Hospitalization in two waves of pandemic influenza A(H1N1) in England.

Uncertainties exist regarding the population risks of hospitalization due to pandemic influenza A(H1N1). Understanding these risks is important for patients, clinicians and policy makers. This study aimed to clarify these uncertainties. A national surveillance system was established for patients hospitalized with laboratory-confirmed pandemic influenza A(H1N1) in England. Information was captured on demographics, pre-existing conditions, treatment and outcomes. The relative risks of hospitalization associated with pre-existing conditions were estimated by combining the captured data with population prevalence estimates. A total of 2416 hospitalizations were reported up to 6 January 2010. Within the population, 4·7 people/100,000 were hospitalized with pandemic influenza A(H1N1). The estimated hospitalization rate of cases showed a U-shaped distribution with age. Chronic kidney disease, chronic neurological disease, chronic respiratory disease and immunosuppression were each associated with a 10- to 20-fold increased risk of hospitalization. Patients who received antiviral medication within 48 h of symptom onset were less likely to be admitted to critical care than those who received them after this time (adjusted odds ratio 0·64, 95% confidence interval 0·44-0·94, P=0·024). In England the risk of hospitalization with pandemic influenza A(H1N1) has been concentrated in the young and those with pre-existing conditions. By quantifying these risks, this study will prove useful in planning for the next winter in the northern and southern hemispheres, and for future pandemics.

Assessment of baseline age-specific antibody prevalence and incidence of infection to novel influenza A/H1N1 2009.

OBJECTIVES: The objectives of the H1N1 2009 serological surveillance project were twofold: to document (1) the prevalence of cross-reactive antibodies to H1N1 2009 by age group in the population of England prior to arrival of the pandemic strain virus in the UK and (2) the age-specific incidence of infection by month as the pandemic progressed by measuring increases in the proportion of individuals with antibodies to H1N1 2009 by age. METHODS: Residual aliquots of samples submitted to 16 microbiology laboratories in eight regions in England in defined age groups in 2008 and stored by the Health Protection Agency serological surveillance programme were used to document age-stratified prevalence of antibodies to H1N1 2009 prior to the arrival of the pandemic in the UK. Functional antibodies to the H1N1 2009 virus were measured by haemagglutination inhibition (HI) and microneutralisation (MN) assays. For timely measurement of monthly incidence of infection with H1N1 2009 between August 2009 and April 2010, the microbiology serum collections were supplemented by collection of residual sera from chemical pathology laboratories in England. Monthly seroincidence samples were tested by HI only, apart from the final sera collected post pandemic in 2010, which were also tested by MN. Incidence during the pandemic was estimated from changes in prevalence between time points and also by a likelihood-based method. SETTING: Eight regions of England. PARTICIPANTS: Serum samples from patients accessing health care in England from whom blood samples were taken for unrelated microbiological or chemical pathology testing. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Baseline age-specific prevalence of functional antibodies to the H1NI 2009 virus prior to the arrival of the pandemic; changes in antibody prevalence during the period August 2009 to April 2010. RESULTS: Pre-existing cross-reactive antibodies to H1N1 2009 were detected in the baseline sera and increased with age, particularly in those born before 1950. The prediction of immunological protection derived from the baseline serological analysis was consistent with the lower clinical attack rates in older age groups. The high levels of susceptibility in children < 15 years, together with their mixing within school, resulted in the highest attack rates in this age group. Serological analysis by region confirms that there were geographical differences in timing of major pandemic waves. London had a big first wave among the 5- to 14-year age group, with the rest of the country reducing the gap after the second wave. Cumulative incidence in London remained higher throughout the pandemic in each age group. By the end of the second wave it is estimated that as many as 70% of school-aged children in London had been infected. Taken together, these observations are consistent with observations from previous pandemics in 1918, 1957 and 1968 - that the major impact of influenza pandemics is on younger age groups, with a pattern of morbidity and mortality distinct from seasonal influenza epidemics. CONCLUSIONS: Serological analysis of appropriately structured, age-stratified and geographically representative samples can provide an immense amount of information to set in context other measures of pandemic impact in a population, and provide the most accurate measures of population exposure. National scale seroepidemiology studies require cross-agency coordination, multidisciplinary working, and considerable scientific resource. FUNDING: The National Institute for Health Research Health Technology Assessment programme and the Health Protection Agency.

