Biomedical subjects
Publications and source records attributed to D N Lawrence.
We report a case of chronic lobomycosis, contracted by a rural resident of the westernmost Brazilian state, Acre, and substantiate that western Amazonia is now an endemic area for Loboa loboi. No changes in lesion morphology resulted from a prolonged course of oral therapy with ketoconazole administered in an attempt to prevent the progressive and destructive extension of the disease.
Longitudinal immune studies of patients with hemophilia A were begun in 1982 by the Regional Hemophilia Center in St. Louis, Missouri. Serum samples collected from 74 participants between 1982 and 1985 were analyzed for antibody to human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-associated virus (LAV). The incidence of antibody to HTLV-III/LAV has increased significantly in this population of patients with hemophilia. Only one of eight hemophiliacs had detectable antibody before July 1982, whereas 88.7% (55/62) were positive in 1985. T-cell surface markers were markedly abnormal in seropositive hemophilia patients with decreased percentage and number of OKT4-positive cells compared with seronegative hemophiliacs and controls. Lymphoproliferative responses to mitogens and antigens were normal in seronegative hemophilia patients. Seropositive hemophiliacs, compared with seronegative hemophiliacs, had significantly decreased lymphoproliferative responses, especially to pokeweed mitogen, tetanus, and Candida stimulations. Immune studies of seven HTLV-III/LAV seropositive hemophiliacs revealed antigen unresponsiveness and decreased T4 cells 2 to 32 months prior to development of full-blown AIDS. Longitudinal immune studies from 1983-85 revealed increasing number of seropositive hemophiliacs with antigen unresponsiveness and decreased T4 cells.
We studied the human T-lymphotropic retrovirus type III/lymphadenopathy-associated virus (HTLV-III/LAV) antibody status of 234 factor VIII concentrate recipients, 36 factor IX concentrate recipients, 69 long-term recipients of frozen packed red blood cells, and 47 persons not receiving routine transfusion therapy. Factor VIII concentrate recipients had a significantly higher rate of seropositivity (74%) than any other group. Factor IX concentrate recipients had a significantly higher rate (39%) than recipients of frozen packed red blood cells (4%) or nontransfused persons (4%). In factor VIII concentrate recipients, HTLV-III/LAV seropositivity was significantly associated with more severe hemophilia, greater factor dosage, elevated immunoglobulin and immune complex levels, lower T-helper lymphocyte numbers, and lower ratios of T-helper to T-suppressor lymphocytes. For factor IX concentrate recipients, seropositivity was associated with more severe hemophilia. Antibody-positive factor IX concentrate recipients had a lower rate of seropositivity to HTLV-III/LAV p41 membrane antigen than did antibody-positive factor VIII concentrate recipients, but factor VIII and factor IX concentrate recipients had similar rates of seropositivity to core antigens. We conclude that both factor VIII and factor IX concentrates may transmit HTLV-III/LAV. For factor VIII recipients, HTLV-III/LAV seropositivity is associated with altered immune test results.
Serum samples from 85 Austrian hemophilia patients treated with lyophilized factor concentrates prepared from U.S. plasma sources, 24 hemophilia patients from Georgia on a home therapy program with factor concentrates, and 10 U.S. hemophilia patients with acquired immunodeficiency syndrome (AIDS) were analyzed by two different methods for the presence of antibodies to the major internal antigen of human T-cell leukemia virus I (HTLV-I) p24. All but one, a Georgia sample, were negative. The absence of antibody to HTLV-I p24 in the serum of European hemophilia patients, of U.S. hemophilia patients with no symptoms of AIDS, and of U.S. hemophilia patients with AIDS is interpreted as an indication of the lack of ready transmissibility of HTLV-I in lyophilized factor concentrates.
The acquired immunodeficiency syndrome (AIDS) was first recognized among hemophiliacs in 1982. The authors have conducted investigations to determine the onset and incidence of AIDS among hemophiliacs and to determine trends in hemophilia mortality since the introduction of clotting-factor concentrates in the late 1960s. A survey of United States hemophilia treatment centers, supported by the Centers for Disease Control and the National Hemophilia Foundation, defined a population of hemophiliacs which was monitored for AIDS cases through June 1984. Death reports from the United States Vital Statistics System and from the hemophilia treatment center survey provided mortality trends for 1968-1979 and for 1978-1982, respectively. The results of these investigations demonstrate the following points. 1) The AIDS epidemic is a new and important cause of illness and mortality among hemophiliacs, although a very low incidence of AIDS among hemophiliacs prior to 1982 cannot be ruled out. 2) The AIDS cases who attended the surveyed hemophilia treatment centers were distributed throughout the United States and were older than hemophilia treatment center patients without AIDS. AIDS cases also used more lyophilized clotting-factor concentrate, but only a small number of cases were reported with this information. 3) Improved care for hemophilia, including the use of clotting-factor concentrates, dramatically reduced hemophilia mortality rates during the 1970s. 4) In 1982, hemorrhage was the major cause of death among hemophiliacs. Deaths from non-alcoholic liver disease were also increased. AIDS incidence among hemophilia treatment center attendees was stable at 0.6 cases per 1,000 hemophilia treatment center attendees per year during 1982 and 1983 but increased sharply to 5.4 cases per 1,000 during the first quarter of 1984.
