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Abstract
Influenza is an acute respiratory illness, caused by influenza A, B, and C viruses, that occurs in local outbreaks or seasonal epidemics. Clinical illness follows a short incubation period and presentation ranges from asymptomatic to fulminant, depending on the characteristics of both the virus and the individual host. Influenza A viruses can also cause sporadic infections or spread worldwide in a pandemic when novel strains emerge in the human population from an animal host. New approaches to influenza prevention and treatment for management of both seasonal influenza epidemics and pandemics are desirable. In this Seminar, we discuss the clinical presentation, transmission, diagnosis, management, and prevention of seasonal influenza infection. We also review the animal–human interface of influenza, with a focus on current pandemic threats.
... There are four types of influenza viruses: A, B, C, and D, of which A and B are most common, and type A is responsible for pandemics and seasonal epidemics. Influenza virus belongs to the Orthomyxoviridae family, and has a diameter of 80-120 nm and mass about 170-200 × 10 6 Da [6]. Genetic material of influenza A and B viruses has eight linear segments in single-stranded RNA, enclosed in a lipid-protein envelope [7,8]. ...
... Particles of aerosols can remain airborne from minutes to hours, while larger droplets can settle within 2 to 3 m from an infected person. Additionally, influenza virus can remain infectious on non-porous surfaces up to 48 h [6]. ...
... Epidemiological data indicate that a large number of children up to four years of age are most likely to be infected [3]. Their young bodies have not yet fully developed their immune system, which in the case of infection with influenza viruses can lead to a severe course of the disease and numerous complications in various systems, in severe cases leading to hospitalization of the children, mainly under the age of two [6]. It is mainly in children that flu leads to gastrointestinal symptoms such as nausea, vomiting, and diarrhea [2]. ...
In Poland, flu supervision is coordinated by the National Influenza Center at the National Institute of Public Health—National Institute of Hygiene. In this publication, we want to determine geographical trends in influenza virus circulation in the region. A detailed analysis of virological and epidemiological data showed the course of the epidemic season in Poland, as well as in neighboring countries. The spatial differentiation of the incidence of infection between voivodships was examined, as well as compared to countries that border a given voivodship. The results show a significant variation in the incidence of infection in terms of time and space. This points to the need to increase the number of tests and to raise awareness among health care professionals and the public about the probability of an influenza pandemic, as undetected viruses can spread further into the European Union.
... Influenza is another acute respiratory illness. The most effective method for preventing and controlling is a vaccination available for many years [9,10]. During the first months of the COVID-19 pandemic, it was often compared to either seasonal flu or the deadliest flu outbreaks in history due to some mortality and morbidity similarities [11]. ...
... During the first months of the COVID-19 pandemic, it was often compared to either seasonal flu or the deadliest flu outbreaks in history due to some mortality and morbidity similarities [11]. It is estimated Vaccines 2021, 9,475 2 of 10 that globally each year, an average of 389,000 respiratory deaths are associated with influenza (the uncertainty ranges from 294,000 to 518,000) [12]. Despite the yearly death toll and the availability of effective and safe vaccines against influenza, most countries' vaccination levels seem to be pretty low. ...
... We asked the respondents to report their intention to receive the influenza vaccine and the COVID-19 vaccine if it is available in the future. A considerable number of study participants (21.0% and 21.5%) reported "Not sure" Vaccines 2021, 9,475 8 of 10 about their intention to receive the COVID-19 and influenza vaccinations, respectively. The real intention could be different when the vaccine is available. ...
Despite research conducted worldwide, there is no treatment specifically targeting SARS-CoV-2 infection with efficacy proven by randomized controlled trials. A chance for a breakthrough is vaccinating most of the global population. Public opinion surveys on vaccine hesitancy prompted our team to investigate Polish healthcare workers’ (HCWs) attitudes towards the SARS-CoV-2 and influenza vaccinations. In-person and online surveys of HCWs: doctors, nurses, medical students, and other allied health professionals (n = 419) were conducted between 14 September 2020 and 5 November 2020. In our study, 68.7% of respondents would like to be vaccinated against COVID-19. The safety and efficacy of COVID-19 vaccinations would persuade 86.3% of hesitant and those who would refuse to be vaccinated. 3.1% of all respondents claimed that no argument would convince them to get vaccinated. 61.6% of respondents declared a willingness to receive an influenza vaccination, of which 83.3% were also inclined to receive COVID-19 vaccinations. Although most respondents—62.5% (262/419) indicated they trusted in the influenza vaccine more, more respondents intended to get vaccinated against COVID-19 in the 2020/2021 season. The study is limited by its nonrandom sample of HCWs but provides a preliminary description of attitudes towards SARS-CoV-2 vaccination.
... The composition of influenza vaccines is updated annually to keep pace with antigenic drift. 11 Adults aged 65 or older have the highest risk for hospitalization, complications, and death resulting from influenza, 12 13 and this risk increases markedly in people over 85. 13 The gradual accumulation of underlying health conditions contributes to this risk. The estimated global mean annual influenza associated respiratory excess mortality is 0.1-6.4 per 100 000 people under 65 and 17.9 to 223.5 for people over 75. ...
... They contain antigens representing two circulating influenza A subtypes and either one or both of the circulating influenza B virus lineages. 11 The standard influenza vaccine is a trivalent or quadrivalent preparation comprised of inactivated split virions, enriched for hemagglutinin and neuraminidase and formulated to contain 15 μg of hemagglutinin of each virus component. Influenza vaccine effectiveness depends on many factors, 88 including the antigenic match between the circulating strain and the strain included in the vaccine, the presence of egg adaptation mutations resulting from growth of the vaccine virus in eggs (discussed below), and age. ...
The proportion of the global population aged 65 and older is rapidly increasing. Infections in this age group, most recently with SARS-CoV-2, cause substantial morbidity and mortality. Major improvements have been made in vaccines for older people, either through the addition of novel adjuvants—as in the new recombinant zoster vaccine and an adjuvanted influenza vaccine—or by increasing antigen concentration, as in influenza vaccines. In this article we review improvements in immunization for the three most important vaccine preventable diseases of aging. The recombinant zoster vaccine has an efficacy of 90% that is minimally affected by the age of the person being vaccinated and persists for more than four years. Increasing antigen dose or inclusion of adjuvant has improved the immunogenicity of influenza vaccines in older adults, although the relative effectiveness of the enhanced influenza vaccines and the durability of the immune response are the focus of ongoing clinical trials. Conjugate and polysaccharide pneumococcal vaccines have similar efficacy against invasive pneumococcal disease and pneumococcal pneumonia caused by vaccine serotypes in older adults. Their relative value varies by setting, depending on the prevalence of vaccine serotypes, largely related to conjugate vaccine coverage in children. Improved efficacy will increase public confidence and uptake of these vaccines. Co-administration of these vaccines is feasible and important for maximal uptake in older people. Development of new vaccine platforms has accelerated following the arrival of SARS-CoV-2, and will likely result in new vaccines against other pathogens in the future.
... In each year of the 2010/2011 through 2014/2015 seasons, there was an estimated 65 to 190 million people infected and 88,100 influenza-associated excess respiratory deaths in China [2]. Although there are antiviral drugs for influenza, such as oseltamivir and zanamivir [3], influenza vaccination is considered the most economical and effective way to prevent influenza [4]. However, with the exception of a few cities where local government subsidize influenza vaccination programs, influenza vaccination has not been introduced in a national, government-funded program for people in mainland China, nor is the influenza vaccine included in health insurance. ...
... Influenza vaccination is widely considered to be the most effective and cost-beneficial way to prevent influenza [4]. Evaluating influenza VE is very important for supporting policy making. ...
Influenza endangers human health but can be prevented in part by vaccination. Assessing influenza vaccine effectiveness (VE) provides scientific evidence for developing influenza vaccination policy. We conducted a systematic review and meta-analysis of studies that evaluated influenza VE in mainland China. We searched six relevant databases as of 30 August 2019 to identify studies and used Review Manager 5.3 software to analyze the included studies. The Newcastle–Ottawa scale was used to assess the risk of publication bias. We identified 1408 publications, and after removing duplicates and screening full texts, we included 21 studies in the analyses. Studies were conducted in Beijing, Guangzhou, Suzhou, and Zhejiang province from the 2010/11 influenza season through the 2017/18 influenza season. Overall influenza VE for laboratory confirmed influenza was 36% (95% CI: 25–46%). In the subgroup analysis, VE was 45% (95% CI: 18–64%) for children 6–35 months who received one dose of influenza vaccine, and 57% (95% CI: 50–64%) who received two doses. VE was 47% (95% CI: 39–54%) for children 6 months to 8 years, and 18% (95% CI: 0–33%) for adults ≥60 years. For inpatients, VE was 21% (95% CI: −11–44%). We conclude that influenza vaccines that were used in mainland China had a moderate effectiveness, with VE being higher among children than the elderly. Influenza VE should be continuously monitored in mainland China to provide evidence for policy making and improving uptake of the influenza vaccine.
... The capacity of IAVs to infect a wide range of hosts, most notably swine, poultry, waterfowl, and humans, can occasionally result in the emergence of a novel viral strain to which humans have little-to-no prior immunity. This process, termed antigenic shift, occurs through genetic reassortment when one cell becomes infected with viruses from multiple host species and can lead to the emergence of a pandemic [75]. The rest of this review will focus on IAVs as these infections are the most robustly described in experimental models and in vivo. ...
... The primary target cells of IAV are epithelial cells found in the respiratory tract and HA facilitates entry into these cells by binding surface sialic acid residues [69,76]. IAVs are further classified into subtypes on the basis of the antigenic properties of HA and NA [75]. There are currently 18 HA and 11 NA subtypes. ...
Influenza viruses are one of the most prevalent respiratory pathogens known to humans and pose a significant threat to global public health each year. Annual influenza epidemics are responsible for 3–5 million infections worldwide and approximately 500,000 deaths. Presently, yearly vaccinations represent the most effective means of combating these viruses. In humans, influenza viruses infect respiratory epithelial cells and typically cause localized infections of mild to moderate severity. Neutrophils are the first innate cells to be recruited to the site of the infection and possess a wide range of effector functions to eliminate viruses. Some well-described effector functions include phagocytosis, degranulation, the production of reactive oxygen species (ROS), and the formation of neutrophil extracellular traps (NETs). However, while these mechanisms can promote infection resolution, they can also contribute to the pathology of severe disease. Thus, the role of neutrophils in influenza viral infection is nuanced, and the threshold at which protective functions give way to immunopathology is not well understood. Moreover, notable differences between human and murine neutrophils underscore the need to exercise caution when applying murine findings to human physiology. This review aims to provide an overview of neutrophil characteristics, their classic effector functions, as well as more recently described antibody-mediated effector functions. Finally, we discuss the controversial role these cells play in the context of influenza virus infections and how our knowledge of this cell type can be leveraged in the design of universal influenza virus vaccines.
... Every year, the world faces seasonal flu caused by influenza viruses. Three types of influenza viruses affect humans, the most common being type A and type B. 9 Approximately 30-50% of cases of common cold are caused by rhinoviruses. The second-most common agents are human coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63), which account for 10-15% of cases of this disease. ...
... 14 In influenza, RT-PCR and viral culturing have a sensitivity close to 100%, but the turnaround time for a viral culture is 3-10 days compared to 1-8 h for RT-PCR. 9 In SARS, RT-PCR is the method of the first choice for detection. 27 ...
Background:
This review focuses on the frequency of symptoms in COVID-19 in comparison to SARS, influenza and common cold.
Objectives:
To evaluate and compare the knowledge about the clinical features, symptoms and differences between patients with COVID-19, SARS, influenza, and common cold. The research can help ear, nose and throat specialists and other health practitioners manage patients during the COVID-19 pandemic.
Material and methods:
The biomedical databases used in the study included PubMed and MEDLINE. Statistical analysis using the Z-score test assessed which symptoms were more characteristic of COVID-19 than other viral diseases.
Results:
Among individuals with COVID-19, the most frequently reported symptoms were cough (70%), fever (45%), muscular pain (29%), and headache (21%), whereas sore throat (12%), and rhinorrhea (4%) were observed at lower rates. Fever was identified as most frequent in COVID-19 (74%), appearing at a higher rate in those cases than in influenza (68%) or the common cold (40%) (p < 0.05). In comparison to other viral diseases, sore throat was rarely reported in COVID-19 and SARS (12% and 18%, respectively) (p < 0.05). In influenza and common cold, a cough was identified in 93% and 80% of cases (p < 0.05). Headache, rhinorrhea, muscular pain, and sore throat were more common in influenza (91%, 91%, 94%, and 84%, respectively) and common cold (89%, 81%, 94%, and 84%, respectively) than in COVID-19 (21%, 4%, 29%, and 12%, respectively) and SARS (45%, 12%, 55%, and 18%, respectively) (p < 0.05).
Conclusion:
The results of the analysis show that a greater number of general symptoms should lead to a diagnosis of influenza or common cold rather than COVID-19.
... Viral pathogens such as smallpox and measles have been completely or nearly eradicated on a global scale owing to the remarkable success of vaccines; however, influenza virus continues to remain a critical public health issue, as repeated exposure through infection or yearly vaccination has yet to yield long-lasting and durable protection [1][2][3][4][5]. This inability to generate broadly protective herd immunity imposes a significant burden to healthcare systems, where influenza virus is responsible for roughly 3-5 million cases of infection globally with up to 650,000 annual deaths [6,7]. ...
... HA can be further subdivided into Group 1 or Group 2 based on further antigenic variation ( Figure 1B). Of the influenza subtypes, H1N1 and H3N2 strains routinely co-circulate in the human population, and, along with influenza B, are responsible for yearly seasonal epidemics [7,12]. Current seasonal vaccines consist of a trivalent or quadrivalent formulation which includes two influenza A strains (H1N1 and H3N2) and one or two strains from the influenza B lineages (Yamagata and Victoria) ( Figure 1B). ...
Influenza virus remains a serious public health burden due to ongoing viral evolution. Vaccination remains the best measure of prophylaxis, yet current seasonal vaccines elicit strain-specific neutralizing responses that favor the hypervariable epitopes on the virus. This necessitates yearly reformulations of seasonal vaccines, which can be limited in efficacy and also shortchange pandemic preparedness. Universal vaccine development aims to overcome these deficits by redirecting antibody responses to functionally conserved sites of viral vulnerability to enable broad coverage. However, this is challenging as such antibodies are largely immunologically silent, both following vaccination and infection. Defining and then overcoming the immunological basis for such subdominant or ‘immuno-recessive’ antibody targeting has thus become an important aspect of universal vaccine development. This, coupled with structure-guided immunogen design, has led to proof-of-concept that it is possible to rationally refocus humoral immunity upon normally ‘unseen’ broadly neutralizing antibody targets on influenza virus.
... Respiratory infections in adults and children have been among the top three leading causes of death and disability in the world for decades (1,2). Novel respiratory pathogens are emerging and can quickly spread due to the ease of transmission, as witnessed in the current coronavirus (3)(4)(5) and past influenza pandemics (6). Vaccines are essential for the control and elimination of these diseases by eliciting antibody and/or T cell-mediated immune responses (CMI). ...
Eliciting durable and protective T cell-mediated immunity in the respiratory mucosa remains a significant challenge. Polylactic-co-glycolic acid (PLGA)-based cationic pathogen-like particles (PLPs) loaded with TLR agonists mimic biophysical properties of microbes and hence, simulate pathogen-pattern recognition receptor interactions to safely and effectively stimulate innate immune responses. We generated micro particle PLPs loaded with TLR4 (glucopyranosyl lipid adjuvant, GLA) or TLR9 (CpG) agonists, and formulated them with and without a mucosal delivery enhancing carbomer-based nanoemulsion adjuvant (ADJ). These adjuvants delivered intranasally to mice elicited high numbers of influenza nucleoprotein (NP)-specific CD8+ and CD4+ effector and tissue-resident memory T cells (TRMs) in lungs and airways. PLPs delivering TLR4 versus TLR9 agonists drove phenotypically and functionally distinct populations of effector and memory T cells. While PLPs loaded with CpG or GLA provided immunity, combining the adjuvanticity of PLP-GLA and ADJ markedly enhanced the development of airway and lung TRMs and CD4 and CD8 T cell-dependent immunity to influenza virus. Further, balanced CD8 (Tc1/Tc17) and CD4 (Th1/Th17) recall responses were linked to effective influenza virus control. These studies provide mechanistic insights into vaccine-induced pulmonary T cell immunity and pave the way for the development of a universal influenza and SARS-CoV-2 vaccines.
