Adults with obesity are more susceptible to influenza A/H1N1pdm – the swine flu virus, according to a new study that did not, however, find a similar association with the seasonal flu.
The results could be relevant in understanding the mechanisms by which infectious diseases such as influenza or the ongoing coronavirus pandemic might affect different segments of the population, the researchers say.
“This research is important because obesity around the whole world is increasing rapidly. It’s approximately tripled since the ’70s,” said first author Hannah Maier, a postdoctoral fellow at the University of Michigan School of Public Health.
“We’re having a lot more obesity, right now we’re dealing with the pandemic, and it was just announced that there might be another potential swine flu pandemic. If obesity is associated with increased risk and there’s a lot more obesity, that could mean a lot more infections.”
Maier and colleagues looked at data from more than 1,500 individuals in 330 households enrolled in the Nicaraguan Household Transmission Study, an ongoing community-based study tracking the health of a community in Managua, Nicaragua. Study participants were followed 10 to 15 days and given swab tests and blood tests to confirm infection.
The study found that adults with obesity had twice the odds of symptomatic H1N1 infection compared to those without obesity.
The association was not seen with the H3N2 seasonal influenza strain.
While the mechanism linking obesity to increased disease severity is not yet known, chronic inflammation increases with age and is associated with chronic diseases. Separate studies have shown that obesity increases proinflammatory and decreases anti-inflammatory cytokine levels, the researchers say.
Obesity can also impair wound healing and lead to mechanical difficulties in breathing and increased oxygen requirements.
In 2009, a strain of flu affecting pigs jumped to humans. This virus, H1N1pdm, infected many people around the world.
Just this week, a new study states that a new strain of H1N1 in swine in China has the potential to become a pandemic, highlighting the importance of continuing this type of research even while facing the coronavirus pandemic, said senior author Aubree Gordon, an epidemiologist at U-M’s School of Public Health.
“This underscores that although we are in the middle of a pandemic, we cannot stop being vigilant for the emergence of other viruses, particularly influenza,” she said.
“In addition, this highlights that the U.S. needs to participate in the World Health Organization. The WHO influenza program provides a critical service to the world monitoring influenza circulation to make vaccine strain recommendations and surveilling for potential emergence of new influenza viruses.”
Obesity rates have nearly tripled worldwide since 1975. Approximately 1.9 billion people are overweight and over 650 million are obese, defined as having a body mass index (BMI) of 25 to 30 and >30, respectively, which translates to nearly 45% of adults worldwide (1, 2).
The obesity-induced inflammatory state has systemic implications for individual and global public health. It is a well-identified risk factor for increased mortality due to heightened rates of heart disease, certain cancers, and musculoskeletal disorders (3).
Overnutrition, as well as undernutrition, has been cited as an important factor in the body’s response to infection for centuries (4–6). More recently, the impact of obesity on communicable diseases has been appreciated.
During the 2009 influenza A virus (IAV) H1N1 pandemic, a plethora of epidemiologic studies revealed obesity to be an independent risk factor for severe disease (7, 8). In initial retrospective studies of laboratory-confirmed H1N1 cases after the 2009 pandemic, obesity was identified as a risk factor for hospitalization, the need for mechanical ventilation, and mortality upon infection (9–11).
Influenza is a potentially severe respiratory infection caused by the influenza virus. Most human cases are caused by H1N1 and H3N2 IAV strains (12, 13). Several case studies of severe and fatal IAV infections have identified possible effects of obesity on disease progression; these effects include extensive viral replication in the deep lung, progression to viral pneumonia, and prolonged and increased viral shedding (14–16).
However, these studies neglected to determine the causality between obesity and severe IAV pathogenesis. Studies in mouse models of obesity, including leptin-deficient (OB) and leptin-receptor-deficient (DB) genetically obese models as well as the high-fat diet-induced-obese (DIO) model (Table 1) have identified several immunological mechanisms for the increased pathogenesis and mortality that mirrors what has been seen in humans (26–29).
Advances in obese ferret models and human primary cell culture are enabling better translational studies of the mechanisms behind the increased disease severity, viral life cycle alterations, and evolutionary dynamics due to the obesogenic environment (30).
In this review, we analyze the current literature for information on the impact of obesity on influenza virus pathogenesis, the immune responses to the virus and the transmission dynamics of IAV including viral shedding and evolution.
