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Biomedical subjects

F Davidson

Publications and source records attributed to F Davidson.

At least 19 recordsLinked to original sources
PubMed1998

Detection of a novel DNA virus (TTV) in blood donors and blood products.

BACKGROUND: A newly discovered DNA virus, transfusion-transmitted virus (TTV), has been implicated as a cause of post-transfusion hepatitis. We investigated the frequency of TTV viraemia in UK blood donors, and the extent to which TTV contaminates blood products such as factor VIII and IX clotting factors. We also investigated the possible aetiological role of TTV in cryptogenic fulminant hepatic failure (FHF). METHODS: We extracted DNA from plasma of blood donors and patients with FHF, and from blood products (factor VIII and IX clotting-factor concentrates, immunoglobulin preparations). We detected TTV by PCR using primers from a conserved region in the TTV genome. FINDINGS: TTV viraemia was detected in 19 (1.9%) of 1000 non-remunerated regular blood donors. Infection occurred more frequently in older donors (mean age 53 years), compared with the age prolife of donors infected with hepatitis C virus and other parenterally-transmitted viruses. TTV contamination was found in ten (56%) of 18 batches of factor VIII and IX concentrate manufactured from such non-remunerated donors, and in seven (44%) of 16 batches of commercially available products. Whereas solvent or detergent treatment had little effect on the detection of TTV in factor VIII and IX by PCR, this virucidal step seemed to inactivate TTV infectivity. TTV infection was detected in four (19%) of 21 patients with FHF; in three cases, infection was detected at the onset of disease and could thus not be excluded from its aetiology. INTERPRETATION: TTV viraemia is frequent in the blood-donor population, and transmission of TTV through transfusion of blood components may have occurred extensively. Clinical assessment of infected donors and recipients of blood and blood products, and assessment of TTV's aetiological role in hepatic and extra-hepatic disease, are urgently needed.

Adult↗
PubMed1998

Intraocular inflammation and the diffuse infiltrative lymphocytosis syndrome.

PURPOSE: To report a case of bilateral panuveitis associated with diffuse infiltrative lymphocytosis syndrome (DILS). METHODS: Case report. A 35-year-old woman with known human immunodeficiency virus (HIV) infection developed bilateral uveitis with retinal periphlebitis in association with diffuse infiltrative lymphocytosis syndrome. RESULTS: Detailed comprehensive examination and investigations were performed and recognized causes of panuveitis excluded. CONCLUSION: To the best of our knowledge, we report the first case of retinal findings associated with diffuse infiltrative lymphocytosis syndrome.

Adult↗
PubMed1998

Prevalence, incidence, and clinical characteristics of hepatitis G virus/GB virus C infection in Scottish blood donors.

The prevalence, incidence, clinical features, and natural history of hepatitis G virus (HGV) or GB virus C (GBV-C) were investigated in a non-remunerated blood donor population to determine its clinical significance and its impact on blood safety. Of 1020 regular blood donors, 23 (2.25%) were positive for plasma HGV/GBV-C RNA. Alanine aminotransferase levels were lower than in uninfected donors (median, 20 IU/mL; 32 IU/mL in controls; P=.015). Clinical examination produced no other evidence for hepatitis or for shared nonhepatic diseases. Fifteen of 17 donors excreted HGV/GBV-C in saliva (mean level, 8x103 copies of RNA/mL). Testing of previous donations indicated an incidence of 170-200 new infections with HGV/GBV-C per 100,000 donor-years. The absence of further clinicopathologic data and the limitations of current polymerase chain reaction-based methods for screening suggests that it is neither necessary nor practical to commence screening.

Adult↗
PubMed1998

Long-term evolution of the hypervariable region of hepatitis C virus in a common-source-infected cohort.

