During a 17-month period, we performed retrospective analyses of the prevalence of and clinical symptoms associated with human metapneumovirus (hMPV) infection, among patients in a university ...hospital in The Netherlands. All available nasal-aspirate, throat-swab, sputum, and bronchoalveolar-lavage samples (N=1515) were tested for hMPV RNA by reverse-transcriptase polymerase chain reaction. hMPV RNA was detected in 7% of samples from patients with respiratory tract illnesses (RTIs) and was the second-most-detected viral pathogen in these patients during the last 2 winter seasons. hMPV was detected primarily in very young children and in immunocompromised individuals. In young children, clinical symptoms associated with hMPV infection were similar to those associated with human respiratory syncytial virus (hRSV) infection, but dyspnea, feeding difficulties, and hypoxemia were reported more frequently in hRSV-infected children. Treatment with antibiotics and corticosteroids was reported more frequently in hMPV-infected children. From these data, we conclude that hMPV is an important pathogen associated with RTI
Abstract Several inactivated influenza vaccine formulations for systemic administration in man are currently available for annual (seasonal) immunization: split virus and subunit (either ...plain-aqueous, or virosomal, or adjuvanted by MF59). From a literature search covering the period 1978–2009, 33 articles could be identified, which described randomized clinical trials comparing at least two of the four vaccine formulations with respect to serum hemagglutination inhibition (HI) antibody response, local and systemic vaccine reactions and serious adverse events after vaccination, and employing seasonal vaccine components and doses. In total, 9121 vaccinees of all ages, either healthy or with underlying diseases, were involved. Most vaccinees were primed or had been vaccinated in previous years. For immunogenicity, homologous post-vaccination geometric mean HI titers (GMTs) were analyzed by a random effects model for continuous data. Unreported standard deviations (SD) were addressed by imputing assumed SD-values. Age and health state of the vaccinees appeared to have little influence on the outcome. The immunogenicity of split, aqueous and virosomal subunit formulations were similar, with geometric mean ratio values (GMR, quotient of paired GMT-values) varying around one (0.93–1.24). The MF59-adjuvanted subunit vaccine induced, on average, larger antibody titers than the non-adjuvanted vaccine formulations, but the absolute increase was small (GMR-values varying between 1.25 and 1.40). Vaccine reactions were analyzed using a random effects model for binary data. Local and systemic reactogenicity was similar among non-adjuvanted formulations. The adjuvanted subunit formulation was more frequently associated with local reactions than the non-adjuvanted formulations (rate ratio: 2.12, significant). Systemic reactions were similar among all vaccine formulations. The original articles emphasized the mild and transient character of the vaccine reactions and the absence of serious vaccine-related adverse events. This adequate amount of evidence led to the conclusion that all the currently available inactivated influenza vaccine formulations are safe, well tolerated and similarly effective to control seasonal influenza outbreaks across primed populations and age ranges.
•Serological and field studies with seasonal influenza vaccines were systematically retrieved for estimates of vaccine effectiveness, pre-seasonal immunity, and antigenic match state.•The impact of ...influenza B lineage mismatch on vaccine effectiveness was largest in trials with low pre-seasonal immunity (infants/young children). QIV would be beneficial in this age group.•In trials with large pre-seasonal immunity (elderly), effectiveness of TIV was similar for match and lineage mismatch. QIV can be used in this age group, although its gain over TIV is limited.
