Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway.
Holze Cathleen,Michaudel Chloé,Mackowiak Claire,Haas Darya A,Benda Christian,Hubel Philipp,Pennemann Friederike L,Schnepf Daniel,Wettmarshausen Jennifer,Braun Marianne,Leung Daisy W,Amarasinghe Gaya K,Perocchi Fabiana,Staeheli Peter,Ryffel Bernhard,Pichlmair Andreas
Nature immunology
Reactive oxygen species (ROS) are generated by virus-infected cells; however, the physiological importance of ROS generated under these conditions is unclear. Here we found that the inflammation and cell death induced by exposure of mice or cells to sources of ROS were not altered in the absence of canonical ROS-sensing pathways or known cell-death pathways. ROS-induced cell-death signaling involved interactions among the cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5 mice showed exacerbated lung inflammation and proinflammatory cytokines in an ozone-exposure model. Similarly, challenge with influenza A virus led to increased infiltration of the virus, lymphocytic bronchiolitis and reduced survival of Pgam5 mice. This pathway, which we have called 'oxeiptosis', was a ROS-sensitive, caspase independent, non-inflammatory cell-death pathway and was important for protection against inflammation induced by ROS or ROS-generating agents such as viral pathogens.
10.1038/s41590-017-0013-y
Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection.
Tsai Sue,Clemente-Casares Xavier,Zhou Angela C,Lei Helena,Ahn Jennifer J,Chan Yi Tao,Choi Okmi,Luck Helen,Woo Minna,Dunn Shannon E,Engleman Edgar G,Watts Tania H,Winer Shawn,Winer Daniel A
Cell metabolism
T cells represent a critical effector of cell-mediated immunity. Activated T cells engage in metabolic reprogramming during effector differentiation to accommodate dynamic changes in energy demands. Here, we show that the hormone, insulin, and downstream signaling through its insulin receptor shape adaptive immune function through modulating T cell metabolism. T cells lacking insulin receptor expression (LckCre+ Insr) show reduced antigen-specific proliferation and compromised production of pro-inflammatory cytokines. In vivo, T cell-specific insulin receptor deficiency reduces T cell-driven colonic inflammation. In a model of severe influenza infection with A/PR8 (H1N1), lack of insulin receptor on T cells curtails antigen-specific immunity to influenza viral antigens. Mechanistically, insulin receptor signaling reinforces a metabolic program that supports T cell nutrient uptake and associated glycolytic and respiratory capacities. These data highlight insulin receptor signaling as an important node integrating immunometabolic pathways to drive optimal T cell effector function in health and disease.
10.1016/j.cmet.2018.08.003
Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation.
Estenssoro Elisa,Ríos Fernando G,Apezteguía Carlos,Reina Rosa,Neira Jorge,Ceraso Daniel H,Orlandi Cristina,Valentini Ricardo,Tiribelli Norberto,Brizuela Matías,Balasini Carina,Mare Sebastián,Domeniconi Gustavo,Ilutovich Santiago,Gómez Alejandro,Giuliani Javiera,Barrios Cecilia,Valdez Pascual,
American journal of respiratory and critical care medicine
RATIONALE:The rapid spread of the 2009 Influenza A (H1N1) around the world underscores the need for a better knowledge of epidemiology, clinical features, outcomes, and mortality predictors, especially in the most severe presentations. OBJECTIVES:To describe these characteristics in patients with confirmed, probable, and suspected viral pneumonia caused by 2009 influenza A (H1N1) admitted to 35 intensive care units with acute respiratory failure requiring mechanical ventilation in Argentina, between June 3 and September 7. METHODS:Inception-cohort study including 337 consecutive adult patients. Data were collected in a form posted on the Argentinian Society of Intensive Care website. MEASUREMENTS AND MAIN RESULTS:Proportions of confirmed, probable, or suspected cases were 39%, 8%, and 53% and had similar outcomes. APACHE II was 18 +/- 7; age 47 +/- 17 years; 56% were male; and 64% had underlying conditions, with obesity (24%), chronic obstructive respiratory disease (18%), and immunosupression (15%) being the most common. Seven percent were pregnant. On admission, patients had severe hypoxemia (Pa(O(2))/Fi(O(2)) 140 [87-200]), extensive lung radiologic infiltrates (2.87 +/- 1.03 quadrants) and bacterial coinfection, (25%; mostly with Streptococcus pneumoniae). Use of adjuvants such as recruitment maneuvers (40%) and prone positioning (13%), and shock (72%) and acute kidney injury requiring hemodialysis (17%), were frequent. Mortality was 46%, and was similar across all ages. APACHE II, lowest Pa(O(2))/Fi(O(2)), shock, hemodialysis, prone positioning, and S. pneumoniae coinfection independently predicted death. CONCLUSIONS:Patients with 2009 influenza A (H1N1) requiring mechanical ventilation were mostly middle-aged adults, often with comorbidities, and frequently developed severe acute respiratory distress syndrome and multiorgan failure requiring advanced organ support. Case fatality rate was accordingly high.
10.1164/201001-0037OC
Is influenza A(H1N1) pneumonia more severe than other community-acquired pneumonias? Results of the GiViTI survey of 155 Italian ICUs.
Bertolini Guido,Rossi Carlotta,Crespi Daniele,Finazzi Stefano,Morandotti Marco,Rossi Sandra,Peta Mario,Langer Martin,Poole Daniele
Intensive care medicine
PURPOSE:Uncertainty about the severity of the A(H1N1) pandemia persists. Information about disease severity can be obtained by investigating intensive care unit (ICU) admissions, especially when historical comparisons can be made with cases of community-acquired pneumonia (CAP). METHODS:This prospective observational study was conducted in 155 ICUs contributing to the GiViTI national database. To assess the impact on ICU workload, the occupancy rate during the epidemic phase was compared with influenza periods in previous years. A logistic regression model was developed to assess the prognostic importance of A(H1N1) influenza. RESULTS:The characteristics of the 319 A(H1N1) cases were similar to those reported in other studies, confirming the young age of patients (mean 43 years) and the higher prevalence among pregnant women and obese people. At the epidemic's peak (October-December 2009) the occupancy rate did not significantly differ from the same period of the previous year, and was significantly lower than the 2009 seasonal influenza outbreak (January-March 2009). Compared with CAP of other origin (3,678 patients), A(H1N1) pneumonia was associated with a lower risk of death. However, after adjusting for confounding this was no longer the case (OR 0.88; 95% CI 0.59-1.31; p = 0.52). CONCLUSION:This study confirmed the specific features of critically ill A(H1N1) patients (i.e., young age, pregnancy, obesity). The pandemic did not increase ICU workload compared with other periods. A(H1N1) pneumonia did not have a higher risk of death than CAP of different origin among patients admitted to the ICU.
10.1007/s00134-011-2339-5
Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009.
MMWR. Morbidity and mortality weekly report
In April 2009, CDC reported the first two cases in the United States of human infection with a novel influenza A (H1N1) virus. As of July 6, a total of 122 countries had reported 94,512 cases of novel influenza A (H1N1) virus infection, 429 of which were fatal; in the United States, a total of 33,902 cases were reported, 170 of which were fatal. Cases of novel influenza A (H1N1) virus infection have included rapidly progressive lower respiratory tract disease resulting in respiratory failure, development of acute respiratory distress syndrome (ARDS), and prolonged intensive care unit (ICU) admission. Since April 26, communitywide transmission of novel influenza A (H1N1) virus has occurred in Michigan, with 655 probable and confirmed cases reported as of June 18 (Michigan Department of Community Health [MDCH], unpublished data, 2009). This report summarizes the clinical characteristics of a series of 10 patients with novel influenza A (H1N1) virus infection and ARDS at a tertiary-care ICU in Michigan. Of the 10 patients, nine were obese (body mass index [BMI] >or=30), including seven who were extremely obese (BMI =40); five had pulmonary emboli; and nine had multiorgan dysfunction syndrome (MODS). Three patients died. Clinicians should be aware of the potential for severe complications of novel influenza A (H1N1) virus infection, particularly in extremely obese patients.
Characteristics of hospitalised patients with 2009 H1N1 influenza in Chile.
Riquelme R,Riquelme M,Rioseco M L,Inzunza C,Gomez Y,Contreras C,Riquelme J,Peyrani P,Wiemken T,Ramirez J
The European respiratory journal
As the pandemic of 2009 H1N1 influenza A virus progressed, more patients required hospitalisation. The objective of this study is to describe the characteristics and clinical course of hospitalised patients with 2009 H1N1 virus infection in Chile. This was a prospective, observational study of 100 consecutive hospitalised patients with RT-PCR-confirmed 2009 H1N1 influenza A, admitted to Puerto Montt General Hospital (Puerto Montt, Chile). Information was obtained regarding contact history, demographics, laboratory values and clinical course. The primary reason for hospitalisation was pneumonia, in 75% of patients. Rapid influenza A test was positive in 51% of patients. Prior exposure to 2009 H1N1 virus was documented in 21% of patients. Clinical failure, documented in 18% of cases, was characterised by respiratory failure and acute respiratory distress syndrome. Failure was more common in patients with obesity, tachypnoea, confusion and multilobar infiltrates. When evaluating a patient hospitalised with influenza-like illness, a negative rapid test for influenza A or negative contact with a suspected case should not alter physicians' considerations regarding the likelihood of 2009 H1N1 virus infection. Patients with 2009 H1N1 virus infection with obesity, tachypnoea, confusion and multilobar infiltrates should be closely monitored since they are at high risk for clinical failure.
10.1183/09031936.00180409
Metabolic Syndrome and Viral Pathogenesis: Lessons from Influenza and Coronaviruses.