... Dynamic decisions are being made at individual and policy levels about the safety of social interactions, including attendance at workplaces and schools (31,32), and throughout the pandemic almost 75% of schools globally have experienced some magnitude of closure (4). This response was based primarily on a large body of existing data which implicates school-aged children as major spreaders of influenza (33). It is now understood that this may not be the case for SARS-CoV-2 (34)(35)(36), and that the incidence of transmission from child to child or child to adult appears to be low (37,38). ...
Introduction: Amidst the evolving COVID-19 pandemic, understanding the transmission dynamics of the SARS-CoV-2 virus is key to providing peace of mind for the community and informing policy-making decisions. While available data suggest that school-aged children are not significant spreaders of SARS-CoV-2, the possibility of transmission in schools remains an ongoing concern, especially among an aging teaching workforce. Even in low-prevalence settings, communities must balance the potential risk of transmission with the need for students' ongoing education. Through the roll out of high-throughput school-based SARS-CoV-2 testing, enhanced follow-up for individuals exposed to COVID-19 and wellbeing surveys, this study investigates the dynamics of SARS-CoV-2 transmission and the current psychosocial wellbeing impacts of the pandemic in school communities.
Methods: The DETECT Schools Study is a prospective observational cohort surveillance study in 79 schools across Western Australia (WA), Australia. To investigate the incidence, transmission and impact of SARS-CoV-2 in schools, the study comprises three “modules”: Module 1) Spot-testing in schools to screen for asymptomatic SARS-CoV-2; Module 2) Enhanced surveillance of close contacts following the identification of any COVID-19 case to determine the secondary attack rate of SARS-CoV-2 in a school setting; and Module 3) Survey monitoring of school staff, students and their parents to assess psycho-social wellbeing following the first wave of the COVID-19 pandemic in WA.
Clinical Trial Registration: Trial registration number: ACTRN12620000922976
... The Influenza virus is a single-strand RNA virus in the Orthomyxoviridae family that causes the flu in humans and other species [259]. The Influenza virus is a constant threat to public health and safety because it can easily spread between hosts, including occasional interspecies spread. ...
The fruit fly, Drosophila melanogaster, has been used to understand fundamental principles of genetics and biology for over a century. Drosophila is now also considered an essential tool to study mechanisms underlying numerous human genetic diseases. In this review, we will discuss how flies can be used to deepen our knowledge of infectious disease mechanisms in vivo. Flies make effective and applicable models for studying host-pathogen interactions thanks to their highly conserved innate immune systems and cellular processes commonly hijacked by pathogens. Drosophila researchers also possess the most powerful, rapid, and versatile tools for genetic manipulation in multicellular organisms. This allows for robust experiments in which specific pathogenic proteins can be expressed either one at a time or in conjunction with each other to dissect the molecular functions of each virulent factor in a cell-type-specific manner. Well documented phenotypes allow large genetic and pharmacological screens to be performed with relative ease using huge collections of mutant and transgenic strains that are publicly available. These factors combine to make Drosophila a powerful tool for dissecting out host-pathogen interactions as well as a tool to better understand how we can treat infectious diseases that pose risks to public health, including COVID-19, caused by SARS-CoV-2.
... Complications include pneumonia, bronchiolitis, toxic shock syndrome, seizures, and bacterial pneumonia. Infection occurs via the carbohydrate-binding protein haemagglutinin (HA) and the enzyme neuraminidase (NA) to cleave the glycosidic bonds of the sialic acid residues of plasma membranes [84]. ...
Neutrophils act as the first line of defense during infection and inflammation. Once activated, they are able to fulfil numerous tasks to fight inflammatory insults while keeping a balanced immune response. Besides well-known functions, such as phagocytosis and degranulation, neutrophils are also able to release “neutrophil extracellular traps” (NETs). In response to most stimuli, the neutrophils release decondensed chromatin in a NADPH oxidase-dependent manner decorated with histones and granule proteins, such as neutrophil elastase, myeloperoxidase, and cathelicidins. Although primarily supposed to prevent microbial dissemination and fight infections, there is increasing evidence that an overwhelming NET response correlates with poor outcome in many diseases. Lung-related diseases especially, such as bacterial pneumonia, cystic fibrosis, chronic obstructive pulmonary disease, aspergillosis, influenza, and COVID-19, are often affected by massive NET formation. Highly vascularized areas as in the lung are susceptible to immunothrombotic events promoted by chromatin fibers. Keeping this fragile equilibrium seems to be the key for an appropriate immune response. Therapies targeting dysregulated NET formation might positively influence many disease progressions. This review highlights recent findings on the pathophysiological influence of NET formation in different bacterial, viral, and non-infectious lung diseases and summarizes medical treatment strategies.
... C oronary heart disease, particularly acute coronary syndrome (ACS), is the leading cause of death and disability in the world, 1 and influenza is one of the most common infections, with high morbidity and mortality. 2 A relationship between both diseases has been suspected for some time. 3 Several systematic reviews and meta-analyses have suggested a significant association between respiratory infection and ACS. ...
Background
Previous studies investigating the relationship of influenza with acute myocardial infarction (AMI) have not distinguished between AMI types 1 and 2. Influenza and cold temperature can explain the increased incidence of AMI during winter but, because they are closely related in temperate regions, their relative contribution is unknown.
Methods and Results
The temporal relationship between incidence rates of AMI with demonstrated culprit plaque (type 1 AMI) from the regional primary angioplasty network and influenza, adjusted for ambient temperature, was studied in Madrid region (Spain) during 5 influenza seasons (from June 2013 to June 2018). A time‐series analysis with quasi‐Poisson regression models and distributed lag‐nonlinear models was used. The incidence rate of type 1 AMI according to influenza vaccination status was also explored. A total of 8240 cases of confirmed type 1 AMI were recorded. The overall risk ratio (RR) of type 1 AMI during epidemic periods, adjusted for year, month, and temperature, was 1.23 (95% CI, 1.03–1.47). An increase of weekly influenza rate of 50 cases per 100 000 inhabitants resulted in an RR for type 1 AMI of 1.16 (95% CI, 1.09–1.23) during the same week, disappearing 1 week after. When adjusted for influenza, a decrease of 1ºC in the minimum temperature resulted in an increase of 2.5% type 1 AMI. Influenza vaccination was associated with a decreased risk of type 1 AMI in subjects aged 60 to 64 years (RR, 0.58; 95% CI, 0.47–0.71) and ≥65 years (RR, 0.53; 95% CI, 0.49–0.57).
Conclusions
Influenza and cold temperature were both independently associated with an increased risk of type 1 AMI, whereas vaccination was associated with a reduced risk among older patients.
... Influenza is another acute respiratory illness, the most effective method for preventing and controlling is a vaccination available for many years [9,10]. During the first months of the COVID-19 pandemic, it was often compared to either seasonal flu or the most deadly flu outbreaks in history due to some mortality and morbidity similarities [11]. ...
... Influenza viruses are recognized globally as persistent threats to human health. They are the primary respiratory pathogens that cause annual epidemics with high economic loss and approximately 250,000-500,000 deaths annually worldwide [1,2]. Influenza viruses are characterized by two mechanisms that direct the evolution of new variants; antigenic drift and genetic shift [3,4]. ...
Introduction:
Influenza infection poses a significant public health threat. The core for disease prevention and control relies on strengthened surveillance activities, particularly in Saudi Arabia, the country that hosts the largest annual mass gathering event worldwide. This study aimed to assess the molecular and seasonal pattern of influenza virus subtypes in western Saudi Arabia to inform policy decisions on influenza vaccine.
Methods:
This cross-sectional study was conducted at King Abdulaziz Medical City, western Saudi Arabia. Medical records and surveillance database of laboratory-confirmed influenza cases were reviewed from October 2015 to 2019. A panel of real-time polymerase chain reactions was performed to detect influenza A and B. Extracted RNA from a subset of positive samples was used to determine influenza A subtypes and influenza B lineages.
Results:
This study included a total of 1928 patients with laboratory-confirmed influenza infections. Influenza peaks were observed in October each season, with variant predominant strains. Influenza virus subtypes co-circulate with no reports of co-infection. Influenza A(H3N2) was reported in 42% of the cases, then influenza B (30.7%) and influenza A(H1N1)pdm09 (27.3%). Healthcare workers represented 9.4% of the cases. One-third of the cases (30.4%) were admitted to the hospital with a median admission duration of 4 days. The influenza B viruses were subtyped in 218 cases. Victoria lineage was predominant (64.1%) in 2015 and 2016; however, Yamagata was predominant in the next two consecutive seasons (94.4% and 85.4%, respectively).
Conclusion:
The burden due to influenza B may be underestimated with an observed vaccine mismatch. A quadrivalent influenza vaccine is recommended to reduce the health impact associated with influenza B infections. Molecular surveillance of the influenza viruses should be enhanced continuously for a better understanding of the influenza activity and assessment of vaccine effectiveness.
... The classic symptoms of uncomplicated influenza virus infection include abrupt onset of fever, headache, myalgia, and malaise, accompanied by respiratory-tract illness manifestations, such as cough, sore throat, and rhinitis [8,9]. Although influenza generally is an acute, self-limited, and usually uncomplicated disease in healthy children, it can be associated with severe morbidity and mortality. ...
Background
Influenza virus and other respiratory viruses have been identified as an essential cause of acute respiratory infections (ARIs) in children worldwide. However, there are few data on its frequency and clinical presentation in Jordan.
Objectives
We aimed to identify the viral etiology of acute respiratory infections and the various clinical presentations in hospitalized children, especially those with influenza viruses compared to other respiratory viruses.
Methods
A retrospective study that was conducted at the Jordan university hospital. All the positive nasopharyngeal aspirates that were collected from hospitalized children aged 0-19 years from January 2017 to January 2019 were reviewed.
Results
A total of 338 nasopharyngeal aspirates (NPAs) with positive viral serology results were reviewed. Among the patients younger than four years, the RSV virus was the most frequently detected. However, the Influenza B virus was the most commonly seen in patients older than 5 years, H1N1 was more frequent in autumn (29.5%), and RSV was the most frequent virus in winter. Bronchopneumonia was the most frequent diagnosis among all hospitalized patients, followed by bronchiolitis. Out of 338 patients, 50.3 % had tachypnea, 70.7% of patients were admitted to the pediatric floor, while 18.6% presented with a severe illness and required admission to the pediatric intensive care unit (PICU). Infants under the age of one were more likely to have higher co-infection rates with other viruses compared to children over five years that had influenza.
Conclusion
Presentations of influenza and other respiratory viruses vary between different age groups, such as sepsis in children younger than one year.
... The ability to rapidly adapt to changing environmental conditions via antigen shift and antigen drift leads to a tendency to form highly infective strains. Transmission mainly occurs by aerosols, but also via inanimate objects [77][78][79][80]. [43]. ...
For the prevention of infectious diseases, knowledge about transmission routes is essential. In addition to respiratory, fecal-oral, and sexual transmission, the transfer of pathogens via surfaces plays a vital role for human pathogenic infections-especially nosocomial pathogens. Therefore, information about the survival of pathogens on surfaces can have direct implications on clinical measures, including hygiene guidelines and disinfection strategies. In this review, we reviewed the existing literature regarding viral, bacterial, and fungal persistence on inanimate surfaces. In particular, the current knowledge of the survival time and conditions of clinically relevant pathogens is summarized. While many pathogens persist only for hours, common nosocomial pathogens can survive for days to weeks under laboratory conditions and thereby potentially form a continuous source of transmission if no adequate inactivation procedures are performed.
... Development of influenza vaccines is challenged by the substantial viral diversity of influenza virus [14]. The RNA polymerase of influenza virus has no proof-reading activity, which results in high mutation rates and substantial antigenic drift [15]. ...
Influenza virus has significant viral diversity, both through antigenic drift and shift, which makes development of a vaccine challenging. Current influenza vaccines are updated yearly to include strains predicted to circulate in the upcoming influenza season, however this can lead to a mismatch which reduces vaccine efficacy. Several strategies targeting the most abundant and immunogenic surface protein of influenza, the hemagglutinin (HA) protein, have been explored. These strategies include stalk-directed, consensus-based, and computationally derived HA immunogens. In this review, we explore vaccine strategies which utilize novel antigen design of the HA protein to improve cross-reactive immunity for development of a universal influenza vaccine.
... It is know that there are some conditions that favor its dissemination such us low temperatures, low humidity and situations that facilitate viral transmission, as for example gathering in closed spaces (schools, hospitals, nursing homes or public transports). 1,2 Worldwide, annual epidemics are estimated to result in about 3 to 5 million cases of severe illness and 290,000 to 650,000 respiratory deaths. 3 Influenza vaccination is the most effective method to prevent the disease and to reduce its morbidity and mortality. ...
Background and objectives: Influenza vaccination rates among medical students (MSs) are below the standards recommended in hospitals where influenza vaccination is not mandatory. We carried out a comparative study in two Spanish university hospitals to reassert this fact and evaluated the impact on vaccination rates of a specific program aimed at promoting influenza vaccination among MSs.
Methods: A descriptive cross-sectional study was performed describing influenza vaccination rates and motivations for vaccination during the 2017/18 campaign among MSs in two hospitals affiliated to the same university. We subsequently performed a community-based intervention study during the 2018/19 campaign evaluating the impact of a strategy for promoting influenza vaccination, comparing the hospital where the intervention took place (hospital A) with the one where it did not take place (hospital B).
Results: During de 2017/18 campaign the overall influenza vaccination rate was 44.8%, with no differences between hospitals A and B (difference: 3.9%; 95% CI: −4.36–12.16; p-value = .4). During the 2018/19 campaign, vaccination rate increased to 76.4% in hospital A, with significant differences compared with the previous campaign in the same hospital (29.8%; OR 5.00; 95% CI: 3.14–8.3; p-value = .0001) and with that observed in hospital B in the same campaign (21.1%; 95% CI: 13.38–28.82; p-value <.001).
Conclusions: Influenza vaccination rates among MSs in two Spanish university affiliated hospitals were below the recommended standards. A new reproducible strategy for promoting influenza vaccination with a specific approach toward MSs achieved a significant improvement in vaccination rate.
... Seasonal influenza-associated severe pneumonia can lead to 6-29% of substantial mortality (Oliveira et al., 2001;Murata et al., 2007;Paules and Subbarao, 2017). Influenza infection accounts for the susceptibility to pneumonia by a factor of ∼100, while approximately 25% of pneumonia patients may exacerbate as continuum of the acute respiratory distress syndrome (ARDS) (Rello and Pop-Vicas, 2009;Shrestha et al., 2015). ...
Viral pneumonia has been a serious threat to global health, especially now we have dramatic challenges such as the COVID-19 pandemic. Approximately six million cases of community-acquired pneumonia occur every year, and over 20% of which need hospital admission. Influenza virus, respiratory virus, and coronavirus are the noteworthy causative agents to be investigated based on recent clinical research. Currently, anaphylactic reaction and inflammation induced by antiviral immunity can be incriminated as causative factors for clinicopathological symptoms of viral pneumonia. In this article, we illustrate the structure and related infection mechanisms of these viruses and the current status of antiviral therapies. Owing to a set of antiviral regiments with unsatisfactory clinical effects resulting from side effects, genetic mutation, and growing incidence of resistance, much attention has been paid on medicinal plants as a natural source of antiviral agents. Previous research mainly referred to herbal medicines and plant extracts with curative effects on viral infection models of influenza virus, respiratory virus, and coronavirus. This review summarizes the results of antiviral activities of various medicinal plants and their isolated substances, exclusively focusing on natural products for the treatment of the three types of pathogens that elicit pneumonia. Furthermore, we have introduced several useful screening tools to develop antiviral lead compounds.
