Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study.

OBJECTIVE: To determine whether maternal influenza virus infection in the second and third trimesters of pregnancy results in transplacental transmission of infection, maternal auto-antibody production or an increase in complications of pregnancy. DESIGN: Case-control cohort study. POPULATION: Study and control cohorts were derived from 3,975 women who were consecutively delivered at two Nottingham teaching hospitals between May 1993 and July 1994. A complete set of three sera was available for 1,659 women. METHODS: Paired maternal ante- and postnatal sera were screened for a rise in anti-influenza virus antibody titre by single radial haemolysis and haemagglutination inhibition. Routine obstetric data collected during and after pregnancy were retrieved from the Nottingham obstetric database. Cord samples were tested for the presence of IgM anti-influenza antibodies, and postnatal infant sera were tested for the persistence of influenza-virus specific IgG. Paired antenatal and postnatal sera were tested against a standard range of auto-antigens by immunofluorescence. MAIN OUTCOME MEASURES: Classification of women as having definite serological evidence of an influenza virus infection in pregnancy (cases) or as controls. RESULTS: Intercurrent influenza virus infections were identified in 182/1,659 (11.0%) pregnancies. None of 138 cord sera from maternal influenza cases was positive for influenza A virus specific IgM. IgG anti-influenza antibodies did not persist in any of 12 infant sera taken at age 6-12 months. Six of 172 postnatal maternal sera from cases of influenza were positive for auto-antibodies. In all cases the corresponding antenatal serum was also positive for the same auto-antibody. There were no significant differences in pregnancy outcome measures between cases and controls. Overall, there were significantly more complications of pregnancy in the cases versus the controls, but no single type of complication achieved statistical significance. CONCLUSIONS: Influenza infection in the second and third trimesters of pregnancy is a relatively common event. We found no evidence for transplacental transmission of influenza virus or auto-antibody production in pregnancies complicated by influenza infections. There was an increase in the complications of pregnancy in our influenza cohort.

Clinical and serological responses to an inactivated influenza vaccine in adults with HIV infection, diabetes, obstructive airways disease, elderly adults and healthy volunteers.

To investigate the clinical and serological responses to an inactivated influenza vaccine (split-virion A/Singapore/6/86-like strains H1N1 (15 ug HA), A/Beijing/353/89-like H3N2 (15 ug HA) and B/Yamagata/16/88-like strain (15 ug HA): MFV-JECT, Merieux, UK) in persons with HIV infection, diabetes, obstructive lung diseases, elderly adults and healthy volunteers. Forty-nine HIV-infected persons received 2 doses of the vaccine at one-month intervals; 34 healthy volunteers, 30 elderly persons, 29 with insulin and non-insulin diabetes and 14 with obstructive airways diseases were vaccinated with one single dose between October 1992 to January 1993. Serological testing of antibody responses was done using haemagglutination assay. Beta2-microglobulin in HIV-infected persons was measured using radioimmunodiffusion between 1st and 2nd dose. Fructosamine levels in diabetic persons were assessed for diabetic control and peak expiratory flow rate (PEFR) was self monitored in persons with lung diseases. All groups apart from the elderly filled in a symptom score chart for the first 5 days following vaccination. A 4-fold rise in titre equal to or more than 1:64 to all the 3 antigens occurred in 20 (58.8%) of healthy volunteers compared with 13 (44.8%) diabetics, 5 (35.7%) with lung diseases, 10 (33.3%) elderly and 13 (26.5%) with HIV infection. A significant correlation of serological response to number of CD4 count in persons with HIV infection was noted (H1N1 P=0.0013, H3N2 P=0.025, BYAM P=0.0018). Mean beta2-microglobulin levels did not change significantly post 1st and 2nd vaccination. Mean fructosamine level did not change significantly. There was no significant change in PEFR. The vaccine was well tolerated. Persons with HIV infection and low CD4 count do not serologically respond well to influenza vaccine even with 2 doses compared to the other 4 groups. The other 4 groups had adequate protective serologic responses. The vaccine was well tolerated in all groups.

Detection of human viruses using primary cells immortalised by oncogene transfection, in comparison with primary cells and established cell lines.

No single established cell line was found capable of substituting for primary baboon kidney (PBK) or primary rhesus macacque kidney (PRK) cells for detection of human viruses. Although a panel of cell lines could detect influenza, parainfluenza, and enteroviruses, which are among the most important viruses encountered in routine diagnostic laboratories, the sensitivity of this panel was not as high as that of PBK or PRK cells. However, in a promising complementary approach, PBK and PRK cells have been immortalised successfully by oncogene transfection, and some of the resulting cell lines have retained susceptibility to human viruses, and may be suitable for routine diagnostic use.