The long-term evolution of the hepatitis C virus hypervariable region (HVR) and flanking regions of the E1 and E2 envelope proteins have been studied in a cohort of women infected from a common source of anti-D immunoglobulin. Whereas virus sequences in the infectious source were relatively homogeneous, distinct HVR variants were observed in each anti-D recipient, indicating that this region can evolve in multiple directions from the same point. Where HVR variants with dissimilar sequences were present in a single individual, the frequency of synonymous substitution in the flanking regions suggested that the lineages diverged more than a decade previously. Even where a single major HVR variant was present in an infected individual, this lineage was usually several years old. Multiple lineages can therefore coexist during long periods of chronic infection without replacement. The characteristics of amino acid substitution in the HVR were not consistent with the random accumulation of mutations and imply that amino acid replacement in the HVR was strongly constrained. Another variable region of E2 centered on codon 60 shows similar constraints, while HVR2 was relatively unconstrained. Several of these features are difficult to explain if a neutralizing immune response against the HVR is the only selective force operating on E2. The impact of PCR artifacts such as nucleotide misincorporation and the shuffling of dissimilar templates is discussed.

Amino Acid Sequence↗
PubMed1997

Complete coding sequence of hepatitis C virus genotype 6a.

Hepatitis C virus (HCV) genotype 6a is found in a restricted part of South East Asia, including Hong Kong, Macau and Vietnam. We determined the full length coding sequence of a type 6a isolate (EUHK2) obtained from a Hong Kong blood donor. The sequence of EUHK2 contained a single open reading frame coding for a polyprotein of 3018 amino acids, within the range of 3008 to 3037 for other HCV genotypes. The full length sequence of EUHK2 showed 30.3%-32.9% nucleotide (24.3%-29.4% amino acid) sequence divergence from genotypes 1-4, but only 27.7% (20.7% amino acid) divergence from JK046 ("type 11a"). These similarity values were intermediate between those of other HCV genotypes (minimum 28.4%) and between subtypes (maximum 25%). The close evolutionary relationship of EUHK2 with JK046 was further indicated by their grouping together by phylogenetic analysis.

Cloning, Molecular↗
PubMed1997

Nosocomial transmission of hepatitis C virus within a British dialysis centre.

Patients on renal replacement therapy are recognized as a group at increased risk of infection with hepatitis C virus (HCV). While the risk has been reduced by the use of erythropoietin for treatment of anaemia and the introduction of HCV screening of blood products and potential renal transplant donors, new cases of HCV are still being documented, with patients on hospital haemodialysis appearing to be particularly at risk. The exact mode of transmission of HCV within dialysis units is unclear, although there is evidence to support nosocomial transmission between patients. Third generation HCV antibody testing was performed on all dialysis patients when a new case of HCV was identified within our unit. Stored monthly serum samples were then examined retrospectively to determine when patients became HCV RNA and HCV antibody positive. Viral typing was carried out to identify the HCV strains responsible for transmission. Four new cases of HCV infection are described within a single dialysis shift. Viral typing identified two distinct strains of HCV as being responsible for these infections, both of which had previously been identified in dialysis patients within the unit known to have HCV infection. This information, taken in conjunction with knowledge of the location of each patient for dialysis, suggests two separate episodes of nosocomial transmission of HCV between haemodialysis patients. While evidence of nosocomial transmission of HCV is accumulating, with modern dialytic procedures evidence of transmission through the dialysis machine or equipment used for dialysis is lacking. This stresses the importance of strict applications of universal precautions as the key to prevention of further transmission of HCV infection. This information is obviously applicable not only to dialysis units but all units that may potentially come in contact with HCV patients.

Cross Infection↗
PubMed1997

The origin of hepatitis C virus genotypes.

