Werner Henle

Epstein-barr virus specific diagnostic tests in infectous mononucleosis*

Abstract Presently available methods for the detection of Epstein-Barr virus, the differentiation of various virus related antigens, and the titration of the corresponding antibodies in human sera are reviewed. Applications of these techniques to the diagnosis of infectious mononucleosis, the determination of immunity to this disease, and seroepidemiologic studies are discussed in general terms with an evaluation of the relative merits of individual test procedures. Results obtained in a recent series of 90 patients with infectious mononucleosis are presented to show that an Epstein-Barr virus specific serodiagnosis can be established in most, if not all, cases, provided the most pertinent tests are performed. The data reaffirm the conclusion that the Epstein-Barr virus is the cause of infectious mononucleosis.

Persisting Illness and Fatigue in Adults with Evidence of Epstein-Barr Virus Infection

Clinical, serologic, virologic, and immunologic evaluations for 31 adults with chronic illness and fatigue suggested that 23 had persisting Epstein-Barr virus infection. Among these 23 patients, cellular immune mechanisms were generally normal, but 4 had mild immunoglobulin deficiencies. However, 20 patients had abnormal serologic profiles specific for Epstein-Barr virus shown by significantly elevated titers of antibodies to the viral capsid antigen or early antigen, or by a deficiency of late-appearing antibodies. In 11 of 15 patients tested, circulating immune complexes were found. Circulating interferon was not found in 18 patients tested, but the activity of 2-5 oligoadenylate synthetase, an interferon-induced enzyme, was increased in 5 patients studied. Of 19 patients, 18 had persisting suppressor T-cell activity typically found in patients recovering from acute infectious mononucleosis. We believe that the Epstein-Barr virus may be associated with chronic illness in adults.

Quantitative studies on viral interference in suspended L cells: III. Effect of interfering viruses and interferon on the growth rate of cells☆

Abstract A 24-hour exposure of suspended L cells to NDV uv or to interferon resulted in a temporary depression of cellular growth of variable duration. Prolonged contact with these agents had a more marked effect which could terminate in almost total cessation of cell multiplication. The intensity of the depressor effect was proportional to the interfering activity of these agents. Some degree of protection persisted for at least as long as the slow growth rate prevailed. Noninterfering, UV-inactivated PR8, or interferon derived from a heterologous host failed to depress cell division. The factor in interferon preparations responsible for this effect was trypsin-sensitive, pH 2-stable, and nonsedimentable at 105,000 g ; it could not be separated from the interfering principle itself. Increasing doses of ultraviolet irradiation destroyed interfering and cell growth depressor activities of NDV at the same rate. Removal of UV-inactivated virus or of interferon after prolonged contact with L cells permitted gradual recovery of the cultures.

Primary Epstein–Barr-Virus Infections in Acute Neurologic Diseases

Infectious mononucleosis has been associated with Guillain--Barré syndrome, Bells palsy, meningoencephalitis and transverse myelitis. Since it is not known that many children with infectious mononucleosis do not develop heterophil antibodies, we looked for evidence of current or recent Epstein-Barr virus infection in young patients with these neurologic diseases by using serodiagnostic procedures for detection and titration of antibodies to various antigens related to Epstein-Barr virus. Seven of 24 cases with Guillain-Barre syndrome and three of 16 with facial palsy were definitely associated with primary infection with Epstein-Barr virus as were two cases each of the other two neurologic diseases. Only one of these patients had obvious clinical infectious mononucleosis, and only a few demonstrated heterophil agglutinins. It is evident that the virus must be considered in the diagnosis of various acute neurologic diseases affecting children and young adults, even in the absence of heterophil-antibody response or other signs of infectious mononucleosis.

Central-Nervous-System Lymphoma Related to Epstein–Barr Virus

We have studied five cases suggesting a relation between Epstein-Barr virus infection and primary lymphoma of the central nervous system. A 48-year-old man had primary lymphoma of the central nervous system in the absence of systemic lymphoma or immunosuppression. Development of the tumor was associated with serologic evidence suggesting a recent primary infection with Epstein-Barr virus. DNA preparations from tumor tissue, but not from adjacent normal brain tissue, contained Epstein-Barr virus genomes when hybridized with a probe consisting of the BamHI K fragment of Epstein-Barr virus strain FF41. Evaluation of serum samples from four additional patients with central-nervous-system lymphoma revealed patterns of Epstein-Barr virus-specific antibody that were suggestive of an ongoing infection with EBV. Our results suggest induction of the lymphoma by Epstein-Barr virus.

Association of Herpesvirus Infections with T-Lymphocyte-Subset Alterations, Glomerulopathy, and Opportunistic Infections after Renal Transplantation

We studied the interrelation among herpes-virus infections, T-lymphocyte subsets, opportunistic infections, and renal histopathology in 28 recipients of renal allografts. All primary or reactivated herpesvirus infections occurring in the first three months after transplantation in recipients of cadaveric grafts accompanied persistent inversions in the ratio of OKT4 (helper/inducer) to OKT8 (cytotoxic/suppressor) lymphocytes. In the less heavily immunosuppressed recipients of organs of living related donors, these inversions were seen only in association with clinically apparent cytomegalovirus infections. Five of seven opportunistic infections occurred in patients with OKT4/OKT8 ratios of less than 1.0. Biopsy specimens from patients with renal dysfunction occurring in association with a low OKT4/OKT8 ratio frequently revealed glomerular damage rather than acute cellular rejection. Monitoring of T-lymphocyte subsets provides early evidence of herpesvirus infections and identifies patients at increased risk for opportunistic infection after renal transplantation.

