By Kevin McCauley, MD, Meadows Senior Fellow
We’re learning so much in the midst of the COVID-19 pandemic, from Zoom etiquette, to the six-feet-of-separation square dance held nightly at Whole Foods, to a host of immunology buzzwords: antigen testing, herd immunity, and the “cytokine storm.” It may be hard to see how any of this is connects to our world – the world of recovery – but there is accumulating evidence that the same processes that make SARS-CoV-2 (aka COVID-19) infections so lethal are those that propel chronic stress, trauma, and addiction. Those things are harmful, at least in part, because they are inflammatory – just like COVID-19, but on a smaller and slower scale. Felitti and Anda’s Adverse Childhood Experiences (ACEs) Study cemented into public consciousness the idea that early life adversity can increase chronic disease in adulthood, and we’ve long understood that chronic stress, including trauma, leads to mental illness. But how? What is the mechanism through which stress damages the brain?
The answer is: the immune system.
Psychoneuroimmunology is the study of how the brain and immunity interact to create vulnerability or resilience to mental illness. The brain and the immune system are in constant communication. The immune system has even been called a sensory organ of stress for the brain. For those of us in recovery from addiction or trauma, this is important to know: chronic stress, trauma, and repeated drug use trigger inflammatory processes in the brain, and strengthening our immune system improves recovery and resilience to relapse.
SAM and HPA
Usually when we think about how stress impacts the brain and the body, we think of hormones, specifically two neurohormonal feedback loops: the Sympathoadrenal Medullary Axis (SAM) and the Hypothalamic-Pituitary Adrenal Axis (HPA).
SAM is the fast one: releasing epinephrine and norepinephrine to produce the “fight, flight or freeze” response. Every cocaine or methamphetamine addict knows the terror of uncontrolled sympathetic discharge: the super-sweaty, heart-pounding, paranoid, and perpetually petrified state of mind that I used to call “bunny rabbit brain.” This is where intoxication and trauma overlap. Hyper-vigilance is adaptive for a bunny rabbit; it ensures survival. For us, it is highly neurotoxic.
HPA follows close behind SAM. A cascade of neurohormones from the hypothalamus to the anterior pituitary to the adrenal glands end in the release of cortisol and glucocorticoids which get the body ready to confront stress. Heart rate and blood flow increase. Pupils and airways open. Glucose stores are liberated for quick energy. Digestion and reproduction shut off. Once we surmount the stressor, SAM and HPA employ feedback loops to shut themselves off.
SAM and HPA are highly adaptable and calibrate themselves to the stress challenges at hand. Unpredictable, uncontrollable, inescapable stressors, however, lower SAM and HPA activation thresholds and weaken their feedback loops of deactivation. The result is continuous, smoldering, and damaging SAM/HPA activity. The same systems that were so adaptable in the immediate are maladaptive over time, with cardiovascular, metabolic, and neurologic consequences in the form of heart attacks, diabetes, and depression.
The Innate and Adaptive Immune Systems
It is increasingly clear that stress has immunologic consequences as well, chiefly through its primary mechanism of action: inflammation.
There are two parts of the immune system: the part we were born with – the innate immune system – and the part that learns over time – the adaptive immune system. Both employ inflammation to get their jobs done.
The innate immune system is often called “fast and feverish.” White blood cells called macrophages patrol the body, especially infection and injury-prone areas such as skin, gut, or lung tissue. They look for small molecules known as pathogen-associated molecular patterns and damage-associated molecular patterns. If they encounter these PAMPs or DAMPs, macrophages release signal molecules called cytokines to sound the alarm.
Cytokines come in many forms: interferons, interleukins, and tumor necrosis factor-alpha to name a few. Cytokines call other immune cells to the scene and trigger changes that characterize inflammation: increased blood flow and metabolism in the infected or injured tissue, blood vessels become leaky so plasma floods in, and body temperature resets to produce fever because innate immunity works better when things are hot. Cytokines also act as pain modulators to create hyper-algesia to protect against further injury. Every medical student knows the rhyme that describes inflammation: “rubor, calor, tumor, dolor” (redness, heat, swelling, pain).
Once they’ve signaled for help by releasing cytokines, the macrophages attack the pathogen. They surround and engulf it in a process known as phagocytosis (means “cell eating”). Macrophages contain lysosomes – little “Ziploc bags” filled with toxic chemicals – which they pour onto the pathogen, killing it. Soon, other white blood cells arrive on scene to join in. Neutrophils, basophils, and eosinophils are white blood cells that contain especially powerfully cytotoxic chemicals. They squeeze through the leaky blood vessel walls and infiltrate the area of infected or injured tissue, killing bad guys and eating dead tissue.