Thirty-four adult and pediatric hemophilia A and B patients and 50 nonhemophilic members belonging to 28 families were enrolled in August 1984 in a study of human T cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) antibody status and T cell subpopulation numbers. All 50 household contacts, including three spouses of LAV antibody-positive adult hemophiliacs, were immunologically normal and serologically negative with respect to HTLV-III/LAV. Based on Western blot serologic testing of blood samples collected intermittently between July 1981 and August 1984 from 33 representative St Louis hemophiliacs studied during the period from 1981 to 1984, the average time since seroconversion was estimated as 20 months. One spouse of a seropositive hemophiliac and 23 parents of 27 seropositive pediatric hemophiliacs assisted regularly with home infusions. These infusion assistants have collectively experienced 44 person-years of concentrate infusion "exposure" without seroconversion. These results suggest that the likelihood for transmission of HTLV-III/LAV from hemophiliacs to persons assisting in their therapy is extremely low.
A comprehensive study was initiated to examine the immunologic status of a sample (n = 47) of the asymptomatic hemophilia A and B populations of metropolitan Atlanta and to determine if any of the abnormalities changed with time or correlated with infection by human T cell leukemia virus type III and lymphadenopathy-associated virus (HTLV-III/LAV) or other viruses either alone or in combination. Patients with hemophilia A (Hem-A) showed a defect in cellular immunity evidenced by a depressed T cell helper/suppressor ratio (P less than .0001), an increased absolute T suppressor cell number (P less than .0001), and a diminished number of T helper cells (P = .003) when compared with health professionals. Lymphocytes from these patients also showed a reduced ability to transform in response to phytohemagglutinin and pokeweed mitogen. No deterioration in immune status was seen during a median ten-month period of follow-up. Sixty-four percent of Hem-A patients had antibodies to HTLV-III/LAV and those who were seropositive had a significantly decreased helper/suppressor cell ratio (P = .018) and a diminished T helper cell number (P = .002); they were also more likely to have had exposure to cytomegalovirus than HTLV-III/LAV-negative Hem-A patients (P = .016). Heavy use of factor VIII concentrate was associated with a decreased number of T helper cells (P = .037) and seropositivity for HTLV-III/LAV (P = .011 in 1982). Hemophilia patients had higher IgG, immune complex, and beta 2-microglobulin levels than health professionals (P less than .0001). Although the most prominent abnormality observed in T cell subsets of patients with hemophilia is an increase in T suppressor cells, a finding likely to be associated with immune augmentation in response to multiple stimuli, the T cell abnormality that was predictive of exposure to HTLV-III/LAV, the putative acquired immunodeficiency syndrome agent, was a diminished number of T helper cells.
We propose an analytical model, which can simultaneously depict many fundamental characteristics of the immunogenicity of various vaccines. This model, the Immune Response (IR) profile, conveniently expresses the mathematical relation between pre- and post-vaccination titers. A vaccine's IR profile is antigen-specific, dose-dependent and post-vaccination interval-dependent. The maximal capability for serological response to a vaccine can be determined using this model irrespective of the dose administered, the post-vaccination assay interval, or the live or killed state of the vaccine. The IR profile obtained from analysis of booster vaccine responses in a limited number of seropositive study subjects can be used to predict maximal antibody titers which are expected after vaccination and can predict the geometric mean post-vaccination antibody titer of a cohort of subjects undergoing primary immunization. Using this model, it is anticipated that the immunoregulation implied by the IR profile may also prove to be correlated with cellular subpopulations and idiotypic antibody functions. Although derived from influenza vaccines analyses, the model successfully describes immune response characteristics following natural infection with malaria and following diphtheria and rubella vaccine administration.
An assay for antibodies to membrane antigens of cells infected by human T-cell leukemia virus was used to examine serum from persons who donated blood to 12 patients with acquired immunodeficiency syndrome (AIDS) associated with blood transfusions. The occurrence of positive results in the assay was significantly greater among donors to the AIDS patients (9 of 117; 7.7 percent) than among random donors (1 of 298; 0.3 percent). Of 12 sets of donors examined, 9 sets included a donor whose serum gave positive results for the presence of the antibodies. In six of these nine sets, the seropositive donor was an individual who was also identified as a possible source of AIDS transmission when epidemiologic and immunologic criteria were used.
