Influenza Infection Control Research Articles

Influenza A subtype H3N2 is associated with an increased risk of hospital dissemination – an observational study over six influenza seasons

Previous studies on hospital-acquired influenza (HAI) have not systematically evaluated the possible impact of different influenza subtypes. HAI has historically been associated with high mortality, but clinical consequences may be less severe in a modern hospital setting. To identify and quantify HAI for each season, investigate possible associations with varying influenza subtypes, and to determine HAI-associated mortality. All influenza-PCR-positive adult patients (>18 years old) hospitalized in Skåne County during 2013-2019, were prospectively included in the study. Positive influenza samples were subtyped. Medical records of patients with suspected HAI were examined to confirm a nosocomial origin and to determine 30-day mortality. Of 4110 hospitalized patients with a positive influenza PCR, 430 (10.5%) were HAI. Influenza A(H3N2) infections were more often HAI (15.1%) than influenza A(H1N1)pdm09, and influenza B (6.3% and 6.8% respectively, P<0.001). The majority of HAI caused by H3N2 were clustered (73.3 %) and were the cause of all 20 hospital outbreaks consisting of ≥4 affected patients. In contrast, the majority of HAI caused by influenza A(H1N1)pdm09 and influenza B were solitary cases (60% and 63.2%, respectively, P<0.001). Mortality associated with HAI was 9.3% and similar between subtypes. HAI caused by influenza A(H3N2) was associated with an increased risk of hospital dissemination. Our study is relevant for future seasonal influenza infection control preparedness and shows that subtyping of influenza may help to define relevant infection control measures. Mortality in HAI remains substantial in a modern hospital setting.

Policy Analysis for Prevention and Control of Influenza in Aged Care.

This study aimed to analyze national influenza infection control policy documents within aged care settings by identifying the consistencies, inconsistencies, and gaps with the current evidence and by evaluating methodological quality. Aged care providers can use these findings to identify their policy documents' strengths and weaknesses. A quality and content analysis of national level policy documents. Aged care settings rely on national agencies' policy recommendations to control and prevent outbreaks. There is limited research on the effectiveness of control measures to prevent and treat influenza within aged care settings. Because of the complexities around aged care governance, the primary responsibility in developing a comprehensive facility-level, infection-prevention policy, falls to the providers. The analysis was conducted using the (1) International Appraisal of Guidelines, Research and Evaluation assessment tool, containing 23 items across 6 domains; and the (2) Influenza Related Control Measures in Aged Care settings checklist, developed by the authors, with 82 recommendations covering: medical interventions, nonmedical interventions, and physical layout. There were 19 documents from 9 different high-income countries, with a moderately high methodological quality in general. The quality assessment's average score was 40.2% (95% CI 31.9%-44.7%). "Stakeholder involvement" ranked third, and "Editorial independence" and "Rigor of development" had the lowest average scores across all domains. The content analysis' average score was 37.2% (95% CI 10.5%-21.5%). The highest scoring document (59.1%) included term definitions, cited evidence for recommendations, and clear measurable instructions. "Physical Layout" had the least coverage and averaged 21.9% (95% CI 4.2%-37.5%), which shows a substantial gap in built environment recommendations. Existing policy documents vary in their comprehensiveness. The higher scoring documents provide an ideal model for providers. The checklist tools can be used to assess and enhance documents. Further research on document end-user evaluation would be useful, as there is room for improvement in methodological quality and coverage of recommendation coverage, especially related to physical layout.

Pathogen-associated T follicular helper cell plasticity is critical in anti-viral immunity.

T follicular helper (Tfh) cells are critical in providing help for B cells in the germinal center reaction. Tfh cell plasticity, especially with regard to their expression of effector Th cytokines, has been described, but lacks in-depth analysis with genetic approaches. In this study, we systemically compared transcriptomic profiles of Tfh cells derived from various types of immune responses and found gene clusters corresponding to effector Th cells were differentially induced in response to pathogens or immune responses. Of special interest, a subset of Tfh cells producing IFN-γ was generated in an influenza virus infection, partially dependent on the innate cytokine IL-12. Lineage-tracing mouse model revealed unique developmental regulation of IFN-γ+ Tfh cells, while selective ablation of these cells impaired the induction of IgG2c+ germinal center B cells and the control of influenza infection. These results indicate that pathogen-associated Tfh cell plasticity is necessary for host immunity, which has implications in vaccine design.

