Effect of ethnicity on care pathway and outcomes in patients hospitalized with influenza A(H1N1)pdm09 in the UK.

Data were extracted from the case records of UK patients admitted with laboratory-confirmed influenza A(H1N1)pdm09. White and non-White patients were characterized by age, sex, socioeconomic status, pandemic wave and indicators of pre-morbid health status. Logistic regression examined differences by ethnicity in patient characteristics, care pathway and clinical outcomes; multivariable models controlled for potential confounders. Whites (n = 630) and non-Whites (n = 510) differed by age, socioeconomic status, pandemic wave of admission, pregnancy, recorded obesity, previous and current smoking, and presence of chronic obstructive pulmonary disease. After adjustment for a priori confounders non-Whites were less likely to have received pre-admission antibiotics [adjusted odds ratio (aOR) 0·43, 95% confidence interval (CI) 0·28-0·68, P < 0·001) but more likely to receive antiviral drugs as in-patients (aOR 1·53, 95% CI 1·08-2·18, P = 0·018). However, there were no significant differences by ethnicity in delayed admission, severity at presentation for admission, or likelihood of severe outcome.

Virus shedding and environmental deposition of novel A (H1N1) pandemic influenza virus: interim findings.

BACKGROUND: The relative importance of different routes of influenza transmission, including the role of bioaerosols, and ability of masks and/or hand hygiene to prevent transmission, remains poorly understood. Current evidence suggests that infectious virus is not typically released from adults after 5 days of illness, however, little is known about the extent to which virus is deposited by infected individuals into the environment and whether deposited virus has the ability to infect new hosts. Further information about the deposition of viable influenza virus in the immediate vicinity of patients with pandemic influenza is fundamental to our understanding of the routes and mechanisms of transmission. OBJECTIVES: To collect data on patients infected with pandemic H1N1 2009 (swine flu). Primary objectives were to correlate the amount of virus detected in a patient's nose with that recovered from his/her immediate environment, and with symptom duration and severity. Secondary objectives were to describe virus shedding and duration according to major patient characteristics: adults versus children, and those with mild illness (community patients) versus those with more severe disease (hospitalised patients). METHODS: Adults and children, both in hospital and from the community, who had symptoms of pandemic H1N1 infection, were enrolled and visited every day during follow-up for a maximum of 12 days. Symptom data was collected and samples were taken, including nose swabs and swabs from surfaces and objects around patients. Samples of air were obtained using validated sampling equipment. The samples were tested for the presence of pandemic H1N1 virus, using polymerase chain reaction (PCR) to detect virus genome and an immunofluorescence technique to detect viable virus. RESULTS: Forty-three subjects were followed up, and 19 of them were subsequently proven to be infected with pandemic H1N1 virus. The median duration of virus shedding from the 19 infected cases was 6 days when detection was performed by PCR, and 3 days when detection was performed by a culture technique. Over 30% of cases remained potentially infectious for at least 5 days. Only 0.5% of all community and none of the hospital swabs taken revealed virus on surfaces. Five subjects had samples of the air around them collected and virus was detected by PCR from four; some of the air particles in which virus was detected were small enough to be inhaled and deposited deep in the lungs. LIMITATION: Small number of subjects recruited. CONCLUSIONS: The finding that over 30% of infected individuals have infectious virus in their noses for 5 days or more has infection control implications. The data suggest that contact transmission of pandemic influenza via fomites may be less important than previously thought, but transmission via bioaerosols at short range may be possible, meaning that high-level personal protective equipment may be needed by health-care workers when attending patients with pandemic influenza. Further work is being undertaken to consolidate these findings, as they have important potential implications for the protection of health-care workers and the formulation of advice to households, nationally and internationally.

Risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May-September 2009).

