Stress, Heart Rate Variability, and the Immune Response to Infection

On our last post, we got familiar with a lot of the players of the immune system. If you missed that post and want to catch up with some of the main cells involved with immunity, you can check it out here:

A Brief Tour of Your Immune System

At the end of the article, I talked about the connection point between the nervous system and the immune system. While it seems like the nervous system and the immune system are mostly separated because of minimal direct nerve connections to immune organs, the brain actually exerts a large influence on immune function.

This is a critical piece to consider because the immune system left to its own devices can simply obliterate an infection with an uncontrolled immune response. This isn’t useful to the organism if an uncontrolled immune response ends up creating widespread tissue damage or killing its host in the process. It would be like setting your house on fire because you saw a roach in your garage.

One easy example is seen with control of a fever. During an infection, your immune system releases a variety of chemicals that will increase your body temperature to slow down the growth of bacteria. The hypothalamus of your brain keeps your body temperature between 98-99 degrees Fahrenheit under normal circumstances. But when an infection occurs, these immune chemicals will raise your body temperature, but the hypothalamus is monitoring your body systems to make sure it doesn’t get too high.

If your body is getting overwhelmed then your body temperature may continue to rise above 103 degrees and cause harm to your own body systems. This is generally a nuclear option that the brain tries to avoid, so there has to be a delicate balance in allowing your body temperature to rise a little bit while neural feedback will trigger inflammation reduction when temperature rises too high.

This is all mediated through a branch of the nervous system known as the autonomic nervous system.

Stress and the Immune System Relationship Status: It’s Complicated

Your autonomic nervous system mediates your response to stress. Your fight or flight system is activated by the sympathetic nervous system, which is countered by the rest and digest function of the parasympathetic system.

I used to be under the simple belief that stress from a fight or flight response suppressed your immune system because it caused your adrenal glands to release cortisol, and cortisol generally reduces white blood cell count and we end up catching more colds. [Source]

Just like everything else, it seems to be more complex than that.

It’s true that people who are chronically stressed out tend to get sick more often and have lower white blood cell counts. It’s also true that patients under with chronic stress are more prone to autoimmunity and hypersensitivity reactions like rheumatoid arthritis and asthma.

So how do we reconcile the fact that stress can reduce your immunity leaving your more susceptible to infection AND leave you prone to illnesses of a hyper-aggressive immune response?

A super insightful paper published in the Journal Neuroimmunomodulation brought this concept to light. The answer might be in the timing and context of the stress response.

It appears that if you are lightly stressed from exercise or acutely stressed during something that gives you an adrenaline rush, your immune system actually gets a surge of immune cells into the blood. From an evolutionary perspective this makes sense right?

If you are fighting or escaping danger, there is a high likelihood that you will have some sort of injury that will expose your blood to wounds and pathogens. You want more immune cells in your blood to get ready to fight. Your adrenaline-based stress hormones (epinephrine and norepinephrine) tell your immune organs to release more white blood cells into circulation. This also causes a drop in monocytes and lymphocytes, and an increase in neutrophils which would seem that you are evolutionarily preparing your innate immune system. [Source]

At the tail end of a stress response, you want to turn the immune cells down, so as your body releases cortisol, this causes a decrease in immune cell production to reduce the opportunity for autoimmunity. You also get a boost of activity from your vagus nerve which turns on an anti-inflammatory reflex to calm the body back down and reduce inflammation by your immune system. [Source]

However, cortisol also triggers a redistribution of the cells in your blood to go into your tissues to wait for any germ challenges that show up in the skin, lungs, or digestive tract. While this can keep the immune cells armed at the sources of common infection, a cycle of chronic stress that continues to dump immune cells into these battleground locations has the potential to prime these locations for autoimmune disease [Source].

Dhabhar described this as the Barracks to Boulevard to Battleground mechanism for how stress mobilizes the immune system. [Source]

Adrenaline in acute stress tells your spleen, thymus, and bone marrow to “mobilize the troops” from their barracks and get on the road to the battle. This means there are loads of white blood cells on the boulevards (blood stream) ready to go to wherever the battle is going to be. At the end of the stress response, cortisol and other corticosteroids maneuver the white blood cells into battle ground tissues like the skin, lungs, and digestive tract that are likely to engage with potential invaders.

We end up in a situation where just a little bit of stress increases immune responsiveness and increases resistance to infection and cancer which is great!

But chronic stress induces hormone signaling that can reduce white blood cells in the blood stream and into tissues. If you are chronically stressed and dumping more soldiers into your tissues, there can be a risk for autoimmune reactions. At the same time, chronic activation of the stress response is reducing troops in the blood which leaves you prone to other infections.

What this likely means is that you don’t have widespread immune suppression from a stress response. In fact, a little bit of stress from things like exercise or being involved in something exciting may actually increase immune protection.

Even chronic stress isn’t necessarily immune suppressive. What chronic stress likely does is redistribute your immune cells to other bodily tissues. Chronic stress is also likely to drive hormone dysregulation which can trigger immune dysregulation leading to the double whammy of increased infections and increased autoimmunity.