Patrolling risky areas, calling for back-up, arresting everyone in sight – if all of this sounds like a Law & Order episode, it’s because the fast-acting, aggressive, and non-specific innate immune system fits the law enforcement metaphor quite well, almost disturbingly so. We can even extend our crime drama metaphor to describe the second separate-but-equally-important part of immunity: the adaptive immune system.
Once they apprehend and kill a pathogen, macrophages take the evidence of the pathogen’s crime (basically, its body parts) to lymph nodes where they present them to the district attorneys of the immune system: lymphocytes. This procedure is known as antigen-presentation, and macrophages are one of a number of antigen-presenting cells (APCs).
Using the shape of the pathogen’s body parts, B lymphocytes make antibodies that circulate in the bloodstream and can recognize the pathogen. If they ever encounter it again, B cells multiply and produce vast quantities of antibodies which adhere to and mark the pathogen for destruction, like a dye pack exploding all over a bank robber. The B cells antibody response constitutes a form of memory that gives the pathogen a criminal record that will follow it long into the future.
T lymphocytes do the prosecuting. Killer T cells destroy our own cells if they become infected, and when our cells die they release even more cytokines. A healthy immune response produces just enough inflammation to limit damage only to infected cells, allowing their rapid clearance. But COVID-19 causes a dysfunctional immune response and excessive infiltration of T cells that now bring their cytotoxic power to bear on healthy lung cells, causing severe edema and pneumonia locally and unrestrained release of cytokines systemically. This is the uncontrolled inflammatory processes known as the “cytokine storm” whose widespread inflammation may culminate in multi-organ damage and a condition notorious in critical care medicine for its lethality: Acute Respiratory Distress Syndrome (ARDS).
One of the hallmark clinical features of SARS-CoV-2 infection is the brief period of improvement patients experience around day seven of their illness, followed by a sudden deterioration into severe pulmonary edema, often requiring intubation. The “second week crash” phenomenon no doubt got the attention of infectious disease experts and immunologists who recognize that it takes seven days for T cells to mobilize, even as viral infection abates.
All of these immunological processes, good and bad, occur in the brain, too, and this inflammation may underlie many mental illnesses.
The predominant antigen-presenting cells of the brain are called microglia. Normally, they are caretakers of brain cells, extending their arms to tend to the needs of the neurons their micro-meter-square area of responsibility, secreting neural growth factors, pruning unused synapses, and generally assisting other glial cells in their task of insulating neurons. Microglia scan the entire brain every few hours. If they encounter a pathogen or tissue damage, they retract their arms and become activated immune cells equivalent to macrophages, phagocytizing bacteria, viruses and damaged tissue, and releasing cytokines to trigger just the right amount of brain inflammation. But if overstimulated by drug use or chronic stress, their caretaking and protective capacities become deranged and cause neurodegeneration. Microglia have been found to play a role in many brain diseases including Alzheimer’s disease, multiple sclerosis, and Parkinson’s Disease.
One drug that blocks the cytokine Interleukin-6, Ibudilast, inhibits microglial activation. This drug has been shown to decrease stress- and drug-induced relapse, block the effects of opioids and methamphetamine, and decrease opioid withdrawal symptoms, suggesting that some of the misery of opioid withdrawal may be inflammation. But activated microglia have also been shown to be part of the process of recovery after cocaine use, and when functioning properly are able to decrease craving. Microglia likely have a complex role in addiction and recovery.
Recovery is Anti-inflammatory
Neuroinflammation is the key to understanding how trauma becomes disease, both physical and mental, and how the immune system plays a part in disease as well as recovery. There is good reason to assume that one of the reasons the habits of recovery work is because they are anti-inflammatory. I’m not saying that taking a Motrin will stop you from relapsing, but I am suggesting that the day may come when we track the strength of our recovery by measuring circulating cytokines or prevent relapse by boosting our immune systems. Serenity may follow immunity, and vice versa, and the idea that the fellowship of people in recovery represents a kind of herd immunity is certainly hopeful.
Most people who become infected with SARS-CoV-2 do not get severely ill, require intubation, or develop ARDS – only about 10 percent. But neither do most people who use drugs become addicted, require treatment, or overdose and die – the vulnerability is also around 10 percent. The overlapping features of these two diseases are striking. I don’t want to suggest that trauma and addiction are equivalent to the severity of the illness of our fellow citizens in ICUs across the country. But both diseases pass through the immune system, and we’ve trudged the same road. What we endured over years, they do all at once and face lethal odds. Because the process is slower for us, we had a better chance to survive and recover. We can all hope that the promise and rewards of recovery will be theirs, too.