David T. Purtilo

Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome.

Investigation of a family with cancer in boys revealed that at least 20 males had the X-linked recessive lymphoproliferative syndrome. A variety of phenotypes occurred: aproliferative phenotypes consisted of aplastic anemia, agranulocytosis or acquired hypogammaglobulinemia; and proliferative phenotypes of B cells included disorders associated with the Epstein-Barr virus, American Burkitts lymphoma, immunoblastic sarcoma of B cells, fatal infectious mononucleosis or plasmacytoma. The lymphoproliferative disorders observed in males could have resulted from an immunodeficiency to Epstein-Barr virus. The variable phenotypic expression could have resulted from individual differences in the viral dose, duration of exposure and age at which the boys were exposed to the virus. Aproliferative phenotypes such as acquired hypogammaglobulinemia could have ensued from excessive suppressor-cell activity on B cells, whereas proliferative phenotypes such as Burkitts lymphoma or fatal infectious mononucleosis could have resulted from infection by Epstein-Barr virus and failure to stop proliferation of B cells.

Fatal strongyloidiasis in immunosuppressed patients

Abstract Cell-mediated immunity is a major bulwark of defense against certain viruses, intracellular bacteria, fungi and protozoa. Cellmediated immunity against helminthic infections is inadequately understood. Thirty-two patients with strongyloidiasis who were studied at autopsy had underlying diseases characterized by depressed cell-mediated immunity, including lepromatous leprosy, malignant tumors, protein-calorie malnutrition, burn, radiation, advanced tuberculosis, tertiary syphilis or pancytopenia. At autopsy defective cell-mediated immunity against strongyloides was manifested by a lack of a granulomatous immune response to larvae in the tissues. Depletion of lymphocytes in thymus glands and in the thymus-dependent areas of lymph nodes and spleens in the hosts indicated in inadequate capacity of cell-mediated immunity for preventing Strongyloides stercoralis.

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.

Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome.

A registry of persons with the X-linked lymphoproliferative syndrome, which is characterized by marked susceptibility to diseases induced by the Epstein-Barr virus, has enrolled 161 patients within 44 kindreds. Fifty-seven percent of the males died of infectious mononucleosis, 29% developed acquired hypogammaglobulinemia, and 24% had malignant lymphoma. The mortality rate was 80%; 70% died by 10 years of age and 100% by 40 years. Thirty-two boys survive, most with malignant lymphoma, acquired hypogammaglobulinemia, or both. We hypothesized that the defective lymphoproliferative control locus on the X chromosome results in unregulated cytotoxic lymphocytic responses to the Epstein-Barr virus; hence, severe hepatitis and virus-associated hemophagocytic syndrome occur with the infectious mononucleosis phenotype. T-cell suppression of immunoglobulin secretion by B cells is responsible for acquired hypogammaglobulinemia. A sustained polyclonal B-cell proliferation probably converts to a monoclonal B-cell malignancy as a result of molecular alterations.

Glomerular Capillary Thrombosis and Acute Renal Failure after Epsilon-Amino Caproic Acid Therapy

WITH increased awareness of the hemorrhagic syndromes produced by spontaneous intravascular coagulation or fibrinolysis, there has been increased use of epsilon-amino caproic acid (EACA, Amicar) as...

Fatal infections in protein-calorie malnourished children with thymolymphatic atrophy.

The clinicopathological features of 25 children who died with protein-calorie malnutrition were studied. All but four subjects were found at necropsy to have nutritional thymectomy and all but 3 died of infectious diseases. The infectious agents were chiefly intracellular micro-organisms including miliary tuberculosis, Herpes simplex, varicella, measles, Pneumocystis carinii, and Plasmodium falciparum. Staphylococcal infections, salmonellosis, shigellosis, strongyloidiasis, and hookworm were other significant infectious agents. Nutritionally acquired defective immunity, especially cell-mediated immunity, probably permitted these infectious agents to multiply and to disseminate widely.

Hematopathology and pathogenesis of the X-linked recessive lymphoproliferative syndrome

Subtle immunodeficiency to infectious agents including measles virus and ten Epstein-Barr virus (EBV) has been described in the X-linked recessive lymphoproliferative syndrome. This syndrome has affected six male cousins and possibly another boy. Three brothers died of an infectious mononucleosis syndrome, in a maternal cousin agammaglobulinemia developed three years after infectious mononucleosis, and two half-brothers of the Duncan kindred died of lymphoma of the brain and intestinal tract, respectively. In three of the boys, unusual measles viral infections had developed. Paramyxovirus-like particles suggestive of measles virus were seen at necropsy in the atrophic lymphoid tissue of two boys. Also, numerous plasma cells were seen in the brains, visceral organs and the thymus glands, and thymic-dependent lymphocytes were sparse in lymph nodes and spleen. The abnormal lymphopoiesis in the syndrome probably results from a subtle immunodeficiency, and concurrent measles and EB virus infections.