Can Heart Rate Variability Tell Us About Our Immune Response?

Now we know that stress can modify our immune response via our autonomic nervous system, can measuring stress tell us about our immune response?

Maybe.

A measurement called Heart Rate Variability (HRV) is a tool we can use to measure your your body’s baseline stress response. I’ve written a lot of thoughts about HRV here.

Long story short, a high HRV score generally tells us that we are have more parasympathetic physiology (less stressed), while a low HRV score generally tells us that we are more Sympathetic physiology (more stressed).

If we are under chronic stress, you are generally going to have lower HRV and a stronger likelihood for stress related illness. It’s shown a strong ability to predict outcomes in cancer and stroke, but it also can tell us if a healthy person is more likely to get injured during exercise.

Heart rate variability is generally tied to the function of the Vagus nerve and the parasympathetic nervous system. An extensive amount of work has been done studying something called the cholinergic anti-inflammatory pathway which is driven by the Vagus nerve.

We know that the vagus nerve plays a role in driving inflammation down, and it’s probably a key piece in what helps us get back to normal after the immune system has fought a war with an infection. This anti-inflammatory pathway is how the vagus nerve tells the immune system to calm down and it has been studied extensively in terms of autoimmune, cariovascular, and metabolic disease associated with inflammation. [Source]

We need vagus/parasympathetic physiology to help us balance out the effects of chronic stress, and HRV seems to be a good and cheap way to let us know if it’s working.

But……

Can a stress reading from HRV tell us anything about our ability to fight infection?

Surprisingly not that much research has been published in this space, but here’s some of what has been studied:

• Low HRV is a predictor for death from sepsis across several studies [Source] It’s unknown whether lower HRV was caused by sepsis, or if lower autonomic capacity allowed for worse disease progression
• Low HRV scores predicted the progression of disease in patients with hand,foot, and mouth disease from enterovirus infection. Lower HRV scores corresponded with higher organ system involvement [Source]
• HRV scores in healthy adults showed correlations with increased inflammatory bio markers and lower white blood cell counts in those with lower HRV. [Source]
• Low HRV after predicted patients who would suffer infection after stroke [Source]
• Loss of sympathetic modulation identified on HRV was associated with worse outcomes in community-acquired pneumonia patients [Source]
• Lower HRV in healthy adults shows a slight shift in immune cells towards neutrophils while higher HRV is associated with more lymphocytes [Source]

Taken altogether, it appears that people with better outcomes from a disease process when they have a higher HRV score. However, we don’t really know if HRV is the chicken or the egg. Did the people with poorer outcomes have a better baseline autonomic function or did someone with a worse infection just wipe out that patient’s autonomic nervous system resulting in poor outcome.

We don’t have answers to that quite yet, at least not from clinical research on infectious disease, but maybe something else can give us a clue.

HRV and Cancer

Besides infectious disease, the immune system is heavily involved in eliminating and controlling the spread of cancer cells. Your body is constantly producing mutated cells during the process of normal cell reproduction, but the vast majority of these mutated cells are eliminated by a healthy immune system.

The relationship between stress, heart rate variability, and cancer has been studied really extensively. So much so that there are multiple systematic reviews suggesting that heart rate variability is a strong measurement to assess a cancer patient’s progress in fighting the disease. [Source] One study even suggested that HRV was more reliable in predicting the prognosis of prostate and colorectal cancer than knowing what stage of cancer the patient had. They also found that the more advanced stage you had, the more important vagal activity was in survival, which is a finding consistent in metastatic cancer cases. [Source] You can read more My thoughts about that particular paper below.

Research: Active Vagus Nerve Predicts Cancer Survival Regardless of Stage

Just stop and think about that for a second. The thought that you can crunch the data from a patient’s heart rate and you can tell who is going to have a better outcome in 6 months with all other factors kept equal. It gives us hope that having a better stress response and higher HRV is a driving factor in protection from cancer and not just the product of cancer’s affect on the autonomic nervous system.

Decouck et al in a 2018 review in the Journal of Oncology explored the concept of vagus nerve activity in cancer even further. Instead of just looking at the studies that measured heart rate variability, they included studies that observed the effect removing the vagus nerve had on cancer progression.

In most animal models, an experimental vagotomy showed higher rates in cancer and worse rates of metastasis implying that a loss of vagus nerve function was causative in developing cancer in mice. We can’t really do these experiments in humans, but we can follow patients who have had their vagus nerve cut in the case of a disease like ulcers. Patients who had a partial vagus nerve removal had higher odds of developing cancer in the organs that lost their vagus nerve connection.

Patients who had a partial vagus nerve removal had higher odds of developing cancer in organs that became disconnected from the nerve.

Do we know if the vagus nerve removal means that there’s less immune surveillance in defending against tumor cells?

Not really.

The effects of the vagus nerve on human physiology are wide spread, so we don’t have any experiments that inform us on this.

But, but but….There are theories.

