Conceptualizing a Traditional Chinese Medicine and Pathology of Arousal Diagnostic and Pathophysiological Framework for Postacute Sequelae of COVID-19

INTRODUCTION

Postacute sequelae of COVID-19 (PASC) is a growing health crisis with negative outcomes across life domains for patients and poses significant burdens on health care systems and communities. The Centers for Disease Control and Prevention (CDC) reports that 35% of survivors had not returned to their prior state of health 14–21 days after infection, whereas more recent study reports persistent symptoms in 62% of cases at 3 months and 30% of cases at 9 months.^1–3 Owing to the prevalence and heterogeneous nature of PASC complaints, it is an urgent imperative to develop both conceptual frameworks and methodical rational approaches to treatment interventions.

Defining PASC from either a symptom or a syndromal perspective is proving challenging due to the heterogeneity of patient presentations and illness courses. The CDC has “…formulated ‘post-COVID conditions' to describe health issues that persist for more than 4 weeks after being infected with COVID-19,” and represent “…a lack of return to a usual state of health following acute COVID-19 illness…[and]…might also include development of new or recurrent symptoms that occur after the symptoms of acute illness have resolved.” ⁴ In a scoping review, Hayes found 108 symptoms described for PASC. ⁵ Multiomic research conducted by Su et al. suggests 4 risk factors (type 2 diabetes, SARS-CoV-2 RNAemia, Epstein–Barr virus viremia [recrudescent], and specific autoantibodies) for developing PASC and immunologically distinct endotypes, ⁶ whereas Davis et al. describe chronologically predictable distinct clusters of symptoms involving on average 9.1 body systems. ⁷

The current article describes with a few examples Traditional Chinese Medicine (TCM) theoretical frameworks relevant to PASC and shared or overlapping with other research and/or theoretical positions.

OVERVIEW OF TCM CONCEPTS WITH RELEVANCE TO PASC

TCM offers several diagnostic frameworks and interventions that may prove useful in the treatment of PASC. Highly relevant and foundational to TCM is emphasis on context, holism, and the relationship between functional systems as they interact over time. Although many schools of thought have developed over the thousands of years of TCM practice, basic principles relevant for the evaluation and management of PASC patients are Five Element theory, Meridian theory, Zang Fu theory, theories of “cold” and “hot” disease progression, and Eight Principles. For this overview perspective, we focus on examples from Five Element and Zang Fu theories.

Five Element theory is based on the concept that physical manifestations and transformations between energy and matter observed in the natural world have resonance within the human body. In the broadest sense, the quality and characteristics that define the interplay of Water, Wood, Fire, Earth, and Metal also apply to the physical structure of the body and the subtler nature of consciousness.

The figure depicts each Organ system “belonging to” an Element with which it has strong correspondence. For example, the Lung's Metal assignment is consistent with iron's role in oxygen transport, whereas the “cutting” nature of Metal relates to separation/loss and ensuing grief as represented by heaving crying. Another aspect of Metal's physiological role in creating divisions is Lung dominion over the immune system. The Lung tissue is itself a membrane that determines what gains entry and what is repelled. These elements interrelate both in a generating cycle, where each element generates the next, and a controlling mechanism in which elements prevent each other from overexpression. As it relates to PASC, early symptoms such as runny nose and sore throat demonstrate an early response to respiratory insult (Lung/Metal); when these conditions are sustained, Lung/Metal may falter in its capacity to give energy to the Kidney/Water system, resulting in the adrenal insufficiency implied by Su's multiomic analysis of a PASC endotype characterized by respiratory dysfunction. ⁶

Zang Fu Theory posits that there are 2 categories of organ: the Yin “Zang” viscera, and the Yang “Fu” bowels—each having their own roles for health and illness. The organs are grouped into Yin–Yang pairs, which are further categorized according to their element within the foundational Five Element model. For example, the Spleen (Yin) and Stomach (Yang) paired and assigned to Earth element, meaning that they are tasked on the physical level with digestion and on the psychological level with thought, cognition, and the “digestion” of experience.

