scholarly journals 1524. Sex Differences in Influenza: The Challenge Study Experience

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S764-S764
Author(s):  
Luca Giurgea ◽  
Adriana Cervantes-Medina ◽  
Alison Han ◽  
Lindsay Czajkowski ◽  
Holly Baus ◽  
...  
Keyword(s):  
Sex Differences ◽  
Influenza A ◽  
Animal Studies ◽  
Influenza Infection ◽  
Reproductive Age ◽  
Experimental Therapy ◽  
Duration Of Symptoms ◽  
Biological Sex ◽  
Viral Shedding ◽  
The Impact

Abstract Background Our understanding of the impact of biological sex on influenza-associated disease and the mechanisms that underpin it is still incomplete. Further investigation of sex-linked effects on influenza pathogenesis and clinical outcomes may help tailor vaccine strategies. Animal studies have shown female mice experience more symptoms than male mice during influenza infection. Similarly, human females of reproductive age have higher rates of influenza and influenza-related hospitalizations. However, data is sometimes conflicting and may be confounded by other important differences in baseline characteristics. Human challenge studies have demonstrated the importance of NAI titers as a correlate of protection and may also provide an ideal opportunity to study sex differences in a homogenous group of participants controlled for confounders. Methods Data from 168 volunteers who underwent Influenza A/California/04/2009/H1N1 challenge studies affiliated with NIAID’s LID Clinical Studies Unit were compiled to compare differences between sexes. Participants were included in the analysis if they received a challenge dose of virus of 107 TCID50 and were excluded if they had received any vaccines or experimental therapy during the study period. Results Baseline differences between male and female participants were observed in NAI titers but not HAI titers or age. Outcomes of interest included presence of viral shedding/duration which were similar among sexes. However, symptom number and duration were higher among female participants (p=0.008 and p=0.045 respectively). Ongoing data analysis also shows females have lower post-challenge NAI titers than males. Conclusion Female participants in our H1N1 challenge studies had more symptoms and a longer duration of symptoms compared to their male counterparts. Differences in NAI titers may potentially explain the observed relationship between sex and symptoms associated with influenza. Disclosures All Authors: No reported disclosures

scholarly journals Sex differences in the developmental origins of hypertension and cardiorenal disease

2008 ◽  
Vol 295 (6) ◽  
pp. R1941-R1952 ◽  
Author(s):  
Jeffrey S. Gilbert ◽  
Mark J. Nijland
Keyword(s):  
Sex Differences ◽  
Birth Weight ◽  
Sex Hormones ◽  
Animal Studies ◽  
Adult Life ◽  
The Body ◽  
Developmental Origins ◽  
Critical Periods ◽  
Biological Sex ◽  
The Impact

The “developmental origins of health and disease” (DOHAD) hypothesis derives from clinical observations, indicating long-term health consequences for persons of low birth weight. There is growing evidence, primarily from animal studies, that supports the idea that processes put in motion during development that contribute to DOHAD do not necessarily reflect as significantly compromised growth and altered birth weight. Throughout the body of work investigating the DOHAD hypothesis, several themes have emerged; the importance of the placenta, the presence of critical periods of vulnerability, the involvement of the kidney in programmed hypertension, the presence of sex differences in the progression and development of adult diseases. Despite compelling findings in recent studies, much remains unclear regarding the impact of biological sex in the progression of human diseases, in general, and in the mechanisms underlying developmentally programmed responses, in particular. Although the contribution of biological sex to DOHAD is increasingly recognized, it also appears that it may exert distinctly different influences during fetal and adult life. The mechanisms by which biological sex contributes to these processes remains nebulous at present; nevertheless, several intriguing mechanistic candidates have been proposed ranging from differences in the amounts of sex hormones (e.g., estrogens, androgens) to recently described sexual dimorphism in the transcriptome of a variety of mammalian tissues. Recognizing the influences of biological sex or sex hormones on DOHAD uniquely situates research in this area to provide significant insights into the development and progression of many diseases, recent examples of which are the subject of this review.