BACKGROUND: During the first wave of pandemic H1N1 influenza in 2009, most cases outside North America occurred in the UK. The clinical characteristics of UK patients hospitalised with pandemic H1N1 infection and risk factors for severe outcome are described. METHODS: A case note-based investigation was performed of patients admitted with confirmed pandemic H1N1 infection. RESULTS: From 27 April to 30 September 2009, 631 cases from 55 hospitals were investigated. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged > or = 65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physician-recorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically-confirmed pneumonia and a raised C-reactive protein (CRP) level (> or = 100 mg/l). 59% of all in-hospital deaths occurred in previously healthy people. CONCLUSIONS: Pandemic H1N1 infection causes disease requiring hospitalisation of previously fit individuals as well as those with underlying conditions. An abnormal chest x-ray or a raised CRP level, especially in patients who are recorded as obese or who have pulmonary conditions other than asthma or COPD, indicate a potentially serious outcome. These findings support the use of pandemic vaccine in pregnant women, children <5 years of age and those with chronic lung disease.

Observational study to investigate vertically acquired passive immunity in babies of mothers vaccinated against H1N1v during pregnancy.

OBJECTIVE: The primary objective was to determine the proportion of babies who acquired passive immunity to A/H1N1v, born to mothers who accepted vaccination as part of the national vaccination programme while pregnant (during the second and/or third trimesters) against the novel A/H1N1v influenza virus (exposed group) compared with unvaccinated (unexposed) mothers. DESIGN: An observational study at three sites in the UK. The purpose was to determine if mothers immunised against A/H1N1v during the pandemic vaccination period transferred that immunity to their child in utero. SETTING: Three sites in the UK [Queen's Medical Centre, Nottingham; City Hospital, Nottingham (both forming University Hospitals Nottingham), and Leicester Royal Infirmary (part of University Hospitals Leicester)]. PARTICIPANTS: All pregnant women in the second and third trimester presenting at the NHS hospitals above to deliver were eligible to participate in the study. Women were included regardless of age, social class, ethnicity, gravida and parity status, past and current medical history (including current medications), ethnicity, mode of delivery and pregnancy outcome (live/stillbirth). INTERVENTIONS: At enrolment, participants provided written consent and completed a questionnaire. At parturition, venous cord blood was obtained for serological antibody analysis. Serological analysis was undertaken by the Respiratory Virus Unit (RVU), Health Protection Agency (HPA) Centre for Infections, London. MAIN OUTCOME MEASURES: The primary end point in the study was the serological results of the cord blood samples for immunity to A/H1N1v. Regarding a suitable threshold for the determination of a serological response consistent with clinical protection, this issue is somewhat complex for pandemic influenza. The European Medicines Agency (EMEA) Committee for Human Medicinal Products (CHMP) judges that a haemagglutination inhibition (HI) titre of 1 : 40 is an acceptable threshold. However, this level was set in the context of licensing plain trivalent seasonal vaccine, where a titre of 1 : 40 is but one of several related immunogenicity criteria, and supported by paired sera capable of demonstrating a fourfold rise in antibody titre in response to vaccination. The current study mainly investigated the effects of an AS03-adjuvanted monovalent vaccine, and it was not possible to obtain paired sera where the initial sample was taken before vaccination (in vaccinated subjects). Of possibly greater relevance is the fact that it has been established from the study of early outbreaks of pandemic influenza in secondary schools in the UK (HPA, unpublished observations) that an HI antibody titre of 1 : 32 seems to be the threshold for a humoral response to 'wild-type' A/H1N1v infection. On that basis, a threshold of 1 : 32 is at least as appropriate as one of 1 : 40, especially in unvaccinated individuals. Given the difficulties that would accrue by applying thresholds of 1 : 32 in unvaccinated patients and 1 : 40 in vaccinated patients, we have therefore applied a threshold of 1 : 32 and 1 : 40, to increase the robustness of our findings. Differences arising are described. A microneutralisation (MN) titre of 1 : 40 may be also used, although it is not part of the CHMP criteria for vaccine licensure. Nonetheless, we utilised this analysis as a secondary end point, based on a conservative threshold of 1 : 60. RESULTS: Reverse cumulative distribution percentage curves for haemagglutinin dilution and MN titres demonstrate background immunity in babies of unvaccinated mothers of 25%-30%. Humoral immunity in babies of vaccinated mothers was present in 80% of the group. The difference in positive immunity between the babies of unvaccinated and vaccinated mothers was statistically significant (chi-squared test, p < 0.001). CONCLUSIONS: Our findings reveal a highly significant difference in HI titres between babies born to mothers vaccinated with pandemic-specific vaccine against A/H1N1v during the 2009-10 pandemic period. The subjects recruited were comparable from a baseline perspective and thus do not represent different groups that otherwise could have introduced bias into the study. Continued circulation of 2009 A/H1N1-like viruses is uncertain, but is possible as seasonal influenza in years to come. It is possible that future seasonal waves may display increased virulence. Given the adverse outcomes experienced for a small proportion of pregnant women during the influenza pandemic of 2009-10, this study provides useful evidence to support vaccination in pregnancy to protect both the mother and baby. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A randomised, partially observer blind, multicentre, head-to-head comparison of a two-dose regimen of Baxter and GlaxoSmithKline H1N1 pandemic vaccines, administered 21 days apart.