The concept of paired Organs that function in tandem to direct nourishing essence inward while removing impurity has several implications for PASC. For example, diabetes as a risk factor for PASC can be conceptualized in TCM as an overburdened Earth element having difficulty integrating nourishment into the cell (insulin resistance), which if left untreated results in reduced functional capacity. When this happens, the Earth element fails to support generation of Metal, and subsequently Metal's role in immune responses is compromised.

Davis notes in her temporally distinct symptom clusters a shifting PASC GI profile. In early stages, GI complaints are primarily diarrhea, loss of appetite, and vomiting. These signify an acute insult to the normal movement of vital energy: Stomach energy erupts upward (vomiting), the digestive system expends energy and foregoes nutrient absorption in the effort to flush out pathogenic influence (diarrhea), and appetite is suspended as the system's energy redirects to rectifying itself. When it is unsuccessful, complaints shift to nausea and abdominal pain.

Nausea represents a less pronounced manifestation of the same pathological upward movement of Stomach energy as the Organ expends itself with effort, whereas pain indicates the energy of the system is becoming stagnant from sustained irregular functioning. Finally, as the entire organism begins to exhaust its efforts to rid itself of pathogenic influence, the GI symptom profile shifts to constipation and gastroesophageal reflux. This is consistent with a digestive capacity that is both locked up and desiccated, resulting in dry stools that are difficult to pass and a relative excess of heat brought on by systemic loss of vital fluids. TCM theory also interprets the most common PASC complaints of fatigue and postexertional malaise as resulting from this pathomechanism.

A special organ in TCM that may have relevance to PASC heterogeneity is the Triple Energizer (TE) (aka Three Heater, San Jiao), known as an organ with a “function but no structure.” ⁵ Others have posited that the extracellular matrix, connective tissues, and lymphatic system are corollaries. Avijgan and Avijgan have developed a compelling theory of TE as mesodermic structures related to the embryonic coelom that is consistent with functions assigned to it. ⁸ Jarrett writes that the TE “may be thought of as the body's thermostat that maintains homeostasis by regulating the distribution of fire (yang) and water (yin) throughout all aspects of being…In order to fulfill this function, the [TE] must maintain constant connection with every relevant aspect of our surroundings.” ⁹

This is consistent with TE's assignment to the Fire element. The TE thus mediates dynamic relationships between systems on the level of the organism, but it is important to keep in mind that TCM's holistic nature means that this is present in every structure and cell, underscoring the TE's relationship with cavitation and extracellular matrix. The acupoint TE-5 (“Outer Gate”) is archetypal of this organ and can be thought of as the outer limits of what belongs and what does not. For this reason, when a pathological condition has multisystemic effects, TCM diagnosis implicates the involvement of the TE. Although much of the heterogeneity in PASC may be effectively addressed by a symptom-driven approach, interventions directed at the TE require a systemic conceptual framework.

SPECIFICITY AND NONSPECIFICITY OF PASC: THE CELL DANGER RESPONSE AND PATHOLOGY OF AROUSE

Early investigators of nonspecific responses to a specific agent or pathogen noted complex psychosocial effects on health and disease. The term “homeostasis” was coined to indicate that to maintain stability, an organism must hold all elements of the internal milieu constant in response to the agent.^10,11 Naviaux has theorized a general cell-level response to threat from a variety of stressors that are common to many illnesses. ¹² The cell danger response (CDR) is an evolutionarily conserved universal metabolic response to environmental threats/injuries that is designed to protect cells and hosts from harm. ¹²

However, chronic disease sets in when threats exceed the cell–system interface capacity to provide homeostasis due to metabolic mismatches between available resources and functional capacity. If the danger is eliminated, a sequence of regenerative pathways is activated to reverse the CDR and promote healing. When, however, the CDR persists due to ongoing threat or perceived threat, the whole body metabolism is disturbed, the interactive and integrative performance of multiple organ systems is impaired, behavior is changed, and illness results. The CDR has been developed using modern high-tech methods and parallels TCM foundational theories regarding the interaction of organs and elements, both external and internal in the genesis of illness and its trajectory.