Table 1
Description of commonly used mouse models of obesity.
| Model | ID | Genetics | Weighta | Diet and behavior | References |
|---|---|---|---|---|---|
| Genetic leptin knockout | OB | Most commonly on C57BL/6 background; spontaneous recessive, homozygous Lepob nonsense mutation | 45 g | Normal chow; hyperphagic due to loss of appetite control and satiety | (17, 18) |
| Genetic leptin receptor knockout | DB | Commonly on C57BL/Ks or C57BL/6J backgrounds; spontaneous mutant in Leprdb allele causing abnormal splicing | 40 g | Normal chow; hyperphagic due to loss of leptin receptor signal transduction | (19, 20) |
| Diet-induced | DIO | Any background, commonly C57BL/6J; some strains more susceptible than others | 35 g | High-fat diet; exhibits typical eating patterns | (21–25) |
| Control | LN/WT | Any matched genetic background | 25 g | Either low-fat diet (LN) or regular chow; diet choice may alter results | (21, 25) |
Pathogenesis and Resolution of IAV Infection
IAV infection is characterized by fever, myalgia, rhinorrhea, sore throat and sneezing. Symptoms peak 3–5 days post infection (p.i.), with viral shedding peaking at day 2–3 p.i. (31).
Most human IAV infections are limited to the upper respiratory tract, including the nasal, tracheal and often bronchial epithelium. In more severe cases, there is infection of the lower respiratory tract (LRT) including the lung occurs, often with severe sequelae requiring hospitalization (32).
Development of viral pneumonia and secondary bacterial infections can lead to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and eventual death (32). Progression of the infection to the LRT and severe sequelae are more common in the obese population, leading to poorer infection resolution and recovery than is seen in non-obese patients.
Lung Pathology and Infection Outcomes
After the 2009 H1N1 pandemic, retrospective studies across the globe found obesity to be comorbid with influenza in nearly one-third of hospitalized patients as well as in fatal cases (33–35).
In both pandemic and non-pandemic influenza seasons, obesity increased the risk of hospitalization for laboratory-confirmed IAV infection, with increasing BMI increasing the odds ratios (36, 37).
The susceptibility extended to heightened disease severity, with obese children and adults experiencing increased morbidity and mortality during LRT infections, including comorbid secondary infections and a risk of ARDS (38, 39).
Obesity was shown to increase both the length of stay in intensive care and the need for mechanical ventilation (40). Most strikingly, severe obesity resulted in a two-times greater risk of death upon IAV infection and hospitalization due to the infection, with moderate obesity also increasing the risks (41, 42).
In other high-risk populations such as pregnant and post-partum women, obesity further increased the risk of IAV infection (43).
Upon infection with IAV, the viral replication process as well as the pro-inflammatory, antiviral immune response, damages the respiratory epithelium and recovery requires proper clearance and remodeling of the damaged surfaces.
Increased lung damage, pulmonary edema, cellularity, inflammatory response, and immunopathology is evident in DIO and OB mice as compared to wild-type (WT) mice inoculated with IAV in both naïve and vaccine challenge experiments (26, 27, 44–48).
The few comparative studies for which no difference in lung pathology was reported used relatively high lethal doses, highlighting the importance of taking into account the viral stock preparation and the means of administration when comparing host responses and pathogenesis (49).
In severe cases, IAV infection can cause a break-down of the respiratory epithelium, leading to fluid influx to the airway space (32). Obese mice are more likely than are lean (LN) mice to have increased lung permeability during infection.
Using Evan’s blue dye, Karlsson et al. found that at day 7 p.i., OB mice showed a significantly greater increase in permeability when compared to LN mice (48). This finding was confirmed by the increased albumin levels in bronchoalveolar lavage fluid (BALF) at days 5–8 p.i., in both OB and DIO mice, showing that there is increased protein leakage from the lung into the BALF (27, 48, 50).
The increased lung permeability is coupled with an increase in lung edema and oxidative stress upon IAV infection, emphasizing the multiple etiologies of increased lung pathology in the obese host (27, 46, 49). Infection resolution requires the repair of the damaged epithelial surface, but OB and DIO hosts are impaired in wound repair (27).
Reduced cellular proliferation as determined through decreased KI-67 staining is evident in OB and DIO mouse lung sections at days 6 and 14 p.i, leaving the lung susceptible to secondary infections and eventual ARDS (27).
The heightened immunopathology and poor wound recovery in OB and DIO mice result in increased mortality. IAV strains H3N2 and H1N1 induce greater mortality in OB and DIO mice than in WT C57BL/6 mice, regardless of their respective vaccine histories (26, 27, 47, 50).