... The incidence attributable to each subtype of influenza virus allowed to compare their burden and study their diffusion overtime. Over the study period, the highest burden was estimated for A(H3N2) viruses, as commonly reported [14]. During season with co-circulation of several influenza (sub)types, we observed that incidences attributable to each subtype were generally synchronous, co-circulation of type A and B [13,15]. ...
Influenza viruses cause seasonal epidemics whose intensity varies according to the circulating virus type and subtype. We aim to estimate influenza-like illness (ILI) incidence attributable to influenza viruses in France from October 2014 to May 2019. Physicians participating in the French Sentinelles network reported the number of patients with ILI seen in consultation and performed nasopharyngeal swabs in a sample of these patients. The swabs were tested by RT-PCR for the presence of influenza viruses. These clinical and virological data were combined to estimate ILI incidence attributable to influenza viruses by subtypes and age groups. Influenza incidence rates over seasons ranged from 1.9 (95% CI, 1.9; 2.0) to 3.4% (95% CI, 3.2; 3.6) of the population. Each season, more than half of ILI cases were attributable to influenza. Children under 15 years were the most affected, with influenza incidence rates ranging from 3.0 (95% CI, 2.8;3.3) to 5.7% (95% CI, 5.3;6.1). Co-circulation of several (sub)types of influenza viruses was observed each year, except in 2016/2017 where A(H3N2) viruses accounted for 98.0% of the influenza cases. Weekly ILI incidences attributable to each influenza virus (sub)type were mostly synchronized with ILI incidence, except in 2014/2015 and 2017/2018, where incidence attributable to type B viruses peaked few weeks later. The burden of medically attended influenza among patients with ILI is significant in France, varying considerably across years and age groups. These results show the importance of influenza surveillance in primary care combining clinical and virological data.
Viral infections are very common and in most cases the virus is well controlled and eliminated by the immune system. Nevertheless, in some cases, damage of the host tissue inflicted by the virus itself or by the elicited immune response may result in severe disease courses. Thus, regulatory mechanisms are necessary to control virus‐induced and immune pathology. This ensures immune responses are elicited in a potent but controlled manner. In this review, we will outline how immune regulation may contribute to this process. We focus on regulatory T cells and co‐inhibitory receptors and outline how these two regulatory immune components allow for and may even promote potent but not pathologic immune responses. By enabling a balanced immune response, regulatory mechanisms can thus contribute to pathogen control as well as tissue and host protection.
Background
Seasonal influenza remains a global health problem; however, there are limited data on the specific relative risks for pneumonia and death among outpatients considered to be at high risk for influenza complications. This population-based study aimed to develop prediction models for determining the risk of influenza-related pneumonia and death.
Methods
We included patients diagnosed with laboratory-confirmed influenza between 2016 and 2017 (main cohort, n = 25,659), those diagnosed between 2015 and 2016 (validation cohort 1, n = 16,727), and those diagnosed between 2017 and 2018 (validation cohort 2, n = 34,219). Prediction scores were developed based on the incidence and independent predictors of pneumonia and death identified using multivariate analyses, and patients were categorized into low-, medium-, and high-risk groups based on total scores.
Results
In the main cohort, age, gender, and certain comorbidities (dementia, congestive heart failure, diabetes, and others) were independent predictors of pneumonia and death. The 28-day pneumonia incidence was 0.5%, 4.1%, and 10.8% in the low-, medium-, and high-risk groups, respectively (c-index: 0.75); the 28-day mortality was 0.05%, 0.7%, and 3.3% in the low-, medium-, and high-risk groups, respectively (c-index: 0.85). In the validation cohort 1, c-indices for the models for pneumonia and death were 0.75 and 0.87, respectively. In the validation cohort 2, c-indices for the models were 0.74 and 0.87, respectively.
Conclusions
We successfully developed and validated simple-to-use risk prediction models, which would promptly provide useful information for treatment decisions in primary care settings.
Rationale: Patients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events.
Objective: Define the molecular mechanisms underlying influenza virus-induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process.
Methods and Results: Hearts from wild-type and necroptosis deficient (MLKL-KO) mice were dissected twelve days after initial Influenza A virus (IAV) infection when viral titers were undetectable in the lungs. Immunofluorescence microscopy and plaque assays showed presence of viable IAV particles in the myocardium without generation of interferon responses. Global proteome and phosphoproteome analyses using high resolution accurate mass based LC-MS/MS and label-free quantitation showed that the global proteome as well as the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts in a strain independent manner. Necroptosis deficient mice had increased survival and reduced weight loss post-IAV infection, as well as increased antioxidant and mitochondrial function, indicating partial protection to IAV infection. These findings were confirmed in vitro by pre-treatment of human and rat myocytes with antioxidants or necroptosis inhibitors, which blunted oxidative stress and mitochondrial damage after IAV infection.
Conclusions: This study provides the first evidence that the cardiac proteome and phosphoproteome are significantly altered post pulmonary influenza infection. Moreover, viral particles can persist in the heart after lung clearance, altering mitochondrial function and promoting cell death without active replication and interferon responses. Finally, our findings show inhibition of necroptosis or prevention of mitochondrial damage as possible therapeutic interventions to reduce cardiac damage during influenza infections.
Epidemics of infectious diseases are an important threat to public health and global economies. Yet, the development of prevention strategies remains a challenging process, as epidemics are non-linear and complex processes. For this reason, we investigate a deep reinforcement learning approach to automatically learn prevention strategies in the context of pandemic influenza. Firstly, we construct a new epidemiological meta-population model, with \(379\) patches (one for each administrative district in Great Britain), that adequately captures the infection process of pandemic influenza. Our model balances complexity and computational efficiency such that the use of reinforcement learning techniques becomes attainable. Secondly, we set up a ground truth such that we can evaluate the performance of the “Proximal Policy Optimization” algorithm to learn in a single district of this epidemiological model. Finally, we consider a large-scale problem, by conducting an experiment where we aim to learn a joint policy to control the districts in a community of 11 tightly coupled districts, for which no ground truth can be established. This experiment shows that deep reinforcement learning can be used to learn mitigation policies in complex epidemiological models with a large state and action space.
Baloxavir marboxil (BXM) is an FDA-approved antiviral prodrug for the treatment of influenza A and B infection and post-exposure prophylaxis. The active form, baloxavir acid (BXA), targets the cap-snatching endonuclease (PA) of the influenza virus polymerase complex. The nuclease activity delivers the primer for transcription and previous reports have shown that BXA blocks the nuclease activity with high potency. However, biochemical studies on the mechanism of action are lacking. Structural data have shown that BXA chelates the two divalent metal ions at the active site, like inhibitors of the human immunodeficiency virus type 1 (HIV-1) integrase or ribonuclease (RNase) H. Here we studied the mechanisms underlying the high potency of BXA and how the I38T mutation confers resistance to the drug. Enzyme kinetics with the recombinant heterotrimeric enzyme (FluB-ht) revealed characteristics of a tight binding inhibitor. The apparent inhibitor constant (Kiapp) is 12 nM, while the I38T mutation increased Kiapp by ∼18-fold. Order-of-addition experiments show that a preformed complex of FluB-ht, Mg²⁺ ions and BXA is required to observe inhibition, which is consistent with active site binding. Conversely, a preformed complex of FluB-ht and RNA substrate prevents BXA from accessing the active site. Unlike integrase inhibitors that interact with the DNA substrate, BXA behaves like RNase H inhibitors that compete with the nucleic acid at the active site. The collective data support the conclusion that BXA is a tight binding inhibitor and the I38T mutation diminishes these properties.
Viral infections have haunted humankind since times immemorial. Overpopulation, globalization, and extensive deforestation have created an ideal environment for a viral spread with unknown and multiple shedding routes. Many viruses can infect the male reproductive tract, with potential adverse consequences to male reproductive health, including infertility and cancer. Moreover, some genital tract viral infections can be sexually transmitted, potentially impacting the resulting offspring's health. We have summarized the evidence concerning the presence and adverse effects of the relevant viruses on the reproductive tract (mumps virus, human immunodeficiency virus, herpes virus, human papillomavirus, hepatitis B and C viruses, Ebola virus, Zika virus, influenza virus, and coronaviruses), their routes of infection, target organs and cells, prevalence and pattern of virus shedding in semen, as well as diagnosis/testing and treatment strategies. The pathophysiological understanding in the male genital tract is essential to assess its clinical impact on male reproductive health and guide future research.
The influenza A virus (IAV) genome consists of eight negative-sense viral RNA (vRNA) segments that are selectively assembled into progeny virus particles through RNA-RNA interactions. To identify relationships between vRNA segments, we examined parallel evolution between vRNA segments of seasonal human IAV, finding that evolutionary relationships between vRNA segments differ between subtypes and antigenically-shifted strains. Intersegmental relationships were distinct between H3N2 and H1N1 viruses, but largely conserved over time in H3N2 viruses. However, parallel evolution of vRNA segments diverged between H1N1 strains isolated before and after the 2009 pandemic. Surprisingly, intersegmental relationships were not driven solely by protein sequence, which is potentially indicative of RNA-RNA driven coevolution. Colocalization of highly coevolved vRNA segments was enriched over other pairs at the nuclear periphery during a productive viral infection. This study illustrates how phylogenetics can be applied to interrogate putative RNA interactions underlying selective assembly of IAV.
Background
Pharmacoeconomic studies have been less performed in Japan. The objective of this study was to clarify which neuraminidase inhibitor (NI; oseltamivir, zanamivir, laninamivir, and peramivir) is most cost-effective in an adult outpatient setting in Japan.
Objective
To clarify which neuraminidase inhibitor (NI; oseltamivir, zanamivir, laninamivir, and peramivir) is most cost-effective in an adult outpatient setting in Japan.
Methods
Cost-effectiveness analysis was constructed from the healthcare payer’s perspective. A decision tree model was constructed with probabilities from relevant randomized controlled trials. Costs included medical costs and drug prices. Medical costs were obtained from the medical fee schedule table (2016 version). We also applied authorized medication costs. Outcomes of effectiveness were measured using EQ-5D-3L questionnaires for adult patients who had experienced influenza virus infections previously. Time horizon was 14 days in this study.
Results
Cost-effectiveness ratios for oseltamivir, zanamivir, laninamivir, and peramivir were 393 674 Yen/quality-adjusted life year (QALY; US$3883.41/QALY), 408 241 (US$4027.10), 407 980 (US$4024.53), and 444 264 (US$4382.45), respectively. The cost-effectiveness analysis base-case analysis revealed oseltamivir as the most cost-effective NI. Zanamivir was dominated. Incremental cost effectiveness ratio (ICER) for laninamivir and peramivir were 1 129 459 Yen/QALY (US$11 141.58/QALY) and 1 287 118 (US$12 696.81), respectively. One-way sensitivity analyses revealed that minimum ICERs for laninamivir based on “quality of life (QOL) values (95% confidence interval)” was −596 850 Yen/QALY (US−$5887.64/QALY) owing to high cost and less effective. Also, maximum ICER for peramivir based on“QOL values” was 14 717 518 Yen/QALY (US$145 181.32/QALY); a value more than the 5 000 000 Yen/QALY threshold.
Conclusions
The study results reveal oseltamivir as the most cost-effective NI for the treatment of influenza virus infection in an adult outpatient setting. Our findings may provide decision makers with scientific evidence for clinical and economic evaluation to achieve optimal therapeutic outcomes.
Influenza virus infection may present with fever, chills, headache, myalgia, malaise, and respiratory symptoms, with a few cases developing into pneumonia, respiratory failure, and other organ damage. Very few cases of atraumatic splenic rupture associated with influenza infection have been reported. Atraumatic splenic rupture, while rare, is associated with high mortality. Here, we report the first case of atraumatic splenic rupture associated with influenza infection in the English literature and review the prior reported literature. The patient was diagnosed with influenza A (H1N1) pneumonia and subsequently developed hemorrhagic shock requiring emergency laparotomy and removal of the ruptured spleen.
1. Introduction
Influenza viruses are divided into three types, influenza A, B, and C viruses. Influenza A viruses cause epidemic influenza and sporadic pandemics, and they are further classified into subtypes on the basis of the antigenic properties of two surface glycopeptides, hemagglutinin (H) and neuraminidase (N). There are 18 different H subtypes and 11 different N subtypes (H1 to H18 and N1 to N11). Influenza A (H1N1), which caused a world pandemic in 2009, is one of the common influenza viruses and is now included in each year’s influenza vaccine [1].
Influenza infection may present with fever, chills, headache, myalgia, malaise, and anorexia, accompanied by respiratory symptoms, including nonproductive cough, nasal discharge, and sore throat [1]. Some patients may develop pneumonia, respiratory failure, and other organ damage [2].
Very few cases [3–7] of atraumatic splenic rupture associated with influenza infection have been reported in the literature. Atraumatic splenic rupture, is rare and, if missed, can be associated with high mortality [8]. We report the first case in the English literature of atraumatic splenic rupture associated with influenza infection and review the prior reported literature.
2. Case Presentation
A 50-year-old man with past medical history of hypothyroidism and cigarette smoking had been on vacation in Florida, USA, with his family for 3 weeks. The day of his return flight in July, he developed a sore throat and body aches followed by fever and a productive cough. He went to urgent care, was diagnosed with acute bronchitis, and was treated as outpatient with azithromycin and prednisone for 5 days without improvement. On the eighth day of symptoms, he developed confusion and was brought to the emergency department (ED) for further evaluation.
In the ED, the patient had mild shortness of breath but denied nausea, vomiting, or abdominal pain. On physical exam, he had temperature 38.3°C, heart rate 120 beats/min, respiratory rate 25 breaths/min, and SpO2 90% on room air, with coarse breath sounds bilaterally on lung exam; he was started on oxygen 2 L/min via nasal cannula. A chest X-ray showed bibasilar lung infiltrates. Testing revealed white blood cell count 9.0 k/uL (4.0–10.0 k/uL), hemoglobin (Hb) 15.8 g/dL (13.0–18.0 g/dL), platelets 249 k/uL (150–400 k/uL), international normalized ratio 1.4 (≤3.5), protime 15.1 seconds (10.0–12.0 seconds), partial thromboplastin time 37.4 seconds (25.0–35.0 seconds), blood urea nitrogen 28 mg/dL (9–20 mg/dL), creatinine 1.46 mg/dL (0.66–1.25 mg/dL), total protein 7.5 g/dL (6.3–8.2 g/dL), albumin 3.9 g/dL (3.5–5.0 g/dL), total bilirubin 1.4 mg/dL (0.2–1.3 mg/dL), alkaline phosphatase 195 U/L (38–126 U/L), alanine aminotransferase 160 U/L (21–72 U/L), and aspartate aminotransferase 243 U/L (17–59 U/L). Urine Legionella antigen and Streptococcus pneumoniae antigen tests were negative. An ultrasound of the abdomen showed a contracted gallbladder with probable calculi and normal pancreas and spleen. He was diagnosed with community acquired pneumonia, started on intravenous ceftriaxone and azithromycin, and admitted to the medical floor. He was also started on heparin 5000 U subcutaneously every 8 hours for thromboembolism prophylaxis.
The patient’s shortness of breath deteriorated overnight. Chest X-ray showed worsening lung infiltrates, predominantly in the left lung. He had increased work of breathing and worsening hypoxemia requiring oxygen via high flow nasal cannula and transfer to the intensive care unit. More information was obtained from the family: his wife and father also had developed a cough and no one in the family including the patient had ever received influenza vaccination. A polymerase chain reaction (PCR) respiratory viral panel on a nasopharyngeal swab sample was positive for influenza A (H1N1) virus, and therapy was started with oseltamivir.