Our group has been developing an integrative theory, the Pathology of Arousal (AROUSE). Like many illnesses, PASC involves a robust general protective host response (GPHR), which is a normal response to threat meant to maintain homeostasis and prevent illness. The GPHR is a concept integrating a century of research about the stress response, allostasis, and allostatic load, and the CDR. It involves a coordinated effort by the autonomic nervous system, hypothalamic–pituitary–adrenal axis, and inflammatory/immune systems, conditioned by a lifetime of allostatic load to maintain homeostasis.

In PASC, the GPHR is likely highly nonspecific with some important components unique to SARS-CoV-2 variants. If the response is not effective, the result is AROUSE. In PASC and other postviral and postexposure syndromes, AROUSE involves the prolonged activation of the CDR by a variety of agents, resulting in fairly diverse and nonspecific presentations with a common feature of loss of homeostasis.

DISCUSSION

There are several parallels to draw between TCM theories of pathomechanism, the emerging heterogeneous and shifting clinical picture of PASC, and AROUSE. TCM diagnosis is rooted in patient-reported symptoms, so the first parallel to draw is the aggregated data related to complaints. Davis et al. draw on 3762 participants with confirmed (1020) or suspected (2742) COVID-19 from 56 countries that meet criteria for PASC and find 203 symptoms across 10 organ systems and traced 66 of those for 7 months, find that that “symptoms varied in their prevalence over time, and…identified three main symptom clusters, each with a characteristic temporal profile.” ⁷

PASC is heterogeneous, has endotypes that change over time, and involves multiple organs and other nonorgan tissues. Both TCM theories, exemplified in the examples mentioned, and AROUSE help explain the “whole body” response to COVID-19 infection in an integrative fashion in some manner of stages over time.

Many findings from the PASC clinical picture correlate with TCM pathogenesis and AROUSE. The first is that those respondents who rated their initial symptoms as very mild to moderate experienced worsening over ∼6 months in contrast to those who initially rated themselves as severe/very severe. This is in line with TCM theories of a successfully mounted systemic immune response—a robust defense at relatively superficial layers expels the pathogenic influence and returns to homeostasis, whereas a weakened initial response allows pathogenic influence to penetrate more deeply, causing multiorgan involvement. Likewise, when the GPHR is significantly robust, AROUSE does not ensue.

The second is that symptom clusters shift over time, which mirrors disease progression outlined in the Treatise on Cold Damage (Table 1). According to this model, Pathogenic Cold gains entry through the Foot Tai Yang Bladder Channel at the nape of the neck and initially causes upper respiratory symptoms. If not successfully repelled at Tai Yang or Yang Ming stages, disease course progresses to deeper layers with symptoms characterized by intransigent fatigue, possible blood deficiency/stasis, and systemic fluid deficiency, all hallmark PASC features. Likewise, models of stress that beget illness and lead to AROUSE if there is an ineffective GPHR occur in a shifting manner.

OPEN IN VIEWER

FIG. 1.

Five element generating and controlling cycles.

CONCLUSIONS

Broadly speaking, PASC presentation over time shifts from HEENT/respiratory/GI to respiratory/GI/cardiovascular/neuropsych, and finally to a very diverse presentation that includes HEENT/respiratory/GI/cardiovascular/neuropsych/genitourinary. The temporally distinct symptom clusters mirror pathogenesis as described in the Treatise on Cold Damage, again similar to the stress response described by Selye. ¹³

This overview has limits in its more detailed description. Early validation of the TCM approach to PASC is described in a case report of a successful treatment with acupuncture (Hollifield, 2022). Further research about the value of integrative approaches to PASC will advance in our holistic understanding and should inform methodical approaches to evidence-based interventions.