Influenza surveillance in England and Wales: October 1994 to June 1995.

This report summarises the information obtained by surveillance of influenza in England and Wales from October 1994 to June 1995 (weeks 40/94 to 25/95). Influenza B viruses were responsible for most infections, with moderate activity occurring throughout the winter, peaking in February. Influenza A became more active towards the end of the winter, and laboratory reports reached a peak in May (week 21/95). Influenza activity was seen first in Wales, then England, followed by Scotland. An increase in 'total respiratory disease' was reported in December 1994 by the Birmingham Research Unit of the Royal College of General Practitioners (RCGP) in England and Wales. This was probably due largely to an increase in reports of acute bronchitis, and was concurrent with the annual increase in respiratory syncytial virus infection which is often associated with bronchiolitis. Circulating influenza viruses were antigenically similar to components of the vaccine chosen for 1994/95. This report summarises the recommendations for the 1995/96 influenza vaccine.

Genetic and antigenic variation in the haemagglutinin of recently circulating human influenza A (H3N2) viruses in the United Kingdom.

Variation in the haemagglutinin (HA) gene of influenza A (H3N2) viruses isolated in the U.K. and abroad from 1992-1994, was determined by nucleotide sequencing of the HA1 domain of the HA gene. Viruses isolated in the U.K. early in the 1992-93 season were from the A/Beijing/353/89 lineage and were replaced later that season by viruses from the A/Beijing/32/92 lineage. Viruses from the new lineage continued to be isolated during the 1993-94 season, but were heterogeneous. Most of these isolates were more closely related to an A/Beijing/32/92 variant, A Hong Kong/23/92, but could be distinguished into three groups by serology (of which one group was circulating during the previous season) and four groups based on sequence variation in the HA gene. However, phylogenetic analysis of antigenically-distinct isolates showed that the HA gene is evolving along one lineage. Sequence analysis identified mainstream, subgroup and strain specific amino acid substitutions. There was a broad correlation between the observed amino acid changes and the antigenic sites of the HA. The results of this study highlight the value of regular molecular analysis of circulating viruses.

Influenza surveillance, England and Wales: October 1993 to June 1994.

This report summarises the information obtained by surveillance of influenza activity in England and Wales from 30 October 1993 to 24 June 1994 (weeks 93/44 to 94/25). A moderate epidemic of influenza occurred, which was earlier than in recent years. It followed an increase in influenza activity reported in Scotland in early October. Activity spread from north to south. Influenza A(H3N2) viruses accounted for over 98% of isolates typed, but a few strains of influenza B were identified.

Surveillance of influenza in the United Kingdom. Pandemic and interpandemic period.

In the United Kingdom the morbidity surveillance is carried out by the General Practitioner Spotter Practice Schemes (RCGP), the Medical Officers of Schools Association (MOSA) and the Emergency Bed Service. Mortality data is provided weekly by the Office of Population and Censuses and Surveys (OPCS). PHLS Communicable Disease Surveillance Centre (CDSC) collects all information and publishes the findings weekly in the Communicable Disease Report (CDR). There are 53 Public Health Laboratories situated in all parts of England and Wales. Most of these laboratories provide diagnostic services for influenza, together with many National Health and academic laboratories. A similar service is also available in Scotland.

Isolation of an influenza A virus of unusual subtype (H1N7) from pigs in England, and the subsequent experimental transmission from pig to pig.

A novel H1N7 influenza virus (A/swine/Eng/191973/92) was isolated from nasal swabs collected from two pigs on a farm where there had been recent clinical disease due to infection with an H1N1 virus (A/swine/Eng/195852/92). Antigenically, the haemagglutinin (HA) of the H1N7 virus was related most closely to the HA of A/USSR/90/77, whilst the neuraminidase (NA) appeared to be related most closely to the NA of A/equine/Prague/1/56 (H7N7). Pigs infected experimentally with A/swine/Eng/191973/92 developed mild clinical signs, excreted virus into the nasal passages for up to nine days after infection, appeared normal at necropsy, transmitted the virus to sentinel pigs, but seven out of eight pigs failed to seroconvert. These findings suggest that the H1N7 virus has a low pathogenicity for pigs, resulting in limited virus multiplication which is insufficient to stimulate a detectable primary humoral immune response.

