A 21-winter seasons retrospective study of antibody response after influenza vaccination in elderly (60-85 years old) and very elderly (>85 years old) institutionalized subjects.

Influenza vaccination is considered the best mean for preventing the higher rates of mortality associated with influenza virus infection in the elderly as compared with younger people. Since the number of very elderly subjects, aged >85 years, is rapidly increasing, and some authors reported increments in influenza-associated mortality with age, the aim of this study was to increase the limited information available on the immunogenicity of the influenza vaccines in this age group. This was a retrospective study which analyzed the antibody response induced by commercially available trivalent inactivated influenza vaccines in 1491 elderly subjects (60-85 years old) and 1139 very elderly subjects (>85 years old) during 21 winter seasons included between 1993-1994 and 2014-2015. The antibody response of the two age groups was, in most instances, acceptable according to the Committee for Medical Products for Human Use and comparable. In accordance with previous data obtained in the elderly, the use of MF59-adjuvanted or intradermal administered vaccines (enhanced vaccines) was found to be preferable as compared with conventional formulations (split or subunit vaccines). Vaccines containing new strains induced higher antibody response as compared with vaccines with the same antigenic composition of the previous years. These results suggest that the current recommendation for use of enhanced influenza vaccines for the elderly is appropriate, but that efforts to improve the effectiveness of the present prophylactic measures against influenza are needed, especially in the years with vaccines with the same antigenic composition of the previous winter season.

Sex Profile and Risk Assessment With Cardiopulmonary Exercise Testing in Heart Failure: Propensity Score Matching for Sex Selection Bias.

BACKGROUND: In heart failure (HF), women show better survival despite a comparatively low peak oxygen consumption (V˙o2): this raises doubt about the accuracy of risk assessment by cardiopulmonary exercise testing (CPET) in women. Accordingly, we aimed to check (1) whether the predictive role of well-known CPET risk indexes, ie, peak V˙o2 and ventilatory response (V˙e/V˙co2 slope), is sex independent and (2) if sex-related characteristics that impact outcome in HF should be considered as associations that may confound the effect of sex on survival. METHODS: The study population consisted of 2985 patients with HF, 498 (17%) of whom were women, from the multicentre Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI): the end point was cardiovascular death within a 3-year period. RESULTS: During the follow-up, 305 (12%) men and 39 (8%) women (P = 0.005) died, and female sex was linked to better survival on univariate analysis (P = 0.008) and independent of peak V˙o2 and V˙e/V˙co2 slope on multivariate analysis. According to propensity score matching for female sex to exclude a sex selection bias and sample discrepancy, 498 men were selected: the standardized percentage bias ranged from 20.8 (P < 0.0001) to 3.3 (P = 0.667). After clinical profile harmonizing, female sex was predictive of HF at univariate analysis. CONCLUSIONS: The low peak V˙o2 and female association with better outcome in HF might be counterfeit: the female prognostic advantage is lost when sex-specific differences are correctly taken into account with propensity score matching, suggesting that for an effective and efficient HF model, adjustment must be made for sex-related characteristics.

Partial Protection Induced by 2011-2012 Influenza Vaccine Against Serologically Evidenced A(H3N2) Influenza Virus Infections in Elderly Institutionalized People.

Ninety-two institutionalized elderly subjects were vaccinated with trivalent influenza inactivated vaccine available for the 2011-2012 season, characterized by a prevalent circulation of A(H3N2) influenza viruses (A/Victoria/208-clade) presenting antigenic and genetic patterns different from the A(H3N2) vaccine component (A/Perth/16/2009-clade). Haemagglutination inhibiting (HI) antibody titers were determined in sera collected before, 1 and 6 months after vaccination and patients were considered positive for serological evidence of recent infection if they had a seroconversion on comparing HI titers found in sera collected 1 and 6 months after vaccination. No seroconversions were found against A(H1N1) and B vaccine components. Instead 17 volunteers seroconverted against all or at least some of the different A(H3N2) antigens examined, i.e. the 2011-2012 (A/Perth/16/2009) and the 2012-2013 (A/Victoria/361/2011) vaccine strains and four drifted viruses belonging to the A/Victoria/208-clade circulating in the area were the elderly people were living. The results obtained suggest that influenza infections in the vaccinated volunteers might be due both to a poor match between vaccine and circulating A(H3N2) viruses, since 1 month after vaccination 15 of the 17 volunteers had post-vaccination HI titers considered protective (≥40) against the A(H3N2) vaccine antigen, but not always against the epidemic strains, and to a waning of vaccine induced immune response, since 6 months after vaccination HI titers of non-infected volunteers were found to be decreased as compared with those found 1 month after vaccination.

The metabolic exercise test data combined with Cardiac And Kidney Indexes (MECKI) score and prognosis in heart failure. A validation study.