Journal of virology
Metabolic syndrome increases the risk of severe disease due to viral infection. Yet few studies have assessed the pathogenesis of respiratory viruses in high-risk populations. Here, we summarize how metabolic dysregulation impairs immune responses, and we define the role of metabolism during influenza virus and coronavirus infections. We also discuss the use of various , , and models to elucidate the contributions of host factors to viral susceptibility, immunity, and disease severity.
10.1128/JVI.00665-20
Severe, critical and fatal cases of 2009 H1N1 influenza in China.
Yang Peng,Deng Ying,Pang Xinghuo,Shi Weixian,Li Xinyu,Tian Lili,Zhang Yi,Wang Xiaoli,Huang Fang,Raina Macintyre C,Wang Quanyi
The Journal of infection
OBJECTIVE:For severe, critical and fatal cases of 2009 H1N1 influenza in the winter in the Northern Hemisphere, the detailed features are not fully known. The aim of this study was to examine these features through describing these cases in Beijing, China in 2009. METHODS:Data on severe, critical and fatal cases were collected via the Notifiable Disease Surveillance System and a designated surveillance system for managing 2009 H1N1 influenza cases in Beijing. The characteristics and risk factors of these cases were elucidated. RESULTS:A total of 475 severe cases, 73 critical ones and 69 deaths were identified in 2009. The proportion of obesity was low, as well as pregnancy. About half of them had no underlying disease. Most of deaths had multi-organ failure, with a median interval from illness onset to death of ten days. Delay in visiting hospital, cardiovascular disease and allergy predicted a higher risk of severe disease, and cases aged 6-17 years were at lower risk. Cases not promptly receiving neuraminidase inhibitors were at increased risk of death. CONCLUSIONS:Age and underlying disease are significantly associated with severity of outcomes of 2009 H1N1 influenza; prompt presentation to hospital and use of neuraminidase inhibitor were protective.
10.1016/j.jinf.2010.07.010
Risk factors for severe illness with 2009 pandemic influenza A (H1N1) virus infection in China.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:Data on risk factors for severe outcomes from 2009 pandemic influenza A (H1N1) virus infection are limited outside of developed countries. METHODS:We reviewed medical charts to collect data from patients hospitalized with laboratory-confirmed 2009 H1N1 infection who were identified across China during the period from September 2009 through February 2010, and we analyzed potential risk factors associated with severe illness (defined as illness requiring intensive care unit admission or resulting in death). RESULTS:Among 9966 case patients, the prevalence of chronic medical conditions (33% vs 14%), pregnancy (15% vs 7%), or obesity (19% vs 14%) was significantly higher in those patients with severe illness than it was in those with less severe disease. In multivariable analyses, among nonpregnant case patients aged ≥ 2 years, having a chronic medical condition significantly increased the risk of severe outcome among all age groups, and obesity was a risk factor among those <60 years of age. The risk of severe illness among pregnant case patients was significantly higher for those in the second and third trimesters. The risk of severe illness was increased when oseltamivir treatment was initiated ≥ 5 days after illness onset (odds ratio, 1.42; 95% confidence interval, 1.20-1.67). For persons <60 years of age, the prevalence of obesity among case patients with severe illness was significantly greater than it was among those without severe illness or among the general population. CONCLUSIONS:Risk factors for severe 2009 H1N1 illness in China were similar to those observed in developed countries, but there was a lower prevalence of chronic medical conditions and a lower prevalence of obesity. Obesity was a risk factor among case patients < 60 years of age. Early initiation of oseltamivir treatment was most beneficial, and there was an increased risk of severe disease when treatment was started ≥ 5 days after illness onset.
10.1093/cid/ciq144
Adiposity and influenza-associated respiratory mortality: a cohort study.
Zhou Ying,Cowling Benjamin J,Wu Peng,Chan Wai Man,Lee Siu Yin,Lau Eric H Y,Schooling C Mary
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:Obesity was first noted as a risk factor for severe illness associated with pandemic H1N1 infection in 2009, but the relationship between obesity and seasonal influenza remains unclear. METHODS:We used data from a population-based cohort comprising 66 820 older (≥65 years) participants with a follow-up period from 1998 to 2012. The impact of influenza activity on respiratory mortality rates was estimated using a Cox proportional hazards model adjusted for comorbidities, meteorological factors, and other co-circulating respiratory viruses. We also tested whether the association of influenza with respiratory mortality varied with obesity and/or health status. As a control outcome, we similarly assessed the association of influenza with deaths from external causes, because these deaths should be unrelated to influenza. RESULTS:Seasonal influenza activity was associated with higher respiratory mortality (hazard ratio [HR], 1.13 for influenza activity in the influenza season vs noninfluenza season; 95% confidence interval [CI], 1.05-1.22). The effect of seasonal influenza was 19% greater in obese individuals than normal-weight individuals (HR, 1.19; 95% CI, 1.01-1.42). The marginally significant and greater effect modification of obesity status on the association between seasonal influenza and respiratory mortality was also observed among older people in good health (HR, 1.35; 95% CI, .97-1.87). No such relations were observed for death from external causes. CONCLUSIONS:Obesity aggravates the effect of seasonal influenza on respiratory mortality. Priority for influenza vaccine should be considered for obese older people to decrease the burden of influenza.
10.1093/cid/civ060
Metformin improves in vivo and in vitro B cell function in individuals with obesity and Type-2 Diabetes.
Diaz Alain,Romero Maria,Vazquez Thomas,Lechner Suzanne,Blomberg Bonnie B,Frasca Daniela
Vaccine
Metformin (MET), the first-line medication for Type-2 Diabetes (T2D), has been shown to reduce chronic inflammation indirectly through reduction of hyperglycemia, or directly acting as anti-inflammatory drug. The effects of MET on B lymphocytes is uncharacterized. In the present study, we measured in vivo and in vitro influenza vaccine responses in 2 groups of T2D patients: recently diagnosed but not taking anti-diabetic drugs, and patients taking MET. Results show that B cell function and vaccine responses, hampered by obesity and T2D, are recovered by MET. Moreover, MET used in vitro to stimulate B cells from recently diagnosed T2D patients is also able to reduce B cell-intrinsic inflammation and increase antibody responses, similar to what we have seen in B cells from patients taking MET, who show increased responses to the influenza vaccine in vivo. These results are the first to show an effect of MET on B cells.
10.1016/j.vaccine.2017.03.078
Obesity, diabetes and pneumonia: the menacing interface of non-communicable and infectious diseases.
Fisher-Hoch Susan P,Mathews Christine E,McCormick Joseph B
Tropical medicine & international health : TM & IH
OBJECTIVES:To review current knowledge on the epidemiological, clinical and biological impact of the pandemic of obesity and diabetes on pneumonias. METHODS:We conducted a literature review using PubMed and EMBASE, supplemented by various sources. Given the disparate and fragmented nature of the literature, a formal systematic review was not possible. RESULTS:In 2008, globally 10% of men and 14% of women were obese and an estimated 371 million had diabetes; half undiagnosed and many obese. Numbers are rising rapidly in low- and middle-income countries where the majority reside, but reliable data are lacking. The most frequent pneumonias in obesity and diabetes are tuberculosis, influenza and pneumococcal, staphylococcal and opportunistic pathogens. Diabetes impacts tuberculosis control and increases drug resistance and mortality. Mortality and morbidity from pneumococcal pneumonia and influenza are increased in obesity and diabetes. In addition to mechanical and physiological effects, there are considerable immunological abnormalities characterised by chronic, low-grade inflammation. Simultaneous up-regulation and dysregulation of both innate and adaptive immune responses impair control and killing of invading organisms. Prevention in those at risk is poorly practised, although screening for tuberculosis in diabetes is beginning in high-burden settings. CONCLUSIONS:Pneumonia is a threat globally in obesity and diabetes with increased incidence and severity of disease. There is uncertainty about whether vaccines are equally effective in those with obesity and diabetes. Increased epidemiological, clinical and biological knowledge will be crucial to face this 21st century challenge.
10.1111/tmi.12206
Risk factors for hospitalization and severe outcomes of 2009 pandemic H1N1 influenza in Quebec, Canada.
Influenza and other respiratory viruses
BACKGROUND/OBJECTIVE:This case-control study was carried out to estimate risk factors associated with hospitalizations and severe outcomes [intensive care unit (ICU) admission or death] among patients with illness because of laboratory-confirmed 2009 pandemic A/H1N1 virus (pH1N1) during the first wave of pH1N1 activity in the province of Quebec, Canada. PATIENTS/METHODS:We collected epidemiologic information by phone using a standardized questionnaire from patients with laboratory-confirmed pH1N1 illness during the first spring/summer pandemic wave in Quebec, Canada. Risk factors associated with hospitalization were assessed by comparing hospitalized to community cases and for ICU admission or death through comparison with hospitalized cases. RESULTS:Cases (321 hospitalized patients including 47 ICU admissions and 15 deaths) were compared to controls (395 non-hospitalized patients) by using multivariable logistic regression adjusted for gender, age, education, being a health care worker, smoking, seasonal influenza vaccination, delay to consultation, antiviral use before admission, pregnancy, underlying medical conditions, and obesity. Age <5 years, underlying medical conditions (neuromuscular, cardiac, pulmonary, and renal conditions, diabetes, asthma, and other), and delayed consultation were associated with hospitalization. The strongest association with hospitalization was observed for neuromuscular disorders. Antiviral medication before hospital admission protected against severe disease. Association of obesity with hospitalization was not significant after adjustment in multivariable analysis. Among hospitalized patients, age ≥60 years and immune suppression were associated with death. CONCLUSIONS:Previously identified risk factors for seasonal influenza were also associated with increased risk of severe pH1N1 outcomes. The independent role of obesity needs to be further defined.
