The use of antiviral drugs for influenza: Guidance for practitioners, 2012/2013; Paediatric summary

This practice point summarizes the use of antiviral drugs to manage influenza illness in children and youth for the 2012/2013 season. It excerpts a recently published, full-length update of Canadian recommendations for clinicians on the use of antiviral drugs for the prevention and treatment of influenza, with a focus on paediatric antiviral therapy. Detailed information on the selective use of chemoprophylaxis can be found in the source document, which also highlights the importance of secondary bacterial infections (Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus) in cases of severe influenza illness.     

Common cold and influenza symptom management: the use of pharmacokinetic considerations to predict the efficacy of a twice-daily treatment for colds and flu

SUMMARY

Objective: The objective of the two pharmacokinetic studies reported here was to compare the relative bioavailability of an ibuprofen/pseudoephedrine modified-release capsule with each of the active ingredients given alone as standard formulations.

Study design: Evaluation of two open, randomised, cross-over studies, one single dose and one multiple dose, in healthy male volunteers.

Methods: Healthy volunteers were randomised in a cross-over design to single or multiple doses of a combination of ibuprofen (600 mg) plus pseudoephedrine (90 mg) in a slow-release formulation and the individual active products alone as standard formulations; ibuprofen 400mg, pseudoephedrine 60 mg.

Results: The single-dose study demonstrated that the bioavailabilities of ibuprofen and pseudoephedrine achieved with the slow-release formulation were not significantly different from those with standard tablets of each ingredient alone. In addition, mean plasma levels of ibuprofen predictive of clinical efficacy were achieved within 0.5-1 h and lasted for 10-12 h thereafter. The time required to reach clinically effective blood levels of pseudoephedrine was longer, starting at approximately 2 h. However, the plasma levels predicted that the clinical effect would then last for at least a further 12 h. Trough levels from the multiple-dose study showed that clinically relevant analgesic and decongestant plasma levels were maintained for 24 h during twice-daily dosing. The slow-release formulation was well tolerated with only mild adverse events.

Conclusion: Blood levels would predict that the present slow-release fo rmulation of ibuprofen plus pseudoephedrine should offer reliable day and night control of cold and flu and sinus symptoms and be associated with a favourable safety profile.     

Safety,tolerability, acceptability and immunogenicity of an influenza vaccine delivered to human skin by a novel high-density microprojection array patch (Nanopatch™)

BackgroundInjection using needle and syringe (N&S) is the most widely used method for vaccination, but requires trained healthcare workers. Fear of needles, risk of needle-stick injury, and the need to reconstitute lyophilised vaccines, are also drawbacks. The Nanopatch (NP) is a microarray skin patch comprised of a high-density array of microprojections dry-coated with vaccine that is being developed to address these shortcomings. Here we report a randomised, partly-blinded, placebo-controlled trial that represents the first use in humans of the NP to deliver a vaccine.MethodsHealthy volunteers were vaccinated once with one of the following: (1) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg haemagglutinin (HA) per dose), applied to the volar forearm (NP-HA/FA), n = 15; (2) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg HA per dose), applied to the upper arm (NP-HA/UA), n = 15; (3) Fluvax® 2016 containing 15 µg of the same H1N1 HA antigen injected intramuscularly (IM) into the deltoid (IM-HA/D), n = 15; (4) NPs coated with excipients only, applied to the volar forearm (NP-placebo/FA), n = 5; (5) NPs coated with excipients only applied to the upper arm (NP-placebo/UA), n = 5; or (6) Saline injected IM into the deltoid (IM-placebo/D), n = 5. Antibody responses at days 0, 7, and 21 were measured by haemagglutination inhibition (HAI) and microneutralisation (MN) assays.FindingsNP vaccination was safe and acceptable; all adverse events were mild or moderate. Most subjects (55%) receiving patch vaccinations (HA or placebo) preferred the NP compared with their past experience of IM injection with N&S (preferred by 24%). The antigen-vaccinated groups had statistically higher HAI titres at day 7 and 21 compared with baseline (p < 0.0001), with no statistical differences between the treatment groups (p > 0.05), although the group sizes were small. The geometric mean HAI titres at day 21 for the NP-HA/FA, NP-HA/UA and IM-HA/D groups were: 335 (189–593 95% CI), 160 (74–345 95% CI), and 221 (129–380 95% CI) respectively. A similar pattern of responses was seen with the MN assays. Application site reactions were mild or moderate, and more marked with the influenza vaccine NPs than with the placebo or IM injection.InterpretationInfluenza vaccination using the NP appeared to be safe, and acceptable in this first time in humans study, and induced similar immune responses to vaccination by IM injection.     

