Oesophageal candidiasis in an HIV-negative individual treated with factor VIII concentrate.
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Aged↗
Biomedical subjects
C A Ludlam
Publications and source records attributed to C A Ludlam.
AIDS: the alternative view.
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Acquired Immunodeficiency Syndrome↗
Convergent and divergent sequence evolution in the surface envelope glycoprotein of human immunodeficiency virus type 1 within a single infected patient.
In an investigation of the evolution of the third hypervariable loop of gp120 (V3), the principal neutralization determinant of human immunodeficiency virus type 1, we have analyzed 89 V3 sequences of plasma viral RNA purified from peripheral blood samples donated over 7 years by an infected hemophiliac. Considerable sequence diversity in the V3 region was found at all time points after seroconversion. Phylogenetic analysis revealed that an important diversification had occurred by 3 years postinfection and that, subsequently, most sequences could be allocated to either one of two major lineages that persisted throughout the remainder of the infection. Rapid changes in frequency of the most common sequences and the observation that the same hexapeptide motif (GPGSAV) at the crown of the V3 loop has evolved convergently provide strong evidence that selective processes determine the evolutionary fate of sequence variants in this region.
Amino Acid Sequence↗
Immunological abnormalities in haemophiliacs.
10 years ago, it became apparent that haemophiliacs were developing diseases which were indicative of underlying immunodeficiency. The results of investigation confirmed that many had abnormal immune systems, particularly with regard to cell-mediated immunity. These abnormalities were thought to be a consequence of the use of clotting factor concentrates, and indeed the discovery of HIV and its mode of transmission, confirmed these suspicions. However, it subsequently became clear that HIV infection did not explain all the abnormalities observed. Many in vivo studies have shown that the immune systems of HIV-negative haemophiliacs are not entirely normal, and in vitro studies have shown that clotting factor concentrates per se have a modulating effect on immune function. We have reviewed particularly the abnormalities seen in HIV-negative haemophiliacs and their possible causes, as well as the specific features of HIV infection in haemophiliacs.
Blood Coagulation Factors↗
The fibrinolytic system and proteins C and S in treated polycythaemia rubra vera.
This study was designed to assess whether factors other than high haemoglobin, thrombocytosis and abnormal platelet function predispose to thrombosis in polycythaemia rubra vera (PRV). Components of the fibrinolytic system and concentrations of the naturally occurring anticoagulants were measured in patients and controls in the resting state; the fibrinolytic capacity was reassessed after venous occlusion. The results were related to presence or absence of a history of thromboembolism. Under resting conditions, patients with PRV had reduced plasminogen activator inhibitor antigen levels and higher fibrin plate lysis area and tissue plasminogen activator activity. Protein C, protein S and factor V levels were reduced. Those patients with a history of thromboembolism had decreased tissue plasminogen activator activity after venous occlusion compared to those who had not experienced a thrombosis. We conclude that reduced fibrinolytic capacity may predispose to thrombosis in PRV. Despite treatment to normalize haemoglobin levels, the patients have persistent activation of their fibrinolytic systems. This, and reduced levels of proteins C and S, may be secondary to a chronic, clinically occult, disseminated intravascular coagulation.
Adult↗
Use of several second generation serological assays to determine the true prevalence of hepatitis C virus infection in haemophiliacs treated with non-virus inactivated factor VIII and IX concentrates.
To investigate the prevalence of hepatitis C virus infection in two risk groups, stored serum samples from treated haemophiliacs and intravenous drug users were tested for anti-HCV by both anti-C-100 based and second generation ELISAs (Abbott and Ortho) followed by testing in two confirmatory immunoblot assays that incorporate core as well as other non-structural antigens (Innogenetics LIA and Chiron RIBA-HCV test). Clear evidence of HCV infection was found in all but one of 78 haemophiliacs treated with non-virus inactivated clotting factor concentrates, but in none exposed only to super dry heat-treated concentrates. Only four samples gave rise to conflicting serological results between the four tests, two of these occurred in patients with advanced HIV related disease and almost certainly reflected loss of humoral immunity associated with disease progression, and the others occurred in the only two patients tested who were chronic carriers of hepatitis B infection and may reflect an interaction between the two viruses. Comparison of anti-C-100 versus second generation tests in immunocompetent drug users revealed a false negative rate of 20% using C-100 alone, indicating the advantage of using second generation assays for detection of past or current HCV infection. Of all of the antigens used in the confirmatory assay, positive sera showed strongest and most frequent reactivity with the C22 and C33c proteins (Ortho RIBA).