10.1111/j.1750-2659.2011.00204.x
Immune response in highly active young men to the 2014/2015 seasonal influenza vaccine.
Stewart Andrew,Vanderkooi Otto G,Reimer Raylene A,Doyle-Baker Patricia K
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
During the 2009 H1N1 pandemic, individuals with obesity were disproportionately affected by H1N1 with increased levels of mortality and morbidity. This led to questions regarding the potential impact of lifestyle on the effectiveness of immunization. Currently, the research is limited on influenza vaccination and the associated changes in immune response with body composition and physical activity. The purpose of this pilot study was to investigate the potential role of adiposity and physical activity in the immune response elicited by the 2014/2015 seasonal trivalent influenza vaccine. A prospective cohort study examining the 2014/2015 seasonal trivalent influenza vaccine was conducted by collecting baseline and 4-week postvaccination fasting blood samples from 45 male Albertans between the ages of 18 and 35 years. Percent body fat (%BF) was assessed through dual X-ray absorptiometry imagining and physical activity through self-reported survey scores. While no differences in median %BF were associated with seroconversion rates in participants, the median physical activity score was higher among those that did not seroconvert to the vaccine. Significant differences were found for the A/Texas strain (p < 0.01) and a similar trend of lower magnitude observed for the remaining 2 influenza strains. These results suggest that higher physical activity levels may influence immune response to vaccination and that assessing factors beyond those commonly used can be of value when identifying vaccine response in the population.
10.1139/apnm-2017-0683
Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus.
Paich Heather A,Sheridan Patricia A,Handy Jean,Karlsson Erik A,Schultz-Cherry Stacey,Hudgens Michael G,Noah Terry L,Weir Samuel S,Beck Melinda A
Obesity (Silver Spring, Md.)
OBJECTIVE:Obese adults have a greater risk of morbidity and mortality from infection with pandemic H1N1 influenza A virus (pH1N1). The objective of the present study was to elucidate the specific mechanisms by which obesity and overweight impact the cellular immune response to pH1N1. DESIGN AND METHODS:Peripheral blood mononuclear cells from healthy weight, overweight, and obese individuals were stimulated ex vivo with live pH1N1 and then markers of activation and function were measured using flow cytometry and cytokine secretion was measured using cytometric bead array assays. RESULTS:CD4(+) and CD8(+) T cells from overweight and obese individuals expressed lower levels of CD69, CD28, CD40 ligand, and interleukin-12 receptor, as well as, produced lower levels of interferon-γ and granzyme B, compared with healthy weight individuals, suggesting deficiencies in activation and function are indicated. Dendritic cells from the three groups expressed similar levels of major histocompatibility complex-II, CD40, CD80, and CD86, as well as, produced similar levels of interleukin-12. CONCLUSIONS:The defects in CD4(+) and CD8(+) T cells may contribute to the increased morbidity and mortality from pH1N1 in obese individuals. These data also provide evidence that both overweight and obesity cause impairments in immune function.
10.1002/oby.20383
Interaction of obesity and infections.
Dhurandhar N V,Bailey D,Thomas D
Obesity reviews : an official journal of the International Association for the Study of Obesity
There is evidence that certain infections may induce obesity. Obese persons may also have more severe infections and have compromised response to therapies. The objective of this study is to review the available literature identifying infections that potentially contribute to greater body mass index (BMI) and differential responses of overweight and obese persons to infections. A systematic literature review of human studies examining associations between infections and weight gain, differential susceptibility, severity, and response to prevention and treatment of infection according to BMI status (January 1980-July 2014) was conducted. Three hundred and forty-three studies were eligible for inclusion. Evidence indicated that viral infection by human adenovirus Ad36 and antibiotic eradication of Helicobacter pylori were followed by weight gain. People who were overweight or obese had higher susceptibility to developing post-surgical infections, H1N1 influenza and periodontal disease. More severe infections tended to be present in people with a larger BMI. People with a higher BMI had a reduced response to vaccinations and antimicrobial drugs. Higher doses of antibiotics were more effective in obese patients. Infections may influence BMI, and BMI status may influence response to certain infections, as well as to preventive and treatment measures. These observations have potential clinical implications.
10.1111/obr.12320
Predictive clinicopathological features derived from systematic autopsy examination of patients who died with A/H1N1 influenza infection in the UK 2009-10 pandemic.
Lucas S
Health technology assessment (Winchester, England)
BACKGROUND:From April 2009 to January 2010, the pandemic of A/H1N1 influenza affected the UK. There were > 30,000 infections and 457 deaths (all ages). Reports from other countries had indicated that certain comorbidities were associated with a higher risk of death from H1N1 infection, and there was a need to identify these factors in the UK population as knowledge of them could lead to improved treatment in the current epidemic and reduced mortality in future epidemics. OBJECTIVES:To gather all the available clinical pathology information from autopsies performed on patients dying with known or suspected influenza A/H1N1 infection, across the UK. To evaluate comorbidities present in these deceased patients; correlate them with the H1N1-related pathology and treatment-associated pathology, determine their relative contributions and estimate the significant features associated with death. METHODS:To obtain the autopsy reports, standard request letters were sent by e-mail to all histopathologists in the UK on the Royal College of Pathologists list, all the coroners' jurisdictions in England, Wales and Northern Ireland, and to procurators fiscal in Scotland. The letters asked for autopsy reports of the autopsied deceased who included: those with H1N1 infection, proven before or after death, and those in whom swine flu was unproven but most likely to have been present; those in whom H1N1 was a minor pathology, as well as those in whom it was the immediate cause of death; those whose cause of death mentioned 'swine flu', 'swine influenza' or 'H1N1 infection'; and those of any age from infancy to old age. RESULTS:Sixty-eight autopsy reports were received: 19 children (0-15 years) and 49 adults (16 + years). All but two autopsies were medico-legal, and only two (3% of the total) were consented. This sample thus represents 15% of the known 457 deaths from H1N1. Median age for children at death was 6 years, for adults it was 41 years. Deaths in children were associated with congenital diseases (47%, 9/19), particularly of the heart and central nervous system. The autopsied children were not obese. Death in adults were associated with pregnancy (three cases in the study, but nationally 12/457 H1N1-associated deaths were noted), obesity (50% of adults had a body mass index ≥ 30 kg/m²) and chronic respiratory disease (12%, 6/49 adults). Diabetes did not emerge as a risk factor for death, but learning difficulties did. Nearly all the deaths (94%, 64/68) were a consequence of H1N1 infection in the respiratory tract. In more than one-third (41%, 28/68) of the deaths, bacterial secondary infection was the significant complication; the pneumococcus was the most common agent identified (25%, 7/28). LIMITATIONS:This review is an incomplete medical study of what happened during the epidemic, and the small sample number (68 reports from 457 deaths) limits further speculation. We have no true measure of whether the cases selected for autopsy are representative of the total deaths in terms of pathology and comorbidities. CONCLUSIONS:The major comorbidities associated with death from H1N1 infection were obesity, chronic respiratory disease and pregnancy. Young age at death was confirmed. Congenital disease in children and learning difficulties in adults were also important, but diabetes was not. This methodology of gathering data for research has potential for use in other public health questions, but is dependent on the co-operation of the medico-legal services. These results reinforce the need to enquire further into the pathogenesis of severe and fatal H1N1 disease, and the circumstances of clinical presentation and rapid evaluation in a time of epidemic influenza. FUNDING:The National Institute for Health Research Health Technology Assessment programme.
10.3310/hta14550-02
Obesity and respiratory infections: does excess adiposity weigh down host defense?
Mancuso Peter
Pulmonary pharmacology & therapeutics
The number of overweight and obese individuals has dramatically increased in the US and other developed nations during the past 30 years. While type II diabetes and cardiovascular disease are well recognized co-morbid conditions associated with obesity, recent reports have demonstrated a greater severity of illness in obese patients due to influenza during the 2009 H1N1 pandemic. Consistent with these reports, diet-induced obesity has been shown to impair anti-viral host defense in murine models of influenza infection. However, the impact of obesity on the risk of community-acquired and nosocomial pneumonia in human patients is not clear. Relatively few studies have evaluated the influence of diet-induced obesity in murine models of bacterial infections of the respiratory tract. Obese leptin deficient humans and leptin and leptin-receptor deficient mice exhibit greater susceptibility to respiratory infections suggesting a requirement for leptin in the pulmonary innate and adaptive immune response to infection. In contrast to these studies, we have observed that obese leptin receptor signaling mutant mice are resistant to pneumococcal pneumonia highlighting the complex interaction between leptin receptor signaling and immune function. Given the increased prevalence of obesity and poor responsiveness of obese individuals to vaccination against influenza, the development of novel immunization strategies for this population is warranted. Additional clinical and animal studies are needed to clarify the relationship between increased adiposity and susceptibility to community-acquired and nosocomial pneumonia.
10.1016/j.pupt.2012.04.006
A Perfect Storm: Increased Colonization and Failure of Vaccination Leads to Severe Secondary Bacterial Infection in Influenza Virus-Infected Obese Mice.
