LELC occurring in the rectum, and there are no reports of distant metastasis only to the pelvic lymph node. We consider it a very valuable case, and report it with literature references.     

Analysis of Epstein-Barr viral genomes in lymphoid malignancy using Southern blotting, polymerase chain reaction and in situ hybridization

109 malignant lymphomas were surveyed by Southern blot analysis and polymerase chain reaction (PCR) for Epstein-Barr virus (EBV) DNA and compared with 16 examples of non-neoplastic lymphadenopathy and 4 normal thymuses. In specimens positive by the method of Southern and PCR, in situ hybridization studies were performed on formalin-fixed, paraffin-embedded sections. By Southern blot analysis, two of seven Hodgkin's disease samples (29%) (one of mixed cellularity and the other of lymphocyte predominance type), three of 56 B-cell lymphomas (5.6%) and five of 46 T-cell lymphomas (11%) demonstrated EBV DNA. However, the 16 examples of lymphadenitis and the 4 normal thymuses showed no EBV DNA. With PCR, EBV DNA was identified in one B-cell lymphoma, nine T-cell lymphomas, ten lymphadenitis specimens and two of the normal thymus, in addition to the positive specimens determined by the Southern blotting method. These results indicate that the presence of EBV DNA is not related to lymphoid malignancy, but enhancement of the DNA is demonstrated in some neoplastic conditions. By in situ hybridization, EBV genomes were not detected in all PCR-positive cases, but only in those positive by Southern blot analysis.     

Relation of HTLV-III seropositivity and lymphadenopathy.

Testing for antibody to human T-lymphotropic retrovirus (HTLV-III) was carried out in five groups of homosexual men: 250 without lymphadenopathy (control group), 37 with slight or nonpersistent lymph node enlargement (intermediate group), 141 with persistent generalized lymphadenopathy, 32 with persistent generalized lymphadenopathy who underwent biopsy and 11 in whom acquired immune deficiency syndrome (AIDS) was diagnosed. The rates of HTLV-III seropositivity in the five groups were 18%, 32%, 61%, 94% and 91% respectively.     

Fine needle aspiration cytology and immunocytochemical characterization of the histiocytes in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman syndrome)

A fine needle aspiration (FNA) biopsy of an enlarged lymph node in a three-year-old boy who had asymptomatic cervical and submandibular lymphadenopathy showed large histiocytes with abundant pale, eosinophilic cytoplasm containing well-preserved lymphocytes and occasional plasma cells and granulocytes. These features were consistent with a diagnosis of sinus histiocytosis with massive lymphadenopathy (SHML). Immunophenotypic study of the histiocytes, performed on the FNA smears and on paraffin-embedded sections, showed reactivity for S-100 protein and alpha-1-antichymotrypsin and negativity for lysozyme. These features, which are characteristic of SHML, demonstrate the reliability of FNA cytology in making the diagnosis of this disorder.     

EBV与HCMV传染性单核细胞增多症患儿的实验室指标比较

目的观察EB病毒（EBV）与人类巨细胞病毒（HCMV）感染所致的传染性单核细胞增多症（IM）患儿超敏C-反应蛋白（hs-CRP）、白细胞（WBC）计数、嗜中性粒细胞比值（N）、异常淋巴细胞（异淋）、嗜异性抗体和血清酶的变化。方法选择70例确诊有EBV病毒感染且具备传染性单核细胞增多症临床特点的患儿（A组）进行实验室检测指标分析及总结;并与37例HCMV相关传染性单核细胞增多症患儿（B组）进行比较。结果与EB组（A组）比较,HCMV组（B组）感染患儿hs-CRP水平、肌酸激酶同功酶（CK-MB）、丙氨酸氨基转移酶（ALT）、外周血WBC计数、异型淋巴细胞增高程度较低（P〈0.05）,嗜异性抗体常为阴性,两组N值差异无统计学意义（P〉0.05）。结论 EBV与HCMV感染所致的传染性单核细胞增多症患儿的实验室指标变化不同,应重视IM患儿的实验室检查以辅助诊断。     

Cytology of leukemic lymphadenopathy

OBJECTIVE: To describe the cytomorphologic features of leukemic cells in lymph node aspiration material. STUDY DESIGN: We studied lymph node fine needle aspiration (FNA) smears of 36 leukemic patients. In 23 cases the lymphadenopathy was noticed simultaneously with marrow leukemia, and in the other 13 cases the lymphadenopathy was noticed during a relapse. Special stains, such as periodic acid Schiff, Sudan Black-B, Oil Red-O and nonspecific esterase, were used in special cases. RESULTS: Thirty-three cases were diagnosed as lymphoma, 1 as extramedullary hematopoiesis and 2 as leukemic involvement. CONCLUSION: Leukemic lymphadenopathy can be misdiagnosed as lymphoma on FNA smears. The clinical findings, previous history, hematologic studies and immunocytochemical studies are essential to the differentiation of leukemic smears from lymphoma. However, in some cases the leukemic infiltration can be diagnosed with certainty, provided that the smears show the characteristic findings, such as Auer rods and neoplastic promyelocytes with azurophilic granules.     