Characterization and use in neutralization assays of avian influenza codon-optimized H5 and H7 retroviral pseudotypes

Influenza is a relevant problem for public and animal health, with a significant economic impact. In recent years, outbreaks of avian influenza virus have resulted in devastating losses in the poultry industry worldwide, and although its transmission to humans is very rare, there is always a potential risk for an even more severe outbreak. Currently, vaccination is considered the most effective tool for the control and prevention of influenza infections in both humans and animals. The maintenance of animal welfare and the successful implementation of animal health programs depend on the timely administration of vaccines, which must comply with quality specifications indicated by health authorities; for example, the capability to ensure a minimum antibody titer. The production of viral antigens used in these tests can pose a biosafety risk, and some viral strains can be difficult to grow. Therefore, new biotechnological alternatives are required to overcome these disadvantages. In this study, we produced pseudotypes carrying H5 and H7 hemagglutinins from lowly and highly pathogenic avian influenza viruses. These pseudotypes were used in neutralization assays to detect neutralizing antibodies in avian sera, which were confirmed positive by inhibition of the hemagglutination test. Our results showed that the pseudotype neutralization assay is a viable alternative for the detection of neutralizing antibodies, by demonstrating subtype specificity and requiring reduced biosafety requirements. Therefore, it represents a versatile platform that can facilitate technology transfer protocols between laboratories, and an immediate application in serological tools for quality control of veterinary vaccines against avian influenza.

Systems Immunology: Revealing Influenza Immunological Imprint.

Understanding protective influenza immunity and identifying immune correlates of protection poses a major challenge and requires an appreciation of the immune system in all of its complexity. While adaptive immune responses such as neutralizing antibodies and influenza-specific T lymphocytes are contributing to the control of influenza virus, key factors of long-term protection are not well defined. Using systems immunology, an approach that combines experimental and computational methods, we can capture the systems-level state of protective immunity and reveal the essential pathways that are involved. New approaches and technological developments in systems immunology offer an opportunity to examine roles and interrelationships of clinical, biological, and genetic factors in the control of influenza infection and have the potential to lead to novel discoveries about influenza immunity that are essential for the development of more effective vaccines to prevent future pandemics. Here, we review recent developments in systems immunology that help to reveal key factors mediating protective immunity.

INFLUENZA : A COMPLETE OVERVIEW

● At first haemophilus influenza was considered as the causative agent for influenza but after the research it has been found that it caused various other types of infections but not influenza. Influenza was caused by some flu virus which was first isolated from pigs in 1931 and from humans in 1933.(4) ● The 1918 influenza pandemic was the most severe pandemic in recent history it was caused by an H1N1 virus with the genes of avian origin although there is not universal consensus regarding where the virus originated it spread worldwide during 1918 and 1919. (3) ● It was first identified in military personnel in spring 1980 it is estimated that about 500 million people or one third of the world's population became infected with this virus.(3) ● The number of deaths was estimated to be at least 50 million worldwide with about 6,75,000 deaths occurring in the United States. (3) ● Mortality was high in people younger than five years old ,20 to 40 years old and in 65 years and older. The high mortality in healthy people including those in the 20 to 40 year age group was a unique feature of this pandemic. (3) ● There was no vaccine to protect against influenza infection and no antibiotics to treat secondary bacterial infections that can be associated with influenza infection control efforts worldwide were limited to non-pharmaceutical intervention such as isolation quarantine good personal hygiene use of disinfectants and limitations of public gathering which were applied unevenly.(3) ● In the northern and southern parts of the world outbreaks occur mainly in the winter while around the equator outbreaks may occur at any time of the year .In the northern and southern parts of the world outbreaks occur mainly in the winter while around the equator outbreaks may occur at any time of the year.(7) ● In the 20th century three influenza pandemics occurred Spanish influenza in 1918 where the death toll ranged from 17- 200 million deaths, Asian influenza in 1957- 2 million deaths and Hong Kong influenza in 1968 -1 million deaths. ● The world health organisation declared an outbreak of a new type of influenza A or H1N1 to be a pandemic in June 2009. ● influenza may also affect other animals including pig horses and birds.(9) ● The name “influenza” originated in 15th century Italy, from an epidemic attributed to “influence of the stars.” The first pandemic that fits the description of influenza was in 1580. At least four pandemics of influenza occurred in the 19th century, and three occurred in the 20th century. The pandemic of “Spanish” influenza in 1918–1919 caused an estimated 21 million deaths worldwide. The first pandemic of the 21st century occurred in 2009–2010. Historically, influenza viruses of three HA subtypes (H1, H2 and H3) have acquired the ability to be transmitted efficiently between humans. Currently, influenza viruses of the H1 and H3 subtype co-circulate in humans, however influenza viruses of the H2, H5, H6, H7 and H9 subtype are also considered to represent a pandemic threat. In 1997, a large outbreak of highly pathogenic avian influenza (HPAI) H5N1 virus in poultry in Hong Kong resulted in the first documented cases of direct transmission of HPAI H5N1 virus from poultry to humans, with a fatal outcome in 6 out of 18 cases [17]. As a result, this outbreak warranted the mass culling of 1.5 million chickens. In 2003, a large outbreak of an HPAI H7N7 virus in poultry in the Netherlands resulted in 89 cases of human infections, one of which was fatal [21]. HPAI H7N7 virus displayed an unusual tissue tropism; the virus targeted the conjunctiva, resulting in conjunctivitis, a symptom rarely reported for other influenza virus subtypes.(1)