Karlsson Erik A,Meliopoulos Victoria A,van de Velde Nicholas C,van de Velde Lee-Ann,Mann Beth,Gao Geli,Rosch Jason,Tuomanen Elaine,McCullers Jon,Vogel Peter,Schultz-Cherry Stacey
mBio
Obesity is a risk factor for developing severe disease following influenza virus infection; however, the comorbidity of obesity and secondary bacterial infection, a serious complication of influenza virus infections, is unknown. To fill this gap in knowledge, lean and obese C57BL/6 mice were infected with a nonlethal dose of influenza virus followed by a nonlethal dose of Strikingly, not only did significantly enhanced death occur in obese coinfected mice compared to lean controls, but also high mortality was seen irrespective of influenza virus strain, bacterial strain, or timing of coinfection. This result was unexpected, given that most influenza virus strains, especially seasonal human A and B viruses, are nonlethal in this model. Both viral and bacterial titers were increased in the upper respiratory tract and lungs of obese animals as early as days 1 and 2 post-bacterial infection, leading to a significant decrease in lung function. This increased bacterial load correlated with extensive cellular damage and upregulation of platelet-activating factor receptor, a host receptor central to pneumococcal invasion. Importantly, while vaccination of obese mice against either influenza virus or pneumococcus failed to confer protection, antibiotic treatment was able to resolve secondary bacterial infection-associated mortality. Overall, secondary bacterial pneumonia could be a widespread, unaddressed public health problem in an increasingly obese population. Worldwide obesity rates have continued to increase. Obesity is associated with increased severity of influenza virus infection; however, very little is known about respiratory coinfections in this expanding, high-risk population. Our studies utilized a coinfection model to show that obesity increases mortality from secondary bacterial infection following influenza virus challenge through a "perfect storm" of host factors that lead to excessive viral and bacterial outgrowth. In addition, we found that vaccination of obese mice against either virus or bacteria failed to confer protection against coinfection, but antibiotic treatment did alleviate mortality. Combined, these results represent an understudied and imminent public health concern in a weighty portion of the global population.
10.1128/mBio.00889-17
Back to the Future: Lessons Learned From the 1918 Influenza Pandemic.
Frontiers in cellular and infection microbiology
2018 marks the 100-year anniversary of the 1918 influenza pandemic, which killed ~50 million people worldwide. The severity of this pandemic resulted from a complex interplay between viral, host, and societal factors. Here, we review the viral, genetic and immune factors that contributed to the severity of the 1918 pandemic and discuss the implications for modern pandemic preparedness. We address unresolved questions of why the 1918 influenza H1N1 virus was more virulent than other influenza pandemics and why some people survived the 1918 pandemic and others succumbed to the infection. While current studies suggest that viral factors such as haemagglutinin and polymerase gene segments most likely contributed to a potent, dysregulated pro-inflammatory cytokine storm in victims of the pandemic, a shift in case-fatality for the 1918 pandemic toward young adults was most likely associated with the host's immune status. Lack of pre-existing virus-specific and/or cross-reactive antibodies and cellular immunity in children and young adults likely contributed to the high attack rate and rapid spread of the 1918 H1N1 virus. In contrast, lower mortality rate in in the older (>30 years) adult population points toward the beneficial effects of pre-existing cross-reactive immunity. In addition to the role of humoral and cellular immunity, there is a growing body of evidence to suggest that individual genetic differences, especially involving single-nucleotide polymorphisms (SNPs), contribute to differences in the severity of influenza virus infections. Co-infections with bacterial pathogens, and possibly measles and malaria, co-morbidities, malnutrition or obesity are also known to affect the severity of influenza disease, and likely influenced 1918 H1N1 disease severity and outcomes. Additionally, we also discuss the new challenges, such as changing population demographics, antibiotic resistance and climate change, which we will face in the context of any future influenza virus pandemic. In the last decade there has been a dramatic increase in the number of severe influenza virus strains entering the human population from animal reservoirs (including highly pathogenic H7N9 and H5N1 viruses). An understanding of past influenza virus pandemics and the lessons that we have learnt from them has therefore never been more pertinent.
10.3389/fcimb.2018.00343
Obesity decreases B cell responses in young and elderly individuals.
Frasca Daniela,Ferracci Franco,Diaz Alain,Romero Maria,Lechner Suzanne,Blomberg Bonnie B
Obesity (Silver Spring, Md.)
OBJECTIVE:To evaluate the effects of obesity-associated inflammation on influenza vaccine responses. METHODS:In young and elderly individuals, both lean and with obesity, antibody responses to influenza vaccination were measured. RESULTS:A decrease in in vivo vaccine responses, circulating switched memory, and transitional B cells and an increase in pro-inflammatory late/exhausted memory B cells were found. In vitro B cell function was measured by activation-induced cytidine deaminase and E47, markers of optimal antibody responses. Moreover, IL-6 production was increased, whereas IL-10 production was decreased in cultures of B cells from individuals with obesity. Markers of immune activation (TNF-α, TLR4, micro-RNAs) in unstimulated B cells were also found increased and were negatively correlated with B cell function. In order to reveal potential mechanisms, we stimulated B cells from lean individuals in vitro with leptin, the adipokine increased in obesity. Leptin increased phospho-STAT3, crucial for TNF-α production, and decreased phospho-AMPK, the energy sensing enzyme upstream of phospho-p38 MAPK and E47. Leptin-induced phospho-STAT3 and phospho-AMPK levels were similar to those in B cells from individuals with obesity. CONCLUSIONS:These results demonstrate that leptin can be responsible for decreased B cell function in obesity.
10.1002/oby.21383
Obese mice have increased morbidity and mortality compared to non-obese mice during infection with the 2009 pandemic H1N1 influenza virus.
Easterbrook Judith D,Dunfee Rebecca L,Schwartzman Louis M,Jagger Brett W,Sandouk Aline,Kash John C,Memoli Matthew J,Taubenberger Jeffery K
Influenza and other respiratory viruses
BACKGROUND:Obesity has been identified as an independent risk factor for severe or fatal infection with 2009 pandemic H1N1 influenza (2009 pH1N1), but was not previously recognized for previous pandemic or seasonal influenza infections. OBJECTIVES:Our aim was to evaluate the role of obesity as an independent risk factor for severity of infection with 2009 pH1N1, seasonal H1N1, or a pathogenic H1N1 influenza virus. METHODS:Diet-induced obese (DIO) and their non-obese, age-matched control counterparts were inoculated with a 2009 pH1N1, A/California/04/2009 (CA/09), current seasonal H1N1, A/NY/312/2001 (NY312), or highly pathogenic 1918-like H1N1, A/Iowa/Swine/1931 (Sw31), virus. RESULTS:Following inoculation with CA/09, DIO mice had higher mortality (80%) than control mice (0%) and lost more weight during infection. No effect of obesity on morbidity and mortality was observed during NY312 or Sw31 infection. Influenza antigen distribution in the alveolar regions of the lungs was more pronounced in DIO than control mice during CA/09 infection at 3 days post-inoculation (dpi), despite similar virus titers. During CA/09 infection, localized interferon-β and proinflammatory cytokine protein responses in the lungs were significantly lower in DIO than control mice. Conversely, serum cytokine concentrations were elevated in DIO, but not control mice following infection with CA/09. The effect of obesity on differential immune responses was abrogated during NY312 or Sw31 infection. CONCLUSIONS:Together, these data support epidemiologic reports that obesity may be a risk factor for severe 2009 pandemic H1N1 influenza infection, but the role of obesity in seasonal or highly virulent pandemic influenza infection remains unclear.
10.1111/j.1750-2659.2011.00254.x
Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease.
PloS one
BACKGROUND:Severe illness due to 2009 pandemic A(H1N1) infection has been reported among persons who are obese or morbidly obese. We assessed whether obesity is a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1), independent of chronic medical conditions considered by the Advisory Committee on Immunization Practices (ACIP) to increase the risk of influenza-related complications. METHODOLOGY/PRINCIPAL FINDINGS:We used a case-cohort design to compare cases of hospitalizations and deaths from 2009 pandemic A(H1N1) influenza occurring between April-July, 2009, with a cohort of the U.S. population estimated from the 2003-2006 National Health and Nutrition Examination Survey (NHANES); pregnant women and children <2 years old were excluded. For hospitalizations, we defined categories of relative weight by body mass index (BMI, kg/m(2)); for deaths, obesity or morbid obesity was recorded on medical charts, and death certificates. Odds ratio (OR) of being in each BMI category was determined; normal weight was the reference category. Overall, 361 hospitalizations and 233 deaths included information to determine BMI category and presence of ACIP-recognized medical conditions. Among >or=20 year olds, hospitalization was associated with being morbidly obese (BMI>or=40) for individuals with ACIP-recognized chronic conditions (OR = 4.9, 95% CI 2.4-9.9) and without ACIP-recognized chronic conditions (OR = 4.7, 95%CI 1.3-17.2). Among 2-19 year olds, hospitalization was associated with being underweight (BMI<or=5(th) percentile) among those with (OR = 12.5, 95%CI 3.4-45.5) and without (OR = 5.5, 95%CI 1.3-22.5) ACIP-recognized chronic conditions. Death was not associated with BMI category among individuals 2-19 years old. Among individuals aged >or=20 years without ACIP-recognized chronic medical conditions death was associated with obesity (OR = 3.1, 95%CI: 1.5-6.6) and morbid obesity (OR = 7.6, 95%CI 2.1-27.9). CONCLUSIONS/SIGNIFICANCE:Our findings support observations that morbid obesity may be associated with hospitalization and possibly death due to 2009 pandemic H1N1 infection. These complications could be prevented by early antiviral therapy and vaccination.
10.1371/journal.pone.0009694
Obesity and respiratory hospitalizations during influenza seasons in Ontario, Canada: a cohort study.