The Vancouver Lymphadenopathy-AIDS Study: 3. Relation of HTLV-III seropositivity,immune status and lymphadenopathy.

In a study of 394 homosexual men recruited at the primary care level the prevalence of antibody to human T-lymphotropic retrovirus (HTLV-III) was higher among those with lymph node enlargement than among controls. The degree of abnormal immune function, as shown by abnormalities in immunoglobulin levels, immune complex activity and T-lymphocyte subsets, was correlated with the extent of lymphadenopathy. A similar pattern of immunologic abnormality was associated with seropositivity for HTLV-III antibody. However, HTLV-III seropositivity was the major determinant of immune function after adjustment for lymph node status. The results suggest that the immune dysfunction seen in patients with lymphadenopathy is due for the most part to the high prevalence of HTLV-III seropositivity in these populations. Lymphadenopathy, in many subjects, may in fact represent a physical sign of a stabilized compensated homeostatic host response. Factors responsible for severe immune decompensation associated with acquired immune deficiency syndrome (AIDS) may best be sought by prospective study of HTLV-III seropositive asymptomatic patients or those with stable persistent generalized lymphadenopathy and relatively normal immune function.     

Prevention of lymphadenopathy in MRL-lpr/lpr mice by blocking peripheral lymph node homing with Mel-14 in vivo

MRL-lpr/lpr mice develop massive lymphadenopathy and autoimmunity. There is evidence that both migration and local proliferation contribute to the accumulation of Ly-2-, L3T4-, 6B2+ T cells in the peripheral lymph node (PLN). Mel-14 is an antibody which binds to the lymphocyte lymph node homing receptor (gp90Mel-14) and can block migration of lymphocytes to the PLN. Treatment of mice from birth to 11 wk of age with Mel-14 and another rat IgG2a mAb, 6B2, resulted in reduction (10- to 20-fold) in lymphadenopathy. Mel-14, but not 6B2, preferentially reduced the percentages of Thy-1+, 6B2+ lymphocytes in the lymph node. Treatment with a third antibody, anti-Ly-1, had no effect on lymphadenopathy. Mel-14 treatment resulted in diversion of the Ly-2-, L3T4-, 6B2+, gp90Mel-14 cells to the spleen and consequently induced marked splenomegaly. Thymocytes from MRL-lpr/lpr and MRL-+/+ mice were analyzed by two-color flow cytometry analysis after depletion of Ly-2+ and L3T4+ T cells. There was no difference in the percent of Ly-2-, L3T4-, 6B2+, gp90Mel-14 positive thymocytes comparing these two strains. Mel-14 treatment did not alter Ig levels or autoantibody production. These studies suggest Mel-14 reduced lymphadenopathy by interfering with homing to PLN, whereas 6B2 may have interfered with marrow production of precursor cells or killed 6B2+ cells after they exited the marrow. The data are consistent with the idea that lymphadenopathy occurs in MRL-lpr/lpr mice due to increased homing gp90-Mel-14 T cells to the PLN and that gp90Mel-14 is a necessary receptor for the abnormal 6B2+ T cells.     

Transbronchial fine needle aspiration cytology in the diagnosis of mediastinal/hilar sarcoidosis

OBJECTIVE: The diagnostic value of transbronchial/transtracheal fine needle aspiration (TBFNA) cytology in the patients with mediastinal and/or hilar lymphadenopathy has been investigated. METHOD: Out of 116 patients with mediastinal/hilar lymphadenopathy, the diagnosis of sarcoidosis was established in 88 (75.9%). One hundred and seventy-one TBFNAs from different lymph node stations were performed using a cytological 26-gauge needle. Adequate lymph node samples were obtained in 157 of 171 (91.8%) TBFNA and 14 of 171 (8.2%) TBFNA samples were inadequate. RESULTS: Cytological findings consistent with sarcoidosis were found in 79 of 88 (89.77%) patients and 133 of 157 (84.71%) samples. The sensitivity of TBFNA cytology in sarcoidosis presenting as mediastinal/hilar lymphadenopathy was 78.7%, specificity 92.3%. CONCLUSIONS: Overall diagnostic accuracy of TBFNA cytology in the diagnosis of sarcoidosis was 86.2%, and cytological findings consistent with sarcoidosis were the only morphological diagnosis of sarcoidosis in 63.6% of patients.     