B lineage mismatch prompted introduction of quadri-valent influenza vaccines (QIV) with two influenza B viruses representing distinct antigenic lineages. To explore the impact on antibody induction and vaccine effectiveness predicted from antibody (VEab), we performed a systematic literature search on immunogenicity studies conducted to assess antibody superiority of QIV over trivalent influenza vaccine (TIV). Thirteen relevant articles described 31 trials from 2007 and 2013. Log-transformed GMT trial estimates and their variances were converted to clinical protection rates predicted from antibody (PRab). VEab estimates were calculated from pre- and post-vaccination PRab. Without specific pre-vaccination immunity, average VEab was 69% for match, and −4% for lineage mismatch. With increasing pre-vaccination seropositivity, mismatch impact declined to 2%. We also performed an umbrella literature search for randomised controlled trials and test-negative case-control trials with TIV, and estimated vaccine effectiveness against laboratory-confirmed influenza B (VEf). Sixty-eight eligible clinical articles described 110 season-trials from 1965 to 2012, covering seasons with B lineage match (n=52), lineage drift (n=15) and lineage mismatch (n=43). With no pre-vaccination antibody levels determined, we used chance of previous exposure to influenza B (Ppe) as pre-seasonal immunity measure. When Ppe was 0%, average VEf for matched seasons was 67%, and for mismatched seasons 35%, indicating a moderate, yet significant mismatch impact on VEf. With increasing Ppe, mismatch impact declined to 3%. Thus serological and field trials indicate that B lineage mismatch impact is negatively related to pre-seasonal immunity and that the gain of QIV over TIV most benefits infants and children not yet exposed to influenza B.
The effect of anti-tumour necrosis factor (TNF) therapy on the antibody responses to vaccines is the subject of ongoing debate. Therefore, we investigated the effect of the three currently available ...anti-TNF agents on influenza vaccination outcomes in a patient population with long-standing disease.
In a prospective cohort study, we assessed the antibody response upon influenza vaccination in 112 patients with long-standing autoimmune disease treated with immunosuppressive medication either with anti-TNF (etanercept, adalimumab or infliximab; n = 64) or without anti-TNF (n = 48) and a control group of 18 healthy individuals. Antibody responses were determined by haemagglutination inhibition assay, before and 4 weeks after vaccination.
The proportion of individuals with a protective titre (>or=40) after vaccination was large (80-94%) and did not significantly differ between the three groups. Post-vaccination geometric mean antibody titres against influenza (A/H3N2 and B) were significantly lower in the 64 patients treated with anti-TNF compared with the 48 patients not receiving anti-TNF, and the healthy controls.
The antibody response to influenza vaccination in patients treated with anti-TNF is only modestly impaired. The proportion of patients that achieves a protective titre is not significantly diminished by the use of TNF blocking therapies.
The availability of accurately aligned, whole-body anatomical (CT) and functional (PET) images could have a significant impact on diagnosing and staging malignant disease and on identifying and ...localizing metastases. Computer algorithms to align CT and PET images acquired on different scanners are generally successful for the brain, whereas image alignment in other regions of the body is more problematic.
A combined PET/CT tomograph with the unique capability of acquiring accurately aligned functional and anatomical images for any part of the human body has been designed and built. The PET/CT scanner was developed as a combination of a Siemens Somatom AR.SP spiral CT and a partial-ring, rotating ECAT ART PET scanner. All components are mounted on a common rotational support within a single gantry. The PET and CT components can be operated either separately, or in combined mode. In combined mode, the CT images are used to correct the PET data for scatter and attenuation. Fully quantitative whole-body images are obtained for an axial extent of 100 cm in an imaging time of less than 1 h. When operated in PET mode alone, transmission scans are acquired with dual 137Cs sources.
The scanner is fully operational and the combined device has been operated successfully in a clinical environment. Over 110 patients have been imaged, covering a range of different cancers, including lung, esophageal, head and neck, melanoma, lymphoma, pancreas, and renal cell. The aligned PET and CT images are used both for diagnosing and staging disease and for evaluating response to therapy. We report the first performance measurements from the scanner and present some illustrative clinical studies acquired in cancer patients.
A combined PET and CT scanner is a practical and effective approach to acquiring co-registered anatomical and functional images in a single scanning session.
