Biomedical subjects
J L Sullivan
Publications and source records attributed to J L Sullivan.
"Chronic Epstein-Barr virus infection" syndrome and polymyalgia rheumatica.
Twenty-three patients with polymyalgia rheumatica (PMR) followed in an academic rheumatology practice frequently reported symptoms commonly found in the recently described "chronic fatigue syndrome" or "chronic Epstein-Barr infection syndrome." These symptoms persisted for months after treatment had reduced the severity of the myalgias and lowered the sedimentation rate: periodically disabling fatigue (33%), recurrent pharyngitis (30%), sleep disorder (65%) and arthralgias (70%). However, antibody titers to Epstein-Barr virus in the patients with PMR were not significantly different from those in age and sex matched control subjects.
Epstein-Barr virus and lymphoproliferative disorders.
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Pathogenesis of Herpesvirus sylvilagus infection in cottontail rabbits.
Experimental infection with Herpesvirus sylvilagus produces clinical and histopathologic changes in its natural host, the cottontail rabbit (Sylvilagus floridanus), similar to those observed in humans acutely infected with Epstein-Barr virus (EBV). Twenty-seven seronegative cottontail rabbits were infected with Herpesvirus sylvilagus and all developed antibodies within 10 days. Neutralizing antibody was detected as early as 7 days after infection. Virus was isolated from blood mononuclear cells, spleen, bone marrow, thymus, lymph nodes, kidneys, lung, and liver as early as 3 days after infection. Infected animals showed leucocytosis, monocytosis, and lymphocytosis with the appearance of atypical lymphocytes. Peripheral blood abnormalities peaked at 10-14 days after infection, and returned to normal by 28 days after infection, with the exception of atypical lymphocytosis that persisted in some animals for more than 2 years after experimental infection. More severe histopathologic changes were seen in virus-infected juvenile rabbits than adult rabbits; these changes included viral myocarditis, interstitial pneumonia, and lymphocytic myositis. Reactive hyperplasia and subsequent lymphocytic depletion of spleen and lymph nodes were reminiscent of that seen in virus-associated hemophagocytosis syndrome. Prominent lymphoid hyperplasia of many nonlymphoid organs, most notably the kidney and lungs, was observed. The development of these lymphoproliferative lesions and other lymphoid changes during H. sylvilagus infection suggest that this system may be a model to study similar lesions induced by EBV infection in humans.
Human immunodeficiency virus isolation studies and antibody testing. Household contacts and sexual partners of persons with hemophilia.
Virus isolation studies and human immunodeficiency virus (HIV) antibody testing were performed on 87 household contacts of 68 HIV antibody-positive hemophilic patients to determine the extent that HIV could be transmitted through heterosexual or through nonsexual, but intimate contact. Human immunodeficiency virus seropositivity was established for the 68 hemophiliacs by immunofluorescence method or enzyme-linked immunosorbent assay and confirmed by Western blot testing (for 66 patients). Fifty-one nonsexual contacts and 36 sexual partners of these hemophiliacs were tested for HIV antibody by immunofluorescence or enzyme-linked immunosorbent assay and Western blot. All sexual partners and all nonsexual household contacts were HIV antibody-negative, including six partners and nine parents of hemophiliacs from whom the virus had been isolated and seven parents and six partners of patients with AIDS. This study further demonstrates lack of transmission of HIV in intimate, but nonsexual settings, and suggests that heterosexual transmission, although well known to occur, may be relatively uncommon in hemophilic couples when the male and female partner have no other risk factors. It is hoped that intensive education and counseling programs will reduce exposure and maintain a low risk of heterosexual transmission.
Activated lymphocytes during acute Epstein-Barr virus infection.
Activated lymphocytes, as identified by HLA-DR expression, associated with acute Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM) were shown to be a heterogeneous population containing significantly elevated cytotoxic/suppressor (CD8) T cells, natural killer (CD16) cells and helper (CD4) T cells. CD8 T cells were the primary activated population representing 24.5% of the total lymphocyte population. The activated CD4 T cells and natural killer cells accounted for 6.7% and 3.5% of the total lymphocyte population, respectively. Analysis of serum soluble interleukin 2 receptors (IL-2R) demonstrated significantly (p less than 0.001) elevated levels in the serum of acute IM patients compared with normal controls. Elevated levels of serum IL-2R were correlated (r = 0.67) with increased percentages of Leu 2a+/HLA-DR+T cells (i.e., activated CD8 T cells). Patients with X-linked lymphoproliferative syndrome and virus-associated hemophagocytic syndrome, two syndromes associated with severe acute EBV infections, demonstrated the most dramatic increase in serum IL-2R levels. These data demonstrate that EBV is associated with intense immune stimulation and that during acute IM activated lymphocytes, other than the CD8 T cells, may contribute to the immune response to EBV.