Interferon-induced Transmembrane Protein 3 Prevents Acute Influenza Pathogenesis in Mice

ObjectiveInterferon-induced transmembrane protein 3 (IFITM3) is an important member of the IFITM family. However, the molecular mechanisms underlying its antiviral action have not been completely elucidated. Recent studies on IFITM3, particularly those focused on innate antiviral defense mechanisms, have shown that IFITM3 affects the body's adaptive immune response. The aim of this study was to determine the contribution of IFITM3 proteins to immune control of influenza infection in vivo. MethodsWe performed proteomics, flow cytometry, and immunohistochemistry analysis and used bioinformatics tools to systematically compare and analyze the differences in natural killer (NK) cell numbers, their activation, and their immune function in the lungs of Ifitm3-/- and wild-type mice. ResultsIfitm3-/- mice developed more severe inflammation and apoptotic responses compared to wild-type mice. Moreover, the NK cell activation was higher in the lungs of Ifitm3-/- mice during acute influenza infection. ConclusionsBased on our results, we speculate that the NK cells are more readily activated in the absence of IFITM3, increasing mortality in Ifitm3-/- mice.

A Novel DNA Vaccine Coding For H5 and N1 Genes of Highly Pathogenic Avian Influenza H5N1 Subtype

Control of avian influenza infection requires a good vaccine that could induce both humoral and cell-mediated immune response, specifically IFN-ɣ production, to maintain a high level of protection along with the minimal level of viral shedding after the infection to prevent secondary epidemics. In the current study, deoxyribonucleic Acid (DNA) vaccine coding for full-length H5 and N1 genes have been produced and evaluated in SPF-chicken. Humoral immune response estimated by haemagglutination inhibition (HI) assay revealed that the DNA vaccine gave a high titer of antibodies at the day 28-post vaccination and 14 days post-challenge. However, the shedding level was minimal with the DNA vaccine (0.1 Log 10 EID50). The IFN-ɣ transcript was upregulated at a higher level in the DNA vaccinated group. The results revealed that the DNA vaccine could induce a high level of humoral and IFN-ɣ level that maintains a high level of protection (92%) with the advantage of limiting the shedding level and thus, prevent secondary epidemics.