scholarly journals 1522. Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S763-S763
Author(s):  
Alison Han ◽  
Lindsay Czajkowski ◽  
Luz Angela Rosas ◽  
Adriana Cervantes-Medina ◽  
Yongli Xiao ◽  
...  
Keyword(s):  
Pharmaceutical Company ◽  
Influenza A ◽  
Controlled Trial ◽  
Influenza Infection ◽  
Healthy Human ◽  
Double Blind ◽  
Duration Of Symptoms ◽  
Viral Shedding ◽  
Influenza A H1n1 ◽  
Significant Difference

Abstract Background Influenza virus infections cause significant morbidity and mortality during yearly seasonal epidemics and during sporadic pandemics. It is imperative to identify new targets for vaccines and therapeutics. One such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein. Methods We conducted a randomized, double-blind, Phase II placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. CR6261 was infused 24 hours after challenge with H1N1pdm09 and the primary efficacy outcome was area under the curve (AUC) of viral shedding. Results Between March 2015-May 2018, 104 healthy volunteers were enrolled and randomized with 91 undergoing influenza challenge, of which 49 participants (54%) received treatment with CR6261 and 42 participants (46%) received placebo. A mean of 1x106 ng/mL of serum CR6261 was detected by 24 hours after infusion. Nasal CR6261 levels reached a peak mean of 5.97x102 ng/ml 2 days after infusion. There was no statistically significant difference in the primary outcome measure between the CR6261 group and placebo (median AUC 48.56 and 25.53 respectively, P=0.31). The severity of illness was compared between the two groups, and no significant difference was observed in number of symptoms, duration of symptoms, or FLU-PRO scores. Conclusion CR6261 had no statistically significant effect on AUC of viral shedding, and no clinically significant effect on overall influenza disease. Preexisting anti-neuraminidase (NA) antibody titers were most predictive of reduced influenza disease. Nasal CR6261 levels were much lower compared to serum, which may be a factor in the limited effect of CR6261 on this upper respiratory infection. These results suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may have limited efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multi-faceted strategy rather than as a standalone therapeutic or vaccine strategy. Funding This study was funded in part by the intramural program of NIAID, NIH, by the NCI Contract No. 75N910D00024, Task Order No. 75N91019F00130, and through a CRADA with Janssen Infectious Diseases and Vaccines. Disclosures Amy Lwin, RN, BSN, Janssen Pharmaceutical Company of J&J (Employee) Jerald Sadoff, MD, Janssen Pharmaceutical Company of J&J (Employee)

scholarly journals 2750. Sequential Influenza A H1N1 and Influenza A H3N2 Challenge Infections in Healthy Volunteers

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S969-S969 ◽  
Author(s):  
Alison Han ◽  
Luca Giurgea ◽  
Adriana Cervantes-Medina ◽  
Kristina Edwards ◽  
Luz Angela Rosas ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Influenza A ◽  
Reverse Genetics ◽  
Clinical Symptoms ◽  
Influenza Infection ◽  
Influenza Viruses ◽  
Wild Type ◽  
Viral Shedding ◽  
Influenza A H1n1 ◽  
The Impact

Abstract Background Seasonal influenza causes significant annual morbidity and mortality. The effects of yearly exposures on immunity are not clear and recent observations have demonstrated that long lasting protection against a matched strain may not naturally occur. The 2018–2019 influenza season consisted of an initial peak of H1N1 infections followed by a wave of H3N2 infections. These consecutive waves raise questions about how influenza immunity is affected by sequential exposure to different influenza strains. Challenge studies provide a unique opportunity to study this phenomenon. Here we describe a subset of participants who were sequentially infected in two separate challenge studies with wild-type H1N1 and H3N2 viruses. Methods Healthy volunteers completed two sequential influenza challenge studies at the NIH Clinical Center. Participants were inoculated with reverse genetics, cell-based, GMP wild-type influenza viruses, A(H1N1)pdm09 and A(H3N2) strains. Participants remained isolated in the hospital for a minimum of 9 days and were monitored daily for viral shedding and clinical symptoms. After discharge, participants were followed for 2 months. Results Between 2014 and 2017, 14 healthy volunteers were exposed to Influenza A(H1N1) and Influenza A(H3N2). Time between infections ranged from 2 months to 2 years. Thirteen (93%) participants developed confirmed influenza infection after H1N1 challenge and 9 (64%) after H3N2 challenge. Eight (57%) participants developed confirmed infections after both exposures. Variable degrees of symptoms, shedding, and disease severity were observed. Systemic antibody responses to the HA and NA of both H1N1 and H3N2 varied over time during these sequential infections. Conclusion More than half of all participants who completed 2 sequential H1N1 and H3N2 challenge studies demonstrated confirmed infection to both viruses. These sequential infections had varying effects on the disease experienced and the immunity that developed after infection. These observations are important in understanding the impact of sequential exposures on influenza immunity. Disclosures All authors: No reported disclosures.