Possible association of influenza A with fetal loss: investigation of a cluster of spontaneous abortions and stillbirths.

It has been suspected that influenza infection is associated with fetal or perinatal mortality, but little recent evidence supports this hypothesis. A small cluster of early and late fetal deaths in early 1986 prompted an epidemiological investigation. Women whose pregnancies were affected (cases) were compared with women whose pregnancies had a normal outcome (controls). Case pregnancies were distinguished by a significant excess of recent flu-like illness (p = 0.006), and were significantly more likely than controls to have serological evidence of influenza A infection (p = 0.00067), predominantly the influenza A H3N2, Christchurch/4/85-like strain. The cluster was recognised because most cases were patients of one health centre. Larger epidemiological studies will be needed to confirm an association between influenza A and fetal death, but this cluster suggests that influenza A may have an adverse influence on fetal survival.

Comparison of influenza serological techniques by international collaborative study.

An international collaborative study was performed to investigate the reproducibility of influenza serological techniques. Participants in seven laboratories representing five countries measured antibody to A/Sichuan/2/87 (H3N2), A/Taiwan/1/86 (H1N1) and B/Beijing/1/87 influenza viruses in 11 human sera and three postinfection ferret sera. Two different serological techniques were used, haemagglutination inhibition (HI) and single-radial haemolysis (SRH) and, although each technique was reproducible within laboratories, variability between laboratories was higher for HI (maximum variability 32-fold; geometric coefficient of variation, GCV, 112%) than for SRH (maximum variability 3.8-fold; GCV 57%). The use of a standard serum allowed direct comparison of HI and SRH data and, for each technique, a standard serum improved inter-laboratory agreement. For influenza A viruses there was a correlation between HI and SRH antibodies (correlation coefficient approximately 0.9). An HI titre of 1:40 in human sera corresponded to an SRH titre of 19-33 mm2. The results of the study indicate that two sera would be expected to contain different antibody levels if their HI titres differed by > fourfold and SRH areas differed by > 50%. Both SRH and HI possessed equivalent sensitivity for measurement of antibody to influenza A viruses but SRH was more sensitive for detection of antibody to influenza B viruses. The study provided valuable information about standardization of antibody assays.

Immunogenicity of inactivated influenza vaccine in residential homes for elderly people.

One hundred and seventy residents of 11 Leicester City Council homes for the elderly, with a total of 515 beds, were studied during a 30-week period from September 1988 to March 1989 to determine the use of influenza vaccine, the levels of influenza antibody, the incidence of influenza, and the protection afforded by vaccination. The study group of 133 women and 37 men had a mean age of 85 years and 59% had one or more chronic medical conditions. The immunization rates by home for the 170 symptomatic residents ranged from 8% to 90% (mean 45%). Seventy-one sera, 36 from vaccinated and 35 from non-vaccinated residents were collected between 1 December 1988 and 24 March 1989 and were assayed for antibody to A/Taiwan/1/86 (H1N1), A Sichuan/2/87 (H3N2) and B/Beijing/1/87. Analysis revealed no statistically significant differences between the antibody profiles of vaccinated and unvaccinated subjects. Six influenza A and 6 influenza B infections were confirmed among the 170 subjects with upper respiratory tract infections. Influenza vaccination was not associated with significant levels of protection against influenza A or B. Studies of the haemagglutinins of the vaccine strains and influenza isolates during 1988/89 showed that they were closely related.

An unusual community outbreak of influenza A.

The Hong Kong H3N2 subtype of influenza A virus appeared in 1968 and since then has caused epidemics of varying degrees of severity. We describe a community outbreak of influenza A H3N2 which occurred in members of a bowls club in an English rural village in late April 1989. The explosive onset, high attack rate (34/41 = 83 per cent) in those exposed, and the clinical presentation initially suggested a toxic or allergic aetiology. Twenty-three persons consulted their general practitioners; before the diagnosis was made all cases were considered to merit antibiotic therapy and 17/23 were prescribed steroids or bronchodilators on account of persisting severe wheeze and chest tightness. One of the 23 was admitted to hospital. There were no deaths. Influenza vaccination is recommended for people at special risk but protective efficacy is relatively low and short-lived. Only two of the group had received influenza vaccination since the beginning of October 1988 and both became symptomatic. The use of amantadine for the prevention and early treatment of influenza A in selected situations merits serious consideration, provided the diagnosis is made sufficiently early.