Another cytokine storm? Revisiting those severe infections in the obese during the 2009 flu pandemic

January 12th, 2015

Early in the 2009 influenza A H1N1 pandemic obese patients comprised a surprisingly high percentage of serious infections for reasons that could not be immediately explained. Obesity was an independent risk factor for the flu infected, increasing the likelihood of hospitalization, admission to the ICU, and death.

Now we have a plausible hypothesis that elevated levels of the hormone leptin in the obese induced a hyperimmune response paradoxically similar to the fabled “cytokine storm" in young healthy patients during the 1918 Spanish Flu pandemic.

A new study shows that high levels of leptin in obese mice were associated with higher levels of pro-inflammatory cytokines and more severe flu. In a mouse model of diet-induced obesity, obese mice infected with H1N1 had significantly higher pulmonary viral titers and mortality compared with age-matched lean mice. Interestingly, blocking leptin with an antibody improved survival rates.(1)

Although leptin inhibits appetite by signaling satiety to the brain, the obese generally have an unusually high circulating concentration of leptin. They appear to be resistant to leptin similar to the way diabetics are resistant to the effects of insulin. Similarly, the obese mice had higher leptin levels in the blood, which in turnd heightened inflammatory cytokine and resulted in more severe pulmonary damage than suffered by lean mice.

In a review of the paper in the June 2013 issue of Infectious Disease Alert, Dean Winslow, MD, an infectious disease physician at Stanford University, concluded:

“This study conducted in a mouse model of obesity induced by diet sheds some light on possible pathogenic mechanisms responsible for the severity of pandemic influenza A seen in obese patients. It seems likely that the pro-inflammatory effect of leptin (likely mediated by increased transcription of inflammatory cytokines by lung macrophages and epithelial cells) is causal. In addition, the low levels of the anti-inflammatory cytokine adiponectin (which induces production of the anti-inflammatory cytokines IL-10 and Il-1 receptor antagonist) may contribute to the severity of disease as well. While these mouse studies must be extrapolated carefully to human disease, the effectiveness of anti-leptin antibody in reducing mortality (without decreasing pulmonary viral load) in mice suggests that modulation of the immune response in severe influenza may improve survival in obese patients with influenza, especially in patients who present more than 48 hours after symptom onset when antiviral treatment may be less effective.”

Reference

1. Zhang AJX, et al. Leptin mediates the pathogenesis of severe 2009 pandemic influenza A (H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity. JID 2013; 207: 1270-80.