Influenza infection directly alters innate IL-23 and IL-12p70 and subsequent IL-17A and IFN-γ responses to pneumococcus in vitro in human monocytes.

IMPORTANCE: Influenza virus is highly contagious and poses substantial public health problems due to its strong association with morbidity and mortality. Approximately 250,000-500,000 deaths are caused by seasonal influenza virus annually, and this figure increases during periods of pandemic infections. Most of these deaths are due to secondary bacterial pneumonia. Influenza-bacterial superinfection can result in hospitalisation and/or death of both patients with pre-existing lung disease or previously healthy individuals. The importance of our research is in determining that influenza and its component haemagglutinin has a direct effect on the classic pneumococcus induced pathways to IL-17A in our human ex vivo model. Our understanding of the mechanism which leaves people exposed to influenza infection during superinfection remain unresolved. This paper demonstrates that early infection of monocytes inhibits an arm of immunity crucial to bacterial clearance. Understanding this mechanism may provide alternative interventions in the case of superinfection with antimicrobial resistant strains of bacteria.

Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery.

BACKGROUND: Return to work is an important indicator of recovery after acute cardiac events. This study aimed to determine rates of work resumption and identify predictors of non-return to work and delayed resumption of work. METHODS: 401 currently employed patients consecutively admitted after acute coronary syndrome or to undergo coronary artery bypass graft surgery were recruited. Patient characteristics, perceptions and occupational outcomes were investigated via interviews and self-report questionnaires. RESULTS: Twenty-three patients were lost to follow-up. Of the 378 completers, 343 (90.7%) patients resumed work, while 35 (9.3%) did not. By four months, 309 (91.1%) patients had returned to work. At 12 months, 302 (79.9%) of the 378 patients were employed, 32 (8.5%) unemployed and 20 (5.3%) retired. The employment status of 24 (6.3%) patients was unknown. Non-return to work was significantly more likely if patients were not intending to return to work or were uncertain, had a negative perception of health, had a comorbidity other than diabetes and reported financial stress. Significant predictors of delayed return to work were cardiac rehabilitation attendance, longer hospital stay, past angina, having a manual job, physically active work, job dissatisfaction, no confidante and depression. CONCLUSIONS: Patients at risk of poor occupational outcomes can be identified early. Strategies to improve vocational rehabilitation require further investigation.

Reproducibility of serology assays for pandemic influenza H1N1: collaborative study to evaluate a candidate WHO International Standard.

Haemagglutination-inhibition (HI) and virus neutralisation (VN) assays are used to evaluate immunogenicity of pandemic H1N1 vaccines; however these bioassays are poorly standardised leading to inter-laboratory variation. A candidate International Standard (IS) for antibody to H1N1 pdm virus (09/194) was prepared from pooled sera of subjects who had either recovered from H1N1 pdm infection or who had been immunised with an adjuvanted subunit vaccine prepared from reassortant virus NYMC X-179A (derived from A/California/7/2009 virus). Ten laboratories from seven countries tested the candidate IS, 09/194 and a panel of human sera by HI and VN using the A/California/7/2009 virus (six laboratories) and/or the reassortant virus NYMC X-179A (ten laboratories). As expected, the inter-laboratory variability for HI and VN assay results was high. For results of antibody tests to NYMC X-179A, the % geometric coefficient of variation (%GCV) for 09/194 between laboratories was 83% for HI and 192% for VN. For tests of all sera, the median %GCV ranged from 95 to 345% for HI (80-fold variation) and 204 to 383% for VN (109-fold variation), but for the titres relative to 09/194 the median %GCV was much reduced (HI 34-231%; VN 44-214%). For tests of antibody to the A/California/7/2009 wild type virus there were similar reductions in %GCV when 09/194 was used. These results suggest that 09/194 will be of use to standardise assays of antibody to A/California/7/2009 vaccine and 09/194 has now been established by WHO as an IS for antibody to A/California/7/2009 with an assigned potency of 1300 IU per ml.

Serological response to trivalent inactive influenza vaccine in HIV-infected children with different immunologic status.

Influenza vaccination is usually recommended for HIV-infected children. One hundred and twenty seven HIV-infected and twenty-one HIV-uninfected children aged ≥6 months to <18 years, all of whom were naïve to influenza vaccine, were enrolled to receive an influenza Trivalent Inactivated Vaccine (TIV). In the HIV group, the post-vaccination immune response (geometric mean titer, seroconversion and seroprotection rates) correlated with their immunological status before vaccination. The HIV-infected children with no immunosuppression had comparable serological response to HIV-uninfected children. For moderately and severely immunosuppressed HIV groups, two doses of TIV resulted in greater serological responses and should be recommended in these groups.