Trends in, and determinants of, HIV testing at genitourinary medicine clinics and general practice in England, 1990-2000.

OBJECTIVES: To describe the trends in and determinants of HIV testing and positivity at genitourinary medicine (GUM) clinics and in general practice (GP) in England between 1990 and 2000. METHODS: Data on all first HIV specimens from GUM and GP clinics and tested at seven sentinel laboratories were related to key demographic, clinical, and behavioural variables. RESULTS: During the observation period, 202 892 eligible first HIV tests were reported. 90% (182 746) of specimens were from GUM clinics, of which 55% were from heterosexuals, 12% from men who have sex with men (MSM), and 3% from injecting drug users (IDU). In contrast, only 3% of GP specimens were from MSM and 13% from IDUs. The total number of first HIV tests increased threefold between 1990 and 2000. Overall, 1.6% of GUM and 0.9% of GP first testers were diagnosed HIV positive. In GUM clinics, HIV positivity was highest among heterosexuals who have lived in Africa (11.7%), MSM (6.9%), and IDUs (2.8%) and lowest among heterosexuals with no other specified risk (0.3%). Consistently lower prevalences were observed in GP settings. HIV positivity among GUM first testers declined in MSM, from 13.6% in 1990 to 5.2% in 2000 (p<0.01), and in IDUs, from 7.5% in 1990 to 2.0% in 2000 (p = 0.03). Prevalence remained constant in the groups heterosexually exposed to HIV infection. CONCLUSIONS: HIV testing in GUM settings increased over the decade, with a concomitant reduction in HIV positivity among MSM and IDUs. Increased testing among heterosexual first testers overall was not associated with declining positivity.

Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association.

BACKGROUND: We undertook an epidemiological study to investigate whether measles, mumps, and rubella (MMR) vaccine may be causally associated with autism. METHODS: Children with autism born since 1979 were identified from special needs/disability registers and special schools in eight North Thames health districts, UK. Information from clinical records was linked to immunisation data held on the child health computing system. We looked for evidence of a change in trend in incidence or age at diagnosis associated with the introduction of MMR vaccination to the UK in 1988. Clustering of onsets within defined postvaccination periods was investigated by the case-series method. FINDINGS: We identified 498 cases of autism (261 of core autism, 166 of atypical autism, and 71 of Asperger's syndrome). In 293 cases the diagnosis could be confirmed by the criteria of the International Classification of Diseases, tenth revision (ICD10: 214 [82%] core autism, 52 [31%] atypical autism, 27 [38%] Asperger's syndrome). There was a steady increase in cases by year of birth with no sudden "step-up" or change in the trend line after the introduction of MMR vaccination. There was no difference in age at diagnosis between the cases vaccinated before or after 18 months of age and those never vaccinated. There was no temporal association between onset of autism within 1 or 2 years after vaccination with MMR (relative incidence compared with control period 0.94 [95% CI 0.60-1.47] and 1.09 [0.79-1.52]). Developmental regression was not clustered in the months after vaccination (relative incidence within 2 months and 4 months after MMR vaccination 0.92 [0.38-2.21] and 1.00 [0.52-1.95]). No significant temporal clustering for age at onset of parental concern was seen for cases of core autism or atypical autism with the exception of a single interval within 6 months of MMR vaccination. This appeared to be an artifact related to the difficulty of defining precisely the onset of symptoms in this disorder. INTERPRETATION: Our analyses do not support a causal association between MMR vaccine and autism. If such an association occurs, it is so rare that it could not be identified in this large regional sample.

Effect of schedule on reactogenicity and antibody persistence of acellular and whole-cell pertussis vaccines: value of laboratory tests as predictors of clinical performance.

