Obesity and asthma prevalence have been increasing over the past decade. Epidemiological evidence demonstrates that obesity results in an increased risk of developing incident asthma. Even modest levels of increased weight increase asthma risk. Recently published data suggest that obese asthma patients may represent a distinct phenotype of asthma. Obese asthma patients demonstrate increased asthma severity, as indicated by increased exacerbations and decreased asthma control; however, they do not appear to have increased airway cellular inflammation. It seems likely that obesity does not contribute to asthma through conventional Th type 2-mediated inflammatory pathways but, rather, through separate mechanisms that are specific to the obese state. This may explain the variable responses of obese asthma patients to conventional asthma therapies, specifically, relative corticosteroid resistance. Small studies suggest improvements in the disease with weight loss in obese asthma patients, and other interventions to target asthma in obese individuals need to be investigated. Several postulated mechanisms for the occurrence of this distinct phenotype have been postulated: 1) the presence of comorbidities, such as gastroesophageal reflux disease and sleep disordered breathing, 2) systemic inflammation associated with obesity (with elevated levels of circulating cytokines, such as IL-6 and TNF-alpha), 3) increased oxidative stress, and 4) hormones of obesity, such as adiponectin, leptin, and resistin. Although the mechanisms underlying obesity in asthma require further investigation, obesity plays a major role in the asthma epidemic and likely results in a distinct phenotype of the disease.

Patients with nocturnal asthma demonstrate circadian variations in airway inflammation. We hypothesized that melatonin, a circadian rhythm regulator, modulates circadian inflammatory variations in asthma. The effect of melatonin stimulation on peripheral blood mononuclear cell cytokine production was evaluated at 4:00 P.M. and 4:00 A.M. in normal control subjects, patients with nocturnal asthma, and patients with non-nocturnal asthma. Melatonin was proinflammatory, causing significantly increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha at 4:00 P.M. and 4:00 A.M. in all subject groups (range, 12.8 +/- 3.3 to 131.72 +/- 16.4%, p 0.05, both cases). At 4:00 P.M., the cytokine response to melatonin of patients with nocturnal asthma was greater than that of control subjects or patients with non-nocturnal asthma and did not change significantly at 4:00 A.M. At 4:00 P.M., the cytokine response of patients with non-nocturnal asthma was less than that of patients with nocturnal asthma and rose significantly at 4:00 A.M. (p = 0.0001, all comparisons). Melatonin is proinflammatory in both patients with asthma and healthy subjects. Patients with nocturnal asthma demonstrate the largest daytime cytokine response and cannot be further stimulated at 4:00 A.M., suggesting chronic overstimulation in vivo. These results suggest differential immunomodulatory effects of melatonin based on asthma clinical phenotype and may indicate an adverse effect of exogenous melatonin in asthma.

Increased airway inflammation at night contributes to the nocturnal worsening of asthma, but the mechanisms regulating circadian variations in airway inflammation are unknown.

The function of the P2X(7) nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied.