Acupoint stimulation for long COVID: A promising intervention

Abstract

“Long COVID” is a sustained symptom following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to recent statistics, at least 65 million people have long COVID, which poses a long-term threat to human health. The pathogenic mechanisms of coronavirus disease 2019 (COVID-19) are complex and affect multiple organs and systems. Common symptoms include palpitations, breathing difficulties, attention and memory deficits, fatigue, anxiety, and depression. It is difficult to achieve satisfactory treatment effect with a single intervention. Currently, treatment strategies for long COVID are still in the exploratory stage, and there is an urgent need to find appropriate and effective methods for long COVID treatment. Traditional Chinese medicine is effective in treating the various phases of COVID-19. Previous studies have shown that acupoint stimulation therapy is effective in improving palpitations, dyspnea, cognitive impairment, anxiety, depression, and other symptoms in patients. According to previous studies, acupoint stimulation may improve various symptoms related to long COVID. This paper discusses the potential application value of acupoint stimulation in the treatment of long COVID-related symptoms, based on the common sequelae of various systems involved in long COVID, and the effect of acupoint stimulation in the treatment of similar symptoms and diseases in recent years.

1. Introduction

“Long COVID” is a series of sustained symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The World Health Organization has defined the long COVID as a post- coronavirus disease 2019 (COVID-19) condition that occurs in individuals with a history of suspected or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis [1]. Most patients with COVID-19 who were infected by SARS-CoV-2 recover spontaneously or after treatment [2], whereas after the acute phase of the disease some suffer from a series of sequelae [3], which is independent of the severity of the initial infection [4]. According to statistics, at least 65 million people have long COVID [3], which poses a long-term threat to human health [5]. Long COVID often involves multiple organs, with its symptoms involving various systems [6], including but not limited to the cardiovascular, respiratory, nervous, gastrointestinal, and endocrine systems, and exhibits complex clinical signs and symptoms [7]. The most frequent symptoms are palpitations [8], dyspnea [9], concentration and memory deficit [10], fatigue [11], anxiety, and depression [12].

Given the high incidence of long COVID, there is an urgent need to find appropriate and effective therapies to alleviate symptoms and improve patients’ quality of life. Currently, the long-term treatment of long COVID is still in the exploratory stage. Paxlovid (co-packaged nimatrelvir 150 mg and ritonavir 100 mg) alleviates some symptoms and has been approved for use in acute COVID-19; however, Pfizer has not tested the efficacy of the drug for long COVID [13]. Several antiviral drugs, such as remdesivir, molnupiravir, and irmatrelvir, remain active in vitro against current variants, including omicron [14], but fail to improve symptoms of long COVID and may cause gastrointestinal, cardiovascular, and sleep disturbances, as well as other side effects [15]. Patients are increasingly turning to complementary and alternative therapies to avoid drug side effects.

In classical traditional Chinese medicine (TCM) therapy, acupoint stimulation has a virtuous regulatory effect on the body through invasive or non-invasive stimulation of specific acupoints, including various forms of stimulation, such as manual acupuncture (MA) [16], electroacupuncture (EA) [17], and moxibustion [18]. Since ancient times, there has been an accumulation of experience in the prevention and control of infectious diseases using acupoint stimulation therapy [19]. Currently, acupoint stimulation is widely used to treat diseases associated with multiple systems such as the circulatory [20], respiratory [21], and nervous systems [22]. Some patients with long COVID may benefit from acupoint stimulation [23].

Several studies have investigated the role of acupuncture in the prevention [24], treatment [25] and rehabilitation [26] of COVID-19, with the aim of promoting greater efficacy of acupuncture in the fight against COVID-19. Zhang Boli, an academician, and Chao Enxiang, a TCM master, led the development of the Expert Consensus on the Treatment of Common Diseases after Negative Nucleic Acid/Antigen of SARS-CoV-2 infection by Traditional Chinese Medicine. It was issued on 16th January 2023, after the Standardization Office of the China Association of Chinese Medicine organized experts to discuss its scientific practicability [27]. However, a consensus has not yet been reached regarding acupoint stimulation. Previous studies have shown the efficacy of acupoint stimulation therapy in improving similar symptoms of other diseases, such as palpitations [28], dyspnea [29], sleep disturbance [30], and cognitive impairment [10]. This study provides preliminary evidence that acupuncture could improve a range of symptoms after recovery from SARS-CoV-2 infection. In this study, given multiple systems involved in and their common sequelae presented with long COVID, we discuss the potential application of acupoint stimulation for long COVID in comparison with recent studies on acupoint stimulation for the relief of symptoms similar to those of long COVID.