OBJECTIVES: To evaluate the immunogenicity of a two-dose schedule of Baxter cell-cultured, non-adjuvanted, whole-virion H1N1 vaccine, and GlaxoSmithKline AS03(A)-adjuvanted split-virion H1N1 vaccine with respect to the EU Committee for Medicinal Products for Human Use (CHMP) and the US Food and Drug Administration (FDA) licensing criteria. DESIGN: An age-stratified, randomised, observer-blind, parallel-group, multicentre controlled trial was carried out in volunteers aged ≥ 18-44, ≥ 45-64 and ≥ 65 years. SETTING: Three teaching hospitals in the UK (Leicester Royal Infirmary, Leicester; Nottingham City Hospital, Nottingham; and Royal Hallamshire Hospital, Sheffield). PARTICIPANTS: Three hundred and forty-seven subjects were identified and randomised to AS03(A)-adjuvanted split-virion H1N1 vaccine or whole-virion (WV) vaccine in age groups [≥ 18-44 years (n = 140), ≥ 45-64 years (n = 136) and ≥ 65 years (n = 71)]. INTERVENTIONS: Vaccine was administered by intramuscular injection into the deltoid muscle of the non-dominant arm. One hundred and seventy-five randomised subjects were allocated AS03(A)-adjuvanted split H1N1 vaccine; one hundred and sixty-nine subjects had a second dose of the same vaccine 21 days later. One hundred and seventy-two subjects were allocated WV vaccine; one hundred and seventy-one subjects had a second dose of the same vaccine 21 days later. Serum samples for antibody measurements were collected on days 0 (before the first vaccination), 7, 14, 21 (before the second vaccination), 28, 35, 42 and 180. Subjects were observed for local and systemic reactions for 30 minutes after each injection, and for the next 7 days they recorded, in self-completed diaries, the severity of solicited local (pain, bruising, erythema and swelling) and systemic symptoms (chills, malaise, muscle aches, nausea and headache), oral temperature and use of analgesic medications. MAIN OUTCOME MEASURES: Vaccine immunogenicity using the CHMP and the FDA licensing criteria. Antibody titres were measured using haemagglutination inhibition (HI) and microneutralisation (MN) assays at baseline and 7, 14 and 21 days after each vaccination and at day 180. The three immunogenicity criteria end points were the seroprotection rate, the seroconversion rate and the mean-fold titre elevation. RESULTS: Both vaccine doses were given in 340 subjects (98%). Data from 680 (99%) of 687 issued diary cards were returned. Sera were obtained from 340 (98.0%), 333 (96.0%), 341 (98.3%), 331 (95.4%), 329 (94.8%) and 332 (95.7%) subjects on days 7, 14, 21, 28, 35 and 42, respectively. Three hundred and forty-six and 345 subjects were included in the safety and immunogenicity analyses, respectively. Prevaccination antibody was detected by HI (titre ≥ 1 : 8) and MN (titre ≥ 1 : 10) in 14% and 31% of subjects, respectively. Among the 298 (85.9%) subjects without baseline antibody on HI assay, a titre of ≥ 1 : 40 (seroprotection) was achieved after a single dose of AS03(A)-adjuvanted vaccine and WV vaccine by day 21 in 93.0% and 65.5%, respectively, of subjects between 18 and 44 years, 76.4% and 36.1% of subjects between 45 and 64 years, and 53.1% and 30.0% of subjects ≥ 65 years. Among all 347 subjects, a titre of ≥ 1 : 40 was achieved after a single dose of AS03(A)-adjuvanted vaccine and WV vaccine by day 21 in 94.0% and 71.4%, respectively, of subjects between 18 and 44 years, 77.3% and 38.8% of subjects between 45 and 64 years, and 51.4% and 32.4% of subjects ≥ 65 years. The age-adjusted odds ratio (OR) for adjuvanted compared with WV vaccine, in terms of seroprotection, was 4.42 [95% confidence interval (CI) 2.63 to 7.44, p < 0.001]. On day 42, among subjects without baseline antibody on HI assay, a titre of ≥ 1 : 40 was achieved after the second dose of AS03(A)-adjuvanted vaccine and WV vaccine by 100% and 67.9%, respectively, of subjects between 18 and 44 years, 89.3% and 41% of subjects between 45 and 64 years, and 76.5% and 34.5% of subjects ≥ 65 years. Among all 347 subjects, a titre of ≥ 1 : 40 was achieved on day 42 after the second dose of AS03(A)-adjuvanted vaccine and WV vaccine in 100% and 73.1%, respectively, of subjects between 18 and 44 years, 90.8% and 43.9% of subjects between 45 and 64 years, and 75.7% and 36.4% of subjects ≥ 65 years. The age-adjusted OR for adjuvanted vaccine compared with WV vaccine, in terms of seroprotection, was 11.21 (95% CI 5.80 to 21.64, p < 0.001). Age-related decline in antibody response occurred after both doses of both vaccines. WV vaccine was associated with fewer local and systemic reactions and lower immune responses than was AS03(A)-adjuvanted vaccine. The most frequent solicited local event was pain, reported by 28% and 76% of subjects after either dose of WV or adjuvanted vaccine, respectively (OR 7.71, 95% CI 4.48 to 13.24, p < 0.0001). The most common systemic event was myalgia, reported by 24% and 49% of subjects after either dose of WV or adjuvanted vaccine (OR 2.99, 95% CI 1.86 to 4.80, p < 0.0001). CONCLUSIONS: AS03(A)-adjuvanted 2009 H1N1 vaccine is more immunogenic and provides greater antigen-sparing capacity than WV 2009 H1N1 vaccine. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92328241. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 14, No. 55. See the HTA programme website for further project information.

