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Suppression of spontaneous in vitro transformation of autologous leukocytes by plasma from convalescent and postconvalescent infectious mononucleosis patients.

All 14 plasma samples from 13 convalescent and postconvalescent infectious mononucleosis (IM) patients suppressed the spontaneous in vitro transformation of autologous leukocytes. In contrast, only 2 of 8 plasma samples from patients with acute IM suppressed this transformation. All 7 patients whose blood was tested both in the acute and convalescent or postconvalescent phases of IM showed either a conversion in transformation suppression status from negative to positive or an increase in the strength of transformation suppression. Thus recovery from IM appeared to be associated with the ability of plasma to suppress the in vitro spontaneous transformation of autologous leukocytes.

Antibodies, Viral↗

Neurologic complications of infectious mononucleosis.

A review of the neurologic complications of Epstein-Barr viral (EBV) infections is presented. EBV has been associated with a wide range of acute neurologic diseases in children. Encephalitis, meningitis, cranial nerve palsies, mononeuropathies, and many other neurologic ailments have been described since the confirmation of EBV as the etiology of infectious mononucleosis. It is important to recognize that EBV can cause a myriad of neurologic illnesses with or without the stigmata of infectious mononucleosis.

Child↗

Lymphocyte subpopulations in man. Expression of HLA-DR determinants on human T cells in infectious mononucleosis.

In a study of lymphocyte subpopulations in peripheral blood during infectious mononucleosis the lymphocytosis was found to be of T-cell origin (i.e. E-RFC), while the number of non T lymphocytes (i.e. EA-, EAC-RFC and SmIg + ve cells) was normal in 7 out of 8 patients. Ten patients were tested for the presence of HLA-DR determinants on their B and T cells and not only B lymphocytes but also a great part (31--75%) of T cells were lysed by the anti HLA-DR testsera, indicating that HLA-DR determinants are expressed on a population of T cells in IM patients. After recovery all patients were retested and showed a normal pattern of HLA-DR typing. This indicates an increase of HLA-DR antigens on T cells or a vigorous proliferation of a small DR-positive T-cell subpopulation during the acute stage of IM.

Absorption↗

Electrophoretic mobility of lymphocyte subpopulations in infectious mononucleosis.

The electrophoretic mobilities (EPM) of lymphocytes from seventeen patients with infectious mononucleosis (IM) and fifteen normal controls were compared. The IM patients were divided into three groups, two in the first week of illness and one in the second week. The lymphocyte EPM distribution was separated by histogram analysis into fast and slow populations and further division of the fast cell population was possible in all but one of the two groups of IM patients during their first week of illness. The percentage of cells of the faster subpopulation in the first week of illness was lower than that of the controls (P less than 0.05) but the absolute lymphocyte count was higher (P less than 0.005). However, the percentage of slow moving cells of both groups in the first week of illness was significantly higher than in either the second week or the normal controls (P less than 0.01-0.001). Absolute counts were higher in all lymphocyte subpopulations of IM (P less than 0.01-0.001).

Adolescent↗

Homology between Burkitt herpes viral DNA and DNA in continuous lymphoblastoid cells from patients with infectious mononucleosis.

At least 90% of the sequences of purified, in vitro labeled, DNA from Epstein-Barr virus (prepared from HR-1, Burkitt's lymphoblastoid cells) are homologous to the DNA of the herpes virus contained in cell lines derived from patients with infectious mononucleosis. The thermal stability of the homologous and heterologous hybrid DNA molecules could not be differentiated, indicating at least 97% matching of base pairs between DNA of Epstein-Barr virus and the herpes viral DNA contained in the lymphoblasts from patients with infectious mononucleosis.

Base Sequence↗

Cold agglutinins in infectious mononucleosis and heterophil-antibody-negative mononucleosis-like syndromes.

Cold agglutinins (CA) were evaluated prospectively in patients with various mononucleosis syndromes and in a large control group. Cold agglutinins with anti-i specificity were seen mainly in heterophil-positive or -negative Epstein-Barr virus (EBV)-induced infectious mononucleosis (31.8% of cases). Unclassified CA with equal reactivity against cord and adult erythrocytes were seen in 56 of 150 (37.3%) cases of heterophil-antibody-positive infectious mononucleosis (IM), in 1 of 7 (14.3%) cases of heterophil-negative EBV-induced IM, and in 12 of 31 (38.7%) cases of the heterophil-negative mononucleosis-like syndrome due to cytomegalovirus or other unspecified agents. One patient with heterophil-positive IM had a persistent, partially papain sensitive CA with anti-Pr-like activity. Anti-i CA were seen in less than 1.0% of healthy young adults (500) or patients without mononucleosis (500) submitted for heterophil studies. Unclassified CA were noted in 3.2% of the latter 1000 samples.

