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Biomedical subjects

W F Carman

Publications and source records attributed to W F Carman.

At least 55 records · Page 3Linked to original sources
PubMed1999

Failed adoptive immunity transfer: reactivation or reinfection?

A 26-year-old female bone marrow transplant (BMT) recipient was hepatitis B surface antigen (HBsAg) and hepatitis B e antibody (HBeAb) positive. The donor, her human leucocyte antigen (HLA)-compatible sister, was HBsAg negative but hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) positive. Twelve weeks post-BMT the patient became HBsAg negative, as determined using a monoclonal antibody-based assay. At 16 weeks post-BMT, HBsAg became undetectable by monoclonal and polyclonal immunoassay with seroconversion to HBsAb; however, at 24 weeks post-BMT the patient again became HBsAg positive. Both the recipient and the donor were retrospectively tested by hepatitis B virus (HBV) polymerase chain reaction (PCR) and found to be positive. The recipient displayed variants at amino acids 4 and 47 of the surface (S) gene prior to BMT. These mutations were not detected 32 weeks post-BMT when the S gene sequence was identical to that of an adr prototype. The donor was found to have four unique amino acid substitutions at positions 30, 98, 101 and 210 of the S gene. However, in vitro-expressed HBsAg from the donor was detected by commercial kits and an immunofluorescence assay, indicating that antigenic alteration did not explain HBsAg negativity. This donor highlights the value of PCR as the gold standard test for current HBV infection. It also demonstrates that discordance between two commercial HBsAg assays may not always be caused by antigenic variants. The second episode of hepatitis may theoretically have been caused by reactivation, selection of an escape mutant by HBsAb, reinfection or recombination. We suggest it was reactivation because none of the donor variants was seen in the recipient post-BMT.

Adoptive Transfer↗
PubMed1999

Treatment of chronic hepatitis B virus infection: an Asia-Pacific perspective.

Chronic hepatitis B infection is a serious health threat in the Asia-Pacific area. A consensus meeting on the treatment of chronic hepatitis B infection was conducted in Hong Kong, in August 1997. It was generally agreed that treatment of chronic hepatitis B infection should be based on the understanding of the natural history of chronic hepatitis B infection. To date, interferon alpha is the only Food and Drug Administration (FDA)-approved form of therapy for chronic hepatitis B infection. The overall response in Asian patients is unsatisfactory: approximately 15-20% will clear hepatitis B e antigen, but less than 5% will clear hepatitis B surface antigen. Newer immunomodulatory therapies are under trial. In contrast, nucleoside analogues, such as lamivudine (pending FDA approval) and famciclovir, have been shown to be potent suppressors of hepatitis B viral replication; however, their role as monotherapy in the treatment of chronic hepatitis B infection remains to be defined. Also, the issues of resistance to nucleoside analogues and withdrawal rebound need to be carefully studied. The future direction of therapy in chronic hepatitis B infection is probably a combination of nucleoside analogues or nucleoside analogues with immunomodulatory therapy.

2-Aminopurine↗
PubMed1999

Serological response to influenza vaccination and nutritional and functional status of patients in geriatric medical long-term care.

INTRODUCTION: in the UK the Department of Health recommends influenza vaccination for elderly people resident in institutional care. However, the efficacy of vaccination may be reduced in very frail elderly people with functional impairment, undernutrition and multiple pathologies. Nutritional and functional status is claimed to affect vaccine responses in healthy elderly subjects. We wished to determine if a relationship could be seen between nutritional and functional status and seroconversion in patients receiving long- term care. METHODS: all patients in geriatric medical long-term care were offered vaccine. Consenting patients had pre- and post-vaccine serology measured using single radial haemolysis. Anthropometry was measured to enable body mass index (BMI) to be calculated. Functional independence was assessed using the 20-point Barthel index. RESULTS: of 260 patients who received influenza vaccine, 137 (36 male, 101 female) consented to venesection for serology and thus form the study population. Mean age was 82 years (SD 7.9). The median Barthel score was 3/20 and the mean BMI was 21.6 (SD 4.6, range 13-36.2). Antibodies to influenza A were undetectable both pre- and post-vaccination in 63/137 patients. In 49 patients the antibody titre rose after vaccination and 25 had detectable antibody titres pre-vaccination which failed to rise post-vaccine. There were no significant associations between post-vaccination influenza antibody responses and BMI, Barthel score or age. CONCLUSION: frail elderly patients in geriatric medical long-term care had a poor antibody response to influenza vaccination. Within this group, serological responses could not be predicted by nutritional or functional status.