BACKGROUND: The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score is a prognostic model to identify heart failure (HF) patients at risk for cardiovascular mortality (CVM) and urgent heart transplantation (uHT) based on 6 routine clinical parameters: hemoglobin, sodium, kidney function by the Modification of Diet in Renal Disease (MDRD) equation, left ventricle ejection fraction (LVEF), percentage of predicted peak oxygen consumption (VO2) and VE/VCO2 slope. OBJECTIVES: MECKI score must be generalizable to be considered useful: therefore, its performance was validated in a new sequence of HF patients. METHODS: Both the development (MECKI-D) and the validation (MECKI-V) cohorts were composed of consecutive HF patients with LVEF <40% able to perform a symptom-limited cardiopulmonary exercise testing. The CVM or uHT rates were analyzed at one, two and three years in both cohorts: all patients with a censoring time shorter than the scheduled follow-up were excluded, while those with events occurring after 1, 2 and 3 years were considered as censored. RESULTS: MECKI-D and MECKI-V consisted of 2009 and 992 patients, respectively. MECKI-V patients had a higher LVEF, higher peak VO2 and lower VE/VCO2 slope, higher prescription of beta-blockers and device therapy: after the 3-year follow-up, CVM or uHT occurred in 206 (18%) MECKI-D and 44 (13%) MECKI-V patients (p<0.000), respectively. MECKI-V AUC values at one, two and three years were 0.81 ± 0.04, 0.76 ± 0.04, and 0.80 ± 0.03, respectively, not significantly different from MECKI-D. CONCLUSIONS: MECKI score preserves its predictive ability in a HF population at a lower risk.

[Nonvalvular atrial fibrillation: data from the Observatory of Cardiovascular Diseases in the province of Trieste (Italy)]. / La fibrillazione atriale non valvolare: dati dall'Osservatorio delle Malattie Cardiovascolari della provincia di Trieste.

BACKGROUND: Nonvalvular atrial fibrillation (NVAF) is the most common arrhythmia in outpatients and is associated with increased mortality, thromboembolic and hemorrhagic events. Although several international studies have evaluated its prognostic impact in the real world, Italian data are still lacking. Our aim was to define the prevalence, comorbidity, treatment and outcome in a population of "real-life" outpatients with NVAF. METHODS: From 2009 to 2013, 21 282 consecutive patients referred to the Cardiovascular Center of Trieste were enrolled in the study. NVAF was defined in the absence of moderate-to-severe valvular disease, valvular interventions, rheumatic heart disease. Events evaluated in the follow-up included mortality, hospitalizations, thromboembolism and hemorrhage. Clinical data and events were derived from the cardiac regional electronic patient records and the ICD-9 hospital discharge records. RESULTS: 3379 patients (15.8%) had NVAF (35.6% paroxysmal, 34.5% persistent, 29.9% permanent); compared to the general population these patients were older, predominantly male, with hypertension, diabetes and history of stroke/transient ischemic attack and heart failure. Oral anticoagulant therapy was prescribed in 54% of cases, above all in persistent or permanent forms, in patients with higher CHA2DS2-VASc score and younger age. The rate of all-cause mortality, cardiovascular hospitalization, thromboembolic and hemorrhagic events during follow-up was higher in patients with NVAF than in the general population. The use of oral anticoagulant therapy reduced the incidence of thromboembolic events. CHA2DS2-VASc score emerged as an independent predictor of thromboembolic events in patients with paroxysmal (35% higher risk), persistent (40% higher risk) and permanent atrial fibrillation (34% higher risk than patients without atrial fibrillation). CONCLUSIONS: In "real-life" outpatients NVAF is associated with older age, more comorbidities and increased cardiovascular events. CHA2DS2-VASc and HAS-BLED scores predict accurately the risk for thromboembolic and hemorrhagic events. Oral anticoagulation reduces thromboembolic events, but its use is limited to just half of the patients.

Immunogenicity of intramuscular MF59-adjuvanted and intradermal administered influenza enhanced vaccines in subjects aged over 60: A literature review.

Because of the age-related immune system decline, 2 potentiated influenza vaccines were specifically licensed for the elderly: Fluad(®), an MF59-adjuvanted vaccine administered intramuscularly (IM-MF59), and Intanza 15 mcg(®), a non adjuvanted vaccine administered intradermally (ID). The objective of this paper was to conduct a systematic review of studies that evaluated antibody responses in the elderly following immunization with IM-MF59 or ID vaccines. The two potentiated vaccines induced immune responses satisfying, in most instances, the European Medicine Agency immunogenicity criteria, both against vaccine antigens and heterovariant drifted strains. Considering pooled data reported in the articles analyzed and papers directly comparing the 2 vaccines, the antibody responses elicited by IM-MF59 and ID were found to be generally comparable. The use of IM-MF59 and ID vaccines can be proposed as an appropriate strategy for elderly seasonal influenza vaccination although further studies are required for a more complete characterization of the 2 vaccines.