For many RNA viruses, relatively recent times of origin of extant viruses are implied by the high rate of substitution observed in longitudinal studies. However, extrapolation of short-term rates of substitution can give misleading estimates of times of divergence. We show here that the common ancestor of different types of hepatitis C virus (HCV) is older than previously thought. The rate of HCV sequence change was measured amongst a cohort of individuals infected following administration of anti-D immunoglobulin. Virus sequences were obtained in the E1 and NS5B genes and compared with each other and with sequences from an infective batch. Taking account of the bias towards synonymous transition substitutions, the time of divergence of variants of subtype 1b is estimated to have occurred 70-80 years ago. The numerous subtypes of HCV are proposed to derive from more than 300 years of endemic infection in certain geographical regions, with recent spread of some subtypes to other parts of the world. Estimation of the time of origin of the major HCV genotypes (types 1-6) is problematic, but our data and analogy with other viruses suggest that divergence occurred at least 500-2000 years ago.

Antibodies, Anti-Idiotypic↗
PubMed1997

Discrimination of hepatitis G virus/GBV-C geographical variants by analysis of the 5' non-coding region.

We have investigated the ability of different subgenomic fragments to reproduce the phylogenetic relationships observed between six complete genome sequences of GBV-C/hepatitis G virus (HGV). While similar relationships were observed following analysis of part of the 5' non-coding region (5'NCR), for the coding region they were not accurately reproduced for some large fragments or for the majority of fragments of 300 or 600 nucleotides. Analysis of 5'NCR sequences from a large number of isolates, including newly obtained sequences from Pakistan, Zaïre and Scotland, produced separate groupings of Asian, African and European/North American variants. These groupings are associated with specific polymorphisms in the 5'NCR, many of which were covariant and consistent with a proposed secondary structure for this region. The relatively low level of amino acid sequence variation observed between these geographically and phylogenetically defined groups of variants suggests that they are unlikely to display significant biological differences.

Base Sequence↗
PubMed1997

Comparison of plasma virus loads among individuals infected with hepatitis C virus (HCV) genotypes 1, 2, and 3 by quantiplex HCV RNA assay versions 1 and 2, Roche Monitor assay, and an in-house limiting dilution method.

The accuracy of different methods for the quantitation of hepatitis C virus in plasma was measured with samples from individuals infected with different genotypes and by using RNA transcripts of predetermined concentrations. Highly reproducible results were observed upon repeat testing of samples by both the original version of the Chiron branched-DNA (bDNA) assay (Quantiplex RNA assay; bDNA-1) and the currently available version (Quantiplex HCV RNA 2.0 assay; bDNA-2). A greater variability was observed in the Roche Monitor assay (correlation coefficient of 0.537, compared with 0.942 and 0.964 for the bDNA-1 and bDNA-2 assays, respectively). Significant differences in the efficiency of detection of genotypes 1, 2, and 3 were observed for the bDNA-1 and Roche Monitor assays, whereas the bDNA-2 assay and nested PCR at limiting dilution were able to quantify genotypes with equal sensitivity. By quantifying RNA transcripts of different genotypes, the sensitivities of the Roche Monitor assay for sequences of the type 2 and type 3 transcripts were estimated to be 11 and 8% of those achieved for genotype 1. When correction factors based upon these results and those from quantitation of circulating viral RNA sequences in samples from blood donors were used, the genotype-specific differences in virus load in samples from blood donors were no longer observed, consistent with previous studies with corrected values from the bDNA-1 assay. These results suggest that many of the previous studies evaluating the effect of genotype and virus load on the response to interferon using methods such as the Roche Monitor assay and other competitive PCR methods require reinterpretation. Differences in efficiency of quantitation should be taken into account in future investigations of the relationship between genotype and virus load.

Genes, Viral↗
PubMed1996

Infection with hepatitis G virus among recipients of plasma products.