My favorite looked at the effect that stress and depression had on immune function the progression of cancer.

Stress and depression-induced immune dysfunction: Implications for the development and progression of cancer

Chronic stress and major depression disorder are associated with reduced cellular immunity which is the branch of your immune system that can destroy infected or mutated cells. This response is mediated by Natural Killer Cells in your innate immune system, and T-Cells in your adaptive immune system. These cells patrol your body looking for tissue that has been infected by a virus or has mutated leading to cancer.

They work by binding to the infected or mutated cell and provide a chemical signal for that cell to self-destruct so it can’t spread.

These cells have been found to be reduced or less active in patients who with untreated depression as well as patients and caregivers with prolonged mental health symptoms related to traumatic events.

These cells are so potent in addressing tumor activity in laboratory models that Immunotherapy for cancer is looking at how to harness T-cells and NK cells in treating active cancer patients. [Source]

So Here’s What we know:

• We know that chronic stress and depression affect heart rate variability negatively.
• We know that chronic stress and depression are associated with worse or dysregulated immune responses.
• We know that chronic stress can increase cancer rates via persistent activation of the HPA axis.
• We know that cancer patients generally have worse HRV and vagal nerve activity than healthy controls.
• We know that cancer patients with higher HRV have better prognosis and survivability than cancer patients with low HRV.
• We know that autonomic activity is related to vagal nerve activity which has immune consequences.

We discussed how we couldn’t be sure if having better autonomic function was the cause or the effect of better outcomes with infectious disease, so we couldn’t be certain that having a better autonomic nervous system in a healthy person could protect us from infectious disease.

But we know that cancer survivability is a product of better autonomic function, then it’s my personal contention that building up your autonomic nervous system is a causative factor in having better immune function against infectious illness.

Can We Improve our HRV and Does It Matter?

This article has gone on way longer than I anticipated, but before I close let’s discuss if therapies to improve autonomic function to stress have any potential value.

So the last question we have to ask ourselves is this. Can we change the output of our autonomic nervous system and vagus nerve and does it really matter?

It’s nice to know that having a high HRV gives you greater resilience and survival to disease, but it’s not helpful if some people are just born and raised to have better autonomic control than others. But if HRV can be improved, and that improvement leads to better outcomes, then it gives us tools to improve our lives across multiple dimensions.

Here’s the good news. At least in short term studies, we have tremendous power over our autonomic nervous system. Many of which are free with various mind-body therapies, and others that utilize practitioners of drug-less healing.

Here are some things that have some evidence for improving heart rate variability that also have carry over into improving general quality of life. I’ve highlighted as to whether they can be done free at home, or whether they require outside help or purchase:

• Free: Systematic review of yoga shows promise for improving Heart Rate Variability [Source]
• Free: Tai-Chi and Tai Chi/yoga for stress reduction [Source]
• Paid Apps/Therapists: HRV Biofeedback Training reduces markers of inflammation in asthma, heart disease, and depression [Source]
• Clinically guided or purchased device: Noninvasive Auricular vagus nerve stimulation reduced depression [Source]
• Free: Employee based Mindfulness training and meditation improves HRV along with overall life and job satisfaction [Source]
• Free: Medium intensity exercise improves HRV and patient outcomes across a wide spectrum of chronic illness [Source]
• Clinically delivered: Upper cervical spine manual techniques [1, 2, 3]

Closing Thoughts

As you look through those sources, you’ll notice that none of those studies really talk about immune function. All this tells us is that improving HRV is possible, and it seems to help us live a better life when we do it.

We can’t measure whether we have optimized our immune system because we have no clue what markers tell us if our immune system is optimized. We know when our immune system is broken, and we know when it is deficient. That’s it.

But we can measure and improve on the function of our autonomic nervous system, and we can do it on the cheap.

Healthy immune function isn’t the goal of improving our autonomic function. It is a potential product of a healthy autonomic nervous system.

We are improving our autonomic function because it is a necessary part of being a healthy human being. Healthy immune function is a product of doing things that we know we should be doing already.

It’ about taking care of yourself mentally.

It’s about building a physical body that is prepared to take on stress.

It’s about ensuring that the function of our nervous systems are not obstructed.

We can’t stop the world from being infected at this point, but we can build a resiliency that will allow ourselves a better chance to fight off disease so we can move on to protect others.

In times of stress, we often forget that we have power and we have control over our lives. During this pandemic, not only do we feel powerless, but we are more afraid than ever. Not just of this invisible virus, but of our fellow human beings.

This fear, this anxiety, this depression that we feel collectively is taking away one of our body’s best weapons to endure our invisible enemy.

In one sense, it’s our immune system, but in another sense it’s something deeper. It is the power human beings discovered when we realized that we are way better fighting together as a village, than as an individual alone in the wild.

While it’s up to experts smarter than I am to give us the best chance to avoid illness, it’s up to us as people to confront this threat without the panic and fear that will not only make us sick physiologically, but will make us a sick species by stripping us of our collective humanity.