The cost-effectiveness of influenza vaccination of healthy adults 50-64 years of age.

Influenza can cause significant morbidity and mortality. Influenza vaccination is an effective and safe strategy in the prevention of influenza. Currently the National Health Service (NHS) vaccinates 'at-risk' individuals only. This definition includes everyone over 65 years of age but excludes individuals 50-64 years of age unless they have an additional risk factor, such as underlying heart disease or lung disease. In order to examine the cost-effectiveness of an extension of the vaccination policy to include this age group we constructed an economic model to estimate the costs and benefits of vaccination from both a health service and a societal perspective. Data to populate the model was obtained from the literature and the outcome measure used was the quality adjusted life year (QALY). Influenza vaccination prevented an estimated 4508 cases (95% CI: 2431-7606) per 100,000 vaccinees per influenza season for a net cost to the NHS of pound653,221 (95% CI: 354,575-1,072,257). The net cost increased to pound1,139,069 (95% CI 27,052-2,030,473) when non-NHS costs were included and the estimated cost-per-QALY were pound6174 and pound10,766 for NHS and all costs respectively. Extension of the current immunisation policy has the potential to generate a significant health benefit at a comparatively low cost.

Detection of anti-H5 responses in human sera by HI using horse erythrocytes following MF59-adjuvanted influenza A/Duck/Singapore/97 vaccine.