2. Acupoint stimulation may improve cardiovascular symptoms of long COVID

The cardiac symptoms of long COVID are mostly caused by acute cardiac injury in patients with COVID-19 [31]. SARS-CoV-2 infection may result in extensive myocardial involvement and various cardiovascular abnormalities. Cardiac symptoms (such as chest pain, shortness of breath, fatigue, and palpitations) persist in some patients with COVID-19 [32]. Laboratory and imaging evidences of myocardial damage and its involvement may be observed in both symptomatic and asymptomatic individuals [33]. Knight et al. reported that the risk of vascular events remained elevated up to 49 weeks after the COVID-19 diagnosis [34]. It is hypothesized that this mechanism is an autoimmune response to cardiac antigens, resulting in delayed damage to the cardiac tissue [35]. These autoantibodies may target multiple systems including platelets, phospholipids, and endothelial cells, and may activate neutrophils or promote thrombosis [36].

Acupoint stimulation can be used to treat cardiovascular diseases and has some effect on the symptoms of cardiovascular dysfunction associated with long COVID. A meta-analysis showed that acupuncture was helpful in the treatment of COVID-19 patients with cardiovascular disease [20], and its circulatory-promoting effects may be beneficial for patients with COVID-19 with elevated D-dimer levels [37]. Some cases of palpitations and postural tachycardia after COVID-19 have been reported in the literature, and researchers believe that autonomic nervous system dysfunction is one of the reasons [38]. Acupuncture modulates the autonomic nerves, thereby improving cardiovascular regulation [39]. Kurono et al. found that acupoint stimulation at the point Danzhong (CV17) in the human body could reduce the heart rate and increase the high-frequency component of heart rate variability [28]. Endothelial dysfunction plays a relevant role in the pathogenesis of hypertension and cardiovascular disease and causes many complications of COVID-19 [40]. Studies have found that EA at unilateral Neiguan (PC5), Daling (PC6), Zusanli (ST36), and Shangjuxu (ST37) may prevent ischemia-reperfusion (IR)-induced endothelial dysfunction via a COX-2 dependent mechanism [41].

3. Acupoint stimulation may relieve respiratory symptoms of long COVID

Respiratory symptoms are common among COVID-19 affected patients, of which more than 50% reported persistent respiratory difficulties [42]. The prevalence of cough one year after SARS-CoV-2 infection was 2.5% among COVID-19 survivors [43]. Radiological abnormalities in the lungs persisted for more than three months after discharge [44]. Clinical studies have suggested that patients recovering from mild to moderate SARS-CoV-2 infection exhibit subclinical signs associated with impaired lung function. The underlying cause of persistent respiratory symptoms may be multifactorial, presumably due to persistent parenchymal abnormalities [45] and consequent ineffective gas exchange [46].

Acupoint stimulation is widely used for the treatment of respiratory diseases. An assessor-blinded, randomized controlled trial conducted in Iran recruited 139 patients with COVID-19 with moderate-to-severe symptoms and investigated the clinical outcomes of acupuncture or warm cupping along with standard care versus standard care alone in these patients. This trial showed that acupuncture or warm cupping could improve respiratory symptoms and reduce the duration of hospital stay [21]. A patient who was a first-line anesthesiologist and medical acupuncturist and had pulmonary symptoms consistent with severe COVID-19 fully recovered with the help of self-administered acupuncture and cupping [23]. A systematic review and meta-analysis showed that acupuncture relieved dyspnea in patients with advanced disease, which was supported by other randomized controlled trials [25]. Inhalation of nitric oxide (NO) increases its level in the lungs, thereby restoring lung function by reducing airway resistance and ameliorating virus-induced pulmonary infections [47]. MA, EA, and transcutaneous electrical nerve stimulation (TENS) induce local nitric oxide–cyclic guanosine monophosphate (NO-cGMP) release in humans and increase NO production in animal and human plasma [48].

