The main underlying causes of obesity are increased caloric intake (versus expenditure), a myriad of genetic factors, and exposure to an increasingly obesogenic environment (e.g., sedentary lifestyle).86,87 The rates of obesity have risen to epidemic proportion worldwide. According to the WHO, in 2008, at least 1·5 billion adults were overweight [body mass index (BMI) ≥25 kg/m2], with 400 million of these individuals being obese (BMI ≥ 30 kg/m2).88 In the US alone, two of every three persons (∼68% of the population) are estimated to be overweight or obese.89
Clinical outcome of A(H1N1)pdm09 virus 2009 in obese individuals
Epidemiologic data have identified obesity as a risk factor for severe morbidity and increased mortality from infection with A(H1N1)pdm09 virus influenza.90,91 Obesity was one of the most commonly reported comorbidities in patients admitted to intensive care units worldwide.92,93 Previously, neither obesity nor morbid obesity was described as a risk factor for severe infection with seasonal influenza in humans, suggesting that obesity-related severity may be associated with certain influenza strains or that levels of obesity have reached a point of ‘critical mass’ and can significantly affect the extent of influenza illness.
Within the first 4 months of the A(H1N1)pdm09 virus pandemic, morbid obesity in adults was reported to be significantly associated with increased risk of hospitalization from A(H1N1)pdm09 virus infection (odds ratio [OR] = 4·9, 95% CI: 2·4–9·9) even while excluding chronic medical conditions commonly associated with obesity (OR = 4·7, 95% CI: 1·3–17·2).94 In California alone, 62% of A(H1N1)pdm09 virus patients had a BMI ≥ 30 kg/m2, 30% of whom had a BMI ≥ 40 kg/m2.95 Obesity was also reported to increase the severity of infection and intensive care requirement. In Michigan, nine of 10 severely ill patients requiring intensive care had a BMI ≥ 30 kg/m2, seven of whom had a BMI ≥ 40 kg/m2.96 Data from other states show that 74% of patients in Utah and 48% of patients at the Mayo Clinic in Minnesota had a BMI ≥ 30 kg/m2.97,98 In New York City, 58·1% of patients who died from A(H1N1)pdm09 virus between April and July 2009 were obese or extremely obese.99
The association between increased BMI and severity of A(H1N1)pdm09 virus has also been reported in other parts of the world.92 A significant number of patients admitted to the intensive care unit (ICU) in Mexico,27 Canada,100 France,101 Romania,102 Spain,103 Italy,104 China,105,106 India,107 the United Kingdom,108 and Turkey109 had a BMI ≥ 30 kg/m2. In the Southern Hemisphere, 28·5%–44% of patients admitted to ICUs were obese110; obesity was identified in patient populations in Chile,111 New Zealand,112 Australia,113 and South Africa.114
The mortality rates in A(H1N1)pdm09 virus-infected, obese individuals vary by geographical region, but diabetes and a BMI ≥ 30 kg/m2 were the most frequent underlying conditions in patients older than 20 years who died from A(H1N1)pdm09 virus infection.115 A study in California suggested that obese persons were more likely to die when hospitalized with A(H1N1)pdm09 virus and extreme obesity (BMI ≥ 40 kg/m2). In the Southern Hemisphere, 14·5%–21·9% of persons who died from influenza-like illness were obese, and this number rose to 57·2% in morbidly obese patients.110 Fatalities from influenza infection in obese persons have been reported in France,116 Turkey,117 United Kingdom,108,118 and China.105 However, not all studies have found associations between obesity and A(H1N1)pdm09 virus-related mortality. In Mexico and Canada, mortality rates for obese and non-obese patients were similar.27,100 Overall, these results indicate that obesity is a significant risk factor for increased mortality from A(H1N1)pdm09 virus infection.
Although obesity does appear to be a major risk factor for morbidity and mortality from A(H1N1)pdm09 virus, there are several reasons why data may vary geographically. Temporally, many of these studies do not encompass the entire infection period, which could affect the numbers of individuals admitted to the hospital or reported cases. Geographically, although obesity is a global problem, rates of obesity vary among countries, leading to changes in size of the at-risk population and differences in infection prevalence. Also, these numbers reflect only those individuals who sought medical attention for severe illness; the real number of infections in healthy and overweight or obese individuals is unknown, as many individuals with mild illness may not have opted to see a physician. Finally, these studies look at A(H1N1)pdm09 virus infection in adult populations only. Although there may be a possible association between A(H1N1)pdm09 virus-related illness and obesity in pediatric patients, there is not yet enough data available to make a significant correlation.119,120 Also, as no standard definition of childhood obesity is used worldwide, it is unclear whether the same definition applies universally.