The Immunogenicity And Protective Efficacy Of Dna Vaccine Coding For Na1 Gene Of Highly Pathogenic Avian Influenza H5n1 Subtype

Control of avian influenza infection depends mainly on biosafety measures and vaccination, DNA vaccination is a novel method to generate antigen-specific antibody and cell-mediated immunity. In the current study, a DNA vaccine for a full-length N1 gene was developed in a trial to decrease the severity of the avian influenza virus spread and shedding. THE full-length N1 gene was cloned in entry clone p ENTER SD/TOPO, followed by homologous recombination with the destination mammalian expression vector (PDEST 40). The PDEST 40-N1 was used in the immunization of SPF chickens. Potency was evaluated through the survival rate that reaches 65%, which was far less than the commercially available inactivated vaccine. Meanwhile, the shedding of the virus from dead birds was 0.46 Log 10 EID50. At the same time, the most surprising result was the shedding level of the vaccinated live birds that were zero sheddings;on the other hand, the inactivated vaccine could not reduce the shedding level which remains very high (3.2 Log 10 EID50 ). IFN-γ transcript level in the DNA vaccinated group was detected by the 3rd-day post-vaccination and remained upregulated till the 28th post-vaccination. After the challenge, the level of IFN-γ was much higher until 14 days post-challenge. The inactivated vaccine could not stimulate any detectable level post-vaccination. These data suggested the ability of DNA vaccine coding for N1 gene of avian influenza to combat the virus shedding from live birds and could be used in combination with DNA vaccine coding for H5 to produce maximum protection with zero sheddings.

Circadian control of lung inflammation in influenza infection

Influenza is a leading cause of respiratory mortality and morbidity. While inflammation is essential for fighting infection, a balance of anti-viral defense and host tolerance is necessary for recovery. Circadian rhythms have been shown to modulate inflammation. However, the importance of diurnal variability in the timing of influenza infection is not well understood. Here we demonstrate that endogenous rhythms affect survival in influenza infection. Circadian control of influenza infection is mediated by enhanced inflammation as proven by increased cellularity in bronchoalveolar lavage (BAL), pulmonary transcriptomic profile and histology and is not attributable to viral burden. Better survival is associated with a time dependent preponderance of NK and NKT cells and lower proportion of inflammatory monocytes in the lung. Further, using a series of genetic mouse mutants, we elucidate cellular mechanisms underlying circadian gating of influenza infection.

Presenteeism among health care workers with laboratory-confirmed influenza infection: A retrospective cohort study in Queensland, Australia

A high prevalence of working while ill (presenteeism) has been documented among health care workers (HCWs). However, previous evidence is primarily based on nonspecific causes of sickness and self-reported data. Our study examined presenteeism among HCWs with laboratory-confirmed influenza. The data pertaining to laboratory-confirmed influenza cases and history of sick leave among HCWs in Queensland, Australia, were collected from 2009-2015. The incidence and duration of sick leave around the time of disease confirmation were analyzed. The associations of factors, such as job category and employment status, on presenteeism were assessed with regression analyses. The overall sick leave incidence was 85.9% in the laboratory-confirmed periods, which translates that 14.1% of HCWs were working while ill with influenza. Among medical doctors, approximately one-quarter of them were attending work in the period. A shorter duration of leave was also observed among medical doctors and full-time employees compared with other HCWs and part-time employees. Presenteeism among HCWs with influenza put both HCWs and patients at risk by increasing potential for transmission. Our findings emphasize the importance of an integrated approach including both HCW sick leave management and vaccination for strategic prevention and control of nosocomial influenza infection.

Accounting for the Spread of Vaccination Behavior to Optimize Influenza Vaccination Programs

Influenza vaccination is the most efficient approach to prevent influenza infection and its complications. While previous studies considered the externalities of vaccination arising from indirect protection for prediction and control of influenza infection, they often neglected another potential externality of a vaccinated individual – the effect on her environment's decision to become vaccinated. Here we model influenza vaccination as a socially contagious process. Our model uses a contact network we developed based on cellular data of 17 Billion records describing the location of 1.8 million Israeli cellphone users. The model was calibrated to high-quality longitudinal data of weekly influenza vaccination uptake and influenza diagnoses over seven years. We demonstrate how a simple coupled transmission-model accurately captures spatiotemporal patterns of both influenza vaccination uptake and influenza transmission. Our simulations indicate that modeling the vaccination spread alongside the propagation of the disease infection, coupled to each other, reveals complex underlying dynamics regarding the timing of the processes. Specifically, we show that higher overall vaccination coverage leads to a more rapid vaccination process and an earlier onset of the influenza activity. We prove this understanding to be useful to improve the timing of influenza vaccination programs.

Novel Approaches for The Development of Live Attenuated Influenza Vaccines.