4. Acupoint stimulation may improve neurological symptoms of long COVID

Severe COVID-19 may damage the nervous system [49], resulting in complications, such as olfactory dysfunction, memory impairment, and cognitive dysfunction. Investigators have used a mouse model to explore how mild respiratory infection with SARS-CoV-2 can lead to neuroinflammation and subsequent brain injury through multilineage neural cells and myelin dysregulation [50]. Researchers have simulated mild respiratory COVID-19 infections by intranasal inoculation with SARS-CoV-2. They did not detect SARS-CoV-2 in the brain. However, elevated levels of chemokines in the cerebrospinal fluid and serum showed signs of neuroinflammation, suggesting that infection did not need to occur directly in the brain to cause long-term damage. An analysis of neuroimaging data collected before and 4-5 months after infection in a large cohort study by Doaud et al. showed that SARS-CoV-2 infection caused substantial structural changes in the brain, including a reduction in gray matter thickness and overall brain volume. These changes are also evident in cases of mild COVID-19 [51].

4.1. Olfactory dysfunction

Many patients with COVID-19 present with olfactory dysfunction for months or even years, resulting in a decreased quality of life. In Japan, Miyazato reported that 16.1% of patients still had olfactory dysfunction at 2 months and 1.1% at 12 months [52]. In Italy, one study reported that 13.3% of patients still had olfactory dysfunction after approximately 110 days [53]. Therefore, post-COVID-19 olfactory dysfunction is a common condition worldwide and is difficult to cure in some patients. In 2020, a German medical team detected SARS-CoV-2 RNA in the human olfactory bulb during an initial assessment of post-mortem olfactory tissue from patients with COVID-19. They concluded that SARS-CoV-2 was a neurotropic virus that could spread along the olfactory nerve, infect the olfactory bulb [54] and cause changes in smell or even complete loss of smell [55].

Acupoint stimulation can effectively improve residual olfactory dysfunction after recovery from COVID-19 [56]. In a case report, a doctor treated olfactory dysfunction after COVID-19 with acupuncture at Yingxiang(LI20) [57]. Acupuncture was performed 1-2 times a week in two patients about 6 and 7 months after the diagnosis of COVID-19. Immediately after the acupuncture treatment, the symptoms of olfactory dysfunction were alleviated, and the improvement in olfactory dysfunction lasted for 2–4 days. As the number of treatments increased, the time until the flare-up of olfactory dysfunction prolonged, and the symptoms tended to decrease. LI20 is located in an area innervated by the second branch of the trigeminal nerve. The second branch (the maxillary nerve) is mixed with the sympathetic and parasympathetic nerves (the posterior nasal nerve) and reaches the nasal cavity, which transmits perceptual signals to the brain after acupuncture. Studies on olfactory abnormalities following upper respiratory tract infections suggested that LI20 acupuncture may have a positive effect on the cognitive processing of smell [56]. Therefore, acupuncture may also improve post-COVID-19 olfactory dysfunction.

4.2. Brain fog

Brain fog is a common persistent symptom after COVID-19. Some researchers believe that the origin of brain fog is from "brain fatigue,” a syndrome characterized by neurasthenia-like physical and cognitive symptoms. Many patients infected with SARS-CoV-2 experience transient or persistent cognitive dysfunction, including deficits in attention, executive function, language, processing speed, and memory. This syndrome of cognitive dysfunction is called “brain fog”, contributing heavily to the long-term morbidity of patients with long COVID [10]. In a population-based matched retrospective cohort study, researchers found a higher incidence of cognitive decline among long-term care inpatients during the COVID-19 pandemic than before the pandemic [58]. Most dementia cases are associated with neuronal loss in the hippocampus. The activation of microglia in the hippocampus is associated with the inhibition of neurogenesis, which may explain impaired memory in patients [50].