Kwong Jeffrey C,Campitelli Michael A,Rosella Laura C
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:Previous studies suggest that obesity may be a risk factor for complications from pandemic influenza A(H1N1) infection. We aimed to examine the association between obesity and respiratory hospitalizations during seasonal influenza epidemics and to determine the extent of this association among individuals without established risk factors for serious complications due to influenza infection. METHODS:We conducted a cohort study over 12 influenza seasons (1996-1997 through 2007-2008) of 82545 respondents to population health surveys in Ontario, Canada. We included individuals aged 18-64 years who had responded to a survey within 5 years prior to the start of an influenza season. We used logistic regression to examine the association between self-reported body mass index (BMI) and hospitalization for selected respiratory diseases (pneumonia and influenza, acute respiratory diseases, and chronic lung diseases), both in the entire cohort and stratified by chronic condition status. RESULTS:Obese class I (BMI, 30-34.9) (odds ratio [OR], 1.45 [95% confidence interval {CI}, 1.03-2.05]) and obese class II or III (BMI, ≥35) individuals (OR, 2.12 [95% CI, 1.45-3.10]) were more likely than normal weight individuals to have a respiratory hospitalization during influenza seasons. Among obese class II or III individuals, the association was present both for those without previously identified risk factors (OR, 5.10 [95% CI, 2.53-10.24]) and for those with 1 risk factor (OR, 2.11 [95% CI, 1.10-4.06]). CONCLUSIONS:Severely obese individuals with and without chronic conditions are at increased risk for respiratory hospitalizations during influenza seasons. They should be considered a priority group for preventive influenza measures, such as vaccination and treatment with antiviral medications.
10.1093/cid/cir442
Review on the impact of pregnancy and obesity on influenza virus infection.
Influenza and other respiratory viruses
A myriad of risk factors have been linked to an increase in the severity of the pandemic H1N1 2009 influenza A virus [A(H1N1)pdm09] including pregnancy and obesity where death rates can be elevated as compared to the general population. The goal of this review is to provide an overview of the influence of pregnancy and obesity on the reported cases of A(H1N1)pdm09 virus infection and of how the concurrent presence of these factors may have an exacerbating effect on infection outcome. Also, the hypothesized immunologic mechanisms that contribute to A(H1N1)pdm09 virus severity during pregnant or obese states are outlined. Identifying the mechanisms underlying the increased disease severity in these populations may result in improved therapeutic approaches and future pandemic preparedness.
10.1111/j.1750-2659.2012.00342.x
Impact of obesity in patients infected with 2009 influenza A(H1N1).
Díaz Emili,Rodríguez Alejandro,Martin-Loeches Ignacio,Lorente Leonardo,Del Mar Martín María,Pozo Juan Carlos,Montejo Juan Carlos,Estella Angel,Arenzana Ángel,Rello Jordi,
Chest
OBJECTIVE:A large proportion of patients infected with 2009 influenza A(H1N1) (A[H1N1]) are obese. Obesity has been proposed as a risk factor influencing outcome in these patients. However, its role remains unclear. We evaluate the outcome of patients who are obese and infected with A(H1N1) in the ICU, determining whether obesity is a risk factor for mortality. METHODS:This was a prospective, observational, and multicenter study performed in 144 ICUs in Spain. Data were obtained from the Grupo de Trabajo en Enfermedades Infecciosas de la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (GTEI/SEMICYUC) registry. Adult patients with A(H1N1) that was confirmed by real-time polymerase chain reaction were included in the analysis. Patients who were obese (BMI > 30) were compared with patients who were nonobese. Cox regression analysis was used to determine adjusted mortality. Differences of P < .05 were considered significant. RESULTS:In January 2010, the GTEI/SEMICYUC registry had complete records for 416 patients. One hundred and fifty patients (36.1%) were obese, of whom 67 (44.7%) were morbidly obese (BMI > 40). Mechanical ventilation (MV) was more frequently applied in patients who were obese (64% vs 52.4%, P < .01) Patients with obesity remained on MV longer than patients who were nonobese (6.5 ± 10.3 days vs 9.3 ± 9.7 days, P = .02), had longer ICU length of stay (10.8 ± 12.1 days vs 13.7 ± 11.7 days, P = .03), and had longer hospitalization (18.2 ± 14.6 days vs 22.2 ± 16.5 days, P = .02). Mortality adjusted by severity and potential confounders identified that obesity was not significantly associated with ICU mortality (hazard ratio, 1.1; 95% CI, 0.69-1.75; P = .68). CONCLUSIONS:In our cohort, patients who were obese and infected with A(H1N1) did not have increased mortality. However, there was an association between obesity and higher ICU resource consumption.
10.1378/chest.10-1160
Obesity-Related Microenvironment Promotes Emergence of Virulent Influenza Virus Strains.
mBio
Obesity is associated with increased disease severity, elevated viral titers in exhaled breath, and significantly prolonged viral shed during influenza A virus infection. Due to the mutable nature of RNA viruses, we questioned whether obesity could also influence influenza virus population diversity. Here, we show that minor variants rapidly emerge in obese mice. The variants exhibit increased viral replication, resulting in enhanced virulence in wild-type mice. The increased diversity of the viral population correlated with decreased type I interferon responses, and treatment of obese mice with recombinant interferon reduced viral diversity, suggesting that the delayed antiviral response exhibited in obesity permits the emergence of a more virulent influenza virus population. This is not unique to obese mice. Obesity-derived normal human bronchial epithelial (NHBE) cells also showed decreased interferon responses and increased viral replication, suggesting that viral diversity also was impacted in this increasing population. Currently, 50% of the adult population worldwide is overweight or obese. In these studies, we demonstrate that obesity not only enhances the severity of influenza infection but also impacts viral diversity. The altered microenvironment associated with obesity supports a more diverse viral quasispecies and affords the emergence of potentially pathogenic variants capable of inducing greater disease severity in lean hosts. This is likely due to the impaired interferon response, which is seen in both obese mice and obesity-derived human bronchial epithelial cells, suggesting that obesity, aside from its impact on influenza virus pathogenesis, permits the stochastic accumulation of potentially pathogenic viral variants, raising concerns about its public health impact as the prevalence of obesity continues to rise.
10.1128/mBio.03341-19
Association between body mass index and laboratory-confirmed influenza in middle aged and older adults: a prospective cohort study.
Karki S,Muscatello D J,Banks E,MacIntyre C R,McIntyre P,Liu B
International journal of obesity (2005)
BACKGROUND:Studies conducted during the 2009 influenza A (H1N1) pandemic found that obesity increases the risk of severe influenza including hospitalization and death. In this study, we examined the relationship of BMI with having laboratory-confirmed seasonal influenza and influenza-related respiratory hospitalization. METHODS:We linked a cohort of 246,494 adults aged ≥45 years with data on BMI to subsequent laboratory-confirmed influenza notifications and cause-specific hospitalizations from 2006 to 2015. Cox-proportional hazard models were used to estimate the risk of incident laboratory-confirmed influenza and influenza-related respiratory hospitalizations according to BMI, adjusting for age, sex and other covariates. RESULTS:After 1,840,408 person-years of follow-up, 1891 participants had laboratory-confirmed influenza notifications (crude rate 10.3/10,000 person-years) of whom 623 were hospitalized for a respiratory illness. Compared to those with healthy BMI (22.5 to <25.0 kg/m, influenza incidence was respectively 27% (adjusted HR [aHR]: 1.27, 95% CI: 1.10-1.46) and 69% (aHR: 1.69, 1.24-2.29) greater among obese (BMI: 30 to <40 kg/m and very obese adults (40 to <50 kg/m. The equivalent aHRs for hospitalization were 1.57 (95% CI: 1.22-2.01) and 4.81 (95% CI: 3.23-7.17). For every 5-unit BMI increase above 22.5 kg/m, there was a 15% (aHR: 1.15, 95% CI: 1.09-1.22) increase in risk of having a diagnosis of influenza and 42% increase in hospitalization (aHR: 1.42, 95% CI: 1.30-1.60). These trends did not differ between the pandemic year (2009) and other years. CONCLUSIONS:Our results suggest that obese adults have a similar risk of hospitalization for seasonal influenza as adults with cardiovascular disease and diabetes, and should therefore be equally prioritized for funded interventions such as targeted immunization programs.
10.1038/s41366-018-0029-x
A novel risk factor for a novel virus: obesity and 2009 pandemic influenza A (H1N1).
Louie Janice K,Acosta Meileen,Samuel Michael C,Schechter Robert,Vugia Duc J,Harriman Kathleen,Matyas Bela T,
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:many critically ill patients with 2009 pandemic influenza A (H1N1) (2009 H1N1) infection were noted to be obese, but whether obesity, rather than its associated co-morbidities, is an independent risk factor for severe infection is unknown. METHODS:using public health surveillance data, we analyzed demographic and clinical characteristics of California residents hospitalized with 2009 H1N1 infection to assess whether obesity (body mass index [BMI] ≥ 30) and extreme obesity (BMI ≥ 40) were an independent risk factor for death among case patients ≥ 20 years old. RESULTS:during the period 20 April-11 August 2009, 534 adult case patients with 2009 H1N1 infection for whom BMI information was available were observed. Two hundred twenty-eight patients (43%) were ≥ 50 years of age, and 378 (72%) had influenza-related high-risk conditions recognized by the Advisory Committee on Immunization Practices as risk factors for severe influenza. Two hundred and seventy-four (51%) had BMI ≥ 30, which is 2.2 times the prevalence of obesity among California adults (23%) and 1.5 times the prevalence among the general population of the United States (33%). Of the 92 case patients who died (17%), 56 (61%) had BMI ≥ 30 and 28 (30%) had BMI ≥ 40. In multivariate analysis, BMI ≥ 40 (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.4-5.9) and BMI ≥ 45 (OR, 4.2; 95% CI, 1.9-9.4), age ≥ 50 years (OR, 2.1; 95% CI, 1.2-3.7), miscellaneous immunosuppressive conditions (OR, 3.9; 95% CI, 1.6-9.5), and asthma (OR, 0.5; 95% CI, 0.3-0.9) were associated with death. CONCLUSION:half of Californians ≥ 20 years of age hospitalized with 2009 H1N1 infection were obese. Extreme obesity was associated with increased odds of death. Obese adults with 2009 H1N1 infection should be treated promptly and considered in prioritization of vaccine and antiviral medications during shortages.
