Abstract
The prevalence of obesity has exponentially risen worldwide. The etiology of obesity is multifactorial, and genetic inheritance and behavioral/environmental causes are considered the main etiological factors. Moreover, evidence that specific infections might promote the development of obesity has steadily accumulated. Only a few works investigate the impact of obesity on the immune response to infections and the risk of infections in the obese population. The aim of this paper was to review the available data regarding the various aspects of the association between obesity and infections and to highlight the possibility that infectious agents may have an etiological role in obesity, an idea known as “infectobesity”. Several microbes have been considered as possible promoter of obesity, but most of the data concern adenovirus-36 that exerts an adipogenic action mainly via a direct effect on adipose tissue leading to weight gain, at least in animal models.
Obesity affects the immune response leading to an increased susceptibility to infections. Obese adults and children show an increased incidence of both nosocomial and community-acquired infections. Furthermore, obesity may alter the pharmacokinetics of antimicrobial drugs and impact on vaccine response. However, the various aspects of the association of obesity infections remain poorly studied, and a call to research is necessary to better investigate the problem.
In conclusion, obesity impacts millions globally, and greater understanding of its etiology and its effects on immunity, infections, and prevention and management strategies is a key public health concern.
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Introduction
Overweight and obesity are a major public health concern both in adults and in children. In 1997, the World Health Organization has declared obesity a global epidemic [84], and the Healthy People 2010 has identified overweight and obesity an indicator of the health of a given population [30]. The prevalence of obesity in children and adolescents has increased over several decades in many industrialized countries although in the most recent years, it seems to have reached a plateau [60]. It affects about 17 % of children and adolescents aged 2–19 years in the US [59] and about 8 % and 12 % of school-age children in Europe and in Italy, respectively [10, 77]. The etiology of obesity is multifactorial, and genetic inheritance and behavioral/environmental causes are considered the most important factors leading to fat accumulation in children [49]. Twin studies have clearly demonstrated a genetic risk of obesity, and the discovery of leptin, ghrelin, adiponectin, and other hormones that influence appetite, satiety, and fat distribution provides insights into metabolic mechanisms for a physiologic risk. However, the exponential increase in the prevalence of childhood obesity in the past decades results from changes in eating and physical activity behaviors that have modified the balance between energy intake and energy expenditure although their influence is difficult to determine [5]. Moreover, in some cases, none of these factors is entirely sufficient to explain obesity [38]. An early identification of the obese population is crucial both to prevent and to detect comorbidities that compromise the quality of life and increase overall mortality [56] particularly as most cases remain obese into adult age [29]. Obese children are in fact a population at risk for developing metabolic, endocrine, gastroenterological, cardiovascular, respiratory, orthopedic, dermatological, neurological, and psychological complications. All of these complications, although not completely clarified, have been widely studied while few papers investigate the impact of obesity on the immune response to infections and the risk of infections in an overweight population. The aim of this review was to summarize the available evidence regarding the association between obesity and infections, including (1) obesity-related mechanisms that lead to predisposition to infections, (2) the epidemiology of nosocomial and community-acquired infections in the obese population, and the (3) management of infections in the obese adults and children. To do it, we searched PubMed, Cochrane, and EMBASE (January 1980–December 2012) to identify studies evaluating the various aspects of the association between obesity and infections. The search terms used included “obesity,” “infections” or “infectious diseases,” “immune system” or “immunity,” “children” (or “adolescents”), “adults,” “antimicrobial drugs” or “antibacterial drugs,” “vaccination” or “vaccine,” and “infectobesity”. These terms were combined in various ways to generate a wide search. In addition, we checked the references of eligible articles for further papers that were not captured by our search strategy and corresponded with authors when a full-length article was not available directly online or when relevant information was missing in the paper. We included only studies in English and both animal and human studies. We evaluated both children and adolescents studies and adults ones. Every type of study design was included.