Influenza virus still represents a considerable threat to global public health, despite the advances in the development and wide use of influenza vaccines. Vaccination with traditional inactivate influenza vaccines (IIV) or live-attenuated influenza vaccines (LAIV) remains the main strategy in the control of annual seasonal epidemics, but it does not offer protection against new influenza viruses with pandemic potential, those that have shifted. Moreover, the continual antigenic drift of seasonal circulating influenza viruses, causing an antigenic mismatch that requires yearly reformulation of seasonal influenza vaccines, seriously compromises vaccine efficacy. Therefore, the quick optimization of vaccine production for seasonal influenza and the development of new vaccine approaches for pandemic viruses is still a challenge for the prevention of influenza infections. Moreover, recent reports have questioned the effectiveness of the current LAIV because of limited protection, mainly against the influenza A virus (IAV) component of the vaccine. Although the reasons for the poor protection efficacy of the LAIV have not yet been elucidated, researchers are encouraged to develop new vaccination approaches that overcome the limitations that are associated with the current LAIV. The discovery and implementation of plasmid-based reverse genetics has been a key advance in the rapid generation of recombinant attenuated influenza viruses that can be used for the development of new and most effective LAIV. In this review, we provide an update regarding the progress that has been made during the last five years in the development of new LAIV and the innovative ways that are being explored as alternatives to the currently licensed LAIV. The safety, immunogenicity, and protection efficacy profile of these new LAIVs reveal their possible implementation in combating influenza infections. However, efforts by vaccine companies and government agencies will be needed for controlled testing and approving, respectively, these new vaccine methodologies for the control of influenza infections.

Th17 serum cytokines in relation to laboratory-confirmed respiratory viral infection: A pilot study.

BackgroundTh17 cytokines are associated with modulation of inflammation and may be beneficial in clearing influenza infection in experimental models. The Th17 cytokine profile was evaluated in a pilot study of respiratory virus infections.MethodsConsecutive patients with symptoms of respiratory tract infection visiting the emergency department of a tertiary care hospital during the winter influenza season of 2014 to 2015 were evaluated. CLART PneumoVir kit, (GENOMICA, Madrid, Spain) was used for viral detection of all known respiratory viruses. Th17 cytokine profile was evaluated with the MILLIPLEX MAP Human TH17 Magnetic Bead Panel (Millipore Corp., Billerica, MA). Correlation of the TH17 profile with viral detection was performed with univariate and multivariate analysis.ResultsSeventy‐six patients were evaluated (median age 56 years, 51.3% female); a respiratory virus was identified in 60 (78.9%) patients; 45% had confirmed influenza. Influenza A (H3N2) correlated with higher levels of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), interleukin 1β (IL‐1β), IL‐17A, IL‐17E, IL‐17F, IL‐21, IL‐22, and IL‐23 (P < 0.05 by analysis of variance [ANOVA]) compared with respiratory syncytial virus (RSV). Parainfluenza virus (PIV) similarly had higher levels of GM‐CSF, IL‐1b, IL‐17A, IL‐22 compared with those detected in RSV, influenza B and any other virus infection ( P < 0.05; ANOVA). Increasing age (β‐coefficient = 1.11, 95% CI, 1.04‐1.2, P < 0.01) as well as IL‐17A levels (β‐coefficient = 1.03, 95% CI, 1.001‐1.05, P = 0.04) predicted hospital admission.ConclusionMain Th17 cell effector cytokines were upregulated in laboratory‐confirmed A(H3N2) influenza and PIV. Excessive amounts of Th17 cytokines may be implicated in the pathogenesis and immune control of acute influenza and PIV infection in humans and may predict the severity of disease.

Therapeutic Administration of Broadly Neutralizing FI6 Antibody Reveals Lack of Interaction Between Human IgG1 and Pig Fc Receptors.