The performance of four acellular pertussis vaccines containing between two and five pertussis antigens combined with diphtheria and tetanus toxoids was compared with that of British whole-cell diphtheria/tetanus/pertussis (DTP) vaccine both in laboratory assays for potency, toxicity and immunogenicity, and for reactogenicity and immunogenicity in infants. Clinical responses were evaluated in double blind randomized Phase II trials using 3/5/9 month and 2/3/4 month schedules. The acellular DTPs had much lower toxicity than whole-cell DTP in laboratory tests and were significantly less pyrogenic than whole-cell DTP under both schedules. Local reactions were not consistently lower in acellular than whole-cell vaccinees and varied with the source of the diphtheria and tetanus antigens used. Differences in endotoxin level and content of active pertussis toxin (PT) between acellular DTP vaccines were not clinically significant. The reactogenicity advantage of the acellular vaccines was substantially reduced under the 2/3/4 month schedule due to the reduced reactogenicity of the whole-cell DTP vaccine when given at a younger age. There was no relationship between antigen content measured in micrograms per dose and ELISA antibody responses to filamentous haemagglutinin (FHA) and PT in infants, nor was murine immunogenicity predictive of immunogenicity in humans. Antibody response to PT was attenuated in the whole-cell group under the 2/3/4 month schedule but was unaffected in the group receiving acellular vaccines with individually purified components; antibody response to pertactin (69 kDa antigen) was similar in recipients of the whole-cell and component acellular vaccines under the 2/3/4 month schedule. PT antibody persistence until 4-5 years of age was significantly better in recipients of the component acellular than either the whole-cell vaccine or the co-purified acellular vaccine under the 3/5/9 month schedule. However, diphtheria antitoxin levels were reduced in acellular vaccine recipients under both schedules. Despite significantly lower tetanus potencies of the acellular vaccines in laboratory tests, no differences were found in tetanus anti-toxin responses in children.

Antibody responses and symptoms after DTP and either tetanus or diphtheria Haemophilus influenzae type B conjugate vaccines given for primary immunisation by separate or mixed injection.

The safety and immunogenicity of two conjugate Haemophilus influenzae type B (Hib) vaccines administered either mixed with, or in separate limbs to, a whole-cell DTP vaccine, was compared in infants vaccinated at 2, 3 and 4 months of age. Antibody titres to purified polyribosylribitol phosphate, diphtheria, and to pertussis antigens between infants who received the Hib and DPT vaccines in separate limbs or in the same limbs were similar (P > 0.1) while antibody titres to tetanus toxoid were higher in the later group (P < 0.05). This study demonstrated that both Hib vaccines can be mixed with whole-cell DTP vaccine without reducing immunogenicity of either vaccine or increasing the incidence of adverse reactions.

Adverse events and antibody response to accelerated immunisation in term and preterm infants.

A study was performed to compare adverse events and antibody response in term and preterm children vaccinated with diphtheria, tetanus, and pertussis vaccine at 2, 3, and 4 months of age. A total of 124 children were recruited and grouped according to gestational age: 37 weeks or more (n = 52), 34 to 36 weeks (n = 40), and less than 34 weeks (n = 32). Study nurses followed up children 24 hours after each vaccination to record temperature, redness, and swelling at the injection site and any systemic symptoms. Proportions of children experiencing adverse events did not differ between groups. Blood samples were obtained six weeks after the vaccination course at which time all children had protective levels of diphtheria and tetanus antitoxins. Geometric mean antibody titres (95% confidence interval) to pertussis toxin were 2754 (2042 to 3715), 5495 (4074 to 7413), and 3690 (2951 to 4677), to filamentous haemagglutinin were 541 (282 to 1023), 951 (537 to 1698), and 614 (426 to 1023), and to agglutinogens 2 and 3 were 12,106 (6918 to 21,380), 21,330 (13,183 to 34,674), and 22,387 (15,136 to 33,113) in children born at a gestational age of less than 34 weeks, 34 to 36 weeks, and 37 weeks or more respectively. These findings support the current recommendations that preterm children are vaccinated at chronological age according to the national schedule.

Drug resistance in initial isolates of Mycobacterium tuberculosis in England and Wales, 1982-1991.

A total of 1833 out of over 16,000 'initial' isolates of Mycobacterium tuberculosis, submitted by hospital laboratories to the PHLS Regional Tuberculosis Centres in England and Wales between 1982 and 1991, were resistant to one or more first line anti-tuberculosis drugs. Isoniazid resistance was found in 6.1% of these strains, half of which were resistant to isoniazid alone. Resistance to isoniazid and rifampicin, with or without resistance to other drugs, was found in 0.6% of isolates. The proportion of initial isolates resistant to one or more drugs was 9.8%. It ranged from 8.0% to 10.9% between 1982 and 1990, and increased to 14.2% in 1991. The incidence of multiple drug resistance remained very low throughout the period. However, in the light of the problems with tuberculosis and drug resistance emerging elsewhere in the world, vigilance is essential, and enhanced surveillance is being planned in England and Wales.