Haemagglutination-inhibition (HI) tests are a simple method used to assess immune responses to influenza haemagglutinin. However, HI tests are insensitive at detection of antibody responses to avian haemagglutinin after vaccination or natural infection, even in the presence of high titres of neutralising antibody or virus isolation. Avian influenza viruses preferentially bind to sialic acid receptors that contain N-acetylneuraminic acid alpha2,3-galactose (alpha2,3Gal) linkages while human viruses preferentially bind to those containing N-acetylneuraminic acid alpha2,6-galactose (alpha2,6Gal) linkages. By using horse erythrocytes in the HI test and thereby increasing the proportion of alpha2,3Gal linkages available for binding, we are able to demonstrate improved detection of antibody to avian H5 in human sera following vaccination with MF59-adjuvanted A/Duck/Singapore/97 surface antigen vaccine. This modified HI test was more sensitive in detection of anti-H5 antibody evoked by revaccination of primed subjects and may be useful in assessing potential avian HA vaccine candidates.

Sialic acid receptor specificity on erythrocytes affects detection of antibody to avian influenza haemagglutinin.

Haemagglutination-inhibition tests (HI) are used to detect increases in influenza antibody in serum. However, they are relatively insensitive for the detection of human antibody responses to avian haemagglutinin, even in the presence of high titres of neutralising antibody after confirmed infection or vaccination. Human influenza viruses bind preferentially sialic acid containing N-acetylneuraminic acid alpha2,6-galactose (SAalpha2,6Gal) linkages while avian and equine viruses bind preferentially those containing N-acetylneuraminic acid alpha2,3-galactose (SAalpha2,3Gal) linkages. Increasing the proportion of SAalpha2,3Gal linkages on the erythrocytes used, by enzymatic modification or change of species, improves the ability of erythrocytes to bind to avian influenza strains and thereby improves the sensitivity of detection of antibody to avian and equine HA in a range of mammalian and human sera using HI tests.

Experience with the clinical development of influenza vaccines for potential pandemics.

During normal interpandemic influenza seasons, immune responses to vaccines are quite predictable and meet the licensing criteria of the European Union (EU) Committee for Proprietary Medicinal Products (CPMP). In a pandemic situation, large sections, if not all of the community will be immunologically naïve and therefore new immunisation strategies will be needed. In 1976 and 1977 H1N1 vaccines were prepared and tested clinically. To stimulate 'protective' antibody responses, two doses of vaccine were needed in people below the age of 24 years (no previous experience of H1N1 virus), whereas one conventional dose was adequate in older people. In 1997, the highly pathogenic avian influenza H5N1 virus caused widespread concern when it infected man, with lethal effects. Due to safety concerns it was necessary to adopt new strategies for vaccine development and one such strategy was to produce vaccine from an avirulent H5N3 virus, A/Duck/Singapore-Q/F119-2/97. Clinical trials of a subunit vaccine prepared from A/Duck/Sing/97 virus revealed that even two doses of twice the normal vaccine concentration (i.e. 30 micro g haemagglutinin) were poorly immunogenic, whereas an H5N3 vaccine adjuvanted with microfluidised emulsion (MF) 59 stimulated antibody levels that complied with CPMP criteria after two half strength doses (i.e. 7.5 micro g haemagglutinin).

Healthcare workers and their attitudes to influenza vaccination.

Despite Department of Health recommendations that healthcare workers (HCWs) receive influenza vaccination, uptake is low. Influenza vaccination has been promoted to reduce nosocomial transmission and staff absenteeism during the winter period. Our study aimed to investigate factors associated with uptake, and non-uptake, of influenza vaccination. In March 2001 we undertook a questionnaire-based cross-sectional survey of 604 hospital HCWs in Leicester and 11 occupational health nurses. Following multivariate analysis, uptake was associated with previous influenza vaccination (OR: Odds ratio 1000, 95% CI 20-3,333), age > 45 years (OR 4.45, 95% CI 1.66-11.9), and belief that influenza is a serious illness (OR 3.8, 95% CI 1.3-10.6). HCWs receive vaccination predominantly as a benefit for themselves. Campaigns should improve accessibility, target younger staff and stress the consequences of influenza infection. Simply raising awareness may not translate into increased uptake. Absenteeism was attributed to vaccine-related adverse effects by 11/83 (13%) vaccinees, resulting in 0.46 workdays lost per dose administered.

Surface cues reduce the latency to name rotated images of objects.

