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.
Obesity is a risk factor for severe disease and mortality for both influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While previous studies show that individuals ...with obesity generate antibody responses following influenza vaccination, infection rates within the obese group were twice as high as those in the healthy-weight group. The repertoire of antibodies raised against influenza viruses following previous vaccinations and/or natural exposures is referred to here as baseline immune history (BIH). To investigate the hypothesis that obesity impacts immune memory to infections and vaccines, we profiled the BIH of obese and healthy-weight adults vaccinated with the 2010-2011 seasonal influenza vaccine in response to conformational and linear antigens. Despite the extensive heterogeneity of the BIH profiles in both groups, there were striking differences between obese and healthy subjects, especially with regard to A/H1N1 strains and the 2009 pandemic virus (Cal09). Individuals with obesity had lower IgG and IgA magnitude and breadth for a panel of A/H1N1 whole viruses and hemagglutinin proteins from 1933 to 2009 but increased IgG magnitude and breadth for linear peptides from the Cal09 H1 and N1 proteins. Age was also associated with A/H1N1 BIH, with young individuals with obesity being more likely to have reduced A/H1N1 BIH. We found that individuals with low IgG BIH had significantly lower neutralizing antibody titers than individuals with high IgG BIH. Taken together, our findings suggest that increased susceptibility of obese participants to influenza infection may be mediated in part by obesity-associated differences in the memory B-cell repertoire, which cannot be ameliorated by current seasonal vaccination regimens. Overall, these data have vital implications for the next generation of influenza virus and SARS-CoV-2 vaccines.
Obesity is associated with increased morbidity and mortality from influenza and SARS-CoV-2 infection. While vaccination is the most effective strategy for preventing influenza virus infection, our previous studies showed that influenza vaccines fail to provide optimal protection in obese individuals despite reaching canonical correlates of protection. Here, we show that obesity may impair immune history in humans and cannot be overcome by seasonal vaccination, especially in younger individuals with decreased lifetime exposure to infections and seasonal vaccines. Low baseline immune history is associated with decreased protective antibody responses. Obesity potentially handicaps overall responses to vaccination, biasing it toward responses to linear epitopes, which may reduce protective capacity. Taken together, our data suggest that young obese individuals are at an increased risk of reduced protection by vaccination, likely due to altered immune history biased toward nonprotective antibody responses. Given the worldwide obesity epidemic coupled with seasonal respiratory virus infections and the inevitable next pandemic, it is imperative that we understand and improve vaccine efficacy in this high-risk population. The design, development, and usage of vaccines for and in obese individuals may need critical evaluation, and immune history should be considered an alternate correlate of protection in future vaccine clinical trials.
A personal physician and enhanced access to care are principles of the patient-centered medical home. Despite the importance of these concepts, measuring and improving interpersonal continuity of ...care and access to care in academic family medicine centers has received little attention. The authors describe their program's methods and results to maximize continuity of care and minimize delays for care using proven principles from improvement science.
In 2004, a diverse quality improvement team from our family medicine center joined a breakthrough collaborative with other primary care practices focused on improving appointment access and continuity of care. We followed the model for improvement with a specific aim, explicit measures, and ambitious goals. The team adapted and applied principles from a change package presented in the collaborative to improve access and continuity. We planned and performed small tests of change that were subsequently optimized and spread to the entire practice.
Average time to third available appointment for a routine physical improved from 22 days to 8 days. Average usual provider continuity (UPC) across all primary care physicians in the practice improved from 54% to 68%. Among resident physicians, UPC improved from 55% to 68%. These results have been sustained over 5 years.
Despite multiple challenges in academic teaching practices, the continuous use of improvement methods to apply proven change concepts minimizes delay for care and maximizes continuity of care. The residency continuity practice can and should be a cornerstone of residency curriculum.
Abstract
Obesity is a risk factor of severe disease and mortality for both influenza and SARS-CoV-2. While previous studies show that obese individuals generate antibody responses following influenza ...vaccination, infection rates within the obese group were twice as high compared to the healthy-weight group. To investigate the hypothesis that obesity impacts immune memory to infections and vaccines, we profiled the baseline immune history of obese and healthy-weight adults vaccinated with 2010–11 seasonal influenza vaccine to influenza antigens. Despite extensive heterogeneity in baseline immune history profiles in both groups, there were striking differences between obese and healthy controls, especially towards A/H1N1 strains and the 2009 pandemic virus (Cal09). Individuals with obesity had lower IgG and IgA magnitude and breadth towards a panel of A/H1N1 whole viruses and hemagglutinin proteins from 1933–2009, but increased IgG magnitude and breadth towards linear peptides from the Cal09 H1 and N1 proteins. Age was also associated with A/H1N1 baseline immune history, with young individuals with obesity more likely to have reduced A/H1N1 baseline immune history. We further found that IgG baseline immune history was associated with baseline and post-vaccination protective antibody responses, as measured by micro-neutralization and hemagglutinin inhibition assays. Taken together our findings suggest that increased susceptibility of obese subjects to influenza infection may be in-part mediated by obesity-associated differences in the memory antibody repertoire, which cannot be ameliorated by seasonal vaccination. Overall, these data have vital implications for the next generation of influenza and SARS-CoV-2 vaccines.