Mechanisms that predispose obese patients to infection
Recent studies have demonstrated altered immune cell function in obese human subjects compared with those of healthy weight. Nieman et al. reported significant differences in leucocyte and lymphocyte subset counts and higher monocyte and granulocyte phagocytosis and oxidative burst activity in obese adult subjects [57]. Furthermore, obese patients show a proinflammatory state of circulating mononuclear cells compared with healthy-weight persons [27]. Additionally, obesity enhances thymic aging and reduces T cell repertoire diversity [85]. The reported findings suggest that obesity may result in an altered immune surveillance and in an impaired host defense. It is well known that obesity is associated with a state of chronic, low-grade inflammation both in white adipose tissue and at systemic level and that adipose tissue participates actively in inflammation and immunity [12, 22, 71]. Therefore, obesity is characterized by altered levels of circulating hormones and nutrients. Circulating immune cells and those resident in peripheral tissues are thus exposed to an energy-rich environment in the context of altered concentrations of metabolic factors and hormones [51]. The primary immunomodulatory adipokines include leptin, adiponectin, and the proinflammatory cytokines TNFα, IL-6, and IL-1β [22, 71]. Adiponectin, levels of which are decreased in obesity, is potently immunosuppressive [82]. In contrast, leptin plays a proinflammatory role. It induces polymorphonuclear neutrophils chemotaxis and reactive oxygen species generation [13, 52], up-regulates monocytes proinflammatory cytokine production and phagocytosis [42], and improves proliferation and cytotoxicity of natural killer cells [87]. Furthermore, leptin exerts an influence on the adaptive arm of the immune response, playing a key role in lymphopoiesis and myelopoiesis and representing a source of prosurvival signals to thymocytes during the maturation of T cells [14, 43]. Leptin induction seems to be a protective component of the immune response, and genetic leptin deficiency has been associated with increased mortality due to infections both in rodent models [48] and in humans [61]. The most used genetically altered obese animal models are the ob/ob and db/db mice lacking leptin and the leptin receptor, respectively. These mice show an increased susceptibility to bacterial and fungal infections although it is difficult to determine if the adiposity excess plays a direct or a secondary role on the immune responses [31, 32, 48, 65]. In humans, leptin-deficient children have normal weight at birth but then rapidly display hyperphagia and early-onset obesity in late infancy [23]. Along with obesity, the presence of immune dysfunction and the development of infections early in life are among the criteria to perform the genetic analysis. Farooqi et al. showed in three morbidly obese children, who were congenitally deficient in leptin, that the deficiency of the adipokine was associated with reduced numbers of circulating CD4+ T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration, opening new therapeutic perspectives and assuming new clinical applications [24]. However, these models do not completely fit non-genetically induced obesity, which constitutes the vast majority of human obesity. Moreover, many papers have considered the fact that obese individuals show hyperleptinemia and central and peripheral leptin resistance. Diet-induced obesity (DIO) mice more closely mimic human obesity. They show several forms of immunity impairment and a higher morbidity and mortality during viral infections although pathophysiological mechanisms have not yet been clarified [37, 68]. Even the use of DIO mice as experimental models presents critical issues as the greater susceptibility to infections can be related to the abundance of adipose tissue, the influence of the high-fat diet or both. Using both genetic obesity models and DIO mice could fill the gap in the knowledge of the impact of fat excess and diet on the immune response.
Obesity is also characterized by metabolic alterations, and hyperinsulinemia and insulin resistance are common features even in obese children [66]. Some cells involved in the immune response, such as monocytes [72], express the insulin receptor while in other cells, such as T cells, the expression of this receptor may be induced by a polyclonal stimulator or a specific antigen [75]. Insulin can modulate T cell activation and function, promoting an anti-inflammatory T helper type 2 cell phenotype [75]. On the other hand, insulin resistance has been related to a proinflammatory T helper type 1 cell response [47]. Although it is clear that insulin can exert several immunomodulatory effects, little is known about the consequences of excess insulin and insulin resistance on the immune system in the context of obesity. Glucose and fatty acids are important sources of energy for host defense and immune function, but elevated levels of these nutrients, as in the obese, have been demonstrated to alter the immune response. The exposition of T cells to high glucose concentrations causes the production of reactive oxygen species and lipid peroxidation [70] and, in mouse T-cells, overexpression of GLUT1 resulted in altered T cell metabolism and cytokine production [34]. Similarly, an excess of fatty acids may be a trigger both for innate and for adaptive immune response [78]. Obesity is thus characterized by complex metabolic and hormonal changes each of which interacts with the immune system; more studies are needed to better understand the consequences of obesity on the host response to infection.