Jolicoeur (1985, Memory & Cognition 13 289-303) found a linear increase in the latency to name line drawings of objects rotated (0 degrees to 120 degrees) from the upright (0 degrees) in the initial trial block. This effect was much shallower in later blocks. He proposed that the initial effect may indicate that mental rotation is the default process for recognising rotated objects, and that the decrease in this effect, seen with practice, may reflect the increased use of learned orientation-invariant features. Initially, we were interested in whether object-colour associations that may be learned during the initial block, could account for the reduced latency to name rotated objects, seen in later blocks. In experiment 1 we used full-cue colour images of objects that depicted colour and other surface cues. Surprisingly, given that Jolicoeur's findings were replicated several times with line drawings, we found that even the initial linear trend in naming latency was shallow. We replicated this result in follow-up experiments. In contrast, when we used less-realistic depictions of the same objects that had fewer visual cues (ie line drawings, coloured drawings, greyscale images), the results were comparable to those of Jolicoeur. Also, the initial linear trends were steeper for these depictions than for full-cue colour images. The results suggest that, when multiple surface cues are available in the image, mental rotation may not be the default recognition process.

Influenza: vaccination and treatment.

Few conditions exert such an enormous toll of absenteeism, suffering, medical consultations, hospitalization, death and economic loss as influenza. Patients at high risk of complications and mortality include the elderly and those with pre-existing cardiopulmonary disease. The outbreak in 1997 in Hong Kong, of avian H5N1 influenza in man, which resulted in six deaths among 18 hospitalized cases, and the recent isolation of H9N2 viruses from two children in Hong Kong, are reminders that preparation must be made for the next pandemic. Since the 1970s, efforts to control influenza have mostly focussed on the split product and surface antigen vaccines. These vaccines are of proven efficacy in healthy adults and are effective in elderly people with and without medical conditions putting them at high risk of complications and death following influenza infection. However, vaccine coverage is patchy and often low, and outbreaks of influenza are not uncommon in well-immunized residents of nursing homes. New vaccines and methods of vaccine delivery are being developed in attempts to overcome the limitations of existing vaccines. The antiviral drugs amantadine and rimantadine were developed in the 1960s, but have not been used widely due to their spectrum of activity, rapid emergence of resistance, and adverse effects associated with amantadine. The site of enzyme activity of the influenza neuraminidase is highly conserved between types, subtypes and strains of influenza and has emerged as the target of an exciting new class of antiviral agents that are effective both prophylactically and as therapy.

Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza.

BACKGROUND: In 1997, pathogenic avian influenza A/Hong Kong/97 (H5N1) viruses emerged as a pandemic threat to human beings. A non-pathogenic variant, influenza A/Duck/Singapore/97 (H5N3), was identified as a leading vaccine candidate. We did an observer-blind, phase I, randomised trial in healthy volunteers to assess safety, tolerability, and antigenicity of MF59-adjuvanted and non-adjuvanted vaccines. METHODS: 32 participants were randomly assigned MF59, and 33 non-adjuvanted vaccine. Two doses were given 3 weeks apart, of 7.5, 15, or 30 microg haemagglutinin surface-antigen influenza A H5N3 vaccine. Antibody responses were measured by haemagglutination inhibition, microneutralisation, and single radial haemolysis (SRH). The primary outcome was geometric mean antibody titre 21 days after vaccination. FINDINGS: The A/Duck/SIngapore vaccines were safe and well tolerated. Antibody response to non-adjuvanted vaccine was poor, the best response occurring after two 30 microgram doses: one, four, four, and one person of eleven seroconverted by haemagglutination inhibition, microneutralisation, H5N3 SRH, and H5N1 SRH, respectively. The geometric mean titres of antibody, and seroconversion rates, were significantly higher after MF59 adjuvanted vaccine. Two 7.5 microg doses of MF59 adjuvanted vaccine gave the highest seroconversion rates: haemagglutination inhibition, six of ten; microneutralisation, eight of ten; H5N3 SRH, ten of ten; H5N1 SRH, nine of ten. Geometric mean titre of antibody to the pathogenic virus, A/Hong Kong/489/97 (H5N1), was about half that to A/Duck/Singapore virus. INTERPRETATION: Non-adjuvanted A/Duck/Singapore/97 (H5N3) vaccines are poorly immunogenic and doses of 7.5-30 microg haemagglutinin alone are unlikely to give protection from A/Hong Kong/97 (H5N1) virus. Addition of MF59 to A/Duck/Singapore/97 vaccines boost the antibody response to protection levels. Our findings have implications for development and assessment of vaccines for future pandemics.

Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group.

BACKGROUND: Use of some antiviral drugs for influenza infection is limited by potential rapid emergence of resistance. We studied the efficacy and safety of oseltamivir, the oral prodrug of the neuraminidase inhibitor GS4071, in adults with naturally acquired laboratory-confirmed influenza. METHODS: We did a randomised controlled trial of 726 previously healthy non-immunised adults with febrile influenza-like illness of up to 36 h duration. Patients were assigned oral oseltamivir 75 mg (n=243), oseltamivir 150 mg (n=245), or placebo (n=238) twice daily for 5 days. We assessed recovery by questionnaire and temperature recordings. The primary endpoint was time to resolution of illness in influenza-infected patients. FINDINGS: 475 (66%) patients had confirmed infection. Duration of illness was significantly shorter by 29 h (25% reduction, median duration 87.4 h [95% CI 73.3-104.7], p=0.02) with oseltamivir 75 mg and by 35 h (30%, 81.8 h [68.2-100.0], p=0.01) with oseltamivir 150 mg than with placebo (116.5 h [101.5-137.8]). The effect of oseltamivir was apparent within 24 h of the start of treatment. In patients treated within 24 h of symptom onset, symptoms were alleviated 43 h (37% reduction) and 47 h (40%) earlier with oseltamivir 75 mg and 150 mg, respectively, compared with placebo (75 mg 74.5 h [68.2-98.0], p=0.02; 150 mg 70.7 h [54.0-89.4], p=0.01; placebo 117.5 h [103.0-143.8]). Oseltamivir was associated with lower [corrected] symptom scores, less viral shedding, and improved health, activity, and sleep quality, and was well tolerated. INTERPRETATION: Oseltamivir was effective and well tolerated in the treatment of natural influenza infection in adults. The efficacy, tolerability, and ease of administration warrant further investigation in children, elderly patients, and at-risk patients.

Influenza A among community-dwelling elderly persons in Leicestershire during winter 1993-4; cigarette smoking as a risk factor and the efficacy of influenza vaccination.

In a prospective study of community-dwelling people 60-90 years of age, we examined the coverage of influenza vaccine during 1992-3 and 1993-4, the efficacy of vaccination in reducing serologically-confirmed clinical episodes of influenza A during 1993, and the effect of cigarette smoking. During 1992 and 1993, influenza vaccine was given to 106/215 (49%) and 120/204 (59%) people with risk conditions, and 84/225 (37%) and 103/235 (44%) without risk conditions. Influenza vaccination and general practitioner consultations during 1992 were independent predictors of vaccination in 1993, but current smoking was a negative predictor. Of 209 unimmunized people, 8/35 (23%) smokers had clinical influenza as compared with 11/174 (6%) non-smokers (OR 4.4, 95% CI 1.6 to 11.9). Of 371 non-smokers, 1/197 (0.5%) vaccinees had influenza as compared with 11/174 (6%) non-vaccinees (OR 0.075, 95% CI 0.587 to 0.009). No cases of influenza occurred among 21 current smokers who were vaccinated.

Cytomegalovirus viraemia has poor predictive value for the development of cytomegalovirus disease in patients with advanced HIV-infection.