BACKGROUND: Hepatitis G virus (HGV or GBV-C) is a newly discovered human flavivirus distantly related to hepatitis C virus (HCV). Little information is available on its natural history or routes of transmission, although it can be transmitted parenterally. We investigated the prevalence of persistent infection of HGV and HCV in patients exposed to non-virus-inactivated pooled blood products associated with transmission of HCV. METHODS: RNA was extracted from the plasma of 112 patients with haemophilia and 57 with hypogammaglobulinaemia, as well as from 64 different batches of archived coagulation-factor concentrates and immunoglobulins. RNA was reverse transcribed and amplified with primers from the 5' non-coding region of HCV and HGV by a nested polymerase chain reaction (PCR). Viral RNA was quantified by titration of complementary DNA before amplification. FINDINGS: Among non-renumerated UK blood donors HGV infection (detected by PCR) was more common than HCV infection (four [3.2%] of 125 compared with 137 [0.076%] of 180658 in southeast Scotland). Testing of batches of factor VIII and factor IX concentrates prepared without viral inactivation procedures showed high frequencies of contamination with HGV (16 of 17 factor VIII batches positive; six of six factor IX batches positive), with no difference between renumerated and non-renumerated donors. However, among 95 haemophiliacs who had received non-virus-inactivated concentrates, 13 (14%) were positive for HGV compared with 79 (83%) who were positive for HCV. Two of 37 recipients of long-term immunoglobulin replacement therapy were positive for HGV. Virus inactivation of blood products substantially reduced or eliminated contamination by HGV RNA sequences. INTERPRETATION: Despite the extremely high level of HGV contamination of non-virus-inactivated blood products, their use was not associated with high rates of persistent infection in recipients. The infectivity of HGV in blood products may be lower than that of HCV, or the virus may be less able to establish persistent infection in humans. Whatever the case, the high prevalence of active HGV infection in the general population remains difficult to explain.

Agammaglobulinemia↗
PubMed1996

Influence of viraemia and genotype upon serological reactivity in screening assays for antibody to hepatitis C virus.

Detection of antibody to recombinant proteins derived from hepatitis C virus (HCV) genotype 1 represents the principal method for diagnosis of HCV infection. A method was developed for quantifying antibody reactivity in two third-generation enzyme immunoassays (Ortho EIA 3.0 and Murex VK48), and the influence of viraemia, HCV genotype, and host factors such as age, gender, and risk group upon antibody levels were investigated in a consecutive series of 117 anti-HCV-positive volunteer blood donors. Viraemic donors (as assessed by the polymerase chain reaction; PCR) showed significantly higher levels of anti-HCV by the Ortho EIA than those who were nonviraemic (adjusted mean difference of 10.1 fold after multiple regression analysis). The only other factor to influence significantly antibody level was genotype, where it was found that donors infected with type 1 showed 4 to 4.5 times greater serological reactivity by the Ortho assay than those infected with type 2 or 3. Antibody levels by the Ortho assay correlated closely to those detected by the Murex VK48 assay, and similar differences between PCR-positive and negative donors and between those infected with different genotypes were found. Differences in serological reactivity between genotypes indicate that a large proportion of epitopes of the type 1a or 1b recombinant proteins used in current assays are genotype specific. Variation in sensitivity of screening assays for different genotypes is of potential concern when used in countries where non-type 1 genotypes predominate in the blood donor or patient population.

Alanine Transaminase↗
PubMed1996

Relevance of RIBA-3 supplementary test to HCV PCR positivity and genotypes for HCV confirmation of blood donors.

HCV antibody screening of 624,910 blood donations resulted in 3,832 samples being referred for confirmation. All were tested by RIBA-3 with 2,710 negative, 945 indeterminate and 177 positive results. HCV RNA was detected by PCR in an average of 69.5% of RIBA-3 positives (4 bands 84.1%; 3 bands 74.1%; 2 bands 34.1%) and only 0.53% of RIBA-3 indeterminates. Eighty-four percent of samples with a total RIBA-3 band intensity score (maximum 16) of > or = 8 were PCR positive compared with only 22% of those with a score of < 8. Total mean band intensities for HCV genotype 1 samples (n = 65) were 13.2, genotype 2 (n = 17) 11.4 and genotype 3 (n = 65) 11.2 with type 1 samples showing greater reactivity with c100 and c33 antibodies. No PCR positive type 1 samples were found with RIBA-3 total band scores less than 8, no PCR positive type 2 samples less than 6, whilst PCR positive type 3 samples were found with scores as low as 2. NS5 indeterminates were the most common (40.2%) single band pattern but yielded no PCR positive samples, followed by c33 (23.3%) with one PCR positive and c100 (20.2%) with one PCR positive whilst c22 indeterminates were least common (16.3%) but included three PCR positive donors. All five RIBA-3 indeterminate PCR positive donors were type 3.

