The pandemic viral illness COVID-19 is especially life-threatening in the elderly and in people with any of a variety of underlying medical conditions. No conceptual framework has been offered as to why this should be. That is the main purpose of this commentary. One might decrease overall COVID-19 mortality by understanding the pathophysiologic bases for the increased risk, which would rationalize biomarkers and treatment. Concepts of integrative physiology and autonomic medicine may help meet this urgent objective. The concepts highlighted in this commentary are homeostasis, allostasis, stress and the central stress system, allostatic load, and dyshomeostasis. The main take-home point is that low efficiency of homeostatic systems (dyshomeostasis) in concert with stress system activation increases the likelihood of transitioning to acute respiratory distress syndrome (ARDS) and multi-organ failure due to induction of positive feedback loops (vicious cycles) in patients with COVID-19.
The term homeostasis refers to the stability of the “inner world” inside the body. In systems biology, homeostasis is an emergent phenomenon. In integrative physiology homeostasis is a goal—it is the goal.
Thus, Claude Bernard, the founding father of integrative physiology, wrote, “The constancy of the internal environment is the condition for free and independent life…All the vital mechanisms, however varied they might be, always have one purpose, that of maintaining the integrity of the conditions of life within the internal environment” (Bernard, 1974). And Walter B. Cannon, who invented the word homeostasis, wrote, “My first article of belief is based on the observation, almost universally confirmed in present knowledge, that what happens in our bodies is directed toward a useful end” (Cannon, 1945).
A classic example of homeostasis is thermoregulation (Fig. 1, left). When you are exposed to cold, sympathetic noradrenergic system (SNS) outflows increase, resulting in cutaneous vasoconstriction, shivering, and piloerection (“goosebumps”), all of which tend to maintain the core temperature. When you are exposed to heat, sympathetic cholinergic system (SCS) outflows to sweat glands increase, resulting in diaphoresis (sweating), which tends to maintain the core temperature by evaporative heat loss.
Fig. 1. From homeostasis to allostasis. In allostasis there is a shift in input-output curves for oppositely-acting effectors (yellow and white), resulting in regulation of the monitored variable (in this case body temperature) at a different level. The acceptable bounds are the vertical dashed lines. A low grade fever when you have the flu is an example of an allostatic state.
Allostasis refers to a temporary shift in input-output curves (Fig. 1, right). A low-grade fever when you have the flu is an example of allostasis. Allostatic adjustments use up more energy than do homeostatic adjustments, and input-output curves generally become flatter, implying decreased homeostatic efficiencies. Allostatic states that are temporary are beneficial. Once you recover, the input-output curves revert to those before the acute illness, with no harm done. Allostatic states, however, also increase wear and tear—allostatic load.
Stress and the “Stress System”
Hans Selye defined stress as the non-specific response of the body to any demand imposed upon it (Selye, 1974).In the 1990s George Chrousos and Philip Gold at the NIH proposed the existence of a central stress system, activation of which would elicit a “stress syndrome,” in line with Selye’s conceptualization (Chrousos and Gold, 1992; Sternberg et al., 1992). Key elements of the stress system are the paraventricular nucleus (PVN) of the hypothalamus, from which corticotropin-releasing hormone (CRH) is derived; and the locus ceruleus (LC) of the pons, from which norepinephrine in the brain is derived (Fig. 2, left panel). CRH drives pituitary release of corticotropin (ACTH) in the hypothalamic-pituitary-adrenocortical (HPA) axis. In addition, arginine vasopressin (AVP, synonymous with anti-diuretic hormone, ADH) is another neuroendocrine factor derived from the PVN.
A more complex schema embeds the stress system in the “central autonomic network” (Benarroch, 1993) (Fig. 2, right panel). The central autonomic network is the source of outflows to components of the autonomic nervous system, including the SNS, for which norepinephrine is the neurotransmitter, the sympathetic adrenergic system (SAS), for which adrenaline is the hormone, and the parasympathetic nervous system (PNS), for which acetylcholine is the neurotransmitter (Goldstein, 2006).
Fig. 2. Central stress systems. The concept diagram on the left (reproduced with permission of the American College of Physicians) shows the Chrousos and Gold model of “the central stress system.” The concept diagram on the right relates the central stress system to the central autonomic network. Abbreviations: CING = cingulate cortex; AMY = amygdala; Hippo = hippocampus; PVN = paraventricular nucleus of the hypothalamus; HACER = hypothalamic area controlling emotional responses; AVP = arginine vasopressin (same as anti; CRH = corticotropin-releasing hormone; VTA = ventral tegmental area; PAG = periaqueductal gray; LC = locus ceruleus; A5 = A5 noradrenergic cell group; RTN = retrotrapezoid nucleus; RVLM = rostral ventrolateral medulla; AP = area postrema; PBN = parabrachial nucleus; Pre-Botz. = pre-Botzinger complex; NTS = nucleus of the solitary tract; CVLM = caudal ventrolateral medulla; NA = nucleus ambiguus; DMNX = dorsal motor nucleus of the vagus nerve; RPG = respiratory pattern generator; ACTH = adrenocorticotrophic hormone (corticotropin); ANS = autonomic nervous system; SNS = sympathetic noradrenergic system (norepinephrine); SAS = sympathetic adrenergic system (adrenaline); PNS = parasympathetic nervous system (acetylcholine).