Drug Contamination↗
Enhancement of human T cell responses to allogeneic stimuli by factor VIII concentrates.
The effect of factor VIII concentrate, from commercial and National Health Services manufacturers, on in vitro lymphocyte proliferative response to allogeneic stimulator cells was investigated. Factor VIII preparations 'purified' by ion exchange or by monoclonal antibody affinity had no effect in this assay but lymphocyte proliferation in response to allogeneic cells was markedly and consistently enhanced by some intermediate purity factor VIII concentrates and, to a lesser extent, by a factor IX preparation. These preparations did not stimulate lymphocyte proliferation in the absence of other mitogens. The co-mitogenic factor(s) present in intermediate purity factor VIII was not identified. However, enhanced proliferation was not due to factor VIII itself, nor to albumin or fibronectin. The clinical relevance of the immunomodulatory activity of intermediate purity factor VIII concentrates in vitro is discussed.
Cell Division↗
Immunological studies in HIV seronegative haemophiliacs: relationships to blood product therapy.
Immunological studies were performed on a group of 44 haemophilia A and 15 haemophilia B patients who were treated exclusively with blood products manufactured by the Scottish National Blood Transfusion Service (SNBTS). All patients were HIV seronegative throughout the study. Of the haemophilia A patients 14 (32%) had CD4+ lymphocyte subset counts less than or equal to 0.5 x 10(9)/l, compared with one (6%) haemophilia B patient and four (8%) controls. The percentage of activated T cells was greater than 5% in 19/33 (57%) with haemophilia A, 5/9 (55%) haemophilia B and 14/50 (28%) of control subjects. beta 2 microglobulin values greater than or equal to 2.0 mg/l were observed in 19 (43%) haemophilia A and four (26%) haemophilia B patients, compared with one (2%) control. No significant increases in serum interleukin-2 receptor concentrations were observed in 15 haemophilia A and one haemophilia B patients. Significantly elevated levels of IgG, IgM and IgA were observed in the haemophilia A group, but elevation of immunoglobulins was restricted to the IgG class in the haemophilia B group. Of the haemophilia A patients 16/30 (53%) and 6/11 (54%) haemophilia B patients had depression of cell-mediated immunity (CMI) as assessed by delayed-type hypersensitivity responses to intradermally injected recall antigens. There was no correlation between factor VIII or factor IX usage and changes in lymphocyte subsets, beta 2 microglobulin, and immunoglobulin levels. There was, however, a strong correlation between annual factor VIII usage and the degree of depression of CMI for those with haemophilia A but not for those with haemophilia B. No correlation between alterations in the immune parameters and disturbance of liver function tests was observed in either haemophilia A or haemophilia B patients. We conclude that alloantigen or non-HIV viral exposure due to repeated administration of factor concentrates brings about alterations in the immune response, and that these changes are more marked following exposure to intermediate purity factor VIII compared with factor IX concentrate.
Factor IX↗
Myocardial dysfunction in patients infected with HIV: prevalence and risk factors.