Safety and immunogenicity of whole-virus, alum-adjuvanted whole-virus, virosomal, and whole-virus intradermal influenza A/H9N2 vaccine formulations.

Avian influenza H9N2 viruses are considered as a pandemic threat. We assessed the safety and immunogenicity of fourteen H9N2 vaccine formulations. A randomized, phase I trial was done in 353 adults, aged 18-82 years. Subjects received two doses of A/Hong Kong/1073/99 (H9N2) whole-virus, alum-adjuvanted whole-virus, virosomal, or intradermal whole-virus vaccine at four doses (1.7, 5, 15 or 45 microg haemagglutinin). Sera were obtained before and three weeks after each vaccination (days 0, 21, and 42) for haemagglutination-inhibition (HAI) and neutralization assays. All formulations were well tolerated. Pre-vaccination sera from subjects aged below or above 40 years had baseline antibody to H9N2 in 1% and 16% of samples. Compared to intramuscular whole-virus vaccine, alum-adjuvanted vaccine was more immunogenic, intradermal vaccine was comparable, and virosomal vaccine less immunogenic. Among subjects under 40 years, two doses (45, 15, and 5 microg) of alum-adjuvanted vaccine achieved seroprotective HAI titres in 50%, 41%, and 39% respectively, and neutralization seroconversions in 83%, 82%, and 78% of recipients. Among subjects over 40 years, one dose (45, 15, and 5 microg) of alum-adjuvanted vaccine achieved seroprotective HAI titres in 50%, 25% and 0% respectively, and neutralization seroconversions in 88%, 63% and 63% of recipients. Among immunologically naive subjects under 40 years, two doses of vaccine are required and alum-adjuvanted vaccines were most immunogenic. Among immunologically primed subjects over 40 years, one dose of whole-virus or alum-adjuvanted vaccine induced immune responses; the second dose provided less additional benefit. However, no vaccine formulation satisfied all European regulatory criteria for pandemic vaccines.

Reproducibility of serologic assays for influenza virus A (H5N1).

Hemagglutination-inhibition (HI) and neutralization are used to evaluate vaccines against influenza virus A (H5N1); however, poor standardization leads to interlaboratory variation of results. A candidate antibody standard (07/150) was prepared from pooled plasma of persons given clade 1 A/Vietnam/1194/2004 vaccine. To test human and sheep antiserum, 15 laboratories used HI and neutralization and reassortant A/Vietnam/1194/2004, A/turkey/Turkey/1/2005 (clade 2.2), and A/Anhui/1/2005 (clade 2.3.4) viruses. Interlaboratory variation was observed for both assays, but when titers were expressed relative to 07/150, overall percentage geometric coefficient of variation for A/Vietnam/1194/2004 was reduced from 125% to 61% for HI and from 183% to 81% for neutralization. Lack of reduced variability to clade 2 antigens suggested the need for clade-specific standards. Sheep antiserum as a standard did not reliably reduce variability. The World Health Organization has established 07/150 as an international standard for antibody to clade 1 subtype H5 and has an assigned potency of 1,000 IU/ampoule.

Natural killer cells regulate T-cell proliferation during human parainfluenza virus type 3 infection.

Human parainfluenza virus type 3 (HPIV3) is a major respiratory pathogen in humans. Failure to induce immunological memory associated with HPIV3 infection has been attributed to inhibition of lymphocyte proliferation. We demonstrate that the inability of mixed lymphocytes to respond to virally infected antigen-presenting cells is due to an interleukin-2-dependent, nonapoptotic mechanism involving natural killer (NK) cells and their influence is exerted in a contact-dependent manner. These results suggest a novel regulatory mechanism for NK cells during HPIV3 infection, offering an explanation for viral persistence and poor memory responses.

Novel mechanism of immunosuppression by influenza virus haemagglutinin: selective suppression of interleukin 12 p35 transcription in murine bone marrow-derived dendritic cells.