This is also true for a viral-bacterial co-infection model. DIO and OB mice inoculated with PR8 IAV, CA/09 IAV, seasonal H3N2 virus, or influenza B virus and challenged with Streptococcus pneumoniae at day 7 post influenza infection had increased mortality when compared to controls (48).
Viral Load and Spread in Respiratory Epithelia
The increased incidence of ALI and ARDS in hospitalized obese patients may be due to increased viral spread to the LRT and alveolar region, thus resulting in impaired lung function and gas exchange (38).
Limited case studies that list obesity as a comorbidity reference heightened viral replication and extensive hemorrhage in the alveoli leading to increased disease severity (16, 51).
Continued investigation using ex vivo human systems as well as following naturally occurring infections in cohorts of obese and lean patients can help determine how the data gleaned from mouse models translates to human infection, as well as how other comorbidities such as metabolic syndrome, chronic disease, age, and gender will affect the pathogenesis of IAV (3, 52, 53).
Although some studies have demonstrated higher viral titers in obese mice than in non-obese animals, others have found no such difference (27, 44). In a viral-bacterial co-infection model, there was no difference in the influenza viral load between obese and WT mice at peak disease, but obese mice had higher viral titers at later timepoints when compared to WT controls (48).
Similarly, the viral titers in OB and DIO mice infected with H1N1 viruses were no different to the titers in WT mice at peak infection at days 3 and 6 p.i., but the obese mice had prolonged infections (27, 54).
Titration of the virus in lung homogenates showed that WT animals had undetectable levels of virus by day 10 p.i. whereas OB mice showed no discernable decrease in viral titer (54). Conversely, some reports have suggested that DIO mice have higher viral titers early in infection with no change at later timepoints post-infection (44, 49).
The disparities between these reports may be due to differences in the inoculation method, dose, heterogeneity of influenza viral strains, or viral stock preparations. Nevertheless, OB mice experience worse outcomes after infection independent of increased viral titers.
Obese mice exhibit increased viral spread to the LRT. More viral antigen was present in the bronchiolar and alveolar regions in DIO mice inoculated with H1N1 virus than in the corresponding regions of infected control animals (55).
In the viral-bacterial co-infection model, OB mice inoculated with a fluorescent reporter virus showed increased viral spread in the nasopharynx, trachea, and lung at day 8 and 9 p.i., as determined through live-animal imaging, along with more extensive areas of active viral infection at days 7 and 9 p.i., as determined by nucleoprotein staining of sectioned lung tissue (48).
Excised lungs from OB mice showed this increased viral spread to be present as early as day 3 p.i (54). The culmination of severe lung pathology and increased viral spread leads to increased mortality in obese mice due to influenza infection and severe sequelae (27).
Systemic immune deficits and obesity-related poor pulmonary mechanics contribute to the observed increased susceptibility of obese hosts to IAV (56); however, ex vivo studies with primary human respiratory epithelial cells have revealed intrinsic cellular differences in viral replication in obese and lean subjects (57, 58).
In limited studies with alveolar epithelial cells (AECs), Huang et al. showed that H7N9 infection of obese-derived cells resulted in a greater increase in viral RNA production from 24 to 72 h post infection (h.p.i.) than was seen in infected of lean-derived cells (58).
These results support the limited data demonstrating that obese AECs are more susceptible to infection (57). Further studies are warranted to elucidate the mechanism behind this increased susceptibility at the epithelial cell level.
Host Antiviral Response to Influenza Infection
Obesity results in a dampened immune response to infectious agents, leading to poorer outcomes post-infection (3, 28, 59). Systemic alterations to antiviral immunity, including both the innate and adaptive responses, have been described for IAV infection of the respiratory epithelium (Figure 1).
Baseline alterations in the obese lung environment affect the viral pathogenesis and immune response and leave the lung susceptible to increased viral spread and secondary infections due to the poor induction of antiviral immunity.
Alterations to the host response to IAV in the lung epithelium due to the obese state. The effects of obesity on antiviral processes are summarized by a green + symbol indicating and increased number or process; a red—sign indicating a decreased number or process; a blue ellipses (…) indicating a delayed response; and a yellow interrogation mark (?) indicating conflicting or scarce literature. IFN, interferon; ISGs, interferon-stimulated genes; Ab, antibody; Ag, antigen; Adapted and updated from references (28, 60).
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