In this work we demonstrate the proof of principle of CT-based attenuation correction of 3D positron emission tomography (PET) data by using scans of bone and soft tissue equivalent phantoms and ...scans of humans. This method of attenuation correction is intended for use in a single scanner that combines volume-imaging (3D) PET with x-ray computed tomography (CT) for the purpose of providing accurately registered anatomical localization of structures seen in the PET image. The goal of this work is to determine if we can perform attenuation correction of the PET emission data using accurately aligned CT attenuation information. We discuss possible methods of calculating the PET attenuation map at 511 keV based on CT transmission information acquired from 40 keV through 140 keV. Data were acquired on separate CT and PET scanners and were aligned using standard image registration procedures. Results are presented on three of the attenuation calculation methods: segmentation, scaling, and our proposed hybrid segmentation/scaling method. The results are compared with those using the standard 3D PET attenuation correction method as a gold standard. We demonstrate the efficacy of our proposed hybrid method for converting the CT attenuation map from an effective CT photon energy of 70 keV to the PET photon energy of 511 keV. We conclude that using CT information is a feasible way to obtain attenuation correction factors for 3D PET.
Since the 1940s, influenza vaccines are inactivated and purified virus or virus subunit preparations (IIV) administered by the intramuscular route. Since decades, attempts have been made to ...construct, as an alternative, attenuated live influenza vaccines (LIV) for intranasal administration. Presently, the most successful LIV is derived from the cold-adapted master strains A/Ann Arbor/6/60 (H2N2) and B/Ann Arbor/1/66 (AA-LIV, for Ann-Arbor-derived live influenza vaccine). It has been claimed that AA-LIV is more efficacious than IIV. In order to assess differences between the two vaccines with respect to systemic reactogenicity, antibody response, and efficacy, we performed a meta-analysis on eighteen randomised comparative clinical trials involving a total of 5000 vaccinees of all ages. Pooled odds ratios (AA-LIV versus IIV) were calculated according to the random effects model. The two vaccines were associated with similarly low frequencies of systemic vaccine reactions (pooled odds ratio: 0.96, 95% confidence interval: 0.74–1.24). AA-LIV induced significantly lower levels of serum haemagglutination inhibiting antibody and significantly greater levels of local IgA antibody (influenza virus-specific respiratory IgA assayed by ELISA in nasal wash specimens) than IIV. Yet, although they predominantly stimulate different antibody compartments, the two vaccines were similarly efficacious in preventing culture-positive influenza illness. In all trials assessing clinical efficacy, the odds ratios were not significantly different from one (point of equivalence). The pooled odds ratio for influenza A-H3N2 was 1.50 (95% CI: 0.80–2.82), and for A-H1N1, 1.03 (95% CI: 0.58–1.82). The choice between the two vaccine types should be based on weighing the advantage of the attractive non-invasive mode of administration of AA-LIV, against serious concerns about the biological risks inherent to large-scale use of infectious influenza virus, in particular the hazard of gene reassortment with non-human influenza virus strains.
...we excluded all-cause mortality studies from our main analysis. Only the entirety of many studies from many years reveals the complete pattern of vaccine effectiveness and allows the estimation of ...an average biological vaccine efficacy. ...we feel that the four objections of Osterholm et al. do not challenge, let alone disprove, our main conclusion that influenza vaccination significantly reduces the risks of infection and disease in elderly adults, even with the imperfect formulations of the inactivated vaccines in common usage during the last four decades.
In 2003 an outbreak of highly pathogenic avian influenza virus (H7N7) struck poultry in The Netherlands. A European Commission directive made vaccination of valuable species in zoo collections ...possible under strict conditions. We determined pre- and post-vaccination antibody titres in 211 birds by haemagglutination inhibition test as a measure of vaccine efficacy. After booster vaccination, 81.5% of vaccinated birds developed a titre of ≥40, while overall geometric mean titre (GMT) was 190 (95% CI: 144–251). Birds of the orders
Anseriformes, Galliformes and
Phoenicopteriformes showed higher GMT, and larger percentages developed titres ≥40 than those of the other orders. Antibody response decreased with increasing mean body weight in birds ≥1.5
kg body weight. In the vicinity of the outbreak, H7N7 was detected by RT-PCR in wild species (mallards and mute swans) kept in captivity together with infected poultry, illustrating the potential threat of transmission from poultry into other avian species, and the importance of protecting valuable avian species by means of vaccination.
We introduce the antibody landscape, a method for the quantitative analysis of antibodymediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among ...pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.
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