A formative research-guided educational intervention to improve the knowledge and attitudes of seniors towards influenza and pneumococcal vaccinations

BackgroundAdult influenza and pneumococcal vaccination rates in Singapore are low, and factors influencing knowledge and attitudes of seniors towards influenza, pneumonia and their respective vaccines are not well-known. Our study aims to understand the barriers and facilitators towards getting influenza and pneumococcal vaccinations among seniors in Singapore, and subsequently inform the conduct of a relevant community-based educational intervention, as well as evaluate the intervention outcomes.MethodsWe performed a mixed methods study with two components: Firstly, formative research was conducted among community-dwelling seniors, using focus group discussions (FGDs), to understand their knowledge and attitudes towards influenza, pneumonia and their respective vaccines. Next, a quantitative study was conducted to evaluate knowledge of seniors and the effectiveness of an educational intervention.ResultsFour FGDs were organised with 32 participants, who were predominantly female, of lower educational background, and residing in government rental flats. Participants had varying levels of knowledge and many misconceptions about influenza, pneumonia and their respective vaccinations, with concerns about side effects and vaccine effectiveness. The formative research results were used to inform a community-based educational intervention for seniors. Our subsequent evaluation included 604 elderly participants, mainly from lower educational and socio-economic strata, who initially demonstrated poor knowledge scores (median score 5 out of 9, IQR 4-5). Following our intervention, median knowledge score improved to 7 (IQR 6-8) (p < .0001). Significant improvements in knowledge scores were observed across genders, age strata, education levels, and housing types.DiscussionOur formative research identified knowledge gaps among community-dwelling seniors which affected their attitudes towards vaccination uptake. Key findings were taken into consideration when implementing the educational intervention. Our community-based intervention was effective in improving knowledge and attitudes, and could be used as a cue to action for short-term behaviour changes.     

Near real-time surveillance for Guillain-Barré syndrome after influenza vaccination among the Medicare population, 2010/11 to 2013/14

BackgroundGuillain-Barré syndrome (GBS) is a serious acute demyelinating disease that causes weakness and paralysis. The Food and Drug Administration (FDA) began collaborating with the Centers for Medicare and Medicaid Services (CMS) to develop near real-time vaccine safety surveillance capabilities in 2006 and has been monitoring for the risk of GBS after influenza vaccination for every influenza season since 2008.MethodsWe present results from the 2010/11 to 2013/14 influenza seasons using the Updating Sequential Probability Ratio Test (USPRT), with an overall 1-sided α of 0.05 apportioned equally using a constant alpha-spending plan among 20 consecutive weekly tests, 5 ad hoc tests, and a 26th final end of season test. Observed signals were investigated using the self-controlled risk interval (SCRI) design.ResultsOver 15 million people were vaccinated in each influenza season. In the 2010/11 influenza season, we observed an elevated GBS risk during the season, with an end of season SCRI analysis finding a nonsignificant increased risk (RR = 1.25, 95% CI: 0.96–1.63). A sensitivity analysis applying the positive predictive value of the ICD-9 code for GBS from the 2009/10 season estimated a RR = 1.98 (95% CI: 1.42–2.76). Although the 2010/11 influenza vaccine suggested an increased GBS risk, surveillance of the identical vaccine in the 2011/12 influenza season did not find an increased GBS risk after vaccination. No signal was observed in the subsequent three influenza seasons.ConclusionsConducting near real-time surveillance using USPRT has proven to be an excellent method for near real-time GBS surveillance after influenza vaccination, as demonstrated by our surveillance efforts during the 2010/11–2013/14 influenza seasons. In the 2010/2011 influenza season, in addition to the 2009 H1N1 influenza pandemic, using near real-time surveillance we were able to observe a signal early in the influenza season and the method has now become routine.     

Improving the selection and development of influenza vaccine viruses – Report of a WHO informal consultation on improving influenza vaccine virus selection,Hong Kong SAR,China, 18–20 November 2015