The patient’s respiratory status continued to worsen. He developed hypotension and severe abdominal pain on the third day of hospitalization. Serum amylase was 157 U/L (30–110 U/L) and lipase 1454 U/L (23–300 U/L). Hb decreased from 15.8 to 7.4 g/dL. Coagulation parameters were normal. Arterial blood gases revealed pH 7.5 (7.35–7.45), PaCO2 21 mm Hg (35–45 mm Hg), and PaO2 52 mm Hg (80–100 mm Hg) on high flow nasal cannula FiO2 70% at 50 L/min and the patient was subsequently intubated. Computed tomography (CT) of the chest and abdomen revealed lung consolidation of the left upper lobe and infiltrates in both lower lobes and right middle lobe, with no evidence of pulmonary embolism (Figure 1). The lateral margin of the spleen was indistinct and with low density areas, concerning for splenic injury or rupture (Figure 2). The patient denied any prior abdominal trauma.
Coronavirus disease 2019 (COVID-19) has spread in more than 100 countries and regions around the world, raising grave global concerns. COVID-19 has a similar pattern of infection, clinical symptoms, and chest imaging findings to influenza pneumonia. In this retrospective study, we analysed clinical and chest CT data of 24 patients with COVID-19 and 79 patients with influenza pneumonia. Univariate analysis demonstrated that the temperature, systolic pressure, cough and sputum production could distinguish COVID-19 from influenza pneumonia. The diagnostic sensitivity and specificity for the clinical features are 0.783 and 0.747, and the AUC value is 0.819. Univariate analysis demonstrates that nine CT features, central–peripheral distribution, superior–inferior distribution, anterior–posterior distribution, patches of GGO, GGO nodule, vascular enlargement in GGO, air bronchogram, bronchiectasis within focus, interlobular septal thickening, could distinguish COVID-19 from influenza pneumonia. The diagnostic sensitivity and specificity for the CT features are 0.750 and 0.962, and the AUC value is 0.927. Finally, a multivariate logistic regression model combined the variables from the clinical variables and CT features models was made. The combined model contained six features: systolic blood pressure, sputum production, vascular enlargement in the GGO, GGO nodule, central–peripheral distribution and bronchiectasis within focus. The diagnostic sensitivity and specificity for the combined features are 0.87 and 0.96, and the AUC value is 0.961. In conclusion, some CT features or clinical variables can differentiate COVID-19 from influenza pneumonia. Moreover, CT features combined with clinical variables had higher diagnostic performance.
Influenza A virus (IAV) can cause high morbidity and mortality globally every year. Myriad host kinases and their related signaling pathways are involved in IAV infection, and the important role of the c-Jun N-terminal kinase signaling pathway during infection has been demonstrated. SP600125, an inhibitor of c-Jun N-terminal kinase, was found in our previous study to suppress IAV replication in vitro. In this study, we established a mouse model of H1N1 IAV infection and treated the mice with SP600125 to study its protective effect. The results showed that SP600125 treatment reduced the pulmonary inflammatory response, lung injury, and pulmonary viral load and increased the survival rate of H1N1-infected mice. Our data confirm the crucial role of c-Jun N terminal kinase in H1N1 virus replication and inflammatory responses in vivo. Hence, we speculate that SP600125 has a potential antiviral therapeutic benefit against IAV infection.
Background:
Although annual influenza vaccination is recommended for persons with asthma, its effectiveness in this patient population is not well described. We evaluated the effect of influenza vaccination in the current and previous seasons in preventing influenza among people with asthma.
Methods:
Using population health data from the Navarre region of Spain for the 2015/16 to 2019/20 influenza seasons, we conducted a test-negative case-control study to assess the effect of influenza vaccination in the current and 5 previous seasons. From patients presenting to hospitals and primary health care centres with influenza-like illness who underwent testing for influenza, we estimated the effects of influenza vaccination among patients with asthma overall and between those presenting as inpatients or outpatients, as well as between patients with and without asthma.
Results:
Of 1032 patients who had asthma and were tested, we confirmed that 421 had influenza and the remaining 611 were test-negative controls. We found that the average effect of influenza vaccination was 43% (adjusted odds ratio [OR] 0.57, 95% confidence interval [CI] 0.40 to 0.80) for current-season vaccination regardless of previous doses, and 38% (adjusted OR 0.62, 95% CI 0.39 to 0.96) for vaccination in previous seasons only. Effects were similar for outpatients and inpatients. Among patients with asthma and confirmed influenza, current-season vaccination did not reduce the odds of hospital admission (adjusted OR 1.05, 95% CI 0.51 to 2.18). Influenza vaccination effects were similar for patients with and without asthma.
Interpretation:
We estimated that, on average, current or previous influenza vaccination of people with asthma prevented almost half of influenza cases. These results support recommendations that people with asthma receive influenza vaccination.
Our murine cancer model studies have demonstrated that Plasmodium infection activates the immune system that has been inhibited by cancer cells, counteracts tumor immunosuppressive microenvironment, inhibits tumor angiogenesis, inhibits tumor growth and metastasis, and prolongs the survival time of tumor-bearing mice. Based on these studies, three clinical trials of Plasmodium immunotherapy for advanced cancers have been approved and are ongoing in China. After comparing the mechanisms of action of Plasmodium immunotherapy with those of immune checkpoint blockade therapy, we propose the notion that cancer is an ecological disease and that Plasmodium immunotherapy is a systemic ecological counterattack therapy for this ecological disease, with limited side effects and without danger to public health based on the use of artesunate and other measures. Recent reports of tolerance to treatment and limitations in majority of patients associated with the use of checkpoint blockers further support this notion. We advocate further studies on the mechanisms of action of Plasmodium infection against cancer and investigations on Plasmodium -based combination therapy in the coming future.
Four hexaphenyl-butadiene pyridine salt derivatives (HPB-Xs) with aggregation-induced emission (AIE) characteristics were designed and synthesized. After comprehensive comparison of the four compounds, HPB-I was selected for protein detection. The good-linear response of HPB-I to hemagglutinin 5 protein (H5) on surface of influenza virus were realized with the characteristics of real-time, high-selective, and sensitive in a wide range of H5 concentration. The limit of detection (LOD) was as low as 179.5 ng/mL (3.04 nM) in throat swaps. HPB-I also achieved colorimetric detection for H5 by naked eyes. The simulation calculations based on molecular docking revealed that HPB-I could well combine with the top-cavity of H5 and achieved single-molecule-limited “turn-on” fluorescence signal. This study is a significant step in the development of a low-cost influenza test at the point of pursuing a new strategy for the molecular design of antiviral drugs or virus staining and tracing.
Developing broad-spectrum antiviral drugs remains an important issue as viral infections continue to threaten public health. Host-directed therapy is a method that focuses on potential targets in host cells or the body, instead of viral proteins. Its antiviral effects are achieved by disturbing the life cycles of pathogens or modulating immunity. In this review, we focus on the development of broad-spectrum antiviral drugs that enhance the immune response. Some natural products present antiviral effects mediated by enhancing immunity, and their structures and mechanisms are summarized here. Natural products with immunomodulatory effects are also discussed, although their antiviral effects remain unknown. Given the power of immunity and the feasibility of host-directed therapy, we argue that both of these categories of natural products provide clues that may be beneficial for the discovery of broad-spectrum antiviral drugs.
Influenza is an important cause of morbidity and mortality in
the population. Vaccination coverage plays an important role
in the reduction of complications due to the disease, besides
being a cost-effective tool; however, the prevalence of myths
around it leads to a decreased national coverage. In the present
work, we analyze the relationship between the prevalence of
complications due to the disease versus the reports of adverse
effects associated with vaccination.
Quadrivalent influenza inactivated vaccine (IIV4) is more likely to provide wider protection against yearly circulating influenza viruses than trivalent inactivated influenza vaccine (IIV3). In this study, a total of 320 participants were allocated to four age cohorts (6–35 months, 3–8 years, 9–17 years, and ≥ 18 years; 80 participants/cohort) according to their actual date of birth. Participants in each cohort were randomly assigned to two groups to receive intramuscular injection of the trial vaccine or the comparative vaccine in a one-dose (3–8 years, 9–17 years,and ≥ 18 years) schedule on day 0 or two-dose (6–35 months cohort) schedule on day 0 and 28. The first objective is to evaluate the safety and immunogenicity of the full-dose subunit non-adjuvanted IIV4 (FD-subunit NAIIV4) we developed versus an active-control, China-licensed split-virion NAIIV4, in people ≥ 3 years. The second objective is to evaluate the safety and immunogenicity of FD-subunit NAIIV4 versus the half-dose (HD-subunit NAIIV4) in toddlers aged 6–35 months. Results showed that all adverse reactions noted were rare, mild, and self-limited. In ≥ 3 years cohorts, systemic adverse reactions in FD-subunit NAIIV4 groups were less than the active control split-virion NAIIV4 groups ([Systemic adverse reaction rates (95%CI)], 15.0 (8.6–21.4) versus 19.2(12.1–26.2), p = 0.391). The overall seroprotection efficacy after vaccination were comparable between FD-subunit NAIIV4 and the active control split-virion NAIIV4([Seroprotection rates (95%CI)], H1N1, 99.2(81.3–100.0) versus 94.9(90.9–98.9), p = 0.117; H3N2, 81.7(74.7–88.6) versus 82.1(75.1–89.0), p = 0.939; BV, 75.8(68.2–83.5) versus 74.4(66.4–82.3), p = 0.793; BY, 94.2(90.0–98.4) versus 92.3(87.5–97.1), p = 0.568). Additionally, FD-subunit NAIIV4 has comparable safety and better seroprotection versus that of the half-dose in 6–35 months toddlers groups ([Total adverse reaction rates (95%CI)], 37.5(18.5–56.5) versus 47.5(26.1–68.9), p = 0.366) ([Seroprotection rates (95%CI)], H1N1, 85(56.4–100.0) versus 75.7(47.6–100.0), p = 0.117; H3N2, 50(28.1–71.9) versus 29.7(12.2–47.3), p = 0.070; BV, 75(48.2–100.0) versus 29.7(12.2–47.3), p < 0.001; BY, 75(48.2–100.0) versus 56.8(32.5–81.0), p = 0.091). As a result, the FD-subunit NAIIV4 we developed is safe and effective to provide broader and adequate protection against the circulating influenza viruses during 2018–2019, which could be an essential component of the global preventive strategy for influenza pandemic.
Influenza viruses continue to be a major public health threat due to the possible emergence of more virulent influenza virus strains resulting from dynamic changes in virus adaptability, consequent of functional mutations and antigenic drift in surface proteins, especially hemagglutinin (HA) and neuraminidase (NA). In this study, we describe the genetic and evolutionary characteristics of H1N1, H3N2, and influenza B strains detected in severe cases of seasonal influenza in Thailand from 2018 to 2019. We genetically characterized seven A/H1N1 isolates, seven A/H3N2 isolates, and six influenza B isolates. Five of the seven A/H1N1 viruses were found to belong to clade 6B.1 and were antigenically similar to A/Switzerland/3330/2017 (H1N1), whereas two isolates belonged to clade 6B.1A1 and clustered with A/Brisbane/02/2018 (H1N1). Interestingly, we observed additional mutations at antigenic sites (S91R, S181T, T202I) as well as a unique mutation at a receptor binding site (S200P). Three-dimensional (3D) protein structure analysis of hemagglutinin protein reveals that this unique mutation may lead to the altered binding of the HA protein to a sialic acid receptor. A/H3N2 isolates were found to belong to clade 3C.2a2 and 3C.2a1b, clustering with A/Switzerland/8060/2017 (H3N2) and A/South Australia/34/2019 (H3N2), respectively. Amino acid sequence analysis revealed 10 mutations at antigenic sites including T144A/I, T151K, Q213R, S214P, T176K, D69N, Q277R, N137K, N187K, and E78K/G. All influenza B isolates in this study belong to the Victoria lineage. Five out of six isolates belong to clade 1A3-DEL, which relate closely to B/Washington/02/2009, with one isolate lacking the three amino acid deletion on the HA segment at position K162, N163, and D164. In comparison to the B/Colorado/06/2017, which is the representative of influenza B Victoria lineage vaccine strain, these substitutions include G129D, G133R, K136E, and V180R for HA protein. Importantly, the susceptibility to oseltamivir of influenza B isolates, but not A/H1N1 and A/H3N2 isolates, were reduced as assessed by the phenotypic assay. This study demonstrates the importance of monitoring genetic variation in influenza viruses regarding how acquired mutations could be associated with an improved adaptability for efficient transmission.
Despite the particular focus given to influenza since the 2009 influenza A(H1N1) pandemic, true burden of influenza-associated critical illness remains poorly known. The aim of this study was to identify factors influencing influenza burden imposed on intensive care units (ICUs) in a catchment population during recent influenza seasons. From 2008 to 2013, all adult patients admitted with a laboratory-confirmed influenza infection to one of the ICUs in the catchment area were prospectively included. A total of 201 patients (mean age: 63 ± 16, sex-ratio: 1.1) were included. The influenza-related ICU-bed occupancy rate averaged 4.3% over the five influenza seasons, with the highest mean occupancy rate (16.9%) observed during the 2012 winter. In-hospital mortality for the whole cohort was 26%. Influenza A(H1N1)pdm infections (pdm in the mentioned nomenclature refers to Pandemic Disease Mexico 2009), encountered in 51% of cases, were significantly associated with neither longer length of stay nor higher mortality (ICU and hospital) when compared to infections with other virus subtypes. SOFA score (OR, 1.12; 95% CI, 1.04–1.29) was the only independent factor significantly associated with a prolonged hospitalization. These results highlight both the frequency and the severity of influenza-associated critical illness, leading to a sustained activity in ICUs. Severity of the disease, but not A(H1N1)pdm virus, appears to be a major determinant of ICU burden related to influenza.
Introduction: As the pathogen that caused the first influenza virus pandemic in this century, the swine A(H1N1) pdm09 influenza virus has caused continuous harm to human public health. The evolution of HA protein glycosylation sites, including the increase in number and positional changes, is an important way for influenza viruses to escape host immune pressure. Based on the traditional influenza virus molecular monitoring, special attention should be paid to the influence of glycosylation evolution on the biological characteristics of virus antigenicity, transmission and pathogenicity. The epidemiological significance of glycosylation mutants should be analyzed as a predictive tool for early warning of new outbreaks and pandemics, as well as the design of vaccines and drug targets.
Areas covered: We review on the evolutionary characteristics of glycosylation on the HA protein of the H1N1pdm09 influenza virus in the last ten years.
Expert opinion: We discuss the crucial impact of evolutionary glycosylation on the biological characteristics of the virus and the host immune responses, summarize studies revealing different roles of glycosylation play during host adaptation. Although these studies show the significance of glycosylation evolution in host-virus interaction, much remains to be discovered about the mechanism.
Background
The incidence and mortality of influenza in children had risen, but data are limited on children with severe influenza virus infection in China.
Method
We conducted a retrospective case-control study and collected the patients’ clinical data. Clinical data including demography, clinical presentation, laboratory findings, radiologic findings, treatment and outcomes were collected. Children were clinically confirmed to have virus infection in Shanghai in three hospitals from June 2014 to June 2019.
Results
During the study, 36,047 children were enrolled. Among them, 118 met the criteria for severe flu. Clinical symptoms such as fever, cough, gastrointestinal symptoms, coma and epilepsy were higher in the severe group. Complications such as pneumorrhagia, heart failure, septic shock, acute renal failure and influenza-associated encephalitis were higher in the severe influenza group than the death group. The laboratory findings including decreased hemoglobin, high alanine aminotransferase, high urea nitrogen and high lactate levels were risk factors for death in children with influenza.