Infections in clinical settings: studies in adults
Several studies reported that obesity increases susceptibility to infection in various clinical settings. Obese individuals show an increased incidence of both nosocomial and community-acquired infections. Most of the epidemiological data concern adult subjects. Obese patients show increased intensive care unit (ICU) length of stay and hospital mortality [8]. Obesity represents an independent risk factor for surgical site infections following various surgical procedures [76]. The increase of adipose tissue and of local tissue damage related to retraction, longer operative time, disturbance of body homeostatic balance, and other local changes may contribute to the increased incidence of surgical site infections. Moreover, obese patients show a relative hypoxia of subcutaneous tissue, and this may predispose to wound infections. Furthermore, obese subjects are more prone to experience prolonged hospitalizations due to a more difficult management, thus increasing their risk of acquiring a nosocomial infection [21].
Obesity can profoundly alter lung mechanics and enhances pulmonary inflammation which could potentially increase the risk for pneumonia or other lung infections [39]. Moreover, obesity is closely associated with obstructive sleep apnea syndrome (OSAS) that is associated with an increased risk for aspiration. In adult women, high body mass index (BMI) was shown to be associated with an increased risk of community-acquired pneumonia [21]. Several studies on the 2009 influenza A (H1N1) pandemic strain have demonstrated a worse outcome of infection in obese subjects that showed a greater number of hospitalizations, a longer duration of ICU admission and mechanical ventilation, and a higher rate of mortality compared with normal-weight patients [44]. Before the advent of the H1N1 pandemic, no study was published on the relationship between obesity and influenza infection in human subjects [51]. Kwong et al. demonstrated with a retrospective study that covered 12 influenza seasons that obese subjects present a greater risk for respiratory hospitalizations during the seasonal flu periods [41]. These data have a strong clinical impact, suggesting that obese individuals should be treated promptly and should undergo vaccination or antiviral therapy with priority during pandemics. Conversely, other studies have reported that obese individuals are not at greater risk for respiratory infections [17]. Therefore, our understanding of the effects of obesity on risk for pulmonary infection remains unclear, and more studies are needed.
Obesity increases risk of gastrointestinal complications such as non-alcoholic fatty liver disease (NAFLD). Several authors have demonstrated that obesity is a risk factor for the development of steatosis in patients with chronic hepatitis C infection, as BMI correlates with the grade of steatosis [86]. Steatosis can impact on the natural course of hepatitis C infection, being associated with fibrosis, reducing the response to antiviral treatment and contributing to the risk of hepatocellular carcinoma. Consequently, hepatitis C infection progresses more rapidly in obese compared with normal-weight patients.
Moreover, obese subjects are more prone to develop various skin infections such as intertrigo, candidiasis, furunculosis, erythrasma, tinea cruris, and folliculitis and to show rapidly progressive bacterial bone and joint infections [21].
Infections in clinical settings: pediatric studies
A few studies have investigated the risk of infections in obese children and adolescents. Indeed, with the regard to surgical site infections, children who undergo complicated surgeries such as children with congenital heart diseases, generally show a normal or a low weight. More data can be found about the incidence of respiratory tract infections in obese children. Even in childhood, obesity is associated with profound alterations of respiratory mechanics and physiology. Obesity represents one of the four clinical phenotypes associated with OSAS in children. The excess of body fat can lead to a reduction in upper airways caliber due to the mechanical effect on soft tissues, increased the airway collapsibility, reduced lung compliance, and increased respiratory work. Moreover, in obese children, higher body weight is associated with a decrease in nocturnal oxygen saturation [40], and they show an altered central response to hypoxia and hypercapnia [2]. Furthermore, leptin resistance seems to be associated to hypercapnia, and ob/ob mice show a suppressed respiratory response to this stimulus [33, 67]. OSAS and obesity, via neuroendocrine changes and oxidative stress, enhance inflammation and cytokine production and reduce nitric oxide production [9]. All these mechanisms may alter the response of the host to infectious agents causing an increased susceptibility of obese children to serious respiratory infections. Jedrychowski et al. have analyzed factors predisposing to recurrent acute respiratory infections in 1,129 9-year-old school children. Susceptibility to acute respiratory infections was significantly associated with BMI; overweight children (BMI ≥ 20 kg/m2) had twice the risk of infections compared with children with a lower BMI (OR 2 · 02, 95 % CI 1 · 13–3 · 59) [35]. Akiyama et al. showed in 243 children admitted for bronchitis, bronchiolitis, pneumonia, and those who were positive for a respiratory syncytial virus (RSV) infection that days of wheezing, days of fever, and days of drip infusion were positively associated with obesity ratio [1]. However, only these studies are available on a significant wide cohort of pediatric patients, and more data are needed to better understand the problem.