Agglutinins↗

Evidence of tinidazole interference in the oropharyngeal inflammatory process during infectious mononucleosis.

The efficacy of tinidazole was studied in 24 patients with infectious mononucleosis (IM), 13 of whom were randomized for 5 days of tinidazole treatment and 11 for control without placebo. In judging the comparability of the 2 groups not only was the distribution of confounding factors such as age, sex or duration of symptoms before admission considered, but also the distribution of the Epstein-Barr virus (EBV) serological stage at entry. In these respects the groups were well matched. The duration of sore throat and pharyngotonsillitis after admission was significantly shorter for the patients treated with tinidazole than for the controls. Orosomucoid and lactodehydrogenase concentrations normalized more readily in IM patients with a short duration of sore throat after admission and in patients treated with tinidazole compared to those with a long duration of sore throat and to the tinidazole controls. Clinical and laboratory findings were thus parallel and showed a clinical effect of tinidazole, believed to be mediated via the well-known activity of this drug against anaerobic bacteria. The EBV serological stage of each patient at entry could not predict the duration of symptoms. The results showed that the course of the angina was not primarily dependent on the virus host interaction but probably on other factors, still unknown. One such factor could be the balance between the mucosal defence and the normal oropharyngeal microflora.

Adolescent↗

Lymphoid tissues from patients with infectious mononucleosis lack monoclonal B and T cells.

In typical cases of infectious mononucleosis (IM), lymphoid tissue is rarely submitted for pathological examination. When lymphoid tissues from IM cases are examined, the histological appearance of IM may be difficult to distinguish from malignant lymphoma. The purpose of this study was to address the utility of clinical molecular assays for T and B cell clonality in distinguishing IM from lymphoid malignancy. DNA was recovered from paraffin-embedded archival lymphoid tissues of 18 cases of IM and 13 control cases representing other reactive lymphoid hyperplasias. T cell receptor gamma (TCR-gamma) and immunoglobulin heavy chain (IgH) gene rearrangements were assayed using our standard clinical polymerase chain reaction procedures targeting each of the four functional variable (V) families and the three joining (J) families of the TCR-gamma gene, and framework III of the IgH gene, respectively. In 17 of 18 cases of IM, no monoclonal T or B cell populations were detectable. One case, the only spleen specimen in the study, had an oligoclonal pattern of TCR-gamma rearrangements. The control cases representing other reactive hyperplasias also lacked monoclonality. The assays used were sensitive to clonal populations as small as 5% of cells. In this case series, no monoclonal lymphoid populations were identified in any case of IM. This finding suggests that molecular studies are useful in distinguishing IM from lymphoid neoplasms.

Adolescent↗

Life-threatening infectious mononucleosis: is it correlated with virus-induced T cell proliferation?

Infectious mononucleosis is a well-established clinical entity characterized by the proliferation of B lymphocytes that are infected with Epstein-Barr virus (EBV). These lymphocytes give rise to an increase in specifically reacting cytotoxic T cells, which leads to self-limitation of the lympho-proliferative process. We describe the case of a 1-year-old boy who developed life-threatening EBV infection in association with liver failure, depletion of bone marrow, and severe encephalitis. The fact that clinical cure was achieved when acyclovir (50 mg/[kg.d]) and prednisolone (1 mg/[kg.d]) were administered indicates a correlation between antiviral therapy and clinical improvement. Hypogammaglobulinemia--which had not been present at the onset of disease--persisted after clinical recovery. During the acute phase of the illness, the patient's blood lymphocytes were predominantly T cells, most of which contained the EBV genome, as shown by in situ hybridization; some of these cells stained positive for EBV-specific latent membrane protein. Examination of peripheral blood mononuclear cells in vitro revealed an exceedingly high histocompatibility antigen-unrestricted cytotoxicity against the K562 cell line, which is normally not an immunogenic target of cytotoxic cells in patients infected with EBV. This anomalous natural killer cell-like T cell function suggests that EBV infection of T cells might cause auto-aggressive activity, which was probably responsible for the severity of the infection in our patient.