Blood Donors↗
PubMed1996

Lymphocyte responses to human cytomegalovirus in different groups of patients in Britain and in adults from west Africa and the Middle East.

Antibody prevalence and lymphocyte proliferation responses to cytomegalovirus (CMV) and herpes simplex virus (HSV) were compared in several different groups of patients: genitourinary medical (GUM) patients, hemophiliacs, men with clinical acquired immunodeficiency syndrome (AIDS) and cases of primary CMV mononucleosis, and also in adults in the general population (control subjects) comprising separate groups native to Britain, West Africa, and the Middle East. Among the British control subjects who were positive for CMV IgG, all were also positive against CMV antigen by the lymphocyte transformation test (LTT). However, among those who were CMV IgG-positive in the various groups of patients, 20-86.9% gave positive responses to CMV antigen by the LTT; moreover, 75.7% and 55.5% of the CMV IgG-positive healthy control subjects from West Africa and the Middle East, respectively, gave positive LTT responses to CMV antigen. When the same groups of patients were tested for responsiveness to HSV antigen by the LTT, there was good agreement between a positive result by this test and by serology in all except those with primary CMV mononucleosis (42.8%). Overall, lymphocyte responses to CMV were significantly impaired in healthy, CMV antibody-positive subjects from West Africa and the Middle East compared to similar subjects from Britain.

Adult↗
PubMed1996

Third-generation recombinant immunoblot assay: comparison of reactivities according to hepatitis C virus genotype.

BACKGROUND: Recombinant immunoblot assay (RIBA) is widely used as a supplemental test in hepatitis C virus (HCV) confirmatory algorithms. As this assay is based on HCV type 1, its performance was examined with the common European HCV genotypes (1, 2, and 3). STUDY DESIGN AND METHODS: A study was performed to retest in third-generation RIBA (RIBA-3) all 146 second-generation RIBA (RIBA-2)-positive polymerase chain reaction-positive samples detected by second-generation enzyme-linked immunosorbent assays and having known HCV genotypes (74 HCV type 1, 21 type 2, 51 type 3). RIBA band intensities were examined according to HCV genotype. An additional 90 RIBA-3-confirmed PCR-positive samples (47 HCV type 1, 5 type 2, 38 type 3) detected by third-generation enzyme-linked immunosorbent assays were also examined. RESULTS: In the first group of 146 samples, the RIBA-3 NS4 (c100p) band showed a marked improvement in sensitivity for the detection of HCV types 2 and 3 over that of the c100 antigen of RIBA-2, but the mean band intensities of HCV types 2 and 3 remained significantly lower than those of type 1. Improved sensitivity of the NS3 band of RIBA-3 to HCV type 3 was also apparent, but, again, the mean band intensity measured was lower for type 3 than for either type 1 or type 2. The c22 band of RIBA-2 and RIBA-3 exhibited equal sensitivity for all HCV genotypes. These differences were also apparent when RIBA-3 was used in conjunction with third-generation enzyme-linked immunosorbent assays. CONCLUSION: The current RIBA-3 lacks sensitivity to the NS4 antibody for HCV types 2 and 3. The incorporation of type-specific components to other genotypes for NS4 (and NS3) antigens should be considered by the manufacturers.

Blood Donors↗