Conclusion
Influenza-associated encephalopathy (IAE), acute respiratory distress syndrome (ARDS) were the common clinical manifestations and complications for the severe influenza, and delayed use of oseltamivir was found to be associated with fatality.
A number of novel amides were synthesized by coupling of 6-[(9H-purin-6-yl)amino]hexanoic acid to heterocyclic amines. The antiviral activity of the obtained compounds, as well as of purine conjugates in which 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine is linked to position 6 of purine through a fragment of ω-amino acids with varying lengths of polymethylene chains against influenza A and B viruses was studied in vitro. Purine derivatives have been shown to have moderate activity against influenza A (H1N1) virus. The antiinfluenza activity and cytotoxicity of conjugates with 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine depend on the length of the linker fragment.
A series of compounds containing a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment were evaluated for their antiviral activity against influenza A virus strain A/Puerto Rico/8/34 (H1N1) in vitro. The most potent antiviral compound proved to be a quaternary ammonium salt based on (-)-borneol, 10a. In in vitro experiments, compound 10a inhibited influenza A viruses (H1, H1pdm09, and H3 subtypes), with an IC50 value of 2.4-16.8 µM (depending on the virus), and demonstrated low toxicity (CC50 = 1311 µM). Mechanism-of-action studies for compound 10a revealed it to be most effective when added at the early stages of the viral life cycle. In direct haemolysis inhibition tests, compound 10a was shown to decrease the membrane-disrupting activity of influenza A virus strain A/Puerto Rico/8/34. According to molecular modelling results, the lead compound 10a can bind to different sites in the stem region of the viral hemagglutinin.
The transmission of airborne pathogens represents a major threat to worldwide public health. Ultraviolet light irradiation can contribute to the sanification of air to reduce the pathogen transmission. We have designed a compact filter for airborne pathogen inactivation by means of UVC LED sources, whose effective irradiance is enhanced thanks to high reflective surfaces. We used ray-tracing and computational fluid dynamic simulations to model the device and to maximize the performance inside the filter volume. Simulations also show the inhibition of SARS-Cov-2 in the case of high air fluxes. This study demonstrates that current available LED technology is effective for air sanification purposes.
Objective
Nosocomial transmission of influenza is a major concern for infection control. We aimed to dissect transmission dynamics of influenza, including asymptomatic transmission events, in acute care.
Design
Prospective surveillance study during 2 influenza seasons.
Setting
Tertiary-care hospital.
Participants
Volunteer sample of inpatients on medical wards and healthcare workers (HCWs).
Methods
Participants provided daily illness diaries and nasal swabs for influenza A and B detection and whole-genome sequencing for phylogenetic analyses. Contacts between study participants were tracked. Secondary influenza attack rates were calculated based on spatial and temporal proximity and phylogenetic evidence for transmission.
Results
In total, 152 HCWs and 542 inpatients were included; 16 HCWs (10.5%) and 19 inpatients (3.5%) tested positive for influenza on 109 study days. Study participants had symptoms of disease on most of the days they tested positive for influenza (83.1% and 91.9% for HCWs and inpatients, respectively). Also, 11(15.5%) of 71 influenza-positive swabs among HCWs and 3 (7.9%) of 38 influenza-positive swabs among inpatients were collected on days without symptoms; 2 (12.5%) of 16 HCWs and 2 (10.5%) of 19 inpatients remained fully asymptomatic. The secondary attack rate was low: we recorded 1 transmission event over 159 contact days (0.6%) that originated from a symptomatic case. No transmission event occurred in 61 monitored days of contacts with asymptomatic influenza-positive individuals.
Conclusions
Influenza in acute care is common, and individuals regularly shed influenza virus without harboring symptoms. Nevertheless, both symptomatic and asymptomatic transmission events proved rare. We suggest that healthcare-associated influenza prevention strategies that are based on preseason vaccination and barrier precautions for symptomatic individuals seem to be effective.
Eradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.
Influenza is an acute viral respiratory infection that affects all age groups and is associated with high mortality during pandemics, epidemics, and sporadic outbreaks. Nearly 10% of the world's population is affected by influenza annually, with about half a million deaths each year. Influenza vaccination is the most effective method for preventing influenza infection and its complications. The influenza vaccine's efficacy varies each season based on the circulating influenza strains and vaccine uptake rates. Currently, three antiviral drugs targeting the influenza virus surface glycoprotein neuraminidase (NA) are available for treatment and prophylaxis of disease. Given the significant burden of influenza infection globally, this review is focused on the latest findings in the etiology, epidemiology, transmission, clinical manifestation, diagnosis, prevention, and treatment of influenza.
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Ethnopharmacological relevance
Liu Shen Wan (LSW) is a traditional Chinese medicine (TCM) with detoxification and antiphlogistic activity; it is composed of bezoar, toad venom, musk, pearl powder, borneol and realgar. In recent years, LSW has been widely used in traditional medicine for the treatment of influenza, tonsillitis, pharyngitis, mumps, cancer and leukaemia.
Aim of study
The anti-influenza virus properties of LSW and its inhibition of the inflammatory response was demonstrated in our previous research; however, the effect and potential mechanism of LSW against influenza induced secondary bacteria have remained obscure. Therefore, in the present study, a model of influenza virus PR8 with secondary infection by Staphylococcus aureus (S. aureus) in vitro and in mice was established to examine the effect and potential mechanism by which LSW inhibits bacterial adhesion and subsequent severe pneumonia after viral infection.
Materials and methods
We investigated the effect of LSW on the PR8-induced adhesion of live S. aureus in A549 cells. qRT-PCR was used to detect the expression of adhesion molecules. Western blotting was used to determine the expression of CEACAM1, RIG-1, MDA5, p-NF-κB, and NF-κB in A549 cells. Inflammatory cytokines were detected using a Bio-Plex Pro Human Cytokine Screening Panel (R&D) in A549 cells and Mouse Magnetic Luminex Assays (R&D) in mice infected with PR8 virus and secondarily with S. aureus, respectively. Moreover, the survival rate, lung index, viral titre, bacterial loads and pathological changes in the lung tissue of mice infected with PR8 and S. aureus were investigated to estimate the effect of LSW in inhibiting severe pneumonia.
Results
LSW significantly decreased S. aureus adhesion following influenza virus infection in A549 cells, which may have occurred by suppressing expression of the adhesion molecule CEACAM1. In addition, treatment with LSW dramatically suppressed the induction of proinflammatory cytokines (CCL2/MCP-1 and CXCL-9/MIG) and chemokines (IL-6 and TNF-α) by PR8 infection following secondary LPS stimulation in A549 cells. Upregulation of related signalling proteins (RIG-I, MDA5 and NF-κB) induced by viruses and bacteria was suppressed by LSW in A549 cells. LSW significantly decreased the viral titres and bacterial load, prolonged survival time, and ameliorated lung inflammation and injury in mice with S. aureus infection secondary to PR8 infection.
Conclusions
We demonstrated that LSW prevents S. aureus adherence to influenza virus-infected A549 cells, perhaps by inhibiting the expression of the adhesion molecule CEACAM1. The upregulation of proinflammatory cytokines and related signalling proteins induced by viruses and bacteria was suppressed by LSW in A549 cells. LSW significantly ameliorated lung injury caused by viral and secondary bacterial infection. These findings provide a further evaluation of LSW and suggest a beneficial effect of LSW for the prevention of secondary bacterial infection and related complications.
p>Influenza virus infection causes seasonal epidemics and occasional pandemics, leading to huge morbidity and mortality worldwide. Vaccination against influenza is needed annually as protection from constantly mutating strains is required. Groups at high risk of poor outcomes include the elderly, the very young, pregnant women and those with chronic health conditions. However, vaccine effectiveness in the elderly is generally poor due to immunosenescence and may be altered due to “original antigenic sin”. Strategies to overcome these challenges in the elderly include high-dose or adjuvant vaccines. Other options include vaccinating healthcare workers and children as this reduces community-level influenza transmission. Current guidelines in the UK are that young children receive a live attenuated nasal spray vaccine, adults aged >65 years receive an adjuvanted trivalent inactivated vaccine and adults aged <65 years with comorbidities receive a quadrivalent inactivated vaccine. The goal of a universal influenza vaccine targeting conserved regions of the virus and avoiding the need for annual vaccination is edging closer with early-phase trials under way.</p
Background:
The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide.
Methods and findings:
We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (<6 mo, <1 y, <2 y, <5 y, 5-17 y, and <18 y). We applied this proportion to global estimates of acute lower respiratory infection hospitalizations among children aged <1 y and <5 y, to obtain the number and per capita rate of influenza-associated hospitalizations by geographic region and socio-economic status. Influenza was associated with 10% (95% CI 8%-11%) of respiratory hospitalizations in children <18 y worldwide, ranging from 5% (95% CI 3%-7%) among children <6 mo to 16% (95% CI 14%-20%) among children 5-17 y. On average, we estimated that influenza results in approximately 374,000 (95% CI 264,000 to 539,000) hospitalizations in children <1 y-of which 228,000 (95% CI 150,000 to 344,000) occur in children <6 mo-and 870,000 (95% CI 610,000 to 1,237,000) hospitalizations in children <5 y annually. Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/100,000 children/year versus 48/100,000). However, differences in hospitalization practices between settings are an important limitation in interpreting these findings.
Conclusions:
Influenza is an important contributor to respiratory hospitalizations among young children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could reduce this burden and protect infants <6 mo.
Background:
high-dose inactivated influenza vaccine (IIV-HD) is an alternative to the standard-dose inactivated influenza vaccine (IIV-SD) in the US for influenza prevention in older adults. IIV-HD improved efficacy relative to IIV-SD in a randomized controlled trial. Recent observational studies suggest that previous influenza vaccination may influence the immunogenicity and effectiveness of current-season vaccination.
Methods:
the original study was a double-blind, randomized trial comparing IIV-HD to IIV-SD in adults ≥65 years over two influenza seasons. A subset of year 1 (Y1) participants re-enrolled in year 2 (Y2), receiving vaccine by random assignment in both years. We evaluated the effect of Y1 vaccination on Y2 relative vaccine efficacy (VE), immunogenicity (hemagglutination inhibition [HAI] titers), and safety among re-enrolled participants.
Results:
Of 14,500 Y1 participants, 7643 re-enrolled in Y2. Relative to participants who received IIV-SD both seasons, VE was higher for IIV-HD vaccinees in Y2 (28.3% overall; 25.1% for Y1 IIV-HD, Y2 IIV-HD; and 31.6% for Y1 IIV-SD, Y2 IIV-HD). In multivariate logistic regression models, Y1 vaccine was not a significant modifier of Y2 VE (p=0.43), while Y2 IIV-HD remained significantly associated with lower influenza risk (p=0.043). Compared to administration of IIV-SD in both years, post-vaccination HAI titers were significantly higher for patterns that included IIV-HD in Y2. No safety concerns were raised with IIV-HD revaccination.
Conclusions:
IIV-HD is likely to provide clinical benefit over IIV-SD irrespective of previous season vaccination with IIV-HD or IIV-SD. IIV-HD consistently improved immune responses, and no safety concerns emerged in the context of IIV-HD revaccination.
Background:
The potential for human influenza viruses to spread through fine particle aerosols remains controversial. The objective of our study was to determine whether influenza viruses could be detected in fine particles in hospital rooms.
Methods and findings:
We sampled the air in 2-bed patient isolation rooms for four hours, placing cyclone samplers at heights of 1.5m and 1.0m. We collected ten air samples each in the presence of at least one patient with confirmed influenza A virus infection, and tested the samples by reverse transcription polymerase chain reaction. We recovered influenza A virus RNA from 5/10 collections (50%); 4/5 were from particles>4 μm, 1/5 from 1-4 μm, and none in particles<1 μm.
Conclusions:
Detection of influenza virus RNA in aerosols at low concentrations in patient rooms suggests that healthcare workers and visitors might have frequent exposure to airborne influenza virus in proximity to infected patients. A limitation of our study was the small sample size. Further studies should be done to quantify the concentration of viable influenza virus in healthcare settings, and factors affecting the detection of influenza viruses in fine particles in the air.
Monoclonal antibodies (mAbs) are increasingly being considered as agents to fight severe viral diseases. So far, they have essentially been selected and used on the basis of their virus-neutralizing activity and/or cell-killing activity to blunt viral propagation via direct mechanisms. There is, however, accumulating evidence that they can also induce long-lasting protective antiviral immunity by recruiting the endogenous immune system of infected individuals during the period of immunotherapy. Exploiting this property may revolutionize antiviral mAb-based immunotherapies, with benefits for both patients and healthcare systems.
Background:
Patients hospitalized with influenza may require extended care upon discharge. We aimed to explore predictors for extended care needs and the potential mitigating effect of antiviral treatment among community-dwelling adults aged ≥65 years hospitalized with influenza.
Methods:
We used laboratory-confirmed influenza hospitalizations from 3 influenza seasons. Extended care was defined as new placement in a skilled nursing home/long-term/rehabilitation facility upon hospital discharge. We focused on those treated with antiviral agents to explore the effect of early treatment on extended care and hospital length of stay (LOS) using logistic regression and competing risk survival analysis, accounting for time from illness onset to hospitalization. Treatment was categorized as early (≤4 days) and late (>4 days) in reference to date of illness onset.
Results:
Among 6,593 community-dwelling adults aged ≥65 years hospitalized for influenza, 18% required extended care at discharge. Need for care increased with age and neurologic disorders, ICU admission, and pneumonia were predictors of care needs. Early treatment reduced the odds of extended care after hospital discharge for those hospitalized ≤2 or >2 days from illness onset (adjusted odds ratio [aOR] 0.38; 95% confidence interval [CI] 0.17, 0.85, and aOR 0.75; 95% CI 0.56, 0.97 respectively). Early treatment was also independently associated with reduction in LOS for those hospitalized ≤2 days from illness onset (adjusted hazard ratio [aHR] 1.81; 95% CI 1.43, 2.30) or >2 days (aHR 1.30; 95% CI 1.20, 1.40).
Conclusions:
Prompt antiviral treatment decreases the impact of influenza on older adults through shorten hospitalization and reduced extended care needs.
Both influenza and respiratory syncytial virus (RSV) are active throughout the year in subtropical or tropical regions, but few studies have reported on age-specific seasonal patterns of these viruses. We examined the age-specific epidemic curves of laboratory-confirmed cases of influenza A (subtyped into seasonal A(H1N1), A(H3N2), and pandemic virus A(H1N1)pdm09), influenza B and respiratory syncytial virus (RSV), in subtropical city Hong Kong from 2004 to 2013. We found that different types and subtypes of influenza showed similar two-peak patterns across age groups, with one peak in winter and another in spring/summer. Age differences were found in epidemic onset time and duration, but none could reach statistical significance (p > 0.05). Age synchrony was found in epidemic peak time for both cool and warm seasons. RSV showed less clear seasonal patterns and non-synchronized epidemic curves across age. In conclusion, age synchrony was found in influenza seasonal epidemics and the 2009 pandemic, but not in RSV. None of the age groups consistently appear as the driving force for seasonal epidemics of influenza and RSV in Hong Kong.