OBJECTIVE: Cytomegalovirus (CMV) continues to be one of the most important opportunistic infections associated with human immunodeficiency virus (HIV) infection. This study investigated the value of CMV-viraemia in predicting the development of clinical CMV disease in patients with advanced HIV infection. METHODS: This was a prospective observational study performed over a 2-year period between 1994-96 in the Department of Infection and Tropical Medicine at Leicester Royal Infirmary. Adult HIV-positive patients attending a hospital clinic were included if they were CMV-seropositive with CD4 counts < or =50 cells/mm3. Subjects were seen at approximately 6-weekly intervals in the clinic and were reviewed by an experienced ophthalmologist. Serum for CMV PCR was taken and stored at regular intervals and qualitative and quantitative PCR was performed at the end of the study period. The value of PCR in predicting the development of CMV disease was then assessed. RESULTS: Twenty-six patients were followed up during the study period and 77 evaluable specimens were analysed for CMV PCR. Twenty-three (30%) samples were positive and 54 negative. Seven (27%) patients developed CMV disease (five retinitis alone, and two with retinitis and oesophagitis) during the study period. Viraemia was often intermittent and there was no significant difference in the proportions of patients with positive or negative tests who subsequently developed CMV disease. The sensitivity, specificity, positive and negative predictive values of the qualitative PCR were 71%, 47%, 33% and 82% respectively and 57%, 74%, 44% and 82% respectively for the quantitative PCR (>10(3) copies/ml). CONCLUSIONS: The results from this study, which was performed before the introduction of protease inhibitors, found that cytomegalovirus PCR was of limited clinical value in predicting the patients at greatest risk of developing CMV-disease and provided little useful prognostic information.

Influenza vaccination and asthma: current studies and recommendations.

Influenza is an important epidemic and pandemic illness associated with serious morbidity and mortality in unprotected communities. Patients at increased risk of infection are those with pre-existing cardiopulmonary disease including asthma. The influenza virus has the ability to produce antigenic changes posing problems for vaccine development. Influenza vaccines have been available for over 50 years. Despite the continuing global threat posed by infection and recommendations in many countries that immunisation should be widely given, uptake rates are variable and often poor. It has been demonstrated that infection with influenza and other respiratory viral pathogens can produce exacerbations of asthma throughout the age groups. Despite this, vaccine uptake rates in asthmatic populations are quite low. Poor uptake rates are attributed to a number of factors and we review the evidence for the widely held view that influenza vaccination produces exacerbations of chronic airflow obstruction including asthma. Observational studies have found conflicting results: some post immunisation changes in bronchial hyperreactivity and increased requirements of bronchodilator therapy have been in some, but not all, studies. Placebo-controlled trials have not demonstrated any clinical deterioration although one study showed a small reduction in peak expiratory flow rate. Intranasal administration of cold-adapted live vaccines and new nucleic acid vaccines are briefly considered. Live adapted vaccines have been shown to be effective in influenza immunoprophylaxis and limited data on their use in patients with asthma suggest that they can be administered safely. In conclusion, based up on current studies and evidence, it seems likely that influenza infection produces morbidity in patients with asthma but that any potential adverse effects of influenza immunisation are outweighed by the benefits in this population. However, placebo-controlled trials are few and only small numbers of asthmatic patients have been investigated.

Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma.

BACKGROUND: Despite current recommendations, many people with asthma do not receive annual vaccination against influenza, partly because of concern that vaccine may trigger exacerbations. Colds can trigger exacerbations, which may be mistaken for vaccine-related adverse events. We undertook a double-blind placebo-controlled multicentre crossover study to assess the safety of influenza vaccine in patients with asthma, with allowance for the occurrence of colds. METHODS: We studied 262 patients, aged 18-75 years, who recorded daily peak expiratory flow (PEF), respiratory symptoms, medication, medical consultations, and hospital admissions for 2 weeks before the first injection and until 2 weeks after the second injection. Order of injection (vaccine and placebo) was assigned randomly. There was an interval of 2 weeks between injections. The main outcome measure was an exacerbation of asthma within 72 h of injection (defined as a fall in PEF of >20%). FINDINGS: Among 255 participants with paired data, 11 recorded a fall in PEF of more than 20% after vaccine compared with three after placebo (McNemar's test p=0.06); a fall of more than 30% was recorded by eight after vaccine compared with none after placebo (binomial test p=0.008). However, when participants with colds were excluded, there was no significant difference in the numbers with falls of more than 20% between vaccine and placebo (six vs three; binomial test p=0.51), although the difference for PEF decreases of more than 30% approached significance (five vs none; binomial test, p=0.06). This association was confined to first-time vaccinees. INTERPRETATION: Our findings indicate that pulmonary-function abnormalities may occur as a complication of influenza vaccination. However, the risk of pulmonary complications is very small and outweighed by the benefits of vaccination.