Aged↗
PubMed1999

T1762/A1764 variants of the basal core promoter of hepatitis B virus; serological and clinical correlations in Chinese patients.

BACKGROUND: A double variant in the basal core promoter, converting nucleotide 1762 from A to T (T1762) and nucleotide 1764 from G to A (A[764), has been described in patients with chronic hepatitis B infection. Its prevalence and significance in Chinese chronic HBV carriers are unknown. METHODS: We studied 177 Chinese patients with chronic HBV infection (chronic hepatitis/asymptomatic: 89/88; hepatitis B e antigen positive/negative: 84/93). The double variant was detected by mismatched polymerase chain reaction and restriction fragment length polymorphism analysis. The reliability of this method was verified by sequencing in 41 serum samples with 100% matching. RESULTS: The double variant T1762/ A1764 was found in 52 of 89 patients with chronic hepatitis, but in only 6 of 59 asymptomatic carriers (p<0.001). The prevalence was significantly lower in hepatitis B e antigen positive patients (23/84) than in hepatitis B e antigen negative patients (35/64) (p<0.005). Precore variant, A1896 was detected in 40 individuals; 31 of them suffered from chronic hepatitis and 9 were asymptomatic (p<0.001). A combination of both variants T1762/A1764 and A1896 was seen in 3 of 59 asymptomatic and 22 of 89 patients with chronic hepatitis (p<0.005). CONCLUSIONS: Mismatched polymerase chain reaction with restriction fragment length polymorphism provides a reliable, easy and fast method for detection of the presence of the T1762/A1764 variant. In Chinese chronic hepatitis B carriers, T1762/A1764 variant was associated with both active liver disease and hepatitis B e antigen negativity.

Adult↗
PubMed1999

Selection of hepatitis B surface "escape" mutants during passive immune prophylaxis following liver transplantation: potential impact of genetic changes on polymerase protein function.

CASE REPORT: A patient is described who developed hepatitis B virus (HBV) reinfection five months following liver transplantation. Failure of hepatitis B immunoglobulin prophylaxis was associated with the emergence of mutations. HBV gene sequencing identified nucleotide substitutions associated with amino acid changes, one within the major hydrophilic region (MHR) of the HBV surface antigen at amino acid position 144 and one outside the MHR. Because of the overlapping reading frames of surface and polymerase genes, the latter surface antigen change was associated with an amino acid change in the polymerase protein. The patient developed significant allograft hepatitis and was treated with lamivudine (3TC) 100 mg daily. Rapid decline of serum HBV DNA was observed with loss of HBV e antigen and HBV surface antigen from serum. There was normalisation of liver biochemistry, and liver immunohistochemistry showed a reduction in HBV core and disappearance of HBs antigen staining. CONCLUSION: Surface antigen encoding gene mutations associated with HBIg escape may be associated with alteration of the polymerase protein. The polymerase changes may affect sensitivity to antiviral treatment. Selection pressure on one HBV reading frame (for example, HBIg pressure on HBsAg, or nucleoside analogue pressure on polymerase protein) may alter the gene product of the overlapping frame. Such interactions are relevant to strategies employing passive immune prophylaxis and antiviral treatment.

Aged↗
PubMed1999

Age related prevalence of hepatitis G virus in South Africans.