Hemophiliacs who are exposed to pooled clotting factor concentrate constitute one group at increased risk for development of acquired immune deficiency syndrome. To determine the prevalence of cellular immune aberrations in asymptomatic hemophiliacs, we studied a group of 65 adult hemophiliacs for T-cell subset abnormalities. Sixty-five percent of concentrate recipients had an abnormal T-helper to T-suppressor cell ratio, 40% had a depressed absolute T-helper cell level, and 29% had an elevated absolute T-suppressor cell count. To determine whether horizontal transmission of T-cell subset abnormalities from hemophiliacs to their female sexual partners occurred, we studied 41 spouses. We found no correlation between paired husband and wife values for T-cell ratio or any other immune parameter studied. There were no significant differences found between wives of hemophiliacs with reversed T-cell ratios and wives of hemophiliacs with T-cell ratios of 1.0 or greater, with respect to immunologic tests. We conclude that there is no evidence to date for heterosexual or household-contact transmission of T-cell subset abnormalities from hemophiliacs to their spouses in our study population.
Of 2157 patients with the acquired immunodeficiency syndrome (AIDS) whose cases were reported to the Centers for Disease Control by August 22, 1983, 64 (3 per cent) with AIDS and Pneumocystis carinii pneumonia had no recognized risk factors for AIDS. Eighteen of these (28 per cent) had received blood components within five years before the onset of illness. These patients with transfusion-associated AIDS were more likely to be white (P = 0.00008) and older (P = 0.0013) than other patients with no known risk factors. They had received blood 15 to 57 months (median, 27.5) before the diagnosis of AIDS, from 2 to 48 donors (median, 14). At least one high-risk donor was identified by interview or T-cell-subset analysis in each of the seven cases in which investigation of the donors was complete; five of the six high-risk donors identified during interview also had low T-cell helper/suppressor ratios, and four had generalized lymphadenopathy according to history or examination. These findings strengthen the evidence that AIDS may be transmitted in blood.
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Recently, antibodies to human T-cell leukemia virus membrane antigens (HTLV-MA) and elevated levels of beta 2-microglobulin and thymosin alpha 1 have been found with high frequency in patients with the acquired immunodeficiency syndrome. Prospective studies of asymptomatic persons at high risk for this syndrome will ascertain whether any of these findings is a predictive marker for the disease. In this study, antibodies to HTLV-MA, beta 2-microglobulin levels, and thymosin alpha 1 levels were determined for a group of asymptomatic adult hemophiliacs and their wives. Five of thirty-nine hemophiliacs had HTLV-MA antibody, compared with none of 21 wives tested. The mean beta 2-microglobulin level for hemophiliacs was significantly higher than the control value (p less than 0.001), whereas the wives had a normal mean value. The mean thymosin alpha 1 values were normal for hemophiliacs and their wives; however, 3 of 22 hemophiliacs and 1 of 16 wives had abnormally high levels. Whether any of these abnormalities correlate with subsequent development of the acquired immunodeficiency syndrome will be ascertained by longitudinal follow-up of this population.
Since mid-1981 the Centers for Disease Control (CDC) has received reports of more than 1900 cases of the acquired immunodeficiency syndrome. These cases had either Kaposi's sarcoma confirmed by biopsy or a life-threatening opportunistic infection confirmed by biopsy or culture. In January 1982 a hemophiliac with Pneumocystis carinii pneumonia was reported to the CDC, and by July 1982 two other hemophiliacs had developed P. carinii pneumonia. During the next 12 months a total of 22 confirmed cases of the acquired immunodeficiency syndrome occurred in hemophiliacs, 17 in the United States and 5 outside the United States. We report the nature of the epidemic of the acquired immunodeficiency syndrome in hemophiliacs and summarize pertinent clinical aspects.
Human T cell leukaemia virus (HTLV), HTLV proviral DNA, and antibodies to HTLV or a related agent have recently been detected in patients with acquired immunodeficiency syndrome (AIDS). Antibodies against HTLV-related antigens were assayed by means of indirect living cell immunofluorescence of HTLV-infected cells in sera recently collected from Georgia haemophiliacs and in sera collected between 1976 and 1981 from New York haemophiliacs. 5 of 45 Georgia haemophiliacs and 8 of 48 New York haemophiliacs had antibodies to HTLV-associated cell membrane antigen (HTLV-MA). None of the control Georgia patients on haemodialysis or with chronic hepatitis had detectable antibodies. The 5 haemophiliac patients from Georgia with HTLV-MA had significantly fewer T4 lymphocytes than similar HTLV-MA-negative patients. There were no other significant immunological differences between these groups. These data suggest that transfusions with blood products may expose haemophiliacs to a substantial risk of acquiring HTLV or a related virus.
Along with homosexual men, Haitians, and intravenous drug abusers, hemophiliacs are at high risk of contracting acquired immunodeficiency syndrome (AIDS). An earlier study revealed that 36 percent of a group of the AIDS patients had antibodies to cell membrane antigens associated with the human T-cell leukemia virus (HTLV-MA), whereas only 1.2 percent of matched asymptomatic homosexual controls had these antibodies. In the present experiments, serum samples from 172 asymptomatic hemophiliacs were examined for the presence of antibodies to HTLV-MA. Such antibodies were detected in 5 to 19 percent of the hemophiliacs examined from four geographical locations, but in only 1 percent or less of laboratory workers, normal blood donors, donors on hemodialysis, or donors with chronic active hepatitis.
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