The effects of lower nitrogen (N, 4 me·L−1 NO3-N) concentration on growth, fruit yield, and yellow-shoulder (YS) disorder of tomatoes (Solanum lycopersicum L.) were investigated at EC 0.9 dS·m−1 (N, 6 me·L−1 NO3-N) combined with potassium (K) supplementation. Tomatoes ‘CF Momotaro York’ were grown in extremely low-volume substrate (ELVS) combined with low-node-order pinching and high-density planting (LN&HD). An experiment with five nutrient solution treatments of Enshi formula nutrient solution at EC 0.6 and EC 0.9 dS·m−1, EC 0.6+KNO3 (in which 1 me·L−1 KNO3 was added to EC 0.6 dS·m−1), EC 0.6/0.9 (nutrient solution ranging from EC 0.6 to EC 0.9 during fruit enlargement and ripening stages) and EC 0.9+P+K (P and K concentrations increased to 4.6 and 5.8 me·L−1 in EC 0.9) was conducted. Tomatoes were grown in 250 mL pots filled with granular rock wool combined with LN&HD from Feb. 10 to May 29, 2012. The fertigation system of high frequency and small volume was based on integrated solar radiation level. Total yield and YS index at EC 0.6+KNO3 almost reached those at EC 0.9, but they were still significantly lower than those at EC 0.9+P+K. YS index decreased significantly when K concentration increased by 1 me·L−1 (2 to 3 me·L−1). The results suggest the possibility of increasing the yield when a lower-N (5.3 me·L−1) nutrient solution is applied in the ELVS culture system, if P and K concentrations are further modified to enhance the uptake. Shoot fresh weight at EC 0.6/0.9 was significantly lower than at EC 0.9, but there was no significant difference in total yield between EC 0.9 and EC 0.6/0.9. Total yield increased with increasing NO3-N uptake per plant (R2 = 0.98, P < 0.01) and YS incidence of fruit decreased with increasing K uptake per plant (R2 = 0.92, P < 0.05) during the entire growing period.
Influenza is a contagious respiratory acute viral disease characterized by a short incubation period, high fever and respiratory and systemic symptoms.
The burden of influenza is very heavy. Indeed, the World Health Organization (WHO) estimates that annual epidemics affect 5-15% of the world's population, causing up to 4-5 million severe cases and from 250,000 to 500,000 deaths.
In order to design anti-influenza molecules and compounds, it is important to understand the complex replication cycle of the influenza virus. Replication is achieved through various stages. First, the virus must engage the sialic acid receptors present on the free surface of the cells of the respiratory tract. The virus can then enter the cells by different routes (clathrin-mediated endocytosis or CME, caveolae-dependent endocytosis or CDE, clathrin-caveolae-independent endocytosis, or macropinocytosis). CME is the most usual pathway; the virus is internalized into an endosomal compartment, from which it must emerge in order to release its nucleic acid into the cytosol. The ribonucleoprotein must then reach the nucleus in order to begin the process of translation of its genes and to transcribe and replicate its nucleic acid. Subsequently, the RNA segments, surrounded by the nucleoproteins, must migrate to the cell membrane in order to enable viral assembly. Finally, the virus must be freed to invade other cells of the respiratory tract. All this is achieved through a synchronized action of molecules that perform multiple enzymatic and catalytic reactions, currently known only in part, and for which many inhibitory or competitive molecules have been studied. Some of these studies have led to the development of drugs that have been approved, such as Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Laninamivir, Ribavirin and Arbidol. This review focuses on the influenza lifecycle and on the currently available drugs, while potential antiviral compounds for the prevention and treatment of influenza are considered in the subsequent review.
In the first part of this overview, we described the life cycle of the influenza virus and the pharmacological action of the currently available drugs. This second part provides an overview of the molecular mechanisms and targets of still-experimental drugs for the treatment and management of influenza.
Briefly, we can distinguish between compounds with anti-influenza activity that target influenza virus proteins or genes, and molecules that target host components that are essential for viral replication and propagation. These latter compounds have been developed quite recently. Among the first group, we will focus especially on hemagglutinin, M2 channel and neuraminidase inhibitors. The second group of compounds may pave the way for personalized treatment and influenza management. Combination therapies are also discussed.
In recent decades, few antiviral molecules against influenza virus infections have been available; this has conditioned their use during human and animal outbreaks. Indeed, during seasonal and pandemic outbreaks, antiviral drugs have usually been administered in mono-therapy and, sometimes, in an uncontrolled manner to farm animals. This has led to the emergence of viral strains displaying resistance, especially to compounds of the amantadane family. For this reason, it is particularly important to develop new antiviral drugs against influenza viruses. Indeed, although vaccination is the most powerful means of mitigating the effects of influenza epidemics, antiviral drugs can be very useful, particularly in delaying the spread of new pandemic viruses, thereby enabling manufacturers to prepare large quantities of pandemic vaccine. In addition, antiviral drugs are particularly valuable in complicated cases of influenza, especially in hospitalized patients.
To write this overview, we mined various databases, including Embase, PubChem, DrugBank and Chemical Abstracts Service, and patent repositories.
Influenza A virus infections in humans generally cause self-limited infections, but can result in severe disease, secondary bacterial pneumonias, and death. Influenza viruses can replicate in epithelial cells throughout the respiratory tree and can cause tracheitis, bronchitis, bronchiolitis, diffuse alveolar damage with pulmonary edema and hemorrhage, and interstitial and airspace inflammation. The mechanisms by which influenza infections result in enhanced disease, including development of pneumonia and acute respiratory distress, are multifactorial, involving host, viral, and bacterial factors. Host factors that enhance risk of severe influenza disease include underlying comorbidities, such as cardiac and respiratory disease, immunosuppression, and pregnancy. Viral parameters enhancing disease risk include polymerase mutations associated with host switch and adaptation, viral proteins that modulate immune and antiviral responses, and virulence factors that increase disease severity, which can be especially prominent in pandemic viruses and some zoonotic influenza viruses causing human infections. Influenza viral infections result in damage to the respiratory epithelium that facilitates secondary infection with common bacterial pneumopathogens and can lead to secondary bacterial pneumonias that greatly contribute to respiratory distress, enhanced morbidity, and death. Understanding the molecular mechanisms by which influenza and secondary bacterial infections, coupled with the role of host risk factors, contribute to enhanced morbidity and mortality is essential to develop better therapeutic strategies to treat severe influenza.
Published by Elsevier Inc.
The emergence of human infection with a novel H7N9 influenza virus in China raises a pandemic concern. Chicken H9N2 viruses provided all six of the novel reassortant's internal genes. However, it is not fully understood how the prevalence and evolution of these H9N2 chicken viruses facilitated the genesis of the novel H7N9 viruses. Here we show that over more than 10 y of cocirculation of multiple H9N2 genotypes, a genotype (G57) emerged that had changed antigenicity and improved adaptability in chickens. It became predominant in vaccinated farm chickens in China, caused widespread outbreaks in 2010-2013 before the H7N9 viruses emerged in humans, and finally provided all of their internal genes to the novel H7N9 viruses. The prevalence and variation of H9N2 influenza virus in farmed poultry could provide an important early warning of the emergence of novel reassortants with pandemic potential.
Unlabelled:
Human infections by avian influenza A(H7N9) virus entail substantial morbidity and mortality. Treatment of infected patients with the neuraminidase (NA) inhibitor oseltamivir was associated with emergence of viruses carrying NA substitutions. In the NA inhibition (NI) assay, R292K conferred highly reduced inhibition by oseltamivir, while E119V and I222K each caused reduced inhibition. To facilitate establishment of laboratory correlates of clinically relevant resistance, experiments were conducted in ferrets infected with virus carrying wild-type or variant NA genes recovered from the A/Taiwan/1/2013 isolate. Oseltamivir treatment (5 or 25 mg/kg of body weight/dose) was given 4 h postinfection, followed by twice-daily treatment for 5 days. Treatment of ferrets infected with wild-type virus resulted in a modest dose-dependent reduction (0.7 to 1.5 log10 50% tissue culture infectious dose [TCID50]) in nasal wash viral titers and inflammation response. Conversely, treatment failed to significantly inhibit the replication of R292K or E119V virus. A small reduction of viral titers was detected on day 5 in ferrets infected with the I222K virus. The propensity for oseltamivir resistance emergence was assessed in oseltamivir-treated animals infected with wild-type virus; emergence of R292K virus was detected in 3 of 6 ferrets within 5 to 7 days postinfection. Collectively, we demonstrate that R292K, E119V, and I222K reduced the inhibitory activity of oseltamivir, not only in the NI assay, but also in infected ferrets, judged particularly by viral loads in nasal washes, and may signal the need for alternative therapeutics. Thus, these clinical outcomes measured in the ferret model may correlate with clinically relevant oseltamivir resistance in humans.
Importance:
This report provides more evidence for using the ferret model to assess the susceptibility of influenza A(H7N9) viruses to oseltamivir, the most prescribed anti-influenza virus drug. The information gained can be used to assist in the establishment of laboratory correlates of human disease and drug therapy. The rapid emergence of viruses with R292K in treated ferrets correlates well with the multiple reports on this NA variant in treated human patients. Our findings highlight the importance of the discovery and characterization of new antiviral drugs with different mechanisms of action and the use of combination treatment strategies against emerging viruses with pandemic potential, such as avian H7N9 virus, particularly against those carrying drug resistance markers.
Because of the age-related immune system decline, two potentiated influenza vaccines were specifically licensed for the elderly: Fluad→, an MF59-adjuvanted vaccine administered intramuscularly (IM-MF59), and Intanza 15mcg→, 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 two 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 two vaccines.
Influenza is an important cause of annual epidemics of respiratory viral infection associated with significant morbidity and mortality. Three classes of drugs, the M2 ion channel, neuraminidase and RNA-dependent RNA polymerase inhibitors, are approved for the prevention and treatment of influenza. Due to widespread resistance to the class, the M2 ion channel inhibitors are not recommended currently for therapy. The only polymerase inhibitor, favipiravir, is approved only in Japan and its use is highly restricted. Despite significant data to support the early use of the neuraminidase inhibitors, their use in all patient populations is suboptimal. The data to support the early use of neuraminidase inhibitors will be reviewed, as will current data on the utilization rates in ambulatory and hospitalized populations.
Between September 2013 and July 2014, 2,482 influenza A(H1N1)pdm09 viruses were screened in Japan for the H275Y substitution in their neuraminidase (NA) protein, which confers cross-resistance to oseltamivir and peramivir. We found that a large cluster of the H275Y mutant virus occurred prior to the main influenza season in Sapporo /: Hokkaido, with the detection rate for this mutant virus reaching 29% in this area. Phylogenetic analysis suggested the clonal expansion of a single mutant virus in Sapporo /: Hokkaido. To understand the reason for this large cluster, we examined the in vitro and in vivo properties of the mutant virus. We found that it grew well in cell culture, comparable to wild-type virus. The cluster virus also replicated well in the upper respiratory tract of ferrets and was transmitted efficiently between ferrets by droplets. Almost all recently circulating A(H1N1)pdm09 viruses including the cluster virus possessed two substitutions in NA, V241I and N369K, known to increase replication and transmission fitness. Structural analysis of NA predicted that a third substitution (N386K) in the NA of the cluster virus destabilized the mutant NA structure in the presence of the V241I and N369K substitutions. Our results suggest that the cluster virus retained viral fitness to spread among humans and, accordingly, caused the large cluster in Sapporo/Hokkaido. However, the mutant NA structure was less stable than that of the wild-type virus. Therefore, once the wild-type virus began to circulate in the community, the mutant virus could not compete and faded out.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
VX-787 is a novel inhibitor of influenza replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support that VX-787 occupies the m(7)GTP cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including delayed start-to-treat experiments, with 100% survival up to 96 h post infection and partial survival in groups where the initiation of therapy was delayed up to 120 h post infection. At different doses, VX-787 showed a 1- to >5-log reduction in lung viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Background
The natural (i.e. unvaccinated population) attack rate of an infectious disease is an important parameter required for understanding disease transmission. As such, it is an input parameter in infectious disease mathematical models. Influenza is an infectious disease that poses a major health concern worldwide and the natural attack rate of this disease is crucial in determining the effectiveness and cost-effectiveness of public health interventions and informing surveillance program design. We estimated age-stratified, strain-specific natural attack rates of laboratory-confirmed influenza in unvaccinated individuals.Methods
Utilizing an existing systematic review, we calculated the attack rates in the trial placebo arms using a random effects model and a meta-regression analysis (GSK study identifier: 117102).ResultsThis post-hoc analysis included 34 RCTs (Randomized Control Trials) contributing to 47 influenza seasons from 1970 to 2009. Meta-regression analyses showed that age and type of influenza were important covariates. The attack rates (95% CI (Confidence Interval)) in adults for all influenza, type A and type B were 3.50% (2.30%, 4.60%), 2.32% (1.47%, 3.17%) and 0.59% (0.28%, 0.91%) respectively. For children, they were 15.20% (11.40%, 18.90%), 12.27% (8.56%, 15.97%) and 5.50% (3.49%, 7.51%) respectively.Conclusions
This analysis demonstrated that unvaccinated children have considerably higher exposure risk than adults and influenza A can cause more disease than influenza B. Moreover, a higher ratio of influenza B:A in children than adults was observed. This study provides a new, stratified and up to-date natural attack rates that can be used in influenza infectious disease models and are consistent with previous published work in the field.
To assess the effectiveness of neuraminidase inhibitors for use in rapid containment of influenza.
We conducted a systematic review and meta-analysis in accordance with the PRISMA statement. Healthcare databases and sources of grey literature were searched up to 2012 and records screened against protocol eligibility criteria. Data extraction and risk of bias assessments were performed using a piloted form. Results were synthesised narratively and we undertook meta-analyses to calculate pooled estimates of effect, statistical heterogeneity and assessed publication bias.
Nine randomised controlled trials (RCTs) and eight observational studies met the inclusion criteria. Neuraminidase inhibitors provided 67 to 89% protection for individuals following prophylaxis. Meta-analysis of individual protection showed a significantly lower pooled odds of laboratory confirmed seasonal or influenza A(H1N1)pdm09 infection following oseltamivir usage compared to placebo or no therapy (n = 8 studies; odds ratio (OR) = 0.11; 95% confidence interval (CI) = 0.06 to 0.20; p<0.001; I2 = 58.7%). This result was comparable to the pooled odds ratio for individual protection with zanamivir (OR = 0.23; 95% CI 0.16 to 0.35). Similar point estimates were obtained with widely overlapping 95% CIs for household protection with oseltamivir or zanamivir. We found no studies of neuraminidase inhibitors to prevent population-wide community transmission of influenza.
Oseltamivir and zanamivir are effective for prophylaxis of individuals and households irrespective of treatment of the index case. There are no data which directly support an effect on wider community transmission.
PROSPERO registration number: CRD42013003880.
H9N2 subtype influenza viruses have been detected in different species of wild birds and domestic poultry in many countries for several decades. Because these viruses are of low pathogenicity in poultry, their eradication is not a priority for animal disease control in many countries, which has allowed them to continue to evolve and spread. Here, we characterized the genetic variation, receptor-binding specificity, replication capability, and transmission in mammals of a series of H9N2 influenza viruses that were detected in live poultry markets in southern China between 2009 and 2013. Thirty-five viruses represented 17 genotypes on the basis of genomic diversity, and one specific "internal-gene-combination" predominated among the H9N2 viruses. This gene combination was also present in the H7N9 and H10N8 viruses that have infected humans in China. All of the 35 viruses preferentially bound to the human-like receptor, although two also retained the ability to bind to the avian-like receptor. Six of nine viruses tested were transmissible in ferrets by respiratory droplet; two were highly transmissible. Some H9N2 viruses readily acquired the 627K or 701N mutation in their PB2 gene upon infection of ferrets, further enhancing their virulence and transmission in mammals. Our study indicates that the widespread dissemination of H9N2 viruses poses a threat to human health not only because of the potential of these viruses to cause an influenza pandemic, but also because they can function as "vehicles" to deliver different subtypes of influenza viruses from avian species to humans.
Background:
The test-negative design is a variant of the case-control study being increasingly used to study influenza vaccine effectiveness (VE). In these studies, patients with influenza-like illness are tested for influenza. Vaccine coverage is compared between those testing positive versus those testing negative to estimate VE.
Objectives:
We reviewed features in the design, analysis and reporting of 85 published test-negative studies.
Data sources:
Studies were identified from PubMed, reference lists and email updates. Study eligibility: All studies using the test-negative design reporting end-of-season estimates were included.