Acupoint stimulation may improve common symptoms of cognitive impairment such as memory deficits, language dysfunction, and executive dysfunction. An analysis of 15 RCTS of acupuncture for mild cognitive impairment (MCI) involving 1,051 subjects found improvements in the Mini-Mental State Examination (MMSE), Montreal cognitive assessment, clock mapping tasks, and activities of daily living (ADL) scores compared to those of controls, suggesting that acupuncture was beneficial for improving cognitive function in older adults with MCI [22]. Acupoint stimulation is also effective in improving cognitive deficits in memory, language, and executive function caused by surgery [59], chemotherapy [60] and schizophrenia [61]. Acupuncture has profound effects on all levels of the nervous system, from the peripheral nerves and spinal cord to the brain, namely, the limbic system, hypothalamus, pituitary gland, and cerebral cortex. Acupuncture at the Yintang (GV29) and Yingxiang (LI20) and 2 Hz EA at the Shenting (GV24) and Benshen (GB13) prevented hippocampal activation by microglial cells in Alzheimer's disease (AD) mice model [62]. Numerous studies have shown that acupoint stimulation, primarily in the form of MA and EA, can ameliorate various primary and secondary cognitive impairments.

4.3. Fatigue

Fatigue is one of the main symptoms of long COVID [2]. A recent study indicated an association between fatigue and dysautonomia in patients with long COVID [63]. Patients who reported post-COVID fatigue underwent multiple behavioral and neurophysiological tests to assess the central, peripheral, and autonomic nervous systems [64]. Differences in specific neural circuits were found among age- and sex-matched patients without fatigue. The primary motor cortex (M1), one of the most important regions for voluntary movement and driving muscle movement, was less excited in the cohort of patients with fatigue. Patients with fatigue had a higher heart rate and lower heart rate variation, both of which were associated with autonomic disorders that were also commonly associated with fatigue [65]. Increasing evidence of vagal dysregulation following COVID-19 infection suggests that insufficient vagal activation may be the underlying cause of autonomic dysfunction. Additionally, chronic fatigue syndrome (CFS) is closely related to neuroinflammation after infection, and some researchers have speculated that COVID-19 is associated with CFS [66].

Acupoint stimulation may also be effective in improving fatigue, with one case report suggesting that acupuncture can relieve fatigue symptoms after COVID-19 [67]. Noninvasive vagus nerve stimulation (nVNS) reduces fatigue and inflammation markers in patients with autoimmune-related fatigue [68,69]. These findings suggest that nVNS is an effective treatment for fatigue. Mechanistic studies have shown that EA improves motor and cardiac function in CFS mice, which may be related to the downregulation of iNOS/NO signaling. Additionally, studies have shown that acupuncture stimulation inhibits microglial activation and reduces neuroinflammation [70]. The SARS-Cov-2 infection has similar clinical symptoms and may be caused by a neurobiological mechanism similar to that of CFS [71]. Given the effect of acupuncture in the treatment of CFS, it is speculated that acupuncture has a potential effect in the treatment of "long COVID fatigue.”

5. Acupoint stimulation may relieve gastrointestinal symptoms of long COVID

COVID-19 may involve the digestive system, with a range of gastrointestinal symptoms. The long-term gastrointestinal symptoms of COVID-19 include abdominal pain, anorexia, diarrhea, vomiting, and nausea, according to a systematic review of 57 studies that included more than 250,000 COVID-19 survivors [70]. The gastrointestinal symptoms of long COVID support virus-induced cellular damage, inflammation, intestinal dysbiosis, and enteric nervous system dysfunction. SARS-CoV-2 nucleic acids have been identified in the small intestines of COVID-19 survivors within 6 months of acute infection [2]. Other studies have identified ongoing aberrant immune activation months after the initial SARS-CoV-2 infection, with enrichment of the cytotoxic T cell repertoire in patients with long-term gastrointestinal symptoms [72]. Thus, it can be speculated that prolonged retention of the SARS-CoV-2 antigen in the small intestine leads to persistent immune activation and inflammation, which contributes to gastrointestinal symptoms after COVID-19.