AIM: To investigate the age related prevalence of hepatitis G virus (HGV) infection and its mode of transmission in relation to hepatitis B (HBV) and C (HCV) co-infection in South African blacks. METHODS: Reverse transcriptase polymerase chain reaction was performed to detect active infection, using primers for the 5'-NCR, NS5a, and NS3 regions. Antibodies to HGV envelope-2 protein (anti-E2), which measures past infection, were also sought. RESULTS: The overall prevalence of active infection was 116/580 (20%). A higher prevalence was noted in HBsAg carriers (28/106; 26.4%) and HCV positive subjects (25/82; 30.5%). In contrast to developed countries, active and past infection was seen in 12.9% and 12.1% of the general population, respectively (subjects negative for HBsAg and anti-HCV markers and with normal alanine aminotransferase values), with a total prevalence of 21.1% (52/248). Viraemia and anti-E2 were almost mutually exclusive. The distribution of viraemia by age was: < or = 15 years, 20/223 (9.0%); 16-35 years, 42/147 (28.6%); > or = 36 years, 37/151 (24.5%), with a significant difference (p = 0.001) in age related prevalence. A similar trend was observed for the prevalence of past infection in the general population. CONCLUSIONS: HGV infection begins in childhood and increases with age in South Africa, but transmission is largely independent of HBV and HCV. No association was found between HGV viraemia and hepatitis, or with co-infection with either HBV or HCV.

Adolescent↗
PubMed1998

Core variability does not affect response to interferon alpha in HBeAg negative chronic hepatitis B.

BACKGROUND/AIMS: The pre-core stop codon variant (A 1896) of hepatitis B virus (HBV) has been associated with chronic active liver disease with acute exacerbations and a high relapse rate after an initial response to alpha-interferon (IFN-alpha) therapy. Poor sustained response has been correlated with a high prevalence of mutations in the core region, potentially enabling escape from the immune system. The aim of this study was to analyse the predictive factors of response to IFN-alpha in such patients. METHODS: We studied the baseline clinical, biochemical, histological, serological and virological parameters in 30 hepatitis B s antigen positive (HBsAg-positive)/hepatitis B e antigen negative (HBeAg-negative) Greek patients with chronic liver disease. The patients were selected from a cohort who received IFN-alpha for 24 weeks. These were divided into three groups of ten sequential patients: those with no response to IFN-alpha treatment, those who relapsed after an initial response, and those with a sustained response. Serum HBV DNA was measured by a liquid hybridisation method, and the anti-HBc IgM was quantitated by the IMx analyser. The amino-acid sequence of core protein residues 40-89, a region where a clustering of mutations has been detected previously in severe hepatitis, was compared with a sequence from an HBeAg positive patient with chronic liver disease. RESULTS: Multiple logistic regression analysis showed that the initial response to IFN-alpha could be predicted by pre-treatment absence of HBcAg staining in the liver and high ALT values, but no parameter could predict sustained response. The pre-treatment extent and pattern of aminoacid substitutions in the core region sequenced was similar in all groups studied and was not associated with IFN-alpha response. CONCLUSIONS: In HBsAg-positive/HBeAg-negative patients with chronic liver disease, response to IFN-alpha therapy was not correlated with genomic variability of the core region. Other parameters such as pre-treatment HBcAg positivity in the liver and alanine aminotransferase values indicative of disease activity before treatment were associated with initial IFN-alpha response.

Adult↗
PubMed1998

Current status of HBV vaccine escape variants--a mathematical model of their epidemiology.

We present a deterministic model of the possible emergence of a vaccine escape variant of hepatitis B virus (HBV). The model identifies the key unknowns determining this process: the protection afforded by the current vaccines against particular HBV variants; the infectiousness of these variants; and the current prevalence of individuals infectious with the variants (each factor relative to wild-type). By making pessimistic assumptions about these unknowns we show that even a highly infectious variant, under a vaccine programme that affords no protection against the variant, would still take decades to emerge. Thus the current low prevalence of variants is not evidence for the cross-reactivity of the current vaccines or for a lack of infectiousness in the variants. As any vaccine failure will be inapparent for decades it may be sensible to recommend vaccine modifications now rather than later.

Hepatitis B Vaccines↗
PubMed1998

Infections associated with medical intervention: hepatitis viruses and HGV.

Transfusion and other medical interventions, as well as their non-medical derivatives, have a lot to answer for. Much of HCV infection can be traced back to this route, HGV is still being transmitted in this way and a substantial proportion of HBV in Africa has been spread around by use of contaminated skin-piercing manoeuvres, medical or otherwise. Many practitioners can still remember the days when blood-borne viruses were not a major feature of medical curricula. Unfortunately, patients currently subjected to cost-cutting medical practices, for example use of unscreened blood and re-use of needles, will have to pay the price in years to come. The evolution of these viruses is linked to their route of introduction, but the relationship between variability and clinical outcome is less certain. Nevertheless, variability is important for clinical practice, especially for the design of sensitive diagnostics and highly effective vaccines.