Frequency of 'chronic active Epstein-Barr virus infection' in a general medical practice.
Twenty-one percent of 500 unselected patients, aged 17 to 50 years, seeking primary care for any reason were found to be suffering from a chronic fatigue syndrome consistent with "chronic active Epstein-Barr virus (EBV) infection," They had been experiencing "severe" fatigue, usually cyclic, for a median of 16 months (range, six to 458 months), associated with sore throat, myalgias, or headaches; 45% of the patients were periodically bedridden; and 25% to 73% reported recurrent cervical adenopathy, paresthesias, arthralgias, and difficulty in concentrating or sleeping. The patients had no recognized chronic "physical" illness and were not receiving psychiatric care. While antibody titers to several EBV-specific antigens were higher in patients than in age- and sex-matched controls subjects, the differences generally were not statistically significant. A chronic fatigue syndrome consistent with the chronic active EBV infection syndrome was prevalent in our primary care practice. However, our data offer no evidence that EBV is causally related to the syndrome. Indeed, we feel that among unselected patients seen in a general medical practice currently available EBV serologic test results must be interpreted with great caution.
The "chronic, active Epstein-Barr virus infection" syndrome and primary fibromyalgia.
Fifty patients with primary fibromyalgia who had been followed in an academic rheumatology practice frequently reported symptoms thought to be typical of "chronic Epstein-Barr virus infection," but not of fibromyalgia: recurrent sore throat (54%), recurrent rash (47%), chronic cough (40%), recurrent adenopathy (33%), and recurrent low-grade fevers (28%). In 55% of the patients, illness had begun suddenly, with what seemed to be a viral syndrome. Antibody titers to Epstein-Barr virus in the patients with fibromyalgia, however, were not significantly different from those in age- and sex-matched "healthy" and "unhealthy" control subjects.
Isolation of human immunodeficiency virus from hemophiliacs: correlation with clinical symptoms and immunologic abnormalities.
As part of a prospective study of human immunodeficiency virus (HIV) infection in hemophilia, peripheral blood mononuclear cells (PBMs) from 72 individuals without acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) were cultured for virus. HIV was isolated from PBMs from 16 (24%) of 66 patients with hemophilia who were seropositive for HIV and from none of six seronegative patients. Cells from five of six patients from which HIV was isolated were again successfully cultured for virus 3 to 12 months later. HIV core P24 antigen was detected in serum from seven of 15 patients with HIV-positive cells and from eight of 50 with HIV-negative cells. Patients with hemophilia with isolation-positive cells had significantly fewer T helper cells and significantly lower T helper/T suppressor ratios, pokeweed mitogen responsiveness, and total platelet counts than did those whose cells did not yield HIV on cultivation. HIV neutralizing antibody titers did not differ between hemophiliacs with or without HIV-positive PBMs. Three of the 16 patients with virus-positive cells developed AIDS, and two ARC, within 18 months of the study, compared with three of 50 seropositive hemophiliacs whose cells did not yield virus, who developed ARC during the same period. The significant decrease in the number of T helper cells, decreased platelet counts, and higher rate of progression to AIDS in the group with HIV isolation may reflect a heavier virus load, indicating that the ability to culture HIV may be an early marker of more significant disease.
Virus-associated hemophagocytic syndrome: identification of an immunoproliferative precursor lesion.
Virus-associated hemophagocytic syndrome (VAHS) is a nonneoplastic, generalized histiocytic proliferation with marked hemophagocytosis associated with a systemic viral infection. Histologic studies of lymph nodes usually show lymphoid depletion and histiocytic proliferation. In this report we describe the case of a patient with Epstein-Barr virus-associated VAHS in which initial lymph node biopsy samples showed an immunoproliferative lesion that preceded the usual generalized histiocytic proliferation. This finding suggests that some cases of VAHS may have an immunoproliferative precursor lesion.
Mapping the X-linked lymphoproliferative syndrome.
The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predict which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.
Use of cytoplasmic dot-blot hybridization to detect human immunodeficiency virus RNA sequences in cultures of peripheral blood.
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Epstein-Barr-virus-related malignant B cell lymphoplasmacytic lymphoma following allogeneic bone marrow transplantation for aplastic anemia.
The development of B cell lymphoma has been reported to occur in recipients of a variety of organ transplants, including some patients who have received an allogeneic bone marrow graft. In this report, we describe a patient with severe aplastic anemia who developed a malignant B cell lymphoplasmacytoid proliferation 48 days after undergoing allogeneic marrow transplantation from her HLA-matched MLC-nonreactive brother. Immunologic studies showed this malignancy to be a mixed polyclonal and monoclonal proliferation in donor cells. Virologic studies documented Epstein Barr infection of the cells. A review of the literature suggests that graft-versus-host disease and treatment of this complication by antithymocyte globulin are related to the development of the EBV-related malignancy in the EBV-infected B cells of the developing bone marrow graft.