Obese subjects show the presence of specific bacteria in the oral flora since obesity is often related to increased sugar consumption and other comorbidities such as diabetes mellitus. This leads to the production of proinflammatory cytokines and reactive oxygen species and to oral inflammation and oxidative stress. It has been reported that obesity is a predisposing factor for periodontal disease, especially among children and adolescents [83]. Willershausen et al. showed in 842 elementary school children that 35.5 % of the pupils with normal weight had healthy teeth, whereas the number dropped to 27.5 % in children that were overweight and to 29.7 % in obese children. The caries prevalence also showed a significant association with weight [81]. Furthermore, Franchini et al. demonstrated that overweight/obese children (age 10–17 years) had a worse attitude towards oral hygiene. In fact, they revealed an effect of obesity status on the gingival index and gingivitis that was dependent on insulin resistance and poor oral hygiene rather than simply on the overweight/obese status. Authors also showed that in obese children, negative psychological features were also risk factors for gingivitis probably because they were related to a generic low self-esteem [25].
Moreover, obese children are at risk for developing severe skin infections as Staphylococcus aureus infections [18], and obesity is associated with dermatoses as skin tags, striae distensae, and plantar hyperkeratosis and with an altered epidermal permeability barrier status that can predispose to cutaneous infections [58].
In conclusion, the studies on the association between obesity and infection in children show that obese pediatric subjects are a population at risk for respiratory, odontogenic, and cutaneous infections. However, more studies are needed to explore this topic.
Management of infections and vaccination in obese patients
Despite the growing prevalence of obesity worldwide and the increased risk for several types of microbial infections, there are no well-defined guidelines about the management of infections in obese patients and a little is known about how obesity may alter the pharmacokinetics of antimicrobial drugs increasing distribution volume and alter the clearance. Studies assessing dosing of antibacterial drugs including vancomycin, aminoglycosides, cephalosporins, and linezolid showed that obese subjects may require different dosages and different dosing intervals compared with non-obese individuals [6, 7, 69]. Moreover, all these studies are performed in adult cohorts while there is no study on pediatric age also because the drugs doses are usually “per kilogram of body weight”.
Furthermore, there is some evidence that obese subjects may respond to vaccination less than normal-weight individuals. Obesity was associated with a poor antibody response to hepatitis B vaccination [79]. Eliakim et al. showed that anti-tetanus IgG antibodies were significantly lower in the overweight children compared to that of the normal weight controls. This reduced response to vaccinations in obese children and adolescent might be due to mechanical factors such as a lower relative vaccination dose, or reduced absorption from the injection site due to increased adipose tissue, or related to reduce immune response due to the chronic low-grade inflammation [19]. Interestingly, a recent study reported that using longer vaccine needles resulted in a higher antibody titers to hepatitis B surface antigen in obese adolescents [50]. Poor responses to vaccination and to antimicrobial drugs have important public health implications, and a careful consideration of infection prevention and treatment in obese subjects is required in the future.