Cross Infection↗
PubMed1998

HGV: the identification, biology and prevalence of an orphan virus.

Hepatitis G virus (HGV) and GB virus C (GBV-C) (both hereinafter referred to as HGV) were independently identified in patients with hepatitis of unknown aetiology. HGV is a positive-sense RNA virus of the family Flaviviridae. The virus can establish both acute and chronic infection and appears to be sensitive to interferon. Horizontal transmission is mainly parenteral, although other routes such as vertical have been well documented. High risk groups include intravenous drug users (i.v.DUs), the multiply transfused, haemodialysis patients and haemophiliacs. Up to 90% of i.v.DUs are positive for either HGV-RNA or antibodies to HGV envelope-2 protein (anti-E2). HGV is frequently detected in patients with HBV and HCV infection. Its link to hepatitis has now become less certain. Only around 3-6% of non-A E hepatitis cases are HGV viraemic, clearly showing that HGV is not the major cause of idiopathic hepatitis as originally hoped. Around 1-5% of volunteer blood donors in developed countries are HGV viraemic, but the prevalence is 10-20% in the general population in some developing countries. At present, it is not known whether HGV is associated with other diseases in humans, is a passenger virus, or only becomes virulent under certain conditions.

Developing Countries↗
PubMed1998

Use of PCR in resolving diagnostic difficulties potentially caused by genetic variation of hepatitis B virus.

AIMS: To assess the relevance of genetic variants of hepatitis B virus (HBV) and to demonstrate the usefulness of the polymerase chain reaction (PCR) in cases of HBV diagnostic difficulty. METHODS: Five serum samples from patients that presented diagnostic difficulty in routine laboratories were sent to a research laboratory for PCR, and if appropriate, S gene sequencing, in vitro expression, and antigenic analysis. RESULTS: The demonstration of HBV in serum by PCR allowed a definitive diagnosis of current infection. One serum sample with poor reactivity in a diagnostic assay had a minor hepatitis B surface antigen (HBsAg) variant and another with very poor reactivity had multiple variants of HBsAg. Transient HBsAg reactivity was observed in a recently vaccinated patient. A hepatitis Be antigen (HBeAg) false positive reaction was noted in a patient from a well defined risk group for HBV. One patient who was strongly HBsAg/HBeAg positive, but anti-hepatitis B core antibody negative, was viraemic. CONCLUSIONS: PCR may become the gold standard for the diagnosis of current HBV infection. HBV variants are responsible for a proportion of diagnostically difficult cases. Modification of commercial assays is necessary to increase the sensitivity of detection of such variants.

Adult↗
PubMed1997

Transmission of a homogenous hepatitis B virus population of A1896-containing strains leading to mild resolving acute hepatitis and seroconversion to hepatitis B e antigen antibodies in an adult.

The pre-core variant, A1896, which switches off hepatitis B e antigen (HBeAg) production, is common in hepatitis B e antigen antibody (anti-HBe)-positive chronic hepatitis patients. It has been observed in occasional case reports of acute hepatitis. However, transmission in the absence of HBeAg-producing strains, leading to acute nonfulminant hepatitis and clearance in adults, has not been reported. Here, we show that this event can occur, further confirming that A1896 strains are "wild-type" and can lead to all the same outcomes as G1896 strains. This is in keeping with phylogenetic evidence that A1896 is transmitted independently on a large scale in the population and explains anti-HBe- positive persons who have not had an HBeAg-positive phase documented.

DNA Primers↗
PubMed1997

The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia.