Two of the main effectors of the stress system—cortisol and adrenaline—play key roles in inflammatory responses. Anti-inflammation exerted by adrenocortical steroids was fundamental in Selye’s stress theory (Selye, 1950), and across a variety of stressful situations adrenaline is strongly associated with elevations of the pro-inflammatory cytokine interleukin-6 (IL-6) (Danobeitia et al., 2012; Hashizaki et al., 2018; Jan et al., 2009; Koelsch et al., 2016; Kulp et al., 2010; Papanicolaou et al., 1996; Piira et al., 2013). This association obtains in conditions associated with increased COVID-19 mortality—coronary artery disease (Piira et al., 2013), diabetes (Asadikaram et al., 2019), hypertension (Carnagarin et al., 2019), and depression (Weinstein et al., 2010).
Stress System Activation Is a Double-Edged Sword
Intensive care physicians know well the risks of high levels of adrenaline, cortisol, and ADH and increased SNS outflows to the kidneys and heart in critically ill patients. Among other things, SNS and adrenaline raise the blood pressure, increase glucose levels, raise core temperature, increase myocardial oxygen consumption, can precipitate myocardial ischemia or a ventricular arrhythmia in patients with coronary artery disease, promote renal sodium reabsorption (Gill, 1979), can induce renal ischemic injury, and can evoke a form of stress cardiopathy (Wittstein et al., 2005). ADH augments renal water retention and consequently promotes hyponatremia. The SNS and adrenaline also stimulate the renin-angiotensin-aldosterone system (RAS), where aldosterone is the main salt-retaining substance of the body. Moreover, adrenaline increases IL-6 levels (Sondergaard et al., 2000), which could contribute to the inflammatory “storm” in ARDS.
As people age the efficiencies of a variety of homeostatic systems decline. Susceptibilities of the elderly to lethal hyperthermia in the summer and hypothermia in the winter are well known. Baroreflex sensitivity, and therefore the ability to keep blood pressure within bounds, declines with age in a manner associated with hypertension (Bristow et al., 1969). Chronic conditions that increase COVID-19 mortality such as diabetes, hypertension, obesity, and metabolic syndrome are all chronic allostatic states that augment the accumulation of allostatic load over years. There may be enough wear and tear to decrease thresholds for induction of rapidly destabilizing positive feedback loops.
A classic example is heart failure. As intrinsic pumping efficiency declines the SNS is activated. This can improve or even normalize levels of cardiac-related variables for years, and the individual has no symptoms. SNS activation, however, comes at the expense of cardiac hypertrophy, increased work of the heart, and a decreased threshold for arrhythmias. Once cardiac pump function declines to below a certain level despite maximal SNS stimulation, blood backs up into the pulmonary veins, bringing on pulmonary edema. The patient becomes short of breath and in a distress response experiences the classic “feeling of impending doom” that has been associated from time immemorial with massive activation of the SAS and high circulating adrenaline levels. Rather than augmenting left ventricular myocardial contractility, adrenaline can be toxic to myocardial cells. Myocardial contractility could decrease further and “stress cardiopathy” could set in, worsening the pulmonary edema. In several ways, physiologic negative feedback loops would now have given way to pathophysiologic positive feedback loops. Within a sometimes surprisingly short period of time from the onset of symptoms, the patient could die—within minutes because of a catecholamine-evoked ventricular arrhythmia, hours because of intractable pulmonary edema, or days because of critically decreased perfusion of body organs such as the kidneys.
In the setting of such increased susceptibility, exposure to an acute stressor, by activating the stress system, increases the likelihood of such vicious cycles and multi-organ failure (Fig. 3). This is especially the case in a novel, distressing situation, such as the COVID-19 pandemic, because when an individual who has habituated to one form of stress is exposed to a novel (heterotypic) stressor, there are exaggerated SNS, SAS, and HPA responses (Kvetnansky, 2004; Uschold-Schmidt et al., 2012).
Fig. 3. From stress system activation to dyshomeostasis to death. Five effector chemicals of the central stress system are on the left. Intervening variables are in the center. Factors contributing the critical illness or death are on the right. The red bar under PNS indicates PNS inhibition. Abbreviations: AI = angiotensin I; ACE = angiotensin-converting enzyme; AII = angiotensin II; Aldo = aldosterone; Myo. = myocardial; Cor. = coronary; IL-6 = interleukein 6; TNF-α = tumor necrosis factor alpha; ATN = acute tubular necrosis.
Given the reasonableness of this conceptual framework, what would be the practical, immediate applications? Two that come to mind are biomarkers of mortal risk and pathophysiology-based treatment.
Biomarkers of dyshomeostasis and stress system activation may predict mortality in COVID-19 patients. Specific biomarkers to consider are plasma adrenaline, ACTH, AVP, and IL-6; heart rate and heart rate variability in the time and frequency domains; and baroreflex-cardiovagal gain from continuous blood pressure and heart rate recordings. The main problem is that by the time the biomarkers are identified as positive it may be too late. A rapid or continuous monitoring and analysis approach is urgently needed. Meanwhile, hyperglycemia, hypertension, hyperthermia, hypokalemia, pallor, sweating, and the feeling of impending doom all may point to adrenaline effects and a life-threatening situation.
In COVID-19 patients who have evidence of stress system activation, treatment with already existing drugs such as the benzodiazepine alprazolam (Breier et al., 1992; Hedrington et al., 2010), the CRH-1 receptor antagonist antalarmin (Ayyadurai et al., 2017), the alpha-2 adrenoceptor agonist dexmedetomidine (Li et al., 2016; Wang et al., 2019), a beta-1 adrenoceptor blocker, or an IL-6 inhibitor (tocilizumab) might prevent positive feedback loops and improve survival.
David S. Goldstein, MD, PhD– Chief, Autonomic Medicine Section, CNP/DIR/NINDS/ National Institutes of Health (NIH), Bethesda, MD, USA,Email: email@example.com, iPhone: 301-675-1110
This research was supported (in part) by the Intramural Research Program of the NIH, NINDS.
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