10.1093/cid/ciq152
Production of interferon α and β, pro-inflammatory cytokines and the expression of suppressor of cytokine signaling (SOCS) in obese subjects infected with influenza A/H1N1.
Terán-Cabanillas Elí,Montalvo-Corral Maricela,Silva-Campa Erika,Caire-Juvera Graciela,Moya-Camarena Silvia Y,Hernández Jesús
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND & AIMS:Obesity was recognized as an independent risk factor for morbidity and mortality during last influenza A/H1N1 pandemic. Mechanisms involved in the high mortality risk from obesity during influenza A virus include reduced type I interferon production and delayed pro-inflammatory response, which lead to a higher rate of morbidity and mortality in murine models. In this study, we evaluated the production of type I interferons, pro-inflammatory and anti-inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) from obese and lean subjects with and without confirmed infection of influenza A/H1N1. The expression levels of the suppressor of cytokine signaling-1 (SOCS1), SOCS3 and nuclear factor-kB were also evaluated. METHODS:Cytokines were measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and/or by ELISA in PBMCs stimulated with toll like receptor-3 (TLR-3) and TLR-7 ligands. The mRNA expression of SOCS1 and SOCS3 were evaluated by qRT-PCR. RESULTS:The obese volunteers infected with influenza A/H1N1 showed a diminished ability to produce type I interferon in response to TLR-3 ligand. Interestingly, the pro-inflammatory response was also affected in TLR-3 stimulated PBMCs. Obese influenza-free volunteers showed an increased basal expression of SOCS3, but not SOCS1. During influenza infection, SOCS1 and SOCS3 expression was higher in the lean infected volunteers in contrast to those who were obese infected. CONCLUSIONS:These data suggest that obesity is related to TLR-3 impairment and explain, at least in part, the inadequate immune response of obese individuals during infection with influenza A/H1N1 virus.
10.1016/j.clnu.2013.10.011
Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis.
Fezeu L,Julia C,Henegar A,Bitu J,Hu F B,Grobbee D E,Kengne A-P,Hercberg S,Czernichow S
Obesity reviews : an official journal of the International Association for the Study of Obesity
The aim of this study was to assess the association between obesity and the risk of intensive care unit (ICU) admission and death among patients hospitalized for influenza A (H1N1) viral infection. A systematic review of the Medline and Cochrane databases using 'obesity', 'hospitalization', 'influenza A viral infection', various synonyms, and reference lists of retrieved articles from January 2009 to January 2010. Studies comparing the prevalence of obesity among patients with confirmed infection for influenza A virus and who were either hospitalized or admitted to ICU/died were included. A total of 3059 subjects from six cross-sectional studies, who were hospitalized for influenza A (H1N1) viral infection, were included in this meta-analysis. Severely obese H1N1 patients (body mass index ≥ 40 kg m(-2), n = 804) were as twice as likely to be admitted to ICU or die (odds ration: 2.01, 95% confidence interval: 1.29-3.14, P < 0.002) compared with H1N1 patients who were not severely obese. Having a body mass index ≥ 30 kg m(-2) was similarly associated with a more than twofold increased risk of ICU admission or death although this did not reach statistical significance (2.14, 0.92-4.99, P < 0.07). This meta-analysis supports the view that obesity is associated with higher risks of ICU admission or death in patients with influenza A (H1N1) infection. Therefore, morbid obese patients should be monitored more intensively when hospitalized.
10.1111/j.1467-789X.2011.00864.x
Obesity and pro-inflammatory mediators are associated with acute kidney injury in patients with A/H1N1 influenza and acute respiratory distress syndrome.
Cruz-Lagunas Alfredo,Jiménez-Alvarez Luís,Ramírez Gustavo,Mendoza-Milla Criselda,García-Sancho Ma Cecilia,Avila-Moreno Federico,Zamudio Pedro,Urrea Francisco,Ortiz-Quintero Blanca,Campos-Toscuento Victoria L,Morán Juan,Barrera Aldo A,Martínez-Briseño David,Fernández-Plata Rosario,Sierra-Vargas Martha Patricia,Muñoz-Perea Carolina,Illescas-Flores Samuel,Bautista Edgar,Suratt Benjamin T,Pérez-Padilla José Rogelio,Zuñiga Joaquín
Experimental and molecular pathology
BACKGROUND:The obesity has been shown to increase the severity of A/H1N1 infection and the development of acute respiratory distress syndrome (ARDS) and organ involvement. METHODS:Circulating levels of C-peptide, insulin, glucagon, leptin, acute phase reactants (procalcitonin, C-reactive protein, tissue plasminogen activator, and serum amyloids A and P), were measured in samples from 32 critically ill patients with A/H1N1 virus infection, 17 of whom had ARDS complicated by acute kidney injury (AKI) and 15 of whom had ARDS but did not develop AKI. RESULTS:Patients with ARDS and AKI (ARDS/AKI) had higher BMI and higher levels of C-peptide, insulin, leptin, procalcitonin and serum amyloid A compared to those ARDS patient who did not develop AKI. Adjusting for confounding variables using logistic regression analysis, higher levels of C-peptide (>0.75 ng/mL) (OR=64.8, 95% CI = 2.1-1980, p = 0.0006) and BMI>30 Kg/m(2) (OR = 42.0, 95% CI = 1.2-1478, p = 0.04) were significantly associated with the development of AKI in ARDS patients. CONCLUSION:High levels of C-peptide and BMI>30 kg/m(2) were associated with the development of AKI in ARDS patients due to A/H1N1 infection. These metabolic/obesity indicators, together with the profiles of pro-inflammatory acute phase proteins, may be important links between obesity and poor outcomes in A/H1N1 09 infection.
10.1016/j.yexmp.2014.10.006
High Body Mass Index as a Risk Factor for Hospitalization Due to Influenza: A Case-Control Study.
Martín Vicente,Castilla Jesús,Godoy Pere,Delgado-Rodríguez Miguel,Soldevila Nuria,Fernández-Villa Tania,Molina Antonio J,Astray Jenaro,Castro Ady,González-Candelas Fernando,Mayoral José María,Quintana José María,Domínguez Ángela,
Archivos de bronconeumologia
INTRODUCTION:Obesity has emerged as a significant independent predictor of severity in pandemic influenzaA (H1N1)pdm09. The aim of this study was to investigate the association between body mass index (BMI) and the risk of hospitalization due to influenza. METHODS:Hospitalized patients (n=755) with laboratory-confirmed influenza were individually matched by age, admission/visit date, and province with an outpatient (n=783) with laboratory-confirmed influenza and an outpatient control (n=950). We compared the BMI using conditional logistic regression adjusted for potential confounding factors (aOR). The population attributable fraction (PAF) was calculated. RESULTS:A higher BMI was associated with an increased risk of hospitalization compared to both outpatient cases (aOR=1.11; 95%CI: 1.07-1.16) and outpatient controls (aOR=1.04; 95%CI: 1.01-1.07). Compared with normal weight, obesity type I, obesity type II and obesity type III was associated with a greater likelihood of hospitalization compared with outpatient cases (aOR=1.85, 95%CI: 1.05-3.26; aOR=5.24, 95%CI: 1.94-14.15 and aOR=44.38, 95%CI: 4.47-440.5). Compared with normal weight, obesity type II and obesity type III was associated with a greater likelihood of hospitalization compared with outpatient controls (aOR=4.37, 95%CI: 1.79-10.69 and aOR=4.95, 95%CI: 1.45-16.87). In persons without influenza vaccination, all categories of BMI≥30kg/m(2) were associated with a greater likelihood of hospitalization compared with normal weight in both outpatient cases and outpatient controls. The PAF of hospitalization by influenza due to BMI ranged from 21.9% to 8.5%; in the case of unvaccinated against influenza between 20.5% to 16.9%. CONCLUSION:A high BMI is associated with an increased risk of hospitalization due to influenza. High percentage of hospital admissions are attributable to their BMI, especially in non vaccinated.
10.1016/j.arbres.2015.11.006
Leptin and leptin-related gene polymorphisms, obesity, and influenza A/H1N1 vaccine-induced immune responses in older individuals.
Ovsyannikova Inna G,White Sarah J,Larrabee Beth R,Grill Diane E,Jacobson Robert M,Poland Gregory A
Vaccine
Obesity is a risk factor for complicated influenza A/H1N1 disease and poor vaccine immunogenicity. Leptin, an adipocyte-derived hormone/cytokine, has many immune regulatory functions and therefore could explain susceptibility to infections and poor vaccine outcomes. We recruited 159 healthy adults (50-74 years old) who were immunized with inactivated TIV influenza vaccine that contained A/California/7/2009/H1N1 virus. We found a strong correlation between leptin concentration and BMI (r=0.55, p<0.0001), but no association with hemagglutination antibody inhibition (HAI), B-cell, or granzyme B responses. We found a slight correlation between leptin concentration and an immunosenescence marker (TREC: T-cell receptor excision circles) level (r=0.23, p=0.01). We found eight SNPs in the LEP/LEPR/GHRL genes that were associated with leptin levels and four SNPs in the PTPN1/LEPR/STAT3 genes associated with peripheral blood TREC levels (p<0.05). Heterozygosity of the synonymous variant rs2230604 in the PTPN1 gene was associated with a significantly lower (531 vs. 259, p=0.005) TREC level, as compared to the homozygous major variant. We also found eight SNPs in the LEP/PPARG/CRP genes associated with variations in influenza-specific HAI and B-cell responses (p<0.05). Our results suggest that specific allelic variations in the leptin-related genes may influence adaptive immune responses to influenza vaccine.