Study appraisal:
Design features that may affect the validity and comparability of reported estimates were reviewed, including setting, study period, source population, case definition, exposure and outcome ascertainment and statistical model.
Results:
There was considerable variation in the analytic approach, with 68 unique statistical models identified among the studies.
Conclusion:
Harmonization of analytic approaches may improve the potential for pooling VE estimates.
Patients with influenza release aerosol particles containing the virus into their environment. However, the importance of airborne transmission in the spread of influenza is unclear, in part because of a lack of information about the infectivity of the airborne virus. The purpose of this study was to determine the amount of viable influenza A virus that was expelled by patients in aerosol particles while coughing. Sixty-four symptomatic adult volunteer outpatients were asked to cough 6 times into a cough aerosol collection system. Seventeen of these participants tested positive for influenza A virus by viral plaque assay (VPA) with confirmation by viral replication assay (VRA). Viable influenza A virus was detected in the cough aerosol particles from 7 of these 17 test subjects (41%). Viable influenza A virus was found in the smallest particle size fraction (0.3 µm to 8 µm), with a mean of 142 plaque-forming units (SD 215) expelled during the 6 coughs in particles of this size. These results suggest that a significant proportion of patients with influenza A release small airborne particles containing viable virus into the environment. Although the amounts of influenza A detected in cough aerosol particles during our experiments were relatively low, larger quantities could be expelled by influenza patients during a pandemic when illnesses would be more severe. Our findings support the idea that airborne infectious particles could play an important role in the spread of influenza.
The Advisory Committee on Immunization Practices recommends that all health care personnel (HCP) be vaccinated annually against influenza. Vaccination of HCP can reduce influenza-related morbidity and mortality among both HCP and their patients. To estimate influenza vaccination coverage among HCP during the 2013-14 season, CDC analyzed results of an opt-in Internet panel survey of 1,882 HCP conducted during April 1-16, 2014. Overall, 75.2% of participating HCP reported receiving an influenza vaccination during the 2013-14 season, similar to the 72.0% coverage among participating HCP reported in the 2012-13 season. Coverage was highest among HCP working in hospitals (89.6%) and lowest among HCP working in long-term care (LTC) settings (63.0%). By occupation, coverage was highest among physicians (92.2%), nurses (90.5%), nurse practitioners and physician assistants (89.6%), pharmacists (85.7%), and "other clinical personnel" (87.4%) compared with assistants and aides (57.7%) and nonclinical personnel (e.g., administrators, clerical support workers, janitors, and food service workers) (68.6%). HCP working in settings where vaccination was required had higher coverage (97.8%) compared with HCP working in settings where influenza vaccination was not required but promoted (72.4%) or settings where there was no requirement or promotion of vaccination (47.9%). Among HCP without an employer requirement for vaccination, coverage was higher for HCP working in settings where vaccination was offered on-site at no cost for 1 day (61.6%) or multiple days (80.4%) compared with HCP working in settings not offering free on-site vaccination (49.0%). Comprehensive vaccination strategies that include making vaccine available at no cost at the workplace along with active promotion of vaccination might be needed to increase vaccination coverage among HCP and minimize the risk for influenza to HCP and their patients.
Pregnant women and infants are at increased risk for influenza-related complications and hospitalization. Influenza vaccination among pregnant women can reduce their risk for respiratory illness and reduce the risk for influenza in their infants aged <6 months. Since 2004, the Advisory Committee on Immunization Practices and the American College of Obstetricians and Gynecologists have recommended influenza vaccination for all women who are or will be pregnant during the influenza season, regardless of trimester. To assess influenza vaccination coverage among pregnant women during the 2013-14 influenza season, CDC analyzed data from an Internet panel survey conducted March 31-April 11, 2014. Among 1,619 survey respondents pregnant at any time during October 2013-January 2014, 52.2% reported vaccination before or during pregnancy (17.6% before and 34.6% during pregnancy), similar to the coverage in the preceding season. Overall, 65.1% of women reported receiving a clinician recommendation and offer of influenza vaccination, 15.1% received a clinician recommendation but no offer of vaccination, and 19.8% received no clinician recommendation or offer. Vaccination coverage among these women was 70.5%, 32.0%, and 9.7%, respectively. Continued efforts are needed to encourage clinicians to strongly recommend and offer influenza vaccination to their pregnant patients.
Observational data suggest that the treatment of influenza infection with neuraminidase inhibitors decreases progression to more severe illness, especially when treatment is started soon after symptom onset. However, even early treatment might fail to prevent complications in some patients, particularly those infected with novel viruses such as the 2009 pandemic influenza A H1N1, avian influenza A H5N1 virus subtype, or the avian influenza A H7N9 virus subtype. Furthermore, treatment with one antiviral drug might promote the development of antiviral resistance, especially in immunocompromised hosts and critically ill patients. An obvious strategy to optimise antiviral therapy is to combine drugs with different modes of action. Because host immune responses to infection might also contribute to illness pathogenesis, improved outcomes might be gained from the combination of antiviral therapy with drugs that modulate the immune response in an infected individual. We review available data from preclinical and clinical studies of combination antiviral therapy and of combined antiviral-immunomodulator therapy for influenza. Early-stage data draw attention to several promising antiviral combinations with therapeutic potential in severe infections, but there remains a need to substantiate clinical benefit. Combination therapies with favourable experimental data need to be tested in carefully designed aclinical trials to assess their efficacy.
Background:
The potential impact of an influenza pandemic can be assessed by calculating a set of transmissibility parameters, the most important being the reproduction number (R), which is defined as the average number of secondary cases generated per typical infectious case.
Methods:
We conducted a systematic review to summarize published estimates of R for pandemic or seasonal influenza and for novel influenza viruses (e.g. H5N1). We retained and summarized papers that estimated R for pandemic or seasonal influenza or for human infections with novel influenza viruses.
Results:
The search yielded 567 papers. Ninety-one papers were retained, and an additional twenty papers were identified from the references of the retained papers. Twenty-four studies reported 51 R values for the 1918 pandemic. The median R value for 1918 was 1.80 (interquartile range [IQR]: 1.47-2.27). Six studies reported seven 1957 pandemic R values. The median R value for 1957 was 1.65 (IQR: 1.53-1.70). Four studies reported seven 1968 pandemic R values. The median R value for 1968 was 1.80 (IQR: 1.56-1.85). Fifty-seven studies reported 78 2009 pandemic R values. The median R value for 2009 was 1.46 (IQR: 1.30-1.70) and was similar across the two waves of illness: 1.46 for the first wave and 1.48 for the second wave. Twenty-four studies reported 47 seasonal epidemic R values. The median R value for seasonal influenza was 1.28 (IQR: 1.19-1.37). Four studies reported six novel influenza R values. Four out of six R values were <1.
Conclusions:
These R values represent the difference between epidemics that are controllable and cause moderate illness and those causing a significant number of illnesses and requiring intensive mitigation strategies to control. Continued monitoring of R during seasonal and novel influenza outbreaks is needed to document its variation before the next pandemic.
Influenza virus infection is a major source of morbidity and mortality worldwide. Due to the variable effectiveness of existing vaccines, especially in the early stages of an epidemic, antiviral drugs represent the first line of defense against the virus. Currently, there are two major classes of anti-influenza drugs approved by the FDA for clinical use: M2 protein inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (zanamivir and oseltamivir). However, increasing resistance to these available influenza antivirals among circulating influenza viruses highlights the need to develop alternative approaches for the prevention and/or treatment of influenza. This review presents an overview of currently available drugs for influenza treatment as well as summarizes some new antiviral strategies that are now being tested covering agents targeting both the viral proteins and the host-virus interaction. We discuss their mechanisms of action, resistance and the therapeutic potential as new antiviral drug for use in future influenza pandemics. Additionally, combination therapy based on these drugs is also described.
The United Kingdom (UK) is in the third season of introducing universal paediatric influenza vaccination with a quadrivalent live attenuated influenza vaccine (LAIV). The 2015/16 season in the UK was initially dominated by influenza A(H1N1)pdm09 and then influenza of B/Victoria lineage, not contained in that season's adult trivalent inactivated influenza vaccine (IIV). Overall adjusted end-of-season vaccine effectiveness (VE) was 52.4% (95% confidence interval (CI): 41.0-61.6) against influenza-confirmed primary care consultation, 54.5% (95% CI: 41.6-64.5) against influenza A(H1N1)pdm09 and 54.2% (95% CI: 33.1-68.6) against influenza B. In 2-17 year-olds, adjusted VE for LAIV was 57.6% (95% CI: 25.1 to 76.0) against any influenza, 81.4% (95% CI: 39.6-94.3) against influenza B and 41.5% (95% CI: -8.5 to 68.5) against influenza A(H1N1)pdm09. These estimates demonstrate moderate to good levels of protection, particularly against influenza B in children, but relatively less against influenza A(H1N1)pdm09. Despite lineage mismatch in the trivalent IIV, adults younger than 65 years were still protected against influenza B. These results provide reassurance for the UK to continue its influenza immunisation programme planned for 2016/17.
This report shows evidence for nosocomial transmission of H7N9 influenza from a patient to two physicians who provided care.
Background:
The predominant strain during the 2013-2014 influenza season was 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09). This vaccine-component has remained unchanged from 2009.
Methods:
The US Flu Vaccine Effectiveness Network enrolled subjects aged ≥6 months with medically attended acute respiratory illness (MAARI), including cough, with illness onset ≤7 days before enrollment. Influenza was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). We determined the effectiveness of trivalent or quadrivalent inactivated influenza vaccine (IIV) among subjects ages ≥6 months and the effectiveness of quadrivalent live attenuated influenza vaccine (LAIV4) among children aged 2-17 years, using a test-negative design. The effect of prior receipt of any A(H1N1)pdm09-containing vaccine since 2009 on the effectiveness of current-season vaccine was assessed.
Results:
We enrolled 5999 subjects; 5637 (94%) were analyzed; 18% had RT-PCR-confirmed A(H1N1)pdm09-related MAARI. Overall, the effectiveness of vaccine against A(H1N1)pdm09-related MAARI was 54% (95% confidence interval [CI], 46%-61%). Among fully vaccinated children aged 2-17 years, the effectiveness of LAIV4 was 17% (95% CI, -39% to 51%) and the effectiveness of IIV was 60% (95% CI, 36%-74%). Subjects aged ≥9 years showed significant residual protection of any prior A(H1N1)pdm09-containing vaccine dose(s) received since 2009, as did children <9 years old considered fully vaccinated by prior season.
Conclusions:
During 2013-2014, IIV was significantly effective against A(H1N1)pdm09. Lack of LAIV4 effectiveness in children highlights the importance of continued annual monitoring of effectiveness of influenza vaccines in the United States.
In this article, a facile one-step strategy for the synthesis of ternary MnO2-Fe2O3-CeO2-Ce2O3/carbon nanotubes (CNT) catalysts was discussed. The as-prepared catalysts exhibited 73.6-99.4% NO conversion at 120-180 °C at a weight hourly space velocity (WHSV) of 210 000 ml·gcat-1·h-1, which benefited from the formation of amorphous MnO2, Fe2O3, CeO2, and Ce2O3, as well as high Ce3+ and surface oxygen (Oε) contents. The mechanism of formation of MnO2-Fe2O3-CeO2-Ce2O3/CNT catalysts was also proposed.
DAS181, (study drug, Fludase®) was developed for treatment of influenza and parainfluenza infections. Delivered by inhalation, DAS181 cleaves sialic acid receptors from respiratory epithelial cells. Treatment of influenza for three days with DAS181 reduced viral shedding. To increase deposition in the upper airways and decrease systemic absorption, the particle size was increased to 10 microns. We conducted two Phase I trials with three cohorts, randomized 2:1, active drug to placebo. The initial cohort got a single 20 mg dose of DAS181, or placebo; the second, 20 mg DAS181 or placebo for 10 days, and the third got 20 mg of DAS181or placebo for 3 days. Formulations differed slightly in their excipients. Subjects in the 1- and 3-day cohorts completed dosing without serious adverse events. Two subjects in the 10-day cohort stopped at Day 9 after developing respiratory and systemic symptoms, and a third experienced a decrease in FEV1 (Forced Expiratory Volume in 1 second) after the 9(th) dose and a further decline after the 10(th) dose. Plasma DAS181, in the 10-day cohort, peaked and began falling before the last dose. Antibodies, predominately IgG with neutralizing activity, were detected in 15/18 subjects by Day 30. The highest IgG concentrations were in the 10-day cohort. The respiratory adverse events occurring after seven days and rapid drug clearance during continued dosing are consistent with the induction of DAS181 antibodies. This could preclude use of this medication for longer than seven days or for repeated courses. (These studies have been registered at ClinicalTrials.gov under registration nos. NCT 00527865 and NCT 01651494.).
Importance:
Pigs are important hosts in the evolution of influenza A viruses (IAV). Human-to-swine transmissions of IAV have resulted in the circulation of reassortant viruses containing human-origin genes in pigs, greatly contributing to the diversity of IAV in swine worldwide. New human-like H3N2 and H3N1 viruses that contain a mix of human and swine gene segments were recently detected by the USDA surveillance system. The human-like viruses efficiently infected pigs and resulted in onward airborne transmission, likely due to multiple changes identified between human and swine H3 viruses. The human-like swine viruses are distinct from contemporary U.S. H3 swine viruses and from the strains used in swine vaccines, which could have a significant impact on the swine industry due to lack of population immunity. Additionally, public health experts should consider appropriate risk assessment for these emerging swine H3N1 for the human population.
In March 2013 the first cases of human avian influenza A(H7N9) were reported to the World Health Organization. Since that time, over 650 cases have been reported. Infections are associated with considerable morbidity and mortality, particularly within certain demographic groups. This rapid increase in cases over a brief time period is alarming and has raised concerns about the pandemic potential of the H7N9 virus. Three major factors influence the pandemic potential of an influenza virus: (1) its ability to cause human disease, (2) the immunity of the population to the virus, and (3) the transmission potential of the virus. This paper reviews what is currently known about each of these factors with respect to avian influenza A(H7N9). Currently, sustained human-to-human transmission of H7N9 has not been reported; however, population immunity to the virus is considered very low, and the virus has significant ability to cause human disease. Several statistical and geographical modelling studies have estimated and predicted the spread of the H7N9 virus in humans and avian species, and some have identified potential risk factors associated with disease transmission. Additionally, assessment tools have been developed to evaluate the pandemic potential of H7N9 and other influenza viruses. These tools could also hypothetically be used to monitor changes in the pandemic potential of a particular virus over time.
A 47-year-old man with a fever was highly suspected of having influenza A infection since his wife and son who lived with him had been diagnosed with influenza A. Although repeated rapid tests with a nasopharyngeal swab showed negative findings, the patient developed bilateral pneumonia and reverse transcription polymerase chain reaction (PCR) for A (H1N1) pdm09 virus in the bronchoalveolar lavage fluid was positive. We therefore diagnosed him with primary influenza pneumonia and initiated treatment with peramivir plus corticosteroids, which rapidly improved his condition. During the influenza season, sample collection from the lower airway and PCR should be considered for the definitive diagnosis of primary influenza viral pneumonia.
Background
Influenza virus infection is very common and a significant cause of morbidity and mortality in specific populations like pregnant women. Following the 2009 pandemic, several reports on the effects of influenza virus infection on maternal health and pregnancy outcome have been published. Also the safety and efficacy of antiviral treatment and vaccination of pregnant women have been studied. In this review, we have analyzed and summarized these data.Objective
To provide information on the influence of influenza virus infection during pregnancy on maternal health and pregnancy outcome and on the effect of treatment and vaccination.Data sourcesWe have searched Medline, Embase and the Cochrane library. We used influenza, influenz*, pregnancy and pregnan* as search terms.Study selectionIn total, 294 reports were reviewed and judged according to the STROBE guidelines or CONSORT statement. 100 studies, published between 1961 and 2015, were included.ResultsCompared to the general population, pregnant women are more often hospitalized and admitted to an intensive care unit due to influenza virus infection. For hospitalized patients, increased rates of preterm birth and fetal/neonatal death are reported. Early treatment with oseltamivir is associated with a reduced risk of severe disease. Vaccination of pregnant women is safe and reduces maternal and neonatal morbidity.Conclusions
There is level 2b evidence that maternal health and pregnancy outcome can be severely affected by influenza virus infection. Antiviral treatment may diminish these effects and vaccination protects pregnant women and neonates from infection (level of evidence 2b and 1b respectively).This article is protected by copyright. All rights reserved.