OBJECTIVES: To determine the prevalence of and risk factors for myocardial dysfunction in HIV infection. SUBJECTS: 173 patients infected with HIV underwent echocardiography. 119 were current or previous injection drug users, 38 were homosexuals, 10 were haemophiliac patients, and six were heterosexual. MAIN OUTCOME MEASURE: Detection of impaired ventricular function. RESULTS: 26 patients with abnormalities of ventricular size or function or both were identified. The abnormality was (a) dilated cardiomyopathy in 13 patients (eight homosexuals, three drug users, and two haemophiliacs) with a mean CD4 count of 38 cells/mm3, which accords with end-stage disease (in addition, three patients were identified as having borderline impairment of left ventricular function); (b) left ventricular dilatation without loss of function in a further six patients; and (c) isolated right ventricular dilation in seven patients. Follow up echocardiograms were obtained in 71 patients, 18 of whom had myocardial dysfunction (103 echocardiograms, mean (SD) 2.5 (0.6) scans per patient, mean interval 200 (116) days, range 14-538 days). These showed that in four cases of isolated right ventricular dilatation, one of isolated left ventricular dilatation, and two with borderline left ventricular dysfunction myocardial function subsequently reverted to normal. There was no excess of exposure to zidovudine in the patients with myocardial dysfunction. Similarly, patients with myocardial dysfunction had no serological evidence of excess secondary infection with Toxoplasma gondii and cytomegalovirus. CONCLUSIONS: There was a high prevalence and wide range of myocardial dysfunction in HIV positive patients. Dilated cardiomyopathy was a feature of advanced HIV disease and affected all major risk groups for HIV infection. In contrast, isolated dilatation of either ventricle occurred at an earlier stage of HIV infection and, particularly in the case of the right ventricle, often was transient. Neither treatment with zidovudine nor infection with Toxoplasma gondii or cytomegalovirus seemed to be responsible for these findings.
Adult↗
An HIV positive haemophiliac with acute lymphoblastic leukaemia successfully treated with intensive chemotherapy and syngeneic bone marrow transplantation.
A 26-year-old HIV positive severe haemophiliac developed Burkitt-type acute lymphoblastic leukaemia with intracranial involvement. He underwent standard combination therapy, and entered complete remission. Syngeneic bone marrow transplantation (BMT) was undertaken; the donor was also HIV positive. The patient died 18 months from transplant of isolated intracranial relapse, with no evidence of systemic relapse. Unlike other types of non-Hodgkin's lymphoma, Burkitt's type occurs in HIV positive patients with relatively normal CD4 cell counts. Remission can be achieved using intensive chemotherapy, and since these patients may otherwise have a reasonable life expectancy, BMT may be appropriate.
Adult↗
Determinants of HIV disease progression: six-year longitudinal study in the Edinburgh haemophilia/HIV cohort.
Markers of immune function present before infection may determine the subsequent course of disease in HIV-infected individuals. In 1983, we measured immune function in a group of haemophiliacs in Edinburgh. In 1984, 18 of these patients became infected with HIV-1 from contaminated factor VIII. We have followed-up these patients since their seroconversion. The rate of disease progression, as assessed by the appearance or not of AIDS symptoms or signs within five years of seroconversion, was related both to the concentration of total plasma IgM before exposure to infection and to the pattern of specific IgM and IgA anti-HIV response around the time of IgG seroconversion. Disease progression also correlated with concentrations of plasma interleukin-2 receptor (a marker of lymphocyte activation) and with the number and percentage of circulating DR + ve (activated) T cells. Our findings show that the extent of host immune reactivity, which may be genetically determined, is a powerful factor in the pathogenesis of HIV-associated disease.
Acquired Immunodeficiency Syndrome↗
The use of porcine factor VIII in the treatment of patients with acquired hemophilia: the United Kingdom experience.
Data have been collected by questionnaire on 15 acute bleeding episodes in 12 patients with acquired hemophilia, treated with porcine factor VIII (FVIII). The median initial anti-human FVIII inhibitor level was 40 Bethesda Units (BU)/ml, whereas that against porcine was 1 BU/ml. The mean initial dose of porcine FVIII infused was 54 micrograms/kg, which resulted in a rise of 0.57 IU/mL in the FVIII concentration. Therapy was continued for a mean of 8.5 days, during which time the average number of infusions was 11. Clinical response was rated as good or excellent in 82% of recipients. Side effects were uncommon; only one patient experienced a severe reaction. Following therapy, no increase in antihuman antibody levels was noted; increased levels of antiporcine antibody was detected in only two patients. One patient bled on three further occasions and was successfully retreated with porcine FVIII. Porcine FVIII is a safe and clinically effective treatment for bleeding episodes in acquired hemophilia and should be considered as first-line therapy for patients with low antiporcine FVIII levels.
