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M Sharland

Publications and source records attributed to M Sharland.

At least 37 records · Page 2Linked to original sources
PubMed2001

Cytomegalovirus treatment options in immunocompromised patients.

Cytomegalovirus (CMV) infection was recognised in congenitally infected infants in the first half of the 20th century. Following the increased use of immunosuppressive regimens for bone marrow and solid organ transplantation, various manifestations of CMV disease were recognised. Milder symptoms included fever, anorexia and malaise but severe symptoms included pneumonitis, hepatitis, gastrointestinal ulceration, choreoretinitis and encephalopathy, all with a high morbidity or mortality. With the onset of the AIDS epidemic, manifestations of CMV became evident, predominantly retinitis. Ganciclovir used intravenously has been the principal anti-CMV agent investigated. However, ganciclovir has problems with suboptimal efficacy, toxicity, poor oral bioavailability and evolution of resistant strains. Additional studies have been performed on foscarnet and cidofovir, although the use of both have been limited by their nephrotoxicity. Combination therapy with ganciclovir and foscarnet for resistant strains has been used. There are promising newer drugs like the methylenecyclopropane nucleoside analogues and benzimidazole. The most novel compound is the antisense oligonucleotide fomivirsen that has been evaluated principally in CMV retinitis. The role of immunotherapy with either immunoglobulin prophylaxis or the novel adoptive immunotherapy needs further evaluation.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Current evidence for the use of paediatric antiretroviral therapy--a PENTA analysis. Paediatric European Network for the Treatment of AIDS Steering Committee.

UNLABELLED: The introduction of combination antiretroviral therapy has been associated with a dramatic clinical improvement in children with human immunodeficiency virus infection. However, the uptake of antiretroviral therapy has been variable across Europe. The Paediatric European Network for the Treatment of AIDS Steering Committee has performed a systematic literature review of paediatric antiretroviral therapy trials. An analysis of the evidence base for the commencement and maintenance of antiretroviral therapy was produced. Suggestions for when to commence antiretroviral therapy, which drugs to start with and how to monitor and sequence drug regimens are given. CONCLUSION: The aim of these guidelines is to help in obtaining equity of access to a uniformly high standard of care for children with human immunodeficiency virus infection in all European countries.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Basic epidemiology and immunopathology of RSV in children.

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in infants and young children. Around 20 000 RSV-infected infants require hospitalization in the UK during each yearly epidemic, which is about 3% of the birth cohort. Most children are infected by 2 years of age. Risk factors for severe disease include young infants, prematurity, chronic lung and cardiac conditions or immunodeficiency. Humoral immunity is incomplete and short-lived, yet reinfections cause less severe disease. RSV infects infants despite the presence of specific neutralizing antibodies. RSV infection can be linked to the development of individual wheezing episodes. A competent cellular immune system is necessary to reduce disease severity. RSV infection provokes an RSV-specific T-lymphocyte response with the release of cytokines. There is a delicate balance between the protective and disease-enhancing effects of the host's immune response to RSV infection.

Child↗
PubMed2000

Synergistic upregulation of interleukin-8 secretion from pulmonary epithelial cells by direct and monocyte-dependent effects of respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection is the major cause of severe bronchiolitis in infants. Pathology of this infection is partly due to excessive proinflammatory leukocyte influx mediated by chemokines. Although direct infection of the respiratory epithelium by RSV may induce chemokine secretion, little is known about the role of cytokine networks. We investigated the effects of conditioned medium (CM) from RSV-infected monocytes (RSV-CM) on respiratory epithelial (A549) cell chemokine release. RSV-CM, but not control CM (both at a 1:5 dilution), stimulated interleukin-8 (IL-8) secretion from A549 cells within 2 h, and secretion increased over 72 h to 11,360 +/- 1,090 pg/ml without affecting cell viability. In contrast, RSV-CM had only a small effect on RANTES secretion. RSV-CM interacted with direct RSV infection to synergistically amplify IL-8 secretion from respiratory epithelial cells (levels of secretion at 48 h were as follows: RSV-CM alone, 8,140 +/- 2,160 pg/ml; RSV alone, 12,170 +/- 300 pg/ml; RSV-CM plus RSV, 27,040 +/- 5,260 pg/ml; P < 0.05). RSV-CM induced degradation of IkappaBalpha within 5 min but did not affect IkappaBbeta. RSV-CM activated transient nuclear binding of NF-kappaB within 1 h, while activation of NF-IL6 was delayed until 8 h and was still detectable at 24 h. Promoter-reporter analysis demonstrated that NF-kappaB binding was essential and that NF-IL6 was important for IL-8 promoter activity in RSV-CM-activated cells. Blocking experiments revealed that the effects of RSV-CM depended on monocyte-derived IL-1 but that tumor necrosis factor alpha was not involved in this network. In summary, RSV infection of monocytes results in and amplifies direct RSV-mediated IL-8 secretion from respiratory epithelial cells by an NF-kappaB-dependent, NF-IL6-requiring mechanism.