10.1016/j.vaccine.2013.12.009
B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection.
Kosaraju Rasagna,Guesdon William,Crouch Miranda J,Teague Heather L,Sullivan E Madison,Karlsson Erik A,Schultz-Cherry Stacey,Gowdy Kymberly,Bridges Lance C,Reese Lauren R,Neufer P Darrell,Armstrong Michael,Reisdorph Nichole,Milner J Justin,Beck Melinda,Shaikh Saame Raza
Journal of immunology (Baltimore, Md. : 1950)
Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.
10.4049/jimmunol.1601031
Obesity and influenza associated mortality: evidence from an elderly cohort in Hong Kong.
Yang Lin,Chan King Pan,Lee Ruby Siu-Yin,Chan Wai Man,Lai Hak Kan,Thach Thuan Quoc,Chan Kwok Hung,Lam Tai Hing,Peiris J S Malik,Wong Chit Ming
Preventive medicine
OBJECTIVE:Obesity was not identified as a risk factor for influenza until the recent 2009 H1N1 pandemic. Based on a cohort of 66,820 subjects aged 65 years and over with the follow-up period from July 1998 to December 2010 in Hong Kong, we assessed the modifying effect of obesity on mortality risks specifically attributable to influenza infections (termed as "influenza associated mortality risks"). METHODS:A Cox proportional model with time dependent covariates was adopted to assess the hazard ratio of mortality in each obesity group when influenza activity increased 10% in the community. RESULTS:Hazard ratio of influenza-associated all-cause mortality was 1.081 (95% confidence interval 1.013, 1.154), 1.047 (1.012, 1.084), 0.981 (0.936, 1.028), 1.018 (0.980, 1.058) and 1.062 (0.972, 1.162) in the underweight, normal, overweight, moderate obesity and severe obesity groups, respectively. A similar U shape pattern across the obesity groups was also observed in influenza associated mortality risks of respiratory diseases, pneumonia and influenza. This pattern was more evident among ever smokers, although the influenza effect estimates in each obesity group had overlapping confidence intervals. CONCLUSION:There is some but limited evidence to suggest that underweight and obesity were associated with higher mortality risks of influenza in old population.
10.1016/j.ypmed.2012.11.017
Influenza in obese travellers: increased risk and complications, decreased vaccine effectiveness.
Journal of travel medicine
BACKGROUND:Obesity is a worldwide epidemic and was empirically shown to increase the risk of developing severe influenza virus infection. As international travel becomes more common and obesity is now prevalent even in low- and middle-income countries, travellers may have an increased risk of contracting influenza virus especially during peak influenza season. METHODS:An analysis of the literature, centred on publications from 2014-19, was performed, with an emphasis on human epidemiological data, human studies ex vivo and studies in mouse models of obesity. Our search efforts focused on influenza disease severity, pathogenesis, evolutionary dynamics and measures of infection control in the obese and overweight host. RESULTS:Obesity is associated with an increased risk of infection, as well as a greater chance for hospitalization and severe complications. Studies in mouse models of obesity have uncovered that obese hosts suffer increased viral spread, delayed viral clearance and heightened damage to the respiratory epithelium. Innate and adaptive immune responses are delayed, thus increasing morbidity and mortality. Further, infection control measures, including vaccination and antivirals, prove less effective in obese hosts. Finally, the obese microenvironment allows for increased duration and amount of viral shedding and potentially increases the chance for emergence of virulent minor variants in the viral population. Together, obese hosts are at high risk of influenza infection, as well as severe sequelae following infection. CONCLUSION:Obese travellers should be aware of influenza activity in the regions visited, as well as take protective measures prior to travel. Vaccination is highly recommended for all travellers, but especially highly susceptible obese travellers.
10.1093/jtm/taz020
Obesity Outweighs Protection Conferred by Adjuvanted Influenza Vaccination.
Karlsson Erik A,Hertz Tomer,Johnson Cydney,Mehle Andrew,Krammer Florian,Schultz-Cherry Stacey
mBio
UNLABELLED:Obesity is a risk factor for developing severe influenza virus infection, making vaccination of utmost importance for this high-risk population. However, vaccinated obese animals and adults have decreased neutralizing antibody responses. In these studies, we tested the hypothesis that the addition of either alum or a squalene-based adjuvant (AS03) to an influenza vaccine would improve neutralizing antibody responses and protect obese mice from challenge. Our studies demonstrate that adjuvanted vaccine does increase both neutralizing and nonneutralizing antibody levels compared to vaccine alone. Although obese mice mount significantly decreased virus-specific antibody responses, both the breadth and the magnitude of the responses against hemagglutinin (HA) and neuraminidase (NA) are decreased compared to the responses in lean mice. Importantly, even with a greater than fourfold increase in neutralizing antibody levels, obese mice are not protected against influenza virus challenge and viral loads remain elevated in the respiratory tract. Increasing the antigen dose affords no added protection, and a decreasing viral dose did not fully mitigate the increased mortality seen in obese mice. Overall, these studies highlight that, while the use of an adjuvant does improve seroconversion, vaccination does not fully protect obese mice from influenza virus challenge, possibly due to the increased sensitivity of obese animals to infection. Given the continued increase in the global obesity epidemic, our findings have important implications for public health. IMPORTANCE:Vaccination is the most effective strategy for preventing influenza virus infection and is a key component for pandemic preparedness. However, vaccines may fail to provide optimal protection in high-risk groups, including overweight and obese individuals. Given the worldwide obesity epidemic, it is imperative that we understand and improve vaccine efficacy. No work to date has investigated whether adjuvants increase the protective capacity of influenza vaccines in the obese host. In these studies, we show that adjuvants increased the neutralizing and nonneutralizing antibody responses during vaccination of lean and obese mice to levels considered "protective," and yet, obese mice still succumbed to infection. This vulnerability is likely due to a combination of factors, including the increased susceptibility of obese animals to develop severe and even lethal disease when infected with very low viral titers. Our studies highlight the critical public health need to translate these findings and better understand vaccination in this increasing population.
10.1128/mBio.01144-16
Epidemiology of severe influenza outcomes among adult patients with obesity in Detroit, Michigan, 2011.
Martin Emily T,Archer Carolyn,McRoberts John,Kulik Janice,Thurston Taylor,Lephart Paul,Kaye Keith S
Influenza and other respiratory viruses
We conducted a retrospective cohort study to evaluate the impact of obesity on influenza disease severity. Individuals with obesity were more likely to have lower pulmonary disease manifestations [OR=1·97 (95% CI 1·05, 3·69), P=0·03] and to be admitted to an inpatient ward [OR=2·93 (95% CI 1·50, 5·71), P=0·002] when compared with non-obese individuals. Among admitted individuals, persons with obesity were more likely to require a lengthy hospital stay [OR=3·86 (95% CI 1·03, 14·42), P=0·045]. Five of the six deaths in study subjects occurred in persons with obesity.
10.1111/irv.12115
Obesity as a risk factor for severe influenza-like illness.
Influenza and other respiratory viruses
BACKGROUND:Obesity was recognized as in independent risk factor for influenza during the 2009 H1N1 influenza pandemic. OBJECTIVES:We evaluated the association between body mass index (BMI) and influenza-like illness (ILI) during two non-pandemic influenza seasons (2003-2004 and 2004-2005) and during the spring and fall waves of the 2009 H1N1 pandemic. METHODS:Adults with severe (inpatient) and mild (outpatient) ILI were compared to those without ILI using a case-cohort design. The study was nested among those insured by a single health insurance company, receiving care from a large multispecialty practice. Data were collected from insurance claims and the electronic health record. The primary exposure was obesity (BMI ≥ 30·0 kg/m(2) ). RESULTS:Across three seasons, the crude and adjusted ORs for obesity and severe ILI were 1·65 (95% CI 1·31, 2·08) and 1·23 (95% CI 0·97, 1·57), respectively. An association was observed for those aged 20-59 years (adjusted OR 1·92, 95% CI 1·26, 2·90), but not for those 60 and older (adjusted OR 1·08, 95% CI 0·80, 1·46). The adjusted ORs for obesity and severe ILI in 2003-2004, 2004-2005, and during H1N1 were 1·14 (95% CI 0·80, 1·64), 1·24 (95% CI 0·86, 1·79), and 1·76 (95% CI 0·91, 3·42), respectively. Among those with a Charlson Comorbidity Index score of zero, the adjusted ORs for 2003-2004, 2004-2005, and H1N1 were 1·60 (95% CI 0·93, 2·76), 1·43 (95% CI 0·80, 2·56), and 1·90 (95% CI 0·68, 5·27), respectively. CONCLUSIONS:Our results suggest a small to moderate association between obesity and hospitalized ILI among adults.
10.1111/irv.12156
Effect of adenovirus and influenza virus infection on obesity.