Animals↗
Aortic aneurysms and consumptive coagulopathy.
We describe three cases of consumptive coagulopathy caused by extensive thrombus formation in otherwise 'uncomplicated' aortic aneurysms. These cases demonstrate the importance of performing a coagulation screen in any patient presenting with thrombocytopenia who may have an aortic aneurysm. Effective therapy with low-dose heparin was demonstrated with subsequent haemostasis being maintained with warfarin.
Aged↗
Detection, quantification and sequencing of HIV-1 from the plasma of seropositive individuals and from factor VIII concentrates.
A highly sensitive and reliable RNA polymerase chain reaction method has been developed which has been used to detect, quantify and sequence cell-free HIV RNA directly from the plasma of seropositive individuals. Plasma from 10 out of 12 haemophiliacs tested was found to contain detectable levels of HIV-1 RNA [log mean value: 1.2 x 10(3) copies for Centers for Disease Control (CDC) group II patients, 5.5 x 10(3) copies for CDC group IV patients]. The presence of cell-free circulating virus in both symptomatic and asymptomatic individuals suggests that viral replication continues throughout the course of infection. The same procedure has been used to detect and sequence HIV-1 RNA in two batches of unheated commercial factor VIII concentrate distributed in 1981 and 1983. The sequences obtained revealed a closer relationship to North American than to African strains of HIV-1.
Amino Acid Sequence↗
Discontinuous sequence change of human immunodeficiency virus (HIV) type 1 env sequences in plasma viral and lymphocyte-associated proviral populations in vivo: implications for models of HIV pathogenesis.
Sequence change in different hypervariable regions of the external membrane glycoprotein (gp120) of human immunodeficiency virus type 1 (HIV-1) was studied. Viral RNA associated with cell-free virus particles circulating in plasma and proviral DNA present in HIV-infected peripheral blood mononuclear cells (PBMCs) were extracted from blood samples of two currently asymptomatic hemophiliac patients over a 5-year period. HIV sequences were amplified by polymerase chain reaction to allow analysis in the V3, V4, and V5 hypervariable regions of gp120. Rapid sequence change, consisting of regular replacements by a succession of distinct viral populations, was found in both plasma virus and PBMC provirus populations. Significant differences between the frequencies of sequence variants in DNA and RNA populations within the same sample were observed, indicating that at any one time point, the predominant plasma virus variants were antigenically distinct from viruses encoded by HIV DNA sequences in PBMCs. How these findings contribute to current models of HIV pathogenesis is discussed.
Acquired Immunodeficiency Syndrome↗
An unusual case of amyloidosis complicating light chain myeloma.
We present an unusual case of light chain myeloma complicated by systemic amyloidosis. There was massive infiltration of the left iliopsoas and quadratus femoris muscles with amyloid, manifesting itself clinically as a progressive, painless limp. We point out that accurate diagnosis by muscle biopsy in such cases has important prognostic implications and may avoid the unnecessary use of potentially toxic and ineffective treatment.
Aged↗
Hepatitis C quantification and sequencing in blood products, haemophiliacs, and drug users.
The polymerase chain reaction (PCR) detected specific hepatitis C viral (HCV) RNA sequences in plasma from 15 of 21 haemophiliacs (12 HCV-antibody positive) and 7 of 27 intravenous drug users (13 HCV-antibody positive). Quantification of RNA-positive samples showed high levels of HCV (10(5) to 10(6) copies of RNA/ml) in infected patients. HCV was more frequently found in haemophiliacs infected with human immunodeficiency virus (11/11 HIV-positive and 4/10 HIV-negative patients). HCV-RNA was detected in all batches of commercially available factor VIII tested and in low concentrations in some pools of plasma donations from volunteers. Factor VIII, manufactured from volunteer donations, was uniformly negative by PCR. Phylogenetic analysis of viral sequences showed two distinct groups: one was associated with intravenous drug users and the other with haemophiliacs infected with Scottish factor VIII preparations. Both were distinct from sequences found in commercially available factor VIII.
Acquired Immunodeficiency Syndrome↗