Animals↗
PubMed2000

Hospitalisation for RSV infection in ex-preterm infants-implications for use of RSV immune globulin.

BACKGROUND: Respiratory syncytial virus (RSV) specific immune globulin is now being marketed for prevention of RSV infection in ex-preterm infants. However, there are no published UK data on the morbidity or mortality from RSV in these infants. AIMS: To determine the morbidity and mortality from RSV infection in a cohort of infants previously treated at a regional neonatal unit, and compare the cost of hospitalisation for RSV with the potential cost of administering RSV immune globulin (RSV-IG) prophylaxis. METHODS: Infants born at a gestation of less than 32 weeks were studied. Details of admissions for respiratory illness in the first two years of life were collected from hospital records, referring hospitals, and general practitioners. RESULTS: Data on 82 infants were collected. Up to three RSV seasons were encountered. The hospitalisation rate for confirmed RSV infection for the first season encountered was 4%. Rates of ward and paediatric intensive care unit admission were higher for infants with chronic lung disease. There were no deaths from RSV. RSV-IG would not have been cost effective for most infants. CONCLUSION: The morbidity and mortality rates from RSV observed in this group do not support the widespread introduction of RSV-IG prophylaxis for ex-preterm infants.

Antibodies, Monoclonal↗
PubMed2000

Current treatment options to prevent perinatal transmission of HIV.

Mother-to-infant transmission is the primary means by which young children become infected with HIV. WHO estimates approximately 1600 infants become infected with HIV every day. Recent advances in identifying the factors determining perinatal transmission have allowed interventions to be made to reduce mother-infant transmission. Paediatric AIDS Clinical Trials Group (PACTG) protocol 076, the pivotal vertical transmission study demonstrated that zidovudine (AZT) in pregnancy could reduce perinatal transmission of HIV-1 by 67%. This was confirmed by PACTG 185, in pregnant women with more advanced disease, which also demonstrated that viral load was the only independent factor determining vertical transmission rate (VTR). More recently, results from several short-course antiretroviral trials have brought new hope, that effective preventative interventions can be extended to developing countries. Although most studies have involved shorter versions of PACTG 076, the latest finding from HIVNET 012 demonstrated a significant reduction in VTR using a two-dose regimen of nevirapine (NVP). This intervention is the simplest, least expensive regimen so far with proven efficacy in diminishing mother-infant transmission. Non-pharmacological interventions have also been studied recently. The benefits of elective caesarean section (ELCS) have been clearly demonstrated in recent studies. These studies were carried out at a time when highly active antiviral therapies (HAART) were not available. There is still no information as to whether ELCS provides any added benefit for women on HAART with an undetectable HIV viral load. Prevention of breastfeeding can also further reduce VTR. This strategy is more applicable to resource-rich countries where access to formula feeds is not a problem. Options to prevent perinatal transmission must take into consideration the economic climate in which the intervention is to be made. In developed countries, effective intervention with perinatal AZT, ELCS and exclusive formula feeding has already reduced the VTR to around 1%. There is limited safety data currently available on the use of other antiretrovirals in pregnancy. A cautious approach to the use of HAART in pregnancy is recommended at present.

Adult↗
PubMed2000

Influenza.