Epstein-Barr virus-induced diseases in boys with the X-linked lymphoproliferative syndrome (XLP): Update on studies of the registry

Analyses of 100 subjects with the X-linked lymphoproliferative syndrome (XLP) in 25 kindreds revealed four major interrelated phenotypes: infectious mononucleosis, malignant B-cell lymphoma, aplastic anemia, and hypogammaglobulinemia. Eighty-one of the patients died. Two male subjects were asymptomatic but showed immunodeficiency to Epstein-Barr virus (EBV). Seventy-five subjects had the infectious mononucleosis phenotype and concurrently, 17 subjects of this group had aplastic anemia. All subjects with aplastic anemia died within a week. Aplastic anemia did not accompany hypogammaglobulinemia or malignant lymphoma phenotypes. Hypogammaglobulinemia had been detected before infectious mononucleosis in three subjects, after infectious mononucleosis in five subjects, and was not associated with infectious mononucleosis in 11 boys with hypogammaglobulinemia. In nine subjects infectious mononucleosis appeared to have evolved into malignant lymphoma; however, the majority of patients with malignant lymphoma showed no obvious antecedent infectious mononucleosis. One subject had infectious mononucleosis following recurrent malignant lymphoma. Twenty-six of 35 lymphomas were in the terminal ileum. Results of immunologic and virologic studies of 15 survivors revealed combined variable immunodeficiency and deficient antibody responses to EBV-specific antigens. Mothers of boys with XLP exhibited abnormally elevated titers of antibodies of EBV. Subjects of both sexes with phenotypes of XLP should be investigated for immunodeficiency to EBV. Persons with inherited or acquired immunodeficiency may be vulnerable to life-threatening EBV-induced diseases.

Biology of the human malignant lymphomas. IV. Functional characterization of ten diffuse histiocytic lymphoma cell lines

Ten consecutive diffuse histiocytic lymphoma (DHL) cell lines established in our laboratory were studied for the presence of Epstein‐Barr virus (EBV) genomes, lysozyme, nonspecific esterase and other cytochemical reactions, phagocytic activity, cytoplasmic immunoglobulin light and heavy chains, and surface receptors to sheep erythrocytes, complement, and the Fc fragment of immunoglobulin. In agreement with previous studies performed on biopsy specimens, our results indicate that the diffuse histiocytic lymphomas, as a histopathologic entity, represent a heterogeneous group of neoplasms, the majority of which are B‐lymphocyte in origin. The cell lines appear to fall into three categories based on the following criteria: 1) presence of monoclonal cytoplasmic immunoglobulins (B‐lymphocytic type, 6/10 cell lines); 2) presence of non‐specific esterase, phagocytic activity, and/or lysozyme (histiocytic type, 2/10 cell lines); and 3) absence of all lymphoid and histiocytic cell characteristics (null cell type, 2/10 cell lines). Despite the fact that many of the lymphoma patients had positive serologies to EBV antigens, all of the DHL cell lines were negative for the presence of EBV genomes. Both of the two B‐lymphocytic type and one of the two histiocytic type lines tested were susceptible to infection with EBV, as indicated by synthesis of early antigen and also, in a small proportion of the infected cells, of viral capsid antigen. These prototypic DHL cell lines may permit the development of new criteria for the differential diagnosis and treatment of this highly malignant and diverse group of lymphomas. Cancer 42:2379–2391, 1978.

A non-X-linked syndrome with susceptibility to severe epstein-barr virus infections

Three siblings developed severe (two) or fatal (one) infectious mononucleosis. This family differed from previously described kindreds with a susceptibility to overwhelming Epstein-Barr virus infections in that: (1) both males and females were affected; (2) they had a history of the recurrent bacterial infections; (3) they produced the full spectrum of antibodies to EBV in the expected range of titers; and (4) survivors recovered completely. Two of these youths, but not their parents or an unaffected sibling with mild IM, had a deficiency of natural killer activity that did not respond to preincubation of their peripheral blood mononuclear cells with interferon. NK activity may have an important role in controlling infections with EBV.

Chronic Epstein-Barr Virus Infection Associated with Fever and Interstitial Pneumonitis: Clinical and Serologic Features and Response to Antiviral Chemotherapy

Two patients developed fever, interstitial pneumonitis, and pancytopenia associated with extremely high titers of antibody to replicative antigens of the Epstein-Barr virus. In contrast to most patients seropositive for Epstein-Barr virus, neither patient had an antibody response to the Epstein-Barr nuclear antigen K polypeptide. In addition, virus isolated from one patient had a deletion of the B95-8 type in the EcoRI C region of the genome. An etiologic relation between Epstein-Barr virus replication and the clinical manifestations of this syndrome is further shown by the response of each patient to acyclovir therapy. These patients have a new Epstein-Barr-virus-associated syndrome and provide additional evidence that acyclovir may play a role in therapy for selected patients with Epstein-Barr virus infection.