Is winter flu worse because of exercise-induced 'window of susceptibility'?

When you exercise or work outside in winter, that dry feeling at the back of your throat indicates the cold air has irritated your throat. Racehorses share a similar experience: exercising in below-freezing air causes mild airway injury. 

Recent research suggests these kinds of experiences, also shared by winter athletes, sled dogs, meatpackers and even fisherman, may be the beginning of a cascade of events leading to more serious conditions later. 

Similarly, both athletes and horses seem open to infection after such strenuous bouts of activity as handicap races or marathons. Exercise physiologists and others have long thought that over-exertion might open a kind of “window of susceptibility” for sickness, but most of the evidence is anecdotal.

Physiologists at Oklahoma State University reporting on new research believe they may have found evidence that could link the problems suffered by horses, athletes and cold-air workers that potentially could lead to progress in understanding the development and perhaps give hints toward cures for asthma and related diseases. Specifically, the Oklahoma State team reported that their research “data are the first to provide a specific mechanism for the exercise-induced open-window effect as a local pulmonary phenomenon.”

The research involved horses exercising while breathing air at 23 degrees Fahrenheit and may “help explain why flu season occurs in the winter, how asthma develops in humans, and why race and other active horses get ‘heaves,’” lead researcher Michael S. Davis said.

The study, entitled “Cold weather exercise and airway cytokine expression,” appears in the June issue of the Journal of Applied Physiology, published by the American Physiological Society. The research was conducted by Michael S. Davis, Jerry R. Malayer, Lori VanDeventer, Christopher M. Royer, Erica C. McKenzie and Katherine K. Williamson of the Department of Physiological Sciences, Oklahoma State University, Stillwater.

Respiratory responses to cold air point to asthma, ‘heaves’ links

The study showed “cold weather exercise can lead to asthma-like airway disease through the local induction of cytokines,” small peptide protein hormones that direct and fine-tune the immune system, in a “profile associated with preferential production of antibodies and down-regulation of cell-mediated immunity…also characteristic of asthma.” 

They added that the “results support the novel contention that exercise while breathing cold air can actually contribute to the development of asthma.”  Specifically, they found that a group of cytokines of the T_H2 phenotype were preferentially upregulated after cold air exercise by manifold amounts: Interleukin-4 (12-fold), IL-5 nine-fold, IL-10 10-fold, while other cytokines were upregulated less (IL-2 six-fold, IL-6 three-fold) or not at all.

Similarity of human and “equine” athletes’ responses

The paper reported: “the potential effect of the cytokine expression shift described in this study and the resulting alteration in antigen responses are consistent with common pulmonary diseases of both equine and human athletes. Antibody-mediated pulmonary hypersensitivity (heaves) is common in horses and has been linked to increased expression of T_H2 cytokine expression. The most prominent antigens identified in this syndrome are mold spores found in hay and straw bedding, thus closely linking the development of heaves to the horse’s environment.”

Furthermore, they note that like cold-induced human “ski asthma,” the clinical signs of heaves (notably persistent coughing due to airway constriction) quickly diminish when the subject is removed from the offending environment. “In this regard, heaves is quite similar to human asthma, including the fact that the initial cause of the hypersensitivity has not been elucidated. The data of this study provide a compelling possibility: that strenuous exercise followed by exposure to environmental antigens promotes over-production of antibodies to those antigens,” the report notes. Again it notes that this uncertain etiology is similar to that of “ski asthma,” which Davis and others have also studied in sled dogs as an animal model for human asthma.

The current data “further raise the possibility of local suppression of cell-mediated immunity through the increased expression of IL-10” supporting the concept of the open window “of transient immune suppression after strenuous exercise (as well as) increased susceptibility to respiratory viruses in animals after strenuous exercise.”

Conclusion and next steps

The authors conclude, stating: “We believe our data are the first to provide a specific mechanism for the exercise-induced open-window effect as a local pulmonary phenomenon. The potential deleterious effect of increased IL-10 expression is increased susceptibility to pathogens, particularly those that are normally cleared by cell-mediated immunity. On the other hand, it is possible that the increase in IL-10 is an appropriate response that moderates the net effect of the increased proinflammatory cytokine expression.

“These issues warrant further investigation, for which the equine model is ideally suited,” the study notes. Some other “next steps” include:

• Looking at viral immunity in these cold-air scenarios, including “challenging” horses to see if blocking short-term inflammation perhaps could block pathogenesis, particularly in heaves.
• Challenging horses with influenza virus after a cold-air challenge.
• Further studying equine airway response to cold air to determine the cell populations active in these responses; i.e., to determine the mast cell activation process and role of resident airway lymphocytes.
• Determining if heaves is more prevalent in colder climates, and among athletic horses (or formerly athletic ones) than in sedentary ones.
• Determining the range of air temperatures where airway damage occurs.

Horses as unique model for human exercise, pulmonary research; good for horses, too

Davis notes that horses are particularly good models of human exercise and especially pulmonary functions.  “As athletic animals, horses’ ventilation requirements actually increase more than humans under comparable conditions, but we’re able to get valid data from horses without running them at their maximum exertion points. Another advantage with horses is that most of our monitoring is noninvasive, and because they’re hardy and well-cared for, they actually can serve as their own controls in most experiments.”

An additional benefit of using animal models, he said, is obvious from the fact that while it looks like “we could make progress from our research in human chronic and acute conditions, probably the first direct beneficial application will be in the area of heaves, which affects many horses, especially as they age.”

One downside, Davis points out, is since horses aren’t widely used as physiology research models, much of the lab work from RNA sequencing to designing reagents is done manually.