scholarly journals Impact of oseltamivir treatment on influenza A and B dynamics in human volunteers

2020 ◽  
Author(s):  
Kyla L. Hooker ◽  
Vitaly V. Ganusov
Keyword(s):  
Clinical Trials ◽  
Influenza Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
Virus Shedding ◽  
Viral Shedding ◽  
Human Volunteers ◽  
The Impact

AbstractInfluenza viruses infect millions of humans every year causing an estimated 400,000 deaths globally. Due to continuous virus evolution current vaccines provide only limited protection against the flu. Several antiviral drugs are available to treat influenza infection, and one of the most most commonly used drugs is oseltamivir (Tamiflu). While the mechanism of action of oseltamivir as a neuraminidase inhibitor is well understood, the impact of oseltamivir on influenza virus dynamics in humans has been controversial. Many clinical trials with oseltamivir have been done by pharmaceutical companies such as Roche but the results of these trials until recently have been reported as summary reports or papers. Typically, such reports included median virus shedding curves for placebo and drug-treated influenza virus infected volunteers often indicating high efficacy of the early treatment. However, median shedding curves may be not accurately representing drug impact in individual volunteers. Importantly, due to public pressure clinical trials data testing oseltamivir efficacy has been recently released in the form of redacted PDF documents. We digitized and re-analyzed experimental data on influenza virus shedding in human volunteers from three previously published trials: on influenza A (1 trial) or B viruses (2 trials). Given that not all volunteers exposed to influenza viruses actually start virus shedding we found that impact of oseltamivir on the virus shedding dynamics was dependent on i) selection of volunteers that were infected with the virus, and ii) the detection limit in the measurement assay; both of these details were not well articulated in the published studies. By assuming that any viral measurement is above the limit of detection we could match previously published data on median influenza A virus (flu A study) shedding but not on influenza B virus shedding (flu B study B) in human volunteers. Additional analyses confirmed that oseltamivir had an impact on the duration of shedding and overall shedding (defined as area under the curve) but this result was varied by the trial. Interestingly, treatment had no impact on the rates at which shedding increased or declined with time in individual volunteers. Additional analyses showed that oseltamivir impacted the kinetics of the start and end of viral shedding and in about 20-40% of volunteers treatment had no impact on viral shedding duration. Our results suggest an unusual impact of oseltamivir on influenza viruses shedding kinetics and caution about the use of published median data or data from a few individuals for inferences. Furthermore, we call for the need to publish raw data from critical clinical trials that can be then independently analyzed.

scholarly journals Influenza infection rewires energy metabolism and induces browning features in adipose cells and tissues

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Asma Ayari ◽  
Manuel Rosa-Calatrava ◽  
Steve Lancel ◽  
Johanna Barthelemy ◽  
Andrés Pizzorno ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Influenza A ◽  
Energy Homeostasis ◽  
Influenza Infection ◽  
Subcutaneous Fat ◽  
Whole Body ◽  
Glucose And Lipid Metabolism ◽  
The Impact

AbstractLike all obligate intracellular pathogens, influenza A virus (IAV) reprograms host cell’s glucose and lipid metabolism to promote its own replication. However, the impact of influenza infection on white adipose tissue (WAT), a key tissue in the control of systemic energy homeostasis, has not been yet characterized. Here, we show that influenza infection induces alterations in whole-body glucose metabolism that persist long after the virus has been cleared. We report depot-specific changes in the WAT of IAV-infected mice, notably characterized by the appearance of thermogenic brown-like adipocytes within the subcutaneous fat depot. Importantly, viral RNA- and viral antigen-harboring cells are detected in the WAT of infected mice. Using in vitro approaches, we find that IAV infection enhances the expression of brown-adipogenesis-related genes in preadipocytes. Overall, our findings shed light on the role that the white adipose tissue, which lies at the crossroads of nutrition, metabolism and immunity, may play in influenza infection.