Infectobesity
Evidence that specific infections might promote the development of obesity has steadily accumulated over the past 25 years [46]. Infectobesity, or obesity of infectious origin, creates new perspectives for prevention strategies and treatment options as pathogen-specific vaccines, the restriction of the spread of infection and antimicrobial therapies. Several microbes have been considered as possible promoter of obesity, but most of the data have been collected in studies concerning adenoviruses [20]. Human adenoviruses are a group of icosahedral, non-enveloped, double-stranded DNA viruses categorized into seven subgroups A to G according to their antigens. Human adenoviruses are implicated in infections of the upper respiratory and gastrointestinal tracts and in conjunctivitis [45]. Most adenovirus infections are acquired in childhood. Cidofovir is considered the drug of choice for the treatment of severe infections, but new drugs are under investigation. Moreover, vaccines effective in preventing AD-4 and AD-7 infections have been developed [45]. AD-36, a human adenovirus belonging to subgroup D, was the first human adipogenic virus reported. The virus was first isolated in the feces of a girl with enteritis and that suggests fecal–oral route of transmission [80]. The most important mechanism of the adipogenic action of AD-36 is a direct effect on adipose tissue [63]. In vivo and in vitro studies demonstrated that AD-36 upregulates the proliferation, adipogenic commitment, and differentiation of adult adipose tissue-derived stem cells and other adipogenic progenitors, leading to an increase in the number of fat cells [64]. Moreover, AD-36 infection seems to determine the early appearance of enzymes involved in lipid and glucose uptake, the accumulation of triglycerides and a reduction of leptin expression and secretion leading to an increase in appetite and a further increase in fat tissue [74]. Furthermore, AD-36 supports chronic inflammation inducing the macrophages infiltration into adipocytes [55]. Pasarica et al. demonstrated that AD-36 infection can determine alterations on the central nervous system (CNS), changing norepinephrine levels in the paraventricular nucleus and decreasing corticosterone secretion which plays a major role in fat metabolism [62]. A series of studies demonstrated that infection with AD-36 increases adiposity in various animal models [16, 36, 62, 77]. AD-36 infection significantly increases body weight, reduces serum total cholesterol and triglyceride concentrations, and determines a shift from high-density lipoprotein to low-density lipoprotein cholesterol [15, 36]. Dhurandhar et al. also showed the possibility of horizontal transmission of the infection. Additionally, they demonstrated that the transfusion of a small amount of blood from AD-36-infected animals to uninfected ones successfully transmitted infection, and the recipients subsequently became obese [16].
Human studies on the association between obesity and AD-36 infection reported discordant results (Table 1). The greatest differences can be found in adult data as some studies indicate a close relationship between serum AD-36 antibodies and BMI or weight gain while others do not confirm this association [3, 11, 28, 54, 73]. The strongest evidence of the adipogenic role of AD-36 in humans comes from a study that screened 90 sets of twins, 26 of them were discordant for AD-36 infection seropositivity. Atkinson et al. demonstrated that the AD-36-seropositive twin had a significantly higher BMI and more body fat than the seronegative sibling [3]. Similarly, discordant results have been reported on the effects of AD-36 infections on total cholesterol and triglyceride levels [3, 11, 28, 54, 73]. In comparison with adult studies, data regarding children are more consistent in establishing a positive correlation between obesity and AD-36 [4, 26, 53]. As Esposito et al. recently pointed out, various factors could explain these discordant results as the use of inappropriate methods of evaluating serum AD-36 antibodies and AD-36 DNA in fat tissue, the inclusion of some confounding factors as the time of infection, the viral load and the persistence of the virus in the body, the use of specific populations, and the age of the infected host [20].
The available data do not completely solve the problem of the possible role of AD-36 as a causative factor of obesity although it seems to be important at least in children. More well-designed longitudinal studies are needed to establish this association with hypotheses of important implications in terms of prevention and therapeutic options.
Conclusions
The best solution to improving health of obese individuals is the weight loss. However, the etiology of this complex disease is multifactorial, and a better definition of the various etiological factors would be essential to develop prevention and treatment strategies. The available data on the possible relationship between AD-36 infection and obesity do not completely solve the problem although AD-36 may be a contributing factor at least in some subjects, such as children.
Although obesity is a well-known risk factor for several morbid conditions, its relation to infections has not been adequately studied. The available evidence suggests that excess adiposity negatively impacts on immune function and host defense in obese individuals. Epidemiological data demonstrate that obese adults and children show an increased incidence of both nosocomial and community-acquired infections. Furthermore, rodent models offer important insights into how metabolic abnormalities associated with excess body weight can impair immunity. However, a call to research is necessary to investigate the specific aspects of immunity impaired in obesity and to better define the risk of specific type of infections.
Additionally, there are no well-defined guidelines about the management of infections in obese patients although some studies have shown that the excess of body fat may alter the pharmacokinetics of antimicrobial drugs. Furthermore, some findings show that obese subjects may respond to vaccination less than normal-weight individuals.
Obesity impacts millions globally, and greater understanding of its effects on immunity, infections, prevention and management strategies is a key public health concern that could likely save millions of lives.
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Genoni, G., Prodam, F., Marolda, A. et al. Obesity and infection: two sides of one coin. Eur J Pediatr 173, 25–32 (2014). https://doi.org/10.1007/s00431-013-2178-1
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DOI: https://doi.org/10.1007/s00431-013-2178-1