Identification of EBV-DNA in lymph nodes from patients with lymphadenopathy and lymphomas associated with AIDS

Fourteen examples of non-Hodgkin's lymphoma (NHL) and four of Hodgkin's disease in patients with AIDS as well as lymph nodes exhibiting changes related to the lymphadenopathy syndrome (LAS) from 11 HIV-positive individuals were studied for the presence of Epstein-Barr virus (EBV) genome both by in situ DNA hybridization and blotting techniques. Both methods were performed using formalin-fixed paraffin-embedded material. All the NHLs were of high malignancy and all but one were of the B-cell type. Of the four examples of Hodgkin's disease, two were lymphocytic predominant, one of mixed cellularity and one of the nodular sclerosing variety. The lymph nodes of patients with LAS were mostly stage I with marked follicular hyperplasia. In 7 of the 14 NHLs the presence of EBV-DNA was clearly demonstrated by dot-blotting and by in situ hybridization. All lymph nodes from the patients with LAS and AIDS-related Hodgkin's disease were negative for EBV by dot-blot and in situ hybridization assays. We conclude that EBV plays a role in the development of AIDS-related lymphomas, but the fact that half these lymphomas are EBV-negative suggests that other mechanisms such as polyclonal stimulation of B-cells by HIV products may also be important.     

Mucocutaneous lymph node syndrome in Canada.

Two Edmonton children recently had a disease seemingly new to North America but a common problem in young children in Japan in the last few years. Named "mucocutaneous lymph node syndrome", it is an acute febrile condition with massive focal cervical lymphadenopathy, conjunctivitis and indurative edema of the hands and feet progressing to desquamation. It may have an infectious basis and therefore may become common in Canada.     

Lymphadenopathy and selective IgA deficiency.

Four men presented with unexplained lymphadenopathy. Three had a history of recurrent respiratory infections for several years, and two had lymph node or hepatic granulomas. None was noted to have symptoms of immunodeficiency at the time of presentation. In one patient routine direct immunofluorescence study failed to detect IgA, and immunological investigations were therefore conducted in the rest. In all patients the findings were similar and characterised by a severe deficiency of IgA. In the absence of a more serious cause selective IgA deficiency may be enough to explain "idiopathic" lymphadenopathy.     

Extrapulmonary Pneumocystis carinii infection in an AIDS patient: a case report

BACKGROUND: Extrapulmonary Pneumocystis carinii (EPC) infection is an uncommon condition, regardless of HIV status, and can occur as a complication of P carinii pneumonia (PCP). However, PCP is the most common severe opportunistic infection in patients with AIDS. The incidence of EPC is variable, and in HIV-1-infected individuals it has been estimated to be 0.06-2.5%. CASE: A case of generalized lymphadenopathy was referred to us for fine needle aspiration cytology (FNAC). The patient was a 9-year-old boy who had a toxic facies and manifested multiple skin lesions all over the body. Fever was present during the examination. HIV status was confirmed from the history and test report. FNAC was done from a cervical lymph node and smears stained with hematoxylin-eosin and with Giemsa and Papanicolaou stain. The presence of P carinii was suspected in Giemsa- and hematoxylin-eosin-stained smears, and silver methenamine stain was used to confirm the diagnosis. Fungal spores were seen as small, spherical cysts of variable sizes, more or less the size of erythrocytes. The diagnosis was thus established as EPC infection. CONCLUSION: Lymph node involvement is the most common site of pneumocystosis in AIDS patients. Fine needle aspiration diagnosis of EPC infection is a possibility in such cases with lymphadenopathy and must be included in the differential diagnosis of lymph node swellings in AIDS.     

Modulation of c-myb transcription in autoimmune disease by cyclophosphamide

This study explores the relationship between autoimmunity and the myb proto-oncogene, a gene important for T cell development. The lpr/lpr mice had very large amounts of myb RNA in the lymph node (LN) cells; but unexpectedly, they had abnormally low levels of myb RNA in the thymus, an organ normally rich in myb RNA. Mice with the gld/gld genotype had high myb RNA levels in peripheral LN, similar to lpr/lpr mice, but had normal thymic myb RNA levels. Both lpr/lpr and gld/gld mice and an AILD patient with lymphadenopathy and high myb RNA in peripheral blood cells were treated with cyclophosphamide (CY). In all cases, the CY eliminated the lymphadenopathy and corrected the abnormal myb expression. However, there were significant differences in the clinical and cellular responses to this drug. A single large dose of CY led to marked regression of the lymphadenopathy of gld/gld mice and long-term amelioration of their autoimmune syndrome. In contrast, similar treatment of lpr/lpr mice failed to alter either the lymphadenopathy or the disease process. Consistent with these clinical findings, LN myb was normalized in gld/gld mice by a single injection of CY, whereas there was no effect on myb expression in lpr/lpr mice. The AILD patient reacted much like the gld/gld mice in that myb RNA levels in the peripheral blood, and bone marrow returned to normal after only three doses of CY. The lymphadenopathy and high levels of LN myb mRNA of the lpr/lpr mice could be normalized; this occurred only after long-term treatment with CY. These events were accompanied by an increase in thymic myb mRNA from low levels. These studies have combined a molecular probe with CY therapy to provide insights into the cellular bases for lymphoproliferative autoimmune diseases.     

Paracoccidioidomycosis in a four-year-old boy

A paracoccidioidomycosis case in a four-year old boy, with fever, lymphadenopathy and hepatosplenomegaly is presented. The diagnosis was confirmed by serology and lymph node biopsy. The patient was treated with amphotericin B. After 48 hours, clinical improvement and considerable adenopathies remission were observed.