The currently available antiviral drugs rimantadine and amantadine are effective only for influenza A viruses. Another class of influenza antiviral drugs is the neuraminidase inhibitors, which selectively inhibit both influenza A and B viruses. Recent studies have found the neuraminidase inhibitors zanamivir and oseltamivir to be 67-82% effective in preventing laboratory-confirmed infection when administered as prophylaxis during the influenza season. As treatment, they reduce the duration of illness by 1-1.5 days when started within 36-48 h of illness onset. The reported adverse effects of these drugs are minimal, and unlike amantadine and rimantadine, the drugs do not appear to affect the central nervous system. Poor oral bioavailability and rapid renal clearance limit the use of zanamivir to inhalation and concern has been raised about its use in asthmatics. The sialic acid analogue, GS4071, has been shown to be a potent inhibitor of neuraminidase activity and is shown to be effective in controlling influenza, and its prodrug form--GS4104 (oseltamivir) can be given orally. Direct comparison of zanamivir and oseltamivir, their use for prophylaxis and treatment in high-risk groups, and evaluation of their cost effectiveness are all required before they enter routine clinical practice.

Animals↗
PubMed2000

Prevention of respiratory syncytial virus infection with palivizumab.

Respiratory syncytial virus (RSV) infects virtually all children by the age of 2 yrs. Premature infants with chronic lung disease (CLD) are at risk of greater morbidity due to RSV infection. However, these infants represent a small proportion of all infants admitted to hospital with RSV infection, and hospitalization rates for this group appear to have decreased over the past decade. Prophylaxis against RSV infection has recently become available in the form of palivizumab, a humanized monoclonal antibody preparation. The IMpact trial demonstrated a 39% relative risk reduction in hospital admissions for RSV in cases in which palivizumab was administered to premature infants with CLD. However, palivizumab is a very expensive drug and cost-effectiveness analyses do not support its use in the majority of premature infants with or without CLD. The only group in which palivizumab should even be considered for use is premature infants with chronic lung disease at home on oxygen during their first respiratory syncytial virus season. In this group of infants, a detailed postlicensing audit needs to be performed to determine efficacy.

Antibodies, Monoclonal↗
PubMed1999

Upper respiratory tract infections.

In reviewing recent advances in upper respiratory tract infections, we focus on five key topics. First, the use of ribavirin in the treatment of respiratory syncytial virus infection has been limited to the immunosuppressed. Prophylaxis in high-risk patients with specific immunoglobulin is effective and a new monoclonal antibody shows promise. Second, the efficacy of neuraminidase inhibitors in the treatment of influenza has become established. There are unresolved concerns about early implementation of therapy without a firm diagnosis; resource implications are enormous. Third, an outbreak of influenza due to avian influenza virus (H5N1) raised the possibility of a new pandemic. However, there was minimal person-to-person spread although much was learned about pathogenesis of infection. Fourth, evidence favoring the use of ciprofloxacin rather than rifampicin for meningococcal chemoprophylaxis is reviewed. Efficacy in eradicating nasopharyngeal carriage is excellent. Finally, the management of sore throat has been considered. This remains controversial but evidence supporting antibiotic therapy in adults is lacking. If treatment is indicated in childhood, shorter courses of antibiotics may be effective.

Adult↗
PubMed1999

Viral loads in dual infection with HIV-1 and cytomegalovirus.

OBJECTIVE: A one year study of the relation between cytomegalovirus (CMV) and human immunodeficiency virus (HIV) viral loads in a cohort of children with vertically acquired HIV-1 infection. DESIGN: Comparative analysis of viral load measurements for CMV and HIV-1 in peripheral blood leucocytes (PBLs) of individual children in relation to age and clinical staging. METHODS: Nested polymerase chain reaction (PCR) was used to measure HIV-1 proviral DNA and CMV genomic DNA in PBLs of 56 children. RESULTS: The CMV load was highest in 0-2 year old HIV positive children with stage C disease (range, 1-7143 copies/100 ng DNA; median, 125) and was significantly lower in older children. Although higher in young children, HIV-1 viral load did not show the same marked reduction with age that is seen with CMV. Over a one year period, testing of serial samples for both viruses in a subgroup of children revealed a discordant relation between viral loads for CMV and HIV-1. CONCLUSIONS: CMV viral load falls much faster than HIV viral load in dually infected children. Screening for clinical CMV disease is most likely to be of benefit in children under 2 years of age with stage C disease. In the few children studied, levels of CMV and HIV replication appear to be independent.

Adolescent↗
PubMed1999

An abnormally long HIV-1 env DNA PCR product due to altered sequences of primer binding sites.