The potential role of acupoint stimulation as a TCM therapy in relieving the long-term gastrointestinal symptoms in patients with long-COVID deserves attention. Functional gastrointestinal disorders, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD) are common sequelae of COVID-19. Acupoint stimulation has been widely used for functional gastrointestinal disorders through a variety of methods such as common acupuncture, abdominal acupuncture, warm acupuncture, EA, mild moxibustion, and heat-sensitive moxibustion [73,74]. During the COVID-19 pandemic, 42 patients with COVID-19 were treated with heat-sensitive moxibustion at the Tianshu (ST25) and Shenque (CV8) as adjuvant therapy. The results showed that heat-sensitive moxibustion significantly improved diarrheal symptoms, with promising results. [75] Animal experiments have shown that moxibustion reduces serum inflammatory factors and improves intestinal dysfunction in rats with diarrhea [76]. Another study showed that transcutaneous auricular electrical vagus nerve stimulation (taVNS) improved gastric motility and mental state in functional dyspepsia (FD) rats, thereby improving FD-related symptoms [77].

6. Acupoint stimulation may improve endocrine symptoms of long COVID

Endocrine diseases such as obesity and diabetes are risk factors for severe COVID-19 [78,79], and endocrine organs such as the pancreas, adrenals, and testes have been identified as potential targets of SARS-CoV-2 [80]. There is also evidence that SARS-CoV-2 can infect and persist in adipose tissue [81]. SARS-CoV-2 can also infect pancreatic β cells, reduce insulin production, and promote β cell apoptosis that affects islet function [82]. In the year after COVID-19 infection, the incidence of diabetes remained higher in COVID-19 group than that in the non-COVID-19 group [83]. A systematic review of eight reports of hospitalized patients during the early phase of the COVID-19 pandemic found that 14.4% of patients developed new-onset diabetes after COVID-19 infection [84]. A follow-up study of children with COVID-19 revealed an increasing incidence of newly diagnosed type 1 diabetes [85].

Acupoint stimulation is beneficial to the endocrine system. EA can improve insulin resistance and blood lipid levels in patients [86]. A study found that taVNS could alleviate hyperglycemia in Zucker diabetic fatty type 2 diabetes mellitus(ZDF-T2DM) rats, control body weight in obese rats, promote insulin secretion from peripheral tissues, and improve the insulin utilization rate, which alleviates insulin resistance in rats [87]. A mechanistic study found that acupuncture reduced blood glucose and body weight primarily through the neurohormone-glucose metabolism pathway [88]. Since obesity is a low-grade inflammation, increased levels of TNF-α and IL-6 in obese patients alter insulin sensitivity by triggering different key steps in the insulin signaling pathway [89]. Acupuncture reduced serum TNF-α and IL-6 levels, enhanced anti-inflammatory mechanisms, and improved insulin sensitivity [90].

7. Acupoint stimulation may relieve other symptoms of long COVID

7.1. Mental symptoms

Patients with long COVID have physical and psychological symptoms [91], exhibiting higher levels of depression and anxiety at 6 and 12 months after admission [92]. Suicide risk was also observed 4 months after the onset of COVID-19 [93]. Social isolation due to long COVID symptom and the anxiety associated with persistent symptoms may cause psychological symptoms in patients after acute infection [94]. From perspective of mechanism, SARS-CoV-2 infects the central nervous system (CNS) and induces neuroinflammation and corresponding psychiatric symptoms [95,96]. A correlation has been reported between the severity of immune inflammatory regulation and depressive symptoms at 3 months in patients infected with SARS-CoV-2 [97]. The initial psychological experiences before and after the onset of infection may predict an individual's risk of developing long COVID [98].

Acupoint stimulation has promising applications in improving psychiatric symptoms, such as anxiety and depression in patients with long COVID. A single-blind, randomized controlled study showed that auricular acupressure in the area of hypodermic, subcortex, hepatic, and endocrine may alleviate anxiety and depression in patients with COVID-19 [99]. In addition, taVNS may improve immune function through the cholinergic anti-inflammatory pathway and modulate brain circuits through the hypothalamic-pituitary-adrenal axis [100]. Therefore, taVNS may be a potential treatment for post-COVID-19 depressive symptoms. Mechanistic studies have shown that acupuncture can effectively relieve depression-like behavior in mice by modulating the central nervous system activity and expression of 5-HT receptors in various brain regions [101].