scholarly journals Maintenance Immunosuppression Is Associated With Better Outcome in the 2017/2018 Influenza Epidemic

2019 ◽  
Vol 6 (10) ◽  
Author(s):  
Klaus Stahl ◽  
Benjamin Seeliger ◽  
Markus Busch ◽  
Olaf Wiesner ◽  
Tobias Welte ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza Infection ◽  
Tertiary Care ◽  
Care Hospital ◽  
Influenza Epidemic ◽  
Icu Admission ◽  
Maintenance Immunosuppression ◽  
Mortality Causes ◽  
The Impact ◽  
Aids Chemotherapy

Abstract Background The impact of immunosuppression on outcomes in influenza is insufficiently understood. We analyzed the morbidity and mortality of immunocompetent (IC) vs immunosuppressed (IS) patients with influenza A and B in the 2017/2018 season. Methods Patients with proven influenza in a German tertiary care hospital were analyzed for hospitalization, intensive care unit (ICU) admission, and mortality. Causes for IS were organ and bone marrow transplantation, AIDS, chemotherapy, and medical immunosuppression. Results In total, 227 patients were included in this analysis (IC, n = 118 [52%]; IS, n = 109 [48%]). Hospitalization (71% vs 91%; P < .001) and ICU admission (7% vs 23%; P = .001) were less frequent in the IS compared with the IC group. IC patients had a higher need for invasive ventilation (20% vs 5%; P = .001), vasopressors (19% vs 4%; P < .001), and renal replacement therapy (15% vs 3%; P = .002). Influenza-associated cardiomyopathy was found in 18% of IC vs 2% of IS patients (P < .001). The 30-day in-hospital mortality was 6.6%, 10.2% in the IC group and 2.8% in the IS group (hazard ratio IS group, 0.259; 95% confidence interval [CI], 0.113–0.855; P = .023). Immunosuppression was associated with reduced mortality (odds ratio, 0.25; 95% CI, 0.07–0.91; P = .036). Conclusions We observed that IS was not associated with a worse outcome in this influenza cohort. Due to the presence of both confounding and referral and selection bias, the conclusion that immunosuppression reduces mortality cannot be drawn. Prospective studies investigating the influence of baseline immunosuppression on severity of influenza infection are desirable.

scholarly journals Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity

2016 ◽  
Vol 311 (2) ◽  
pp. R211-R216 ◽  
Author(s):  
C. Griffin ◽  
N. Lanzetta ◽  
L. Eter ◽  
K. Singer
Keyword(s):  
Sex Differences ◽  
Animal Studies ◽  
Inflammatory Responses ◽  
Disease Risk ◽  
Reproductive Age ◽  
Sexually Dimorphic ◽  
Metabolic Dysfunction ◽  
Diet Induced Obesity ◽  
Dietary Obesity ◽  
Males And Females

It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses.

scholarly journals Influenza and Community-acquired Pneumonia Interactions: The Impact of Order and Time of Infection on Population Patterns

2012 ◽  
Vol 175 (5) ◽  
pp. 363-367 ◽  
Author(s):  
Brian M. Davis ◽  
Allison E. Aiello ◽  
Suzanne Dawid ◽  
Pejman Rohani ◽  
Sourya Shrestha ◽  
...  
Keyword(s):  
Influenza A ◽  
Animal Studies ◽  
Severe Disease ◽  
Severity Of Illness ◽  
Population Level ◽  
Community Acquired Pneumonia ◽  
Swine Flu ◽  
1918 Influenza ◽  
The Impact

