Localized and Systemic Stressors

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Why do we feel so terrible when we get sick? Recently, it has been cold, flu and RSV season here in New Mexico, as in most of North America. So, I have been seeing patients in the emergency department with body aches, fever, and nausea, elevated heart rates and breathing rates. Are these symptoms useful? If they are not, we should treat them. In fact, many of the treatments we give patients are aimed at reducing body-wide inflammation. We give Tylenol for fever, powerful non-steroidal anti-inflammatory medications like ketorolac for pain, and corticosteroids for inflammation*. Patients feel better. We pat ourselves on the back.

Most of these patients have self-limited viral infections, and are going to eventually improve no matter what we do. But does that mean that we are making our patients better with these symptomatic treatments?

A fascinating recent paper by Judy Day and Ed LeGrand suggests that the body-wide symptoms  are so distressing to patients and caregivers have a unique role in ridding the body of infection. This should be of no surprise to readers of this blog. Still, it might seem like a bad strategy for the immune system to generate an immune response that affects the whole body. Some of our patients with respiratory syncytial virus or influenza have symptoms that seem to go from head to toe? Why not just target the area that is infected, like the nose or throat during an upper respiratory infection?  The answer might be that local and body-wide (aka systemic) stresses are especially effective in combination. The combination of local and systemic stresses might life especially difficult for the invading pathogen. We perceive these stresses as difficult too, but maybe it is better in some cases to let these evolved defenses do their job, instead of treating them.

Day and LeGrand’s recent paper used a modeling technique to determine the costs and benefits of localized and systemic stresses, e.g. fever, on host defense and pathogen replication. They conclude that a variety of patient findings that we often presume to be harmful or useless might, in fact, be critically important in fighting off invasive infections. These include free radical production, high temperatures, increased blood clotting, and increased lactic acid production.

From the paper:

“An agent-based model validates and expands a conceptual model in which hosts can use non-specific stress for defense at local, regional, and systemic levels to preferentially harm pathogens.

For pathogens to spread during an active infection, replication is necessary; but the replication process diverts resources for expansion that could otherwise be used for protection against stress.

In our model, while localized non-specific stress has little efficacy as a host defense when used alone, it has strong synergy in combination with regional and systemic stressors.

Systemic stress is particularly costly and risky as a defense since host cells throughout the body are harmed while the host attempts to kill localized pathogens.

Based on the modeling results, host-induced non-specific stressors can provide a formidable defense in fighting pathogens, despite the detrimental effects on the host.”

*(In the interest of full disclosure – I sometimes…okay often…prescribe these medications myself. Not only that, I had an illness  that was probably RSV recently, and was tempted to take anti-inflammatory medications. It probably only temporarily relieved my symptoms, and may have made me feel worse the next day. Somebody needs to study this further!)

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