To investigate the generation of an abnormally long HIV-1 env PCR DNA product the latter was cloned and sequenced followed by sequence analysis of HIV-1 primer binding sites. We found that the formation of an abnormally long PCR product was due to HIV-1 env sequence alteration (a) in the reverse primer binding site resulting in faulty primer binding and (b) downstream from the forward primer sequence resulting in a new binding site with reverse complementary sequence with respect to the forward primer at the opposite end of the PCR product. Both changes led to amplification of a longer PCR product with forward primer alone. Our results indicate that the HIV-1 genetic diversity in the env gene can lead to amplification of a specific PCR product of unexpected size which can be disregarded in the absence of its cross-validation.

Adolescent↗
PubMed1999

Enterovirus infections in England and Wales: laboratory surveillance data: 1975 to 1994.

Microbiology laboratories in England and Wales reported 40,366 culture confirmed isolates of echovirus (24,628; 61%) and coxsackievirus (B 11,714; 29%, A 4024; 10%) infections to the PHLS Communicable Disease Surveillance Centre (CDSC) in the 20 years from 1975 to 1994. Nearly half of the organisms were isolated from faeces, and 5741 were isolated from cerebrospinal fluid (75% of them echovirus, 13% coxsackie B, and 12% coxsackie A). Isolation rates for all enteroviruses were highest among infants aged 1 to 2 months. Sixty per cent of patients were aged under 5 years, 10% 5 to 9 years, and only 6% 35 years or over. Predominant serotypes were similar to those reported in other countries including the United States, Finland, and Belgium. Seventy-one per cent of reports were made between July and mid December. Periodicity varied between groups and serotypes: some demonstrated peaks at intervals of two to five years. There was evidence of spread of epidemic serotypes across Europe in certain years. Data collected between March and May each year enabled the strains circulating in the following 'season' to be predicted. Such information might be used to warn clinicians to anticipate particular clinical presentations.

Adolescent↗
PubMed1998

Respiratory syncytial virus-induced RANTES production from human bronchial epithelial cells is dependent on nuclear factor-kappa B nuclear binding and is inhibited by adenovirus-mediated expression of inhibitor of kappa B alpha.

Respiratory syncytial virus (RSV) infection is an important cause of lower respiratory tract illness, the severity of which may be partly due to cellular recruitment. RSV infection activates chemokine secretion from airway epithelial cells by largely unknown mechanisms. We investigated the regulation of RSV-induced activation of the chemokine RANTES in the bronchial epithelial cell line BEAS-2B and primary normal human tracheobronchial epithelial cultures. RANTES protein and mRNA were detected at 24 h and up until 72 h from cultures of BEAS-2B infected with replicating virus, but not with UV-inactivated RSV. RSV infection of BEAS-2B or normal human tracheobronchial epithelial cells stimulated NF-kappa B translocation to the nucleus and binding to the RANTES-specific kappa B-binding sequences within 2 h, with levels peaking at 24 h. Supershift assays indicated that binding was due to p50/p65 heterodimers. BEAS-2B cells were transfected with a replication-deficient adenoviral vector, expressing a mutated, nondegradable form of I kappa B alpha. I kappa B alpha overexpression specifically blocked NF-kappa B translocation and inhibited mRNA accumulation and secretion of RANTES induced by RSV or TNF-alpha plus IFN-gamma. Adenoviral transfection did not interfere with RSV replication or significantly induce apoptosis. Further, a control adenovirus, expressing the beta-galactosidase gene, did not alter cellular functions. Thus, NF-kappa B nuclear translocation is a critical step in RSV induction of RANTES secretion. Elucidating the mechanisms of cellular activation by RSV and targeting specific areas may lead to novel therapeutic approaches in the treatment of RSV.

Adenoviridae↗
PubMed1998

Predominant enteroviral serotypes causing meningitis.

All enteroviral reports to the Public Health Laboratory Service from 1975 to 1994 which had been proved by culture were analysed. Of the 40,366 isolates, 5741 reports (14%) were from cultures of cerebrospinal fluid. The groups and serotypes accounting for the largest number of cerebrospinal fluid isolates were A9, E7, E9, E11, E19, and E30, accounting for 70% of all cultured isolates of cerebrospinal fluid. It may be possible to prevent most cases of viral meningitis in the UK with the development of an enteroviral vaccine.

Adolescent↗