Cell Division↗

Multiple HLA class I-dependent cytotoxicities constitute the "non-HLA-restricted" response in infectious mononucleosis.

Primary Epstein-Barr virus (EBV) infection, when manifest as infectious mononucleosis (IM), induces a broad-ranging and apparently non-HLA-restricted cytotoxic response whose nature has not been resolved. In the present experiments the ability to cryo-preserve IM mononuclear cell preparations, after depletion of CD16+ natural killer cells, has allowed detailed analysis of the response on appropriately constructed target cell panels. The results show that IM effector preparations are polyclonal with separate HLA class I antigen-dependent reactivities against the autologous EBV-transformed lymphoblastoid cell line (LCL) and particular HLA class I-mismatched LCLs. The autologous LCL-directed response shows the hallmarks of immunologically specific T cell cytotoxicity; only EBV+ B cell blasts are recognized and the interaction can be blocked by monoclonal antibodies to CD3 and CD8 on the effector cell surface and to HLA class I antigens on the target cell. Such findings demonstrate, for the first time, that the primary cytotoxic response to EBV infection includes a virus-specific HLA-restricted component like that found in the T cell memory of persistently infected individuals. Separate components of the response are preferentially active against some (but not all) HLA-mismatched LCLs, the pattern of reactivity being distinct for each individual IM patient and reproducible on repeated testing. Monoclonal antibody blocking experiments show that these HLA-mismatched interactions also involve CD3 and CD8 antigens on the effector cell and HLA class I antigens on the target cell. Where tested, such lysis affected both EBV+ and EBV- B cell blasts from the relevant HLA-mismatched donors. We postulate that a widespread primary infection of the B cell system by EBV leads to a generalized expansion not just of the virus-specific response but also of other T cell responses coincidentally active at the time. The unusual activity of IM effector preparations against HLA-mismatched LCLs arises from fortuitous cross-recognition of allogeneic cells by immunologically specific cytotoxic T cell clones coincidentally expanded in vivo alongside the EBV-specific response.

Antibodies, Monoclonal↗

Clinical evaluation of patients with infectious mononucleosis and development of antibodies to the R component of the Epstein-Barr virus-induced early antigen complex.

Previous reports have emphasized that the transitory antibody responses to Epstein-Barr virus (EBV)-induced early antigens (EA) in the course of infectious mononucleosis are usually directed against the D (diffuse) component of the EA complex. In this report clinical and serologic data have been presented on 14 patients with infectious mononucleosis who responded either solely with antibodies to the R (restricted) component of the EA complex or revealed anti-R after the initial anti-D responses had subsided weeks or months after onset of the disease. Anti-R persisted usually for many months , as many as 39, but in some patients it was no longer detectable in late follow-up serum spectimens. Although many patients had an unremarkable course of illness, others, mostly those with late anti-R responses, showed unusual or protracted clinical manifestations and several complained over periods of 4 to 28 months of recurrent symptoms resembling those experienced during the acute stage of disease. The presence of anti-R and the relatively high continuous titers of antibodies to EB viral capsid antigens (VCA) may reflect a more than usual, persistent EBV activity which, in turn, may account for the recurrent symptoms.

Adolescent↗

Evaluation of six commercially available kits using purified heterophile antigen for the rapid diagnosis of infectious mononucleosis compared with Epstein-Barr virus-specific serology.

BACKGROUND: Novel commercial kits based on antibody reactivity to purified heterophile antigens have recently been introduced for the diagnosis of Epstein-Barr (EB) virus-associated infectious mononucleosis (IM). It is important to determine possible improvements in the performance and reliability of such tests for the diagnosis of IM. OBJECTIVE: To evaluate the reliability of six commercially available kits for the rapid diagnosis of IM in comparison to EB-virus-specific serology. STUDY DESIGN: In total, 100 sera, 53 from patients with serologically verified primary EB virus infection and 47 from EB-virus-immune or -susceptible patients, were used to evaluate the six rapid test kits: Monolatex, Mono-Latex, Mono-Lex (latex agglutination-based kits), Mono-Plus, IM-Check and Clearview IM (solid-phase-based kits). EB-virus-specific serologies including detection of viral capsid antigen IgM and IgG and EB nuclear antigen-1 IgG, were used as reference methods. RESULTS: Compared with the reference methods, the sensitivities and specificities of the heterophile antibody test kits were 70-92% and 96-100%, respectively. IM-Check had a low sensitivity and was difficult to read. The remaining kits performed well. CONCLUSION: Monolatex, Mono-Latex, Mono-Lex, Mono-Plus and Clearview IM can be recommended for the confirmation of EB-virus-associated infectious mononucleosis. Clearview IM combined a high sensitivity and specificity with very simple one-step solid-phase-based procedure.