7.2. Sleep disturbances

Long-term sleep disturbances more frequent after Covid-19 are characterized by difficulty falling asleep [102], frequent nighttime awakenings, and excessive daytime sleepiness. A cohort study showed that 54% of patients with COVID-19 experienced insomnia after 4 months of hospitalization [103]. Economic and other stressors, side effects of anti-inflammatory drugs, or other physical discomfort (such as headache and cough) may cause insomnia [104]. Endocrine examinations have shown that COVID-19 patients with long-term sleep disturbances have significantly higher plasma adrenocorticotropic hormone levels, lower serum growth hormone levels, and hypothalamic-pituitary stress [30]. The frontal lobe plays an important role in hyperarousal process [105]. Cross-sectional studies of COVID-19 patients using magnetic resonance imaging found a reduction in gray matter volume (GMV) in the left frontal lobe, suggesting that insomnia symptoms in COVID-19 patients were associated with a decrease in GMV in the left frontal lobe [106].

Acupoint stimulation is an effective therapy for sleep disturbance [107]. Meta-analyses have shown that acupuncture is more effective against insomnia than placebo [108]. EA can improve sleep structure and prolong the duration of slow-wave and rapid-eye-movement (REM) sleep [109]. Mechanistic studies have found that EA inhibits HPA axis activity and reduces plasma corticosterone (CORT) content in rats with chronic stress and anxiety [110]. Auricular acupressure effectively improved the sleep-wake cycle in rats with acute insomnia. Clinical studies have shown that auricular bleeding (AB) and auricular acupoint pressing (AA) can promote the secretion of melatonin (MT) and increase the levels of glutamate (Glu) and γ-aminobutylene acid (GABA) which are beneficial in the treatment of insomnia [111]. This study provides a theoretical basis for acupuncture to improve long-term insomnia in patients with COVID-19.

8. Discussion

A series of acupoint stimulation methods such as acupuncture and moxibustion have potential benefits in the treatment of some modern acute infectious diseases such as epidemic hemorrhagic fever, influenza, and severe acute respiratory syndrome (SARS) [112]. Its advantages include enhancing respiratory function, relieving gastrointestinal symptoms, and improving mood [113]. Some researchers have explored the safety and effectiveness of acupuncture in the treatment of patients with long COVID through systematic reviews and meta-analyses based on the related symptoms of long COVID [114]. At present, some researchers are planning to further explore acupoint stimulation therapy for patients with long COVID, and design research programs that can generate higher-level evidence involving improvements in taste abnormalities [115], anorexia [116], functional dyspepsia [74], diarrhea [18] and other symptoms.

Long COVID may include multiple symptoms with varied mechanisms that make a single treatment difficult to achieve ideal efficacy for the condition [117]. Acupoint stimulation has a holistic and personalized nature involving multiple cooperative mechanisms. During acupuncture, traumatic physical stimuli are generated at the acupuncture point, activating the neuroendocrine immune regulatory network [118]. Bioinformatics and network topology analyses have shown that acupuncture exerts an overall regulatory effect through multiple targets [119]. Targeting the multi-system involvement and various symptoms of long COVID, acupuncture has great potential in the treatment of various complications of long COVID. Studies have shown that acupuncture affects multiple pathological states of long COVID, including the regulation of inflammation and the production of NO [120], to change the outcome of the disease.

Although acupoint stimulation may be effective against long COVID, no studies have systematically investigated the underlying mechanism of action against long COVID. With the pathogenesis of long COVID gradually becoming clear, further physiological and/or laboratory studies of acupoint stimulation are needed to explore the pathological mechanisms responsible for its effects on long COVID. At present, there is limited evidence that acupoint stimulation improves the symptoms associated with long COVID, with only a few documented cases. Moreover, the sample sizes of the related studies reported in the literature were small. Therefore, large-sample, high-quality randomized controlled trials are needed to support this result and provide rigorous clinical evidence for acupuncture for patients with long COVID [121].

Acupoint stimulation does not directly affect pathogens. However, the therapy plays a crucial role in controlling infections and restoring health. Exploring effective and less invasive interventions will significantly improve the quality of life of patients with long COVID. For those patients who are resistant to modern medical treatment or unable to continue treatment due to strong side effects, acupoint stimulation may be one of the complementary therapies to effectively treat long COVID. We expect a variety of TCM therapies to play a positive role in the treatment of patients with long COVID.

CRediT authorship contribution statement

Bo-Wen Feng: Writing – original draft. Pei-Jing Rong: Formal analysis, Conceptualization, Methodology.