AbstractDiscoveries made during the 1918 influenza A pandemic and reports of severe disease associated with coinfection during the 2009 hemagglutinin type 1 and neuraminidase type 1 (commonly known as H1N1 or swine flu) pandemic have renewed interest in the role of coinfection in disease pathogenesis. The authors assessed how various timings of coinfection with influenza virus and pneumonia-causing bacteria could affect the severity of illness at multiple levels of interaction, including the biologic and population levels. Animal studies most strongly support a single pathway of coinfection with influenza inoculation occurring approximately 7 days before inoculation with Streptococcus pneumoniae, but less-examined pathways of infection also may be important for human disease. The authors discussed the implications of each pathway for disease prevention and what they would expect to see at the population level if there were sufficient data available. Lastly, the authors identified crucial gaps in the study of timing of coinfection and proposed related research questions.

scholarly journals Sex Differences of the Diabetic Heart

2021 ◽  
Vol 12 ◽  
Author(s):  
Natacha Fourny ◽  
Christophe Beauloye ◽  
Monique Bernard ◽  
Sandrine Horman ◽  
Martine Desrois ◽  
...  
Keyword(s):  
Sex Differences ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Vascular Complications ◽  
Clinical Findings ◽  
Personalized Care ◽  
Increased Risk ◽  
Treatment Of Diabetes ◽  
The Impact

Type 2 diabetes is a chronic disease associated with micro- and macro-vascular complications, including myocardial ischemia, and also with a specific and intrinsic cardiac dysfunction called diabetic cardiomyopathy (DCM). Both clinical and animal studies demonstrate significant sex differences in prevalence, pathophysiology, and outcomes of cardiovascular diseases (CVDs), including those associated with diabetes. The increased risk of CVDs with diabetes is higher in women compared to men with 50% higher risk of coronary artery diseases and increased mortality when exposed to acute myocardial infarction. Clinical studies also reveal a sexual dimorphism in the incidence and outcomes of DCM. Based on these clinical findings, growing experimental research was initiated to understand the impact of sex on CVDs associated with diabetes and to identify the molecular mechanisms involved. Endothelial dysfunction, atherosclerosis, coagulation, and fibrosis are mechanisms found to be sex-differentially modulated in the diabetic cardiovascular system. Recently, impairment of energy metabolism also emerged as a determinant of multiple CVDs associated with diabetes. Therefore, future studies should thoroughly analyze the sex-specific metabolic determinants to propose new therapeutic targets. With current medicine tending toward more personalized care of patients, we finally propose to discuss the importance of sex as determinant in the treatment of diabetes-associated cardiac diseases to promote a more systemic inclusion of both males and females in clinical and preclinical studies.

scholarly journals Introduction of Cobas Liat Influenza A/B for rapid point-of-care diagnosis of influenza infection in an acute trust

2019 ◽  
Vol 20 (6) ◽  
pp. 297-300 ◽  
Author(s):  
Fran Brooke-Pearce ◽  
Elli Demertzi
Keyword(s):  
Influenza A ◽  
Positive Impact ◽  
Point Of Care ◽  
Influenza Infection ◽  
Cost Savings ◽  
Potential Cost ◽  
Bed Management ◽  
Point Of Care Test ◽  
The Impact ◽  
Acute Trust

Background: We aimed to evaluate the impact of a new molecular point-of-care test (POCT), the Cobas Liat Influenza A/B for rapid diagnosis of influenza within 20 min, on the operational workflow of the Trust, accurate diagnosis and potential cost savings during the winter of 2017–2018. Methods: A retrospective cohort study was conducted on all patients aged > 18 years tested for flu A/B by laboratory PCR in January 2017 and by POCT in January 2018. Results: From 21 December 2017 to 30 April 2018, a total of 1375 POCTs were performed with a total of 479 (35%) influenza-positive cases. Results demonstrated that 1046 (76%) suspected cases did not require isolation or were able to be discharged from Emergency Department (ED), once other risks had been ruled out. We particularly looked into the differences between the month of January 2017 (before POCT) and the month of January 2018. Discussion: Results demonstrate that influenza POCT had a positive impact on the Trust regarding prompt patient diagnosis and treatment, discharge decisions, improvement of patient bed management by avoiding unnecessary patient isolation and reducing bay closures, and significant reduction in length of stay in both positive and negative cases. Estimated cost savings were significant.

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