Antibody responses to intradermal or intramuscular MF59-adjuvanted influenza vaccines as evaluated in elderly institutionalized volunteers during a season of partial mismatching between vaccine and circulating A(H3N2) strains.

BACKGROUND: The age-related weakening of the immune system makes elderly subjects less responsive to influenza vaccination. In the last years, two "enhanced vaccines" were licensed for individuals aged ≥65 years, one being a subunit vaccine (Fluad®) containing the MF59 adjuvant administered intramuscularly (IM-MF59) and the other one a split non-adjuvanted vaccine administered intradermally (Intanza® 15mcg) (ID). In the present study, we evaluated and compared the antibody responses against the three vaccine antigens and heterovariant A(H3N2) circulating viruses induced by IM-MF59 and ID influenza vaccines in 80 elderly institutionalized volunteers (40 per group) during the Winter season 2011-2012. RESULTS: Hemagglutination inhibiting (HI) antibody titers were assessed in blood samples collected before, 1 and 6 months after vaccination. One month after vaccination both the IM-MF59 and ID vaccines induced increases in HI titers against all the three vaccine strains. The results in the two groups were similar against the A(H3N2) and A(H1N1) strains. Responses against the B strain typically tended to be higher after ID than IM-MF59, yet both vaccines stimulated lower responses against the B strain than against the two A strains. The two vaccines induced favorable results also against four epidemic drifted A(H3N2) viruses circulating in Winter 2011-2012. Six months after vaccination, the HI titers decreased in both groups. CONCLUSION: The responses induced by IM-MF59 and ID vaccines in institutionalized elderly people were similar against the A(H3N2) and A(H1N1) strains but frequently higher, for the ID, against the B strain. The two vaccines induced positive responses against drifted A(H3N2) circulating viruses.

Pandemic influenza A/H1N1pdm in Italy: age, risk and population susceptibility.

BACKGROUND: A common pattern emerging from several studies evaluating the impact of the 2009 A/H1N1 pandemic influenza (A/H1N1pdm) conducted in countries worldwide is the low attack rate observed in elderly compared to that observed in children and young adults. The biological or social mechanisms responsible for the observed age-specific risk of infection are still to be deeply investigated. METHODS: The level of immunity against the A/H1N1pdm in pre and post pandemic sera was determined using left over sera taken for diagnostic purposes or routine ascertainment obtained from clinical laboratories. The antibody titres were measured by the haemagglutination inhibition (HI) assay. To investigate whether certain age groups had higher risk of infection the presence of protective antibody (≥1∶40), was calculated using exact binomial 95% CI on both pre- and post- pandemic serological data in the age groups considered. To estimate age-specific susceptibility to infection we used an age-structured SEIR model. RESULTS: By comparing pre- and post-pandemic serological data in Italy we found age- specific attack rates similar to those observed in other countries. Cumulative attack rate at the end of the first A/H1N1pdm season in Italy was estimated to be 16.3% (95% CI 9.4%-23.1%). Modeling results allow ruling out the hypothesis that only age-specific characteristics of the contact network and levels of pre-pandemic immunity are responsible for the observed age-specific risk of infection. This means that age-specific susceptibility to infection, suspected to play an important role in the pandemic, was not only determined by pre-pandemic levels of H1N1pdm antibody measured by HI. CONCLUSIONS: Our results claim for new studies to better identify the biological mechanisms, which might have determined the observed pattern of susceptibility with age. Moreover, our results highlight the need to obtain early estimates of differential susceptibility with age in any future pandemics to obtain more reliable real time estimates of critical epidemiological parameters.

An Observational Retrospective Study Provide Information on Hospitalization and Severe Outcomes of the 2009 A(H1N1) Infection in Italy.

BACKGROUND: The aim of this study was to try to ascertain whether, in the absence of a pre-organized programme, locally collected data might provide information about the epidemiological and clinical characteristics of the recent A(H1N1) pandemic in Italy. METHODS: The study was an observational retrospective analysis of the clinic-epidemiological features performed by reviewing medical charts from 141 hospitalized patients with laboratory confirmed pandemic A(H1N1) infection in Umbria, a region of central Italy, in the period July 2009 to March 2010. RESULTS: The pandemic virus was found capable of inducing severe illness requiring hospitalization or intensive care unit admission (ICU), or resulting in death. Age and comorbidity were found to be potential risk factors for severe disease. The mean age of the hospitalized patients was 37 years (range 0 - 93 yrs), however the mean age of ICU admitted patients, including people who did not survive, was higher as compared with those admitted to general medical ward (54 vs 35 yrs). The highest incidence of hospitalization was observed in the youngest group (0 - 17 yrs), the greatest rate of ICU admission in adults (18 - 64 years), and the risk of death in the oldest population (≥ 65 yrs). Comorbity conditions were present in some (55%), but not all hospitalized patients and increased with the age and the severity of the illness. CONCLUSIONS: The data obtained are compatible with the identified epidemiological characteristics of the A(H1N1) pandemic derived from partial information previously collected in Italy and from studies conducted in other European and non European countries. The results of our retrospective observational study suggest that locally organized data collection may give information on the epidemiological and clinical characteristics of a pandemic that are compatible with those obtained from more complex and complete studies.