Abstract only
We have previously shown that obesity impairs expression of CD4
+
and CD8
+
T cell markers of activation and function. Obesity is associated with type II diabetes; however, not all ...obese individuals develop type II diabetes. Type II diabetes is associated with low levels of chronic inflammation and a higher prevalence of infections. The objective of our study was to elucidate the differences in the human cellular immune response between obese individuals with type II diabetes and obese individuals without type II diabetes. We stimulated peripheral blood mononuclear cells, obtained from obese individuals with and without type II diabetes,
ex vivo
with live pandemic influenza virus A and anti‐CD3/anti‐CD28 beads. Markers of activation, function, and signaling were measured using flow cytometry. We also measured three parameters of cellular glycolysis, including glycolytic rate, glycolytic capacity, and glycolytic reserve capacity, in T cells stimulated with or without anti‐CD3/anti‐CD28 bead stimulation and with or without insulin stimulation. We found significant differences between obese individuals with and without type II diabetes, demonstrating that metabolic disruptions in insulin signaling further increase immune dysfunction in obese adults.
Grant Funding Source
: NIH ROI
AI078090
and P30DK056350
The association between hyperinsulinemia and atherogenic risk factors has not been well studied in blacks and may be different for obese versus lean individuals. To investigate this possibility and ...to confirm the associations of hyperinsulinemia with cardiovascular disease risk factors in blacks and whites, we analyzed the joint associations of fasting serum insulin and obesity with risk factors in the Atherosclerosis Risk in Communities (ARIC) Study (1,293 black men, 4,797 white men, 2,033 black women, and 5,445 white women). Insulin values ≥90th percentile (≥.21 μU/mL) constituted hyperinsulinemia; body mass index (BMI) values ≥27.3 kg/m
2 for women and ≥27.8 for men constituted obesity. Participants with hyperinsulinemia in all four race-sex groups had more atherogenic levels of most risk factors studied than those with normoinsulinemia. Among black men and women, mean levels of triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo) B, glucose, and fibrinogen (men only) were higher in hyperinsulinemic lean participants as compared with the normoinsulinemic obese group. Furthermore, most associations between insulin level and risk factors were stronger among lean versus obese subjects. For example, among lean black men, the difference in mean triglyceride concentration between those with hyperinsulinemia and those with normoinsulinemia was 147 − 99 = 48 mg/dL; among obese black men, the difference was 155 − 121 = 34 mg/dL (
P < .05 for the interaction). Generally, similar negative interactions between BMI and insulin concentration were also observed among whites. We conclude that the association between hyperinsulinemia and many atherogenic risk factors holds for both blacks and whites and is stronger among lean versus obese adults.
Background Allergic sensitization is an important risk factor for the development of atopic disease. The National Health and Nutrition Examination Survey (NHANES) 2005-2006 provides the most ...comprehensive information on IgE-mediated sensitization in the general US population. Objective We investigated clustering, sociodemographic, and regional patterns of allergic sensitization and examined risk factors associated with IgE-mediated sensitization. Methods Data for this cross-sectional analysis were obtained from NHANES 2005-2006. Participants aged 1 year or older (n = 9440) were tested for serum specific IgEs (sIgEs) to inhalant and food allergens; participants 6 years or older were tested for 19 sIgEs, and children aged 1 to 5 years were tested for 9 sIgEs. Serum samples were analyzed by using the ImmunoCAP System. Information on demographics and participants' characteristics was collected by means of questionnaire. Results Of the study population aged 6 years and older, 44.6% had detectable sIgEs, whereas 36.2% of children aged 1 to 5 years were sensitized to 1 or more allergens. Allergen-specific IgEs clustered into 7 groups that might have largely reflected biological cross-reactivity. Although sensitization to individual allergens and allergen types showed regional variation, the overall prevalence of sensitization did not differ across census regions, except in early childhood. In multivariate modeling young age, male sex, non-Hispanic black race/ethnicity, geographic location (census region), and reported pet avoidance measures were most consistently associated with IgE-mediated sensitization. Conclusions The overall prevalence of allergic sensitization does not vary across US census regions, except in early life, although allergen-specific sensitization differs based on sociodemographic and regional factors. Biological cross-reactivity might be an important but not the sole contributor to the clustering of allergen-specific IgEs.
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