Three assays, one based on monoclonal antibodies and the others on polyclonal antibodies, were employed to detect hepatitis B surface antigen (HBsAg)-reactive samples in both vaccinated and unvaccinated populations in areas of the world where hepatitis B virus (HBV) is endemic. Any discordant sera were tested by polymerase chain reaction (PCR) to confirm current infection, and sequence data were obtained from the DNA coding for the major hydrophilic region (MHR) of HBsAg of those samples positive for PCR. In all countries studied, samples that reacted in one HBsAg assay but not another were found. In the most extreme case, about 5% of viremic sera in Papua New Guinea were nonreactive in the monoclonal HBsAg assay; 9 of the 13 PCR-positive samples had novel or once-described variants, or a variant out of its usual genotype context. In South Africa, samples with sequences of subtype ayw2 reacted poorly, particularly in the polyclonal assay. Two had novel variants. In Sardinia, antibody to hepatitis B core antigen (anti-HBc) was analyzed as a marker of infection. A significant proportion of anti-HBc-positive, but monoclonal HBsAg-negative, vaccinees and unvaccinated persons were found to be PCR positive, as were some individuals without any markers of hepatitis B virus infection. Five more novel variants were found in these groups. There are implications for the design of HBsAg assays, which may have to be modified according to local sequence variability. Not all discordant samples were explained by variants, indicating that assay sensitivity is fundamental to diagnostic efficacy. Overall, this study defined 16 novel variants and 2 new potential epitope clusters.

Amino Acid Sequence↗
PubMed1997

Hepatitis B virus core protein mutations are concentrated in B cell epitopes in progressive disease and in T helper cell epitopes during clinical remission.

The distribution and temporal and clinical features of amino acid substitutions of the core protein of hepatitis B (HB) virus were analyzed, using at least 2 sequential samples from 27 patients. Six patients seroconverted from HBe antigen (HBeAg)-positive to anti-HBe-positive (3 went into remission), and 21 were continuously anti-HBe positive with progressive hepatitis. Precore mutations, which terminate HBeAg translation, all appeared by the second sample. Most core mutations occurred between the first and second samples; significantly fewer occurred after the second. In seroconverters who went into remission, mutations occurred in the T helper epitope from aa 50 to 69 (P = .00045); for anti-HBe-positive patients with ongoing disease, mutations occurred in B cell epitopes (P = .0007 for aa 74-83). An ineffective anti-HBc B cell response accounts for ongoing disease and selection of mutations after seroconversion. In those who remit, mutations in the major T helper epitope allow immune escape, thus minimizing immune-mediated hepatitis.

Adult↗
PubMed1997

Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients.

Vaccination of health care workers (HCWs) is recommended as a strategy for preventing influenza in elderly patients in long-term care. However, there have been no controlled studies to show whether this approach is effective. During the winter of 1994-1995, 1059 patients in 12 geriatric medical long-term-care sites, randomized for vaccination of HCWs, were studied. In hospitals where HCWs were offered vaccination, 653 (61%) of 1078 were vaccinated. Vaccination of HCWs was associated with reductions in total patient mortality from 17% to 10% (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.40-0.80) and in influenza-like illness (OR, 0.57; 95% CI, 0.34-0.94). Vaccination of patients was not associated with significant effects on mortality (OR, 1.15; 95% CI, 0.81-1.64). Results of this study support recommendations for vaccination against influenza of HCWs in long-term geriatric care. Vaccination of frail elderly long-term-care patients may not give clinically worthwhile benefits.

Aged↗
PubMed1997

The clinical significance of surface antigen variants of hepatitis B virus.

Hepatitis B surface antigen (HBsAg) is not only critical to the biology of hepatitis B virus (HBV), it is also the basis of the currently available vaccines, assays to detect it in serum are crucial for diagnosis of infection and antibodies against it are used clinically to suppress infection of transplanted livers. All of these rely on antigenic interactions between HBsAg and HBsAb. Thus, it should not be surprise that changes in epitopes will affect all these situations. It is useful to classify such changes simplistically as variants, found in natural isolates, and mutants, which are observed to emerge, usually under immunological pressure, often medical in origin. The former tend to affect the sensitivity of diagnostic assays and the latter allow escape of viruses in vaccinees and those being treated with HBsAb. The majority of these changes cluster in the hydrophilic central core of HBsAg, from aa99 up to 169. They are gaining importance as causes of mistaken diagnosis and are associated with infection of vaccinees and transplanted livers. There is a danger that they will become the dominant strains as vaccination becomes universal. More data are required on the epidemiology and antigenicity of these changes.

Amino Acid Sequence↗