Obesity is also associated with decreases in lung function as well as the development of chronic respiratory conditions both of which can be risk factors for developing severe influenza infection.121–124 Recent epidemiologic studies have suggested a relationship between asthma and obesity. Although the exact nature of this association has not been fully elucidated, epidemiologic data suggest that the prevalence and severity of asthma may be increased in obese people and that the effectiveness of drugs normally used in treatment might be less effective. These changes may occur because of the systemic, chronic, low-grade inflammation, and oxidative stress associated with the obesogenic state.125–129
Diabetes is also significantly associated with severe A(H1N1)pdm09 virus influenza infection. A study showed that diabetes tripled the risk of hospitalization from A(H1N1)pdm09 virus and quadrupled the risk of ICU admission once hospitalized.130,131 The global prevalence of diabetes in 2010 was 6·4%, a significant increase from 4% in 1995. This prevalence is projected to increase to approximately 7·7% of the world population by 2030. The close association between obesity and diabetes, famously coined ‘diabetsity,’ has been known for a number of years.132,133 Indeed, individuals with a BMI ≥ 30 kg/m2 have a 60- to 80-fold increased risk of developing T2D 53). The association of obesity with the development of asthma and diabetes could contribute to the increased risk of severe A(H1N1)pdm09 virus influenza infection. In summary, further studies are needed to understand whether obesity and/or one of its commonly associated comorbidities are responsible for the increased severity of influenza virus infection, and whether modifications in vaccine or therapeutic management are required in light of these newly identified comorbidities in obese populations.
Prophylaxis and treatment of A(H1N1)pdm09 virus infection in obese patients
Obesity and increased BMI are associated with decreased antibody titers or non-response to vaccination for both hepatitis B and tetanus vaccines in children and adults.134–137 More recently, this decreased antibody response to hepatitis B has also been shown in genetically obese rodents.138 The reduction in vaccine response in obese individuals may help explain the significant increase in obese patients admitted with severe A(H1N1)pdm09 virus infection. Although further studies are needed to understand the efficacy of influenza vaccination in an increasingly obese population, a recent study demonstrated that a higher BMI was associated with a greater decline in influenza antibody titers and decreased CD8+ T-cell activation as compared with healthy weight individuals.139 These results suggest obesity may impair the ability to mount a protective immune response to influenza virus.
In terms of antiviral therapy, there have not been many studies on the efficacy of these antivirals in an obese population. Ariano et al.140 recently showed that there are no significant differences in oseltamivir pharmacokinetics in obese and non-obese patients. Studies by our group have also shown that oseltamivir treatment protects against severe A(H1N1)pdm09 virus in obese mice.141 Overall, these results suggest that antiviral treatment could be a good option for treating A(H1N1)pdm09 virus infection in an obese population if started within the first few days of infection.
Mechanisms for increased disease severity in obese patients
Like pregnancy, obesity is associated with significant changes in respiratory physiology and lung function including mechanical changes, reduced lung volumes, and increased respiratory rates (reviewed in.124,142 However, we will focus our review on changes to the immune response. Obesity can be considered an immunocompromised state, and the consequences of the obesogenic state on the response to infectious diseases have been reviewed elsewhere.137 Although the exact mechanism for altered immune cell functionality in obese individuals has not yet been elucidated, several studies have shown altered immune responses in obesity models. In terms of the innate immune system, diet-induced obese (DIO) mice have reduced antiviral cytokine expression, and both genetic and DIO rodent models have decreased natural killer (NK) cell activation and cytotoxicity, reduced macrophage functionality, and decreased numbers of dendritic cells (DCs) with impaired antigen presentation.16,18,143–147 In terms of the adaptive immune response, obesity has been shown to alter numbers of circulating T-cell subsets and decrease T-cell functionality, especially CD8+ T-cell subsets, in both human and animal models.15,148–151
One possible mechanism by which obesity could result in both an inflammatory and immunocompromised state is via the overexpression of adipokines. Obesity results from the overaccumulation of white adipose tissue (WAT) within the body. Research in the past two decades has shown that WAT is not only a storage depot for fats within the body but can also act as an endocrine organ, secreting numerous factors that affect several metabolic pathways. These adipokines participate in a wide variety of physiologic and/or physiopathologic pathways such as food intake, insulin sensitivity, and inflammation. In addition, many adipokines play an intricate role in various aspects of the innate and adaptive immune response.152–156 The secretion of adipokines is directly correlated with adipose tissue mass, and the overaccumulation of WAT in obese individuals has been hypothesized to result in a low-grade, chronic inflammatory state. Obese individuals have increased expression of interleukin (IL)-6, tumor necrosis factor-α, and C-reactive protein (CRP).157–160
Leptin is an adipokine linked to obesity that has been implicated in immune functionality. Leptin, a 16-kDa peptide derived mainly from adipocytes, functions primarily in the hypothalamus as an anorexigenic signal to decrease food intake and increase energy expenditure.161 Leptin mediates its effects through receptors that signal through the Jak-STAT pathway, and leptin receptors are present in human circulating CD4+ and CD8+ T lymphocytes as well as many other cells of the immune system.162 In terms of influenza infection, leptin induces an acute-phase shift toward a Th1 cytokine-production profile,163,164 which is necessary for recovery from influenza infection. The few reported human patients with leptin deficiency have reduced numbers of circulating CD4 T cells and impaired T-cell proliferation and cytokine release, all of which can be reversed by recombinant human leptin administration.165,166 It is unclear whether obesity-associated ‘leptin resistance,’ which is more common than genetic leptin deficiency in adult obesity, is also associated with the same extent of changes in immune cells and cytokines. Although these studies are still in their infancy, it is apparent that the changes in circulating factors in the obese state could affect the ability to respond to influenza infection.