Since 2010 the WHO has held a series of informal consultations to explore ways of improving the currently highly complex and time-pressured influenza vaccine virus selection and development process. In November 2015 experts from around the world met to review the current status of efforts in this field.Discussion topics included strengthening influenza surveillance activities to increase the availability of candidate vaccine viruses and improve the extent, timeliness and quality of surveillance data. Consideration was also given to the development and potential application of newer laboratory assays to better characterize candidate vaccine viruses, the potential importance of antibodies directed against influenza virus neuraminidase, and the role of vaccine effectiveness studies. Advances in next generation sequencing and whole genome sequencing of influenza viruses were also discussed, along with associated developments in synthetic genomics technologies, evolutionary analysis and predictive mathematical modelling.Discussions were also held on the late emergence of an antigenic variant influenza A(H3N2) virus in mid-2014 that could not be incorporated in time into the 2014–15 northern hemisphere vaccine. There was broad recognition that given the current highly constrained influenza vaccine development and production timeline it would remain impossible to incorporate any variant virus which emerged significantly long after the relevant WHO biannual influenza vaccine composition meetings. Discussions were also held on the development of pandemic and broadly protective vaccines, and on associated regulatory and manufacturing requirements and constraints.With increasing awareness of the health and economic burdens caused by seasonal influenza, the ever-present threat posed by zoonotic influenza viruses, and the significant impact of the 2014–15 northern hemisphere seasonal influenza vaccine mismatch, this consultation provided a very timely opportunity to share developments and exchange views. In all areas, a renewed and strengthened emphasis was placed on developing concrete and measurable actions and identifying the key stakeholders responsible for their implementation.     

Rational design of medium supplementation strategy for improved influenza viruses production based on analyzing nutritional requirements of MDCK Cells

Influenza vaccine production using cell culture technology has become popular nowadays. However, to meet the ever increasing demand of influenza vaccine, it is prerequisite to improve the yield of influenza virus in cells. To achieve this, in the present study, the nutritional requirements of MDCK cells in the virus production process were analyzed and a nutrient-feeding strategy was developed accordingly. Based on the consumption rates and corresponding concentration optimization, glucose and fast metabolized amino acids were supplemented into the maintaining medium at the time of infection. Compared with the non-supplemented culture, the average cell specific death rate during 0–48 h post-infection was 0.013 h⁻¹, which was 40.91% lower in the nutrient-supplemented culture. Total virus titer, HA antigen protein concentration and cell-specific virus yield were (1.88 ± 0.23) × 10³ HA units/50 μL, 11.70 ± 0.22 μg/mL and (10.06 ± 1.16) × 10³ virions/cell, respectively, which were 84.04 ± 22.50%, 31.46 ± 2.87% and 86.64 ± 25.81% higher than those in the control, respectively. These data showed that the appropriate supplementation of nutrients during virus production process could reduce cell death, and improve cell-specific virus yield and total influenza virus output. This study laid foundation for the development of cell culture technology for influenza vaccine production.     

Influenza vaccination in older people with diabetes and their household contacts

BackgroundPeople with diabetes are at a higher risk of influenza infections and severe complications. The vaccination of close contacts could offer indirect protection to people with diabetes; this is known as “herd immunity.” The aim of this study is to investigate the vaccination rates of people with diabetes and their household contacts in Hong Kong.Research design and methodsFace-to-face interviews with 158 patients diagnosed with Type 2 diabetes and aged ⩾65 years were conducted in clinics. Telephone interviews were then conducted with 281 adult household contacts.ResultsSeasonal influenza vaccination rates were 54.5% and 27.4%, in people with diabetes and their contacts, respectively. The vaccination status of patients was not significantly associated with the vaccination of their household contacts (p = 0.073). Among household contacts, children or the elderly, the partners or couples of patients, and those with more hours of daily contact, or with chronic conditions, were associated with higher vaccination rates. However, only age remained significant after adjusting for confounding factors in logistic regression models.ConclusionsThe low vaccination rates of people with diabetes and their close contacts highlight the need to promote vaccination in susceptible populations and to educate the public about herd immunity.     

Influenza-associated global amnesia and hippocampal imaging abnormality

The acute phase of influenza infection is rarely associated with significant cognitive dysfunction. We describe a case of a 24 year-old man who developed global amnesia in the acute phase of influenza A infection. His deficits resolved over the course of several weeks. Transient abnormalities of diffusion and T2-weighted imaging were seen in the bilateral hippocampi. We review cerebral complications of influenza and discuss the possible role of previously proposed mechanisms in our patient’s case.     

Respiratory syncytial virus and influenza hospitalizations in Danish children 2010–2016

ObjectiveTo pave the way for universal or risk factor-based vaccination strategies, the present study aimed to describe the epidemiology and compare risk factors for hospitalization associated with respiratory syncytial virus (RSV) and influenza virus infections in Danish children.MethodsNational register-based cohort study among 403,422 Danish children born 2010–2016.ResultsPrior asthma hospitalization, number of children in the household, chronic disease and maternal history of asthma hospitalization were the most important risk factors for both RSV and influenza hospitalization. The incidence of influenza increased at school start.ConclusionsOur findings enable targeted vaccination programs for high-risk children with asthma-like disease, chronic disease, siblings in the household, or maternal history of asthma hospitalization.