Non-Hodgkin's Lymphoma After Treatment of Hodgkin's Disease: Association with Epstein-Barr Virus

Non-Hodgkins lymphoma occurs infrequently as a late complication of obscure cause after treatment of Hodgkins disease. We investigated the possible role of Epstein-Barr virus in the pathogenesis of such secondary malignancies of B-cell lineage. Two patients, aged 25 and 43 years, developed high-grade non-Hodgkins lymphomas 12 and 8 years after radiation therapy for Hodgkins disease. Serologic profiles in these patients showed evidence of acute and past Epstein-Barr virus infections, respectively. Molecular hybridization analysis showed the presence of multiple cellular equivalents of virus genome in tumor specimens from each patient. Our findings suggest that Epstein-Barr virus may play an integral role in the pathogenesis of non-Hodgkins lymphoma of B-cell lineage that develops after treatment of Hodgkins disease.

Malignant lymphoma in Nebraska and Guangzhou, China: A comparative study

Two hundred thirty-four consecutive cases of malignant lymphoma (192 non-Hodgkins lymphomas and 42 Hodgkins disease) from Guangzhou, China, and 589 cases (498 non-Hodgkins lymphomas and 91 Hodgkins disease) from the University of Nebraska Lymphoma Registry were examined in a retrospective histopathologic analysis and the results compared to those of the National Cancer Institute (NCI) Working Formulation Summary. Aggressive non-Hodgkins lymphoma was excessive in Guangzhou (82.3 per cent; P less than 0.001) and Nebraska (80.3 per cent; P less than 0.001) when compared with the NCI data (54.2 per cent). The small noncleaved cell, lymphoblastic, and diffuse mixed-cell subtypes were more frequent in China (15.6 per cent each; P less than 0.001), whereas the small lymphocytic, follicular large cell, and immunoblastic subtypes predominated in Nebraska (8 per cent, 8.4 per cent, and 21.8 per cent, respectively; P less than 0.001). The overall median age of onset for non-Hodgkins lymphoma was 42.0 years in Guangzhou and 63.5 years in Nebraska. Hodgkins disease represented 18 per cent of the malignant lymphomas in Guangzhou and 15 per cent in Nebraska. The mixed-cellularity type was most common in Guangzhou (52 per cent; P less than 0.001) and the nodular-sclerosing type in Nebraska (56 per cent; P less than 0.010). The low median age and excess of certain aggressive subtypes of non-Hodgkins disease in Guangzhou suggest a possible viral etiology, whereas the excess of certain subtypes of non-Hodgkins lymphoma in Nebraska may be related to intense agricultural activity.

Effect of different Epstein-Barr virus-determined antigens (EBNA, EA, and VCA) on the leukocyte migration of healthy donors and patients with infectious mononucleosis and certain immunodeficiencies

Abstract Leukocytes from healthy Epstein-Barr virus (EBV)-seropositive (SP) subjects show significant migration (LMI) with EBNA (EBV-determined nuclear antigen)-containing extracts derived from nonproducer, EBV-genome-carrying cells, or presented in the form of partially purified EBNA-preparation. Additional EBV antigens, EA and VCA, presented in the form of induced cell extracts do not add any measurable increase to their response. Leukocytes from acute infectious mononucleosis (IM) patients, on the other hand, do not respond to EBNA, but they show a good response to induced EA- or EA and VCA-containing cell extracts. This is in accordance with known differences in EBV-antibody pattern in healthy SPs as contrasted to acute IM patients. Leukocytes from chronic mononucleosis patients resemble those from acute IM patients in their preferential EA/VCA and deficient EBNA response in the LMI test. Cells from four X-linked lymphoproliferative disease (XLP) patients showed complete absence of reactivity to PHA and to EBV antigens in the LMI test, showing a general defect in cell-mediated immune responses. Leukocytes from a group of patients with lymphoproliferative malignancies in remission and elevated EBV-antibody titers showed a variety of responses, resembling normal SP donors, or IM patients, or showing a complete unresponsiveness in the LMI test.