Influenza virus infection is a significant global health threat. Because of the lack of cross-protective universal vaccines, short time window during which antivirals are effective and drug resistance, new therapeutic anti-influenza strategies are required. Broadly, cross-protective antibodies that target conserved sites in the hemagglutinin (HA) stem region have been proposed as therapeutic agents. FI6 is the first proven such monoclonal antibody to bind to H1–H16 and is protective in mice and ferrets. Multiple studies have shown that Fc-dependent mechanisms are essential for FI6 in vivo efficacy. Here, we show that therapeutic administration of FI6 either intravenously or by aerosol to pigs did not reduce viral load in nasal swabs or broncho-alveolar lavage, but aerosol delivery of FI6 reduced gross pathology significantly. We demonstrate that pig Fc receptors do not bind human IgG1 and that FI6 did not mediate antibody-dependent cytotoxicity (ADCC) with pig PBMC, confirming that ADCC is an important mechanism of protection by anti-stem antibodies in vivo. Enhanced respiratory disease, which has been associated with pigs with cross-reactive non-neutralizing anti-HA antibodies, did not occur after FI6 administration. Our results also show that in vitro neutralizing antibody responses are not a robust correlate of protection for the control of influenza infection and pathology in a natural host model.

Health-seeking behavior and transmission dynamics in the control of influenza infection among different age groups.

BackgroundIt has been found that health-seeking behavior has a certain impact on influenza infection. However, behaviors with/without risk perception on the control of influenza transmission among age groups have not been well quantified.ObjectivesThe purpose of this study was to assess to what extent, under scenarios of with/without control and preventive/protective behaviors, the age-specific network-driven risk perception influences influenza infection.Materials and methodsA behavior-influenza model was used to estimate the spread rate of age-specific risk perception in response to an influenza outbreak. A network-based information model was used to assess the effect of network-driven risk perception information transmission on influenza infection. A probabilistic risk model was used to assess the infection risk effect of risk perception with a health behavior change.ResultsThe age-specific overlapping percentage was estimated to be 40%–43%, 55%–60%, and 19%–35% for child, teenage and adult, and elderly age groups, respectively. Individuals perceive the preventive behavior to improve risk perception information transmission among teenage and adult and elderly age groups, but not in the child age group. The population with perceived health behaviors could not effectively decrease the percentage of infection risk in the child age group, whereas for the elderly age group, the percentage of decrease in infection risk was more significant, with a 97.5th percentile estimate of 97%.ConclusionThe present integrated behavior-infection model can help health authorities in communicating health messages for an intertwined belief network in which health-seeking behavior plays a key role in controlling influenza infection.

Lactobacillus paracasei feeding improves immune control of influenza infection in mice.

Respiratory tract infections such as flu cause severe morbidity and mortality and are among the leading causes of death in children and adults worldwide. Commensal microbiota is critical for orchestrating tissue homeostasis and immunity in the intestine. Probiotics represent an interesting source of immune modulators and several clinical studies have addressed the potential beneficial effects of probiotics against respiratory infections. Therefore, we have investigated the mechanisms of protection conferred by L. paracasei CNCM I-1518 strain in a mouse model of influenza infection. Notably, local myeloid cells accumulation is generated in the lungs after seven days feeding with L. paracasei prior to viral infection. L. paracasei-fed mice showed reduced susceptibility to the influenza infection, associated with less accumulation of inflammatory cells in the lungs, faster viral clearance and general health improvement. Interestingly, Allobaculum was significantly increased in L. paracasei-fed mice 7 days after influenza infection, even if the gut microbiota composition was not altered overall. L. paracasei-purified peptidoglycan partially recapitulated the protective phenotype observed with the entire bacteria. Collectively, our results demonstrate that oral consumption of L. paracasei CNCM I-1518 modulates lung immunity was associated with an improved control of influenza infection. These results further extend the beneficial role for certain lactobacilli to alleviate the burden of respiratory tract infections.