Rubella surveillance to December 1992: second joint report from the PHLS and National Congenital Rubella Surveillance Programme.

The high uptake of measles/mumps/rubella vaccine since October 1988 has had a major impact on rubella susceptibility in children under five years of age, with interruption of the epidemic cycle and reduction in incidence to a low endemic level. The number of infections in pregnancy reported in England and Wales to the PHLS Communicable Disease Surveillance Centre fell to 23 in 1990, and to 12 and two, respectively, in 1991 and 1992. The reduction was greatest in parous women, a group who were previously at risk through exposure to their own children. During 1991, however, susceptibility in parous antenatal women rose from 0.7% to 1%, suggesting that post-partum immunisation rates may have declined recently. If continued, this could give rise to outbreaks of congenital rubella in the future during the brief periods of rubella resurgence expected before disease elimination is achieved. Susceptibility among Asian women was four times higher than among non-Asians. Of the total of 94 births of congenitally infected infants since January 1987, only 19 occurred during 1990-92 (but this may increase due to late diagnoses). Factors contributing to the continuing occurrence of congenital rubella include missed opportunities for immunisation at school or post-partum, maternal reinfection, and recent immigration into the United Kingdom. Twenty-two (24%) of the women giving birth to congenitally infected infants since 1987 were Asian or Oriental women, of whom at least three acquired their infections abroad. Imported cases will be distinguished in future surveillance reports.

Surveillance of HIV infection by voluntary testing in England.

Eighteen laboratories, which together provide primary HIV antibody testing for 43% of the population in England, collaborated in a study to record epidemiological information for all individuals voluntarily tested by them over a five year period. From the 184,113 individuals who had a first test during the study period, it is estimated that 1 in 12 adults in London, and 1 in 50 outside London have been voluntarily tested for HIV since testing became widely available in 1985. The majority of those tested were individuals whose perceived risk was heterosexual exposure. Infection in this group was concentrated in individuals whose partner had an identified risk and in those who had lived in or visited Africa. The rise in antibody prevalence observed in the latter group during 1990/91 may have been partly due to infection recently acquired in the UK. Antibody prevalence in heterosexuals without a high risk partner or a history of exposure abroad also rose during the study period, suggesting a recent increase in transmission through casual heterosexual exposure in the UK. The study also provided strong evidence of continuing high risk behaviour among homosexual men, particularly in the younger age groups. Homosexuals aged under 30 years and living in London had the greatest risk of acquiring HIV infection since 1988.

Heterosexually acquired HIV-1 infection: cases reported in England, Wales and Northern Ireland, 1985 to 1991.

By the end of 1991, there had been 417 reports of AIDS and 1620 reports of HIV-1 infection in persons in England, Wales and Northern Ireland who probably acquired their infection through sexual intercourse between men and women. Between 1986 and 1991, the proportion of AIDS cases attributable to heterosexual transmission increased from 2% to 14% and of diagnosed HIV-1 infections from 4% to 23%. Reported HIV-1 infections inadequately reflect the extent of infection as only individuals choosing to be tested can be reported. HIV-1 infection acquired during heterosexual intercourse may be the result of transmission from partners who were infected by routes other than heterosexual transmission (first generation transmission) or of transmission from infected partners who were themselves infected through heterosexual intercourse (second generation transmission). Of the 417 cases in which AIDS was acquired through heterosexual intercourse, 42 (10%) were categorised as due to first generation transmission, 328 (79%) as second generation transmission--abroad, and 47 (11%) as second generation transmission--UK. Transmission categories could be allocated to 1438 of the 1620 reports of HIV infection: 17% were categorised as first generation, 74% as second generation--abroad, and 9% as second generation--UK. Heterosexual transmission of HIV infection is increasing, both in individuals acquiring their infection abroad as well as those who become infected in the United Kingdom.

A survey of invasive Haemophilus influenzae infections.

A survey of invasive H. influenzae infections has been underway in six regions of England and Wales since September 1990. In the first year, there were 433 cases of which 362 (84%) were due to H. influenzae type b (Hib). The majority of Hib infections were in children aged less than 5 years; there being an annual incidence of 26.4/100,000 in this age group. Meningitis occurred in 56% of cases of Hib infection. The results confirm previous evidence of the need to incorporate Hib vaccination into the childhood immunisation schedule. The ongoing survey data will provide useful information to assess the impact of an Hib immunisation programme.