Objective:
This study was performed to determine predictors of clinical influenza diagnosis among patients with laboratory-confirmed influenza.
Methods:
Prospective, laboratory-confirmed surveillance for influenza was conducted among patients of all ages who were hospitalized or presented to the emergency department with fever and respiratory symptoms during 2009-2013. We evaluated all enrolled persons who had influenza confirmed by viral culture and/or polymerase chain reaction and received any discharge diagnosis. The primary outcome, clinical influenza diagnosis, was defined as (1) a discharge diagnosis of influenza, (2) a prescription of neuraminidase inhibitor, or (3) a rapid test positive for influenza virus. Bivariate analyses and multiple logistic regression modeling were performed.
Results:
Influenza was diagnosed for 29% of 504 enrolled patients with laboratory-confirmed influenza and for 56% of 236 patients with high-risk conditions. Overall, clinical influenza diagnosis was predicted by race/ethnicity, insurance status, year, being hospitalized, having high-risk conditions, and receiving no diagnosis of bacterial infection. Being diagnosed with a bacterial infection reduced the odds of receiving an influenza diagnosis by >3-fold for all patients and for patients with high-risk conditions.
Conclusions:
Many influenza virus-positive patients, including those with high-risk conditions, do not receive a clinical diagnosis of influenza. The pattern of clinical diagnoses among influenza virus-positive patients suggests preferential consideration of bacterial diseases as a diagnosis.
Influenza A viruses cause respiratory infections that range from asymptomatic to deadly in humans. Widespread outbreaks (pandemics) are attributable to 'novel' viruses that possess a viral hemagglutinin (HA) gene to which humans lack immunity. After a pandemic, these novel viruses form stable virus lineages in humans and circulate until they are replaced by other novel viruses. The factors and mechanisms that facilitate virus transmission among hosts and the establishment of novel lineages are not completely understood, but the HA and basic polymerase 2 (PB2) proteins are thought to play essential roles in these processes by enabling avian influenza viruses to infect mammals and replicate efficiently in their new host. Here, we summarize our current knowledge of the contributions of HA, PB2, and other viral components to virus transmission and the formation of new virus lineages.
Copyright © 2015 Elsevier Inc. All rights reserved.
In recent years there has been much debate and controversy surrounding the efficacy and safety of neuraminidase inhibitors for influenza, in part because the data underlying certain efficacy claims were not available for independent scrutiny. In 2014, a Cochrane review was published, based exclusively on an almost complete set of clinical study reports and other regulatory documents. Clinical study reports can run to thousands of pages, providing an extensive amount of information on the planning, conduct and results of each trial. After a protracted campaign to obtain the reports, the manufacturers of the medications provided them unconditionally. The review authors subsequently published the underlying documents simultaneously with the Cochrane review, endorsing the concept of open science. In the following commentary, the background to and results of this review are summarized and put into clinical context.
Antiviral drugs are a proposed medical intervention to reduce household transmission of influenza viruses. In a previously described randomised, placebo-controlled trial in Dhaka, Bangladesh, we showed that oseltamivir treatment of index patients was able to reduce influenza symptom duration and virus shedding. In a further analysis that is part of the same study, we aimed to assess efficacy of oseltamivir to reduce secondary household illnesses in the same cohort.
In this double-blind oseltamivir efficacy trial, we identified index patients aged older than 1 year through surveillance of households in Dhaka, Bangladesh. We randomly allocated eligible patients (1:1) to receive oseltamivir or placebo twice-daily for 5 days, and we stratified them by enrolment 48 h versus 48-120 h since illness onset. Participants provided nasal wash specimens at enrolment and 2, 4, and 7 days after enrolment and were visited daily by a research assistant to record symptoms, both in index patients and in household members. For this part of the study, household members were asked to give respiratory specimens for influenza PCR testing. Our primary outcomes were household secondary illness and PCR-confirmed influenza virus infection, assessed in household members of all randomly allocated index patients. This trial is registered with ClinicalTrials.gov, number NCT00707941.
From May 11, 2008, to Dec 31, 2010, we enrolled 1190 index patients with 4694 household members. 592 patients were allocated to placebo (2292 household members) and 598 to oseltamivir (2402 household members). Household secondary illness was lower in the oseltamivir group (196 [8%] influenza cases) than in the placebo group (233 [10%]; odds ratio [OR] 0·77, 95% CI 0·60-0·98, p=0·031). PCR-confirmed influenza virus infection did not differ between the placebo (103 [5%]) and oseltamivir groups (92 [4%]; 0·84, 0·59-1·19, p=0·319); however, only 243 (57%) of ill household members gave a specimen for analysis.
In a crowded, low income setting, oseltamivir treatment of index patients resulted in a small reduction of secondary influenza in their households. Even this slight reduction, in the setting of widespread antiviral use during a community influenza outbreak, might result in reductions in overall disease burden.
Centers for Disease Control and Prevention (in an agreement with the International Centre for Diarrhoeal Disease Research, Bangladesh).
Copyright © 2015 Elsevier Ltd. All rights reserved.
The interferon-inducible transmembrane protein 3 (IFITM3), as one of the key genes involved in the interferon pathway, is critical for defending the host against influenza virus, and the rs12252 T>C variant in IFITM3 might be associated with susceptibility to severe influenza. Owing to contradictory and inconclusive results, we performed a meta-analysis to assess the association between rs12252 T>C polymorphism and severe influenza risk. A comprehensive literature search up to 1 August 2014 was conducted in EMBASE, Pubmed, Web of Science, VIP, Wanfang and CNKI databases. Four eligible studies with a total of 445 influenza patients and 3396 controls were included in this meta-analysis. Overall, our results demonstrated a significant association between the IFITM3 rs12252 T>C polymorphism and influenza risk [C vs. T: odds ratio (OR) 1·68, 95% confidence interval (CI) 1·32-2·13; CC vs. CT+TT: OR 2·38, 95% CI 1·52-3·73; CC+CT vs. TT: OR 1·62, 95% CI 1·18-2·22]. Stratification by ethnicity indicated that the variant C allele was associated with an 88% increased risk of influenza in Asians (C vs. T: OR 1·88, 95% CI 1·34-2·62). Moreover, subjects carrying the variant C allele had an increased risk of developing severe illness upon influenza infection (C vs. T: OR 2·70, 95% CI 1·86-3·94). However, no significant association was observed in patients with mild infection (C vs. T: OR 1·26, 95% CI 0·93-1·71). Our meta-analysis suggests that IFITM3 rs12252 T>C polymorphism is significantly associated with increased risk of severe influenza but not with the chance of initial virus infection.
Vaccination is the best method for the prevention and control of influenza. Vaccination can reduce illness and lessen severity of infection. This review focuses on how currently licensed influenza vaccines are generated in the U.S., why the biology of influenza poses vaccine challenges, and vaccine approaches on the horizon that address these challenges.
Copyright © 2015 Elsevier Inc. All rights reserved.
Influenza viruses cause annual seasonal epidemics and pandemics at irregular intervals. Several cases of human infections with avian and swine influenza viruses have been detected recently, warranting enhanced surveillance and the development of more effective countermeasures to address the pandemic potential of these viruses. The most effective countermeasure against influenza virus infection is the use of prophylactic vaccines. However, vaccines that are currently in use for seasonal influenza viruses have to be re-formulated and re-administered in a cumbersome process every year due to the antigenic drift of the virus. Furthermore, current seasonal vaccines are ineffective against novel pandemic strains. This paper reviews zoonotic influenza viruses with pandemic potential and technological advances towards better vaccines that induce broad and long lasting protection from influenza virus infection. Recent efforts have focused on the development of broadly protective/universal influenza virus vaccines that can provide immunity against drifted seasonal influenza virus strains but also against potential pandemic viruses.
Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Like other respiratory viruses, influenza is responsible for devastating nosocomial epidemics in nursing homes as well as in conventional wards and emergency departments. Patients, healthcare workers, and visitors may be the source of nosocomial influenza. Despite their limited sensitivity, rapid diagnostic tests for influenza can be of real value; they enable early introduction of measures to prevent spread and early specific antiviral treatment of cases. However, these tests cannot detect oseltamivir resistance, susceptibility testing being carried out only in specialist laboratories. Although resistance is rare, it can emerge during treatment, especially of very young children or immunocompromised patients. In the latter, the shedding of resistant influenza virus can last several weeks. Sporadic instances of nosocomial transmission among immunocompromised patients have been reported. The limitations of bedside tests for influenza make them unsuitable for use as stand-alone diagnostic tools. However, their limitations do not preclude their use for detection and subsequent management of nosocomial influenza, for which they are rapid, easy, and cost-effective. Recent developments in these tests look promising, offering prospects of increased sensitivity, increased specificity, and screening for antiviral susceptibility.
Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Corticosteroids are used empirically in influenza A (H1N1) treatment despite lack of clear evidence for effective treatment. This study aims to assess the efficacy of corticosteroids treatment for H1N1 infection.
Systematic review and meta-analysis were used to estimate the efficacy of corticosteroids for the prevention of mortality in H1N1 infection. Databases searched included MEDLINE, EMBASE, PubMed, Cochrane Central Register of Controlled Clinical Trials and so on, and bibliographies of retrieved articles, from April 2009 to October 2014. We included both cohort studies and case-control studies reported in English or Chinese that compared treatment effects between corticosteroids and non-corticosteroids therapy in inpatients with H1N1 virus infection. Cohort studies employed mortality as outcome, and case-control studies employed deaths as cases and survivors as controls; both were assessed in this meta-analysis.
In total twenty-three eligible studies were included. Both cohort studies (nine studies, n = 1,405) and case-control studies (14 studies, n = 4,700) showed a similar trend toward increased mortality (cohort studies relative risk was 1.85 with 95% confidence interval (CI) 1.46 to 2.33; case-control studies odds ratio was 4.22 with 95% CI 3.10 to 5.76). The results from both subgroup analyses and sensitive analyses were consistent with each other, showing that steroid treatment is associated with mortality. However, considering the fact that corticosteroids were tend to be used in sickest case-patients and heterogeneity was observed between studies, we cannot make a solid conclusion.
Available evidence did not support the use of corticosteroids as standard care for patients with severe influenza. We conclude that further research is required.
Despite widespread use, questions remain about the efficacy of oseltamivir in the treatment of influenza. We aimed to do an individual patient data meta-analysis for all clinical trials comparing oseltamivir with placebo for treatment of seasonal influenza in adults regarding symptom alleviation, complications, and safety.
We included all published and unpublished Roche-sponsored randomised placebo-controlled, double-blind trials of 75 mg twice a day oseltamivir in adults. Trials of oseltamivir for treatment of naturally occurring influenza-like illness in adults reporting at least one of the study outcomes were eligible. We also searched Medline, PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov trials register for other relevant trials published before Jan 1, 2014 (search last updated on Nov 27, 2014). We analysed intention-to-treat infected, intention-to-treat, and safety populations. The primary outcome was time to alleviation of all symptoms analysed with accelerated failure time methods. We used risk ratios and Mantel-Haenszel methods to work out complications, admittances to hospital, and safety outcomes.
We included data from nine trials including 4328 patients. In the intention-to-treat infected population, we noted a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio 0·79, 95% CI 0·74-0·85; p<0·0001). The median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo groups (difference -25·2 h, 95% CI -36·2 to -16·0). For the intention-to-treat population, the estimated treatment effect was attenuated (time ratio 0·85) but remained highly significant (median difference -17·8 h). In the intention-to-treat infected population, we noted fewer lower respiratory tract complications requiring antibiotics more than 48 h after randomisation (risk ratio [RR] 0·56, 95% CI 0·42-0·75; p=0·0001; 4·9% oseltamivir vs 8·7% placebo, risk difference -3·8%, 95% CI -5·0 to -2·2) and also fewer admittances to hospital for any cause (RR 0·37, 95% CI 0·17-0·81; p=0·013; 0·6% oseltamivir, 1·7% placebo, risk difference -1·1%, 95% CI -1·4 to -0·3). Regarding safety, oseltamivir increased the risk of nausea (RR 1·60, 95% CI 1·29-1·99; p<0·0001; 9·9% oseltamivir vs 6·2% placebo, risk difference 3·7%, 95% CI 1·8-6·1) and vomiting (RR 2·43, 95% CI 1·83-3·23; p<0·0001; 8·0% oseltamivir vs 3·3% placebo, risk difference 4·7%, 95% CI 2·7-7·3). We recorded no effect on neurological or psychiatric disorders or serious adverse events.
Our findings show that oseltamivir in adults with influenza accelerates time to clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admittance to hospital, but increases the occurrence of nausea and vomiting.
Multiparty Group for Advice on Science (MUGAS) foundation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Published evidence regarding the use of the antiinfluenza agent oseltamivir outside of the standard dosing recommendations is reviewed.
Oseltamivir is a neuraminidase inhibitor indicated for the treatment of uncomplicated influenza in patients two weeks of age or older who have been symptomatic for no more than two days; the recommended dosage is 75 mg twice daily by mouth for five days. A literature search identified six studies evaluating the effects of administering oseltamivir 48 hours or more after the onset of influenza symptoms, administering the drug at double the standard dose, or continuing therapy for more than five days. Two randomized controlled trials found that double-dose oseltamivir therapy conferred no significant survival benefit. The results of one retrospective study of intensive care unit (ICU) patients infected with the influenza H1N1 strain suggested improved survival among those who received oseltamivir no later than five days after symptom onset.
Oseltamivir may increase survival when used within five days of symptom onset in influenza H1N1-infected patients who require ICU admission. There appears to be no benefit in starting treatment more than 48 hours after symptom onset in hospitalized general medicine patients or outpatients infected with either H1N1 or other influenza strains or in doubling the dose of oseltamivir in hospitalized patients or outpatients. There are scant data supporting the use of oseltamivir for longer than five days in any patient population, with the possible exception of critically ill H1N1-infected ICU patients, who may benefit from extended treatment in some cases.
Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.
Background:
The efficacy of TCN-032, a human monoclonal antibody targeting a conserved epitope on M2e, was explored in experimental human influenza.
Methods:
Healthy volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2) and received a single dose of the study drug, TCN-032, or placebo 24 hours later. Subjects were monitored for symptoms, viral shedding, and safety, including cytokine measurements. Oseltamivir was administered 7 days after inoculation.
Results:
Although the primary objective of reducing the proportion of subjects developing any grade ≥2 influenza symptom or pyrexia, was not achieved, TCN-032-treated subjects showed 35% reduction (P = .047) in median total symptom area under the curve (days 1-7) and 2.2 log reduction in median viral load area under the curve (days 2-7) by quantitative polymerase chain reaction (P = .09) compared with placebo-treated subjects. TCN-032 was safe and well tolerated with no additional safety signals after administration of oseltamivir. Serum cytokine levels (interferon γ, tumor necrosis factor α, and interleukin 8 and 10) were similar in both groups. Genotypic and phenotypic analyses showed no difference between virus derived from subjects after TCN-032 treatment and parental strain.
Conclusions:
These data indicate that TCN-032 may provide immediate immunity and therapeutic benefit in influenza A infection, with no apparent emergence of resistant virus. TCN-032 was safe with no evidence of immune exacerbation based on serum cytokine expression. Clinicaltrials.gov registry number. NCT01719874.