Influenza vaccination and vitamin K antagonist treatment: a placebo-controlled, randomized, double-blind crossover study.

BACKGROUND: Among millions of persons vaccinated against influenza virus each year, many are older patients treated with several drugs, including vitamin K antagonists (VKAs), among which warfarin is the most commonly used. Due to high interpatient and intrapatient variability, the therapeutic dose of VKA has to be individualized by monitoring of international normalized ratio (INR) values. The objectives of this study were to evaluate variation in the INR and warfarin weekly dose variation after influenza vaccination administration and to follow up patients for related hemorrhagic and thrombotic events to evaluate the safety of the influenza vaccine and to assess the immunogenicity of the influenza vaccination in patients receiving VKAs. METHODS: One hundred four patients on a stable VKA regimen and with an indication for influenza vaccination were randomized to receive influenza vaccination and subsequent placebo administration, or vice versa. All patients were tested for coagulation variables, clinical events, and antibody response against vaccine components. RESULTS: Similar mean prothrombin times, expressed as the INR and VKA weekly dose, were found in patients after receiving vaccine or placebo. The absence of any vaccination effect on VKA treatment was confirmed using a linear mixed-effects model. The percentages of time that patients were in therapeutic range were 70.7% after receiving vaccine and 72.4% after receiving placebo (P = .57). There were no fatal or major bleeding events and 11 minor mucocutaneous hemorrhagic events. After vaccination, the percentage of seroprotected patients ranged from 92.0% to 100.0% depending on the vaccine antigen examined. CONCLUSIONS: Influenza vaccination had no significant effect on INR values or warfarin sodium weekly doses. Close monitoring of INR values is not required after influenza vaccination in patients on stable long-term VKA regimens. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00222638.

Immunosenescence and vaccine failure in the elderly.

An age-related decline in immune responses in the elderly results in greater susceptibility to infection and reduced responses to vaccination. This decline in immune function affects both innate and adaptive immune systems. A meeting of experts in immunology and gerontology in Paris, France, in April 2008, considered current understanding of immunosenescence and its clinical consequences. Essential features of immunosenescence include: reduced natural killer cell cytotoxicity on a per cell basis; reduced number and function of dendritic cells in blood; decreased pools of naive T and B cells; and increases in the number of memory and effector T and B cells. In particular, an accumulation of late differentiated effector T cells, commonly associated with cytomegalovirus infection, contributes to a decline in the capacity of the adaptive immune system to respond to novel antigens. Consequently, vaccine responsiveness is compromised in the elderly, especially frail patients. Strategies to address the effects of immunosenescence include ensuring that seroprotective antibody levels against preventable infectious diseases are maintained throughout adulthood, and improving diet and exercise to address the effects of frailty. New vaccines are being developed, such as intradermal and high-dose vaccines for influenza, to improve the efficacy of immunization in the elderly. In the future, the development and use of markers of immunosenescence to identify patients who may have impaired responses to vaccination, as well as the use of end-points other than antibody titers to assess vaccine efficacy, may help to reduce morbidity and mortality due to infections in the elderly.

Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation.

Reactivation of latent human cytomegalovirus (HCMV) following allogeneic transplantation is a major cause of morbidity and mortality and predisposes to severe complications, including superinfection by Aspergillus species (spp). Antimicrobial polypeptides, including defensins and mannan-binding lectin, are known to block viral fusion by cross-linking sugars on cell surface. Pentraxin 3 (PTX3), a member of the long pentraxin family, successfully restored antifungal immunity in experimental hematopoietic transplantation. We assessed here whether PTX3 binds HCMV and murine virus (MCMV) and the impact on viral infectivity and superinfection in vivo. We found that PTX3 bound both viruses, reduced viral entry and infectivity in vitro, and protected from MCMV primary infection and reactivation as well as Aspergillus superinfection. This occurred through the activation of interferon (IFN) regulatory factor 3 (IRF3) in dendritic cells via the TLR9/MyD88-independent viral recognition sensing and the promotion of the interleukin-12 (IL-12)/IFN-gamma-dependent effector pathway.