The in vitro growth, heterotransplantation, and immunohistochemical characterization of the blastemal component of Wilms' tumor.
Wilms' tumor has been proposed to originate from a developmental abnormality of the metanephric blastema. This undifferentiated component of Wilms' tumors has previously eluded efforts for in vitro growth. Blastema from a "classical" Wilms' tumor was transplanted into nude mice and passaged through 12 generations of heterotransplantation. Tumors from heterotransplants were grown for 12 serial passages in a serum-free growth medium supplemented with hormones and conditioned media from human kidney proximal tubule cells. The blastema initially grew on a collagen-fetal calf serum matrix as multicellular spheroids, and the cells proliferating from the rim of the spheroids had a flattened shape. Pulse-labeling with bromodeoxyuridine (BrdU) identified the proliferating cell population as blastemal in origin. Except for a loss of extracellular matrix, ultrastructural studies demonstrated morphologic similarities in the cultured cells, compared with the primary tumor and heterotransplants. Lectin histochemical stains for the peanut lectin (PNA) and immunohistochemical stains for cytokeratin (CYTO), vimentin (VIM), and epithelial membrane antigen (EMA) were performed on the original tumor, successive heterotransplants, and cells grown in vitro. The PNA stained the surface of the blastemal cells after sialidase digestion in the original tumor, heterotransplants, and cultured cells. The blastema of the original tumors was negative for CYTO and EMA but reactive for vimentin. This lack of differentiation was maintained in heterotransplants through 12 passages. However, blastemal cells demonstrated coexpression of CYTO and VIM intermediate filaments when grown in a serum-free medium on a matrix material. These studies demonstrate that the blastemal component of Wilms' tumor can be successfully grown in culture, passaged in nude mouse heterotransplants, and shown to undergo early stages of blastemal differentiation in vitro by growth in serum-free medium. This in vitro system provides a model for testing the factors that influence the growth and differentiation of the blastemal component of Wilms' tumors.
Hematologic consequences of Epstein-Barr virus infection.
This article reviews the immunobiology of Epstein-Barr Virus infection in humans. It details the effects of this ubiquitous herpesvirus on the hematopoietic and lymphoreticular systems.
Immunologic aberrations, HIV seropositivity and seroconversion rates in patients with hemophilia B.
Because there have been reports that factor IX concentrate is less immunosuppressive and therefore factor IX users have less immunologic aberrations, we have studied a group of 22 patients with hemophilia B and six patients with factor VIII deficiency and high titer inhibitors with respect to lymphocyte numbers and function, human immunodeficiency virus (HIV) serology, and factor usage. This group was compared to 111 patients with hemophilia A and a group of 28 healthy male volunteer controls. When the study began in 1983, the majority of patients with hemophilia B and with higher titer factor VIII inhibitors were seronegative, 77% and 83% respectively, as compared to only 30% of patients with hemophilia A. At that time the factor IX users also had milder immune aberrations than the hemophilia A group. However, with time and increasing clotting factor concentrate usage, seroconversion and more striking abnormalities in immune function have occurred in the hemophilia B group. In a subgroup of 16 patients with hemophilia B studied twice, the incidence of seropositivity increased from 31% in 1983 to 69% in 1985. We thus conclude that factor IX concentrate in itself is not less immunosuppressive than factor VIII concentrate. Seroconversion in factor IX concentrate users appears to be lagging behind seroconversion in factor VIII concentrate users, perhaps secondary to the lower cumulative dosage of concentrate that patients with hemophilia B utilize.
Sex, iron, and heart disease.
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Delayed cutaneous hypersensitivity reactions in hemophiliac subjects treated with factor concentrate.
Cutaneous delayed-type hypersensitivity was measured using the Multitest CMI in a group of 97 patients with hemophilia who were enrolled in the New England Area Comprehensive Clinic. The Multitest CMI is a multipuncture system that dispenses seven test antigens including tetanus, diphtheria, Streptococcus, Proteus, tuberculin, Candida, and Trichophyton, and a glycerine-saline control solution. A reaction was considered positive if there was induration of at least 2 mm. If the results of one or more skin tests were positive, the patient was considered to have a positive reaction. Of the 83 patients with severe or moderate hemophilia A, 51 percent had negative reactions. No study control subject and only one patient with hemophilia B had a negative reaction. The 42 patients with hemophilia A who showed no reaction used a significantly greater amount of factor VIII concentrate than did those with hemophilia A who responded positively (1,960 units/kg per year versus 1,360 units/kg per year; p less than 0.025) and included a higher percent of patients who had seropositive results for human T lymphotropic virus type III (HTLV-III) antibody (89 percent versus 69 percent, p less than 0.025).