Voluntary antenatal HIV testing--results of a pilot study.

Voluntary testing for antibody to human immunodeficiency virus (HIV) was offered to 4929 antenatal patients attending two hospitals in South Manchester during a 12 month period in 1989/90 in order to assess the feasibility of obtaining seroprevalence data by this method. Of these patients, 1728 (35%) agreed to a named test, 1396 (28%) to an unlinked anonymous test and the remaining 37% declined to be tested. The proportion of women tested increased from 22% to 88% over the period, and was similar in those with and without an identified risk factor for infection. One HIV antibody positive patient was found; she was tested anonymously and had no identified risk. The substantial cost in time and money required to establish the universal voluntary testing programme and the incomplete patient compliance confirm the importance of the unlinked anonymous surveys currently being established in the UK to monitor seroprevalence in sentinel populations.

Phase II trial of whole-cell pertussis vaccine vs an acellular vaccine containing agglutinogens.

An acellular pertussis vaccine containing agglutinogens 2 and 3, pertussis toxin, and filamentous haemagglutinin was developed by the Centre for Applied Microbiology and Research in the UK. 188 infants were entered into a randomised blind trial and received either the acellular or a whole-cell vaccine, combined with diphtheria and tetanus toxoids, in a 3, 5, and 8-10 month schedule. Local reactions were similar in the two groups but significantly fewer infants had systemic symptoms after the acellular vaccine. Mean log-antibody titres to the agglutinogen and toxin components were higher with the acellular than with the whole-cell vaccine. Persistence of antibodies one year after the third dose was also better in the acellular group.

Alterations in the U3 region of the long terminal repeat of an infectious thymotropic type B retrovirus.

We isolated and characterized a type B thymotropic retrovirus (DMBA-LV) which is highly related to mouse mammary tumor virus (MMTV) isolates and which induces T-cell thymomas with a high incidence and a very short latent period. Regions of nonhomology between the DMBA-LV genome and the MMTV genome were identified by heteroduplex mapping and nucleotide sequence studies. In the electron microscope heteroduplex mapping studies the EcoRI-generated 5' and 3' fragments of the DMBA-LV genome were compared with the corresponding fragments of the MMTV (C3H and GR) genome isolated from mammary tumors. The results indicated that DMBA-LV contained a region of nonhomologous nucleotide sequences in the 3' half of the U3 region of the long terminal repeat (LTR). Nucleotide sequence studies confirmed these results and showed that in this region 440 nucleotides of the MMTV (C3H) sequences were deleted and substituted with a segment of 122 nucleotides. This substituted segment in the form of a tandem repeat structure contained nucleotide sequences derived exclusively from sequences which flanked the substitution loop. The distal glucocorticoid regulatory element was unaltered, and two additional copies of the distal glucocorticoid regulatory element-binding site were present in the substituted region. The restriction endonuclease map of the reconstructed molecular clone of DMBA-LV was identical to that corresponding to unintegrated linear DMBA-LV DNA present in DMBA-LV-induced tumor cell lines. Since the nucleotide sequences of the LTRs present in four different DMBA-LV proviral copies isolated from a single thymoma were identical, we concluded that they were derived from the same parental virus and that this type B retrovirus containing an alteration in the U3 region of its LTR could induce thymic lymphomas. Thus, DMBA-LV represents the first example of a productively replicating type B retrovirus that contains an LTR modified in the U3 region and that has target cell and disease specificity for T cells.

Rational programme for screening travellers for antibodies to hepatitis A virus.

A blood test and a saliva test for antibody to hepatitis A virus (anti HAV) were offered to British travellers seeking human normal immunoglobulin (HNIG) prophylaxis. The specimens were tested by an IgG capture and a competitive radioimmunoassay (GACRIA, COMPRIA). By GACRIA 211 subjects were anti-HAV positive and 358 anti-HAV negative on both serum and saliva. 10 other seropositive subjects had weakly positive saliva reactions. There were three discrepant results. For the population investigated HNIG use could be minimised at no extra cost by first testing the saliva of those greater than 40 years old, frequent or long-stay travellers, those born in HAV endemic areas, and those with a history of jaundice. Of the 51% of travellers tested for these reasons 20% were anti-HAV positive. They made up 76% of all those with antibody.