Adolescent↗

Cold urticaria and infectious mononucleosis in children.

Physical urticaria includes a heterogeneous group of disorders characterized by the development of urticarial lesions and/or angioedema after exposure to certain physical stimuli. The authors present the case of a child with severe acquired cold urticaria secondary to infectious mononucleosis. Avoidance of exposure to cold was recommended; prophylactic treatment with ketotifen and cetirizine was begun and a self-administered epinephrine kit was prescribed. The results of ice cube test and symptoms significantly improved. Physical urticaria, which involves complex pathogenesis, clinical course and therapy, may be potentially life threatening. Evaluation and diagnosis are especially important in children. To our knowledge this is the first description of persistent severe cold-induced urticaria associated with infectious mononucleosis in a child.

Adolescent↗

Studies on the heterophile antibodies of infectious mononucleosis. I. Separation of four antibody populations, one of which contains lymphocytotoxic activity.

With the aid of insolubilized immunoadsorbents made with glycoproteins, extracted from cow red blood cells (RBC), and with guinea-pig kidney tissue, heterophile antibody populations of the Paul--Bunnell type and the Forssman type were eluted from infectious mononucleosis sera. Two Paul--Bunnell-type antibody populations were separated on the basis of their affinity for cow RBC antigens. The lymphocytotoxic antibodies in the infectious mononucleosis sera were eluted among the low-affinity Paul--Bunnell antibodies.

Adult↗

Massive splenomegaly and Epstein-Barr virus-associated infectious mononucleosis in a patient with Gaucher disease.

PURPOSE: Gaucher disease should be considered in the differential diagnosis of a patient with Epstein-Barr virus (EBV) infection who has unexplained or disproportionate splenomegaly. PATIENTS AND METHODS: A previously asymptomatic adolescent with EBV-associated infectious mononucleosis and massive splenomegaly is described. He was found to have Gaucher disease on bone marrow biopsy, which was performed to exclude a hematologic malignancy. The diagnosis was confirmed by assay of beta-glucosidase enzyme activity. RESULTS: Regression of splenomegaly and improving hematologic indices. CONCLUSION: Patients with infectious mononucleosis and disproportionate organomegaly should be investigated to exclude a hematologic malignancy or an underlying storage disorder such as Gaucher disease.

Adolescent↗

Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction.

To assess the impact of the germinal center (GC) reaction on viral spread in Epstein-Barr virus (EBV) infection, we isolated EBV(+) GC B cells from the tonsils of two infectious mononucleosis patients, sequenced their rearranged V genes, and determined expression of the EBV latency genes EBV nuclear antigen 2 and latent membrane protein 1. Most EBV(+) GC B cells belonged to clones of cells harboring somatically mutated V gene rearrangements. Ongoing somatic hypermutation, the hallmark of the GC reaction, was seen only in uninfected GC B cell clones, not in EBV(+) B cell clones. Thus, in infectious mononucleosis, GC and/or memory B cells are directly infected by EBV and expand without somatic hypermutation, whereas the GC passage of EBV-infected naive B cells does not contribute detectably to the generation of infected memory B cells, the main reservoir of EBV during persistence. Most, if not all, EBV-infected cells in GCs exhibited an unusual EBV gene expression pattern in that they were positive for EBV nuclear antigen 2 but negative for latent membrane protein 1. Although the three main types of EBV-associated B cell lymphomas (Burkitt's, Hodgkin's, and posttransplant lymphomas) presumably are derived from GC B cells, EBV(+) GC B cells resembling these EBV(+) GC B cell lymphomas in terms of EBV gene expression and somatic hypermutation pattern could not be identified.

Adolescent↗