Antiviral Drugs for the Treatment and Prevention of Influenza

This paper provides an overview of the currently available treatment options for influenza infections. Currently, the options are limited to only one class of drugs known as the neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir and peramivir) as there is widespread resistance against the adamantanes, an older class of antivirals. This review therefore discusses the mode of action, dosing, summary of clinical trial data and resistance within the context of NAIs. Newer antiviral therapies in late-phase clinical trials are also summarized in this review. Oseltamivir is the most commonly used NAI amongst the four different types available. The most recent meta-analysis of placebo-controlled trials demonstrates that for uncomplicated seasonal influenza, oseltamivir reduces symptoms by 16–24 h, while observational studies cumulatively suggest that oseltamivir treatment reduces mortality in severely ill patients. NAIs also play an important role in the treatment and control of avian influenza infections in humans, which is a public health concern due to their high case fatality rate. The latest analysis of data suggests that early treatment with oseltamivir can be attributed to reducing mortality in patients with avian A(H5N1) infections; data regarding oseltamivir effectiveness against A(H7N9) infections is however more limited. During the 2014–2015 influenza season, the frequency of resistance to the NAIs in all circulating viruses was below 1%, but immunocompromised patients infected with influenza are often at higher risk of shedding resistant viruses due to slow viral clearance and extended treatment regimens. Favipiravir, a polymerase inhibitor, has received limited approval for use in Japan, but its use is restricted to novel viruses that are resistant to other antiviral therapies. Antivirals such as thiazolide, nitazoxanide and endonuclease inhibitor, S-033188, are currently in phase III clinical trials and other influenza antivirals are in early or mid-phase clinical trials. This review highlights a lack of different treatment options for influenza infections. While there are four different types of NAIs, in many countries, oseltamivir is the only available option. New therapies are being rapidly developed to meet the need for a greater variety of antivirals, and as such, it is likely that over the next decade, a broader range of influenza therapeutics will become available for treatment.

Assessing the oseltamivir-induced resistance risk and implications for influenza infection control strategies.

BackgroundOseltamivir-resistant mutants with higher drug resistance rates and low trans-mission fitness costs have not accounted for influenza (sub)type viruses. Predicting the impacts of neuraminidase inhibitor therapy on infection rates and transmission of drug-resistant viral strains requires further investigation.ObjectivesThe purpose of this study was to assess the potential risk of oseltamivir-induced resistance for influenza A (H1N1) and A (H3N2) viruses.Materials and methodsAn immune-response-based virus dynamic model was used to best fit the oseltamivir-resistant A (H1N1) and A (H3N2) infection data. A probabilistic risk assessment model was developed by incorporating branching process-derived probability distribution of resistance to estimate oseltamivir-induced resistance risk.ResultsMutation rate and sensitive strain number were key determinants in assessing resistance risk. By increasing immune response, antiviral efficacy, and fitness cost, the spread of resistant strains for A (H1N1) and A (H3N2) were greatly decreased. Probability of resistance depends most strongly on the sensitive strain number described by a Poisson model. Risk of oseltamivir-induced resistance increased with increasing the mutation rate for A (H1N1) only. The ≥50% of resistance risk induced by A (H1N1) and A (H3N2) sensitive infected cells were 0.4 (95% CI: 0.28–0.43) and 0.95 (95% CI 0.93–0.99) at a mutation rate of 10−6, respectively. Antiviral drugs must be administrated within 1–1.5 days for A (H1N1) and 2–2.5 days for A (H3N2) virus infections to limit viral production.ConclusionProbabilistic risk assessment of antiviral drug-induced resistance is crucial in the decision-making process for preventing influenza virus infections.

Re-emergence of amantadine-resistant variants among highly pathogenic avian influenza H5N1 viruses in Egypt

Highly pathogenic avian influenza (HPAI) H5N1 virus continues to undergo substantial evolution. Emergence of antiviral resistance among H5N1 avian influenza viruses is a major challenge in the control of pandemic influenza. Numerous studies have focused on the genetic and evolutionary dynamics of the hemagglutinin and neuraminidase genes; however, studies on the susceptibility of HPAI H5N1 viruses to amantadine and genetic diversity of the matrix (M) gene are limited. Accordingly, we studied the amantadine susceptibility of the HPAI H5N1 viruses isolated in Egypt during 2006–2015 based on genotypic and phenotypic characteristics. We analyzed data on 253 virus sequences and constructed a phylogenetic tree to calculate selective pressures on sites in the M2 gene associated with amantadine-resistance among different clades. Selection pressure was identified in the transmembrane domain of M2 gene at positions 27 and 31. Amantadine-resistant variants emerged in 2007 but were not circulating between 2012 and 2014. By 2015, amantadine-resistant HPAI H5N1 viruses re-emerged. This may be associated with the uncontrolled prescription of amantadine for prophylaxis and control of avian influenza infections in the poultry farm sector in Egypt. More epidemiological research is required to verify this observation.