Hur Sun Jin,Kim Doo Hwan,Chun Se Chul,Lee Si Kyung
Life sciences
The purpose of this review is to provide an overview of the effects of adenovirus and influenza virus infections on obesity in various experimental models. We reviewed studies that were conducted within the past 10 years and were related to virus infection and obesity prevalence. Here, we discuss a different causal relationship between adenovirus and influenza infections with obesity. Adenovirus infection can cause obesity, whereas obesity can be a risk factor for increasing influenza virus infection and increases the risk of morbidity and mortality. The prevalence of obesity due to adenovirus infections may be due to an increase in glucose uptake and reduction in lipolysis caused by an increase in corticosterone secretion. Adenovirus infections may lead to increases in appetite by decreasing norepinephrine and leptin levels and also cause immune dysfunction. The relationship between obesity and influenza virus infection could be summarized by the following features: decreases in memory T-cell functionality and interferon (IFN)-α, IFN-β, and IFN-γ mRNA expression, increases in viral titer and infiltration, and impaired dendritic cell function in obese individuals. Moreover, leptin resistance may play an important role in increasing influenza virus infections in obese individuals. In conclusion, prevention of adenovirus infections could be a good approach for reducing obesity prevalence, and prevention of obesity could reduce influenza virus infections from the point of view of viral infections and obesity.
10.1016/j.lfs.2013.08.016
Relationship between community prevalence of obesity and associated behavioral factors and community rates of influenza-related hospitalizations in the United States.
Charland Katia M,Buckeridge David L,Hoen Anne G,Berry Jay G,Elixhauser Anne,Melton Forrest,Brownstein John S
Influenza and other respiratory viruses
BACKGROUND:Findings from studies examining the association between obesity and acute respiratory infection are inconsistent. Few studies have assessed the relationship between obesity-related behavioral factors, such as diet and exercise, and risk of acute respiratory infection. OBJECTIVE:To determine whether community prevalence of obesity, low fruit/vegetable consumption, and physical inactivity are associated with influenza-related hospitalization rates. METHODS:Using data from 274 US counties, from 2002 to 2008, we regressed county influenza-related hospitalization rates on county prevalence of obesity (BMI ≥ 30), low fruit/vegetable consumption (<5 servings/day), and physical inactivity (<30 minutes/month recreational exercise), while adjusting for community-level confounders such as insurance coverage and the number of primary care physicians per 100,000 population. RESULTS:A 5% increase in obesity prevalence was associated with a 12% increase in influenza-related hospitalization rates [adjusted rate ratio (ARR) 1.12, 95% confidence interval (CI) 1.07, 1.17]. Similarly, a 5% increase in the prevalence of low fruit/vegetable consumption and physical inactivity was associated with an increase of 12% (ARR 1.12, 95% CI 1.08, 1.17) and 11% (ARR 1.11, 95% CI 1.07, 1.16), respectively. When all three variables were included in the same model, a 5% increase in prevalence of obesity, low fruit/vegetable consumption, and physical inactivity was associated with 6%, 8%, and 7% increases in influenza-related hospitalization rates, respectively. CONCLUSIONS:Communities with a greater prevalence of obesity were more likely to have high influenza-related hospitalization rates. Similarly, less physically active populations, with lower fruit/vegetable consumption, tended to have higher influenza-related hospitalization rates, even after accounting for obesity.
10.1111/irv.12019
Obesity Increases the Duration of Influenza A Virus Shedding in Adults.
Maier Hannah E,Lopez Roger,Sanchez Nery,Ng Sophia,Gresh Lionel,Ojeda Sergio,Burger-Calderon Raquel,Kuan Guillermina,Harris Eva,Balmaseda Angel,Gordon Aubree
The Journal of infectious diseases
Epidemiologic studies indicate that obesity increases the risk of severe complications and death from influenza virus infections, especially in elderly individuals. This work investigates the effect of obesity on the duration of viral shedding within household transmission studies in Managua, Nicaragua, over 3 seasons (2015-2017). Symptomatic obese adults were shown to shed influenza A virus 42% longer than nonobese adults (adjusted event time ratio [ETR], 1.42; 95% confidence interval [CI], 1.06-1.89); no association was observed with influenza B virus shedding duration. Even among paucisymptomatic and asymptomatic adults, obesity increased the influenza A shedding duration by 104% (adjusted ETR, 2.04; 95% CI, 1.35-3.09). These findings suggest that obesity may play an important role in influenza transmission.
10.1093/infdis/jiy370
Immunity to influenza: Impact of obesity.
Rojas-Osornio Sandra Angélica,Cruz-Hernández Teresita Rocío,Drago-Serrano Maria Elisa,Campos-Rodríguez Rafael
Obesity research & clinical practice
Obesity is a health concern that is recognized as a critical factor for vulnerability to influenza A/pdmH1N1 virus infection, with epidemiological and clinical impacts. In humans, obesity induces disturbances in inflammatory and immune responses to the influenza virus and in some cases, this leads to severe complications, with fatal outcomes. Obesity impairs immunity by altering the response of cytokines, resulting in a decrease in the cytotoxic cell response of immunocompetent cells which have a key anti-viral role. Additionally, obesity seems to disturb the balance of endocrine hormones, such as leptin, that affect the interplay between metabolic and immune systems. This contribution focuses on reviewing the current epidemiologic data for the immune response to immunity in obese humans and animal models. In doing so, we aim to provide potential mechanisms to enhance immunity to influenza A/pdmH1N1 virus infection and protective factors in obese people.
10.1016/j.orcp.2019.05.003
Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic.
Acta diabetologica
AIMS:Analyze the relationship between obesity and influenza. METHODS:Basal hormone milieu, defective response of both innate and adaptive immune system and sedentariness are major determinants in the severity of influenza viral infection in obese patients. Being overweight not only increases the risk of infection and of complications for the single obese person, but a large prevalence of obese individuals within the population might increase the chance of appearance of more virulent viral strain, prolongs the virus shedding throughout the total population and eventually might increase overall mortality rate of an influenza pandemic. RESULTS:Waiting for the development of a vaccination against COVID-19, isolation of positive cases and social distancing are the primary interventions. Nonetheless, evidence from previous influenza pandemics suggests the following interventions aimed at improving immune response: (1) lose weight with a mild caloric restriction; (2) include AMPK activators and PPAR gamma activators in the drug treatment for obesity associated with diabetes; and (3) practice mild-to-moderate physical exercise. CONCLUSIONS:Due to prolonged viral shedding, quarantine in obese subjects should likely be longer than normal weight individuals.
10.1007/s00592-020-01522-8
Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice.
Namkoong Ho,Ishii Makoto,Fujii Hideki,Asami Takahiro,Yagi Kazuma,Suzuki Shoji,Azekawa Shuhei,Tasaka Sadatomo,Hasegawa Naoki,Betsuyaku Tomoko
Biochemical and biophysical research communications
Increasing evidence indicates that obesity is a risk factor for increased severity of influenza virus infection. However, its precise immunological mechanism is not fully understood. To investigate this, diet-induced obese (DIO) mice were established by feeding C57BL/6 male mice a high-fat diet for 16 weeks. DIO and lean control mice were infected intranasally with 3000 pfu of influenza A virus (IAV) (PR8/H1N1). Interestingly, we found adipose tissue located along the bronchus in naïve DIO mice. In addition, the Nos2 level was significantly higher and Arg1 level was significantly lower in lung macrophages of naïve DIO mice, consistent with an M1-skewed phenotype. The survival rate and body weight of DIO mice infected with IAV were significantly lower than those of lean control mice and associated with higher viral load in the lungs of DIO mice. Histopathological analysis demonstrated higher numbers of inflammatory cells in the lungs of DIO mice after IAV infection. Levels of cytokines, including TNF-α, IL-6, IL-10, and type I IFN (IFN-α and IFN-β), in bronchoalveolar lavage fluid (BALF) were altered after IAV infection; in particular, IFN-α and IFN-β levels were significantly suppressed in the BALF of DIO mice. In vitro, bone marrow-derived macrophages were stimulated with ligands of toll-like receptor (TLR) 7/8, a pattern recognition receptor for single-stranded RNA, and levels of TNF-α, IL-6, and IL-10 were similarly altered. In addition, levels of IFN-α and IFN-β were significantly lower in culture supernatants of alveolar macrophages sorted from naïve DIO mice and infected with IAV, compared to those in macrophages sorted from lean control mice. Collectively, these results suggest that macrophages may be the main contributors to poor outcomes of influenza virus infection in obesity.
10.1016/j.bbrc.2019.03.211
Targeting acute kidney injury in COVID-19.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in >21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid-base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia-reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.
10.1093/ndt/gfaa231
Thrombosis in COVID-19.
American journal of hematology
Thrombotic complications are frequent in COVID-19 and contribute significantly to mortality and morbidity. We review several mechanisms of hypercoagulability in sepsis that may be upregulated in COVID-19. These include immune-mediated thrombotic mechanisms, complement activation, macrophage activation syndrome, antiphospholipid antibody syndrome, hyperferritinemia, and renin-angiotensin system dysregulation. We highlight biomarkers within each pathway with potential prognostic value in COVID-19. Lastly, recent observational studies have evaluated a role for the expanded use of therapeutic anticoagulation in COVID-19. We review strengths and weaknesses of these studies, and we also discuss the hypothetical benefit and anticipated challenges of fibrinolytic therapy in COVID-19.
10.1002/ajh.25982
Microvascular dysfunction in COVID-19: the MYSTIC study.
Angiogenesis
RATIONALE:Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. OBJECTIVES:To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. METHODS:Hospitalized adult patients with moderate-to-severe or critical COVID-19 (n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity (V), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS:COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4-6 µm), and also significant reductions of V. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. CONCLUSIONS:Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.
10.1007/s10456-020-09753-7