Infection with influenza virus strongly predisposes an individual to bacterial superinfection, which is often the significant cause of morbidity and mortality during influenza epidemics. Little is known about the immunomodulating properties of the virus that lead to this phenomenon, but the effect of the viral components on the development of immune dendritic cells (DCs) may prove vital. In this study, activation of and cytokine secretion by bacterial lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) following treatment with the influenza virus major antigen haemagglutinin (HA) were examined. HA selectively inhibits the release of LPS-induced interleukin 12 (IL12) p70, which is independent of IL10 secretion. Suppression occurs at the transcriptional level, with selective inhibition of p35- and not p40-subunit mRNA expression. The downregulation of IL12 p70 by influenza HA is a novel and unexplored pathway that may be relevant in the predisposition to bacterial superinfection associated with influenza virus infections.

Safety and antigenicity of whole virus and subunit influenza A/Hong Kong/1073/99 (H9N2) vaccine in healthy adults: phase I randomised trial.

BACKGROUND: In 1999, avian influenza A/Hong Kong/1073/99 (H9N2) virus emerged as a pandemic threat to human beings. We aimed to assess safety, tolerability, and antigenicity of whole virus and subunit H9N2 vaccines in healthy volunteers. METHODS: In a phase I randomised trial we randomly assigned 60 participants to whole virus or subunit H9N2 vaccine. Two doses of 7.5 microg, 15 microg, or 30 microg haemagglutinin influenza A H9N2 vaccine, were given 3 weeks apart. We measured antibody responses by haemagglutination-inhibition and microneutralisation. The primary outcome was geometric mean antibody titre 21 days after vaccination. Analysis was per protocol. FINDINGS: Both vaccines were safe and well tolerated. The antibody titres after vaccination did not differ significantly between subunit and whole virus vaccine. 24 of 60 prevaccination serum samples had unexpected reactivity to H9N2, but only in participants older than 32 years, in whom one dose of either vaccine evoked antibody responses associated with protection. In participants aged 32 years or younger, antibody responses to one dose of whole virus or subunit vaccine were poor, fulfilling none of the criteria used for yearly relicensing of interpandemic vaccines. Whole virus vaccine produced a significantly higher probability of seroconversion compared with subunit virus for this age-group. INTERPRETATION: In immunologically naive patients whole-virus vaccine produced better responses than subunit vaccine. Two doses of subunit or whole virus vaccine would leave a large proportion of the naive population (< or =32 years) unprotected against A/Hong Kong/1073/99 (H9N2). Primed patients should be protected with a single dose of either vaccine.

Coaching patients On Achieving Cardiovascular Health (COACH): a multicenter randomized trial in patients with coronary heart disease.

BACKGROUND: Disease management programs in which drugs are prescribed by dietitians or nurses have been shown to improve the coronary risk factor profile in patients with coronary heart disease. However, those disease management programs in which drugs are not prescribed by allied health professionals have not improved coronary risk factor status. The objective of the Coaching patients On Achieving Cardiovascular Health (COACH) study was to determine whether dietitians or nurses who did not prescribe medications could coach patients with coronary heart disease to work with their physicians to achieve the target levels for their total cholesterol (TC) and other risk factors. METHODS: Multicenter randomized controlled trial in which 792 patients from 6 university teaching hospitals underwent a stratified randomization by cardiac diagnosis within each hospital: 398 were assigned to usual care plus The COACH Program and 394 to usual care alone. Patients in The COACH Program group received regular personal coaching via telephone and mailings to achieve the target levels for their particular coronary risk factors. There was one coach per hospital. The primary outcome was the change in TC (DeltaTC) from baseline (in hospital) to 6 months after randomization. Secondary outcomes included measurement of a wide range of physical, nutritional, and psychological factors. The analysis was performed by intention to treat. RESULTS: The COACH Program achieved a significantly greater DeltaTC than usual care alone: the mean DeltaTC was 21 mg/dL (0.54 mmol/L) (95% confidence interval [CI], 16-25 mg/dL [0.42-0.65 mmol/L]) in The COACH Program vs 7 mg/dL (0.18 mmol/L) (95% CI, 3-11 mg/dL [0.07-0.29 mmol/L]) in the usual care group (P<.0001). Thus, the reduction in TC from baseline to 6 months after randomization was 14 mg/dL (0.36 mmol/L) (95% CI, 8-20 mg/dL [0.20-0.52 mmol/L]) greater in The COACH Program group than in the usual care group. Coaching produced substantial improvements in most of the other coronary risk factors and in patient quality of life. CONCLUSIONS: Coaching, delivered as The COACH Program, is a highly effective strategy in reducing TC and many other coronary risk factors in patients with coronary heart disease. Coaching has potential effectiveness in the whole area of chronic disease management.